Japanese Encephalitis Virus Prophylaxis Medications


Drugs associated with Japanese Encephalitis Virus Prophylaxis

The following drugs and medications are in some way related to, or used in the treatment of Japanese Encephalitis Virus Prophylaxis. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.


Drug List: Ixiaro Je-Vax-Nakayama
read more


Japanese encephalitis virus vaccine SA14-14-2


Generic Name: Japanese encephalitis virus vaccine (SA14-14-2)
Brand Names: Ixiaro

What is Japanese encephalitis virus vaccine (SA14-14-2)?

Japanese encephalitis is a serious disease caused by a virus. It is the leading cause of viral encephalitis (inflammation of the brain) in Asia. Encephalitis is an infection of the membrane around the brain and spinal cord. This infection often causes only mild symptoms, but prolonged swelling of the brain can cause permanent brain damage or death.

Japanese encephalitis virus is carried and spread by mosquitos.

The Japanese encephalitis SA14-14-2 vaccine is used to help prevent this disease in adults and adolescents who are at least 17 years old.

This vaccine works by exposing you to a small dose of the virus, which causes the body to develop immunity to the disease. This vaccine will not treat an active infection that has already developed in the body.

This vaccine is recommended for people who live in or travel to areas where Japanese encephalitis is known to exist, or where an epidemic has recently occurred.

You should receive the vaccine and booster dose at least 1 week prior to your arrival in an area where you may be exposed to the virus.

Not everyone who travels to Asia needs to receive a Japanese encephalitis vaccine. Follow your doctor instructions or the recommendations of the Centers for Disease Control and Prevention (CDC).

This vaccine is also recommended for people who work in a research laboratory and may be exposed to Japanese encephalitis virus through needle-stick accidents or inhalation of viral droplets in the air.

Like any vaccine, the Japanese encephalitis SA14-14-2 vaccine may not provide protection from disease in every person.

What is the most important information I should know about this vaccine?

The Japanese encephalitis SA14-14-2 vaccine is given in a series of 2 shots. The shots are usually 28 days apart. Your individual booster schedule may be different from these guidelines. Follow your doctor's instructions or the schedule recommended by the health department of the state you live in.

Japanese encephalitis SA14-14-2 vaccine is for use in adults and adolescents who are at least 17 years old.

This vaccine is recommended for people who live in or travel to areas where Japanese encephalitis is known to exist, or where an epidemic has recently occurred.

You should receive the vaccine and booster dose at least 1 week prior to your arrival in an area where you may be exposed to the virus.

This vaccine is also recommended for people who work in a research laboratory and may be exposed to Japanese encephalitis virus through needle-stick accidents or inhalation of viral droplets in the air.

Becoming infected with Japanese encephalitis is much more dangerous to your health than receiving the vaccine to protect against it. Like any medicine, this vaccine can cause side effects, but the risk of serious side effects is extremely low.

What should I discuss with my healthcare provider before receiving this vaccine? You should not receive this vaccine if you have ever had a life-threatening allergic reaction to a Japanese encephalitis vaccine.

Before receiving this vaccine, tell the doctor if you are allergic to any foods or drugs, or if you have:

a bleeding or blood clotting disorder;

a weak immune system caused by disease such as HIV or AIDS, bone marrow transplant, or by using certain medicines or receiving cancer treatments.

You can still receive a vaccine if you have a cold or low fever. In the case of a more severe illness with a high fever (more than 100 degrees) or any type of infection, wait until you get better before receiving this vaccine.

Vaccines may be harmful to an unborn baby and generally should not be given to a pregnant woman. However, not vaccinating the mother could be more harmful to the baby if the mother becomes infected with a disease that this vaccine could prevent. Your doctor will decide whether you should receive this vaccine, especially if you have a high risk of infection with the Japanese encephalitis virus. It is not known whether Japanese encephalitis vaccine passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. How is this vaccine given?

This vaccine is given as an injection (shot) into a muscle of your upper arm. You will receive this injection in a doctor's office or other clinic setting.

The Japanese encephalitis SA14-14-2 vaccine is given in a series of 2 shots. The shots are usually 28 days apart. Your individual booster schedule may be different from these guidelines. Follow your doctor's instructions or the schedule recommended by the health department of the state you live in.

In addition to receiving the Japanese encephalitis vaccine, use protective clothing, insect repellents, and mosquito netting around your bed to further prevent mosquito bites that could infect you with the Japanese encephalitis virus.

What happens if I miss a dose?

Contact your doctor if you will miss a booster dose or if you get behind schedule. The next dose should be given as soon as possible. There is no need to start over.

Be sure you receive all recommended doses of this vaccine. If you do not receive the full series of vaccines, you may not be fully protected against the disease.

What happens if I overdose?

An overdose of this vaccine is unlikely to occur.

What should I avoid before or after receiving this vaccine?

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

This vaccine side effects You should not receive a booster vaccine if you had a life-threatening allergic reaction after the first shot. Keep track of any and all side effects you have after receiving this vaccine. When you receive a booster dose, you will need to tell the doctor if the previous shots caused any side effects.

Becoming infected with Japanese encephalitis is much more dangerous to your health than receiving the vaccine to protect against it. Like any medicine, this vaccine can cause side effects, but the risk of serious side effects is extremely low.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; dizziness, weakness, fast heart rate; swelling of your face, lips, tongue, or throat.

Less serious side may include:

headache, tired feeling;

muscle pain, back pain;

low fever, chills, flu symptoms;

cold symptoms such as stuffy nose, sneezing, sore throat, cough;

mild itching or skin rash.

nausea, diarrhea; or

pain, redness, tenderness, or a hard lump where the shot was given.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Japanese encephalitis virus vaccine Dosing Information

Usual Adult Dose for Japanese Encephalitis Virus Prophylaxis:

0.5 mL intramuscularly into the deltoid muscle on days 0 and 28. Immunization series should be completed at least 1 week prior to potential exposure to Japanese encephalitis virus.

Usual Pediatric Dose for Japanese Encephalitis Virus Prophylaxis:

17 years or older:
0.5 mL intramuscularly into the deltoid muscle on days 0 and 28. Immunization series should be completed at least 1 week prior to potential exposure to Japanese encephalitis virus.

What other drugs will affect Japanese encephalitis virus vaccine (SA14-14-2)? Before receiving this vaccine, tell the doctor about all other vaccines you have recently received.

Also tell the doctor if you have recently received drugs or treatments that can weaken the immune system, including:

an oral, nasal, inhaled, or injectable steroid medicine;

medications to treat psoriasis, rheumatoid arthritis, or other autoimmune disorders, such as azathioprine (Imuran), efalizumab (Raptiva), etanercept (Enbrel), leflunomide (Arava), and others; or

medicines to treat or prevent organ transplant rejection, such as basiliximab (Simulect), cyclosporine (Sandimmune, Neoral, Gengraf), muromonab-CD3 (Orthoclone), mycophenolate mofetil (CellCept), sirolimus (Rapamune), or tacrolimus (Prograf).

This list is not complete and there may be other drugs that can affect Japanese encephalitis vaccine. Tell your doctor about all the prescription and over-the-counter medications you have received. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Japanese encephalitis virus vaccine resources Japanese encephalitis virus vaccine Use in Pregnancy & Breastfeeding Japanese encephalitis virus vaccine Drug Interactions Japanese encephalitis virus vaccine Support Group 0 Reviews for Japanese encephalitis virus vaccine - Add your own review/rating Ixiaro Advanced Consumer (Micromedex) - Includes Dosage Information Ixiaro Consumer Overview Compare Japanese encephalitis virus vaccine with other medications Japanese Encephalitis Virus Prophylaxis Where can I get more information? Your doctor or pharmacist may have information about this vaccine written for health professionals that you may read. You may also find additional information from your local health department or the Centers for Disease Control and Prevention.
read more


Interferon Alfa


Interferon Alfa may be available in the countries listed below.

Ingredient matches for Interferon Alfa Interferon alfa

Interferon Alfa (BAN, JAN) is also known as Interferon alfa (Rec.INN)

International Drug Name Search

Glossary

BAN British Approved Name JAN Japanese Accepted Name Rec.INN Recommended International Nonproprietary Name (World Health Organization)
Click for further information on drug naming conventions and International Nonproprietary Names.
read more


Interferon Gamma-1a:


Interferon Gamma-1a: may be available in the countries listed below.

Ingredient matches for Interferon Gamma-1a: Interferon gamma

Interferon Gamma-1a: (BAN, JAN) is also known as Interferon gamma (Rec.INN)

International Drug Name Search

Glossary

BAN British Approved Name JAN Japanese Accepted Name Rec.INN Recommended International Nonproprietary Name (World Health Organization)
Click for further information on drug naming conventions and International Nonproprietary Names.
read more


Imidapril Hydrochloride


Imidapril Hydrochloride may be available in the countries listed below.

Ingredient matches for Imidapril Hydrochloride Imidapril

Imidapril Hydrochloride (BANM, JAN) is also known as Imidapril (Rec.INN)

International Drug Name Search

Glossary

BANM British Approved Name (Modified) JAN Japanese Accepted Name Rec.INN Recommended International Nonproprietary Name (World Health Organization)
Click for further information on drug naming conventions and International Nonproprietary Names.
read more


japanese encephalitis virus vaccine, inactivated adsorbed Intramuscular


jap-a-NEEZ en-sef-a-LYTE-is VYE-rus VAX-een, in-AK-ti-vay-ted ad-SORBD

Commonly used brand name(s)

In the U.S.

Ixiaro

Available Dosage Forms:

Suspension

Therapeutic Class: Vaccine

Uses For japanese encephalitis virus vaccine, inactivated adsorbed

Japanese encephalitis virus vaccine, inactivated adsorbed (IXIARO®) is used to prevent infection caused by the Japanese encephalitis virus. It works by causing your body to produce its own protection (antibodies) against the virus.

Japanese encephalitis is caused by the bite of a mosquito that lives in certain parts of Asia. It is a serious infection that can cause flu-like symptoms (e.g., fever, chills, tiredness, headache, nausea, and vomiting), confusion, agitation, brain damage, and possibly death. This vaccine does not protect against encephalitis caused by other viruses.

This vaccine is only available from your doctor or other authorized health care professional.

Before Using japanese encephalitis virus vaccine, inactivated adsorbed

In deciding to use a vaccine, the risks of taking the vaccine must be weighed against the good it will do. This is a decision you and your doctor will make. For this vaccine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to japanese encephalitis virus vaccine, inactivated adsorbed or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of Japanese encephalitis virus vaccine, inactivated adsorbed in children and teenagers younger than 17 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of Japanese encephalitis virus vaccine, inactivated adsorbed in the elderly.

Pregnancy Pregnancy Category Explanation All Trimesters B Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus. Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this vaccine. Make sure you tell your doctor if you have any other medical problems, especially:

Bleeding problems or Hypersensitivity to protamine sulfate, history of or Thrombocytopenia (low blood platelet count)—May cause side effects to become worse. High fever (more than 100°F) or Infection—The symptoms of the condition may be confused with the possible side effects of the vaccine. Immune deficiency or Immune system problem—May not work properly in patients with these conditions and may cause side effects to become worse. Proper Use of japanese encephalitis virus vaccine, inactivated adsorbed

A nurse or other trained health professional will give you this vaccine. This vaccine is given as a shot into the muscle of your upper arm.

This vaccine is given in 2 doses. Dose 2 is scheduled 28 days after Dose 1. It is very important that you receive both doses of the vaccine at least 7 days before you plan to travel out of the country. If you miss the second shot, call your doctor to make another appointment as soon as possible.

If you have received the second dose of the vaccine series more than 1 year ago, consult first with your doctor. A booster dose may be given before you plan to travel out of the country.

japanese encephalitis virus vaccine, inactivated adsorbed comes with a patient information sheet. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

Precautions While Using japanese encephalitis virus vaccine, inactivated adsorbed

It is very important that you return to your doctor at the right time for the second dose. Be sure to tell your doctor about any side effects that occur after you receive this vaccine.

Since the vaccine may not protect everyone completely, it is very important that you use precautions to reduce your chance of mosquito bites. These include using insect repellents and mosquito nets, wearing protective clothing, and staying indoors during twilight and after dark.

japanese encephalitis virus vaccine, inactivated adsorbed Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common Chills cough diarrhea fever general feeling of discomfort or illness headache joint pain loss of appetite muscle aches and pains nausea runny nose shivering sore throat sweating trouble sleeping unusual tiredness or weakness vomiting Less common Body aches or pain difficulty with breathing ear congestion loss of voice nasal congestion sneezing Incidence not known Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings numbness or tingling of the hands, feet, or face

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common Difficulty with moving joint pain muscle cramps or stiffness swollen joints Less common Back pain pain, itching, redness, or swelling where the shot was given rash stuffy nose

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More japanese encephalitis virus vaccine, inactivated adsorbed Intramuscular resources Japanese encephalitis virus vaccine, inactivated adsorbed Intramuscular Use in Pregnancy & Breastfeeding Japanese encephalitis virus vaccine, inactivated adsorbed Intramuscular Drug Interactions Japanese encephalitis virus vaccine, inactivated adsorbed Intramuscular Support Group 0 Reviews for Japanese encephalitis virus vaccine, inactivated adsorbed Intramuscular - Add your own review/rating Compare japanese encephalitis virus vaccine, inactivated adsorbed Intramuscular with other medications Japanese Encephalitis Virus Prophylaxis
read more


Isosorbide


In the US, Isosorbide (isosorbide mononitrate systemic) is a member of the drug class miscellaneous uncategorized agents.

US matches:

Isosorbide Isosorbide Dinitrate Isosorbide Dinitrate Extended-Release Isosorbide Dinitrate/Hydralazine Isosorbide Mononitrate Isosorbide Mononitrate Sustained-Release Tablets Isosorbide dinitrate Oral, Sublingual Isosorbide Mononitrate Extended Release Isosorbide Dinitrate/Hydralazine Hydrochloride

UK matches:

Isosorbide Dinitrate Tablets 10mg, 20mg Isosorbide Mononitrate Tablets 10mg, 20mg, 40mg (Actavis UK Ltd) Isosorbide Dinitrate Injection Concentrate BP 1mg/ml (SPC) Isosorbide Dinitrate Tablets BP 10mg (SPC) Isosorbide Dinitrate Tablets BP 20mg (SPC) Isosorbide mononitrate 20mg tablets (SPC) Isosorbide Mononitrate 40mg (SPC) Isosorbide Mononitrate Tablets 40mg (SPC) Ingredient matches for Isosorbide Isosorbide

Isosorbide (BAN, JAN, USAN) is known as Isosorbide in the US.

Isosorbide Mononitrate

Isosorbide Mononitrate is reported as an ingredient of Isosorbide in the following countries:

Bosnia & Herzegowina Cyprus

International Drug Name Search

Glossary

BAN British Approved Name JAN Japanese Accepted Name SPC Summary of Product Characteristics (UK) USAN United States Adopted Name
Click for further information on drug naming conventions and International Nonproprietary Names.
read more


Iomeprol


Scheme

Rec.INN

ATC (Anatomical Therapeutic Chemical Classification)

V08AB10

CAS registry number (Chemical Abstracts Service)

0078649-41-9

Chemical Formula

C17-H22-I3-N3-O8

Molecular Weight

777

Therapeutic Category

Contrast medium

Chemical Name

1,3-Benzenedicarboxamide, N,N'-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-

Foreign Names Iomeprolum (Latin) Iomeprol (German) Iomeprol (French) Iomeprol (Spanish) Generic Names Iomeprol (OS: USAN, JAN, BAN) Iomeprolo (OS: DCIT) B 16880 (IS: Bracco) Brand Names Imeron
Bracco Imaging, Germany Iomeron
Altana, Belgium; Altana, Luxembourg; Auremiana, Slovenia; Bracco, Austria; Bracco, Czech Republic; Bracco, Hungary; Bracco, Israel; Bracco, Italy; Bracco, Luxembourg; Bracco, Norway; Bracco, Poland; Bracco Eisai, Japan; Bracco SpA, Denmark; Bracco Suisse, Switzerland; Initios, Finland; Initios, Sweden; png Gerolymatos, Greece; Regional, Australia; Regional Health, New Zealand; Rovi, Spain; Santa-Farma, Turkey Iom?ron
Bracco, France

International Drug Name Search

Glossary

BAN British Approved Name DCIT Denominazione Comune Italiana IS Inofficial Synonym JAN Japanese Accepted Name OS Official Synonym Rec.INN Recommended International Nonproprietary Name (World Health Organization) USAN United States Adopted Name
Click for further information on drug naming conventions and International Nonproprietary Names.
read more


Entereg


Pronunciation: AL-vi-MOE-pan
Generic Name: Alvimopan
Brand Name: Entereg

Entereg is only approved for use in patients who are in the hospital. Only hospitals enrolled in the Entereg Access Support and Education (E.A.S.E) program may dispense Entereg to patients.

Entereg is for short-term use after bowel resection surgery only. Patients should not receive more than 15 doses of Entereg or use it for longer than 7 days.


Entereg is used for:

Shortening recovery time in certain patients who have had bowel resection surgery.

Entereg is an opioid receptor blocker. It works in the stomach and bowel to block the effects of opioids and certain substances found in the body. This helps to keep stomach and bowel muscles moving properly.

Do NOT use Entereg if: you are allergic to any ingredient in Entereg you will be having surgery for complete bowel obstruction you have severe liver problems or end-stage kidney disease you have taken an opioid (eg, codeine) regularly for the past 7 days

Contact your doctor or health care provider right away if any of these apply to you.

Before using Entereg:

Some medical conditions may interact with Entereg. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

if you are pregnant, planning to become pregnant, or are breast-feeding if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement if you have allergies to medicines, foods, or other substances if you have bowel blockage or a history of liver or kidney problems if you take or have taken opioids for chronic pain or any other medical condition if you have taken more than 3 doses of an opioid within the past week

Some MEDICINES MAY INTERACT with Entereg. Tell your health care provider if you are taking any other medicines, especially any of the following:

Opioids (eg, codeine) because side effects such as nausea, vomiting, stomach pain, or diarrhea may be more likely to occur

This may not be a complete list of all interactions that may occur. Ask your health care provider if Entereg may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Entereg:

Use Entereg as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Entereg should be used only in the hospital. Do not take Entereg if you are not in the hospital. Take Entereg by mouth with or without food. If you miss a dose of Entereg, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Entereg.

Important safety information: Do not take more than 15 doses of Entereg. Do not take Entereg for longer than 7 days. If you have recently taken an opioid, you may be more sensitive to the effects of Entereg. You may develop nausea, vomiting, stomach pain, or diarrhea. Tell your doctor if these effects are severe or persistent. The risk of side effects (eg, diarrhea, stomach or intestinal pain or cramping) may be greater in Japanese patients. Tell your doctor if any of these effects occur. Lab tests, including blood counts and potassium levels, may be performed while you use Entereg. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments. Entereg should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed. PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Entereg while you are pregnant. It is not known if Entereg is found in breast milk. If you are or will be breast-feeding while you use Entereg, check with your doctor. Discuss any possible risks to your baby. Possible side effects of Entereg:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; gas; indigestion.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain, numbness of an arm or leg, fainting, or sudden, severe headache or vomiting; fast, slow, or irregular heartbeat; muscle cramps, pain, or weakness; severe or persistent diarrhea, stomach pain, or stomach cramps; trouble urinating or inability to urinate; unusual tiredness or weakness.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Entereg side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Entereg:

Store Entereg at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Entereg out of the reach of children and away from pets.

General information: If you have any questions about Entereg, please talk with your doctor, pharmacist, or other health care provider. Entereg is to be used only by the patient for whom it is prescribed. Do not share it with other people. If your symptoms do not improve or if they become worse, check with your doctor. Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Entereg. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012 Database Edition 12.1.1.002 Copyright © 2012 Wolters Kluwer Health, Inc. More Entereg resources Entereg Side Effects (in more detail) Entereg Use in Pregnancy & Breastfeeding Entereg Drug Interactions Entereg Support Group 0 Reviews for Entereg - Add your own review/rating Entereg Prescribing Information (FDA) Entereg Consumer Overview Entereg Monograph (AHFS DI) Entereg Advanced Consumer (Micromedex) - Includes Dosage Information Alvimopan Professional Patient Advice (Wolters Kluwer) Compare Entereg with other medications Gastrointestinal Surgery Postoperative Ileus
read more


Promacta


Pronunciation: el-TROM-boe-pag
Generic Name: Eltrombopag
Brand Name: Promacta

Promacta may cause serious and sometimes fatal liver problems. Your doctor will perform blood tests to check your liver before you start Promacta and for as along as you take it. Contact your doctor right away if you experience yellowing of the skin or eyes, dark urine, stomach pain, or unusual tiredness or weakness.


Promacta is used for:

Treating low blood platelets in certain patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP).

Promacta is a thrombopoietin (TPO) receptor agonist. It works by causing the bone marrow to produce more clot-forming cells (platelets).

Do NOT use Promacta if: you are allergic to any ingredient in Promacta you have low blood platelets caused by chemotherapy or by a condition other than chronic ITP (eg, certain bone marrow problems, such as myelodysplastic syndrome or blood cancer; chronic liver disease)

Contact your doctor or health care provider right away if any of these apply to you.

Before using Promacta:

Some medical conditions may interact with Promacta. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

if you are pregnant, planning to become pregnant, or are breast-feeding if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement if you have allergies to medicines, foods, or other substances if you have a history of liver or kidney problems, cataracts, other bleeding problems, or bone marrow problems, or if you have had surgery to remove your spleen if you have a blood clot, a history of blood clots, a high number of clot-forming cells (platelets) in the blood, or a condition that may increase your risk of getting a blood clot (eg, antithrombin III deficiency, antiphospholipid syndrome) if you use tobacco products if you take a blood thinner (eg, warfarin) or an antiplatelet medicine (eg, clopidogrel)

Some MEDICINES MAY INTERACT with Promacta. Tell your health care provider if you are taking any other medicines, especially any of the following:

Ciprofloxacin, fluvoxamine, gemfibrozil, omeprazole, rifampin, or trimethoprim because they may increase the risk of Promacta's side effects Acetaminophen, benzylpenicillin, doxorubicin, HMG-CoA reductase inhibitors (eg, atorvastatin, rosuvastatin), meglitinides (eg, nateglinide), methotrexate, narcotic pain medications (eg, codeine), or nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen) because the risk of their side effects may be increased by Promacta

This may not be a complete list of all interactions that may occur. Ask your health care provider if Promacta may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Promacta:

Use Promacta as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Promacta comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Promacta refilled. Take Promacta by mouth on an empty stomach at least 1 hour before or 2 hours after a meal. Take Promacta at least 4 hours before or 4 hours after you take certain other medicines (eg, antacids), calcium-rich foods (eg, dairy products, calcium-fortified juices), or supplements that contain iron, calcium, aluminum, magnesium, selenium, or zinc. Do not suddenly stop taking Promacta. You may have an increased risk of severe low platelets and bleeding. If you need to stop Promacta, your doctor will need to monitor your condition. If you miss a dose of Promacta, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once. Do not take more than 1 dose in 1 day.

Ask your health care provider any questions you may have about how to use Promacta.

Important safety information: If you stop taking Promacta, the number of clot-forming cells (platelets) in your blood may return to a similar low platelet count as before you started taking Promacta. Low blood platelets may increase your risk of bleeding, especially if you are also taking certain other medicines (eg, anticoagulants such as warfarin, antiplatelet medicines such as clopidogrel). These effects are most likely to occur within 4 weeks after you stop taking Promacta. Your doctor will check your blood platelet counts for at least 4 weeks after you stop taking Promacta. Tell your doctor if you have unusual bruising or bleeding after you stop taking Promacta. Avoid activities that may cause bruising or injury. Discuss any questions or concerns with your doctor. Tell your doctor or dentist that you take Promacta before you receive any medical or dental care, emergency care, or surgery. Serious blood clots have occurred in patients taking Promacta. Some serious blood clots may be fatal. The risk of developing a blood clot may be greater if you have a high number of clot-forming cells (platelets) in the blood. However, blood clots have occurred in patients with normal or low blood platelet levels. Tell your doctor immediately if you notice any signs of a blood clot (eg, pain, redness, tenderness, or swelling in the legs; chest pain; shortness of breath; coughing up blood). Lab tests, including liver function, complete blood cell counts, peripheral blood smears, and eye exams, may be performed while you use Promacta and for at least 4 weeks after you stop Promacta. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments. Use Promacta with caution in East Asian patients (eg, Chinese, Japanese, Taiwanese, Korean) and in patients who have moderate to severe liver problems. They may be more sensitive to the medicine and may require a lower dose than other patients. Discuss any questions or concerns with your doctor. Use Promacta with caution in the ELDERLY; they may be more sensitive to its effects. Promacta should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed. PREGNANCY and BREAST-FEEDING: It is not known if Promacta can cause harm to the fetus. If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Promacta while you are pregnant. It is not known if Promacta is found in breast milk. Do not breast-feed while taking Promacta. Possible side effects of Promacta:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Back pain; diarrhea; indigestion; menstrual changes; mild flu-like symptoms (eg, fever, headache, tiredness, sore throat, body aches); minor muscle aches or pain; nausea; runny or stuff nose; sneezing; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bleeding of the eye or eyelid; chest pain; coughing; coughing up blood; dark urine; frequent, painful, or urgent urination; new or worsening vision problems (eg, cloudy vision); pain, redness, tenderness, or swelling in the legs; severe or persistent nausea, vomiting, or stomach pain; symptoms of heart attack (eg, pain in the chest or jaw; numbness or an arm or leg; sudden, severe vomiting or headache; fainting); symptoms of stroke (eg, confusion, slurred speech, sudden vision changes, one-sided weakness); trouble breathing; unusual bruising or bleeding; unusual burning, itching, numbness, or tingling of the skin; unusual tiredness or weakness; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Promacta side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include bleeding; chest pain; confusion; coughing; dark urine; one-sided weakness; pain, redness, tenderness, or warmth in the legs; slurred speech; trouble breathing; unusual tiredness or weakness; vision problems; yellowing of the skin or eyes.

Proper storage of Promacta:

Store Promacta at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Promacta out of the reach of children and away from pets.

General information: If you have any questions about Promacta, please talk with your doctor, pharmacist, or other health care provider. Promacta is to be used only by the patient for whom it is prescribed. Do not share it with other people. If your symptoms do not improve or if they become worse, check with your doctor. Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Promacta. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012 Database Edition 12.1.1.002 Copyright © 2012 Wolters Kluwer Health, Inc. More Promacta resources Promacta Side Effects (in more detail) Promacta Use in Pregnancy & Breastfeeding Promacta Drug Interactions Promacta Support Group 1 Review for Promacta - Add your own review/rating Promacta Prescribing Information (FDA) Promacta Consumer Overview Promacta Monograph (AHFS DI) Promacta Advanced Consumer (Micromedex) - Includes Dosage Information Eltrombopag Professional Patient Advice (Wolters Kluwer) Compare Promacta with other medications Idiopathic Thrombocytopenic Purpura Thrombocytopenia Idiopathic
read more


Allopurinol Tablets BP 300mg


1. Name Of The Medicinal Product

ALLOPURINOL TABLETS BP 300mg

2. Qualitative And Quantitative Composition

Each tablet contains 300mg Allopurinol PhEur

3. Pharmaceutical Form

White uncoated tablets

White, circular, biconvex, uncoated tablets impressed with the identifying letters “AG” and “C” on either side of a central division line on one face.

4. Clinical Particulars 4.1 Therapeutic Indications

Allopurinol and its major metabolite, oxipurinol, act by inhibiting the enzyme xanthine oxidase, which catalyses the end stage of the metabolism of purines to uric acid. Allopurinol and its metabolites are excreted by the kidney but the renal handling is such that allopurinol has a plasma half-life of about 1 hour whereas that of oxipurinol exceeds 18 hours. Thus therapeutic effect may be achieved by once-a-day dosage.

1) Prophylactic management of gout and other conditions of excess body urate: Allopurinol is used to reduce excessive urate levels (serum is theoretically saturated with urate at a concentration between 0.38-0.42mmol/l). The higher levels seen in practice may be accounted for by: a) the formation of saturated solutions; b) protein binding of urate. Excess body urate may be indicated by hyperuricaemia and/or hyperuricosuria. It may lead to disposition of urate in the tissues or it may be present with no obvious signs or symptoms.

The main clinical manifestations of urate disposition are gouty arthritis, skin tophi and/or renal involvement: Excess body urate is frequently of idiopathic origin but may also be found in association with the following other conditions: neoplastic disease and its treatment; certain enzyme disorders (especially Lesch-Nyhan syndrome); renal failure; renal calculus formation; diuretic therapy and psoriasis.

2) Calcium renal lithiasis: Allopurinol is of benefit in the prophylaxis and treatment of calcium renal lithiasis in patients with raised serum or urinary uric acid.

4.2 Posology And Method Of Administration

Posology

Initiation of therapy: In the initial stages of treatment with allopurinol, as with uricosuric agents, an acute attack of gouty arthritis may be precipitated. It is therefore advisable to give a suitable anti-inflammatory agent or colchicine for at least one month prophylactically.

Adults: Initially 100-300mg daily which may be given as a single dose. Doses in excess of 300mg should be administered in divided doses. It has rarely been necessary to exceed 900mg daily. The dose should be adjusted by monitoring serum uric acid and urinary uric acid levels at appropriate intervals in order that the dose may be adjusted until the desired effect is attained (this may take 1-3 weeks). The maintenance dose is usually 200-600mg daily.

Children: Use in children is mainly indicated for malignant conditions especially leukaemia, and certain enzyme disorders (eg Lesch-Nyhan syndrome) when the dosage is 10-20mg/kg bodyweight daily.

Use in the elderly: Dosage should be the minimum necessary to maintain normal serum and urinary urate levels.

Use with uricosurics: Oxipurinol, allopurinol's major metabolite which is itself therapeutically active, is excreted by the kidney in a similar way to urate. Drugs with uricosuric activity (eg probenecid or large doses of salicylate) may therefore accelerate the excretion of oxipurinol. This may decrease the therapeutic effect of allopurinol, however, the significance should be assessed on an individual basis.

In order to prevent acute uric acid nephropathy in neoplastic conditions, treatment with allopurinol should precede treatment with cytotoxic drugs.

Dose recommendations with impaired renal function: Impairment of renal function may lead to retention of allopurinol and its metabolites (which are excreted via the kidney) with consequent prolongation of action. Serum uric acid levels should therefore be monitored and the dose adjusted accordingly. The following dose recommendation is for use in adults:

Creatinine clearance:

Dosage:

Over 20ml/minute

Standard dose

10-20ml/minute

100-200mg daily

Under 10ml/minute

100mg daily or less frequently

Dose recommendations in renal disease: Allopurinol and it metabolites are removed by renal dialysis. If frequent dialysis is required, an alternative schedule of 300-400mg after each dialysis, with none in the interim, should be considered.

Method of Administration

For oral administration

4.3 Contraindications

Known hypersensitivity to allopurinol or to any of the ingredients of the product. Treatment for an acute attack of gout; prophylactic therapy may be commenced when the acute attack has completely subsided, provided anti-inflammatory agents are also taken.

4.4 Special Warnings And Precautions For Use

Allopurinol should be withdrawn immediately when a skin rash or other evidence of sensitivity occurs as this could result in more serious hypersensitivity reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) (see section 4.8).

A reduction in dosage should be considered in the presence of severe renal or hepatic disorders.

Patients under treatment for hypertension or cardiac insufficiency, for example with diuretics or ACE inhibitors, may have some concomitant impairment of renal function and allopurinol should be used with care in this group.

Asymptomatic hyperuricaemia per se is generally not considered an indication for use of allopurinol. Fluid and dietary modification with management of the underlying cause may correct the condition.

Acute gouty attacks: Allopurinol treatment should not be started until an acute attack of gout has completely subsided, as further attacks may be precipitated.

In the early stages of treatment with allopurinol, as with uricosuric agents, an acute attack of gouty arthritis may be precipitated. Therefore it is advisable to give prophylaxis with a suitable anti-inflammatory agent or colchicine for at least one month. The literature should be consulted for details of appropriate dosage and precautions and warnings.

If acute attacks develop in patients receiving allopurinol, treatment should continue at the same dosage while the acute attack is treated with a suitable anti-inflammatory agent.

Xanthine deposition: In conditions where the rate of urate formation is greatly increased (e.g. malignant disease and its treatment, Lesch-Nyhan syndrome) the absolute concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract. This risk may be minimised by adequate hydration to achieve optimal urine dilution.

Impaction of uric acid renal stones: Adequate therapy with Allopurinol will lead to dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in the ureter.

Lactose intolerance: Allopurinol tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

6-mercaptopurine and azathioprine: If azathioprine or 6-mercaptopurine is given concurrently with allopurinol, the dose of these agents should only be one quarter of that usually given as inhibition of xanthine oxidase will prolong their activity.

Vidarabine (Adenine Arabinoside): Evidence suggests that the plasma half-life of adenine arabinoside is increased in the presence of allopurinol and hence when these two agents are administered concomitantly, extra vigilance is required to recognise enhanced toxic effects. There is no unequivocal evidence that allopurinol potentiates the activity of other cytotoxic drugs.

Salicylates and uricosuric agents: oxipurinol, the major metabolite of allopurinol and itself therapeutically active, is excreted by the kidney in a similar way to urate. Hence, drugs with uricosuric activity such as probenecid or large doses of salicylate may accelerate the excretion of oxipurinol. This may decrease the therapeutic activity of Zyloric, but the significance needs to be assessed in each case.

Coumarin anticoagulants: Although there is no evidence that an interaction between allopurinol and the coumarins seen under experimental conditions has any clinical significance, this possibility should be borne in mind when a patient on oral anticoagulants is given allopurinol.

Chlorpropamide: If allopurinol is given concomitantly with chlorpropamide when renal function is poor, there may be an increased risk of prolonged hypoglycaemic activity.

Phenytoin: Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical significance has not been demonstrated.

Theophylline: Inhibition of the metabolism of theophylline has been reported. The mechanism of the interaction may be explained by xanthine oxidase being involved in the biotransformation of theophylline in man. Theophylline levels should be monitored in patients starting or increasing allopurinol therapy.

Ampicillin/Amoxicillin: An increase in the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared to patients who are not receiving both drugs. The cause of the reported association has not been established. However, it is recommended that in patients receiving allopurinol an alternative to ampicillin or amoxicillin is used where available.

Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechloroethamine: Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease (other than leukaemia), in the presence of allopurinol. However, in a well-controlled study of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine and/or mechloroethamine (chlormethine hydrochloride) allopurinol did not appear to increase the toxic reaction of these cytotoxic agents.

Ciclosporin: Reports suggest that the plasma concentration of ciclosporin may be increased during concomitant treatment with allopurinol. The possibility of enhanced ciclosporin toxicity should be considered if the drugs are co-administered.

Didanosine: In healthy volunteers and HIV patients receiving didanosine, plasma didanosine Cmax and AUC values were approximately doubled with concomitant allopurinol treatment (300 mg daily) without affecting terminal half life. Co-administration of these 2 drugs is generally not recommended. If concomitant use is unavoidable, a dose reduction of didanosine may be required, and patients should be closely monitored.

Antacids: Allopurinol may fail to reduce the blood-uric-acid concentrations when given at the same time as aluminium hydroxide. Intake of antacids and allopurinol should not separated by 3 hours.

Ace inhibitors: Concurrent use of allopurinol and ACE inhibitors may lead to an increased risk of haematological reactions such as leucopenia, especially if there is pre-existing renal failure.

4.6 Pregnancy And Lactation

High dose intraperitoneal allopurinol in mice has been associated with foetal abnormalities but extensive animal studies with oral allopurinol have shown none. In human pregnancy, there is no evidence that allopurinol taken orally causes foetal abnormalities; however, as with all drugs, caution should be exercised in the use of allopurinol during pregnancy. Reports indicate that allopurinol and oxipurinol are excreted in human breast milk. Concentrations of 1.4mg/litre allopurinol and 53.7mg/litre oxipurinol have been demonstrated in breast milk from women taking allopurinol 300mg/day. However, there is no data concerning the effects of allopurinol or its metabolites on the breast fed baby.

4.7 Effects On Ability To Drive And Use Machines

Since adverse reactions such as somnolence, vertigo and ataxia have been reported in patients receiving allopurinol, patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that allopurinol does not adversely affect performance.

4.8 Undesirable Effects

These are usually rare and mostly of a minor nature; the incidence is higher in the presence of renal and/or hepatic disorders.

For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.

The frequency categories assigned to the adverse drug reactions below are estimates: for most reactions, suitable data for calculating incidence are not available. Adverse drug reactions identified through post-marketing surveillance were considered to be rare or very rare. The following convention has been used for the classification of frequency:

Very common (

Infections and infestations

Very Rare: furunculosis,

Blood and lymphatic system disorders

Very rare: thrombocytopenia, aplastic anaemia, agranulocytosis

Frequency not known: leucopenia, eosinophilia, haemolytic anaemia

Reports of transient reduction in the number of circulating formed elements of the blood, are usually in association with a renal and/or hepatic disorder reinforcing the need for particular care in this group of patients.

Immune system disorders

Uncommon: Hypersensitivity reactions

Very rare: Angioimmunoblastic lymphadenopathy, anaphylaxis

Frequency not known: arthralgia

Associated vasculitis and tissue response may be manifested in various ways including hepatitis, interstitial nephritis and, very rarely, epilepsy. Corticosteroids may be beneficial in overcoming them. When generalised hypersensitivity reactions have occurred, a renal and/or hepatic disorder has usually been present, particularly when the outcome has been fatal.

Metabolism and nutrition disorders

Very rare: diabetes mellitus, hyperlipidaemia

Frequency not known: exacerbation of gouty attacks (see section 4.4)

Psychiatric disorders

Very rare: depression,

Nervous system disorders

Very rare: ataxia, coma, headache, neuropathy, paraesthesia, paralysis, somnolence, taste perversion

Frequency not known: dizziness

Eye disorders

Very rare: cataract, macular changes, visual disorders

Ear and labyrinth disorders

Very rare: vertigo

Cardiac disorders

Very rare: angina, bradycardia

Vascular disorders

Very rare: hypertension

Frequency not known: vasculitis

Gastrointestinal disorders

Uncommon: nausea, vomiting

Very rare: changed bowel habit, stomatitis, steatorrhoea, haematemisis

Frequency not known: diarrhoea, abdominal pain,

Hepatobiliary disorders

Uncommon: asymptomatic increases in liver function tests

Rare: Hepatitis (including hepatic necrosis and granulomatous hepatitis)

Skin and subcutaneous tissue disorders

Common: rash

Rare: Stevens-Johnson syndrome/toxic epidermal necrolysis

Very Rare: alopecia, angioedema, discoloured hair, fixed drug eruptions,

Frequency not known: skin reaction associated with eosinophilia, urticaria

Skin reactions are the most common reactions and may occur at any time during treatment.

They may be pruritic, maculopapular, sometimes scaly or purpuric, associated with exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia resembling Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and/or Lyell's. Allopurinol should be withdrawn immediately should such reactions occur.

If desired, after recovery from mild reactions, allopurinol may be reintroduced at a low dose (eg 50mg/day) which may be gradually increased. If the rash recurs, allopurinol should be permanently withdrawn.

The HLA-B*5801 allele has been has been identified as a genetic risk factor for allopurinol associated SJS/TEN in retrospective, case-control, pharmacogenetic studies in patients of Han Chinese, Japanese and European descent. Up to 20-30% of some Han Chinese, African and Indian populations carry the HLA-B*5801 allele whereas only 1-2% of Northern European, US European and Japanese patients are estimated to be HLA-B*5801 carriers. However, the use of genotyping as a screening tool to make decisions about treatment with allopurinol has not been established.

The clinical diagnosis of SJS/TEN remains the basis for decision making. If such reactions occur at any time during treatment, allopurinol should be withdrawn immediately and permanently.

Renal and urinary disorders

Very rare: haematuria, uraemia

Frequency not known: nephrolithiasis

Reproductive system and breast disorders

Very rare: gynaecomastia, impotence, infertility

Frequency not known: nocturnal emissions

General disorders and administration site conditions

Very rare: asthenia, fever, general malaise, oedema

4.9 Overdose

No reports of overdosage or acute intoxication are available. Massive absorption of allopurinol may lead to considerable inhibition of xanthine oxidase activity, which should have no untoward effects unless adenine arabinoside, azathioprine or 6-mercaptopurine is being taken concurrently. In this case, the risk of increased activity of these drugs must be recognised.

Symptoms

Nausea, vomiting, diarrhoea, dizziness, headache, somnolence and abdominal pain. Rarely, there may be renal insufficiency and hepatitis.

Treatment

The benefit of gastric decontamination is uncertain. Consider activated charcoal (charcoal dose: 50 g for adults; 1 g/ kg for children) if the patient presents within 1 hour of ingestion of more than 50 mg/kg. If more than 50 mg/kg has been ingested check U&Es and LFTs.

Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. Other measures as indicated by the patient's clinical condition.

Haemodialysis is unlikely to be required. Hameodialysis may be considered in patients with severe renal or hepatic impairment.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Allopurinol is used in the prevention and treatment of gout.

5.2 Pharmacokinetic Properties

Allopurinol is absorbed from the GI tract and is reported to have a plasma half life of about one hour. It is rapidly converted in the body to oxipurinol (alloxanthine) which is also an inhibitor of xanthine oxidase with a reported half life of 18-30 hours. Allopurinol and oxipurinol are not bound to serum proteins and are excreted mainly in the urine.

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars 6.1 List Of Excipients

Also contains: maize starch, carmellose sodium, cellulose, sodium lauryl sulphate, lactose, magnesium stearate.

6.2 Incompatibilities

None known

6.3 Shelf Life

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable

Shelf-life after first opening

Not applicable

6.4 Special Precautions For Storage

Store below 25°C in a dry place.

6.5 Nature And Contents Of Container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers with snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps.

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-7g/M? PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28's, 30's, 56's, 60's, 84's, 90's, 100's, 112's, 1000's.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 25,000.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

Administrative Data 7. Marketing Authorisation Holder

Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing Authorisation Number(S)

PL 0142/0147

9. Date Of First Authorisation/Renewal Of The Authorisation

November 1980

(Renewed: November 1985; January 1992)

10. Date Of Revision Of The Text

11/10/2010


read more


Ciclopirox Olamine


Class: Hydroxypyridones
Chemical Name: 6-Cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridinone compound with 2-aminoethanol (1:1)
Molecular Formula: C12H17NO2?C2H7NO
CAS Number: 41621-49-2
Brands: Loprox, Penlac Nail Lacquer

Introduction

Antifungal;1 2 3 chemically unrelated to imidazoles or other antifungal agents currently available in US.4

Uses for Ciclopirox Olamine Dermatophytoses and Cutaneous Candidiasis

Treatment of tinea pedis, tinea cruris, and tinea corporis caused by Trichophyton mentagrophytes, T. rubrum, Epidermophyton floccosum, or Microsporum canis.1 25 27 31 66

Efficacy in the treatment of plantar and vesicular types of tinea pedis not established.28 Oral antifungal agent usually necessary for the treatment of hyperkeratotic areas on palms and soles or chronic moccasin-type tinea pedis.31 32 36

Oral antifungal agents preferred when tinea corporis or tinea cruris is extensive, dermatophyte folliculitis is present, infection is chronic or does not respond to topical therapy, or patient is immunocompromised or has coexisting disease.31 32 35 36 37

Treatment of cutaneous candidiasis caused by Candida albicans.1 66

Pityriasis (Tinea) Versicolor

Treatment of pityriasis (tinea) versicolor caused by Malassezia furfur (Pityrosporum orbiculare or P. ovale).1 25 66

Oral antifungal agents preferred in patients who have extensive or severe infections or who fail to respond to or have frequent relapses with topical therapy.33 34 36

Seborrheic Dermatitis

Treatment of seborrheic dermatitis of the scalp.28 65

Has not been studied in immunocompromised patients (e.g., HIV or transplant patients),28 65 patients with a history of immunosuppression (e.g., extensive, persistent, or unusual distribution of dermatomycoses; recent or recurring herpes zoster; persistent herpes simplex), 65 or those with diabetic neuropathy.65

Onychomycosis

Treatment of mild to moderate onychomycosis of fingernails and toenails, without lunula involvement, caused by T. rubrum in immunocompetent patients.40 43 45 49 56 57 58 59 60

Oral antifungal therapy usually preferred for extensive (e.g., >30%) nail involvement.46

Has not been studied in immunocompromised individuals (e.g., those with insulin-dependent diabetes, diabetic neuropathy, severe plantar/moccasin-type tinea pedis, HIV infection, or solid organ transplantation).40

Ciclopirox Olamine Dosage and Administration Administration Topical Administration

Apply topically to the skin as a cream,1 gel,28 lotion,66 or shampoo65 and to nails as a solution (nail lacquer).40

Do not apply to the eye1 25 28 40 65 66 or administer orally or intravaginally.23 24 40 65 Avoid contact with mucous membranes.28 40 65

Cream, Gel, or Lotion

Apply a sufficient amount of cream, gel, or lotion in the morning and evening; rub gently into cleansed, affected area and surrounding skin.1 23 25 31 66

Do not use with occlusive dressings or wrappings.1 28 66

Shampoo

If contact with eye(s) occurs, rinse thoroughly with water.65

Solution (Nail Lacquer)

Use in conjunction with frequent (e.g., monthly) appointments with a qualified clinician in nail disorders and weekly self-trimming of infected nail(s).40

Remove any loose nail or nail material (using nail clippers or nail files) before initiating therapy.40

Apply solution evenly over entire nail bed, undersurface of nail plate (if free of nail bed), and 5 mm of surrounding skin using applicator brush provided by the manufacturer.40

Avoid contact with skin other than that immediately surrounding the treated nail(s) (because of risk of adverse dermatologic reactions).40

After applying solution, wait ?8 hours before bathing.40

Allow nail(s) to dry (about 30 seconds) before wearing socks or stockings.40

Do not apply nail polish or other cosmetic nail products on treated nail(s).40

Dosage

Available as ciclopirox and ciclopirox olamine; dosage expressed in terms of ciclopirox.1 28 40 65 66

Pediatric Patients Dermatophytoses and Cutaneous Candidiasis Topical

Children ?10 years of age: Apply 0.77% cream or lotion twice daily.1 23 25 31 66

If clinical improvement does not occur after 4 weeks of treatment, reevaluate the diagnosis.1 25 66

Pityriasis (Tinea) Versicolor Topical

Children ?10 years of age: Apply 0.77% cream or lotion twice daily.1 23 25 31 66

Clinical improvement usually occurs after 2 weeks of treatment.1 25 66

Adults Dermatophytoses and Cutaneous Candidiasis Topical

Apply 0.77% cream or lotion twice daily.1 23 25 31 66 Alternatively, in the treatment of interdigital tinea pedis or tinea corporis, apply 0.77% gel twice daily.28

If clinical improvement does not occur after 4 weeks of treatment, reevaluate the diagnosis.1 25 66

Pityriasis (Tinea) Versicolor Topical

Apply 0.77% cream or lotion twice daily.1 23 25 31 66

Clinical improvement usually occurs after 2 weeks of treatment.1 25 66

Seborrheic Dermatitis Topical

Apply 0.77% gel to affected areas twice daily.28

Alternatively, apply approximately 5 mL (10 mL for long hair) of 1% shampoo to wet hair and scalp and lather.65 Allow drug to remain on the scalp for 3 minutes and then rinse.65 Repeat treatment twice weekly for 4 weeks, with a minimum of 3 days between applications.65

If clinical improvement does not occur after 4 weeks of treatment, reevaluate the diagnosis.65

Onychomycosis Topical

Apply 8% topical solution (nail lacquer) once daily (preferably at bedtime).40 Remove accumulated applications of the drug with alcohol every 7 days; daily removal of solution is not recommended.40

Initial improvement of symptoms may require 6 months of therapy and up to 48 weeks of continuous comprehensive therapy to achieve clear or almost clear nail(s).40

Cautions for Ciclopirox Olamine Contraindications

Known hypersensitivity to ciclopirox, ciclopirox olamine, or any ingredient in the formulation.1 25 28 40 65 66

Warnings/Precautions Sensitivity Reactions

If irritation or sensitivation occurs, discontinue the drug and initiate appropriate therapy.1 25 40 66

General Precautions Local Effects

Possible pruritus, transient burning sensation, and/or pain at the site of application.1 28 40 66

Specific Populations Pregnancy

Category B.1 28 65 66

Lactation

Not known whether ciclopirox is distributed into milk.1 28 40 65 66 Use with caution in nursing women.1 25 28 40 65 66

Pediatric Use

Safety and efficacy of topical ciclopirox solution (nail lacquer) not established in children.40

Safety and efficacy of topical ciclopirox olamine preparations (i.e., cream, lotion) and topical ciclopirox gel not established in children ?10 and 16 years of age, respectively.1 28 66

Insufficient experience with ciclopirox shampoo in children ?16 years of age to determine whether pediatric patients respond differently than adults.65

Geriatric Use

No substantial differences in safety and efficacy of ciclopirox topical solution (nail lacquer) relative to younger adults.40

No substantial differences in safety of ciclopirox shampoo relative to younger adults.65 Insufficient experience in patients ?65 years of age to determine whether efficacy in geriatric patients is different from that in younger adults.65

Race

Insufficient experience in black patients to determine whether they respond differently to ciclopirox shampoo than other races.65

Common Adverse Effects

Local burning sensation or pain; mild, transient erythema.1 28 40 66

Interactions for Ciclopirox Olamine Systemic Antifungal Agents

No studies conducted in patients with onychomycosis to determine whether topical ciclopirox solution might reduce efficacy of systemic antifungals; combined use of the topical solution with a systemic antifungal agent is not recommended.40

Ciclopirox Olamine Pharmacokinetics Absorption

Percutaneous absorption appears to be rapid but minimal following topical application to intact skin.11 40

Penetration of drug following topical application of 0.77% lotion is equivalent to that of 0.77% cream.25 27

Systemic absorption of 0.77% gel is higher than that of 0.77% cream.28

Distribution Extent

Penetrates into hair and nail40 and is absorbed through the epidermis and hair follicles into sebaceous glands and dermis, while a portion remains in the stratum corneum.1 11 25 66

Crosses the placenta in very small amounts in animals.11

Plasma Protein Binding

Approximately 94–98%.11

Elimination Metabolism

Almost completely conjugated with glucuronic acid;11 about 1–2% of the drug appears to be metabolized to N-desoxyciclopirox and another unidentified metabolite.11

Elimination Route

Excreted rapidly and almost completely in urine;11 25 negligible fecal excretion.1 11 25 66

Half-life

Biologic half-life of approximately 1.7 hours following application of 0.77% cream or lotion.1 11 25 66

Renal elimination half-life of approximately 5.5 hours following application of 0.77% gel.28

Stability Storage Topical Cream, Gel, or Shampoo

15–30°C.1 28 65

Lotion

5–25°C.66

Solution

15–30°C.40 Keep away from heat and flame.40

Actions and SpectrumActions

Chelates polyvalent cations (e.g., aluminum, iron), which can result in inhibition of metal-dependent enzymes that are responsible for degradation of peroxides within the fungal cell.28 40 65

Active in vitro against Trichophyton equinum,10 T. mentagrophytes,1 8 9 10 25 27 28 40 66 T. rubrum,1 8 9 10 25 28 40 66 T. schoenleinii,8 10 T. tonsurans,8 10 T. verrucosum,8 T. violaceum,8 10 E. floccosum,1 8 9 10 25 28 66 Microsporum audouinii,1 8 10 M. canis,8 10 25 66 C. albicans,1 8 9 10 25 27 66 and M. furfur (P. orbiculare).1 65 66

Advice to Patients

Importance of consulting clinician if treated area becomes irritated (e.g., erythema, pruritus, burning, blistering, swelling, oozing).1 25 28 40 66

Importance of completing full course of therapy and of contacting clinician if symptoms of skin condition do not improve after 4 weeks of treatment.1 25 28 66 Six months of therapy may be required for initial improvement of infected nail(s).40

Importance of adhering to prescribed directions for use, including using the drug only for prescribed indications.28 40 (See Administration under Dosage and Administration.)

If topical solution (nail lacquer) is to be used, provide patient a copy of manufacturer’s patient information.40

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 28 40 65 66

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1 28 40 65 66

Importance of informing patients of other important precautionary information.1 28 40 65 66 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Ciclopirox

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Gel

0.77%

Loprox (with isopropyl alcohol)

Medicis

Shampoo

1%

Loprox

Medicis

Solution

8%

Penlac Nail Lacquer (with isopropyl alcohol)

Dermik

Ciclopirox Olamine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Cream

0.77% (of ciclopirox)

Loprox (with benzyl alcohol 1%)

Medicis

Lotion

0.77% (of ciclopirox)

Loprox (with benzyl alcohol 1%)

Medicis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Ciclopirox 0.77% Gel (PADDOCK): 100/$175.98 or 300/$499.95

Ciclopirox 0.77% Gel (PADDOCK): 30/$75.99 or 90/$199.97

Ciclopirox 0.77% Gel (PADDOCK): 45/$99.99 or 135/$255.96

Ciclopirox 8% Solution (PERRIGO PHARMACEUTICALS): 6/$29.99 or 19/$75.97

Ciclopirox Olamine 0.77% Cream (PERRIGO PHARMACEUTICALS): 15/$24.99 or 45/$69.97

Ciclopirox Olamine 0.77% Cream (FOUGERA): 30/$44.99 or 90/$124.98

Ciclopirox Olamine 0.77% Cream (FOUGERA): 90/$109.99 or 180/$199.98

Ciclopirox Olamine 0.77% Suspension (FOUGERA): 60/$95.99 or 180/$259.98

Ciclopirox Olamine 0.77% Suspension (PERRIGO PHARMACEUTICALS): 30/$44.99 or 90/$122.98

CNL8 Nail 8 & 2% Kit (JSJ PHARMACEUTICALS): 1/$210.56 or 3/$601.56

Loprox 0.77% Cream (MEDICIS): 30/$107.88 or 90/$313.42

Loprox 0.77% Gel (MEDICIS): 100/$429.99 or 300/$1175.97

Loprox 0.77% Gel (MEDICIS): 30/$163.78 or 90/$472.1

Loprox 0.77% Gel (MEDICIS): 45/$240.99 or 135/$685.97

Penlac 8% Solution (DERMIK): 6/$239.99 or 19/$699.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Medicis Pharmaceutical Corp. Loprox (ciclopirox olamine) cream 0.77% prescribing information. Scottsdale, AZ; 2002 Oct.

2. Hoechst-Roussel Pharmaceuticals, Inc. Pharmacy and therapeutics committee report: Loprox (ciclopirox olamine) cream 1%. Somerville, NJ; 1983 Mar.

3. Dittmar W, Druckey E, Urbach H. Quantitative structure-activity analysis in a series of antimycotically active N-hydroxypyridones. J Med Chem. 1974; 17:753-6. [PubMed 4836409]

4. Anon. New topical antifungal drugs. Med Lett Drugs Ther. 1983; 25:98-100. [PubMed 6621505]

5. Reynolds JEF, ed. Martindale: the extra pharmacopeia. 28th ed. London: The Pharmaceutical Press; 1982:720.

6. Sakurai K, Sakaguchi T, Yamaguchi H et al. Mode of action of 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone ethanolamine salt (Hoe 296). Chemotherapy. 1978; 24:68-76. [IDIS 93074] [PubMed 340169]

7. Iwata VK, Yamaguchi H. Studies on the mechanism of antifungal action of ciclopiroxolamine: inhibition of transmembrane transport of amino acid, K+ and phosphate in Candida albicans cells. (German) Arzneim-Forsch. 1981; 31:1323-7.

8. Dittmar W, Lohaus G. HOE 296, a new antimycotic compound with a broad antimicrobial spectrum. (German) Arzneim-Forsch. 1973; 23:670-4.

9. Dittmar W, Grau W, Raether W et al. Microbiological laboratory studies with ciclopiroxolamine. (German) Arzneim-Forsch. 1981; 31:1317-22.

10. Sakurai K, Sakaguchi T, Yamaguchi H et al. Antimicrobial activity of Hoe 296, a new synthetic antifungal agent. I. In vitro antimicrobial activity and curative effect against experimental Trichophyton mentagrophytes infection. (Japanese) Jpn J Med Mycol. 1975; 16:35-40.

11. Kellner, HM, Arnold C, Christ OE et al. Studies on pharmacokinetics and biotransformation of the antimycotic drug ciclopiroxolamine in animals and man after topic and systemic application. (German) Arzneim-Forsch. 1981; 31:1337-53.

12. Dittmar W. Penetration and antifungal activity of ciclopiroxolamine in hornified tissue. (German) Arzneim-Forsch. 1981; 31:1353-9.

13. Adam, VW, Peil HG, Savopoulos C et al. Clinical results with the antimycotic agent ciclopiroxolamine. (German) Arzneim-Forsch. 1981; 31:1360-8.

14. Fredriksson T, Savopoulos C. Comparative double-blind study on ciclopiroxolamine cream and placebo cream in dermatophytoses. (German) Arzneim-Forsch. 1981; 31:1376-8.

15. Dittmar VW. Non-European open clinical studies on the efficacy and tolerance of ciclopiroxolamine in dermatomycoses. (German) Arzneim-Forsch. 1981; 31:1381-5.

16. Hoechst-Roussel Pharmaceuticals, Inc. Loprox (ciclopiroxolamine) cream 1% effectiveness and safety. Somerville, NJ; 1983.

17. Torres VJ, Savopoulos C, Dittmar W. Open clinical trial in dermal mycoses of a 1% ciclopiroxolamine solution in polyethylene glycol 400 carried out in FR Germany/Study with shortened therapy. (German) Arzneim-Forsch. 1981; 31:1373-6.

18. Beyer M. Selected double-blind comparative studies on the efficacy and tolerance of ciclopiroxolamine solution and cream. (German) Arzneim-Forsch. 1981; 31:1378-81.

19. Anon. Drugs for athlete’s foot and tinea cruris. Med Lett Drugs Ther. 1976; 18:101-2. [PubMed 1036605]

20. Qadripur SA, Horn G, Hohler T. On the local efficacy of ciclopiroxolamine in onychomycoses. (German) Arzneim-Forsch. 1981; 31:1369-72.

21. Sehgal VN. Ciclopirox: a new topical pyrodonium antimycotic agent. A double-blind study in superficial dermatomycoses. Br J Dermatol. 1976; 95:83-8. [IDIS 71889] [PubMed 782504]

22. Peil VHG. Open clinical study on the efficacy and tolerance of ciclopiroxolamine in vulvovaginal candidosis. (German) Arzneim-Forsch. 1981; 31:1366-8.

23. Roney JV (Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ): Personal communication; 1984 Mar 12.

24. Reviewers’ comments (personal observations); 1984 Mar 20.

25. Hoechst-Roussel Pharmaceuticals, Inc. Loprox (ciclopirox olamine) lotion 1% prescribing information (dated 1995 Mar). In Physicians’ desk reference. 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998:1221-2.

26. Hoechst-Roussel Pharmaceuticals, Inc. Pharmacy and therapeutics committee report supplement: Loprox (ciclopirox olamine) lotion 1%. Somerville, NJ; 1989 Apr.

27. Aly R, Maibach HI, Bagatell FK et al. Ciclopirox olamine lotion 1%: bioequivalence to ciclopirox olamine cream 1% and clinical efficacy in tinea pedis. Clin Ther. 1989; 11:290-303. [PubMed 2663159]

28. Medicis Pharmaceutical Corp. Loprox (ciclopirox) gel 0.77%. prescribing information. Scottsdale, AZ; 2002 Mar.

29. H?nel H, Smith-Kurtz E, Pastowsky S. Treatment of seborrhoic eczema using an antimycotic with antiphlogistic properties. (German; with English abstract.) Mycoses. 1991; 34 (Suppl):91-3.

30. Schmidt A. Malassezia furfur: a fungus belonging to the physiological skin flora and its relevance in skin disorders. Cutis. 1997; 59:21-4. [PubMed 9013067]

31. Gupta AK, Einarson TR, Summerbell RC et al. An overview of topical antifungal therapy in dermatomycoses: a North American perspective. Drugs. 1998; 55:645-74. [PubMed 9585862]

32. Pi?rard GE, Arrese JE, Pi?rard-Franchimont C. Treatment and prophylaxis of tinea infections. Drugs. 1996; 52:209-24. [PubMed 8841739]

33. Sunenshine PJ, Schwartz RA, Janniger CK. Tinea versicolor: an update. Cutis. 1998; 61:65-72. [PubMed 9515210]

34. Assaf RR, Weil ML. The superficial mycoses. Dermatol Clin. 1996; 14:57-67. [PubMed 8821158]

35. Lesher JL. Recent developments in antifungal therapy. Dermatol Clin. 1996; 14:163-9. [PubMed 8821170]

36. Hay RJ. Dermatophytosis and other superficial mycoses. In: Mandel GL, Douglas RG Jr, Bennett JE, eds. Principles and practices of infectious disease. 4th ed. New York: Churchill Livingston; 1995: 2375-86.

37. Drake LA, Dincehart SM, Farmer ER et al. Guidelines of care for superficial mycotic infections of the skin: tinea corporis, tinea cruris, tinea faciei, tinea manuum, and tinea pedis. J Am Acad Dermatol. 1996; 34:282-6. [IDIS 363962] [PubMed 8642094]

38. Drake LA, Dinehart SM, Farmer ER et al. Guidelines of care for superficial mycotic infections of the skin: pityriasis (tinea) versicolor. J Am Acad Dermatol. 1996; 34:287-9. [IDIS 363963] [PubMed 8642095]

39. Reviewers’ comments (personal observations) on Sulconazole 84:04.08.

40. Dermik Laboratories. Penlac (ciclopirox) 8% topical solution prescribing information. Berwyn, PA; 2003 Jun.

41. Bohn M, Kraemer KT. Dermatopharmacology of ciclopirox nail lacquer solution 8% in the treatment of onychomycosis. J Am Acad Dermatol. 2000; (Suppl):S57-69. [PubMed 11051135]

42. Janssen Pharmaceutica. Sporanox (itraconazole) capsules prescribing information (dated 2000 Jan). In: Physicians’ desk reference. 55th ed. Montvale, NJ: Medical Economics Company Inc; 2001:1584-7.

43. Gupta AK, Baran R. Ciclopirox nail lacquerl solution 8% in the 21st century. J Am Acad Dermatol. 2000; 43(Suppl):S86-102.

44. Novartis Pharmaceuticals. Lamisil (terbinafine hydrochloride) tablets prescribing information (dated 1999 Nov). In: Physicians’ desk reference. 55th ed. Montvale, NJ: Medical Economics Company Inc; 2001:2179-81.

45. Anon. Ciclopirox (Penlac) nail lacquer for onychomycosis. Med Lett Drugs Ther. 2000; 42:51-2. [PubMed 10859733]

46. Niewerth M, Korting HC. Management of onychomycoses. Drugs. 1999; 58:283-96. [PubMed 10473020]

47. Rodgers P, Bassler M. Treating onychomycosis. Am Fam Physician. 2001; 63:663-72, 677-8. [IDIS 466690] [PubMed 11237081]

48. Reisberger EM, Szeimies RM. Therapy of onychomicosis. (German; with English abstract.) Med Klin. 2000; 95:618-28.

49. Gupta AK. Onychomycosis in the elderly. Drugs Aging. 2000; 16:397-407. [PubMed 10939306]

50. Roberts DT. Onychomycosis: current treatment and future challenges. Br J Dermatol. 1999; 141(Suppl 56):1-4. [IDIS 440525] [PubMed 10730907]

51. Balfour JA, Faulds D. Terbinafine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial mycoses. Drugs. 1992; 43:259-84. [PubMed 1372222]

52. Brodell RT, Elewski BE. Clinical Pearl: Systemic antifungal drugs and drug interactions. J Am Acad Dermatol. 1995; 33:259-260. [IDIS 350771] [PubMed 7622654]

53. Anon. Terbinafine for onychomycosis. Med Lett Drugs Ther. 1996; 38:72-4. [PubMed 8699988]

54. Dupin N, Gorin I, Djien V et al. Acute generalized exanthematous pustulosis induced by terbinafine. Arch Dermatol. 1996; 132:1253-4. [IDIS 374113] [PubMed 8859047]

55. Odom RB. New therapies for onychomycosis. J Am Acad Dermatol. 1996; 35:S26-30. [IDIS 372795] [PubMed 8784308]

56. Gupta AK, Malkin K. Ciclopirox nail lacquer and podiatric practice. J Am Podiatr Med Assoc. 2000; 90:502-7. [PubMed 11107711]

57. Gupta AK, Joseph WS. Ciclopirox 8% nail lacquer in the treatment of onychomycosis of the toenails in the United States. J Am Podiatr Med Assoc. 2000; 90:495-501. [PubMed 11107710]

58. Gupta AK. Pharmacoeconomic analysis of ciclopirox nail lacquer solution 8% and the new oral antifungal agents used to treat dermatophyte toe onychomycosis in the United States. J Am Acad Dermatol. 2000; 43(Suppl 4):S81-95.

59. Gupta AK, Fleckman P, Baran R. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J Am Acad Dermatol. 2000; 43(Suppl 4):S70-80.

60. Gupta AK. Ciclopirox nail lacquer topical solution 8%. Skin Therapy Lett. 2000; 6:1-5. [PubMed 11027420]

61. Baran R, Feuilhade M, Datry A et al. A randomized trial of amorolfine 5% solution nail lacquer combined with oral terbinafine compared with terbinafine alone in the treatment of dermatophytic toenail onychomycoses affecting the matrix region. Br J Dermatol. 2000; 42:1177-83.

62. Bonifaz A, Ibarra G. Onychomycosis in children: treatment with bifonazole-urea. Pediatr Dermatol. 2000; 17:310-4. [PubMed 10990584]

63. Tsuboi R, Unno K, Komatsuzaki H et al. [Topical treatment of onychomycosis by occlusive dressing using bifonazole cream containing 40% urea.] (Japanese with English abstract.) Nippon Ishinkin Gakkai Zasshi. 1998; 39:11-6.

64. Friedman-Birnbaum R, Cohen A, Shemer A et al. Treatment of onychomycosis: a randomized, double-blind comparison study with topical bifonazole-urea ointment alone and in combination with short-duration oral griseofulvin. Int J Dermatol. 1997; 36:67-9. [PubMed 9071624]

65. Medicis Pharmaceutical Corp. Loprox (ciclopirox) shampoo 1% prescribing information. Scottsdale, AZ; 2003 Feb.

66. Medicis Pharmaceutical Corp. Loprox (ciclopirox olamine) lotion 0.77% prescribing information. Scottsdale, AZ; 2002 Feb.

More Ciclopirox Olamine resources Ciclopirox Olamine Side Effects (in more detail) Ciclopirox Olamine Use in Pregnancy & Breastfeeding Ciclopirox Olamine Support Group 9 Reviews for Ciclopirox Olamine - Add your own review/rating ciclopirox topical Concise Consumer Information (Cerner Multum) Ciclodan Prescribing Information (FDA) Loprox Prescribing Information (FDA) Loprox Cream MedFacts Consumer Leaflet (Wolters Kluwer) Loprox Topical Advanced Consumer (Micromedex) - Includes Dosage Information Compare Ciclopirox Olamine with other medications Cutaneous Candidiasis Onychomycosis, Fingernail Onychomycosis, Toenail Seborrheic Dermatitis Tinea Corporis Tinea Cruris Tinea Pedis Tinea Versicolor
read more


Tamoxifen Citrate


Class: Antineoplastic Agents
VA Class: AN500
Chemical Name: 2-Hydroxy-1,2,3-propanetricarboxylate-(Z)-2-[4-(1,2-diphyl-1-butenyl)phenoxy]-N,Ndimethyl ethanamine
Molecular Formula: C26H29NO•C6H8O7
CAS Number: 54965-24-1
Brands: Nolvadex

For women with ductal carcinoma in situ (DCIS) and women at high risk for breast cancer: serious and life-threatening events associated with tamoxifen in the risk reduction setting include uterine malignancies, stroke, and pulmonary embolism.a Incidence rates for these events have been estimated from the NSABP P-1 trial (median length of follow-up 6.9 years).a

Uterine malignancies consist of both endometrial adenocarcinoma (incidence rate per 1000 women-years of 2.2 for tamoxifen versus 0.71 for placebo) and uterine sarcoma (incidence rate per 1000 women-years of 0.17 for tamoxifen versus 0 for placebo).

For stroke, the incidence rate per 1000 women-years was 1.43 for tamoxifen versus 1 for placebo.a

For pulmonary embolism, the incidence rate per 1000 women-years was 0.75 for tamoxifen versus 0.25 for placebo.a

Health care providers should discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast cancer and women with DCIS considering tamoxifen to reduce their risk of developing breast cancer.a

The benefits of tamoxifen outweigh its risks in women already diagnosed with breast cancer.a

Introduction

A nonsteroidal estrogen agonist-antagonist; an antineoplastic agent.128

Uses for Tamoxifen Citrate Breast Cancer

An adjuvant to surgery and radiation therapy for the treatment of breast cancer in women with negative axillary lymph nodes and in postmenopausal women with positive axillary lymph nodes.110 121 128 130 133 136 194 195 196 198 204 205 253 254 258 Also reduces the occurrence of contralateral breast cancer in these women.128 253 254 258

Reduction of risk of invasive breast cancer in patients with DCIS following surgery and radiation therapy.a

Palliative treatment of metastatic breast cancer in men and women.128 An alternative to ovarian ablative therapy (oopherectomy or radiation) in premenopausal women.128 133 158 159 160 161 162 163 164 165 166 167 168 169 183

Reduction in the incidence of breast cancer in women at high risk for developing the disease.128 293

Albright’s Syndrome

Has been used to reduce the frequency of vaginal bleeding episodes and to reduce the rate of increase in bone age in girls with Albright’s syndrome (McCune-Albright syndrome†) and precocious puberty.a

Long-term effects not established.a

Tamoxifen Citrate Dosage and Administration General

Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.

Administration

Administered orally as a single daily dose or in divided doses; dosages exceeding 20 mg daily should be given in divided doses (morning and evening).128

Initiate therapy during menstruation when used to reduce the incidence of breast cancer in sexually active women.a In women with menstrual irregularity, a negative ?-human chorionic gonadotropin test immediately prior to therapy is sufficient.a

Dosage

Available as tamoxifen citrate; dosage expressed in terms of tamoxifen.128

Adults Breast Cancer Adjuvant Therapy Oral

20–40 mg daily.100 102 110 121 128 129 130 194 195 196 205 Current data from clinical studies support 5 years of adjuvant therapy.128 194 195 196 253 254 256 257 291 328

Ductal Carcinoma in Situ Oral

20 mg daily for 5 years.a

Metastatic Breast Cancer Oral

20–40 mg daily.128

Reduction in the Incidence of Breast Cancer in Women at High Risk Oral

20 mg daily for 5 years.128 270 284 291

Prescribing Limits Adults Breast Cancer Adjuvant Therapy Oral

No evidence that dosages >20 mg daily are more effective.112 128

Cautions for Tamoxifen Citrate Contraindications

Known hypersensitivity to tamoxifen or any ingredient in the formulation.128

When used in women with DCIS and women at high risk for breast cancer, history of DVT or pulmonary embolism.a

When used in women with DCIS and women at high risk for breast cancer, concurrent anticoagulant therapy with a warfarin derivative.a 278 293 309

Warnings/Precautions Warnings Hypercalcemia

Hypercalcemia reported in patients with metastatic breast cancer who have bone metastases.128 129 If hypercalcemia occurs, take appropriate measures; if severe, discontinue tamoxifen.128

Effects on the Uterus

Increased incidence of uterine malignancies, sometimes fatal, reported.128 330 Most uterine malignancies have been classified as adenocarcinoma of the endometrium; rare uterine sarcomas also reported.128 330 (See Boxed Warning.) Gynecologic symptoms (i.e., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, pelvic pain or pressure) should be promptly evaluated.128 163 183

Endometrial changes, including hyperplasias and polyps, endometriosis and uterine fibroids reported.128 180 258 259 274 Ovarian cysts reported in a small number of premenopausal women with advanced breast cancer.128

Cardiovascular Effects

Increased incidence of thromboembolic events, including DVT128 293 and pulmonary embolism; 269 270 293 stroke also reported.128 269 277 293 Some cases of stroke and pulmonary emboli have been fatal.128 (See Boxed Warning.) Concomitant use with chemotherapy may increase incidence of these events.128

Hepatic Effects

Liver cancer reported.128

Changes in AST, ALT, bilirubin and/or alkaline phosphatase concentrations reported; severe hepatic abnormalities including fatty changes in the liver, cholestasis, hepatitis, and hepatic necrosis (some fatal) reported rarely.128

Ocular Effects

Visual disturbances, decrement in color vision perception, corneal changes, cataracts, optic neuritis, retinal vein thrombosis, intraretinal crystals, posterior subcapsular opacities, and/or retinopathy reported.128 190 191 192 193 258 268 326

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.128 If inadvertently used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard, including possible long-term risk of a diethylstilbestrol-like syndrome.128

General Precautions Hematologic Effects

Thrombocytopenia, neutropenia, pancytopenia, and leukopenia reported; caution in patients with leukopenia or thrombocytopenia.128 Periodic CBCs, including platelet count recommended.128

Specific Populations Pregnancy

Category D.128 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether tamoxifen is distributed into milk.128 Discontinue nursing or the drug because of potential risk to nursing infant.128

Pediatric Use

Safety and efficacy in girls 2–10 years of age with Albright’s syndrome and precocious puberty not studied beyond 1 year; long-term effects not established and continued monitoring recommended.a (See Special Populations under Pharmacokinetics.)

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.a

Common Adverse Effects

Hot flashes, vaginal discharge, menstrual irregularities, weight loss.128

Interactions for Tamoxifen Citrate

A substrate of CYP3A, 2C9, 2D6.a

Effect of tamoxifen on drugs that require mixed function oxidases for activation unknown.a

Cytotoxic Agents

Increased risk of thromboembolic events.128

Specific Drugs

Drug

Interaction

Comments

Aminoglutethimide

Decreased plasma tamoxifen and N-desmethyltamoxifen concentrations128

Anticoagulants (e.g., warfarin)

Enhanced warfarin effects128 170 171 172

Careful monitoring of PT is recommended128 170 171 172

When used in women with DCIS or at high risk for breast cancer, concomitant use contraindicateda

Bromocriptine

Increased plasma tamoxifen and N-desmethyltamoxifen concentrations128

Cyclosporine

Competitively inhibited formation of N-desmethyltamoxifen in vitroa

Clinicial importance unknowna

Diltiazem

Competitively inhibited formation of N-desmethyltamoxifen in vitroa

Clinicial importance unknowna

Erythromycin

Competitively inhibited formation of N-desmethyltamoxifen in vitroa

Clinicial importance unknowna

Letrozole

Decreased plasma letrozole concentrationsa

Medroxyprogesterone

Decreased plasma N-desmethyltamoxifen concentrations but did not reduce plasma tamoxifen concentrationsa

Nifedipine

Competitively inhibited formation of N-desmethyltamoxifen in vitroa

Clinicial importance unknowna

Phenobarbital

Decreased plasma tamoxifen concentrations128

Clinical importance unknown128

Rifampin

Decreased plasma tamoxifen and N-desmethyltamoxifen concentrationsa

Tamoxifen Citrate Pharmacokinetics Absorption Bioavailability

Absorbed slowly following oral administration; peak serum concentrations of tamoxifen occur about 3–6 hours after a single dose.128 137 138 139 140 141

Plasma Concentrations

Steady-state concentrations of tamoxifen are attained after 3–4 weeks and those of N-desmethyltamoxifen, an active metabolite, are attained after 3–8 weeks.128 137 140 143 145

Distribution Extent

Not fully characterized.128

Not known whether tamoxifen is distributed into milk.128

Elimination Metabolism

Rapidly and extensively metabolized.26 28 140 142 143 144 145 146 148 149 150 151 The major metabolite, N-desmethyltamoxifen,128 140 143 144 145 146 148 150 151 has biologic activity similar to that of the parent drug.128

Elimination Route

Excreted principally in feces as polar conjugates.128

Half-life

Tamoxifen: 5–7 days.28 137 139 145

N-Desmethyltamoxifen: 9–14 days.128 139 145

Special Populations

Clearance higher in female children 2–10 years of age than in women; exposure to N-desmethyltamoxifen in these pediatric patients similar to adults.a

Stability Storage Oral Tablets

Well-closed, light-resistant containers 20–25°C.128

ActionsActions

Acts as an estrogen antagonist on breast tissue and in the CNS and as an estrogen agonist on endometrium, bone, and lipids.311

In breast epithelial tissue, increases production of inhibitory factors and decreases production of stimulatory factors that influence breast cell growth.271 286 287 323

Reduces bone resorption and bone turnover.265 266 267 316

Decreases total and LDL-cholesterol concentrations.318 319 320 Less favorably, decreases HDL-cholesterol concentrations and increases triglyceride concentrations.318 319 320

Acts as an estrogen agonist on the uterus and exhibits proliferative and tumor-promoting effects on the endometrium.311

Advice to Patients

Importance of receiving routine gynecologic care and of immediately informing clinician if any new breast lumps or abnormal gynecologic symptoms, including abnormal vaginal bleeding, change in vaginal discharge, menstrual irregularities, or pelvic pain/pressure occur.128 163 183

Importance of informing clinician of any changes in vision.128 190 191 192 193 258 268

Importance of immediately informing clinician of unexplained shortness of breath or leg swelling/tenderness.128

Importance of periodic monitoring, including liver function test monitoring and blood counts.128

Advise patients at high risk of breast cancer that tamoxifen may decrease the incidence of breast cancer, but may not eliminate the risk of the disease.128

Importance of women informing clinicians immediately if they are or plan to become pregnant; importance of avoiding pregnancy during therapy;119 128 243 importance of using effective nonhormonal contraception while receiving tamoxifen and for 2 months after discontinuing the drug.a Necessity of advising pregnant patients of the risk to the fetus.128

Importance of reading the medication guide; the guide is for women using tamoxifen to lower their risk of breast cancer or with DCIS.128

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.128

Importance of women informing clinicians if they are or plan to breast-feed.128

Importance of informing patients of other important precautionary information.128 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Tamoxifen Citrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg (of tamoxifen)*

Nolvadex

AstraZeneca

Tamoxifen Citrate Tablets

Aegis, Andrx, Barr, Mylan, Roxane, Teva

20 mg (of tamoxifen)*

Nolvadex

AstraZeneca

Tamoxifen Citrate Tablets

Aegis, Andrx, Barr, Mylan, Roxane, Teva

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Nolvadex 20MG Tablets (ASTRAZENECA): 30/$120.99 or 60/$239.98

Tamoxifen Citrate 20MG Tablets (TEVA PHARMACEUTICALS USA): 30/$21.99 or 90/$49.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

26. Fromson JM, Sharp DS. The selective uptake of tamoxifen by human uterine tissue. J Obstet Gynaecol Br Comm. 1974; 81:321-3.

28. Fromson JM, Pearson S. The metabolism of tamoxifen (I.C.I. 46,474). Part II: in female patients. Xenobiotica. 1973; 3:711-4. [PubMed 4783632]

100. Nolvadex Adjuvant Trial Organisation. Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer: interim analysis at four years. Lancet. 1983; 1:257-61. [IDIS 164603] [PubMed 6130291]

101. Nolvadex Adjuvant Trial Organisation. Improved survival amongst patients treated with adjuvant tamoxifen after mastectomy for early breast cancer. Lancet. 1983; 2:450.

102. Ribeiro G, Palmer MK. Adjuvant tamoxifen for operable carcinoma of the breast: report of clinical trial by the Christie Hospital and Holt Radium Institute. BMJ. 1983; 286:827-30. [IDIS 168605] [PubMed 6403101]

103. Brinkley D. Adjuvant questions. BMJ. 1984; 288:1709-10. [PubMed 6428507]

104. Patterson JS, Battersby LA, Bach BK. Use of tamoxifen in advanced male breast cancer. Cancer Treat Rep. 1980; 64:801-4. [PubMed 7427964]

105. Becher R, H?ffken K, Pape H et al. Tamoxifen treatment before orchiectomy in advanced breast cancer in men. N Engl J Med. 1981; 305:169-70. [IDIS 133415] [PubMed 7242589]

106. Hortobagyi GN, Distefano A, Legha SS et al. Hormonal therapy with tamoxifen in male breast cancer. Cancer Treat Rep. 1979; 63:539-41. [IDIS 112371] [PubMed 221118]

107. Stathopoulos GP, Karvountzis GG, Yiotis J. Tamoxifen in carcinoid syndrome. N Engl J Med. 1981; 305:52. [IDIS 133352] [PubMed 7231519]

108. Myers CF, Ershler WB, Tannenbaum MA et al. Tamoxifen and carcinoid tumor. Ann Intern Med. 1982; 96:383. [IDIS 146199] [PubMed 7059114]

109. Moertel CG, Engstrom PF, Schutt AJ. Tamoxifen therapy for metastatic carcinoid tumor: a negative study. Ann Intern Med. 1984; 100:531-2. [IDIS 183832] [PubMed 6200021]

110. Nolvadex Adjuvant Trial Organisation. Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer: analysis at six years. Lancet. 1985; 1:836-40. [IDIS 199145] [PubMed 2858709]

111. Rose C, Thorpe SM, Andersen KW et al. Beneficial effect of adjuvant tamoxifen therapy in primary breast cancer patients with high oestrogen receptor values. Lancet. 1985; 1:16-9. [PubMed 2856949]

112. National Institutes of Health Office of Medical Applications of Research. Consensus conference: adjuvant chemotherapy for breast cancer. JAMA. 1985; 254:3461-3. [IDIS 207936] [PubMed 4068189]

113. Ludwig Breast Cancer Study Group. Randomised trial of chemo-endocrine therapy, endocrine therapy, and mastectomy alone in postmenopausal patients with operable breast cancer and axillary node metastasis. Lancet. 1984; 1:1256-60. [IDIS 186376] [PubMed 6144974]

114. Fisher B, Fisher ER, Redmond C. A brief overview of findings from NSABP trials of adjuvant therapy. Recent Results Cancer Res. 1984; 96:55-65. [PubMed 6101262]

115. Hubay CA, Gordon NH, Crowe JP et al. Antiestrogen-cytotoxic chemotherapy and Bacillus Calmette-Guerin vaccination in stage II breast cancer: seventy-two-month follow-up. Surgery. 1984; 96:61-72. [PubMed 6740497]

116. Cummings FJ, Gray R, Davis TE et al. Adjuvant tamoxifen treatment of elderly women with Stage II breast cancer: a double-blind comparison with placebo. Ann Intern Med. 1985; 103:324-9. [IDIS 205815] [PubMed 3896085]

117. Gau T (Stuart Pharmaceuticals, Wilmington, DE): Personal communication; 1986 Jan 13.

118. Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer Treat Rep. 1978; 62:315-20. [PubMed 647693]

119. Diver JMJ, Jackson IM, Fitzgerald JD. Tamoxifen and non-malignant indications. Lancet. 1986; 1:733. [IDIS 213703] [PubMed 2870236]

120. Kaiser-Kupfer MI, Kupfer C, Rodrigues MM. Tamoxifen retinopathy: a clinicopathologic report. Ophthalmology. 1981; 88:89-93. [PubMed 7243233]

121. Report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office (MRC), Edinburgh. Adjuvant tamoxifen in the management of operable breast cancer: the Scottish trial. Lancet. 1987; 2:171-5. [IDIS 233071] [PubMed 2885637]

122. Fisher B, Brown A, Wolmark N et al. Prolonging tamoxifen therapy for primary breast cancer: findings from the National Surgical Adjuvant Breast and Bowel Project Clinical Trial. Ann Intern Med. 1987; 106:649-54. [IDIS 229430] [PubMed 3551710]

123. Tormey DC. Long-term adjuvant therapy with tamoxifen in breast cancer: how long is long? Ann Intern Med. 1987; 106:762-4. Editorial.

124. Zielinski CC, Kubista E, Salzer H et al. Adjuvant chemotherapy combined with tamoxifen in postmenopausal patients with stage II breast cancer. Lancet. 1986; 2:1164. [IDIS 223328] [PubMed 2877314]

125. Fentiman IS, Caleffi M, Brame E et al. Double-blind controlled trial of tamoxifen therapy for mastalgia. Lancet. 1986; 1:287-8. [IDIS 211071] [PubMed 2868162]

126. Fentiman IS. Tamoxifen and mastalgia: an emerging indication. Drugs. 1986; 32:477-80. [IDIS 223766] [PubMed 3539572]

127. Fisher B, Redmond C, Brown A et al. Influence of tumor estrogen and progesterone receptor levels on the response to tamoxifen and chemotherapy in primary breast cancer. J Clin Oncol. 1983; 1:227-41. [PubMed 6366135]

128. Zeneca Pharmaceuticals. Nolvadex (tamoxifen citrate) prescribing information. Wilmington, DE; 1998 Oct 28.

129. Legha SS. Tamoxifen in the treatment of breast cancer. Ann Intern Med. 1988; 109:219-28. [IDIS 244745] [PubMed 3291659]

130. National Cancer Institute. Clinical alert on breast cancer. Bethesda, MD: National Cancer Institute; 1988 May 18.

131. Bradbeer JW, Kyngdon J. Primary treatment of breast cancer in elderly women with tamoxifen. Clin Oncol. 1983; 9:31-4. [PubMed 6851305]

132. Taylor SG IV, Gelman RS, Falkson G et al. Combination chemotherapy compared to tamoxifen as initial therapy for stage IV breast cancer in elderly women. Ann Intern Med. 1986; 104:455-61. [IDIS 213853] [PubMed 3513684]

133. Glick JH. Meeting highlights: adjuvant therapy for breast cancer. J Natl Cancer Inst. 1988; 80:471-5. [PubMed 3367387]

134. Delozier T, Julien JP, Juret P et al. Adjuvant tamoxifen in postmenopausal breast cancer: preliminary results of a randomized trial. Breast Cancer Res Treat. 1986; 7:105-10. [PubMed 3521767]

135. Fisher B, Redmond C, Brown A et al. Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial. J Clin Oncol. 1986; 4:459-71. [PubMed 2856857]

136. Early Breast Cancer Trialists’ Collaborative Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer: an overview of 61 randomized trials among 28,896 women. N Engl J Med. 1988; 319:1681-92. [IDIS 248808] [PubMed 3205265]

137. Fabian C, Sternson L, Barnett M. Clinical pharmacology of tamoxifen in patients with breast cancer: comparison of traditional and loading dose schedules. Cancer Treat Rep. 1980; 64:765-73. [PubMed 7427961]

138. Adam HK, Gay MA, Moore RH. Measurement of tamoxifen in serum by thin-layer densitometry. J Endocrinol. 1980; 84:35-42. [PubMed 7359080]

139. Adam HK, Patterson JS, Kemp JV. Studies on the metabolism and pharmacokinetics of tamoxifen in normal volunteers. Cancer Treat Rep. 1980; 64:761-4. [PubMed 7427960]

140. McVie JG, Simonetti GPC, Stevenson D et al. The bioavailability of Tamoplex(tamoxifen). Part 1: a pilot study. Methods Find Exp Clin Pharmacol. 1986; 8:505-12. [PubMed 3747644]

141. Wilkinson P, Ribeiro G, Adam H et al. Clinical pharmacology of tamoxifen and N-desmethyltamoxifen in patients with advanced breast cancer. Cancer Chemother Pharmacol. 1980; 5:109-11. [PubMed 7471314]

142. Fromson JM, Pearson S, Bramah S. The metabolism of tamoxifen (I.C.I. 46,474). Part I: in laboratory animals. Xenobiotica. 1973; 3:693-709. [PubMed 4361333]

143. Milano G, Etienne MC, Frenay M et al. Optimised analysis of tamoxifen and its main metabolites in the plasma and cytosol of mammary tumours. Br J Cancer. 1987; 55:509-12. [PubMed 3606944]

144. Daniel P, Gaskell SJ, Bishop H et al. Determination of tamoxifen and biologically active metabolites in human breast tumours and plasma. Eur J Cancer Clin Oncol. 1981; 17:1183-9. [PubMed 7199465]

145. Jordan VC. Metabolites of tamoxifen in animals and man: identification, pharmacology, and significance. Breast Cancer Res Treat. 1982; 2:123-38. [PubMed 6184101]

146. Soininen K, Kleimola T, Elomaa I et al. The steady-state pharmacokinetics of tamoxifen and its metabolites in breast cancer patients. J Int Med Res. 1986; 14:162-5. [PubMed 3522312]

147. Ribeiro GG, Wilkinson PM. A clinical assessment of loading dose tamoxifen for advanced breast carcinoma. Clin Oncol. 1984; 10:363-7. [PubMed 6509818]

148. Adam HK, Douglas EJ, Kemp JV. The metabolism of tamoxifen in humans. Biochem Pharmacol. 1979; 27:145-7.

149. Bain RR, Jordan VC. Identification of a new metabolite of tamoxifen in patient serum during breast cancer therapy. Biochem Pharmacol. 1983; 32:373-5. [PubMed 6870963]

150. Jordan VC, Bain RR, Brown RR et al. Determination and pharmacology of a new hydroxylated metabolite of tamoxifen observed in patient sera during therapy for advanced breast cancer. Cancer Res. 1983; 43:1446-50. [IDIS 165659] [PubMed 6825112]

151. Murphy C, Fotsis T, Pantzar P et al. Analysis of tamoxifen and its metabolites in human plasma by gas chromatography-mass spectrometry (GC-MS) using selected ion monitoring (SIM). J Steroid Biochem. 1987; 26:547-55. [PubMed 3586671]

152. Kemp JV, Adam HK, Wakeling AE et al. Identification and biological activity of tamoxifen and metabolites in human serum. Biochem Pharmacol. 1983; 32:2045-52. [PubMed 6870933]

153. Jordan VC, Collins MM, Rowsby L et al. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol. 1977; 75:305-16. [PubMed 591813]

154. Wakeling AE, Slater SR. Estrogen-receptor binding and biologic activity of tamoxifen and its metabolites. Cancer Treat Rep. 1980; 64:741-4. [PubMed 7427959]

155. Fabian C, Tilzer L, Sternson L. Comparative binding affinities of tamoxifen, 4-hydroxytamoxifen, and desmethyltamoxifen for estrogen receptors isolated from human breast carcinoma: correlation with blood levels in patients with metastatic breast cancer. Biopharm Drug Dispos. 1981; 2:381-90. [IDIS 143191] [PubMed 7317574]

156. Borgna JL, Rochefort H. Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues. J Biol Chem. 1981; 256:859-68. [PubMed 7451477]

157. Coezy E, Borgna JL, Rochefort H. Tamoxifen and metabolites in MCF, cells: correlation between binding to estrogen receptor and inhibition of cell growth. Cancer Res. 1982; 42:317-23. [PubMed 7053859]

158. Pritchard KI, Thomson DB, Myers RE et al. Tamoxifen therapy in premenopausal patients with metastatic breast cancer. Cancer Treat Rep. 1980; 64:787-96. [PubMed 7427962]

159. Manni A, Pearson OH. Antiestrogen-induced remissions in premenopausal women with stage IV breast cancer: effects on ovarian function. Cancer Treat Rep. 1980; 64:779-85. [PubMed 6775808]

160. Sawka CA, Pritchard KI, Paterson AH et al. Role and mechanism of action of tamoxifen in premenopausal women with metastatic breast carcinoma. Cancer Res. 1986; 46:3152-6. [IDIS 217168] [PubMed 3084082]

161. Ingle JN, Krook JE, Green SJ et al. Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer. J Clin Oncol. 1986; 4:178-85. [PubMed 3511184]

162. Buchanan RB, Blamey RW, Durrant KR et al. A randomized comparison of tamoxifen with surgical oophorectomy in premenopausal patients with advanced breast cancer. J Clin Oncol. 1986; 4:1326-30. [PubMed 3528402]

163. Legha SS. Tamoxifen in the treatment of breast cancer. Ann Intern Med. 1988; 109:219-28. [IDIS 244745] [PubMed 3291659]

164. Hoogstraten B, Fletcher WS, Gad-el-Mawla N et al. Tamoxifen and oophorectomy in the treatment of recurrent breast cancer. A Southwest Oncology Group study. Cancer Res. 1982; 42:4788-91. [IDIS 159551] [PubMed 7127314]

165. Yoshida M, Murai H, Miura S. Tamoxifen therapy for premenopausal and postmenopausal Japanese females with advanced breast cancer. Jpn J Clin Oncol. 1982; 12:57-63.

166. Margreiter R, Wiegele J. Tamoxifen (Nolvadex) for premenopausal patients with advanced breast cancer. Breast Cancer Res Treat. 1984; 4:45-8. [PubMed 6365211]

167. Planting AS, Alexieva-Figusch J, Blonk-VdWijst J et al. Tamoxifen therapy in premenopausal women with metastatic breast cancer. Cancer Treat Res. 1985; 69:363-8.

168. Wada T, Koyama H, Terasawa T. Effect of tamoxifen in premenopausal Japanese women with advanced breast cancer. Cancer Treat Rep. 1981; 65:728-9. [IDIS 137005] [PubMed 7248991]

169. Hoogstraten B, Gad-el-Mawla N, Maloney TR et al. Combined modality therapy for first recurrence of breast cancer. A Southwest Oncology Group study. Cancer. 1984; 54:2248-56. [IDIS 193333] [PubMed 6488144]

170. Lodwick R, McConkey B, Brown AM. Life threatening interaction between tamoxifen and warfarin. BMJ. 1987; 295:1141. [IDIS 235136] [PubMed 3120919]

171. Tenni P, Lalich DL, Byrne MJ. Life threatening interaction between tamoxifen and warfarin. BMJ. 1989; 298:93. [IDIS 249683] [PubMed 2493305]

172. Ritchie LD, Grant SMT. Tamoxifen–Warfarin interaction: the Aberdeen hospitals drug file. BMJ. 1989; 298:1253.

173. Fornander T, Rutquist LE, Cedermark B et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet. 1989; 1:117-20. [IDIS 249801] [PubMed 2563046]

174. Hardell L. Tamoxifen as risk factor for carcinoma of corpus uteri. Lancet. 1988; 2:563. [IDIS 245548] [PubMed 2900934]

175. Killackey MA, Hakes TB, Pierce VK. Endometrial adenocarcinoma in breast cancer patients receiving antiestrogens. Cancer Treat Rep. 1985; 69:237-8. [IDIS 196903] [PubMed 3971394]

176. Jordan VC. Tamoxifen and endometrial cancer. Lancet. 1989; 1:733-4. [IDIS 254039] [PubMed 2564550]

177. Gottardis MM, Robinson SP, Satyaswaroop PG et al. Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res. 1988; 48:812-5. [PubMed 3338079]

178. Neven P, De Muylder X, Van Belle Y et al. Tamoxifen and the uterus and endometrium. Lancet. 1989; 1:375. [IDIS 250800] [PubMed 2563519]

179. Stewart HJ, Knight GM. Tamoxifen and the uterus and endometrium. Lancet. 1989; 1:375-6. [PubMed 18446929]

180. Cano A, Matallin P, Legua V et al. Tamoxifen and the uterus and endometrium. Lancet. 1989; 1:376. [PubMed 18446930]

181. Boccardo F, Bruzzi P, Rubagotti A et al. Estrogen-like action of tamoxifen on vaginal epithelium in breast cancer patients. Oncology. 1981; 38:281-5. [PubMed 7266969]

182. Boccardo F, Guarneri D, Rubagotti A et al. Endocrine effects of tamoxifen in postmenopausal breast cancer patients. Tumori. 1984; 70:61-8. [PubMed 6538707]

183. Buckley MMT, Goa KL. Tamoxifen: a reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic use. Drugs. 1989; 37:451-90. [IDIS 257967] [PubMed 2661195]

184. Cuzick J, Baum M. Tamoxifen and contralateral breast cancer. Lancet. 1985; 2:282. [IDIS 203072] [PubMed 2862460]

185. Brun LD, Gagne C, Rousseau C et al. Severe lipemia induced by tamoxifen. Cancer. 1986; 57:2123-6. [IDIS 216127] [PubMed 3697911]

186. Noguchi M, Taniya T, Tajiri K et al. Fatal hyperlipaemia in a case of metastatic breast cancer treated by tamoxifen. Br J Surg. 1987; 74:586-7. [PubMed 3620865]

187. Taniya T, Noguchi M, Tajiri K et al. [A case report of hyperlipemia with giant fatty liver during adjuvant endocrine therapy by tamoxifen]. Gan No Rinsho. 1987; 33:300-4. [PubMed 3108557]

188. Rossner S, Wallgren A. Serum lipoproteins and proteins after breast cancer surgery and effects of tamoxifen. Atherosclerosis. 1984; 52:339-46. [PubMed 6497936]

189. McKeown CA, Swartz M, Blom J et al. Tamoxifen retinopathy. Br J Ophthalmol. 1981; 65:177-9. [PubMed 7225310]

190. Vinding T, Nielsen NV. Retinopathy caused by treatment with tamoxifen in low dosage. Acta Ophthalmol. 1983; 61:45-50.

191. Griffiths MF. Tamoxifen retinopathy at low dosage. Am J Ophthalmol. 1987; 104:185-6. [IDIS 232920] [PubMed 3039846]

192. Ashford AR, Donev I, Tiwari RP et al. Reversible ocular toxicity related to tamoxifen therapy. Cancer. 1988; 61:33-5. [IDIS 237645] [PubMed 3334951]

193. Pugesgaard T, Von Eyben FE. Bilateral optic neuritis evolved during tamoxifen treatment. Cancer. 1986; 58:383-6. [IDIS 218074] [PubMed 3719532]

194. National Institutes of Health Office of Medical Applications of Research. Consensus conference: treatment of early-stage breast cancer. JAMA. 1991; 265:391-5. [PubMed 1984541]

195. Fisher B, Redmond C, Wickerham L et al. Systemic therapy in patients with node-negative breast cancer: a commentary based on two national surgical adjuvant breast and bowel project (NSABP) clinical trials. Ann Intern Med. 1989; 111:703-12. [IDIS 260416] [PubMed 2679288]

196. Fisher B, Costantino J, Redmond C et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989; 320:479-84. [IDIS 308825] [PubMed 2644532]

197. Rosner D, Lane WW. One-third of node-negative breast cancer patients are highly curable by surgery alone, without need for adjuvant systemic therapy. Proc Annu Meet Am Soc Clin Oncol. 1990; 9:A63.

198. Redmond CK, Fisher B, Costantino J et al. Treatment of stage I breast cancer: the NSABP experience. Horm Res. 1989; 32(Suppl 1):175-80. [PubMed 2613203]

199. Hillner BE, Smith TJ. Efficacy and cost effectiveness of adjuvant chemotherapy in women with node-negative breast cancer. N Engl J Med. 1991; 324:160-8. [IDIS 276489] [PubMed 1898533]

200. Anon. Adjuvant tamoxifen in early breast cancer. Lancet. 1987; 2:191-2. [PubMed 2885643]

201. McGuire WL. Adjuvant therapy of node-negative breast cancer. N Engl J Med. 1989; 320:525-7. [PubMed 2915655]

202. DeVita VT Jr. Breast cancer therapy: exercising all our options. N Engl J Med. 1989; 320:527-9. [PubMed 2915656]

203. Wolmark N. 1989: The year of adjuvant therapy in node-negative breast cancer. Cancer: Princ Pract Oncol Updates. 1989; 3:1-10.

204. Anon. Tamoxifen for node-negative breast cancer. FDA Drug Bull. 1990; 20:5.

205. Bianco AR, De Placido S, Gallo C et al. Adjuvant therapy with tamoxifen in operable breast cancer. Lancet. 1988; 2:1095-9. [IDIS 247823] [PubMed 2903322]

206. McGuire WL. Adjuvant therapy of node-negative breast cancer: another point of view. J Natl Cancer Inst. 1988; 80:1075-6. [


read more


Epanutin 300mg hard capsules


1. Name Of The Medicinal Product

Epanutin 300 mg Hard Capsules

2. Qualitative And Quantitative Composition

Each capsule contains 300mg phenytoin sodium

Each capsule also contains 61.88 mg lactose monohydrate

For full list of excipients, see Section 6.1

3. Pharmaceutical Form

Capsules, hard

Epanutin Capsules 300mg: A white powder in a No 1 hard gelatin capsule with a white opaque body and green cap, radially printed 'EPANUTIN 300'.

4. Clinical Particulars 4.1 Therapeutic Indications

Control of tonic-clonic seizures (grand mal epilepsy), partial seizures (focal including temporal lobe) or a combination of these, and the prevention and treatment of seizures occurring during or following neurosurgery and/or severe head injury. Epanutin has also been employed in the treatment of trigeminal neuralgia but it should only be used as second line therapy if carbamazepine is ineffective or patients are intolerant to carbamazepine.

4.2 Posology And Method Of Administration

For oral administration only.

Dosage:

Dosage should be individualised as there may be wide interpatient variability in phenytoin serum levels with equivalent dosage. Epanutin should be introduced in small dosages with gradual increments until control is achieved or until toxic effects appear. In some cases serum level determinations may be necessary for optimal dosage adjustments - the clinically effective level is usually 10-20mg/l (40-80 micromoles/l) although some cases of tonic-clonic seizures may be controlled with lower serum levels of phenytoin. With recommended dosage a period of seven to ten days may be required to achieve steady state serum levels with Epanutin and changes in dosage should not be carried out at intervals shorter than seven to ten days. Maintenance of treatment should be the lowest dose of anticonvulsant consistent with control of seizures.

Epanutin Capsules, Suspension and Infatabs:

Epanutin Capsules contain phenytoin sodium whereas Epanutin Suspension and Epanutin Infatabs contain phenytoin. Although 100mg of phenytoin sodium is equivalent to 92mg of phenytoin on a molecular weight basis, these molecular equivalents are not necessarily biologically equivalent. Physicians should therefore exercise care in those situations where it is necessary to change the dosage form and serum level monitoring is advised.

Adults:

Initially 3 to 4mg/kg/day with subsequent dosage adjustment if necessary. For most adults a satisfactory maintenance dose will be 200 to 500mg daily in single or divided doses. Exceptionally, a daily dose outside this range may be indicated. Dosage should normally be adjusted according to serum levels where assay facilities exist.

Elderly:

Elderly (over 65 years): As with adults the dosage of Epanutin should be titrated to the patient's individual requirements using the same guidelines. As elderly patients tend to receive multiple drug therapies, the possibility of drug interactions should be borne in mind.

Infants and Children:

Initially, 5mg/kg/day in two divided doses, with subsequent dosage individualised to a maximum of 300mg daily. A recommended daily maintenance dosage is usually 4-8mg/kg.

Neonates:

The absorption of phenytoin following oral administration in neonates is unpredictable. Furthermore, the metabolism of phenytoin may be depressed. It is therefore especially important to monitor serum levels in the neonate.

4.3 Contraindications

Phenytoin is contraindicated in those patients who are hypersensitive to phenytoin, or its excipients, or other hydantoins.

4.4 Special Warnings And Precautions For Use

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Phenytoin Sodium.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When, in the judgement of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative anti-epileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anti-epileptic drug not belonging to the hydantoin chemical class.

Phenytoin is highly protein bound and extensively metabolised by the liver. Reduced dosage to prevent accumulation and toxicity may therefore be required in patients with impaired liver function. Where protein binding is reduced, as in uraemia, total serum phenytoin levels will be reduced accordingly. However, the pharmacologically active free drug concentration is unlikely to be altered. Therefore, under these circumstances therapeutic control may be achieved with total phenytoin levels below the normal range of 10-20mg/l (40-80 micromoles/l). Patients with impaired liver function, elderly patients or those who are gravely ill may show early signs of toxicity.

Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence seizures are present together, combined drug therapy is needed.

Phenytoin may affect glucose metabolism and inhibit insulin release. Hyperglycaemia has been reported in association with toxic levels. Phenytoin is not indicated for seizures due to hypoglycaemia or other metabolic causes.

Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as "delirium", "psychosis", or "encephalopathy", or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, serum drug level determinations are recommended. Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination of therapy with phenytoin is recommended.

Herbal preparations containing St John's wort (Hypericum perforatum) should not be used while taking phenytoin due to the risk of decreased plasma concentrations and reduced clinical effects of phenytoin (see Section 4.5).

Anticonvulsant Hypersensitivity Syndrome (AHS) is a rare drug induced, multiorgan syndrome which is potentially fatal and occurs in some patients taking anticonvulsant medication. It is characterized by fever, rash, lymphadenopathy, and other multiorgan pathologies, often hepatic. The mechanism is unknown. The interval between first drug exposure and symptoms is usually 2-4 weeks but has been reported in individuals receiving anticonvulsants for 3 or more months. Patients at higher risk for developing AHS include black patients, patients who have a family history of or who have experienced this syndrome in the past, and immuno-suppressed patients. The syndrome is more severe in previously sensitized individuals. If a patient is diagnosed with AHS, discontinue the phenytoin and provide appropriate supportive measures.

Serious skin reactions

Phenytoin can cause rare, serious skin adverse events such as exfoliative dermatitis, Stevens- Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should seek medical advice from their physician immediately when observing any indicative signs or symptoms. The physician should advise the patient to discontinue treatment if the rash appears. If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further phenytoin medication is contraindicated. Published literature has suggested that there may be an increased, although still rare, risk of hypersensitivity reactions, including skin rash, SJS, TEN, and hepatotoxicity in black patients.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLAB* 1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of drugs associated with SJS/TEN, including phenytoin, in HLA-B*1502 positive patients when alternative therapies are otherwise equally available.

HLAB* 1502 may be associated with an increased risk of developing Stevens Johnson Syndrome (SJS) in individuals of Thai and Han Chinese Origin when treated with phenytoin. If these patients are known to be positive for HLAB*1502, the use of phenytoin should only be considered if the benefits are thought to exceed risks.

In the Caucasian and Japanese population, the frequency of HLAB*1502 allele is extremely low, and thus it is not possible at present to conclude on risk association. Adequate information about risk association in other ethnicities is currently not available.

Musculoskeletal Effect

Phenytoin and other anticonvulsants that have been shown to induce the CYP450 enzyme are thought to affect bone mineral metabolism indirectly by increasing the metabolism of Vitamin D3. This may lead to Vitamin D deficiency and heightened risk of osteomalacia, bone fractures, osteoporosis, hypocalcemia, and hypophosphatemia in chronically treated epileptic patients.

In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using the medication in patients suffering from this disease.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose metabolism should not take this medicine

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

1. Drugs which may increase phenytoin serum levels include:

Amiodarone, antifungal agents (such as, but not limited to, amphotericin B, fluconazole, ketoconazole, miconazole and itraconazole), chloramphenicol, chlordiazepoxide, diazepam, dicoumarol, diltiazem, disulfiram, fluoxetine, fluvoxamine, sertraline, H2-antagonists e.g. cimetidine,, halothane, isoniazid, methylphenidate, nifedipine, omeprazole, oestrogens, phenothiazines, phenylbutazone, salicylates, succinimides, sulphonamides, tolbutamide, trazodone and viloxazine.

2. Drugs which may decrease phenytoin serum levels include:

Folic acid, reserpine, rifampicin, sucralfate, theophylline and vigabatrin.

Serum levels of phenytoin can be reduced by concomitant use of the herbal preparations containing St John's wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes by St John's wort. Herbal preparations containing St John's wort should therefore not be combined with phenytoin. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's wort. If a patient is already taking St John's wort check the anticonvulsant levels and stop St John's wort. Anticonvulsant levels may increase on stopping St John's wort. The dose of anticonvulsant may need adjusting.

A pharmacokinetic interaction study between nelfinavir and phenytoin both administered orally showed that nelfinavir reduced AUC values of phenytoin (total) and free phenytoin by 29% and 28%, respectively. Therefore, phenytoin concentration should be monitored during co-administration with nelfinavir, as nelfinavir may reduce phenytoin plasma concentration.

3. Drugs which may either increase or decrease phenytoin serum levels include:

Carbamazepine, phenobarbital, valproic acid, sodium valproate, antineoplastic agents, certain antacids and ciprofloxacin. Similarly, the effect of phenytoin on carbamazepine, phenobarbital, valproic acid and sodium valproate serum levels is unpredictable.

Acute alcohol intake may increase phenytoin serum levels while chronic alcoholism may decrease serum levels.

4. Although not a true pharmacokinetic interaction, tricyclic antidepressants and phenothiazines may precipitate seizures in susceptible patients and phenytoin dosage may need to be adjusted.

5. Drugs whose effect is impaired by phenytoin include:

Antifungal agents (e.g. azoles), antineoplastic agents, calcium channel blockers, clozapine, corticosteroids, ciclosporin, dicoumarol, digitoxin, doxycycline, furosemide, lamotrigine, methadone, neuromuscular blockers, oestrogens, oral contraceptives, paroxetine, sertraline, quinidine, rifampicin, theophylline and vitamin D.

6. Drugs whose effect is altered by phenytoin include:

Warfarin. The effect of phenytoin on warfarin is variable and prothrombin times should be determined when these agents are combined.

Serum level determinations are especially helpful when possible drug interactions are suspected.

Drug/Laboratory Test Interactions:

Phenytoin may cause a slight decrease in serum levels of total and free thyroxine, possibly as a result of enhanced peripheral metabolism. These changes do not lead to clinical hypothyroidism and do not affect the levels of circulating TSH. The latter can therefore be used for diagnosing hypothyroidism in the patient on phenytoin. Phenytoin does not interfere with uptake and suppression tests used in the diagnosis of hypothyroidism. It may, however, produce lower than normal values for dexamethasone or metapyrone tests. Phenytoin may cause raised serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase and lowered serum levels of calcium and folic acid. It is recommended that serum folate concentrations be measured at least once every 6 months, and folic acid supplements given if necessary. Phenytoin may affect blood sugar metabolism tests.

4.6 Pregnancy And Lactation

There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans. Genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or foetus.

Anticonvulsants including phenytoin may produce congenital abnormalities in the offspring of a small number of epileptic patients. The exact role of drug therapy in these abnormalities is unclear and genetic factors, in some studies, have also been shown to be important. Epanutin should only be used during pregnancy, especially early pregnancy, if in the judgement of the physician the potential benefits clearly outweigh the risk.

In addition to the reports of increased incidence of congenital malformations, such as cleft lip/palate and heart malformations in children of women receiving phenytoin and other antiepileptic drugs, there have more recently been reports of a foetal hydantoin syndrome. This consists of prenatal growth deficiency, micro-encephaly and mental deficiency in children born to mothers who have received phenytoin, barbiturates, alcohol, or trimethadione. However, these features are all interrelated and are frequently associated with intrauterine growth retardation from other causes.

There have been isolated reports of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

An increase in seizure frequency during pregnancy occurs in a proportion of patients, and this may be due to altered phenytoin absorption or metabolism. Periodic measurement of serum phenytoin levels is particularly valuable in the management of a pregnant epileptic patient as a guide to an appropriate adjustment of dosage. However, postpartum restoration of the original dosage will probably be indicated.

Neonatal coagulation defects have been reported within the first 24 hours in babies born to epileptic mothers receiving phenytoin. Vitamin K1 has been shown to prevent or correct this defect and may be given to the mother before delivery and to the neonate after birth.

Infant breast-feeding is not recommended for women taking phenytoin because phenytoin appears to be secreted in low concentrations in human milk.

4.7 Effects On Ability To Drive And Use Machines

Caution is recommended in patients performing skilled tasks (e.g. driving or operating machinery) as treatment with phenytoin may cause central nervous system adverse effects such as dizziness and drowsiness (see Section 4.8).

4.8 Undesirable Effects

Immune system reactions: Anaphylactoid reaction, and anaphylaxis.

Central Nervous System:

The most common manifestations encountered with phenytoin therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased co-ordination, mental confusion, paraesthesia, somnolence, drowsiness and vertigo. Dizziness, insomnia, transient nervousness, motor twitchings, taste perversion and headaches have also been observed. There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. There are occasional reports of irreversible cerebellar dysfunction associated with severe phenytoin overdosage. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

Gastrointestinal:

Nausea, vomiting and constipation, toxic hepatitis, and liver damage.

Dermatological:

Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash is the most common; dermatitis is seen more rarely. Other more serious and rare forms have included bullous, exfoliative or purpuric dermatitis, lupus erythematosus, Stevens-Johnson syndrome and toxic epidermal necrolysis (see Section 4.4).

Connective Tissue:

Coarsening of the facial features, enlargement of the lips, gingival hyperplasia, hirsutism, hypertrichosis, Peyronie's Disease and Dupuytren's contracture may occur rarely.

Haemopoietic:

Haemopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis, pancytopenia with or without bone marrow suppression, and aplastic anaemia. While macrocytosis and megaloblastic anaemia have occurred, these conditions usually respond to folic acid therapy.

There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local and generalised) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's Disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling serum sickness, eg fever, rash and liver involvement. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

Frequent blood counts should be carried out during treatment with phenytoin.

Immune System:

Hypersensitivity syndrome has been reported and may in rare cases be fatal (the syndrome may include, but is not limited to, symptoms such as arthralgias, eosinophilia, fever, liver dysfunction, lymphadenopathy or rash), systemic lupus erythematosus, polyarteritis nodosa, and immunoglobulin abnormalities may occur. Several individual case reports have suggested that there may be an increased, although still rare, incidence of hypersensitivity reactions, including skin rash and hepatotoxicity, in black patients.

Other:

Polyarthropathy, interstitial nephritis, pneumonitis.

Musculoskeletal System: Bone fractures and osteomalacia have been associated with longterm (>10 years) use of phenytoin by patients with chronic epilepsy. Osteoporosis and other disorders of bone metabolism such as hypocalcemia, hypophophatemia and decreased levels of Vitamin D metabolites have also been reported.

4.9 Overdose

The lethal dose in children is not known. The mean lethal dose for adults is estimated to be 2 to 5g. The initial symptoms are nystagmus, ataxia and dysarthria. The patient then becomes comatose, the pupils are unresponsive and hypotension occurs followed by respiratory depression and apnoea. Death is due to respiratory and circulatory depression.

There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus on lateral gaze usually appears at 20mg/l, and ataxia at 30mg/l, dysarthria and lethargy appear when the serum concentration is greater than 40mg/l, but a concentration as high as 50mg/l has been reported without evidence of toxicity.

As much as 25 times therapeutic dose has been taken to result in serum concentration over 100mg/l (400 micromoles/l) with complete recovery.

Treatment:

Treatment is non-specific since there is no known antidote. If ingested within the previous 4 hours the stomach should be emptied. If the gag reflex is absent, the airway should be supported. Oxygen, and assisted ventilation may be necessary for central nervous system, respiratory and cardiovascular depression. Haemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been utilised in the treatment of severe intoxication in children.

In acute overdosage the possibility of the presence of other CNS depressants, including alcohol, should be borne in mind.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Phenytoin is effective in various animal models of generalised convulsive disorders, reasonably effective in models of partial seizures but relatively ineffective in models of myoclonic seizures.

It appears to stabilise rather than raise the seizure threshold and prevents spread of seizure activity rather than abolish the primary focus of seizure discharge.

The mechanism by which phenytoin exerts its anticonvulsant action has not been fully elucidated however, possible contributory effects include:

1. Non-synaptic effects to reduce sodium conductance, enhance active sodium extrusion, block repetitive firing and reduce post-tetanic potentiation

2. Post-synaptic action to enhance gaba-mediated inhibition and reduce excitatory synaptic transmission

3. Pre-synaptic actions to reduce calcium entry and block release of neurotransmitter.

5.2 Pharmacokinetic Properties

Phenytoin is absorbed from the small intestine after oral administration. Various formulation factors may affect the bioavailability of phenytoin, however, non-linear techniques have estimated absorption to be essentially complete. After absorption it is distributed into body fluid including CSF. Its volume of distribution has been estimated to be between 0.52 and 1.19 litres/kg, and it is highly protein bound (usually 90% in adults).

The plasma half-life of phenytoin in man averages 22 hours with a range of 7 to 42 hours. Steady state therapeutic drug levels are achieved at least 7 to 10 days after initiation of therapy.

Phenytoin is hydroxylated in the liver by an enzyme system which is saturable. Small incremental doses may produce very substantial increases in serum levels when these are in the upper range of therapeutic concentrations.

The parameters controlling elimination are also subject to wide interpatient variation. The serum level achieved by a given dose is therefore also subject to wide variation.

5.3 Preclinical Safety Data

Pre-clinical safety data do not add anything of further significance to the prescriber.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Core:

Lactose monohydrate

Magnesium stearate

Silica

Shell:

Gelatin

Patent blue V (E131)

Quinoline yellow (E104)

Titanium dioxide (E171)

Sodium laurilsulfate

Printing ink:

Shellac

Black iron oxide (E172)

Propylene glycol

6.2 Incompatibilities

None known

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package in order to protect from light.

6.5 Nature And Contents Of Container

PVC/PVdC blister pack containing 28 capsules

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Pfizer Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

PL 00057/0525

9. Date Of First Authorisation/Renewal Of The Authorisation

1st February 2004

10. Date Of Revision Of The Text

11 July 2010

Ref: EP 16_0 UK


read more


Gianvi


drospirenone and ethinyl estradiol
Dosage Form: tablets
Gianvi™
(drospirenone and ethinyl estradiol tablets)
Rev. D 6/2010
11001685

Rx only

PATIENTS SHOULD BE COUNSELED THAT THIS PRODUCT DOES NOT PROTECT AGAINST HIV INFECTION (AIDS) AND OTHER SEXUALLY TRANSMITTED DISEASES

Gianvi Description

Gianvi™ (drospirenone and ethinyl estradiol tablets) 3 mg/0.02 mg provides an oral contraceptive regimen consisting of 24 active film-coated tablets each containing 3 mg of drospirenone and 0.02 mg of ethinyl estradiol and 4 inert film-coated tablets. Other ingredients are anhydrous lactose, corn starch, crospovidone, FD&C red no. 40 aluminum lake, FD&C yellow no. 6 aluminum lake, hypromellose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, pregelatinized starch and titanium dioxide. The inert tablets contain anhydrous lactose, hypromellose, magnesium stearate, and microcrystalline cellulose.

Drospirenone (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3’,4’,6,6a,7,8,9,10,11, 12,13,14,15,15a,16 - hexadecahydro - 10,13 - dimethylspiro - [17H - dicyclopropa - [6,7:15,16]cyclopenta[a]phenanthrene - 17,2’(5H) - furan] - 3,5’(2H) - dione) is a synthetic progestational compound. Ethinyl estradiol (19-nor-17?-pregna 1,3,5(10)-triene-20-yne-3, 17-diol) is a synthetic estrogenic compound. The structural formulas are as follows:

Drospirenone

C24H30O3 Molecular Weight: 366.5

Ethinyl Estradiol

C20H24O2 Molecular Weight: 296.4

Gianvi - Clinical Pharmacology Pharmacodynamics Oral Contraception

Combination oral contraceptives (COCs) act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increases the difficulty of sperm entry into the uterus) and the endometrium (which reduces the likelihood of implantation).

Drospirenone is a spironolactone analogue with antimineralocorticoid activity. Preclinical studies in animals and in vitro have shown that drospirenone has no androgenic, estrogenic, glucocorticoid, or antiglucocorticoid activity. Preclinical studies in animals have also shown that drospirenone has antiandrogenic activity.

Acne

Acne vulgaris is a skin condition with a multifactorial etiology including androgen stimulation of sebum production. While the combination of ethinyl estradiol and drospirenone increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established. The impact of the antiandrogenic activity of drospirenone on acne is not known.

Pharmacokinetics Absorption

The absolute bioavailability of drospirenone (DRSP) from a single entity tablet is about 76%. The absolute bioavailability of ethinyl estradiol (EE) is approximately 40% as a result of presystemic conjugation and first-pass metabolism.  The absolute bioavailability of drospirenone and ethinyl estradiol tablets,  which is a combination tablet of drospirenone and ethinyl estradiol stabilized by betadex as a clathrate (molecular inclusion complex), has not been evaluated. The bioavailability of EE is similar when dosed via a betadex clathrate formulation compared to when it is dosed as a free steroid. Serum concentrations of DRSP and EE reached peak levels within 1 to 2 hours after administration of drospirenone and ethinyl estradiol tablets.

The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1 to 10 mg. Following daily dosing of drospirenone and ethinyl estradiol tablets, steady-state DRSP concentrations were observed after 8 days. There was about 2 to 3 fold accumulation in serum Cmax and AUC (0-24h) values of DRSP following multiple dose administration of drospirenone and ethinyl estradiol tablets  (see Table I).

For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of drospirenone and ethinyl estradiol tablets  serum Cmax and AUC (0-24h) values of EE accumulate by a factor of about 1.5 to 2 (see Table I).

TABLE I: TABLE OF PHARMACOKINETIC PARAMETERS OF DROSPIRENONE AND ETHINYL ESTRADIOL TABLETS (Drospirenone 3 mg and Ethinyl Estradiol 0.02 mg) * geometric mean (geometric coefficient of variation) † median (range) Drospirenone

Cycle /

Day

No. of

Subjects

Cmax * 

(ng/mL)

Tmax†

(h)

AUC (0-24h)*

(ng•h/mL)

t1/2*

(h) 1/1 23 38.4 (25) 1.5 (1 to 2) 268 (19) NA 1/21 23 70.3 (15) 1.5 (1 to 2) 763 (17) 30.8 (22) Ethinyl Estradiol

Cycle /

Day

No. of

Subjects

Cmax*

(pg/mL)

Tmax†

(h)

AUC (0-24h)*

(pg•h/mL)

t1/2*

(h) 1/1 23 32.8 (45) 1.5 (1 to 2) 108 (52) NA 1/21 23 45.1 (35) 1.5 (1 to 2) 220 (57) NA NA = Not available Effect of Food

The rate of absorption of DRSP and EE following single administration of a formulation similar to drospirenone and ethinyl estradiol tablets was slower under fed (high fat meal) conditions with the serum Cmax being reduced about 40% for both components. The extent of absorption of DRSP, however, remained unchanged. In contrast, the extent of absorption of EE was reduced by about 20% under fed conditions.

Distribution

DRSP and EE serum levels decline in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4 to 5 L/kg.

DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough levels).  EE is reported to be highly but non-specifically bound to serum albumin (approximately 98.5%) and induces an increase in the serum concentrations of both SHBG and CBG. EE induced effects on SHBG and CBG were not affected by variation of the DRSP dosage in the range of 2 to 3 mg.

Metabolism

The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate. These metabolites were shown not to be pharmacologically active. In in vitro studies with human liver microsomes, DRSP was metabolized only to a minor extent mainly by Cytochrome P450 3A4 (CYP3A4).

EE has been reported to be subject to presystemic conjugation in both small bowel mucosa and the liver. Metabolism occurs primarily by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as conjugates with glucuronide and sulfate. CYP3A4 in the liver is responsible for the 2-hydroxylation which is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion.

Excretion

DRSP serum levels are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of DRSP was nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38 to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17 to 20% of the metabolites were excreted as glucuronides and sulfates.

For EE the terminal disposition phase half-life has been reported to be approximately 24 hours. EE is not excreted unchanged. EE is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.

Special Populations Ethnic Groups

No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women (age 20 to 35) when drospirenone and ethinyl estradiol tablets were administered daily for 21 days. Other ethnic groups have not been studied.

Hepatic Dysfunction

Drospirenone and ethinyl estradiol tablets are contraindicated in patients with hepatic dysfunction (see CONTRAINDICATIONS and BOLDED WARNING).  The mean exposure to DRSP in women with moderate liver impairment is approximately three times higher than the exposure in women with normal liver function. Drospirenone and ethinyl estradiol tablets have not been studied in women with severe hepatic impairment.

Renal Insufficiency

Drospirenone and ethinyl estradiol tablets are contraindicated in patients with renal insufficiency (see CONTRAINDICATIONS and BOLDED WARNING).

The effect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effect of DRSP on serum potassium levels were investigated in female subjects (n = 28, age 30 to 65) with normal renal function and mild and moderate renal impairment. All subjects were on a low potassium diet. During the study 7 subjects continued the use of potassium sparing drugs for the treatment of the underlying illness. On the 14th day (steady-state) of DRSP treatment, serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50 to 80 mL/min) were comparable to those in the group with normal renal function (CLcr, >80 mL/min). The serum DRSP levels were on average 37% higher in the group with moderate renal impairment (CLcr, 30 to 50 mL/min) compared to those in the group with normal renal function. DRSP treatment was well tolerated by all groups. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in five of the seven subjects who continued use of potassium sparing drugs during the study, mean serum potassium levels increased by up to 0.33 mEq/L. Therefore, potential exists for hyperkalemia to occur in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs.

Indications and Usage for Gianvi

Gianvi™ (drospirenone and ethinyl estradiol tablets) 3 mg/0.02 mg is indicated for the prevention of pregnancy in women who elect to use an oral contraceptive.

Oral contraceptives are highly effective. Table II lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization and contraceptive implants and IUDs, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

Gianvi™ (drospirenone and ethinyl estradiol tablets) is indicated for the treatment of moderate acne vulgaris in women at least 14 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. Gianvi™ (drospirenone and ethinyl estradiol tablets) should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control.

TABLE II: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF TYPICAL USE AND FIRST YEAR OF PERFECT USE OF CONTRACEPTION AND THE PERCENTAGE CONTINUING USE AT THE END OF THE FIRST YEAR: UNITED STATES. * Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. † Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. ‡ Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly). The percentage who experience an accidental pregnancy during the first year if they do not stop use for any reason. § The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percentage who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. ¶ Foams, creams, gels, vaginal suppositories, and vaginal film. # Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. ? With spermicidal cream or jelly. ? Without spermicides. ? The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 2 light-orange pills), Lo/Ovral (1 dose is 4 white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills). ? However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches six months of age.

 

  % of Women Experiencing an Unintended Pregnancy Within the First Year of Use % of Women Continuing Use at One Year* Method (1) Typical Use†  (2) Perfect Use‡  (3) (4) Chance§  85 85 40 Spermicides¶  26 6 63 Periodic abstinence 25 Calendar 9 Ovulation method 3 Sympto-thermal# 2 Post-ovulation 1 Withdrawal 19 4 Cap? Parous women 40 26 42 Nulliparous women 20 9 56 Sponge Parous women 40 20 42 Nulliparous women 20 9 56 Diaphragm? 20 6 56 Condom?  Female (Reality) 21 5 56 Male 14 3 61 Pill 5 71 progestin only 0.5 combined 0.1 IUD Progesterone T 2 1.5 81 Copper T 380A 0.8 0.6 78 Lng 20 0.1 0.1 81 Depo Provera 0.3 0.3 70 Norplant and Norplant-2 0.05 0.05 88 Female sterilization 0.5 0.5 100 Male sterilization 0.15 0.1 100 Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.?  Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.?  Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Guest F, Kowal D, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. Oral Contraceptive Clinical Trial

In the primary contraceptive efficacy study of drospirenone and ethinyl estradiol tablets (3 mg DRSP/0.02 mg EE) of up to 1 year duration, 1,027 subjects were enrolled and completed 11,480 28-day cycles of use. The age range was 17 to 36 years. The racial demographic was: 87.8% Caucasian, 4.6% Hispanic, 4.3% Black, 1.2% Asian, and 2.1% other. Women with a BMI greater than 35 were excluded from the trial. The pregnancy rate (Pearl Index) was 1.41 per 100 woman-years of use based on 12 pregnancies that occurred after the onset of treatment and within 14 days after the last dose of drospirenone and ethinyl estradiol tablets in women 35 years of age or younger during cycles in which no other form of contraception was used.

Acne Clinical Trials

In two multicenter, double blind, randomized, placebo-controlled studies, 889 subjects, ages 14 to 45 years, with moderate acne received drospirenone and ethinyl estradiol tablets or placebo for six 28 day cycles. The primary efficacy endpoints were the percent change in inflammatory lesions, non-inflammatory lesions, total lesions, and the percentage of subjects with a “clear” or “almost clear” rating on the Investigator’s Static Global Assessment (ISGA) scale on day 15 of cycle 6, as presented in Table III:

TABLE III: EFFICACY RESULTS FOR ACNE TRIALS* * Evaluated at day 15 of cycle 6, last observation carried forward for the Intent to treat population Study 1 Study 2 Drospirenone and Ethinyl Estradiol Tablets N=228 Placebo N=230 Drospirenone and Ethinyl Estradiol Tablets N=218 Placebo N=213 ISGA Success Rate 35 (15%) 10 (4%) 46 (21%) 19 (9%)

Inflammatory Lesions

Mean Baseline Count

Mean Absolute (%) Reduction

33

15 (48%)

33

11 (32%)

32

16 (51%)

32

11 (34%)

Non-inflammatory Lesions

Mean Baseline Count

Mean Absolute (%) Reduction

47

18 (39%)

47

10 (18%)

44

17 (42%)

44

11 (26%)

Total lesions

Mean Baseline Count

Mean Absolute (%) reduction

80

33 (42%)

80

21 (25%)

76

33 (46%)

76

22 (31%) Contraindications

Gianvi™ (drospirenone and ethinyl estradiol tablets) should not be used in women who have the following:

Renal insufficiency Hepatic dysfunction Adrenal insufficiency Thrombophlebitis or thromboembolic disorders A past history of deep-vein thrombophlebitis or thromboembolic disorders Cerebral-vascular or coronary-artery disease (current or history) Valvular heart disease with thrombogenic complications Severe hypertension Diabetes with vascular involvement Headaches with focal neurological symptoms Major surgery with prolonged immobilization Known or suspected carcinoma of the breast Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia Undiagnosed abnormal genital bleeding Cholestatic jaundice of pregnancy or jaundice with prior pill use Known or suspected pregnancy Liver tumor (benign or malignant) or active liver disease Heavy smoking (? 15 cigarettes per day) and over age 35 Hypersensitivity to any component of this product Warnings

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

Gianvi™ (drospirenone and ethinyl estradiol tablets) contains 3 mg of the progestin drospirenone that has antimineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. Gianvi™ (drospirenone and ethinyl estradiol tablets) should not be used in patients with conditions that predispose to hyperkalemia (i.e., renal insufficiency, hepatic dysfunction and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium should have their serum potassium level checked during the first treatment cycle. Medications that may increase serum potassium include ACE inhibitors, angiotensin – II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs.

The use of oral contraceptives is associated with increased risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, stroke), hepatic neoplasia, gallbladder disease, and hypertension. The risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.

The information contained in this package insert is based principally on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiologic studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiologic methods.

1. Thromboembolic Disorders and Other Vascular Problems a. Myocardial Infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Table IV) among women who use oral contraceptives.

TABLE IV: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN- YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE (Adapted from P.M. Layde and V. Beral) AGE EVER-USERS
NON-SMOKERS

EVER-USERS

SMOKERS

CONTROLS

NON-SMOKERS

CONTROL

SMOKERS 15 to 24 0 10.5 0 0 25 to 34 4.4 14.2 2.7 4.2 35 to 44 21.5 63.4 6.4 15.2 45+ 52.4 206.7 11.4 27.9

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

b. Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.

A two- to four-fold increase in the relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued from at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, combined oral contraceptives should be started no earlier than four to six weeks after delivery and at that time only in women who elect not to breast feed.

Several studies have investigated the relative risks of thromboembolism in women using a different drospirenone-containing COC (Yasmin, which contains 0.030 mg of ethinyl estradiol and 3 mg of drospirenone) compared to those in women using COCs containing other progestins. Two prospective cohort studies, both evaluating the risk of venous and arterial thromboembolism and death, were initiated at the time of Yasmin approval.1, 2 The first (EURAS) showed the risk of thromboembolism (particularly venous thromboembolism) and death in Yasmin users to be comparable to that of other oral contraceptive preparations, including those containing levonorgestrel (a so-called second generation COC). The second prospective cohort study (Ingenix) also showed a comparable risk of thromboembolism in Yasmin users compared to users of other COCs, including those containing levonorgestrel. In the second study, COC comparator groups were selected based on their having similar characteristics to those being prescribed Yasmin.

Two additional epidemiological studies, one case-control study (van Hylckama Vlieg et al.3) and one retrospective cohort study (Lidegaard et al.4) suggested that the risk of venous thromboembolism occurring in Yasmin users was higher than that for users of levonorgestrel-containing COCs and lower than that for users of desogestrel/gestodene-containing COCs (so-called third generation COCs). In the case-control study, however, the number of Yasmin cases was very small (1.2% of all cases) making the risk estimates unreliable. The relative risk for Yasmin users in the retrospective cohort study was greater than that for users of other COC products when considering women who used the products for less than one year. However, these one-year estimates may not be reliable because the analysis may include women of varying risk levels. Among women who used the product for 1 to 4 years, the relative risk was similar for users of Yasmin to that for users of other COC products.

c. Cerebrovascular Diseases

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor, for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias, hyperlipidemias, and obesity. Women with migraine (particularly migraine with aura) who take combination oral contraceptives may be at an increased risk of stroke.

d. Dose-Related Risk of Vascular Disease From Oral Contraceptives

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content that is judged appropriate for the individual patient.

e. Persistence of Risk of Vascular Disease

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women aged 40 to 49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens.

2. Estimates of Mortality From Contraceptive Use

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table V). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is below that associated with childbirth.


read more


Epanutin Ready Mixed Parenteral


1. Name Of The Medicinal Product

Epanutin™ Ready Mixed Parenteral 250 mg/5 ml Solution for Injection or infusion.

2. Qualitative And Quantitative Composition

Each 5 ml ampoule contains phenytoin sodium 250 mg (50 mg/ml).

For excipients see 6.1.

3. Pharmaceutical Form

Solution for Injection or Infusion.

Clear, colourless, sterile solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Parenteral Epanutin is indicated for the control of status epilepticus of the tonic-clonic (grand mal) type and prevention and treatment of seizures occurring during or following neurosurgery and/or severe head injury.

It is of use in the treatment of cardiac arrhythmias where first line therapy is not effective. It is of particular value when these are digitalis induced.

4.2 Posology And Method Of Administration

For parenteral administration.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Parenteral Epanutin is suitable for use as long as it remains free of haziness and precipitate. Upon refrigeration or freezing a precipitate might form; this will dissolve again after the solution is allowed to stand at room temperature. The product is still suitable for use. Only a clear solution should be used. A faint yellow colouration may develop, however, this has no effect on the potency of this solution.

There is a relatively small margin between full therapeutic effect and minimally toxic doses of this drug. Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 and 20 mg/l (40-80 micromoles/l).

Parenteral Epanutin should be injected slowly directly into a large vein through a large-gauge needle or intravenous catheter.

Each injection or infusion of intravenous Epanutin should be preceded and followed by an injection of sterile saline through the same needle or catheter to avoid local venous irritation due to alkalinity of the solution.

(See section 4.4)

For infusion administration the parenteral phenytoin should be diluted in 50-100 ml of normal saline, with the final concentration of phenytoin in the solution not exceeding 10 mg/ml. Administration should commence immediately after the mixture has been prepared and must be completed within one hour (the infusion mixture should not be refrigerated). An in-line filter (0.22-0.50 microns) should be used.

The diluted form is suitable for use as long as it remains free of haziness and precipitate.

Continuous monitoring of the electrocardiogram and blood pressure is essential. Cardiac resuscitative equipment should be available. The patient should be observed for signs of respiratory depression. If administration of intravenous Epanutin does not terminate seizures, the use of other measures, including general anaesthesia, should be considered.

Epanutin Ready Mixed Parenteral contains phenytoin sodium whereas Epanutin Suspension and Epanutin Infatabs contain phenytoin. Although 100 mg of phenytoin sodium is equivalent to 92 mg of phenytoin on a molecular weight basis, these molecular equivalents are not necessarily biologically equivalent. Physicians should therefore exercise care in those situations where it is necessary to change the dosage form and serum level monitoring is advised.

Status Epilepticus:

In a patient having continuous seizure activity, as compared to the more common rapidly recurring seizures, i.e. serial epilepsy, injection of intravenous diazepam or a short acting barbiturate is recommended because of their rapid onset of action, prior to administration of Epanutin.

Following the use of diazepam in patients having continuous seizures and in the initial management of serial epilepsy a loading dose of Epanutin 10-15 mg/kg should be injected slowly intravenously, at a rate not exceeding 50 mg per minute in adults (this will require approximately 20 minutes in a 70 kg patient). The loading dose should be followed by maintenance doses of 100 mg orally or intravenously every 6 to 8 hours.

Recent work in neonates has shown that absorption of phenytoin is unreliable after oral administration, but a loading dose of 15-20 mg/kg of Epanutin intravenously will usually produce serum concentrations of phenytoin within the generally accepted therapeutic range (10-20 mg/l).

The drug should be injected slowly intravenously at a rate of 1-3 mg/kg/min.

Determination of phenytoin serum levels is advised when using Epanutin in the management of status epilepticus and in the subsequent establishing of maintenance dosage. The clinically effective level is usually 10-20 mg/l although some cases of tonic-clonic seizures may be controlled with lower serum levels of phenytoin.

Intramuscular administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours.

Use in Cardiac Arrhythmias:

3.5-5 mg per kg of bodyweight intravenously initially, repeated once if necessary. The solution should be injected slowly, intravenously and at a uniform rate which should not exceed 1ml (50 mg) per minute.

Other clinical conditions:

It is not possible to set forth a universally applicable dosage schedule.

The intravenous route of administration is preferred. Dosage and dosing interval will, of necessity, be determined by the needs of the individual patient. Factors such as previous antiepileptic therapy, seizure control, age and general medical condition must be considered. Notwithstanding the slow absorption of Epanutin, when given intramuscularly, its use in certain conditions may be appropriate.

When short-term intramuscular administration is necessary for a patient previously stabilised orally, compensating dosage adjustments are essential to maintain therapeutic serum levels. An intramuscular dose 50% greater than the oral dose is necessary to maintain these levels. When returned to oral administration, the dose should be reduced by 50% of the original oral dose, for the same period of time the patient received Epanutin intramuscularly, to prevent excessive serum levels due to continued release from intramuscular tissue sites.

Neurosurgery:

In a patient who has not previously received the drug, Parenteral Epanutin 100-200 mg (2-4 ml) may be given intramuscularly at approximately 4-hour intervals prophylactically during neurosurgery and continued during the postoperative period for 48-72 hrs. The dosage should then be reduced to a maintenance dose of 300 mg and adjusted according to serum level estimations.

If the patient requires more than a week of intramuscular Epanutin, alternative routes should be explored such as gastric intubation. For time periods less than one week, the patient switched from intramuscular administration should receive one half the original oral dose for the same period of time the patient received Epanutin intramuscularly.

Measurement of serum levels is of value as a guide to an appropriate adjustment of dosage.

Elderly (over 65 years):

As for adults. However, complications may occur more readily in elderly patients.

Neonates:

Recent work in neonates has shown that absorption of phenytoin is unreliable after oral administration, but a loading dose of 15-20 mg/kg of Epanutin intravenously will usually produce serum concentrations of phenytoin within the generally accepted therapeutic range (10-20 mg/l).

The drug should be injected slowly intravenously at a rate of 1-3 mg/kg/min.

Infants and children:

As for adults, however, it has been shown that children tend to metabolise phenytoin more rapidly than adults. This should be borne in mind when determining dosage regimens; the use of serum level monitoring being particularly beneficial in such cases.

4.3 Contraindications

Phenytoin is contra-indicated in patients who are hypersensitive to phenytoin or other hydantoins. Intra-arterial administration must be avoided in view of the high pH of the preparation.

Because of its effect on ventricular automaticity, phenytoin is contra-indicated in sinus bradycardia, sino-atrial block, and second and third degree A-V block, and patients with Adams-Stokes syndrome.

4.4 Special Warnings And Precautions For Use

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Phenytoin Sodium.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

In adults, intravenous administration should not exceed 50 mg per minute.

In neonates, the drug should be administered at a rate of 1-3 mg/kg/min.

The most notable signs of toxicity associated with the intravenous use of this drug are cardiovascular collapse and/or central nervous system depression. Severe cardiotoxic reactions and fatalities due to depression of atrial and ventricular conduction and ventricular fibrillation, respiratory arrest and tonic seizures have been reported particularly in elderly or gravely ill patients, if the preparation is given too rapidly or in excess.

Hypotension usually occurs when the drug is administered rapidly by the intravenous route. Soft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of intravenous phenytoin. Soft tissue irritation may vary from slight tenderness to extensive necrosis, sloughing and in rare instances has led to amputation. Subcutaneous or perivascular injection should be avoided because of the highly alkaline nature of the solution.

The intramuscular route is not recommended for the treatment of status epilepticus because of slow absorption. Serum levels of phenytoin in the therapeutic range cannot be rapidly achieved by this method.

General:

Intravenous Epanutin should be used with caution in patients with hypotension and severe myocardial insufficiency.

Phenytoin should be discontinued if a skin rash appears. If the rash is exfoliative, purpuric, or bullous or if lupus erythematosus, Stevens-Johnson syndrome, or toxic epidermal necrolysis is suspected, use of this drug should not be resumed and alternative therapy should be considered. If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further phenytoin medication is contra-indicated.

Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present together, combined drug therapy is needed.

Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as "delirium", "psychosis", or "encephalopathy", or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, serum drug level determinations are recommended. Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination of therapy with phenytoin is recommended.

Herbal preparations containing St John's Wort (Hypericum perforatum) should not be used while taking phenytoin due to the risk of decreased plasma concentrations and reduced clinical effects of phenytoin (see Section 4.5).

Phenytoin is highly protein bound and extensively metabolised by the liver.

Reduced maintenance dosage to prevent accumulation and toxicity may therefore be required in patients with impaired liver function. Where protein binding is reduced, as in uraemia, total serum phenytoin levels will be reduced accordingly. However, the pharmacologically active free drug concentration is unlikely to be altered. Therefore, under these circumstances therapeutic control may be achieved with total phenytoin levels below the normal range of 10-20 mg/l. Dosage should not exceed the minimum necessary to control convulsions.

The liver is the chief site of biotransformation of phenytoin. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.

Phenytoin may affect glucose metabolism and inhibit insulin release.

Hyperglycaemia has been reported. Phenytoin is not indicated for seizures due to hypoglycaemia or other metabolic causes. Caution is advised when treating diabetic patients.

In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.

HLAB* 1502 may be associated with an increased risk of developing Stevens Johnson Syndrome (SJS) in individuals of Thai and Han Chinese Origin when treated with phenytoin. If these patients are known to be positive for HLAB*1502, the use of phenytoin should only be considered if the benefits are thought to exceed risks.

In the Caucasian and Japanese population, the frequency of HLAB*1502 allele is extremely low, and thus it is not possible at present to conclude on risk association. Adequate information about risk association in other ethnicities is currently not available.

Laboratory Tests:

Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments.

This product contains a number of excipients known to have a recognised action or effect. These are:

Propylene glycol (may cause alcohol-like symptoms)

Sodium (1.1 mmol per 5 ml ampoule)

Ethanol (440.4 mg per 5 ml ampoule).This may be harmful for those suffering from alcoholism and should be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Drugs which may increase phenytoin serum levels include: amiodarone, antifungal agents (such as, but not limited to, amphotericin B, fluconazole, ketoconazole, miconazole and itraconazole), chloramphenicol, chlordiazepoxide, diazepam, dicoumarol, diltiazem, disulfiram, oestrogens, fluoxetine, H2-antagonists, halothane, isoniazid, methylphenidate, nifedipine, omeprazole, phenothiazines, phenylbutazone, salicylates, succinimides, sulphonamides, tolbutamide, trazodone, and viloxazine.

Drugs which may decrease phenytoin serum levels include: folic acid, reserpine, rifampicin, sucralfate, theophylline and vigabatrin.

Serum levels of phenytoin can be reduced by concomitant use of the herbal preparations containing St John's wort (Hypericum perforatum).

This is due to induction of drug metabolising enzymes by St John's wort. Herbal preparations containing St John's wort should therefore not be combined with phenytoin. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's wort. If a patient is already taking St John's wort check the anticonvulsant levels and stop St John's wort. Anticonvulsant levels may increase on stopping St John's wort. The dose of anticonvulsant may need adjusting.

Drugs which may either increase or decrease phenytoin serum levels include: carbamazepine, phenobarbital, valproic acid, sodium valproate, antineoplastic agents, certain antacids and ciprofloxacin. Similarly the effect of phenytoin on carbamazepine, phenobarbital, valproic acid and sodium valproate serum levels is unpredictable.

Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels.

Although not a true pharmacokinetic interaction, tricyclic antidepressants and phenothiazines may precipitate seizures in susceptible patients and phenytoin dosage may need to be adjusted.

Drugs whose effect is impaired by phenytoin include: antifungal agents, antineoplastic agents, calcium channel blockers, clozapine, corticosteroids, ciclosporin, dicoumarol, digitoxin, doxycycline, furosemide, lamotrigine, methadone, neuromuscular blockers, oestrogens, oral contraceptives, paroxetine, quinidine, rifampicin, theophylline and vitamin D.

Drugs whose effect is enhanced by phenytoin include: warfarin.

The effect of phenytoin on warfarin is variable and prothrombin times should be determined when these agents are combined.

Serum level determinations are especially helpful when possible drug interactions are suspected.

Drug/Laboratory Test Interactions:

Phenytoin may cause a slight decrease in serum levels of total and free thyroxine, possibly as a result of enhanced peripheral metabolism.

These changes do not lead to clinical hypothyroidism and do not affect the levels of circulating TSH. The latter can therefore be used for diagnosing hypothyroidism in the patient on phenytoin. Phenytoin does not interfere with uptake and suppression tests used in the diagnosis of hypothyroidism.

It may, however, produce lower than normal values for dexamethasone or metapyrone tests. Phenytoin may cause raised serum levels of glucose, alkaline phosphatase, gamma glutamyl transpeptidase and lowered serum levels of calcium and folic acid. It is recommended that serum folate concentrations be measured at least every 6 months, and folic acid supplements given if necessary. Phenytoin may affect blood sugar metabolism tests.

4.6 Pregnancy And Lactation

In considering the use of Epanutin intravenously in the management of status epilepticus in pregnancy, the following information should be weighed in assessing the risks and the benefits. The potential adverse effects upon the foetus of status epilepticus, specifically hypoxia, make it imperative to control the condition in the shortest possible time.

There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans. Genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects.

The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus and attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or foetus.

There is some evidence that phenytoin may produce congenital abnormalities in the offspring of a small number of epileptic patients, therefore it should not be used as the first drug during pregnancy, especially early pregnancy, unless in the judgement of the physician the potential benefits outweigh the risk.

In addition to the reports of increased incidence of congenital malformations, such as cleft lip/palate and heart malformations in children of women receiving phenytoin and other antiepileptic drugs, there have been recent reports of a foetal hydantoin syndrome. This consists of prenatal growth deficiency, microencephaly and mental deficiency in children born to mothers who have received phenytoin, barbiturates, alcohol, or trimethadione. However, these features are all interrelated and are frequently associated with intrauterine growth retardation from other causes.

There have been isolated reports of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

An increase in seizure frequency during pregnancy occurs in a proportion of patients, because of altered phenytoin absorption or metabolism.

Periodic measurement of serum phenytoin levels is particularly valuable in the management of a pregnant epileptic patient as a guide to an appropriate adjustment of dosage. However, post partum restoration of the original dosage will probably be indicated. Neonatal coagulation defects have been reported within the first 24 hours in babies born to epileptic mothers receiving phenytoin. Vitamin K has been shown to prevent or correct this defect and may be given to the mother before delivery and to the neonate after birth.

Infant breast-feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Signs of toxicity are associated with cardiovascular and central nervous system depression.

Central Nervous System:

The most common manifestations encountered with phenytoin therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased coordination, mental confusion, paraesthesia, drowsiness and vertigo. Dizziness, insomnia, transient nervousness, motor twitching, and headache have also been observed.

There have also been rare reports of phenytoin-induced dyskinesia, including chorea, dystonia, tremor, and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving longterm phenytoin therapy. Tonic seizures have also been reported.

Cardiovascular:

Severe cardiotoxic reactions and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Severe complications are most commonly encountered in elderly or gravely ill patients.

Respiratory:

Alterations in respiratory function including respiratory arrest may occur.

Injection Site:

Local irritation, inflammation and tenderness. Necrosis and sloughing have been reported after subcutaneous or perivascular injection. Subcutaneous or perivascular injection should be avoided. Soft tissue irritation and inflammation have occurred at the site of injection with and without extravasation of intravenous phenytoin.

Dermatological System:

Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common. Other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, lupus erythematosus, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Haemopoietic System:

Haemopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression and aplastic anaemia. While macrocytosis and megaloblastic anaemia have occurred, these conditions usually respond to folic acid therapy. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalised) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's Disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling serum sickness, e.g. fever, rash and liver involvement.

In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

Gastrointestinal System:

Nausea, vomiting, constipation, toxic hepatitis, and liver damage.

Connective Tissue System:

Coarsening of the facial features, enlargement of the lips, gingival hyperplasia, hirsutism, hypertrichosis, Peyronie's disease and Dupuytren's contracture may occur rarely.

Immune System:

Hypersensitivity syndrome has been reported and may in rare cases be fatal (the syndrome may include, but is not limited to, symptoms such as arthralgias, eosinophilia, fever, liver dysfunction, lymphadenopathy or rash), systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities may occur. Several individual case reports have suggested that there may be an increased, although still rare, incidence of hypersensitivity reactions, including skin rash and hepatotoxicity, in black patients.

Other:

Polyarthropathy, interstitial nephritis, pneumonitis.

4.9 Overdose

The lethal dose in children is not known.The mean lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia and dysarthria. Other signs are tremor, hyperflexia, lethargy, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression.

Attempts to relate serum levels of the drug to toxic effects have shown wide interpatient variation. Nystagmus on lateral gaze usually appears at 20 mg/l, and ataxia at 30 mg/l, dysarthria and lethargy appear when the serum concentration is>40 mg/l, but a concentration as high as 50 mg/l has been reported without evidence of toxicity.

As much as 25 times the therapeutic dose, which resulted in a serum concentration of 100 mg/l, was taken with complete recovery.

Treatment:

Treatment is non-specific since there is no known antidote.

The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed.

Haemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in children.

In acute overdosage the possibility of the presence of other CNS depressants, including alcohol, should be borne in mind.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Phenytoin is effective in various animal models of generalised convulsive disorders and reasonably effective in models of partial seizures but relatively ineffective in models of myoclonic seizures.

It appears to stabilize rather than raise the seizure threshold and prevents spread of seizure activity rather than abolish the primary focus of seizure discharge.

The mechanism by which phenytoin exerts its anticonvulsant action has not been fully elucidated, however, possible contributory effects include:

1 .Non-synaptic effects to reduce sodium conductance, enhance active sodium extrusion, block repetitive firing and reduce post-tetanic potentiation.

2. Post-synaptic action to enhance GABA-mediated inhibition and reduce excitory synaptic transmission.

3. Pre-synaptic actions to reduce calcium entry and block release of neurotransmitter.

5.2 Pharmacokinetic Properties

After injection phenytoin is distributed into body fluids including CSF.

Its volume of distribution has been estimated to be between 0.52 and 1.19 litres/kg, and it is highly protein bound (usually 90% in adults).

In serum, phenytoin binds rapidly and reversibly to proteins. About 90% of phenytoin in plasma is bound to albumin.The plasma half-life of phenytoin in man averages 22 hours with a range of 7 to 42 hours.

Phenytoin is hydroxylated in the liver by an enzyme system which is saturable. Small incremental doses may produce very substantial increases in serum levels when these are in the upper range of therapeutic concentrations.

The parameters controlling elimination are also subject to wide interpatient variation. The serum level achieved by a given dose is therefore also subject to wide variation.

5.3 Preclinical Safety Data

Pre-clinical safety data do not add anything of further significance to the prescriber.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Each 5 ml contains: Propylene glycol, Ethanol 96%, Water for injection, Sodium hydroxide.

6.2 Incompatibilities

Epanutin Ready Mixed Parenteral should not be mixed with other drugs because of precipitation of phenytoin acid.

6.3 Shelf Life

Unopened: 30 months

Once opened, use immediately and discard any unused contents.

6.4 Special Precautions For Storage

Do not store above 25°C. Keep the ampoule in the outer carton.

6.5 Nature And Contents Of Container

5 ml, colourless neutral glass,Type 1, Ph Eur, with a white colour break band. Each pack contains 10 ampoules.

6.6 Special Precautions For Disposal And Other Handling

For single use only.

Epanutin Ready Mixed Parenteral should be used immediately after opening. Discard any unused product once opened. See sections 4.2 and 6.2 for further information.

The product should not be used if a precipitate or haziness develops in the solution in the ampoule.

7. Marketing Authorisation Holder

United Kingdom: Pfizer Limited, Sandwich, Kent CT13 9NJ

8. Marketing Authorisation Number(S)

PL 00057/0527

9. Date Of First Authorisation/Renewal Of The Authorisation

1st March 2004

10. Date Of Revision Of The Text

25 May 2010

Ref: EPF 12_0 UK


read more


Zomig



Dosage Form: tablet ; tablet, orally disintegrating
Zomig®
(zolmitriptan)
TABLETS
Zomig-ZMT®
(zolmitriptan)
ORALLY DISINTEGRATING TABLETS Zomig Description

Zomig® (zolmitriptan) Tablets and Zomig-ZMT® (zolmitriptan) Orally Disintegrating Tablets contain zolmitriptan, which is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Zolmitriptan is chemically designated as (S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone and has the following chemical structure:

The empirical formula is C­16­H­21­N­3­O­­2­, representing a molecular weight of 287.36. Zolmitriptan is a white to almost white powder that is readily soluble in water. Zomig Tablets are available as 2.5 mg (yellow) and 5 mg (pink) film coated tablets for oral administration. The film coated tablets contain anhydrous lactose NF, microcrystalline cellulose NF, sodium starch glycolate NF, magnesium stearate NF, hydroxypropyl methylcellulose USP, titanium dioxide USP, polyethylene glycol 400 NF, yellow iron oxide NF (2.5 mg tablet), red iron oxide NF (5 mg tablet), and polyethylene glycol 8000 NF.

Zomig-ZMT® Orally Disintegrating Tablets are available as 2.5 mg and 5.0 mg white uncoated tablets for oral administration. The orally disintegrating tablets contain mannitol USP, microcrystalline cellulose NF, crospovidone NF, aspartame NF, sodium bicarbonate USP, citric acid anhydrous USP, colloidal silicon dioxide NF, magnesium stearate NF and orange flavor SN 027512.

Zomig - Clinical Pharmacology Mechanism of Action:

Zolmitriptan binds with high affinity to human recombinant 5-HT1D and 5-HT1B receptors. Zolmitriptan exhibits modest affinity for 5-HT1A receptors, but has no significant affinity (as measured by radioligand binding assays) or pharmacological activity at 5-HT2, 5-HT3, 5-HT4, alpha1-, alpha2-, or beta1- adrenergic; H1, H2, histaminic; muscarinic; dopamine1, or dopamine2 receptors. The N-desmethyl metabolite also has high affinity for 5-HT1B/1D and modest affinity for 5-HT1A receptors.

Current theories proposed to explain the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of zolmitriptan for the treatment of migraine headache can most likely be attributed to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

Clinical Pharmacokinetics and Bioavailability Absorption:

Zolmitriptan is well absorbed after oral administration for both the conventional tablets and the orally disintegrating tablets. Zolmitriptan displays linear kinetics over the dose range of 2.5 to 50 mg.

The AUC and Cmax of zolmitriptan are similar following administration of Zomig Tablets and Zomig-ZMT Orally Disintegrating Tablets, but the Tmax is somewhat later with Zomig-ZMT, with a median Tmax of 3 hours for the orally disintegrating tablet compared with 1.5 hours for the conventional tablet. The AUC, Cmax,and Tmax for the active N-desmethyl metabolite are similar for the two formulations.

During a moderate to severe migraine attack, mean AUC0-4 and Cmax for zolmitriptan, dosed as a conventional tablet, were decreased by 40% and 25%, respectively, and mean Tmax was delayed by one-half hour compared to the same patients during a migraine free period.

Food has no significant effect on the bioavailability of zolmitriptan. No accumulation occurred on multiple dosing.

Distribution:

Mean absolute bioavailability is approximately 40%. The mean apparent volume of distribution is 7.0 L/kg. Plasma protein binding of zolmitriptan is 25% over the concentration range of 10- 1000ng/mL.

Metabolism:

Zolmitriptan is converted to an active N-desmethyl metabolite such that the metabolite concentrations are about two-thirds that of zolmitriptan. Because the 5HT1B/1D potency of the metabolite is 2 to 6 times that of the parent, the metabolite may contribute a substantial portion of the overall effect after zolmitriptan administration.

Elimination:

Total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively. About 8% of the dose was recovered in the urine as unchanged zolmitriptan. Indole acetic acid metabolite accounted for 31% of the dose, followed by N-oxide (7%) and N-desmethyl (4%) metabolites. The indole acetic acid and N-oxide metabolites are inactive.

Mean total plasma clearance is 31.5mL/min/kg, of which one-sixth is renal clearance. The renal clearance is greater than the glomerular filtration rate suggesting renal tubular secretion.

Special Populations:

Age: Zolmitriptan pharmacokinetics in healthy elderly non-migraineur volunteers (age 65?76 yrs) were similar to those in younger non-migraineur volunteers (age 18 - 39 yrs).

Gender: Mean plasma concentrations of zolmitriptan were up to 1.5-fold higher in females than males.

Renal Impairment: Clearance of zolmitriptan was reduced by 25% in patients with severe renal impairment (Clcr ? 5 ? 25 mL/min) compared to the normal group (Clcr > = 70 mL/min); no significant change in clearance was observed in the moderately renally impaired group (Clcr ? 26 ? 50 mL/min).

Hepatic Impairment: In severely hepatically impaired patients, the mean Cmax, Tmax, and AUC0-? of zolmitriptan were increased 1.5, 2 (2 vs 4 hr), and 3-fold, respectively, compared to normals. Seven out of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a 10 mg dose. Zolmitriptan should be administered with caution in subjects with liver disease, generally using doses less than 2.5 mg (see WARNINGS and PRECAUTIONS).

Hypertensive Patients: No differences in the pharmacokinetics of zolmitriptan or its effects on blood pressure were seen in mild to moderate hypertensive volunteers compared to normotensive controls.

Race:: Retrospective analysis of pharmacokinetic data between Japanese and Caucasians revealed no significant differences.

Drug Interactions:

All drug interaction studies were performed in healthy volunteers using a single 10 mg dose of zolmitriptan and a single dose of the other drug except where otherwise noted.

Fluoxetine: The pharmacokinetics of zolmitriptan, as well as its effect on blood pressure, were unaffected by 4 weeks of pretreatment with oral fluoxetine (20 mg/day).

MAO Inhibitors: Following one week of administration of 150 mg bid moclobemide, a specific MAO-A inhibitor, there was an increase of about 25% in both Cmax and AUC for zolmitriptan and a 3-fold increase in the Cmax and AUC of the active N-desmethyl metabolite of zolmitriptan (see CONTRAINDICATIONS and PRECAUTIONS).

Selegiline, a selective MAO-B inhibitor, at a dose of 10 mg/day for 1 week, had no effect on the pharmacokinetics of zolmitriptan and its metabolite.

Propranolol: Cmax and AUC of zolmitriptan increased 1.5-fold after one week of dosing with propranolol (160 mg/day). Cmax and AUC of the N-desmethyl metabolite were reduced by 30% and 15%, respectively. There were no interactive effects on blood pressure or pulse rate following administration of propranolol with zolmitriptan.

Acetaminophen: A single 1 g dose of acetaminophen does not alter the pharmacokinetics of zolmitriptan and its N-desmethyl metabolite. However, zolmitriptan delayed the Tmax of acetaminophen by one hour.

Metoclopramide: A single 10 mg dose of metoclopramide had no effect on the pharmacokinetics of zolmitriptan or its metabolites.

Oral Contraceptives: Retrospective analysis of pharmacokinetic data across studies indicated that mean plasma concentrations of zolmitriptan were generally higher in females taking oral contraceptives compared to those not taking oral contraceptives. Mean Cmax and AUC of zolmitriptan were found to be higher by 30% and 50%, respectively, and Tmax was delayed by one-half hour in females taking oral contraceptives. The effect of zolmitriptan on the pharmacokinetics of oral contraceptives has not been studied.

Cimetidine: Following the administration of cimetidine, the half-life and AUC of a 5 mg dose of zolmitriptan and its active metabolite were approximately doubled (see PRECAUTIONS).

Clinical Studies:

The efficacy of Zomig Tablets in the acute treatment of migraine headaches was demonstrated in five randomized, double-blind, placebo controlled studies, of which 2 utilized the 1 mg dose, 2 utilized the 2.5 mg dose and 4 utilized the 5 mg dose; all studies used the marketed formulation. In study 1, patients treated their headaches in a clinic setting. In the other studies, patients treated their headaches as outpatients. In study 4, patients who had previously used sumatriptan were excluded, whereas in the other studies no such exclusion was applied. Patients enrolled in these 5 studies were predominantly female (82%) and Caucasian (97%) with a mean age of 40 years (range 12-65). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed at 1, 2, and, in most studies, 4 hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours postdose. A second dose of Zomig Tablets or other medication was allowed 2 to 24 hours after the initial treatment for persistent and recurrent headache. The frequency and time to use of these additional treatments were also recorded. In all studies, the effect of zolmitriptan was compared to placebo in the treatment of a single migraine attack.

In all five studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients receiving Zomig Tablets at all doses (except for the 1 mg dose in the smallest study) compared to those who received placebo. In the two studies that evaluated the 1 mg dose, there was a statistically significant greater percentage of patients with headache response at 2 hours in the higher dose groups (2.5 and/or 5 mg) compared to the 1 mg dose group. There were no statistically significant differences between the 2.5 and 5 mg dose groups (or of doses up to 20 mg) for the primary end point of headache response at 2 hours in any study. The results of these controlled clinical studies are summarized in Table 1.

Comparisons of drug performance based upon results obtained in different clinical trials are never reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.

Table 1: Percentage of Patients with Headache Response (Mild or no Headache) 2 Hours Following Treatment (n=number of patients randomized). * This was the only study in which patients treated the headache in a clinic setting. † NA - not applicable ‡ p<0.05 in comparison with placebo. § p<0.05 in comparison with 1 mg. ¶ This was the only study where patients were excluded who had previously used sumatriptan.

Placebo

Zomig

1.0 mg

Zomig

2.5 mg

Zomig

5 mg

Study 1*

16%

(n=19)

27%

(n=22)

NA†

60%‡§

(n=20)

Study 2

19%

(n=88)

NA†

NA†

66%‡

(n=179)

Study 3

34%

(n=121)

50%‡

(n=140)

65%‡§

(n=260)

67%‡§

(n=245)

Study 4¶

44%

(n=55)

NA†

NA†

59%‡

(n=491)

Study 5

36%

(n=92)

NA†

NA†

62%‡

(n=178)

NA†

The estimated probability of achieving an initial headache response by 4 hours following treatment is depicted in Figure 1.

Figure 1: Estimated Probability Of Achieving Initial Headache ResponseWithin 4 Hours*

*Figure 1 shows the Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with zolmitriptan. The averages displayed are based on pooled data from 3 placebo controlled, outpatient trials providing evidence of efficacy (Trials 2, 3 and 5). Patients not achieving headache response or taking additional treatment prior to 4 hours were censored at 4 hours.

For patients with migraine associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of Zomig as compared to placebo.

Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.

Figure 2: The Estimated Probability Of Patients Taking A Second Dose Or Other Medication For Migraines Over The 24 Hours Following The Initial Dose Of Study Treatment*

*This Kaplan-Meier plot is based on data obtained in 3 placebo controlled clinical trials (Study 2, 3 and 5). Patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. It should be noted that the protocols did not allow remedication within 2 hours postdose.

The efficacy of Zomig was unaffected by presence of aura; duration of headache prior to treatment; relationship to menses; gender, age, or weight of the patient; pretreatment nausea, or concomitant use of common migraine prophylactic drugs.

Zomig-ZMT Orally Disintegrating Tablets

The efficacy of Zomig-ZMT 2.5 mg was demonstrated in a randomized, placebo-controlled trial that was similar in design to the trials of Zomig Tablets. Patients were instructed to treat a moderate to severe headache. Of the 471 patients treated in the study, 87% were female and 97% were Caucasian, with a mean age of 41 years (range 18-62). At 2 hours post-dosing response rates in patients treated with Zomig-ZMT 2.5 mg were 63% compared to 22% in the placebo group. The difference was statistically significant. The estimated probability of achieving an initial headache response by 2 hours following treatment with Zomig-ZMT Tablets is depicted in Figure 3.

Figure 3: Estimated Probability of Achieving Initial Headache Response by 2 Hours

Figure 3 shows the Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with Zomig-ZMT Tablets or placebo. Patients taking additional treatment or not achieving headache response prior to 2 hours were censored at 2 hours.

For patients with migraine-associated photophobia, phonophobia and nausea at baseline, there was a decreased incidence of these symptoms following administration of Zomig-ZMT as compared to placebo.

Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 4.

Figure 4: The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraines Over the 24 Hours Following The Initial Dose of Study Treatment

In this Kaplan-Meier plot, patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. Remedication was allowed 2 hours post-dose, and unlike the conventional tablet, remedication prior to 4 hours was not discouraged.

Indications and Usage for Zomig

Zomig is indicated for the acute treatment of migraine with or without aura in adults.

Zomig should only be used where a clear diagnosis of migraine has been established.

Zomig is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine (see CONTRAINDICATIONS). Safety and effectiveness of Zomig have not been established for cluster headache, which is present in an older, predominantly male population.

Contraindications

Zomig should not be given to patients with ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia) or to patients who have symptoms or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal’s variant angina, or other significant underlying cardiovascular disease (see WARNINGS and PRECAUTIONS).

Zomig should not be given to patients with cerebrovascular syndromes including (but not limited to) stroke of any type as well as transient ischemic attacks (see WARNINGS).

Zomig should not be given to patients with peripheral vascular disease including (but not limited to) ischemic bowel disease (see WARNINGS and PRECAUTIONS).

Because Zomig may increase blood pressure, it should not be given to patients with uncontrolled hypertension (see WARNINGS).

Zomig should not be used within 24 hours of treatment with another 5-HT1 agonist, or an ergotamine-containing or ergot-type medication like dihydroergotamine or methysergide.

Zomig should not be administered to patients with hemiplegic or basilar migraine.

Concurrent administration of MAO-A inhibitors or use of zolmitriptan within 2 weeks of discontinuation of MAO-A inhibitor therapy is contraindicated (see CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions).

Zomig is contraindicated in patients who are hypersensitive to zolmitriptan or any of its inactive ingredients.

Warnings

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events: Zomig should not be given to patients with documented ischemic or vasospastic coronary artery disease (see CONTRAINDICATIONS). It is strongly recommended that zolmitriptan not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history, electrocardiographic or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, zolmitriptan should not be administered (see CONTRAINDICATIONS). For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of zolmitriptan take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received zolmitriptan. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following Zomig, in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of Zomig and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use Zomig.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to zolmitriptan.

Cardiac Events and Fatalities:

Serious adverse cardiac events, including acute myocardial infarction, have been reported within a few hours following administration of zolmitriptan. Life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of other 5-HT1 agonists. Considering the extent of use of 5-HT1 agonists in patients with migraine, the incidence of these events is extremely low.

Zomig can cause coronary vasospasm; at least one of these events occurred in a patient with no cardiac disease history and with documented absence of coronary artery disease. Because of the close proximity of the events to Zomig use, a causal relationship cannot be excluded. In the cases where there has been known underlying coronary artery disease, the relationship is uncertain.

Patients with symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders should not receive Zomig.

Premarketing experience with zolmitriptan:

Among the more than 2,500 patients with migraine who participated in premarketing controlled clinical trials of Zomig Tablets, no deaths or serious cardiac events were reported.

Postmarketing experience with zolmitriptan:

Serious cardiovascular events have been reported in association with the use of Zomig Tablets, and in very rare cases, these events have occurred in the absence of known cardiovascular disease. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by zolmitriptan or to reliably assess causation in individual cases.

Cerebrovascular Events and Fatalities with 5-HT1 agonists:

Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5-HT1 agonists; and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). (See CONTRAINDICATIONS.)

Serotonin Syndrome:

The development of a potentially life-threatening serotonin syndrome may occur with triptans, including Zomig treatment, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with Zomig and an SSRI (e.g. fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea). (See PRECAUTIONS, Drug Interactions).

Other Vasospasm-Related Events:

5-HT1 agonists may cause vasospastic reactions other than coronary artery vasospasm such as peripheral and gastrointestinal vascular ischemia. As with other serotonin 5HT1 agonists, very rare gastrointestinal ischemic events including ischemic colitis and gastrointestinal infarction or necrosis have been reported with Zomig Tablets; these may present as bloody diarrhea or abdominal pain. (See CONTRAINDICATIONS.)

Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5- HT1 agonists. Visual disorders may also be part of a migraine attack.

Increase in Blood Pressure:

As with other 5-HT1 agonists, significant elevations in systemic blood pressure have been reported on rare occasions with Zomig Tablet use, in patients with and without a history of hypertension; very rarely these increases in blood pressure have been associated with significant clinical events. Zolmitriptan is contraindicated in patients with uncontrolled hypertension. In volunteers, an increase of 1 and 5 mm Hg in the systolic and diastolic blood pressure, respectively, was seen at 5 mg. In the headache trials, vital signs were measured only in the small inpatient study and no effect on blood pressure was seen. In a study of patients with moderate to severe liver disease, 7 of 27 experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a dose of 10 mg of zolmitriptan (see CONTRAINDICATIONS).

An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT1 agonist in a study evaluating subjects undergoing cardiac catheterization.

Precautions General:

As with other 5-HT1B/1D agonists, sensations of tightness, pain, pressure, and heaviness have been reported after treatment with Zomig Tablets in the precordium, throat, neck, and jaw. Because zolmitriptan may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD or a predisposition to Prinzmetal’s variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud’s syndrome following the use of any 5-HT1 agonist are candidates for further evaluation. (see CONTRAINDICATIONS and WARNINGS.)

Zolmitriptan should also be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as impaired hepatic function (see CLINICAL PHARMACOLOGY).

For a given attack, if a patient does not respond to the first dose of zolmitriptan, the diagnosis of migraine headache should be reconsidered before administration of a second dose.

Binding to Melanin-Containing Tissues:

When pigmented rats were given a single oral dose of 10 mg/kg of radiolabeled zolmitriptan, the radioactivity in the eye after 7 days, the latest time point examined, was still 75% of the value measured after 4 hours. This suggests that zolmitriptan and/or its metabolites may bind to the melanin of the eye. Because there could be accumulation in melanin rich tissues over time, this raises the possibility that zolmitriptan could cause toxicity in these tissues after extended use. However, no effects on the retina related to treatment with zolmitriptan were noted in any of the toxicity studies. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects.

Phenylketonurics:

Phenylketonuric patients should be informed that Zomig-ZMT contain phenylalanine (a component of aspartame). Each 2.5 mg orally disintegrating tablet contains 2.81 mg phenylalanine. Each 5 mg orally disintegrating tablet contains 5.62 mg phenylalanine.

Information for Patients

See PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided for patients.

Zomig-ZMT Orally Disintegrating Tablets

The orally disintegrating tablet is packaged in a blister. Patients should be instructed not to remove the tablet from the blister until just prior to dosing. The blister pack should then be peeled open, and the orally disintegrating tablet placed on the tongue, where it will dissolve and be swallowed with the saliva.

Patients should be cautioned about the risk of serotonin syndrome with the use of Zomig or other triptans, especially during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

Laboratory Tests:

No monitoring of specific laboratory tests is recommended.

Drug Interactions

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and zolmitriptan within 24 hours of each other should be avoided (see CONTRAINDICATIONS).

MAO-A inhibitors increase the systemic exposure of zolmitriptan. Therefore, the use of zolmitriptan in patients receiving MAO-A inhibitors is contraindicated (see CLINICAL PHARMACOLOGYand CONTRAINDICATIONS).

Concomitant use of other 5-HT1B/1D agonists within 24 hours of Zomig treatment is not recommended. (see CONTRAINDICATIONS).

Following administration of cimetidine, the half-life and AUC of zolmitriptan and its active metabolites were approximately doubled (see CLINICAL PHARMACOLOGY).

Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans (See WARNINGS).

Drug/Laboratory Test Interactions:

Zolmitriptan is not known to interfere with commonly employed clinical laboratory tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis:

Carcinogenicity studies by oral gavage were carried out in mice and rats at doses up to 400 mg/kg/day. Mice were dosed for 85 weeks (males) and 92 weeks (females). The exposure (plasma AUC of parent drug) at the highest dose level was approximately 800 times that seen in humans after a single 10 mg dose (the maximum recommended total daily dose). There was no effect of zolmitriptan on tumor incidence. Control, low dose, and middle dose rats were dosed for 104-105 weeks; the high dose group was sacrificed after 101 weeks (males) and 86 weeks (females) due to excess mortality. Aside from an increase in the incidence of thyroid follicular cell hyperplasia and thyroid follicular cell adenomas seen in male rats receiving 400 mg/kg/day, an exposure approximately 3000 times that seen in humans after dosing with 10 mg, no tumors were noted.

Mutagenesis:

Zolmitriptan was mutagenic in an Ames test, in 2 of 5 strains of S. typhimurium tested, in the presence of, but not in the absence of, metabolic activation. It was not mutagenic in an in vitro mammalian gene cell mutation (CHO/HGPRT) assay. Zolmitriptan was clastogenic in an in vitro human lymphocyte assay both in the absence of and the presence of metabolic activation; it was not clastogenic in an in vivo mouse micronucleus assay. It was also not genotoxic in an unscheduled DNA synthesis study.

Impairment of Fertility:

Studies of male and female rats administered zolmitriptan prior to and during mating and up to implantation have shown no impairment of fertility at doses up to 400 mg/kg/day. Exposure at this dose was approximately 3000 times exposure at the maximum recommended human dose of 10 mg/day.

Pregnancy: Pregnancy Category C:

There are no adequate and well controlled studies in pregnant women; therefore, zolmitriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals was associated with embryolethality and fetal abnormalities. When pregnant rats were administered oral zolmitriptan during the period of organogenesis at doses of 100, 400, and 1200 mg/kg/day, there was a dose-related increase in embryolethality which became statistically significant at the high dose. The maternal plasma exposures at these doses were approximately 280, 1100, and 5000 times the exposure in humans receiving the maximum recommended total daily dose of 10 mg. The high dose was maternally toxic, as evidenced by a decreased maternal body weight gain during gestation. In a similar study in rabbits, embryolethality was increased at the maternally toxic doses of 10 and 30 mg/kg/day (maternal plasma exposures equivalent to 11 and 42 times exposure in humans receiving the maximum recommended total daily dose of 10 mg), and increased incidences of fetal malformations (fused sternebrae, rib anomalies) and variations (major blood vessel variations, irregular ossification pattern of ribs) were observed at 30 mg/kg/day. Three mg/kg/day was a no effect dose (equivalent to human exposure at a dose of 10 mg). When female rats were given zolmitriptan during gestation, parturition, and lactation, an increased incidence of hydronephrosis was found in the offspring at the maternally toxic dose of 400 mg/kg/day (1100 times human exposure).

Nursing Mothers:

It is not known whether zolmitriptan is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when zolmitriptan is administered to a nursing woman. Lactating rats dosed with zolmitriptan had milk levels equivalent to maternal plasma levels at 1 hour and 4 times higher than plasma levels at 4 hours.

Pediatric Use:

Safety and effectiveness of Zomig Tablets in pediatric patients have not been established. Therefore, Zomig is not recommended for use in patients under 18 years of age.

One randomized, placebo-controlled clinical trial evaluating zolmitriptan tablets (2.5, 5 and 10 mg) in pediatric patients aged 12-17 years evaluated a total of 696 adolescent migraineurs. This study did not establish the efficacy of zolmitriptan compared to placebo in the treatment of migraine in adolescents. Adverse events observed were similar in nature and frequency to those reported in clinical trials in adults.

Postmarketing experience with Zomig and other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults.

Geriatric Use:

Although the pharmacokinetic disposition of the drug in the elderly is similar to that seen in younger adults, there is no information about the safety and effectiveness of zolmitriptan in this population because patients over age 65 were excluded from the controlled clinical trials. (see CLINICAL PHARMACOLOGY: Special Populations)

ADVERSE REACTIONS:

Serious cardiac events, including myocardial infarction, have occurred following the use of Zomig Tablets. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported, in association with drugs of this class, have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).

Incidence in Controlled Clinical Trials:

Among 2,633 patients treated with Zomig Tablets in the active and placebo controlled trials, no patients withdrew for reasons related to adverse events, but as patients treated a single headache in these trials, the opportunity for discontinuation was limited. In a long-term, open label study where patients were allowed to treat multiple migraine attacks for up to 1 year, 8% (167 out of 2,058) withdrew from the trial because of adverse experience. The most common events were paresthesia, asthenia, nausea, dizziness, pain, chest or neck tightness or heaviness, somnolence, and warm sensation.

Table 2 lists the adverse events that occurred in ? 2% of the 2,074 patients in any one of the Zomig 1 mg, Zomig 2.5 mg or Zomig 5 mg Tablets dose groups of the controlled clinical trials. Only events that were more frequent in a Zomig Tablets group compared to the placebo groups are included. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ.

Several of the adverse events appear dose related, notably paresthesia, sensation of heaviness or tightness in chest, neck, jaw, and throat, dizziness, somnolence, and possibly asthenia and nausea.

Table 2: Adverse Experience Incidence in Five Placebo-Controlled Migraine Clinical Trials: Events Reported By ? 2% Patients Treated With Zomig Tablets

Adverse Event Type

Placebo

(n=401)

Zomig

1 mg

(n=163)

Zomig

2.5 mg

(n=498)

Zomig

5 mg

(n=1012)

ATYPICAL SENSATIONS

6%

12%

12%

18%

Hyperesthesia

1%

1%

1%

2%

Paresthesia (all types)

2%

5%

7%

9%

Sensation warm/cold

4%

6%

5%

7%

PAIN AND PRESSURE SENSATIONS

7%

13%

14%

22%

Chest - pain/tightness/pressure and/or heaviness

1%

2%

3%

4%

Neck/throat/jaw - pain/tightness/pressure

3%

4%

7%

10%

Heaviness other than chest or neck

1%

1%

2%

5%

Pain ? location specified

1%

2%

2%

3%

Other ? Pressure/tightness/heaviness

0

2%

2%

2%

DIGESTIVE

8%

11%

16%

14%

Dry mouth

2%

5%

3%

3%

Dyspepsia

1%

3%

2%

1%

Dysphagia

0%

0%

0%

2%

Nausea

4%

4%

9%

6%

NEUROLOGICAL

10%

11%

17%

21%

Dizziness

4%

6%

8%

10%

Somnolence

3%

5%

6%

8%

Vertigo

0%

0%

0%

2%

OTHER

Asthenia

3%

5%

3%

9%

Palpitations

1%

0%

<1%

2%

Myalgia

<1%

1%

1%


read more


NovoSeven RT


coagulation factor viia (recombinant)
Dosage Form: injection
FULL PRESCRIBING INFORMATION Warning: Serious thrombotic adverse events are associated with the use of NovoSeven RT outside labeled indications

Arterial and venous thrombotic and thromboembolic events following administration of NovoSeven have been reported during postmarketing surveillance. Clinical studies have shown an increased risk of arterial thromboembolic adverse events with NovoSeven RT when administered outside the current approved indications. Fatal and non-fatal thrombotic events have been reported. Discuss the risks and explain the signs and symptoms of thrombotic and thromboembolic events to patients who will receive NovoSeven RT. Monitor patients for signs or symptoms of activation of the coagulation system and for thrombosis. See WARNINGS AND PRECAUTIONS section of prescribing information.

Safety and efficacy of NovoSeven RT has not been established outside the approved indications.

Indications and Usage for NovoSeven RT

NovoSeven RT Coagulation Factor VIIa (Recombinant) Room Temperature Stable is indicated for:

Treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX and in patients with acquired hemophilia Prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX and in patients with acquired hemophilia Treatment of bleeding episodes in patients with congenital FVII deficiency Prevention of bleeding in surgical interventions or invasive procedures in patients with congenital FVII deficiency NovoSeven RT Dosage and Administration General NovoSeven RT is intended for intravenous bolus administration only. Evaluation of hemostasis should be used to determine the effectiveness of NovoSeven RT and to provide a basis for modification of the NovoSeven RT treatment schedule. Coagulation parameters do not necessarily correlate with or predict the effectiveness of NovoSeven RT. NovoSeven RT should be administered to patients only under the supervision of a physician experienced in the treatment of bleeding disorders. Hemophilia A or B with Inhibitors

Treatment of Acute Bleeding Episodes

Hemostatic Dosing

90 micrograms/kg given every two hours by bolus infusion until hemostasis is achieved, or until the treatment has been judged to be inadequate. Doses between 35 and 120 micrograms/kg have been used successfully in clinical trials for hemophilia A or B patients with inhibitors, and both the dose and administration interval may be adjusted based on the severity of the bleeding and degree of hemostasis achieved.1 The minimum effective dose has not been established. For patients treated for joint or muscle bleeds, a decision on outcome was reached for a majority of patients within eight doses although more doses were required for severe bleeds. A majority of patients who reported adverse experiences received more than twelve doses.

Post-hemostatic Dosing

The appropriate duration of post-hemostatic dosing has not been studied. For severe bleeds, dosing should continue at 3-6 hour intervals after hemostasis is achieved, to maintain the hemostatic plug. The biological and clinical effects of prolonged elevated levels of Factor VIIa have not been studied; therefore, the duration of post-hemostatic dosing should be minimized. Patients should be appropriately monitored by a physician experienced in the treatment of hemophilia during this time period.

Dosing for Surgical Interventions

Minor Surgery

An initial dose of 90 micrograms per kg body weight should be given immediately before the intervention and repeated at 2-hour intervals for the duration of the surgery. For minor surgery, post-surgical dosing by bolus injection should occur at 2-hour intervals for the first 48 hours and then at 2- to 6-hour intervals until healing has occurred.

Major Surgery

An initial dose of 90 micrograms per kg body weight should be given immediately before the intervention and repeated at 2-hour intervals for the duration of the surgery. For major surgery, post-surgical dosing by bolus injection should occur at 2 hour intervals for 5 days, followed by 4 hour intervals until healing has occurred. Additional bolus doses should be administered if required. Congenital Factor VII deficiency The recommended dose range for treatment of bleeding episodes or for prevention of bleeding in surgical interventions or invasive procedures in congenital Factor VII deficient patients is 15-30 micrograms per kg body weight every 4-6 hours until hemostasis is achieved. Effective treatment has been achieved with doses as low as 10 micrograms/kg. Dose and frequency of injections should be adjusted to each individual. The minimum effective dose has not been determined. Acquired Hemophilia The recommended dose range for the treatment of patients with acquired hemophilia is 70-90 micrograms/kg repeated every 2-3 hours until hemostasis is achieved. The minimum effective dose in acquired hemophilia has not been determined. The majority of the effective outcomes were observed with treatment in the recommended dose range. The largest number of treatments with any single dose was 90 micrograms/kg; of the 15 treated, 10 (67%) were effective and 2 (13%) were partially effective. Reconstitution

Calculate the NovoSeven RT dosage you will need and select the appropriate NovoSeven RT vial package. The selected package contains 1 vial of NovoSeven RT powder and 1 vial of histidine diluent required to prepare reconstituted NovoSeven RT solution. Reconstitute only with the histidine diluent provided with NovoSeven RT. Do not reconstitute with sterile water or other diluent.

Reconstitution should be performed using the following procedures:

1. Always use aseptic technique.

2. Bring NovoSeven RT (white, lyophilized powder) and the specified volume of histidine (diluent) to room temperature, but not above 37° C (98.6° F). The specified volume of diluent corresponding to the amount of NovoSeven RT is as follows:

1 mg (1000 micrograms) vial + 1.1 mL Histidine diluent

2 mg (2000 micrograms) vial + 2.1 mL Histidine diluent

5 mg (5000 micrograms) vial + 5.2 mL Histidine diluent

8 mg (8000 micrograms) vial + 8.1 mL Histidine diluent

After reconstitution with the specified volume of diluent, each vial contains approximately 1 mg/mL NovoSeven RT (1000 micrograms/mL).

3. Remove caps from the NovoSeven RT vials to expose the central portion of the rubber stopper. Cleanse the rubber stoppers with an alcohol swab and allow to dry prior to use.

4. Draw back the plunger of a sterile syringe (attached to sterile needle) and admit air into the syringe. It is recommended to use syringe needles of gauge size 20-26.

5. Insert the needle of the syringe into the Histidine diluent vial. Inject air into the vial and withdraw the quantity required for reconstitution.

6. Insert the syringe needle containing the diluent into the NovoSeven RT vial through the center of the rubber stopper, aiming the needle against the side so that the stream of liquid runs down the vial wall (the NovoSeven RT vial does not contain a vacuum). Do not inject the diluent directly on the NovoSeven RT powder.

7. Gently swirl the vial until all the material is dissolved. The reconstituted solution is a clear, colorless solution which may be stored either at room temperature or refrigerated for up to 3 hours after reconstitution.

Administration NovoSeven RT is intended for intravenous bolus injection only and should not be mixed with infusion solutions. Reconstituted NovoSeven RT should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter or discoloration is observed. Administration should take place within 3 hours after reconstitution. Any unused solution should be discarded. Do not freeze reconstituted NovoSeven RT or store it in syringes.

Administration should be performed using the following procedures:

Always use aseptic technique. Draw back the plunger of a sterile syringe (attached to sterile needle) and admit air into the syringe. Insert needle into the vial of reconstituted NovoSeven RT. Inject air into the vial and then withdraw the appropriate amount of reconstituted NovoSeven RT into the syringe. Remove and discard the needle from the syringe. Administer as a slow bolus injection over 2 to 5 minutes, depending on the dose administered. If line needs to be flushed before or after NovoSeven RT administration, use 0.9% Sodium Chloride Injection, USP. Discard any unused reconstituted NovoSeven RT after 3 hours. Dosage Forms and Strengths

NovoSeven RT is supplied as a white lyophilized powder in single-use vials containing 1 mg (1000 micrograms), 2 mg (2000 micrograms), 5 mg (5000 micrograms), or 8 mg (8000 micrograms) rFVIIa per vial. The diluent for reconstitution of NovoSeven RT is a 10 mmol solution of L-histidine in water for injection and is supplied as a clear colorless solution and is referred to as the histidine diluent. After reconstitution with the histidine diluent, each vial contains approximately 1 mg/mL NovoSeven RT (1000 micrograms/mL).

Contraindications

None

Warnings and Precautions Thrombotic Events within the Licensed Indications

Clinical trials within the approved indications revealed that thrombotic events of possible or probable relationship to NovoSeven occurred in 0.28% of bleeding episodes treated, with the incidence within hemophilia patients with inhibitors to be 0.20%, and in acquired hemophilia an incidence of 4%. Thrombotic events have been identified through postmarketing surveillance following NovoSeven RT use for each of the approved indications2. The incidence of thrombotic events can not be determined from postmarketing data. Patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with aPCCs/PCCs (activated or nonactivated prothrombin complex concentrates) have an increased risk of developing thrombotic events due to circulating tissue factor (TF) or predisposing coagulopathy [See Adverse Reactions (6.1) and Drug Interactions (7.1)]. Caution should be exercised when administering NovoSeven RT to patients with an increased risk of thromboembolic complications. These include, but are not limited to, patients with a history of coronary heart disease, liver disease, disseminated intravascular coagulation, post-operative immobilization, elderly patients and neonates. In each of these situations, the potential benefit of treatment with NovoSeven RT should be weighed against the risk of these complications.

Patients who receive NovoSeven RT should be monitored for development of signs or symptoms of activation of the coagulation system or thrombosis. When there is laboratory confirmation of intravascular coagulation or presence of clinical thrombosis, the NovoSeven RT dosage should be reduced or the treatment stopped, depending on the patient's symptoms.

Thrombotic Events outside the Licensed Indications

NovoSeven has been studied in placebo controlled trials outside the approved indications to control bleeding in intracerebral hemorrhage, advanced liver disease, trauma, cardiac surgery, spinal surgery, and other therapeutic areas. Safety and effectiveness has not been established in these settings and the use is not approved by FDA. Two meta analyses of these pooled data indicate an increased risk of thrombotic events (10.0% in patients treated with NovoSeven versus 7.5% in placebo-treated patients). Arterial thromboembolic adverse events including myocardial infarction, myocardial ischemia, cerebral infarction and cerebral ischemia were statistically significantly increased with the use of NovoSeven compared to placebo (5.3 to 5.6% in subjects treated with NovoSeven versus 2.8 to 3.0% in placebo-treated patients). Other arterial thromboembolic events (such as retinal artery embolism, renal artery thrombosis, arterial thrombosis of limb, bowel infarction and intestinal infarction) have also been reported.3,4,5,6,7 While venous thromboembolic events such as deep venous thrombosis, portal vein thrombosis and pulmonary embolism have been reported in clinical trials, the meta analysis of these pooled data from placebo-controlled trials performed outside the currently approved indications did not suggest an increased risk of venous thromboembolic events in patients treated with NovoSeven versus placebo (4.8% in patients treated with NovoSeven versus 4.7% in placebo-treated patients).

In spontaneous reports of women without a prior diagnosis of bleeding disorders receiving NovoSeven for uncontrolled post-partum hemorrhage, thrombotic events were observed. During this period, patients are at increased risk for thrombotic complications.

Post-Hemostatic Dosing

Precautions should be exercised when NovoSeven RT is used for prolonged dosing [See Dosage and Administration (2.2)].

Antibody Formation in Factor VII Deficient Patients

Factor VII deficient patients should be monitored for prothrombin time (PT) and factor VII coagulant activity before and after administration of NovoSeven RT. If the factor VIIa activity fails to reach the expected level, or prothrombin time is not corrected, or bleeding is not controlled after treatment with the recommended doses, antibody formation may be suspected and analysis for antibodies should be performed.

Hypersensitivity Reactions

NovoSeven RT should be administered with caution in patients with known hypersensitivity to NovoSeven RT or any of its components, or in patients with known hypersensitivity to mouse, hamster, or bovine proteins.

Laboratory Tests

Laboratory coagulation parameters (PT/INR, aPTT, FVII:C) have shown no direct correlation to achieving hemostasis. Assays of prothrombin time (PT/INR), activated partial thromboplastin time (aPTT), and plasma FVII clotting activity (FVII:C), may give different results with different reagents. Treatment with NovoSeven has been shown to produce the following characteristics:

Adverse Reactions

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug product cannot be directly compared to rates in clinical trials of another drug, and may not reflect rates observed in practice.

Clinical Trials Experience

Thrombotic events following the administration of NovoSeven occurred in 0.28% of bleeding episodes treated, with the incidence in acquired hemophilia of 4% and in hemophilia patients of 0.20% in clinical trials within the approved indications [See Warnings and Precautions (5.1)].

Adverse reactions observed in clinical trials for all labeled indications of NovoSeven included pyrexia, hemorrhage, injection site reaction, arthralgia, headache, hypertension, hypotension, nausea, vomiting, pain, edema, rash (including allergic dermatitis and rash erythematous), pruritus, urticaria, hypersensitivity, cerebral artery occlusion, cerebrovascular accident, pulmonary embolism, deep vein thrombosis, angina pectoris, increased levels of fibrin degradation products, disseminated intravascular coagulation and related laboratory findings including elevated levels of D-dimer and AT-III, thrombosis at i.v. site, non-specified thrombosis, thrombophlebitis, superficial thrombophlebitis.

The following sections describe the adverse event profile observed during clinical studies for each of the labeled indications.

Hemophilia A or B Patients with Inhibitors

Two studies (Studies 1 and 2) are described for hemophilia A or B patients with inhibitors treated for bleeding episodes [See Clinical Studies (14.1)]. The table below lists adverse events that were reported in ?2% of the 298 patients with hemophilia A or B with inhibitors that were treated with NovoSeven for 1,939 bleeding episodes. The events listed are considered to be at least possibly related or of unknown relationship to NovoSeven administration.

Body System

Event

# of episodes reported

(n=1,939 treatments)

# of unique patients

(n=298 patients)

Body as a whole   Fever

16

13

Platelets, Bleeding, and Clotting   Hemorrhage NOS   Fibrinogen plasma decreased

15

10

8

5

Skin and Musculoskeletal   Hemarthrosis

14

8

Cardiovascular   Hypertension

9

6

Events which were reported in 1% of patients and were considered to be at least possibly or of unknown relationship to NovoSeven administration were: allergic reaction, arthrosis, bradycardia, coagulation disorder, DIC, edema, fibrinolysis increased, headache, hypotension, injection site reaction, pain, pneumonia, prothrombin decreased, pruritus, purpura, rash, renal function abnormal, therapeutic response decreased, and vomiting.

Serious adverse events that were probably or possibly related, or where the relationship to NovoSeven was not specified, occurred in 14 of the 298 patients (4.7%). Six of the 14 patients died of the following conditions: worsening of chronic renal failure, anesthesia complications during proctoscopy, renal failure complicating a retroperitoneal bleed, ruptured abscess leading to sepsis and DIC, pneumonia, and splenic hematoma and gastrointestinal bleeding. Thrombosis was reported in two of the 298 patients with hemophilia.

Surgery Studies

Two clinical trials (Studies 3 and 4) were conducted to evaluate the safety and efficacy of NovoSeven administration during and after surgery in hemophilia A or B patients with inhibitors [See Clinical Studies (14.1)].

In Study 3, six patients experienced serious adverse events: two of these patients had events which were considered probably or possibly related to study medication (acute post-operative hemarthrosis, internal jugular thrombosis). No deaths occurred during the study.

In Study 4, seven of 24 patients had serious adverse events (4 for bolus injection, 3 for continuous infusion). There were 4 serious adverse events which were considered probably or possibly related to NovoSeven treatment (2 events of decreased therapeutic response in each treatment arm). No deaths occurred during the study period.

Congenital Factor VII Deficiency

Data collected from the compassionate/emergency use programs, the published literature, a pharmacokinetics study, and the Hemophilia and Thrombosis Research Society (HTRS) registry showed that at least 75 patients with Factor VII deficiency had received NovoSeven - 70 patients for 124 bleeding episodes, surgeries, or prophylaxis regimens; 5 patients in the pharmacokinetics trial.

In the compassionate/emergency use programs, 28 adverse events in 13 patients and 10 serious adverse events in 9 patients were reported. Non-serious adverse events in the compassionate/emergency use programs were single events in one patient, except for fever (3 patients), intracranial hemorrhage (3 patients), and pain (2 patients). The most common serious adverse event in the compassionate/emergency programs was serious bleeding in critically ill patients. All nine patients with serious adverse events died. One adverse event (localized phlebitis) was reported in the literature. No adverse events were reported in the pharmacokinetics reports or for the HTRS registry. No thromboembolic complications were reported for the 75 patients included here.

As with all therapeutic proteins, there is a potential for immunogenicity. Isolated cases of factor VII deficient patients developing antibodies against factor VII were reported after treatment with NovoSeven. These patients had previously been treated with human plasma and/or plasma-derived factor VII. In some cases the antibodies showed inhibitory effect in vitro. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to NovoSeven RT with the incidence of antibodies to other products may be misleading.

Acquired Hemophilia

Data collected from four compassionate use programs, the HTRS registry, and the published literature showed that 139 patients with acquired hemophilia received NovoSeven for 204 bleeding episodes, surgeries and traumatic injuries.

Of these 139 patients, 10 experienced 12 serious adverse events that were of possible, probable, or unknown relationship to treatment with NovoSeven. Thrombotic serious adverse events included cerebral infarction, cerebral ischemia, angina pectoris, myocardial infarction, pulmonary embolism and deep vein thrombosis. Additional serious adverse events included shock and subdural hematoma.

Data collected for mortality in the compassionate use programs, the HTRS registry and the publications spanning a 10 year period, was overall 32/139 (23%). Deaths due to hemorrhage were 10, cardiovascular failure 4, neoplasia 4, unknown causes 4, respiratory failure 3, thrombotic events 2, sepsis 2, arrhythmia 2 and trauma 1.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of NovoSeven. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship.

The following additional adverse events were reported following the use of NovoSeven in labeled and unlabeled indications that included individuals with and without coagulopathy: high D-dimer levels and consumptive coagulopathy, thrombosis, thrombophlebitis, arterial thrombosis, and thromboembolic events including myocardial ischemia, myocardial infarction, bowel infarction, cerebral ischemia, cerebral infarction, hepatic artery thrombosis, renal artery thrombosis, portal vein thrombosis, phlebitis, peripheral ischemia, deep vein thrombosis and related pulmonary embolism, injection site pain and isolated cases of hypersensitivity/allergic reactions including anaphylactic shock, flushing, urticaria, rash, and angioedema [See Warnings and Precautions (5.1)].

Fatal and non-fatal thromboembolic events have been reported with use of NovoSeven when used for off-label or labeled indications.

The Hemophilia and Thrombosis Research Society (HTRS) Registry surveillance program is designed to collect data on the treatment of congenital and acquired bleeding disorders.8 All prescribers can obtain information regarding contribution of patient data to this program by calling 1-877-362-7355 or at www.novosevensurveillance.com.

Drug Interactions Coagulation Factor Concentrates

The risk of a potential interaction between NovoSeven RT and coagulation factor concentrates has not been adequately evaluated in preclinical or clinical studies. Simultaneous use of activated prothrombin complex concentrates or prothrombin complex concentrates should be avoided.

Infusion Solutions

NovoSeven RT should not be mixed with infusion solutions.

USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. NovoSeven RT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Treatment of rats and rabbits with NovoSeven in reproduction studies has been associated with mortality at doses up to 6 mg/kg and 5 mg/kg. At 6 mg/kg in rats, the abortion rate was 0 out of 25 litters; in rabbits at 5 mg/kg, the abortion rate was 2 out of 25 litters. Twenty-three out of 25 female rats given 6 mg/kg of NovoSeven gave birth successfully, however, two of the 23 litters died during the early period of lactation. No evidence of teratogenicity was observed after dosing with NovoSeven.

Labor and Delivery

NovoSeven was administered to a FVII deficient patient (25 years of age, 66 kg) during a vaginal delivery (36 micrograms/kg) and during a tubal ligation (90 micrograms/kg). No adverse reactions were reported during labor, vaginal delivery, or the tubal ligation.

There are no adequate and well-controlled studies in labor, delivery, and postpartum periods. In spontaneous reports of women without a prior diagnosis of bleeding disorders receiving NovoSeven for uncontrolled post-partum hemorrhage, thrombotic events were observed. During this period, patients are at increased risk for thrombotic complications. It is not known to what extent NovoSeven contributed to the occurrence of these events.

Nursing Mothers

It is not known whether NovoSeven RT is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Clinical trials enrolling pediatric patients were conducted with dosing determined according to body weight and not according to age. The safety and effectiveness of NovoSeven RT has not been studied to determine if there are differences among various age groups, from infants to adolescents (0 to 16 years of age).

Geriatric Use

Clinical studies of NovoSeven in congenital factor deficiencies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Overdosage

There are no adequate and well controlled studies to support the safety or efficacy of using higher than labeled doses in the indicated populations.

Dose limiting toxicities of NovoSeven RT have not been investigated in clinical trials. The following are examples of accidental overdose.

Congenital Factor VII Deficiency

A newborn female with congenital factor VII deficiency was administered an overdose of NovoSeven (single dose: 800 micrograms/kg). Following additional administration of NovoSeven and various plasma products, antibodies against rFVIIa were detected, but no thrombotic complications were reported. A Factor VII deficient male (83 years of age, 111.1 kg) received two doses of 324 micrograms/kg (10-20 times the recommended dose) and experienced a thrombotic event (occipital stroke).

Hemophilia A or B with Inhibitors

One hemophilia B patient (16 years of age, 68 kg) received a single dose of 352 micrograms/kg and one hemophilia A patient (2 years of age, 14.6 kg) received doses ranging from 246 micrograms/kg to 986 micrograms/kg on five consecutive days. There were no reported complications in either case.

NovoSeven RT Description

NovoSeven RT is recombinant human coagulation Factor VIIa (rFVIIa), intended for promoting hemostasis by activating the extrinsic pathway of the coagulation cascade.9 NovoSeven RT is a vitamin K-dependent glycoprotein consisting of 406 amino acid residues (MW 50 K Dalton). NovoSeven RT is structurally similar to human plasma-derived Factor VIIa.

The gene for human Factor VII is cloned and expressed in baby hamster kidney cells (BHK cells). Recombinant FVII is secreted into the culture media (containing newborn calf serum) in its single-chain form and then proteolytically converted by autocatalysis to the active two-chain form, rFVIIa, during a chromatographic purification process. The purification process has been demonstrated to remove exogenous viruses (MuLV, SV40, Pox virus, Reovirus, BEV, IBR virus). No human serum or other proteins are used in the production or formulation of NovoSeven RT.

NovoSeven RT is supplied as a sterile, white lyophilized powder of rFVIIa in single-use vials. Each vial of lyophilized drug contains the following:

Contents 1 mg Vial 2 mg Vial 5 mg Vial 8 mg Vial rFVIIa 1000 micrograms 2000 micrograms 5000 micrograms 8000 micrograms sodium chloride* 2.34 mg 4.68 mg 11.7 mg 18.72 mg calcium chloride dihydrate* 1.47 mg 2.94 mg 7.35 mg 11.76 mg glycylglycine 1.32 mg 2.64 mg 6.60 mg 10.56 mg polysorbate 80 0.07 mg 0.14 mg 0.35 mg 0.56 mg mannitol 25 mg 50 mg 125 mg 200 mg Sucrose 10 mg 20 mg 50 mg 80 mg Methionine 0.5 mg 1.0 mg 2.5 mg 4 mg * per mg of rFVIIa: 0.4 mEq sodium, 0.01 mEq calcium

The diluent for reconstitution of NovoSeven RT is a 10 mmol solution of histidine in water for injection and is supplied as a clear colorless solution.

After reconstitution with the appropriate volume of histidine diluent, each vial contains approximately 1 mg/mL NovoSeven RT (corresponding to 1000 micrograms/mL). The reconstituted vials have a pH of approximately 6.0 in sodium chloride (2.3 mg/mL), calcium chloride dihydrate (1.5 mg/mL), glycylglycine (1.3 mg/mL), polysorbate 80 (0.1 mg/mL), mannitol (25 mg/mL), sucrose (10 mg/mL), methionine (0.5 mg/mL), and histidine (1.6 mg/mL).

The reconstituted product is a clear colorless solution which contains no preservatives. NovoSeven RT contains trace amounts of proteins derived from the manufacturing and purification processes such as mouse IgG (maximum of 1.2 ng/mg), bovine IgG (maximum of 30 ng/mg), and protein from BHK-cells and media (maximum of 19 ng/mg).

NovoSeven RT - Clinical Pharmacology Mechanism of Action

NovoSeven RT is recombinant Factor VIIa and, when complexed with tissue factor can activate coagulation Factor X to Factor Xa, as well as coagulation Factor IX to Factor IXa. Factor Xa, in complex with other factors, then converts prothrombin to thrombin, which leads to the formation of a hemostatic plug by converting fibrinogen to fibrin and thereby inducing local hemostasis. This process may also occur on the surface of activated platelets.

Pharmacodynamics

The effect of NovoSeven RT upon coagulation in patients with or without hemophilia has been assessed in different model systems. In an in vitro model of tissue-factor-initiated blood coagulation (Figure A)10, the addition of rFVIIa increased both the rate and level of thrombin generation in normal and hemophilia A blood, with an effect shown at rFVIIa concentrations as low as 10 nM. In this model, fresh human blood was treated with corn trypsin inhibitor (CTI) to block the contact pathway of blood coagulation. Tissue factor (TF) was added to initiate clotting in the presence and absence of rFVIIa for both types of blood.

In a separate model, and in line with previous reports11, escalating doses of rFVIIa in hemophilia plasma demonstrate a dose-dependent increase in thrombin generation (Figure B). In this model, platelet rich normal and hemophilia plasma was adjusted with autologous plasma to 200,000 platelets/microliter. Coagulation was initiated by addition of tissue factor and CaCl2. Thrombin generation was measured in the presence of a thrombin substrate and various added concentrations of rFVIIa.

Figure A

Figure B

Pharmacokinetics

Healthy Subjects

The pharmacokinetics of NovoSeven was investigated in 35 healthy Caucasian and Japanese subjects in a dose-escalation study. Subjects were stratified according to gender and ethnic group and dosed with 40, 80 and 160 micrograms/kg NovoSeven12. The pharmacokinetics of rFVII were linear over the dose range of 40 to 180 micrograms/kg. Pharmacokinetics were similar across gender and ethnic groups. Mean steady state volume of distribution ranged from 130 to 165 mL/kg, mean values of clearance ranged from 33 to 37 mL/h x kg, and mean terminal half-life ranged from 3.9 to 6.0 hours.

Hemophilia A or B

Single-dose pharmacokinetics of NovoSeven (17.5, 35, and 70 micrograms/kg) exhibited dose-proportional behavior in 15 subjects with hemophilia A or B.13 Factor VII clotting activities were measured in plasma drawn prior to and during a 24-hour period after NovoSeven administration. The median apparent volume of distribution at steady state was 103 mL/kg (range 78-139). Median clearance was 33 mL/kg/hr (range 27-49). The median residence time was 3.0 hours (range 2.4-3.3), and the t1/2 was 2.3 hours (range 1.7-2.7). The median in vivo plasma recovery was 44% (30-71%). The products NovoSeven RT and NovoSeven are pharmacokinetically equivalent.14

In a bolus single-dose pharmacokinetic study, 5 male adults (90 micrograms/kg) and 10 male pediatric (2-12 years) patients (crossover, 90 and 180 micrograms/kg) with severe hemophilia A (10 of 18 subjects had inhibitors) received NovoSeven15. The PK of rFVII following 90 and 180 micrograms/kg IV dose in children indicated dose linearity. Based on the FVII:C assay, the terminal half-life of NovoSeven was 2.6 hrs in pediatric patients and 3.1 hrs in adults. Based on the 90 microgram/kg dose, the total clearance of NovoSeven in adults and children was 2767 ± 385 mL/hr (37.6 ± 13.1 mL/hr/kg) and 1375 ± 396 mL/hr (57.3 ± 9.5 mL/hr/kg), respectively. The volume of distribution at steady state (Vss) in adults and children was 121 ± 30 and 153 ± 29 mL/kg, respectively.

Congenital Factor VII deficiency

Single dose pharmacokinetics of NovoSeven in congenital Factor VII deficiency, at doses of 15 and 30 micrograms per kg body weight, showed no significant difference between the two doses used with regard to dose-independent parameters: total body clearance (70.8-79.1 mL/hr x kg), volume of distribution at steady state (280-290 mL/kg), mean residence time (3.75-3.80 hr), and half-life (2.82-3.11 hr). The mean in vivo plasma recovery was approximately 20% (18.9%-22.2%).

The normal Factor VII plasma concentration is 0.5 micrograms/mL. Factor VII levels of 15-25% (0.075 – 0.125 micrograms/mL) are generally sufficient to achieve normal hemostasis.16 For example, a 70 kg individual with FVII deficiency (plasma volume of approximately 3000 mL) would thus require 3.2 - 5.4 micrograms/kg of NovoSeven RT to secure hemostasis, assuming 100% recovery but, since the mean plasma recovery for NovoSeven is 20% for FVII-deficient patients, a NovoSeven RT dose range of 16-27 micrograms/kg would be required to achieve sufficient FVII plasma levels for hemostasis, which is consistent with the recommended dose range.

Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility

Two mutagenicity studies have given no indication of carcinogenic potential for NovoSeven. The clastogenic activity of NovoSeven was evaluated in both in vitro studies (i.e., cultured human lymphocytes) and in vivo studies (i.e., mouse micronucleus test). Neither of these studies indicated clastogenic activity of NovoSeven. Other gene mutation studies have not been performed with NovoSeven RT (e.g., Ames test). No chronic carcinogenicity studies have been performed with NovoSeven RT.

A reproductive study in male and female rats at dose levels up to 3.0 mg/kg/day had no effect on mating performance, fertility, or litter characteristics.

Treatment of rats and rabbits with NovoSeven in reproduction studies has been associated with mortality at doses up to 6 mg/kg and 5 mg/kg. At 6 mg/kg in rats, the abortion rate was 0 out of 25 litters; in rabbits at 5 mg/kg, the abortion rate was 2 out of 25 litters. Twenty-three out of 25 female rats given 6 mg/kg of NovoSeven gave birth successfully, however, two of the 23 litters died during the early period of lactation. No evidence of teratogenicity was observed after dosing with NovoSeven.

Clinical Studies

No direct comparisons to other coagulation products have been conducted, therefore no conclusions regarding the comparative safety or efficacy can be made.

Hemophilia A or B with Inhibitors

Open Protocol Use

The largest number of patients who received NovoSeven during the investigational phase of product development were in an open protocol study (Study 1)17,18,19 that began enrollment in 1988, shortly after the completion of the pharmacokinetic study. These patients included persons with hemophilia types A or B (with or without inhibitors), persons with acquired inhibitors to Factor VIII or Factor IX, and a few FVII deficient patients. The clinical situations were diverse and included muscle/joint bleeds, mucocutaneous bleeds, surgical prophylaxis, intracerebral bleeds, and other emergent situations. Dose schedules were suggested by Novo Nordisk, but they were subject to the option of the investigator. Clinical outcomes were not reported in a standardized manner. Therefore, the clinical data from Study 1 are problematic for the evaluation of the safety and efficacy of the product by statistical methods.

Dosing Study

Study 220 was a double-blind, randomized comparison trial of two dose levels of NovoSeven in the treatment of joint, muscle and mucocutaneous hemorrhages in hemophilia A and B patients with and without inhibitors. Patients received NovoSeven as soon as they could be evaluated in the treatment centers (4 to 18 hours after experiencing a bleed). Thirty-five patients were treated at the 35 micrograms/kg dose (59 joint, 15 muscle and 5 mucocutaneous bleeding episodes) and 43 patients were treated at the 70 micrograms/kg dose (85 joint and 14 muscle bleeding episodes).

Dosing was to be repeated at 2.5 hour intervals but ranged up to four hours for some patients. Efficacy was assessed at 12 ± 2 hours or at end of treatment, whichever occurred first. Based on a subjective evaluation by the investigator, the respective efficacy rates for the 35 and 70 micrograms/kg groups were: excellent 59% and 60%, effective 12% and 11%, and partially effective 17% and 20%. The average number of injections required to achieve hemostasis was 2.8 and 3.2 for the 35 and 70 micrograms/kg groups, respectively.

One patient in the 35 micrograms/kg group and three in the 70 micrograms/kg group experienced serious adverse events that were not considered related to NovoSeven. Two unrelated deaths occurred; one patient died of AIDS and the other of intracranial hemorrhage secondary to trauma.

Surgery Studies

Two clinical trials (Studies 3 and 4) were conducted to evaluate the safety and efficacy of NovoSeven administration during and after surgery in hemophilia A or B patients with inhibitors.

Study 3  was a randomized, double-blind, parallel group clinical trial (29 patients with hemophilia A or B and inhibitors or acquired inhibitors to FVIII/FIX, undergoing major or minor surgical procedures).21 Patients received bolus intravenous NovoSeven (either 35 micrograms/kg, N=15; or 90 micrograms/kg, N=14) prior to surgery, intra-operatively as required, then every 2 hours for the following 48 hours beginning at closure of the wound. Additional doses were administered every 2 to 6 hours up to an additional 3 days to maintain hemostasis. After a maximum of 5 days of double-blind treatment, therapy could be continued in an open-label manner if necessary (90 micrograms/kg NovoSeven every 2-6 hours). Efficacy was assessed during the intra-operative period, and post-operatively from the time of wound closure (Hour 0) through Day 5.

When efficacy assessments at each time point were tabulated by a last value carried forward approach (patients who completed the study early having achieved effective hemos


read more


Related Search: