Myasthenia Gravis Medications


Definition of Myasthenia Gravis: Myasthenia gravis is a neuromuscular disorder characterized by variable weakness of voluntary muscles, which often improves with rest and worsens with activity. The condition is caused by an abnormal immune response.

Drugs associated with Myasthenia Gravis

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

Learn more about Myasthenia Gravis

Micromedex Care Notes:

Myasthenia Gravis

Medical Encyclopedia:

Myasthenia gravis

Harvard Health Guide:

Symptoms and treatment for Myasthenia Gravis
Drug List: Mestinon Mestinon-Timespan Mytelase Mytelase-Chloride Prostigmin Prostigmin-Bromide Regonol Soliris
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Mestinon Controlled-Release Tablets


Pronunciation: peer-id-oh-STIG-meen
Generic Name: Pyridostigmine
Brand Name: Mestinon
Mestinon Controlled-Release Tablets are used for:

Treating myasthenia gravis. It may also be used for other conditions as determined by your doctor.

Mestinon Controlled-Release Tablets are a cholinesterase inhibitor. It works by improving nerve impulses in muscles so that the muscles are better able to work.

Do NOT use Mestinon Controlled-Release Tablets if: you are allergic to any ingredient in Mestinon Controlled-Release Tablets you are taking quinine or quinidine you have a stomach, intestinal, or urinary blockage

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

Before using Mestinon Controlled-Release Tablets:

Some medical conditions may interact with Mestinon Controlled-Release Tablets. 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 heart problems (eg, heart block, slow heartbeat), a urinary tract infection, asthma, or kidney problems

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

Quinine or quinidine because effectiveness of Mestinon Controlled-Release Tablets may be decreased Succinylcholine because actions and side effects may be increased by Mestinon Controlled-Release Tablets

This may not be a complete list of all interactions that may occur. Ask your health care provider if Mestinon Controlled-Release Tablets 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 Mestinon Controlled-Release Tablets:

Use Mestinon Controlled-Release Tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Mestinon Controlled-Release Tablets may be taken with or without food. Take with food if it upsets your stomach. Swallow Mestinon Controlled-Release Tablets whole. Do not break, crush, or chew before swallowing. If you miss a dose of Mestinon Controlled-Release Tablets, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Mestinon Controlled-Release Tablets.

Important safety information: Before you have any medical or dental treatments, emergency care, or surgery, tell the doctor or dentist that you are using Mestinon Controlled-Release Tablets. Use Mestinon Controlled-Release Tablets with extreme caution in CHILDREN. Safety and effectiveness have not been confirmed. PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Mestinon Controlled-Release Tablets, discuss with your doctor the benefits and risks of using Mestinon Controlled-Release Tablets during pregnancy. Mestinon Controlled-Release Tablets are excreted in breast milk. If you are or will be breast-feeding while you are using Mestinon Controlled-Release Tablets, check with your doctor or pharmacist to discuss the risks to your baby. Possible side effects of Mestinon Controlled-Release Tablets:

All medicines may cause side effects, but many people have no, or minor, side effects. When used in small doses, no COMMON side effects have been reported with this product. 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); diarrhea; fainting; increased production of saliva; increased sweating; muscle weakness; nausea; small pupils; stomach cramps; trouble breathing; vision changes; vomiting; 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: Mestinon 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 diarrhea; fainting; increased production of saliva; increased sweating; muscle weakness; nausea; small pupils; stomach cramps; trouble breathing; vision changes; vomiting; weakness.

Proper storage of Mestinon Controlled-Release Tablets:

Store Mestinon Controlled-Release Tablets between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Mestinon Controlled-Release Tablets out of the reach of children and away from pets.

General information: If you have any questions about Mestinon Controlled-Release Tablets, please talk with your doctor, pharmacist, or other health care provider. Mestinon Controlled-Release Tablets are 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 Mestinon Controlled-Release Tablets. 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 Mestinon resources Mestinon Side Effects (in more detail) Mestinon Use in Pregnancy & Breastfeeding Drug Images Mestinon Drug Interactions Mestinon Support Group 6 Reviews for Mestinon - Add your own review/rating Compare Mestinon with other medications Dysautonomia Myasthenia Gravis Nerve Agent Pretreatment Reversal of Nondepolarizing Muscle Relaxants
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Mestinon Timespan


Generic Name: pyridostigmine (py rid o STIG meen)
Brand Names: Mestinon, Mestinon Timespan

What is Mestinon Timespan (pyridostigmine)?

Pyridostigmine affects chemicals in the body that are involved in the communication between nerve impulses and muscle movement.

Pyridostigmine is used to treat the symptoms of myasthenia gravis. It is also used in military personnel who have been exposed to nerve gas.

Pyridostigmine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Mestinon Timespan (pyridostigmine)? You should not use pyridostigmine if you are allergic to it, or if you have a bladder or bowel obstruction.

Before taking pyridostigmine, tell your doctor if you have asthma, kidney disease, an ulcer or other serious stomach disorder, high blood pressure, heart disease, overactive thyroid, or a history of seizures.

The amount and timing of this medicine is extremely important to the success of your treatment. Carefully follow your doctor's instructions about how much medicine to take and when to take it.

This medication may cause blurred vision or impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

Your doctor may occasionally change your dose to make sure you get the best results. You may be asked to keep a daily record of when you took each dose and how long the effects lasted. This will help your doctor determine if your dose needs to be adjusted.

If you need surgery, tell the surgeon ahead of time that you are using pyridostigmine. You may need to stop using the medicine for a short time. What should I discuss with my health care provider before taking Mestinon Timespan (pyridostigmine)? You should not use pyridostigmine if you are allergic to it, or if you have a bladder or bowel obstruction.

To make sure you can safely take pyridostigmine, tell your doctor if you have any of these other conditions:

asthma;

kidney disease;

an ulcer or other serious stomach disorder;

high blood pressure, heart disease;

overactive thyroid; or

a history of seizures.

It is not known whether pyridostigmine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether pyridostigmine 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 should I take Mestinon Timespan (pyridostigmine)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Take this medicine with food or milk if it upsets your stomach. Do not crush, chew, or break an extended-release tablet. Swallow it whole. Breaking or opening the pill may cause too much of the drug to be released at one time.

Measure liquid medicine with a special dose measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose measuring device, ask your pharmacist for one.

The amount and timing of this medicine is extremely important to the success of your treatment. Carefully follow your doctor's instructions about how much medicine to take and when to take it.

Your doctor may occasionally change your dose to make sure you get the best results. You may be asked to keep a daily record of when you took each dose and how long the effects lasted. This will help your doctor determine if your dose needs to be adjusted.

If you need surgery, tell the surgeon ahead of time that you are using pyridostigmine. You may need to stop using the medicine for a short time. Store at room temperature away from moisture and heat.

Keep the tablets in their original container, along with the canister of moisture-absorbing preservative that comes with this medicine.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, vomiting, diarrhea, stomach cramps, sweating, blurred vision, drooling, and weak or shallow breathing.

Worsening muscle weakness, or no change in your myasthenia gravis symptoms, may also be signs of overdose.

What should I avoid while taking Mestinon Timespan (pyridostigmine)? This medication may cause blurred vision or impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly. Drinking alcohol can increase certain side effects of pyridostigmine. Mestinon Timespan (pyridostigmine) side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using pyridostigmine and call your doctor at once if you have any of these serious side effects:

extreme muscle weakness, muscle twicthing;

slurred speech, vision problems;

severe vomiting or diarrhea;

cough with mucus;

confusion, anxiety, panic attacks;

seizure (convulsions); or

worsening or no improvement in your symptoms of myasthenia gravis.

Less serious side effects may include:

cold sweat, pale skin;

urinating more than usual;

watery eyes;

mild nausea, vomiting, or upset stomach;

warmth or tingly feeling; or

mild rash or itching.

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.

What other drugs will affect Mestinon Timespan (pyridostigmine)?

Tell your doctor about all other medicines you use, especially:

atropine (Atreza, Sal-Tropine);

belladonna (Donnatal, and others);

benztropine (Cogentin);

clidinium (Quarzan);

clozapine (Clozaril, FazaClo);

dimenhydrinate (Dramamine);

methscopolamine (Pamine), scopolamine (Transderm Scop);

glycopyrrolate (Robinul);

mepenzolate (Cantil);

bladder or urinary medications such as darifenacin (Enablex), flavoxate (Urispas), oxybutynin (Ditropan, Oxytrol), tolterodine (Detrol), or solifenacin (Vesicare);

bronchodilators such as ipratropium (Atrovent) or tiotropium (Spiriva);

cold medicine, allergy medicine, or sleeping pills that contain an antihistamine such as diphenhydramine (Tylenol PM) or doxylamine (Unisom);

heart rhythm medication such as quinidine (Quin-G), procainamide (Procan, Pronestyl), disopyramide (Norpace), flecaininde (Tambocor), mexiletine (Mexitil), propafenone, (Rythmol), and others;

irritable bowel medications such as dicyclomine (Bentyl), hyoscyamine (Hyomax), or propantheline (Pro Banthine);

medicine to treat Alzheimer's dementia, such as donepezil (Aricept), rivastigmine (Exelon), or tacrine (Cognex); or

a steroid such as betamethasone (Celestone) or dexamethasone (Cortastat, Dexasone, Solurex, DexPak).

This list is not complete and other drugs may interact with pyridostigmine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Mestinon Timespan resources Mestinon Timespan Side Effects (in more detail) Mestinon Timespan Use in Pregnancy & Breastfeeding Drug Images Mestinon Timespan Drug Interactions Mestinon Timespan Support Group 1 Review for Mestinon Timespan - Add your own review/rating Pyridostigmine Prescribing Information (FDA) Mestinon MedFacts Consumer Leaflet (Wolters Kluwer) Mestinon Prescribing Information (FDA) Pyridostigmine Bromide Monograph (AHFS DI) Regonol Prescribing Information (FDA) Compare Mestinon Timespan with other medications Dysautonomia Myasthenia Gravis Nerve Agent Pretreatment Reversal of Nondepolarizing Muscle Relaxants Where can I get more information? Your pharmacist can provide more information about pyridostigmine.

See also: Mestinon Timespan side effects (in more detail)


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antimyasthenic Oral, Parenteral


Class Name: antimyasthenic (Oral route, Parenteral route)

Commonly used brand name(s)

In the U.S.

Aricept Cognex Exelon Mestinon Mestinon Timespan Mytelase Chloride Prostigmin Bromide Razadyne Razadyne ER Razadyne IR

In Canada

Reminyl

Available Dosage Forms:

Tablet Syrup Tablet, Extended Release Capsule, Extended Release Solution Tablet, Disintegrating Capsule Uses For This Medicine

Antimyasthenics are given by mouth or by injection to treat myasthenia gravis. Neostigmine may also be given by injection as a test for myasthenia gravis. Sometimes neostigmine is given by injection to prevent or treat certain urinary tract or intestinal disorders. In addition, neostigmine or pyridostigmine may be given by injection as an antidote to certain types of muscle relaxants used in surgery.

These medicines are available only with your doctor's prescription.

Before Using This Medicine Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group 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

Although there is no specific information comparing use of antimyasthenics in children with use in other age groups, these medicines are not expected to cause different side effects or problems in children than they do in adults.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults. Although there is not much information comparing use of antimyasthenics in the elderly with use in other age groups, these medicines are not expected to cause different side effects or problems in older people than they do in younger adults.

Pregnancy

Antimyasthenics have not been reported to cause birth defects; however, muscle weakness has occurred temporarily in some newborn babies whose mothers took antimyasthenics during pregnancy.

Breast Feeding

Antimyasthenics have not been reported to cause problems in nursing babies.

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. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

Atropine Metoclopramide

Using medicines in this class with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Succinylcholine 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 medicines in this class. Make sure you tell your doctor if you have any other medical problems, especially:

Intestinal blockage or Urinary tract blockage or Urinary tract infection—These medicines may make the condition worse. Proper Use of This Medicine

Your doctor may want you to take this medicine with food or milk to help lessen the chance of side effects. If you have any questions about how you should be taking this medicine, check with your doctor.

Take this medicine only as directed. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

If you are taking this medicine for myasthenia gravis:

When you first begin taking this medicine, your doctor may want you to keep a daily record of: the time you take each dose. how long you feel better after taking each dose. how long you feel worse. any side effects that occur.

This is to help your doctor decide whether the dose of this medicine should be increased or decreased and how often the medicine should be taken in order for it to be most effective in your condition.

Dosing

The dose medicines in this class will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For ambenonium For oral dosage form (tablets): For myasthenia gravis: Adults and teenagers—At first, the dose is 5 milligrams (mg) three or four times per day. Then, if needed, the dose will be adjusted by your doctor. Children—The dose is based on body weight or size and must be determined by your doctor. The total daily dose is usually 300 micrograms (mcg) per kilogram (kg) (136 mcg per pound) of body weight or 10 mg per square meter of body surface area. This dose may be divided into three or four smaller doses. If needed, the total daily dose will be increased to 1.5 mg per kg (0.68 mg per pound) of body weight or 50 mg per square meter of body surface area. This dose may be divided into three or four smaller doses. For neostigmine For oral dosage form (tablets): For myasthenia gravis: Adults and teenagers—At first, the dose is 15 milligrams (mg) every three or four hours. Then, the dose is 150 mg taken over a twenty-four-hour period. Children—The dose is based on body weight or size and must be determined by your doctor. The total daily dose is usually 2 mg per kilogram (kg) (0.91 mg per pound) of body weight or 60 mg per square meter of body surface area. This dose may be divided into six to eight smaller doses. For injection dosage form: For myasthenia gravis: Adults and teenagers—The usual dose is 500 micrograms (mcg) injected into a muscle or under the skin. Children—The dose is based on body weight and must be determined by your doctor. It is usually 10 to 40 mcg per kg (4.5 to 18.2 mcg per pound) of body weight, injected into a muscle or under the skin, every two or three hours. For urinary tract or intestinal disorders: Adults and teenagers—The usual dose is 250 to 500 mcg, injected into a muscle or under the skin, as needed. Children—Use and dose must be determined by your doctor. For pyridostigmine For oral dosage forms (syrup and tablets): For myasthenia gravis: Adults and teenagers—At first, the dose is 30 to 60 milligrams (mg) every three or four hours. Then, the dose is 60 mg to 1.5 grams (usually 600 mg) per day. Children—The dose is based on body weight or size and must be determined by your doctor. The total daily dose is usually 7 mg per kilogram (kg) (3.2 mg per pound) of body weight or 200 mg per square meter of body surface area. This dose may be divided into five or six smaller doses. For long-acting oral dosage form (extended-release tablets): For myasthenia gravis: Adults and teenagers—The usual dose is 180 to 540 mg one or two times per day. Children—Dose must be determined by your doctor. For injection dosage form: For myasthenia gravis: Adults and teenagers—The usual dose is 2 mg, injected into a muscle or vein, every two or three hours. Children—The dose is based on body weight and must be determined by your doctor. It is usually 50 to 150 micrograms (mcg) per kg (22.7 to 68.1 mcg per pound) of body weight, injected into a muscle every four to six hours. Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Do not keep outdated medicine or medicine no longer needed.

Keep the syrup form of pyridostigmine from freezing.

Side Effects of This Medicine

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:

Symptoms of overdose Blurred vision clumsiness or unsteadiness confusion convulsions (seizures) diarrhea (severe) increase in bronchial secretions or watering of mouth (excessive) increasing muscle weakness (especially in the arms, neck, shoulders, and tongue) muscle cramps or twitching nausea or vomiting (severe) shortness of breath, troubled breathing, wheezing, or tightness in chest slow heartbeat slurred speech stomach cramps or pain (severe) unusual irritability, nervousness, restlessness, or fear unusual tiredness or weakness

Check with your doctor as soon as possible if any of the following side effects occur:

Rare Redness, swelling, or pain at place of injection (for pyridostigmine injection only) skin rash (does not apply to ambenonium)

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 Diarrhea increased sweating increased watering of mouth nausea or vomiting stomach cramps or pain Less common Frequent urge to urinate increase in bronchial secretions unusually small pupils unusual watering of eyes

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.

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Pyridostigmine Tablets


Pronunciation: peer-id-oh-STIG-meen
Generic Name: Pyridostigmine
Brand Name: Mestinon
Pyridostigmine is used for:

Treating myasthenia gravis. It may also be used for other conditions as determined by your doctor.

Pyridostigmine is a cholinesterase inhibitor. It works by improving nerve impulses in muscles so that the muscles are better able to work.

Do NOT use Pyridostigmine if: you are allergic to any ingredient in Pyridostigmine you are taking quinine or quinidine you have a stomach, intestinal, or urinary blockage

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

Before using Pyridostigmine:

Some medical conditions may interact with Pyridostigmine. 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 heart problems (eg, heart block, slow heartbeat), a urinary tract infection, asthma, or kidney problems

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

Quinine or quinidine because effectiveness of Pyridostigmine may be decreased Succinylcholine because actions and side effects may be increased by Pyridostigmine

This may not be a complete list of all interactions that may occur. Ask your health care provider if Pyridostigmine 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 Pyridostigmine:

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

Pyridostigmine may be taken with or without food. Take with food if it upsets your stomach. If you miss a dose of Pyridostigmine, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

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

Important safety information: Before you have any medical or dental treatments, emergency care, or surgery, tell the doctor or dentist that you are using Pyridostigmine. Use Pyridostigmine with extreme caution in CHILDREN. Safety and effectiveness have not been confirmed. PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Pyridostigmine, discuss with your doctor the benefits and risks of using Pyridostigmine during pregnancy. Pyridostigmine is excreted in breast milk. If you are or will be breast-feeding while you are using Pyridostigmine, check with your doctor or pharmacist to discuss the risks to your baby. Possible side effects of Pyridostigmine:

All medicines may cause side effects, but many people have no, or minor, side effects. When used in small doses, no COMMON side effects have been reported with this product. 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); diarrhea; fainting; increased production of saliva; increased sweating; muscle weakness; nausea; small pupils; stomach cramps; trouble breathing; vision changes; vomiting; 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: Pyridostigmine 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 diarrhea; fainting; increased production of saliva; increased sweating; muscle weakness; nausea; small pupils; stomach cramps; trouble breathing; vision changes; vomiting; weakness.

Proper storage of Pyridostigmine:

Store Pyridostigmine between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Pyridostigmine out of the reach of children and away from pets.

General information: If you have any questions about Pyridostigmine, please talk with your doctor, pharmacist, or other health care provider. Pyridostigmine 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 Pyridostigmine. 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 Pyridostigmine resources Pyridostigmine Side Effects (in more detail) Pyridostigmine Dosage Pyridostigmine Use in Pregnancy & Breastfeeding Drug Images Pyridostigmine Drug Interactions Pyridostigmine Support Group 12 Reviews for Pyridostigmine - Add your own review/rating Compare Pyridostigmine with other medications Dysautonomia Myasthenia Gravis Nerve Agent Pretreatment Reversal of Nondepolarizing Muscle Relaxants
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Travatan Z


Generic Name: travoprost ophthalmic (TRA voe prost off THAL mik)
Brand Names: Travatan, Travatan Z

What is travoprost ophthalmic?

Travoprost ophthalmic (for the eye) reduces pressure in the eye by increasing the amount of fluid that drains from the eye.

Travoprost ophthalmic is used to treat certain types of glaucoma and other causes of high pressure inside the eye.

Travoprost ophthalmic may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about travoprost ophthalmic?

Travoprost ophthalmic may cause a gradual change in the color of your eyes or eyelids and lashes, as well as increased growth or thickness of your eyelashes. These color changes, usually an increase in brown pigment, occur slowly and you may not notice them for months or years. Color changes may be permanent even after your treatment ends, and may occur only in the eye being treated. This could result in a cosmetic difference in eye or eyelash color from one eye to the other.

Do not allow the dropper to touch any surface, including the eyes or hands. If the dropper becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye.

After using this medication, wait at least 5 minutes before using any other eye drops that your doctor has prescribed.

What should I discuss with my health care provider before using travoprost ophthalmic? Do not use this medication if you are allergic to travoprost.

Before using travoprost, tell your doctor if you are allergic to any drugs, or if you have swelling or infection of your eye.

Travoprost ophthalmic may cause a gradual change in the color of your eyes or eyelids and lashes, as well as increased growth or thickness of your eyelashes. These color changes, usually an increase in brown pigment, occur slowly and you may not notice them for months or years. Color changes may be permanent even after your treatment ends, and may occur only in the eye being treated. This could result in a cosmetic difference in eye or eyelash color from one eye to the other.

FDA pregnancy category C. It is not known whether travoprost is harmful to an unborn baby. Before using this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether travoprost 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 should I use travoprost ophthalmic?

Use this medication exactly as it was prescribed for you. Do not use the medication in larger amounts, or use it for longer than recommended by your doctor. Follow the instructions on your prescription label.

Wash your hands before using the eye drops.

To apply the eye drops:

Tilt your head back slightly and pull down on the lower eyelid to create a small pocket. Hold the dropper above the eye with the dropper tip down. Look up and away from the dropper. Squeeze out a drop and close your eye. Gently press your finger to the inside corner of the eye (near the nose) for about 1 minute to keep the liquid from draining into your tear duct.

If you use more than one drop in the same eye, wait about 5 minutes before putting in the next drop. Also wait at least 5 minutes before using any other eye drops that your doctor has prescribed.

Do not allow the dropper to touch any surface, including the eyes or hands. If the dropper becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye. At any time during your use of travoprost ophthalmic, tell your doctor at once if you have an eye injury, if you develop an eye infection, or if you plan to have eye surgery. Do not use the eye drops if the liquid changes colors or has particles in it. Store the drops at room temperature away from heat and moisture. Keep the bottle tightly closed when not in use. What happens if I miss a dose?

Use the medication as soon as you remember. If it is almost time for the next dose, skip the missed dose and use the medicine at the next regularly scheduled time. Do not use extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention if you think you have used too much of this medicine.

An overdose of travoprost ophthalmic used in the eyes is not expected to produce life-threatening symptoms.

What should I avoid while using travoprost ophthalmic? Avoid using too much of this medication, which can actually make it less effective in lowering the pressure inside the eye.

Avoid using any eyedrop medicine that has not been prescribed by your doctor.

Travoprost ophthalmic side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using travoprost ophthalmic and call your doctor at once if you have any of these serious side effects:

redness, swelling, itching, or pain in or around your eye;

oozing or discharge from your eye;

increased sensitivity to light;

vision changes; or

chest pain.

Less serious side effects may include:

mild eye discomfort;

headache;

feeling like something is in your eye;

blurred vision;

dry or watery eyes; or

stinging or burning of the eyes after using the drops.

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.

What other drugs will affect travoprost ophthalmic?

There may be other drugs that can affect travoprost ophthalmic. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Travatan Z resources Travatan Z Side Effects (in more detail) Travatan Z Use in Pregnancy & Breastfeeding Travatan Z Drug Interactions Travatan Z Support Group 1 Review for Travatan Z - Add your own review/rating Travatan Z Consumer Overview Travatan Z Drops MedFacts Consumer Leaflet (Wolters Kluwer) Travatan Prescribing Information (FDA) Travatan Monograph (AHFS DI) Travatan Advanced Consumer (Micromedex) - Includes Dosage Information Travatan Consumer Overview Travatan Drops MedFacts Consumer Leaflet (Wolters Kluwer) Compare Travatan Z with other medications Glaucoma, Open Angle Intraocular Hypertension Where can I get more information? Your pharmacist can provide more information about travoprost ophthalmic.

See also: Travatan Z side effects (in more detail)


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travoprost ophthalmic


Generic Name: travoprost ophthalmic (TRA voe prost off THAL mik)
Brand Names: Travatan, Travatan Z

What is travoprost ophthalmic?

Travoprost ophthalmic (for the eye) reduces pressure in the eye by increasing the amount of fluid that drains from the eye.

Travoprost ophthalmic is used to treat certain types of glaucoma and other causes of high pressure inside the eye.

Travoprost ophthalmic may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about travoprost ophthalmic?

Travoprost ophthalmic may cause a gradual change in the color of your eyes or eyelids and lashes, as well as increased growth or thickness of your eyelashes. These color changes, usually an increase in brown pigment, occur slowly and you may not notice them for months or years. Color changes may be permanent even after your treatment ends, and may occur only in the eye being treated. This could result in a cosmetic difference in eye or eyelash color from one eye to the other.

Do not allow the dropper to touch any surface, including the eyes or hands. If the dropper becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye.

After using this medication, wait at least 5 minutes before using any other eye drops that your doctor has prescribed.

What should I discuss with my health care provider before using travoprost ophthalmic? Do not use this medication if you are allergic to travoprost.

Before using travoprost, tell your doctor if you are allergic to any drugs, or if you have swelling or infection of your eye.

Travoprost ophthalmic may cause a gradual change in the color of your eyes or eyelids and lashes, as well as increased growth or thickness of your eyelashes. These color changes, usually an increase in brown pigment, occur slowly and you may not notice them for months or years. Color changes may be permanent even after your treatment ends, and may occur only in the eye being treated. This could result in a cosmetic difference in eye or eyelash color from one eye to the other.

FDA pregnancy category C. It is not known whether travoprost is harmful to an unborn baby. Before using this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether travoprost 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 should I use travoprost ophthalmic?

Use this medication exactly as it was prescribed for you. Do not use the medication in larger amounts, or use it for longer than recommended by your doctor. Follow the instructions on your prescription label.

Wash your hands before using the eye drops.

To apply the eye drops:

Tilt your head back slightly and pull down on the lower eyelid to create a small pocket. Hold the dropper above the eye with the dropper tip down. Look up and away from the dropper. Squeeze out a drop and close your eye. Gently press your finger to the inside corner of the eye (near the nose) for about 1 minute to keep the liquid from draining into your tear duct.

If you use more than one drop in the same eye, wait about 5 minutes before putting in the next drop. Also wait at least 5 minutes before using any other eye drops that your doctor has prescribed.

Do not allow the dropper to touch any surface, including the eyes or hands. If the dropper becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye. At any time during your use of travoprost ophthalmic, tell your doctor at once if you have an eye injury, if you develop an eye infection, or if you plan to have eye surgery. Do not use the eye drops if the liquid changes colors or has particles in it. Store the drops at room temperature away from heat and moisture. Keep the bottle tightly closed when not in use. What happens if I miss a dose?

Use the medication as soon as you remember. If it is almost time for the next dose, skip the missed dose and use the medicine at the next regularly scheduled time. Do not use extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention if you think you have used too much of this medicine.

An overdose of travoprost ophthalmic used in the eyes is not expected to produce life-threatening symptoms.

What should I avoid while using travoprost ophthalmic? Avoid using too much of this medication, which can actually make it less effective in lowering the pressure inside the eye.

Avoid using any eyedrop medicine that has not been prescribed by your doctor.

Travoprost ophthalmic side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using travoprost ophthalmic and call your doctor at once if you have any of these serious side effects:

redness, swelling, itching, or pain in or around your eye;

oozing or discharge from your eye;

increased sensitivity to light;

vision changes; or

chest pain.

Less serious side effects may include:

mild eye discomfort;

headache;

feeling like something is in your eye;

blurred vision;

dry or watery eyes; or

stinging or burning of the eyes after using the drops.

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.

Travoprost ophthalmic Dosing Information

Usual Adult Dose for Intraocular Hypertension:

Instill 1 drop in the affected eye(s) once daily in the evening.

Usual Adult Dose for Glaucoma (Open Angle):

Instill 1 drop in the affected eye(s) once daily in the evening.

Usual Pediatric Dose for Intraocular Hypertension:

16 years and older:
Instill 1 drop in the affected eye(s) once daily in the evening.

Usual Pediatric Dose for Glaucoma (Open Angle):

16 years and older:
Instill 1 drop in the affected eye(s) once daily in the evening.

What other drugs will affect travoprost ophthalmic?

There may be other drugs that can affect travoprost ophthalmic. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More travoprost ophthalmic resources Travoprost ophthalmic Side Effects (in more detail) Travoprost ophthalmic Dosage Travoprost ophthalmic Use in Pregnancy & Breastfeeding Travoprost ophthalmic Drug Interactions Travoprost ophthalmic Support Group 2 Reviews for Travoprost - Add your own review/rating Travatan Advanced Consumer (Micromedex) - Includes Dosage Information Travatan Consumer Overview Travatan Drops MedFacts Consumer Leaflet (Wolters Kluwer) Travatan Prescribing Information (FDA) Travatan Monograph (AHFS DI) Travatan Z Drops MedFacts Consumer Leaflet (Wolters Kluwer) Travatan Z Consumer Overview Compare travoprost ophthalmic with other medications Glaucoma, Open Angle Intraocular Hypertension Where can I get more information? Your pharmacist can provide more information about travoprost ophthalmic.

See also: travoprost side effects (in more detail)


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latanoprost ophthalmic


Generic Name: latanoprost ophthalmic (la TAN oh prost)
Brand Names: Xalatan, Xalatan Multi-Pack

What is latanoprost ophthalmic?

Latanoprost reduces pressure in the eye by increasing the amount of fluid that drains from the eye.

Latanoprost ophthalmic (for the eyes) is used to treat certain types of glaucoma and other causes of high pressure inside the eye.

Latanoprost ophthalmic may also be used for purposes not listed in this medication guide.

What is the most important information I should know about latanoprost ophthalmic? Do not use this medication while wearing contact lenses. Latanoprost ophthalmic may contain a preservative that can discolor soft contact lenses. Wait at least 15 minutes after using latanoprost ophthalmic before putting your contact lenses in.

Latanoprost ophthalmic may cause a gradual change in the color of your eyes or eyelids and lashes, as well as increased growth or thickness of your eyelashes. These color changes, usually an increase in brown pigment, occur slowly and you may not notice them for months or years. Color changes may be permanent even after your treatment ends, and may occur only in the eye being treated. This could result in a cosmetic difference in eye or eyelash color from one eye to the other.

Do not allow the tip of the dropper to touch any surface, including your eyes or hands. If the dropper becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye.

After using this medication, wait at least 5 minutes before using any other eye drops that your doctor has prescribed.

What should I discuss with my health care provider before using latanoprost ophthalmic? Do not use this medication if you are allergic to latanoprost.

To make sure you can safely use latanoprost ophthalmic, tell your doctor if you have swelling or infection of your eye.

Latanoprost ophthalmic may cause a gradual change in the color of your eyes or eyelids and lashes, as well as increased growth or thickness of your eyelashes. These color changes, usually an increase in brown pigment, occur slowly and you may not notice them for months or years. Color changes may be permanent even after your treatment ends, and may occur only in the eye being treated. This could result in a cosmetic difference in eye or eyelash color from one eye to the other.

FDA pregnancy category C. It is not known whether latanoprost ophthalmic will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether latanoprost 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 should I use latanoprost ophthalmic? Do not use this medication while wearing contact lenses. Latanoprost ophthalmic may contain a preservative that can discolor soft contact lenses. Wait at least 15 minutes after using latanoprost ophthalmic before putting your contact lenses in.

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Wash your hands before using the eye drops.

To apply the eye drops:

Tilt your head back slightly and pull down your lower eyelid to create a small pocket. Hold the dropper above the eye with the tip down. Look up and away from the dropper as you squeeze out a drop, then close your eye.

Use only the number of drops your doctor has prescribed.

Gently press your finger to the inside corner of the eye (near your nose) for about 1 minute to keep the liquid from draining into your tear duct.

If you use more than one drop in the same eye, wait about 5 minutes before putting in the next drop.

Wait at least 10 minutes before using any other eye drops that your doctor has prescribed.

Do not allow the tip of the dropper to touch any surface, including your eyes or hands. If the dropper becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye. Tell your doctor right away if you have any eye injury or infection, or if you need to have any type of surgery, especially eye surgery. Do not use the eye drops if the liquid changes colors or has particles in it. Store an unopened bottle of latanoprost eye drops in a refrigerator. Once you have opened and begun using the drops, you may store them at room temperature, away from moisture, heat, and light. Keep the bottle tightly closed when not in use.

Do not use the eye drops if it has been longer than 6 weeks since you first opened the bottle. If you still need to use the medication, call your doctor for a new prescription.

What happens if I miss a dose?

If you forget to use the eye drops, skip the missed dose and use the medicine at the next regularly scheduled time. Do not use extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. What should I avoid while using latanoprost ophthalmic? Avoid using too much of this medication, which can actually make it less effective in lowering the pressure inside the eye.

Do not use other eye medications unless your doctor tells you to.

Latanoprost ophthalmic side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using latanoprost ophthalmic and call your doctor at once if you have any of these serious side effects:

redness, swelling, itching, or pain in or around your eye;

oozing or discharge from your eye;

increased sensitivity to light;

vision changes; or

chest pain.

Less serious side effects may include:

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

headache, dizziness;

mild eye discomfort;

blurred vision;

feeling like something is in your eye;

dry or watery eyes; or

stinging or burning of the eyes after using the drops.

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.

Latanoprost ophthalmic Dosing Information

Usual Adult Dose for Intraocular Hypertension:

1 drop in the affected eye(s) once a day in the evening.

Usual Adult Dose for Glaucoma (Open Angle):

1 drop in the affected eye(s) once a day in the evening.

What other drugs will affect latanoprost ophthalmic?

There may be other drugs that can interact with latanoprost ophthalmic. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More latanoprost ophthalmic resources Latanoprost ophthalmic Side Effects (in more detail) Latanoprost ophthalmic Dosage Latanoprost ophthalmic Use in Pregnancy & Breastfeeding Latanoprost ophthalmic Drug Interactions Latanoprost ophthalmic Support Group 5 Reviews for Latanoprost - Add your own review/rating Xalatan Prescribing Information (FDA) Xalatan Monograph (AHFS DI) Xalatan Advanced Consumer (Micromedex) - Includes Dosage Information Xalatan Drops MedFacts Consumer Leaflet (Wolters Kluwer) Xalatan Consumer Overview Compare latanoprost ophthalmic with other medications Glaucoma, Open Angle Intraocular Hypertension Where can I get more information? Your pharmacist can provide more information about latanoprost ophthalmic.

See also: latanoprost side effects (in more detail)


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Cetrimide Cream BP


1. Name Of The Medicinal Product

CETRIMIDE CREAM BP

BELLS ANTISEPTIC CREAM

LLOYDSPHARMACY ANTISEPTIC CREAM

WILKO ANTISEPTIC CREAM

GALPHARMMEDICAL ANTISEPTIC CREAM

ASDA ANTISEPTIC FIRST AID CREAM

NUMARK ANTISEPTIC CREAM

2. Qualitative And Quantitative Composition

Cetrimide BP 0.5% w/w

3. Pharmaceutical Form

Cream

4. Clinical Particulars 4.1 Therapeutic Indications

For application to minor burns, minor wounds, cuts, grazes, minor abrasions and minor scalds to prevent infection.

4.2 Posology And Method Of Administration

For topical application to the affected areas, there is no difference in use for children, adults or the elderly.

4.3 Contraindications

Avoid contact with eyes, brain, meninges and middle ear. Do not use in body cavities or as an enema.

4.4 Special Warnings And Precautions For Use

Cetostearyl alcohol may cause local skin reactions (e.g. contact dermatitis).

Hydroxybenzoates may cause allergic reactions (possibly delayed).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None stated

4.6 Pregnancy And Lactation

None stated

4.7 Effects On Ability To Drive And Use Machines

None stated

4.8 Undesirable Effects

Some patients may become hypersensitive to cetrimide on repeated application.

4.9 Overdose

Overdose may cause nausea and vomiting. The product has depolarising muscle relaxant properties and toxic symptoms including dyspnoea and cyanosis (due to paralysis of the respiratory muscles and possibly leading to asphyxia), depression of the central nervous system, hypotension and coma may also occur. Treatment of poisoning is symptomatic.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Cetrimide is a quaternary ammonium disinfectant with properties and uses typical of cationic surfactants. These surfactants dissociate in aqueous solution into a relatively large and complex cation, which is responsible for the surface activity, and a smaller inactive anion. In addition to the emulsifying and detergent properties, Cetrimide has bactericidal activity against gram positive and some gram negative organisms.

5.2 Pharmacokinetic Properties

Plasma concentrations for topical applications are extremely low, therefore clinically not significant.

5.3 Preclinical Safety Data

None stated

6. Pharmaceutical Particulars 6.1 List Of Excipients

Cetostearyl Alcohol BP

Liquid Paraffin BP

Nipastat*

Purified Water BP

* Nipastat is a mixture of Methyl (E218), Ethyl (E214), Propyl (E216), iso-Butyl and n-Butyl Hydroxybenzoates.

6.2 Incompatibilities

None stated

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

15g, 30g and 50g aluminium tubes.

6.6 Special Precautions For Disposal And Other Handling

None stated

7. Marketing Authorisation Holder

Ecolab Ltd, Lotherton Way, Garforth, Leeds, LS25 2JY.

8. Marketing Authorisation Number(S)

PL 04509/0007

9. Date Of First Authorisation/Renewal Of The Authorisation

1 March 2003

10. Date Of Revision Of The Text

November 2004 / August 2006


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Endometrin



Dosage Form: vaginal tablet
FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE

Endometrin is indicated to support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of an Assisted Reproductive Technology (ART) treatment program for infertile women.

DOSAGE AND ADMINISTRATION General Dosing Information

The dose of Endometrin is 100 mg administered vaginally two or three times daily starting the day after oocyte retrieval and continuing for up to 10 weeks total duration. Efficacy in women 35 years of age and older has not been clearly established. The appropriate dose of Endometrin in this age group has not been determined.

Dosage Forms and Strengths

100 mg vaginal insert is a white to off-white oblong-shaped tablet debossed with “FPI” on one side and “100” on the other side.

Contraindications

Endometrin should not be used in individuals with any of the following conditions:

Previous allergic reactions to progesterone or any of the ingredients of Endometrin [see Description (11)] Known missed abortion or ectopic pregnancy Liver disease Known or suspected breast cancer Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events Warnings and Precautions Cardiovascular or Cerebrovascular Disorders

The physician should be alert to earliest signs of myocardial infarction, cerebrovascular disorders, arterial or venous thromboembolism (venous thromboembolism or pulmonary embolism), thrombophlebitis, or retinal thrombosis. Endometrin should be discontinued if any of these are suspected.

Depression

Patients with a history of depression need to be closely observed. Consider discontinuation if symptoms worsen.

Use of Other Vaginal Products

Endometrin is not recommended for use with other vaginal products (such as antifungal products) as this may alter progesterone release and absorption from the vaginal insert [see Drug Interactions (7)].

Adverse Reactions Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data reflect exposure to Endometrin in 808 infertile women (74.9% White, 10.3% Hispanic, 5.4% Black, 5% Asian, and 4.6% Other) in a single Assisted Reproductive Technology 10 week clinical study conducted in the U.S. Endometrin was studied at doses of 100 mg twice daily and 100 mg three times daily. The adverse reactions that occurred at a rate greater than or equal to 2% in either Endometrin group are summarized in Table 1.

Table 1: Number and Frequency of Reported Adverse Reactions in Women Treated with Endometrin in an Assisted Reproductive Technology Study Body System Endometrin
100 mg twice
daily
(N=404) Endometrin
100 mg three
times daily
(N=404)   Preferred Term     Gastrointestinal Disorders   Abdominal pain 50 (12%) 50 (12%)   Nausea 32 (8%) 29 (7%)   Abdominal distension 18 (4%) 17 (4%)   Constipation 9 (2%) 14 (3%)   Vomiting 13 (3%) 9 (2%) General Disorders & Administration Site Conditions   Fatigue 7 (2%) 12 (3%) Infections and Infestations   Urinary tract infection 9 (2%) 4 (1%) Injury, Poisoning and Procedural Complications   Post-oocyte retrieval pain 115 (28%) 102 (25%) Nervous System Disorders   Headache 15 (4%) 13 (3%) Reproductive System and Breast Disorders   Ovarian hyperstimulation syndrome 30 (7%) 27 (7%)   Uterine spasm 15 (4%) 11 (3%)   Vaginal bleeding 13 (3%) 14 (3%)

Other less common reported adverse reactions included vaginal irritation, itching, burning, discomfort, urticaria, and peripheral edema.

Expected Adverse Reaction Profile Seen with Progesterone

Endometrin is also expected to have adverse reactions similar to other drugs containing progesterone that may include breast tenderness, bloating, mood swings, irritability, and drowsiness.

Drug Interactions

No formal drug-drug interaction studies have been conducted for Endometrin. Drugs known to induce the hepatic cytochrome-P450-3A4 system (such as rifampin, carbamazepine) may increase the elimination of progesterone. The effect of concomitant vaginal products on the exposure of progesterone from Endometrin has not been assessed. Endometrin is not recommended for use with other vaginal products (such as antifungal products) as this may alter progesterone release and absorption from the vaginal insert [see Warnings and Precautions(5.3)].

USE IN SPECIFIC POPULATIONS Pregnancy

Endometrin has been used to support embryo implantation and maintain clinical pregnancy in one clinical study. The livebirth outcomes of these pregnancies were as follows:

Among the 404 subjects treated with Endometrin twice daily, 143 subjects had livebirths consisting of 85 singletons, 56 twins, and 2 triplets. In this treatment group, 13 subjects had a spontaneous abortion, 1 subject had an ectopic pregnancy, and 7 subjects reported fetal birth defects (3.4% based on 203 livebirths). Among the 404 subjects treated with Endometrin three times daily, 155 subjects had livebirths consisting of 91 singletons, 60 twins, and 4 triplets. In this treatment group, 22 subjects had a spontaneous abortion, 4 subjects had an ectopic pregnancy, and 7 subjects reported fetal birth defects (3.1% based on 223 livebirths).

Birth defects reported in the Endometrin twice daily group included: one fetus with a cleft palate and intrauterine growth retardation, one fetus with spina bifida, three fetuses with congenital heart defects, one fetus with an umbilical hernia, and one fetus with an intestinal anomaly.

Birth defects reported in the Endometrin three times daily group included: one fetus with an esophageal fistula, one fetus with hypospadias and an underdeveloped right ear, one fetus with Down’s and an atrial septal defect, one fetus with congenital heart anomalies, one fetus with DiGeorge’s syndrome, one fetus with a hand deformity, and one fetus with cleft palate.

For additional information on the pharmacology of Endometrin and pregnancy outcome information [see Clinical Pharmacology (12) and Clinical Studies Sections (14)].

Nursing Mothers

Detectable amounts of progesterone have been identified in the milk of nursing mothers. The effect of this on the nursing infant has not been determined.

Pediatric Use

This drug is not intended for pediatric use and no clinical data have been collected in children. Therefore, the safety and effectiveness of Endometrin in pediatric patients have not been established.

Geriatric Use

No clinical data have been collected in patients over age 65.

Overdosage

Treatment of overdosage consists of discontinuation of Endometrin together with institution of appropriate symptomatic and supportive care.

Endometrin Description

Endometrin (progesterone) Vaginal Insert contains micronized progesterone. Endometrin is supplied with polyethylene vaginal applicators.

The active ingredient, progesterone, is present in 100 mg amount along with other excipients. The chemical name for progesterone is pregn-4-ene-3,20-dione. It has an empirical formula of C21H30O2 and a molecular weight of 314.5. Progesterone exists in two polymorphic forms. The form used in Endometrin, the alpha-form, has a melting point of 127-131°C.

The structural formula is:

C21H30O2

Each Endometrin Vaginal Insert delivers 100 mg of progesterone in a base containing lactose monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidal silicone dioxide.

Endometrin - Clinical Pharmacology Mechanism of Action

Progesterone is a naturally occurring steroid that is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate estrogen, progesterone transforms a proliferative endometrium into a secretory endometrium. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain a pregnancy.

Pharmacokinetics

Absorption

Progesterone serum concentrations increased following the administration of the Endometrin Vaginal Insert in 12 healthy pre-menopausal females. On single dosing, the mean Cmax was 17.0 ng/mL in the Endometrin twice daily group and 19.8 ng/mL in the Endometrin three times daily group. On multiple dosing, steady-state concentrations were attained within approximately 1 day after initiation of treatment with Endometrin. Both Endometrin regimens provided average serum concentrations of progesterone exceeding 10 ng/mL on Day 5. The pharmacokinetic results are summarized in Table 2.

Table 2: Mean (±Standard Deviation) Serum Progesterone Pharmacokinetic Parameters Cmax Maximum progesterone serum concentration.
Tmax Time to maximum progesterone serum concentration.
Cavg Average progesterone serum concentration.
AUC0-24 Area under the drug concentration versus time curve from 0-24 hours post dose.
Cmin Minimum progesterone serum concentration. Pharmacokinetic
Parameter (unit) Endometrin
100 mg twice
daily (N=6) Endometrin
100 mg three times
daily (N=6)   Single Dosing Cmax (ng/mL) 17.0 ± 6.5 19.8 ± 7.2 Tmax (hr) 24.0 ± 0.0 17.3 ± 7.4 AUC0-24
(ng•hr/mL) 217 ± 113 284 ± 143 Day 5 of Multiple Dosing Cmax (ng/mL) 18.5 ± 5.5 24.1 ± 5.6 Tmax (hr) 18.0 ± 9.4 18.0 ± 9.4 Cmin (ng/mL) 8.9 ± 4.5 10.9 ± 6.7 Cavg (ng/ml) 14.0 ± 4.8 15.9 ± 4.3 AUC0-24
(ng•hr/mL) 327 ± 127 436 ± 106

Distribution

Progesterone is approximately 96% to 99% bound to serum proteins, primarily to serum albumin and corticosteroid binding globulin.

Metabolism

Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites that are excreted in the bile may be deconjugated and may be further metabolized in the gut via reduction, dehydroxylation, and epimerization.

Excretion

Progesterone undergoes renal and biliary elimination. Following injection of labeled progesterone, 50-60% of the excretion of metabolites occurs via the kidney; approximately 10% occurs via the bile and feces. Overall recovery of the labeled material accounts for 70% of an administered dose. Only a small portion of unchanged progesterone is excreted in the bile.

Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility

Nonclinical toxicity studies to determine the potential of Endometrin to cause carcinogenicity or mutagenicity have not been performed. The effect of Endometrin on fertility has not been evaluated in animals.

Clinical Studies Luteal Supplementation During Assisted Reproductive Treatment Study

A randomized, open-label, active-controlled study evaluated the efficacy of 10 weeks of treatment with two different daily dosing regimens of Endometrin (100 mg twice daily and 100 mg three times daily) for support of implantation and early pregnancy in infertile women participating in an Assisted Reproductive Technology treatment program. Efficacy was assessed on the endpoint of ongoing pregnancies, defined as the presence of at least one fetal heartbeat seen on ultrasound at 6 weeks post-embryo transfer. The study randomized to Endometrin 808 infertile women (74.9% White; 10.3% Hispanic, 5.4% Black, 5 % Asian, and 4.6% Other) between 19 and 42 years of age (mean age 33) who had a body mass index < 34 kg/m2 at screening.

The ongoing pregnancy rates for subjects treated with both dosing regimens of Endometrin were non-inferior (lower bounds of the 95% confidence interval of the difference between Endometrin and the active comparator excluded a difference greater than 10%) to the ongoing pregnancy rate for subjects treated with the active comparator. The results of this study are shown in Table 3.

Table 3: Ongoing Pregnancy Rates* in Patients Receiving Endometrin for Luteal Supplementation and Early Pregnancy While in an Assisted Reproductive Technology Treatment Program *Ongoing pregnancy defined as the presence of at least one fetal heartbeat seen on ultrasound at 6 weeks post-embryo transfer.   Endometrin
100 mg twice
daily Endometrin
100 mg three
times daily Number of subjects 404 404 Ongoing pregnancy: n (%) 156 (39%) 171 (42%) 95% Confidence Interval of
pregnancy rate [33.8,43.6] [37.5,47.3] Pregnancy rate percentage
difference between
Endometrin and comparator -3.6% 0.1% 95% Confidence Interval for
difference vs. comparator [-10.3, 3.2] [-6.7, 6.9]

Subjects participating in the study were stratified at randomization by age and ovarian reserve (as measured by serum FSH levels). The ongoing pregnancy rates for these subgroups are shown in Table 4.

Table 4: Ongoing Pregnancy Rates in Age- and Ovarian Reserve-Defined Subgroups Receiving Endometrin for Luteal Supplementation and Early Pregnancy While in an Assisted Reproductive Technology Treatment Program   Endometrin
100 mg twice
daily Endometrin
100 mg three
times daily Subjects age < 35 years (N) 247 247 Ongoing pregnancy: n (%) 111 (45%) 117 (47%) Pregnancy rate percentage difference between Endometrin and comparator 0.5% 2.9% 95% Confidence Interval for difference vs. comparator [-8.3, 9.3] [-5.9, 11.7] Subjects 35-42 years of age (N) 157 157 Ongoing pregnancy: n (%) 45 (28%) 54 (34%) Pregnancy rate percentage difference between Endometrin and comparator -10.1% -4.4% 95% Confidence Interval for difference vs. comparator [-20.3, 0.3] [-14.9, 6.3] Subjects with FSH < 10 IU/L (N) 350 347 Ongoing pregnancy: n (%) 140 (40%) 150 (43%) Pregnancy rate percentage difference between Endometrin and comparator -2.0% 1.2% 95% Confidence Interval for difference vs. comparator [-9.3, 5.3] [-6.1, 8.5] Subjects with FSH between 10 and 15 IU/L (N) 46 51 Ongoing pregnancy: n (%) 16 (35 %) 20 (39%) Pregnancy rate percentage difference between Endometrin and comparator -12.2% -7.7% 95% Confidence Interval for difference vs. comparator [-31.0, 7.7] [-26.6, 11.6]

In subjects under the age of 35 or with serum FSH levels less than 10 IU/L, results from both dosing regimens were non-inferior to the results from the comparator with respect to ongoing pregnancy rates. In women age 35 and older and in women with serum FSH levels between 10 and 15 IU/L, the results with respect to ongoing pregnancy rate for both dosing regimens of Endometrin did not reach the criteria for non-inferiority.

Subjects who became pregnant received study medication for a total of 10 weeks. Patients over 34 kg/m2 were not studied. The efficacy of Endometrin in this patient group is unknown.

How Supplied/Storage and Handling

Each Endometrin Vaginal Insert is a white to off-white oblong-shaped insert debossed with “FPI” on one side and “100” on the other side. Each Endometrin® (progesterone) Vaginal Insert, 100 mg, is packed individually in a sealed foil pouch. These pouches are available in cartons packed:

21 vaginal inserts with 21 disposable vaginal applicators (NDC 55566-6500-3)

Store at 25°C (77°F); excursions permitted between 15-30°C (59-86°F).

Patient Counseling Information

See FDA-Approved Patient Labeling (17.4)

Vaginal Bleeding

Inform patients of the importance of reporting irregular vaginal bleeding to their doctor as soon as possible.

Common Adverse Reactions with Progesterone

Inform patients of the possible side effects of progesterone therapy such as headaches, breast tenderness, bloating, mood swings, irritability, and drowsiness.

Coadministration of Vaginal Products

Inform patients that Endometrin is not recommended for use with other vaginal products.

FDA-Approved Patient Labeling

IMPORTANT:For Vaginal Use Only.

Read the patient information that comes with Endometrin before you start to use it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment. Your doctor may do a physical exam before prescribing Endometrin.

What is Endometrin?

Endometrin is a vaginal insert that contains the hormone progesterone. Endometrin is for women who need extra progesterone while undergoing treatment in an Assisted Reproductive Technology (ART) program.

Progesterone is one of the hormones essential for helping you to become and to stay pregnant. If you are undergoing ART treatment, your doctor may prescribe Endometrin to provide the progesterone your body needs.

Who should not use Endometrin?

Do not use Endometrin if you:

Are allergic to anything in Endometrin. See the end of this leaflet for a complete list of ingredients. Have unusual vaginal bleeding that has not been evaluated by a doctor. Currently have or have had liver problems. Have or have had blood clots in the legs, lungs, eyes, or elsewhere in your body.

Endometrin may not be right for you. Before starting Endometrin, tell your doctor about all your health problems.

Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vaginal products, vitamins, herbal supplements. Some medicines may affect Endometrin.

Know what medicines you take. Keep a list of your medicines to show to the doctor and pharmacist.

How should I use Endometrin? Use Endometrin exactly as prescribed. The usual dose of Endometrin is one insert placed in your vagina 2 to 3 times a day for up to a total of 10 weeks, unless your healthcare provider advises otherwise. Place an Endometrin insert in your vagina with the disposable applicator provided.

Follow the steps below:

Unwrap the applicator. Put one insert in the space provided at the end of the applicator. The insert should fit snugly and not fall out. Place applicator with the insert into the vagina while you are standing, sitting, or when lying on your back with your knees bent. Gently place the thin end of the applicator well into the vagina. Push the plunger to release the insert. Remove the applicator and throw it away in the trash.

Other information for using Endometrin

If you forget a dose of Endometrin, take the dose as soon as you remember, but do not use more than your daily dose. Call your doctor if you use too much Endometrin. Do not use any other vaginal products when you are using Endometrin. What are the possible side effects of Endometrin?

Common side effects seen with ART and Endometrin included pelvic pain after surgery, abdominal pain, nausea, and swollen ovaries (ovarian hyperstimulation syndrome).

Other reported side effects included abdominal bloating, headache, urinary infections, uterine cramping, constipation, vomiting, tiredness, and vaginal bleeding.

Vaginal products with progesterone may also cause vaginal irritation, burning, and discharge.

Serious Risks of Progesterone

Progesterone can increase your chance of getting blood clots. Blood clots can be serious and lead to death.

Serious blood clots include those in the:

legs (thrombophlebitis) lungs (pulmonary embolus) eyes (blindness) heart (heart attack) brain (stroke)

Call your doctor or get medical help right away if you have:

persistent pain in the lower leg (calf) sudden shortness of breath coughing up blood sudden blindness, partial or complete severe chest pain sudden, severe headache, vomiting, dizziness, or fainting weakness in an arm or leg, or trouble speaking yellowing of the skin and/or white of the eyes indicating possible liver problem

Other risks of progesterone use include:

headache breast tenderness bloating or fluid retention mood swings and depression irritability drowsiness

Call your doctor immediately if you have abnormal vaginal bleeding

These are not all the side effects with Endometrin. Ask your doctor or pharmacist for more information.

How should I store Endometrin? Store Endometrin at room temperature, 25°C (77°F); excursions permitted between 15 to 30°C (59 to 86°F). Do not use Endometrin after the expiration date that is printed on the carton. Keep Endometrin and all medicines out of the reach of children. General information about Endometrin

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use Endometrin for a condition for which it was not prescribed. Do not give Endometrin to other women, even if they have the same condition as you do. It may harm them.

This leaflet summarizes the most important information about Endometrin. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Endometrin that was written for healthcare professionals. For more information call Ferring Pharmaceuticals at 1-800-822-8214.

What are the ingredients in Endometrin?

Active Ingredient: progesterone

Inactive Ingredients: lactose monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidal silicone dioxide

Manufactured by:
Pharmaceutics International Inc., Hunt Valley, MD 21031

Manufactured for:
Ferring Pharmaceuticals Inc., Parsippany, NJ 07054

6323-02

PACKAGE LABEL - FOIL PACK LABEL

Endometrin®

(progesterone) Vaginal Insert 100 mg

Manufactured for:

Ferring Pharmaceuticals Inc.

Parsippany, NJ 07054

By: Pharmaceutics International Inc.

Hunt Valley, MD 21031

Store at 20°-25°C (68°-77°F);

exercurstions permitted between

15°-30°C (59°-86°F).

FOR VAGINAL USE ONLY

NDC 55566-6500-1

Rx only 6320-04

LOT XXXX.XXX

EXP XX/XX

PACKAGE LABEL - INNER CARTON

NDC 55566-6500-2

Endometrin®

(progesterone) Vaginal Insert 100 mg

Contents: 21 foil blisters, each containing

1 individually sealed 100 mg vaginal insert.

Endometrin®

(progresterone) Vaginal Insert 100 mg

Manufactured for: Ferring Pharmaceuticals Inc. Parsippany, NJ 07054

By: Pharmaceutics International Inc. Hunt Valley MD 21031

Patent Pending

6321-04

PACKAGE LABEL - OUTER CARTON

NDC 55566-6500-3

Endometrin®

(progesterone) Vaginal Insert 100 mg

Contents:

21 vaginal inserts with 21 disposable vaginal applicators

Each insert contains 100 mg progesterone, USP

FOR VAGINAL USE ONLY

Rx only

Endometrin®

6322-04


Endometrin 
progesterone  insert Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 55566-6500 Route of Administration VAGINAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength progesterone (progesterone) progesterone 100 mg Inactive Ingredients Ingredient Name Strength lactose monohydrate   povidone K29/32   adipic acid   sodium bicarbonate   sodium lauryl sulfate   magnesium stearate   starch, pregelatinized corn   colloidal silicon dioxide   Product Characteristics Color WHITE Score      Shape OVAL Size Flavor Imprint Code 100 Contains          Packaging # NDC Package Description Multilevel Packaging 1 55566-6500-3 1 CARTON In 1 CARTON contains a CARTON (55566-6500-2) 1 55566-6500-2 21 BLISTER PACK In 1 CARTON This package is contained within the CARTON (55566-6500-3) and contains a BLISTER PACK (55566-6500-1) 1 55566-6500-1 1 INSERT In 1 BLISTER PACK This package is contained within a CARTON (55566-6500-2) and a CARTON (55566-6500-3)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022057 06/21/2007
Labeler - Ferring Pharmaceuticals Inc. (103722955) Establishment Name Address ID/FEI Operations Pharmaceutics International Inc. 878265586 manufacture Revised: 02/2008Ferring Pharmaceuticals Inc.
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Metvixia


methyl aminolevulinate
Dosage Form: cream
FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE

Metvixia Cream in combination with Aktilite CL128 lamp red light illumination is indicated for treatment of thin and moderately thick, non-hyperkeratotic, non-pigmented actinic keratoses of the face and scalp in immunocompetent patients. This photodynamic therapy should be used in conjunction with appropriate lesion preparation in the physician’s office when other therapies are considered medically less appropriate  [See Dosage and Administration (2)]

The safety and efficacy have not been established for the treatment of cutaneous malignancies or for skin lesions other than non-hyperkeratotic face and scalp actinic keratoses using PDT with Metvixia Cream. The safety and efficacy of Metvixia Cream have not been established in patients with immunosuppression, porphyria or pigmented actinic keratoses.

DOSAGE AND ADMINISTRATION

Photodynamic therapy (PDT) for non-hyperkeratotic actinic keratoses with Metvixia Cream is a multi-stage process as described below: Two treatment sessions one week apart should be administered. Not more than one gram (half tube) of Metvixia Cream should be applied per treatment session. Multiple lesions may be treated during the same treatment session using a total of one gram of Metvixia Cream. Lesion response should be assessed 3 months after the last treatment session. Nitrile gloves should be worn when applying and removing the cream.

The Aktilite CL128 lamp, which is equipped with light emitting diodes (LEDs), emits red light with a narrow spectrum at approximately 630 nm, and a half-width of approximately 20 nm. The light dose to be used is 37 J/cm2, and the lamp should be placed 50 to 80 mm from the skin. The area of skin that can be illuminated is 80 x 180 mm. Calibration by the operator is not needed, and the illumination time is calculated automatically. The LED panel window should be cleaned daily with a slightly moist clean cloth.

If Aktilite red light treatment is interrupted or stopped for any reason, it may be restarted. If the patient for any reason cannot have the red light treatment during the prescribed period after application (the 3 hour timespan), the cream should be rinsed off and the patient should protect the exposed area from sunlight, prolonged or intense light for at least 48 hours.

Use of Metvixia Cream without subsequent red light illumination is not recommended.

This product is to be used only by physicians in the physician’s office. Metvixia Cream is not for ophthalmic, oral or intravaginal use. Physicians should be knowledgeable about photodynamic therapy and familiar with the Aktilite Operators Manual prior to use of Metvixia Cream.

One Metvixia-PDT session consists of:

Lesion preparation [See Dosage and Administration (2.1)]

Application of Metvixia Cream [See Dosage and Administration (2.2)]

Application of occlusive dressing [See Dosage and Administration (2.3)]

Occlusion for 3 hours [See Dosage and Administration (2.4)]

Removal of excess cream with saline [See Dosage and Administration (2.5)]

Positioning Aktilite CL128 lamp [See Dosage and Administration (2.6)]

Illumination with red light (Aktilite CL128 lamp) [See Dosage and Administration (2.7)]

Lesion preparation Before applying Metvixia Cream, the surface of the lesions should be prepared with a small dermal curette to remove scales and crusts and roughen the surface of the lesion. This is to facilitate access of the cream and light to all parts of the lesion. Figure 1A Lesion debriding   Only nitrile gloves should be worn during this and subsequent steps and Universal Precautions should be taken. Vinyl and latex gloves do not provide adequate protection when using this product. Figure 1B Lesion debriding   Application of Metvixia Cream

Using a spatula, apply a layer of Metvixia Cream about 1 mm thick to the lesion and the surrounding 5 mm of normal skin. Do not apply more than one gram (half tube) of Metvixia Cream per treatment session.

Figure 2: Cream application   Occlusive Dressing

Cover - The area where the cream has been applied should then be covered with an occlusive, non-absorbent dressing for 3 hours. Multiple lesions may be treated during the same treatment session. Each treatment field is limited to an area of 80 x 180 mm.

Figure 3: Occlusive dressing application   Occlusion for 3 hours

(at least 2.5 hours, but no more than 4 hours). After Cream application, patients should avoid exposure of the photosensitive treatment sites to sunlight or bright indoor light (e.g., examination lamps, operating room lamps, tanning beds, or lights at close proximity) during the period prior to Aktilite red light treatment. Exposure to light may result in a stinging and/or burning sensation and may cause erythema and/or edema of the lesions. Patients should protect treated areas from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque material. Sunscreens will not protect against photosensitivity reactions caused by visible light. It has not been determined if perspiration can spread the Metvixia Cream outside the treatment site to the eyes or surrounding skin. The treated site should be protected from extreme cold with adequate clothing or remaining indoors between application of Metvixia Cream and Aktilite PDT light treatment.

Removal of Excess Cream with Saline

Following removal of the occlusive dressing, clean the area with saline and gauze. Wear nitrile gloves.

Figure 4: Cream removal   Positioning Aktilite CL128 Lamp

See Aktilite CL128 Operators Manual for specific warnings, cautions and instructions. If necessary adjust the dose to 37 J/cm2 . Calibration by the operator is not required. Position the lamp over the area to be illuminated by the use of guide light. The distance between the LED panel and the lesion surface should be 50 to 80 mm (2 to 3.2 in). Do not stare into the beam. The patient and operator should wear appropriate eye protection during illumination. Patient protective goggles or eye shields are dark or of metal to block visible light.

Figure 5: Positioning Aktilite CL128  

2.7 Illumination with Aktilite CL128 Lamp Red Light

The required illumination time (7-10 minutes) is calculated automatically, and remaining time will be displayed at the control panel. The illumination stops automatically. The illumination may be paused and started again. Patients should be advised that transient pain, burning or stinging at the target lesion sites may occur during the period of light exposure.

Figure 6: Illumination   DOSAGE FORMS AND STRENGTHS

16.8% cream in 2 g tubes

CONTRAINDICATIONS

Metvixia Cream is contraindicated in patients with cutaneous photosensitivity, or known allergies to porphyrins, and in patients with known sensitivities to any of the components of Metvixia Cream, which includes peanut and almond oil [See WARNINGS and PRECAUTIONS (5)]

WARNINGS AND PRECAUTIONS General

Metvixia Cream is intended for topical use in the physician’s office by physicians. Metvixia Cream has not been studied for more than one course which consists of two treatment sessions one week apart. There is no information available regarding the recurrence rate for lesions treated with this therapy. Clinical studies did not follow patients beyond 3 months, and the recurrence rate of treated lesions is unknown.

Photosensitivity

During the time period between the application of Metvixia Cream and exposure to Aktilite red light illumination, the treatment site will become photosensitive.

If for any reason the patient cannot have the Aktilite red light treatment after application of Metvixia Cream, the cream should be rinsed off, and the patient should protect the treated area from sunlight, prolonged or intense light for two days. Prolonged exposure for greater than 4 hours to Metvixia Cream should be avoided.

After Metvixia Cream application, patients should avoid exposure of the photosensitive treatment sites to sunlight or bright indoor light (e.g., examination lamps, operating room lamps, tanning beds, or lights at close proximity) during the period prior to red light treatment. Exposure to light may result in a stinging and/or burning sensation and may cause erythema and/or edema of the lesions. Before exposure to sunlight, patients should, therefore, protect treated lesions from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque material. Sunscreens will not protect against photosensitivity reactions caused by visible light. The treated site should be protected from extreme cold with adequate clothing or remaining indoors between application of Metvixia Cream and Aktilite red light treatment.

After illumination of Metvixia Cream, the area treated should be kept covered and away from light for at least 48 hours.

Because of the potential for skin to become photosensitized, the Metvixia Cream should be used by a trained physician to apply drug only to non-hyperkeratotic actinic keratoses and perilesional skin within 5 mm of the lesion. Redness, swelling, burning, and stinging are expected as a result of therapy; however, if these symptoms increase in severity and persist longer than 3 weeks, the patient should contact their doctor.

Hypersensitivity

Metvixia Cream has demonstrated a high rate of contact sensitization (allergenicity) [See ADVERSE REACTIONS (6.1)]. Care should be taken by the physician applying Metvixia Cream to avoid inadvertent skin contact. Nitrile gloves should be worn when applying and removing the cream. Vinyl and latex gloves do not provide adequate protection when using this product.

Metvixia Cream is formulated with peanut oil and refined almond oil.

Metvixia Cream has not been tested in patients who are allergic to peanuts.

Coagulation defects

Metvixia Cream has not been tested on patients with inherited or acquired coagulation defects.

Aktilite Lamp

Before operating the Aktilite CL128 lamp, personnel should refer to the Operators Manual for specific warnings, cautions and instructions. Care should be exercised when positioning and operating the lamp. During the red light illumination period, the patient, operator and other persons present should wear protective goggles that sufficiently screen out the appropriate spectrum of red light. The protective goggles or eye shields provided for the patient are dark or of metal to block visible light. The green professional protective glasses provided for the operator screen out the relevant spectrum of red light and the room will still appear bright for the operator to see. Do not stare into the beam. For lamp assembly, maintenance, service and technical data the personnel should refer to the Operators Manual.

ADVERSE REACTIONS Dermal Safety Studies

Studies in healthy volunteer subjects and subjects with actinic keratoses previously treated with Metvixia-PDT on at least 4 previous occasions have demonstrated that Metvixia Cream has the potential to cause irritancy and sensitization. A cumulative irritancy and sensitization (allergenicity) study of Metvixia Cream with a cross-sensitization challenge with aminolevulinic acid (ALA) was performed in 156 subjects. Metvixia Cream was applied 3 times each week for 3 weeks (total of 9 applications), to separate sites on the back of healthy volunteers. After each application, the area was covered by aluminum Finn Chamber. After the 3-week continuous treatment period and a 2-week interval without further applications, subjects were challenged with Metvixia Cream, Metvixia vehicle, ALA, and ALA-vehicle creams for 48 hours. Assessment of skin reactions was performed 48, 72, and 96 h after start of the challenge cream application. Only 98 of the 156 subjects tested entered the challenge phase because of a high incidence of local irritancy evident as erythema. Of the 58 subjects who were challenged with Metvixia Cream, 30 (52 %) showed contact sensitization. Of the 98 subjects who were challenged with ALA, only 2 (2 %) showed equivocal reactions the remaining subjects having negative responses.

The potential for sensitization was also assessed by patch testing a total of 21 patients with actinic keratoses previously treated with Metvixia-PDT on at least 4 previous occasions. Metvixia Cream 16.8 % and vehicle cream were applied to different sites on the lower back for 48 hours. Three of the 21 patients (14%) showed contact sensitization associated with erythema scores ?4 (strong erythema spreading outside the patch) and edema, vesiculation, papules and glazing.

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 231 subjects, each with 4 - 10 actinic keratoses were enrolled in 2 double-blind, randomized, vehicle-controlled clinical trials. Subjects were randomized to receive Aktilite PDT with Metvixia Cream 16.8 % or Vehicle cream on 2 occasions 1 week apart. Cream was applied for approximately 3 hours under occlusion followed immediately by illumination using the Aktilite CL128 lamp, delivering red light at a dose of 37 J/cm2.

Table 1 shows the incidence and severity of local (treatment site) adverse reactions in these two trials. The most frequent adverse reactions were associated with phototoxicity at the treatment site. Pain and burning sensation typically begin during illumination and generally resolve completely within a few minutes or hours, but may last up to a few days. Erythema and other signs generally resolve within a few days to 3 weeks.

In these two studies, out of 126 subjects treated with Metvixia Cream, six Metvixia Aktilite PDT subjects did not complete the full two treatment session regimen due to adverse reactions such as headache, pain or burning. These subjects either stopped illumination early or did not have the second treatment. In addition, 12 Metvixia PDT subjects paused illumination due to pain, burning or stinging but did subsequently complete treatment.

Table 1: Incidence of Treatment Site Adverse Reactions in ? 1% of Subjects in Studies 1 and 2 (Safety Population) Metvixia & Aktilite
PDT
n=126 Vehicle & Aktilite
PDT
n=105 * Mild, Moderate, or Severe Any Treatment Site
Adverse Reaction All Grades* Severe All Grades* Severe 113 (90%) 28 (22%) 48 (46%) 0 (0%)   Skin burning/pain/discomfort 109 (86%) 25 (20%) 38 (36%) 0 (0%) Erythema   80 (63%)   7 (6%) 11 (10%) 0 (0%) Scabbing/crusting/blister/erosions   36 (29%)   2 (2%)   1 (1%) 0 (0%) Pruritus   28 (22%)   0 (0%)   8 (8%) 0 (0%) Skin or eyelid edema   23 (18%)   2 (2%)   1 (1%) 0 (0%) Skin exfoliation   17 (14%)   4 (3%)   3 (3%) 0 (0%) Skin warm     5 (4%)   0 (0%)   2 (2%) 0 (0%) Application site discharge     3 (2%)   0 (0%)   0 (0%) 0 (0%) Skin hemorrhage     2 (2%)   0 (0%)   0 (0%) 0 (0%) Skin tightness     2 (2%)   0 (0%)   0 (0%) 0 (0%) Skin hyperpigmentation     2 (2%)   0 (0%)   0 (0%) 0 (0%) Postmarking Experience

The following adverse reactions have been identified during post approval use of Metvixia Cream outside of the United States. Because these reactions are reported voluntary from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Reports of serious adverse reactions at or near the application site include pain, erythema, edema, pustules, scab, crusting, and hyperpigmentation. Allergic reactions reported include eczema, allergic contact dermatitis and urticaria. Most cases were localized to the treatment area; rarely erythema and swelling have been more extensive. At sites distant from the application site there have been reports of squamous cell carcinoma of the skin, as expected in this population. There have been occasional reports of eye disorders including edema, eyelid swelling, macular edema, vitreous detachment and keratitis.

Drug Interactions

There have been no studies of the interaction of Metvixia Cream with other drugs, including local anesthetics. It is possible that concomitant use of other known photosensitizing agents might increase the photosensitivity reaction of actinic keratoses treated with Metvixia Cream.

USE IN SPECIFIC POPULATIONS   Pregnancy

Teratogenic effects: Pregnancy Category C:

There are no adequate and well-controlled studies with Metvixia Cream in pregnant women. Intravenous methyl aminolevulinate hydrochloride (HCI) was teratogenic in rabbits at a high dose. Metvixia Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

A Maximum Topical Human Dose (MTHD) of 2 g of Metvixia Cream 16.8% containing 420 mg methyl aminolevulinate hydrochloride corresponding to 7 mg/kg or 259 mg/m2 for a 60 kg patient and an estimated maximum systemic uptake of 1% was used for the animal multiple of human systemic exposure calculations presented in this labeling.

In development toxicity studies, pregnant rabbits received intravenous doses of methyl aminolevulinate hydrochloride up to 926 times the MTHD on Days 6 to 18 of gestation. Slightly lower fetal body weights and increased incidences of fetuses with jugals connected/fused to maxilla, supernumerary ribs, incompletely ossified cranial bones and other ossification irregularities were noted in the high dose (926 times the MTHD) group, compared to the control group. The embryo-fetal effects in the high dose group were associated with maternal toxicity. These effects did not occur at 463 times the MTHD based on mg/m2 comparisons and an estimated maximum systemic uptake of 1%. Developmental toxicity studies in rats were negative at daily exposure levels up to 1622 times the MTHD on a mg/m2 basis.

In the prenatal and postnatal development toxicity study, pregnant rats received intravenous doses of methyl aminolevulinate hydrochloride up to 1160 x the MTHD from Day 6 of gestation to Day 24 of lactation. There were no treatment-related effects on litter size, pup mortality, pup weights, or post weaning performance in the pups (including development and reproduction). A slightly longer duration of gestation and a slight delay in pup physical development were noted in the 580-1160 x the MTHD groups. [See Section 13.3]

  Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Metvixia Cream is administered to a nursing woman.

  Pediatric Use

Actinic keratosis is not a condition generally seen within the pediatric population. The safety and effectiveness in pediatric patients below the age of 18 have not been established.

  Geriatric Use

Of the 211 subjects in the clinical studies with Metvixia-PDT, 136 subjects were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

OVERDOSAGE   Metvixia Cream Overdose

Metvixia Cream overdose has not been reported. If the patient for any reason cannot have the red light treatment during the prescribed period after application (the 3 hour timespan), the cream should be rinsed off with saline and water, and the patient should protect the exposed area from sunlight, prolonged or intense light for two days.

  Aktilite Red Light Overdose

Red light overdose (excess illumination time) using Aktilite CL128 following Metvixia Cream application has not been reported. If red light overexposure were to result in a burn, the patient should be treated in accordance with standard practice for treatment of cutaneous burns.

DESCRIPTION

Metvixia Cream is an oil in water emulsion. Metvixia Cream contains methyl aminolevulinate hydrochloride equivalent to 168 mg/g of methyl aminolevulinate.

Methyl aminolevulinate hydrochloride is a white to slightly yellow powder that is freely soluble in water and methanol, soluble in ethanol and practically insoluble in most organic solvents.

The chemical formula for methyl aminolevulinate HCl is C6H11NO3•HCl (MW=181.62) and it has the following structural formula:

Metvixia Cream, for topical use only, is cream to pale yellow in color, contains glyceryl monostearate, cetostearyl alcohol, polyoxyl stearate, cholesterol and oleyl alcohol as emulsifying agents. It also contains glycerin, white petrolatum, isopropyl myristate, peanut oil, refined almond oil as emollients, edetate disodium as a chelating agent and methylparaben and propylparaben as preservatives.

CLINICAL PHARMACOLOGY   Mechanism of Action

Photosensitization following application of Metvixia Cream occurs through the metabolic conversion of methyl aminolevulinate (prodrug) to photoactive porphyrins (PAPs), which accumulate in the skin lesions to which Metvixia Cream has been applied. When exposed to light of appropriate wavelength and energy, the accumulated photoactive porphyrins produce a photodynamic reaction, resulting in a cytotoxic process dependent upon the simultaneous presence of oxygen. The absorption of light results in an excited state of porphyrin molecules, and subsequent spin transfer from photoactive porphyrins to molecular oxygen generates singlet oxygen. Metvixia photodynamic therapy (PDT) of actinic (solar) keratosis lesions is the combination of photosensitization by topical application of Metvixia Cream to the lesions and subsequent illumination with red light of narrow spectrum using a light dose of 37 J/cm2 delivered by the Aktilite CL128 lamp.

  Pharmacokinetics

The time-course of Protoporphyrin IX in actinic keratosis lesions and surrounding skin after application of Metvixia Cream has been monitored by means of fluorescence. The optimum concentration of methyl aminolevulinate cream (16.8%) and duration of application (3 h) were derived from such studies of pharmacokinetics in skin using a range of concentrations (1.6%, 8% and 16.8%) and cream application times (up to 28 h). Three hours after the application of Metvixia Cream fluorescence in the treated lesions was significantly greater than that seen in both treated and untreated normal skin, and after application of vehicle cream (not containing methyl aminolevulinate) to normal skin. In a fluorescence study of 8 patients with actinic keratoses using Metvixia Cream 16.8% applied for 3 h and illumination with the Aktilite CL128 lamp, 88% photodegradation of Protoporphyrin IX was observed immediately after illumination, followed by a transient small secondary increase in fluorescence 2 hours after illumination. At 24 and 48 hours, 94% and 96% degradation of Protoporphyrin IX, respectively from baseline, was observed.

NONCLINICAL TOXICOLOGY   Carcinogenesis, Mutagenesis and Impairment of Fertility

Long-term studies to evaluate the carcinogenic potential of Metvixia Cream have not been performed. Methyl aminolevulinate was negative for genetic toxicity in the Ames assay, and the chromosomal aberration assay in Chinese hamster ovary cells, tested with and without metabolic activation and in the presence and absence of light. Methyl aminolevulinate was also negative in the in vivo micronucleus assay in the rat. In contrast, at least one report in the literature has noted genotoxic effects in cultured rat hepatocytes after aminolevulinate (ALA) exposure with PpIX formation. Other studies have documented oxidative DNA damage in vivo and in vitro as a result of ALA exposure.

A fertility study was performed in male and female rats with intravenous doses of methyl aminolevulinate hydrochloride up to 500 mg/kg/day (3000 mg/m2, 1158 times the MTHD based on mg/m2 comparisons and an estimated maximum systemic uptake of 1%). Males were treated for 4 weeks prior to mating and for 5 additional weeks after mating. The females were treated for 2 weeks prior to mating and then until Day 6 of gestation. There were no treatment-related effects on fertility and mating performance seen in this study.

  Reproductive Toxicology

Development toxicity studies have been performed in pregnant rats with intravenous doses of methyl aminolevulinate hydrochloride up to 700 mg/kg/day on Days 6 to 16 of gestation. There were no treatment-related effects on fetal body weight, sex ratio, external malformations and variations, and skeletal abnormalities and ossification extent. Only a slight non-significant increase in early embryonic death was noted in the 700 mg/kg/day group, compared to the control group. The fetal NOAEL (No Adverse Effect Level) was 350 mg/kg/day methyl aminolevulinate hydrochloride in pregnant rats (2100 mg/m2, 811 times the MTHD based on mg/m2 comparisons and an estimated maximum systemic uptake of 1%).

Development toxicity studies have also been performed in pregnant rabbits with intravenous doses of methyl aminolevulinate hydrochloride up to 200 mg/kg/day on Days 6 to 18 of gestation. Slightly lower fetal body weights and increased incidences of fetuses with jugals connected/fused to maxilla, supernumerary ribs, incompletely ossified cranial bones and other ossification irregularities were noted in the high dose (200 mg/kg/day) group, compared to the control group. The fetal NOAEL was 100 mg/kg/day methyl aminolevulinate hydrochloride in pregnant rabbits (1200 mg/m2, 463 times the MTHD based on mg/m2 comparisons and an estimated maximum systemic uptake of 1%).

In the prenatal and postnatal development toxicity study in rats treated with intravenous doses of methyl aminolevulinate hydrochloride up to 500 mg/kg/day from Day 6 of gestation to Day 24 of lactation, there were no treatment-related effects on litter size, pup mortality, pup weights, and post weaning performance of the F1 animals including development and reproductive capacity. Only a slightly longer duration of gestation and a slight delay in pup physical development were noted in the 250 and 500 mg/kg/day groups. The NOAEL was 125 mg/kg/day methyl aminolevulinate hydrochloride (750 mg/m2, 290 times the MTHD based on mg/m2 comparisons and an estimated maximum systemic uptake of 1%).

CLINICAL STUDIES

Metvixia Cream 16.8% for photodynamic therapy (PDT) by illumination using the Aktilite CL128 lamp was studied in 211 randomized subjects with a total of 1555 non-hyperkeratotic actinic keratoses in two multicenter, randomized, double-blind vehicle-controlled clinical trials. One study was conducted in the USA and the other in the USA and Germany.

Each subject had 4 to 10 previously untreated, nonpigmented, grade 1 (thin) or 2 (moderate) actinic keratoses on the face and or scalp. Grade 3 (very thick and obvious) actinic keratoses were not treated in the studies. Two sessions of PDT were administered at an interval of one week with patients randomized 1:1 to receive Metvixia-PDT or Vehicle-PDT on both occasions. Each session comprised lesion preparation (debridement with sharp curette) to roughen the surface, application of cream with subsequent maintenance for 3 hours under occlusion using an adhesive, non-absorbent dressing, removal of residual cream followed immediately by light activation. Red light illumination (630 nm) was provided by the Aktilite CL128 lamp and the light dose was 37 J/cm2.

The subject complete response rate was assessed 3 months after the last treatment. Lesion clinical complete response was defined as complete disappearance of a lesion upon visual inspection and palpation. If all treated lesions within a subject were in clinical complete response 3 months after treatment, the subject was assessed as a complete responder. The subject complete response rates are shown in Table 2 for each of the two studies.

Table 2:  Subject Complete Response after Lesion Debridement followed by Aktilite PDT with Metvixia Cream vs. Vehicle – Studies 1 and 2   Study 1 Study 2 Metvixia
n=49 Vehicle
n=47 Metvixia
n=57 Vehicle
n=58 Subjects with Complete
Response 29
59.2% 7
14.9% 39
68.4% 4
6.9%

The overall lesion complete response rates and the response rates by lesion grade and location are shown in Table 3 for the two studies.

Table 3:  Lesion Complete Response Rate by Grade and Location Studies 1 and 2 conducted with Aktilite photodynamic therapy   Study 1 Study 2   Metvixia
n=363 Vehicle
n=360 Metvixia
n=418 Vehicle
n=414 Lesions with Complete Response 313 (86%) 188 (52%) 348 (83%) 119 (29%)  
Grade 1   259 267 182 161 Face      Total 191 201 99 88      CR 167 (87%) 121 (60%) 90 (91%) 33 (38%)   Scalp      Total 68 66 76 73      CR 63 (93%) 29 (44%) 66 (87%) 31 (42%)    
Grade 2   104 93 236 253 Face      Total 76 68 119 157      CR 65 (86%) 29 (43%) 103 (87%) 35 (22%)   Scalp      Total 28 25 115 96      CR 18 (64%) 9 (36%) 89 (77%) 20 (21%)  

There was no difference between response rates to Metvixia Aktilite PDT for Grade 1 lesions on the face and scalp (CR rates of 89% and 90% respectively). For Grade 2 lesions, the corresponding CR rates to Metvixia Aktilite PDT were 86% and 75% respectively. Metvixia Cream has not been studied for more than one course which consists of two treatment sessions one week apart. There is no information regarding the recurrence rate for lesions treated with this therapy. Clinical studies did not follow patients beyond 3 months, and the recurrence rate of treated lesions is unknown.

HOW SUPPLIED/STORAGE AND HANDLING

Metvixia Cream, 16.8%, is available as the following:

2 gram aluminum tube, box of 1 (NDC 0299-6300-02)

Keep out of reach of children

For topical use only by physicians in the physician’s office. Dispense only to physicians and only to be applied by a physician.

Physicians should wear nitrile gloves when applying and removing Metvixia Cream. Vinyl and latex gloves do not provide adequate protection when using this product.

Store/Transport refrigerated, 2? - 8?C (36? - 46?F).

Use contents within one week after opening.

Should not be used after 24 hours out of refrigerator.

P24202-0 Revised: June 2008

Patient Counseling Information

The physician should provide and discuss the attached Patient Package Insert with each patient.

PATIENT INFORMATION

Metvixia (met vik see a)
(methyl aminolevulinate hydrochloride) Cream, 16.8%

Read this Patient Information before you are treated with Metvixia Cream and each time you are treated. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or treatment. Ask your doctor provider about anything you do not understand about Metvixia Cream.

Important note: Metvixia Cream is for use on the skin only. Tell your doctor right away if Metvixia Cream gets in your eyes or mouth.          

What is the most important thing I need to know about Metvixia Cream?

Metvixia Cream with light treatment (Photodynamic therapy or PDT) is only done in medical offices by trained doctors.

Metvixia Cream is not applied by patients and should not be applied by doctors who have not been trained in its use.

Metvixia Cream is for use in PDT with the Aktilite CL128 lamp.

What is Metvixia Cream?

Metvixia Cream is a prescription cream used with PDT to treat skin growths on the face and scalp called actinic keratoses (AK). Metvixia Cream is only used for AK skin growths that are thin and not dark colored. AK skin growths are caused partly by too much sun exposure. Metvixia Cream and PDT work together to treat AK skin growths.

Metvixia Cream has not been studied in children for any condition and should not be used in children.

Who should not use Metvixia Cream?

Do not use Metvixia Cream if:

your skin over reacts to sun or light (photosensitivity). Talk with your doctor to be sure.

you are allergic to porphyrins or to any of the ingredients in Metvixia Cream including peanut and almond oil. See the end of this leaflet for a complete list of ingredients in Metvixia Cream.

What should I tell my doctor before treatment with Metvixia Cream?

Tell your doctor about all your medical conditions, including if you

have or had skin cancer or other skin growths on your body

have bleeding problems

are pregnant or planning to become pregnant. It is not known if Metvixia Cream can harm your unborn baby.

are breastfeeding. It is not known if Metvixia Cream passes into your milk and if it can harm your baby. You should decide whether or not to stop breastfeeding while getting treatment with Metvixia Cream. Talk to your doctor for help with this choice.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. It is not known if Metvixia Cream and other medicines can affect each other.

Know your medicines. Keep a list of your medicines and show it to your doctor and pharmacist when you start a new medicine.

How should I use Metvixia Cream?

Metvixia Cream and PDT treatment is only done by trained doctors.

You will receive 2 treatments with Metvixia Cream and PDT 1 week apart. Your doctor will check you three months after treatment to see if the treatment worked for you. (See the end of this leaflet for the section “Treatment with Metvixia Cream and PDT.”)

Metvixia Cream is for skin use only. Do not get Metvixia Cream in your eyes or mouth. Tell your doctor right away if this happens.

What should I avoid while using Metvixia Cream?

During the 3 hours that Metvixia Cream is on your skin:

Avoid sunlight or bright indoor light (for example: examination lights, operating room lights, tanning beds, or lights that are close to you.) During this time, the treated areas of your skin are more sensitive to light. You may feel burning or stinging. Your treated skin may become red or your lesions may become swollen. Wear a protective hat and clothing if you need to be outside in the sun.

Avoid cold temperatures. Wear warm clothing and keep your treated skin areas covered if you are in cold temperatures, or stay indoors.

After treatment with Metvixia Cream and PDT, avoid sunlight or bright indoor light (for example: examination lights, operating room lights, tanning beds or lights that are close to you) for two days. During this time, the treated areas of your skin are more sensitive to light. Keep the treated areas
of your skin covered. Wear a protective hat and clothing if you need to be outside in the sun.

If for any reason you are not treated with the lamp after Metvixia Cream has been applied to your skin:

Carefully rinse off the Cream.

Avoid sunlight, indoor light that is bright (for example: examination lights, operating room lights, tanning beds or lights that are close to you) for two days after treatment. During this time, the treated areas of your skin are more sensitive to light. Wear a protective hat and clothing if you need to be outside in the sun.

What are the possible side effects of Metvixia Cream with PDT treatment?

Common side effects of Metvixia Cream with PDT treatment include the following skin reactions at the treated site:

redness

pain

burning feeling

stinging

swelling

crusting, peeling, blisters, bleeding, itching ulcers

Burning pain and stinging usually decline over a few hours. If skin redness, swelling and other signs of inflammation get worse and last longer than 3 weeks, call your doctor.

Tell your doctor about any side effects that bother you or do not go away. Your doctor should be able to treat them if needed.

These are not all the side effects of Metvixia Cream with PDT. Ask your doctor or pharmacist for more information.

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

General information about Metvixia Cream

This leaflet summarizes the most important information about Metvixia Cream. If you would like more information, talk with your doctor. You can ask your doctor for information about Metvixia Cream that is written for health professionals.

What are the ingredients in Metvixia Cream?

Active Ingredient: methyl aminolevulinate hydrochloride.

Inactive Ingredients: Glyceryl monostearate, cetostearyl alcohol, poloxyl stearate, cholesterol, oleyl alcohol glycerin, white petrolatum, isopropyl myristate, peanut oil, refined almond oil, edetate disodium, methylparaben and propylparaben.

Treatment with Metvixia Cream and PDT

Figure 1: Lesion debriding
Your doctor will prepare your skin by gently scraping (debriding) your skin growths before treating with Metvixia Cream and PDT. A small skin scraper is used to remove scales and crusts and to roughen the surface of any skin growths. This is to help Metvixia Cream and PDT to reach all parts of the skin growths. Figure 2: Cream application
Metvixia Cream is applied to the actinic keratosis skin growths and to a small area of the skin around the growths. Figure 3: Clear bandage application
The treated skin areas will be covered with a special clear bandage for about 3 hours.

During these 3 hours avoid sunlight or bright indoor light (for example: examination lights, operating room lights, tanning beds or lights that are close to you). During this time, the treated areas of your skin are more sensitive to light. You may feel burning or stinging. Your treated skin area may turn red or become swollen (photosensitive reactions). Wear a hat and protective clothes if you need to be out in the sun during this time. Sunscreens will not help protect your treated skin during this time. In cold weather, protect your treated skin site from the cold with warm clothes or stay indoors for these 3 hours between the cream and light treatment.

Figure 4: Cream removal
The bandage will be removed and the area will be rinsed with a saline solution before the PDT (light) treatment. Figure 5: Positioning the lamp
The lamp will be positioned over the area to be illuminated by the use of guide light of reduced intensity. The distance between the lamp and the skin will be 50 to 80 mm (2-3.2 inch).
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Transvasin Heat Spray


1. Name Of The Medicinal Product

Transvasin Heat Spray

Radian B Heat Spray

2. Qualitative And Quantitative Composition

2-Hydroxyethyl Salicylate 5% w/w

Diethylamine Salicylate 5% w/w

Methyl Nicotinate 1% w/w

For excipients, see 6.1

3. Pharmaceutical Form

Cutaneous spray, solution (Cutaneous Spray)

A pale yellow, clear liquid.

4. Clinical Particulars 4.1 Therapeutic Indications

For the symptomatic relief of muscular and rheumatic pain.

4.2 Posology And Method Of Administration

There is no difference between the dosage for adults, children or the elderly.

Shake the can well before use. Holding the can about 6 inches from the skin surface, point nozzle arrow towards painful area. Spray evenly using short bursts. There is no need to massage.

4.3 Contraindications

Do not use on children under five years of age.

The spray is for external use only.

Do not allow the spray to enter the eyes.

Do not use on skin which is inflamed or broken or where there is known hypersensitivity to salicylates or any of the other constituents of the spray.

4.4 Special Warnings And Precautions For Use

If symptoms persist consult your doctor.

Discontinue use if excessive irritation occurs.

Avoid inhalation of the spray

Caution: The Spray is flammable. Do not use near fire or flame.

Pressurised container: Protect from sunlight and do not expose to temperatures exceeding 50°C.

Keep away from the eyes, nose and other sensitive areas.

Do not pierce or burn the can, even after use.

Do not spray on a naked flame or any incandescent material.

Do not use near, and do not place the container on, polished or painted surfaces.

Keep out of the reach and sight of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

As with all medicinal compounds care should be taken when administering the product to pregnant or lactating women.

4.7 Effects On Ability To Drive And Use Machines

No or negligible influence.

4.8 Undesirable Effects

After application a slight transient erythema may develop.

Contact dermatitis has been reported for hydroxyethyl salicylate.

4.9 Overdose

Overdose is unlikely when applied externally. Ingestion of very large amounts may result in symptoms of salicylate toxicity e.g. dizziness, tinnitus, deafness, nausea, vomiting, headache and mental confusion.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

M02A C Topical products for joint and muscular pain. Preparations with salicylic acid derivatives.

The active ingredients are commonly found in topical analgesic and rubefacient preparations. 2-Hydroxyethyl Salicylate is a rubefacient as is Methyl Nicotinate and Diethylamine Salicylate is a topical analgesic for rheumatic and muscular pain.

5.2 Pharmacokinetic Properties

Methyl Nicotinate percutaneous absorption may occur dependent on the vehicle base and is via the intercellular route. There is no evidence to suggest that percutaneous absorption of the other constituents occurs to any great extent.

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars 6.1 List Of Excipients

Isopropyl Alcohol

Butane Propellant

6.2 Incompatibilities

None known

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Protect from sunlight and do not expose to temperatures exceeding 50°C.

6.5 Nature And Contents Of Container

Internally lacquered, three piece, tin plate aerosol can containing 125ml or 150ml of product with a standard aerosol valve and high density polyethylene cap.

6.6 Special Precautions For Disposal And Other Handling

None stated

7. Marketing Authorisation Holder

Thornton & Ross Limited

Linthwaite

Huddersfield

West Yorkshire

HD7 5QH

United Kingdom

8. Marketing Authorisation Number(S)

PL 00240/0070

9. Date Of First Authorisation/Renewal Of The Authorisation

6 September 2002

10. Date Of Revision Of The Text

27/01/2011


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Nicam 4% w / w Gel


1. Name Of The Medicinal Product

NICAM™ 4% w/w GEL

2. Qualitative And Quantitative Composition

Nicotinamide 4% w/w.

3. Pharmaceutical Form

Topical gel.

4. Clinical Particulars 4.1 Therapeutic Indications

For the topical treatment of mild to moderate inflammatory acne vulgaris.

4.2 Posology And Method Of Administration

Apply to the affected area twice daily after the skin has been thoroughly washed with warm water and soap. Enough gel should be used to cover the affected area.

No difference in dose or dose schedule is recommended for adults, children or the elderly.

For topical administration only.

4.3 Contraindications

Contraindicated in persons who have shown hypersensitivity to any of its components.

4.4 Special Warnings And Precautions For Use

For external use only and to be kept away from the eyes and mucous membranes, including those of the nose and mouth. If excessive dryness, irritation or peeling occurs reduce the dosage to one application per day or every other day.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Vitamin B derivative requirements such as nicotinamide, are increased during pregnancy and infancy. Nicotinamide is excreted in breast milk. As with all medicines, care should be exercised during the first trimester of pregnancy.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

The most frequently encountered adverse effect reported is dryness of the skin. Other less frequent adverse effects include pruritus, erythema, burning sensation and irritation.

4.9 Overdose

Not applicable.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Niacin (nicotinic acid) is an essential B complex Vitamin (B3), whose deficiency results in the clinical syndrome known as pellagra. Nicotinic acid is converted in the body to nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP), which function as coenzymes for a wide variety of vital oxidation-reduction reactions. Nicotinamide (niacinamide), the active ingredient, is the physiologically active form of niacin and is the chemical form of Vitamin B3 found in virtually all multivitamin products. Though nicotinic acid and nicotinamide are so closely related chemically, they differ somewhat in pharmacological properties. Nicotinic acid products exhibit moderately intense cutaneous vasodilation, resulting frequently in mild headaches and flushing or tingling of the skin, but such reactions have not been observed with nicotinamide. Nicotinic acid has also been used for its effect to lower plasma cholesterol, again a property not shared by nicotinamide.

Nicotinamide has demonstrated beneficial effects on inflammatory acne. It is considered that these effects are related to its significant anti-inflammatory activity.

5.2 Pharmacokinetic Properties

Following oral administration, nicotinamide is readily absorbed from the gastro-intestinal tract and widely distributed in the body tissues. The main route of metabolism is the conversion to N-methylnicotinamide and the 2-pyridone and 4-pyridone derivatives; nicotinuric acid is also formed. Small amounts of nicotinamide are excreted unchanged in the urine; this amount increases with larger doses.

5.3 Preclinical Safety Data

Nicotinic acid amide (nicotinamide) has been recognised since 1937 as an essential B complex vitamin whose deficiency results in the clinical syndrome known as pellagra. It is widely available, in tablets and in sterile solution in water for intravenous administration, for the prophylaxis and treatment of pellagra and nutritional deficiency.

In the United States, nicotinamide is included in the Food and Drug Administration's listing of nutritional agents which are Generally Recognised As Safe (GRAS).

6. Pharmaceutical Particulars 6.1 List Of Excipients

Aluminium Magnesium Silicate; Hypromellose; Citric Acid Anhydrous; Macrogol Lauryl Ether; Ethanol Anhydrous; Purified Water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

60g LDPE or co-extruded low density polyethylene laminate tube with white polypropylene cap.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Dermal Laboratories

Tatmore Place, Gosmore

Hitchin, Herts SG4 7QR, UK.

8. Marketing Authorisation Number(S)

00173/0166.

9. Date Of First Authorisation/Renewal Of The Authorisation

10 September 2002.

10. Date Of Revision Of The Text

October 2008.


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Anastrozole tablets


1. Name Of The Medicinal Product

Anastrozole 1 mg, film-coated tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 1 mg anastrozole.

Excipient: each tablet contains 93 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

White film-coated round biconvex tablets, debossed with “ANA” and “1” on one side.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of advanced breast cancer in postmenopausal women. Efficacy has not been demonstrated in oestrogen receptor negative patients unless they had a previous positive clinical response to tamoxifen.

4.2 Posology And Method Of Administration

Adults including the elderly

One tablet (1 mg) to be taken orally once a day.

Children

Anastrozole is not recommended for use in children due to insufficient data on safety and efficacy (see sections 4.4 and 5.1).

Renal impairment

No dose change is recommended in patients with mild or moderate renal impairment.

Hepatic impairment

No dose change is recommended in patients with mild hepatic disease.

4.3 Contraindications

Anastrozole is contraindicated in:

– Premenopausal women.

– Pregnant or lactating women.

– Patients with severe renal impairment (creatinine clearance less than 20 ml/min).

– Patients with moderate or severe hepatic disease.

– Patients with known hypersensitivity to anastrozole or to any of the excipients as referenced in section 6.1.

Oestrogen-containing therapies should not be co-administered with anastrozole as they would negate its pharmacological action.

Concurrent tamoxifen therapy (see section 4.5).

4.4 Special Warnings And Precautions For Use

Anastrozole is not recommended for use in children as safety and efficacy have not been established in this group of patients (see section 5.1)

Anastrozole should not be used in boys with growth hormone deficiency in addition to growth hormone treatment. In the pivotal clinical trial, efficacy was not demonstrated and safety was not established (see section 5.1). Since anastrozole reduces estradiol levels, it must not be used in girls with growth hormone deficiency in addition to growth hormone treatment. Long-term safety data in children and adolescents are not available.

The menopause should be defined biochemically in any patient where there is doubt about hormonal status.

There are no data to support the safe use of anastrozole in patients with moderate or severe hepatic impairment, or patients with severe impairment of renal function (creatinine clearance less than 20 ml/min).

Women with osteoporosis or at risk of osteoporosis, should have their bone mineral density formally assessed by bone densitometry e.g. DEXA scanning at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored.

There are no data available for the use of anastrozole with LHRH analogues. This combination should not be used outside clinical trials.

As anastrozole lowers circulating oestrogen levels it may cause a reduction in bone mineral density with a possible consequential increased risk of fracture. The use of bisphosphonates may stop further bone mineral loss caused by anastrozole in postmenopausal women and should be considered.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Antipyrine and cimetidine clinical interaction studies indicate that the co-administration of anastrozole with other drugs is unlikely to result in clinically significant drug interactions mediated by cytochrome P450

A review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with anastrozole who also received other commonly prescribed drugs. There were no clinically significant interactions with bisphosphonates (see section 5.1)

Oestrogen-containing therapies should not be co-administered with anastrozole as they would negate its pharmacological action.

Tamoxifen should not be co-administered with anastrozole, as this may diminish its pharmacological action (see section 4.3).

4.6 Pregnancy And Lactation

Anastrozole is contraindicated in pregnant and lactating women.

4.7 Effects On Ability To Drive And Use Machines

Anastrozole is unlikely to impair the ability of patients to drive and operate machinery. However, asthenia and somnolence have been reported with the use of anastrozole and caution should be observed when driving or operating machinery while such symptoms persist.

4.8 Undesirable Effects

Unless specified, the following frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for five years (ATAC study)

System Organ Class

Frequency

Adverse Reaction

Metabolism and nutrition

Common

(

Anorexia, mainly mild in nature

Hypercholesterolaemia, mainly mild or moderate in nature

Nervous system disorders

Very common

(

Headache, mainly mild or moderate in nature

 

Common

(

Somnolence, mainly mild or moderate in nature

Carpal Tunnel Syndrome

Vascular disorders

Very common

(

Hot flushes, mainly mild or moderate in nature

Gastrointestinal disorders

Very common

(

Nausea, mainly mild or moderate in nature

 

Common

(

Diarrhoea, mainly mild or moderate in nature

Vomiting, mainly mild or moderate in nature

Hepatobiliary disorders

Common

(

Increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase

 

Uncommon

(

Increases in gamma-GT and bilirubin Hepatitis

Skin and subcutaneous disorders

Very common

(

Rash, mainly mild or moderate in nature

 

Common

(

Hair thinning (Alopecia), mainly mild or moderate in nature.

Allergic reactions

 

Uncommon

(

Urticaria

 

Rare

(

Erythema multiforme

Anaphylactoid reaction

 

Not known

Stevens-Johnson syndrome**

Angioedema**

Musculoskeletal and connective tissue disorders

Very common

(

Joint pain/stiffness, mainly mild or moderate in nature

 

Common

(

Bone pain

 

Uncommon

(

Trigger finger

Reproductive system and breast disorders

Common

(

Vaginal dryness, mainly mild or moderate in nature

Vaginal bleeding, mainly mild or moderate in nature*

General disorders and administration site conditions

Very common

(

Asthenia, mainly mild or moderate in nature

*Vaginal bleeding has been reported commonly, mainly in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further evaluation should be considered.

**Cannot be estimated from the available data.

As anastrozole lowers circulating oestrogen levels, it may cause a reduction in bone mineral density placing some patients at a higher risk of fracture (see section 4.4)The table below presents the frequency of pre-specified adverse events in the ATAC study, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy.

Undesirable effect

anastrozole (n=3092)

tamoxifen (n=3094)

Hot flushes

1104 (35.7%)

1264 (40.9%)

Joint pain/stiffness

1100 (35.6%)

911 (29.4%)

Mood disturbances

597 (19.3%)

554 (17.9%)

Fatigue/asthenia

575 (18.6%)

544 (17.6%)

Nausea and vomiting

393 (12.7%)

384 (12.4%)

Fractures

315 (10.2%)

209 (6.8%)

Fractures of the spine, hip or wrist/Colles

133 (4.3%)

91 (2.9%)

Wrist/Colles fractures

67 (2.2%)

50 (1.6%)

Spine fractures

43 (1.4%)

22 (0.7%)

Hip fractures

28 (0.9%)

26 (0.8%)

Cataracts

182 (5.9%)

213 (6.9%)

Vaginal bleeding

167 (5.4%)

317 (10.2%)

Ischaemic cardiovascular disease

127 (4.1%)

104 (3.4%)

Angina pectoris

71 (2.3%)

51 (1.6%)

Myocardial infarct

37 (1.2%)

34 (1.1%)

Coronary artery disorder

25 (0.8%)

23 (0.7%)

Myocardial ischaemia

22 (0.7%)

14 (0.5%)

Vaginal discharge

109 (3.5%)

408 (13.2%)

Any venous thromboembolic event

87 (2.8%)

140 (4.5%)

Deep venous thromboembolic events including PE

48 (1.6%)

74 (2.4%)

Ischaemic cerebrovascular events

62 (2.0%)

88 (2.8%)

Endometrial cancer

4 (0.2%)

13 (0.6%)

Fracture rates of 22 per 1000 patient-years and 15 per 1000 patient-years were observed for the anastrozole and tamoxifen groups, respectively, after a median follow-up of 68 months. The observed fracture rate for anastrozole is similar to the range reported in age-matched postmenopausal populations. It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on anastrozole treatment reflect a protective effect of tamoxifen, a specific effect of anastrozole, or both.

The incidence of osteoporosis was 10.5% in patients treated with anastrozole and 7.3% in patients treated with tamoxifen.

4.9 Overdose

There is limited clinical experience of accidental overdosage.

In animal studies, anastrozole demonstrated low acute toxicity.

Clinical trials have been conducted with various doses of anastrozole, up to 60 mg in a single dose given to healthy male volunteers, and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were well tolerated. A single dose of anastrozole that results in life-threatening symptoms has not been established.

There is no specific antidote to overdosage and treatment must be symptomatic.

In the management of an overdose, consideration should be given to the possibility that multiple agents may have been taken.

Vomiting may be induced if the patient is alert.

Dialysis may be helpful because anastrozole is not highly protein-bound.

General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Enzyme inhibitors

ATC Code: L02B G03

Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, oestradiol is produced primarily by the conversion of androstenedione to oestrone through the aromatase enzyme complex in peripheral tissues. Oestrone is subsequently converted to oestradiol. Lowering circulating oestradiol levels has been shown to produce a beneficial effect in women with breast cancer.

In postmenopausal women, a daily dose of 1 mg of anastrozole produced oestradiol suppression of greater than 80% using a highly sensitive assay.

Anastrozole does not possess any progestogenic, androgenic or oestrogenic activity.

Daily doses of anastrozole up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed.

Primary adjuvant treatment of early breast cancer

In a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for 5 years, anastrozole was shown to be statistically superior to tamoxifen in disease-free survival. A greater magnitude of benefit was observed for disease-free survival in favour of anastrozole versus tamoxifen for the prospectively defined hormone receptor positive population. Anastrozole was statistically superior to tamoxifen in time to recurrence. The difference was of even greater magnitude than in disease-free survival for both the Intention To Treat (ITT) population and hormone receptor positive population. Anastrozole was statistically superior to tamoxifen in terms of time to distant recurrence. The incidence of contralateral breast cancer was statistically reduced for anastrozole compared to tamoxifen. Following 5 years of therapy, anastrozole is at least as effective as tamoxifen in terms of overall survival. However, due to low death rates, additional follow-up is required to determine more precisely the long-term survival for anastrozole relative to tamoxifen. With 68 months median follow-up, patients in the ATAC study have not been followed up for sufficient time after 5 years of treatment, to enable a comparison of long-term post treatment effects of anastrozole relative to tamoxifen.

ATAC endpoint summary: 5-year treatment completion analysis

       

Efficacy endpoints

Number of events (frequency)

     

Intention to treat population

Hormone receptor positive tumour status

     

anastrozole (n=3125)

tamoxifen (n=3116)

anastrozole (n=2618)

tamoxifen (n=2598)

 

Disease-free survivala

575 (18.4)

651 (20.9)

424 (16.2)

497 (19.1)

Hazard ratio

0.87

0.83

   

2-sided 95% CI

0.78 to 0.97

0.73 to 0.94

   

p-value

0.0127

0.0049

   

Distant disease-free survivalb

500 (16.0)

530 (17.0)

370 (14.1)

394 (15.2)

Hazard ratio

0.94

0.93

   

2-sided 95% CI

0.83 to 1.06

0.80 to 1.07

   

p-value

0.2850

0.2838

   

Time to recurrencec

402 (12.9)

498 (16.0)

282 (10.8)

370 (14.2)

Hazard ratio

0.79

0.74

   

2-sided 95% CI

0.70 to 0.90

0.64 to 0.87

   

p-value

0.0005

0.0002

   

Time to distant recurrenced

324 (10.4)

375 (12.0)

226 (8.6)

265 (10.2)

Hazard ratio

0.86

0.84

   

2-sided 95% CI

0.74 to 0.99

0.70 to 1.00

   

p-value

0.0427

0.0559

   

Contralateral breast primary

35 (1.1)

59 (1.9)

26 (1.0)

54 (2.1)

Odds ratio

0.59

0.47

   

2-sided 95% CI

0.39 to 0.89

0.30 to 0.76

   

p-value

0.0131

0.0018

   

Overall survival

411 (13.2)

420 (13.5)

296 (11.3)

301 (11.6)

Hazard ratio

0.97

0.97

   

2-sided 95% CI

0.85 to 1.12

0.83 to 1.14

   

p-value

0.7142

0.7339

   

a Disease-free survival includes all recurrence events and is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death (for any reason).

b Distant disease-free survival is defined as the first occurrence of distant recurrence or death (for any reason).

c Time to recurrence is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death due to breast cancer.

d Time to distant recurrence is defined as the first occurrence of distant recurrence or death due to breast cancer.

e Number (%) of patients who had died.

As with all treatment decisions, women with breast cancer and their physician should assess the relative benefits and risks of the treatment.

When anastrozole and tamoxifen were co-administered, the efficacy and safety were similar to tamoxifen when given alone, irrespective of hormone receptor status. The exact mechanism of this is not yet clear. It is not believed to be due to a reduction in the degree of estradiol suppression produced by anastrozole.

Adjuvant treatment of early breast cancer for patients being treated with adjuvant tamoxifen

In a phase III trial (ABCSG 8) conducted in 2579 postmenopausal women with hormone receptor positive early breast cancer who had received surgery with or without radiotherapy and no chemotherapy, switching to anastrozole after 2 years adjuvant treatment with tamoxifen was statistically superior in disease-free survival when compared to remaining on tamoxifen, after a median follow-up of 24 months.

Time to any recurrence, time to local or distant recurrence and time to distant recurrence confirmed a statistical advantage for anastrozole, consistent with the results of disease-free survival. The incidence of contralateral breast cancer was very low in the two treatment arms with a numerical advantage for anastrozole. Overall survival was similar for the two treatment groups.

ABCSG 8 trial endpoint and results summary

   

Efficacy endpoints

Number of events (frequency)

 

anastrozole (n=1297)

tamoxifen (n=1282)

 

Disease-free survival

65 (5.0)

93 (7.3)

Hazard ratio

067

 

2-sided 95% CI

0.49 to 0.92

 

p-value

0.014

 

Time to any recurrence

36 (2.8)

66 (5.1)

Hazard ratio

0.53

 

2-sided 95% CI

0.35 to 0.79

 

p-value

0.002

 

Time to local or distant recurrence

29 (2.2)

51 (4.0)

Hazard ratio

0.55

 

2-sided 95% CI

0.35 to 0.87

 

p-value

0.011

 

Time to distant recurrence

22 (1.7)

41 (3.2)

Hazard ratio

0.52

 

2-sided 95% CI

0.31 to 0.88

 

p-value

0.015

 

New contralateral breast cancer

7 (0.5)

15 (1.2)

Odds ratio

0.46

 

2-sided 95% CI

0.19 to 1.13

 

p-value

0.090

 

Overall survival

43(3.3)

45 (3.5)

Hazard ratio

0.96

 

2-sided 95% CI

0.63 to 1.46

 

p-value

0.840

 

Two further similar trials (GABG/ARNO 95 and ITA), in one of which patients had received surgery and chemotherapy, as well as a combined analysis of ABCSG 8 and GABG/ARNO 95, supported these results.

The anastrozole safety profile in these 3 studies was consistent with the known safety profile established in postmenopausal women with hormone receptor positive early breast cancer.

Study of anastrozole with the bisphosphonate risedronate (SABRE)

Bone Mineral Density (BMD)

In the phase III/IV SABRE study, 234 postmenopausal women with hormone receptor positive early breast cancer scheduled for treatment with anastrozole 1mg/day were stratified to low, moderate and high risk groups according to their existing risk of fragility fracture. The primary efficacy parameter was the analysis of lumbar spine bone mass density using DEXA scanning. All patients received treatment with vitamin D and calcium. Patients in the low risk group received anastrozole alone (N=42), those in the moderate group were randomised to anastrozole plus risedronate 35mg once a week (N=77) or anastrozole plus placebo (N=77) and those in the high risk group received anastrozole plus risedronate 35mg once a week (N=38). The primary endpoint was changed from baseline in lumbar spine bone mass density at 12 months.

The 12-month main analysis has shown that patients already at moderate to high risk of fragility fracture showed no decrease in their bone mass density (assessed by lumbar spine bone mineral density using DEXA scanning) when managed by using anastrozole 1mg/day in combination with risedronate 35mg once a week. In addition, a decrease in BMD which was not statistically significant was seen in the low risk group treated with anastrozole 1mg/day alone. These findings were mirrored in the secondary efficacy variable of change from baseline total hip BMD at 12 months.

This study provides evidence that the use of bisphosphonates should be considered in the management of possible bone mineral loss in postmenopausal women with early breast cancer scheduled to be treated with anastrozole.

Lipids

In the SABRE study there was a neutral effect on plasma lipids in those patients treated with anastrozole plus risedronate.

Paediatrics

Anastrozole is not indicated for use in children. Efficacy has not been established in the paediatric populations studied (see below). The number of children treated was too limited to draw any reliable conclusions on safety. No data on the potential long-term effects of anastrozole treatment in children are available (see also section 5.3)

The European Medicines Agency has waived the obligation to submit the results of studies with anastrozole in one or several subsets of the paediatric population in short stature due to growth hormone deficiency (GHD), testotoxicosis, gynaecomastia, and McCune-Albright syndrome.

Short stature due to Growth Hormone Deficiency

A randomised, double-blind, multi-centre study evaluated 52 pubertal boys (aged 11-16 years inclusive) with GHD treated for 12 to 36 months with anastrozole 1mg/day or placebo in combination with growth hormone. Only 14 subjects on anastrozole completed 36 months. After 3 years anastrozole was found to statistically significantly slow bone maturation in pubertal boys on growth hormone therapy. No statistically significant difference with placebo was observed for the growth related parameters of predicted adult height, height, height SDS and height velocity. Final height data were not available. While the number of children treated was too limited to draw any reliable conclusions on safety, there was an increased fracture rate and a trend towards reduced bone mineral density in the anastrozole arm compared to placebo.

Testotoxicosis

An open-label, non-comparative, multi-centre study evaluated 14 male patients (aged 2-9) with familial male-limited precocious puberty, also known as testotoxicosis, treated with a combination of anastrozole and bicalutamide. The primary objective was to assess the efficacy and safety of this combination regimen over 12 months. Thirteen out of the 14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). There was no significant difference in growth rate after 12 months of treatment, relative to the growth rate during the 6 months prior to entering the study.

Gynaecomastia studies

Trial 0006 was a randomised, double-blind, multi-centre study of 82 pubertal boys (aged 11-18 years inclusive) with gynaecomastia of greater than 12 months duration treated with anastrozole 1mg/day or placebo daily for up to 6 months. No significant difference in the number of patients who had a 50% or greater reduction in total breast volume after 6 months of treatment was observed b


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Nolvadex


tamoxifen citrate
Dosage Form: tablets
BOXED WARNING

For Women with Ductal Carcinoma in Situ (DCIS) and Women at High Risk for Breast Cancer: Serious and life-threatening events associated with Nolvadex in the risk reduction setting (women at high risk for cancer and women with DCIS) include uterine malignancies, stroke and pulmonary embolism. Incidence rates for these events were estimated from the NSABP P-1 trial (see CLINICAL PHARMACOLOGY-Clinical Studies ? Reduction in Breast Cancer Incidence In High Risk Women). Uterine malignancies consist of both endometrial adenocarcinoma (incidence rate per 1,000 women-years of 2.20 for Nolvadex vs 0.71 for placebo) and uterine sarcoma (incidence rate per 1,000 women-years of 0.17 for Nolvadex vs 0.04 for placebo)*. For stroke, the incidence rate per 1,000 women-years was 1.43 for Nolvadex vs 1.00 for placebo**. For pulmonary embolism, the incidence rate per 1,000 women-years was 0.75 for Nolvadex versus 0.25 for placebo**.

Some of the strokes, pulmonary emboli, and uterine malignancies were fatal.

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 Nolvadex to reduce their risk of developing breast cancer.

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

*Updated long-term follow-up data (median length of follow-up is 6.9 years) from NSABP P-1 study. See WARNINGS: Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma.

**See Table 3 under CLINICAL PHARMACOLOGY-Clinical Studies

Nolvadex Description

Nolvadex® (tamoxifen citrate) Tablets, a nonsteroidal antiestrogen, are for oral administration. Nolvadex Tablets are available as:

10 mg Tablets:

Each tablet contains 15.2 mg of tamoxifen citrate which is equivalent to 10 mg of tamoxifen.

20 mg Tablets:

Each tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20 mg of tamoxifen.

Inactive Ingredients: carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.

Chemically, Nolvadex is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-[4-(1,2-diphenyl-1-butenyl) phenoxy]-N, N-dimethylethanamine 2 hydroxy-1,2,3- propanetricarboxylate (1:1). The structural and empirical formulas are:

Tamoxifen citrate has a molecular weight of 563.62, the pKa' is 8.85, the equilibrium solubility in water at 37°C is 0.5 mg/mL and in 0.02 N HCl at 37°C, it is 0.2 mg/mL.

Nolvadex - Clinical Pharmacology

Nolvadex is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, tamoxifen appears to exert its antitumor effects by binding the estrogen receptors.

In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for estrogen receptor protein.

Absorption and Distribution:

Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67-183 ng/mL) for tamoxifen and 336 ng/mL (range 148-654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for 3 months are 122 ng/mL (range 71-183 ng/mL) and 353 ng/mL (range 152-706 ng/mL), respectively. After initiation of therapy, steady state concentrations for tamoxifen are achieved in about 4 weeks and steady-state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a half-life of approximately 14 days for this metabolite. In a steady-state, crossover study of 10 mg Nolvadex tablets given twice a day vs. a 20 mg Nolvadex tablet given once daily, the 20 mg Nolvadex tablet was bioequivalent to the 10 mg Nolvadex tablets.

Metabolism:

Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients' plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein.

Excretion:

Studies in women receiving 20 mg of 14C tamoxifen have shown that approximately 65% of the administered dose was excreted from the body over a period of 2 weeks with fecal excretion as the primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.

Special Populations:

The effects of age, gender and race on the pharmacokinetics of tamoxifen have not been determined. The effects of reduced liver function on the metabolism and pharmacokinetics of tamoxifen have not been determined.

Pediatric Patients:

The pharmacokinetics of tamoxifen and N-desmethyl tamoxifen were characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 27 female pediatric patients aged 2 to 10 years enrolled in a study designed to evaluate the safety, efficacy, and pharmacokinetics of Nolvadex in treating McCune-Albright Syndrome. Rich data from two tamoxifen citrate pharmacokinetic trials in which 59 postmenopausal women with breast cancer completed the studies were included in the analysis to determine the structural pharmacokinetic model for tamoxifen. A one-compartment model provided the best fit to the data.

In pediatric patients, an average steady state peak plasma concentration (Css, max) and AUC were of 187 ng/mL and 4110 ng hr/mL, respectively, and Css, max occurred approximately 8 hours after dosing. Clearance (CL/F) as body weight adjusted in female pediatric patients was approximately 2.3-fold higher than in female breast cancer patients. In the youngest cohort of female pediatric patients (2-6 year olds), CL/F was 2.6-fold higher; in the oldest cohort (7-10.9 year olds) CL/F was approximately 1.9-fold higher. Exposure to N-desmethyl tamoxifen was comparable between the pediatric and adult patients. The safety and efficacy of Nolvadex for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of Nolvadex therapy in girls have not been established. In adults treated with Nolvadex an increase in incidence of uterine malignancies, stroke and pulmonary embolism has been noted (see BOXED WARNING).

Drug-Drug Interactions:

In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem competitively inhibited formation of N-desmethyl tamoxifen with apparent K1 of 20, 1, 45 and 30 µM, respectively. The clinical significance of these in vitro studies is unknown.

Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were co-administered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cmax by 86% and 55%, respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.

In the anastrozole adjuvant trial, co-administration of anastrozole and Nolvadex in breast cancer patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole alone; however, the coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen (see PRECAUTIONS -Drug Interactions). Nolvadex should not be co-administered with anastrozole.

Clinical Studies Metastatic Breast Cancer: Premenopausal Women (Nolvadex vs. Ablation):

Three prospective, randomized studies (Ingle, Pritchard, Buchanan) compared Nolvadex to ovarian ablation (oophorectomy or ovarian irradiation) in premenopausal women with advanced breast cancer. Although the objective response rate, time to treatment failure, and survival were similar with both treatments, the limited patient accrual prevented a demonstration of equivalence. In an overview analysis of survival data from the 3 studies, the hazard ratio for death (Nolvadex/ovarian ablation) was 1.00 with two-sided 95% confidence intervals of 0.73 to 1.37. Elevated serum and plasma estrogens have been observed in premenopausal women receiving Nolvadex, but the data from the randomized studies do not suggest an adverse effect of this increase. A limited number of premenopausal patients with disease progression during Nolvadex therapy responded to subsequent ovarian ablation.

Male Breast Cancer:

Published results from 122 patients (119 evaluable) and case reports in 16 patients (13 evaluable) treated with Nolvadex have shown that Nolvadex is effective for the palliative treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to Nolvadex which constitutes a 50% objective response rate.

Adjuvant Breast Cancer: Overview:

The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and again in 1995. In 1998, 10-year outcome data were reported for 36,689 women in 55 randomized trials of adjuvant Nolvadex using doses of 20-40 mg/day for 1-5+ years. Twenty-five percent of patients received 1 year or less of trial treatment, 52% received 2 years, and 23% received about 5 years. Forty-eight percent of tumors were estrogen receptor (ER) positive (> 10 fmol/mg), 21% were ER poor (< 10 fmol/l), and 31% were ER unknown. Among 29,441 patients with ER positive or unknown breast cancer, 58% were entered into trials comparing Nolvadex to no adjuvant therapy and 42% were entered into trials comparing Nolvadex in combination with chemotherapy vs. the same chemotherapy alone. Among these patients, 54% had node positive disease and 46% had node negative disease.

Among women with ER positive or unknown breast cancer and positive nodes who received about 5 years of treatment, overall survival at 10 years was 61.4% for Nolvadex vs. 50.5% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 59.7% for Nolvadex vs. 44.5% for control (logrank 2p < 0.00001). Among women with ER positive or unknown breast cancer and negative nodes who received about 5 years of treatment, overall survival at 10 years was 78.9% for Nolvadex vs. 73.3% for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 79.2% for Nolvadex versus 64.3% for control (logrank 2p < 0.00001).

The effect of the scheduled duration of tamoxifen may be described as follows. In women with ER positive or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of Nolvadex, the proportional reductions in mortality were 12%, 17% and 26%, respectively (trend significant at 2p < 0.003). The corresponding reductions in breast cancer recurrence were 21%, 29% and 47% (trend significant at 2p < 0.00001).

Benefit is less clear for women with ER poor breast cancer in whom the proportional reduction in recurrence was 10% (2p = 0.007) for all durations taken together, or 9% (2p = 0.02) if contralateral breast cancers are excluded. The corresponding reduction in mortality was 6% (NS). The effects of about 5 years of Nolvadex on recurrence and mortality were similar regardless of age and concurrent chemotherapy. There was no indication that doses greater than 20 mg per day were more effective.

Anastrozole Adjuvant ATAC Trial Study of Anastrozole compared to Nolvadex for Adjuvant Treatment of Early Breast Cancer:

An anastrozole adjuvant trial was conducted in 9366 postmenopausal women with operable breast cancer who were randomized to receive adjuvant treatment with either anastrozole 1 mg daily, Nolvadex 20 mg daily, or a combination of these two treatments for five years or until recurrence of the disease. At a median follow-up of 33 months, the combination of anastrozole and Nolvadex did not demonstrate any efficacy benefit when compared with Nolvadex therapy alone, in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial. Please refer to CLINICAL PHARMACOLOGY-Special Populations-Drug-Drug Interactions, PRECAUTIONS-Laboratory Tests, PRECAUTIONS-Drug Interactions and ADVERSE REACTIONS sections for safety information from this trial. Please refer to the full prescribing information for ARIMIDEX® (anastrozole) 1 mg Tablets for additional information on this trial.

Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127] in the anatrozole arm compared to the Nolvadex arm.

Node Positive - Individual Studies:

Two studies (Hubay and NSABP B-09) demonstrated an improved disease-free survival following radical or modified radical mastectomy in postmenopausal women or women 50 years of age or older with surgically curable breast cancer with positive axillary nodes when Nolvadex was added to adjuvant cytotoxic chemotherapy. In the Hubay study, Nolvadex was added to "low-dose" CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09 study, Nolvadex was added to melphalan [L-phenylalanine mustard (P)] and fluorouracil (F).

In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more likely to benefit. In the NSABP B-09 study in women age 50-59 years, only women with both estrogen and progesterone receptor levels 10 fmol or greater clearly benefited, while there was a nonstatistically significant trend toward adverse effect in women with both estrogen and progesterone receptor levels less than 10 fmol. In women age 60-70 years, there was a trend toward a beneficial effect of Nolvadex without any clear relationship to estrogen or progesterone receptor status.

Three prospective studies (ECOG-1178, Toronto, NATO) using Nolvadex adjuvantly as a single agent demonstrated an improved disease-free survival following total mastectomy and axillary dissection for postmenopausal women with positive axillary nodes compared to placebo/no treatment controls. The NATO study also demonstrated an overall survival benefit.

Node Negative - Individual Studies:

NSABP B-14, a prospective, double-blind, randomized study, compared Nolvadex to placebo in women with axillary node-negative, estrogen-receptor positive (?10 fmol/mg cytosol protein) breast cancer (as adjuvant therapy, following total mastectomy and axillary dissection, or segmental resection, axillary dissection, and breast radiation). After five years of treatment, there was a significant improvement in disease-free survival in women receiving Nolvadex. This benefit was apparent both in women under age 50 and in women at or beyond age 50.

One additional randomized study (NATO) demonstrated improved disease-free survival for Nolvadex compared to no adjuvant therapy following total mastectomy and axillary dissection in postmenopausal women with axillary node-negative breast cancer. In this study, the benefits of Nolvadex appeared to be independent of estrogen receptor status.

Duration of Therapy:

In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy.

In the NSABP B-14 trial, in which patients were randomized to Nolvadex 20 mg/day for 5 years vs. placebo and were disease-free at the end of this 5-year period were offered rerandomization to an additional 5 years of Nolvadex or placebo. With 4 years of follow-up after this rerandomization, 92% of the women that received 5 years of Nolvadex were alive and disease-free, compared to 86% of the women scheduled to receive 10 years of Nolvadex (p=0.003). Overall survivals were 96% and 94%, respectively (p=0.08). Results of the B-14 study suggest that continuation of therapy beyond 5 years does not provide additional benefit.

A Scottish trial of 5 years of tamoxifen vs. indefinite treatment found a disease-free survival of 70% in the five-year group and 61% in the indefinite group, with 6.2 years median follow-up (HR=1.27, 95% CI 0.87-1.85).

In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of adjuvant Nolvadex 40 mg/day for 2 or 5 years, overall survival at 10 years was estimated to be 80% in the patients in the 5-year tamoxifen group, compared with 74% among corresponding patients in the 2-year treatment group (p=0.03). Disease-free survival at 10 years was 73% in the 5-year group and 67% in the 2-year group (p=0.009). Compared with 2 years of tamoxifen treatment, 5 years of treatment resulted in a slightly greater reduction in the incidence of contralateral breast cancer at 10 years, but this difference was not statistically significant.

Contralateral Breast Cancer:

The incidence of contralateral breast cancer is reduced in breast cancer patients (premenopausal and postmenopausal) receiving Nolvadex compared to placebo. Data on contralateral breast cancer are available from 32,422 out of 36,689 patients in the 1995 overview analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). In clinical trials with Nolvadex of 1 year or less, 2 years, and about 5 years duration, the proportional reductions in the incidence rate of contralateral breast cancer among women receiving Nolvadex were 13% (NS), 26% (2p = 0.004) and 47% (2p < 0.00001), with a significant trend favoring longer tamoxifen duration (2p = 0.008). The proportional reductions in the incidence of contralateral breast cancer were independent of age and ER status of the primary tumor. Treatment with about 5 years of Nolvadex reduced the annual incidence rate of contralateral breast cancer from 7.6 per 1,000 patients in the control group compared with 3.9 per 1,000 patients in the tamoxifen group.

In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant Nolvadex 40 mg/day for 2-5 years, the incidence of second primary breast tumors was reduced 40% (p < 0.008) on tamoxifen compared to control. In the NSABP B-14 trial in which patients were randomized to Nolvadex 20 mg/day for 5 years vs. placebo, the incidence of second primary breast cancers was also significantly reduced (p < 0.01). In NSABP B-14, the annual rate of contralateral breast cancer was 8.0 per 1000 patients in the placebo group compared with 5.0 per 1,000 patients in the tamoxifen group, at 10 years after first randomization.

Ductal Carcinoma in Situ:

NSABP B-24, a double-blind, randomized trial included women with ductal carcinoma in situ (DCIS). This trial compared the addition of Nolvadex or placebo to treatment with lumpectomy and radiation therapy for women with DCIS. The primary objective was to determine whether 5 years of Nolvadex therapy (20 mg/day) would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast.

In this trial 1,804 women were randomized to receive either Nolvadex or placebo for 5 years: 902 women were randomized to Nolvadex 10 mg tablets twice a day and 902 women were randomized to placebo. As of December 31, 1998, follow-up data were available for 1,798 women and the median duration of follow-up was 74 months.

The Nolvadex and placebo groups were well balanced for baseline demographic and prognostic factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum dimension, were not palpable, and were detected by mammography alone. Over 60% of the study population was postmenopausal. In 16% of patients, the margin of the resected specimen was reported as being positive after surgery. Approximately half of the tumors were reported to contain comedo necrosis.

For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among women assigned to Nolvadex (44 cases - Nolvadex, 74 cases - placebo; p=0.004; relative risk (RR)=0.57, 95% CI: 0.39-0.84). No data are available regarding the ER status of the invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that reported annually in the SEER data base.

Results are shown in Table 1. For each endpoint the following results are presented: the number of events and rate per 1,000 women per year for the placebo and Nolvadex groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between Nolvadex and placebo. Relative risks less than 1.0 indicate a benefit of Nolvadex therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits of Nolvadex therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists.

Table 1Major Outcomes of the NSABP B-24 Trial

Type of Event

Lumpectomy, radiotherapy and placebo

Lumpectomy, radiotherapy, and Nolvadex

RR

95% CI Limits

No. of events

Rate per 1000 women per year

No. of events

Rate per 1000 women per year

* Updated follow-up data (median 8.1 years)

Invasive breast cancer (Primary endpoint)

74

16.73

44

9.60

0.57

0.39 to 0.84

-Ipsilateral

47

10.61

27

5.90

0.56

0.33 to 0.91

-Contralateral

25

5.64

17

3.71

0.66

0.33 to 1.27

-Side undetermined

2

--

0

--

--

Secondary Endpoints

DCIS

56

12.66

41

8.95

0.71

0.46 to 1.08

-Ipsilateral

46

10.40

38

8.29

0.88

0.51 to 1.25

-Contralateral

10

2.26

3

0.65

0.29

0.05 to 1.13

All Breast Cancer Events

129

29.16

84

18.34

0.63

0.47 to 0.83

-All ipsilateral events

96

21.70

65

14.19

0.65

0.47 to 0.91

-All contralateral events

37

8.36

20

4.37

0.52

0.29 to 0.92

Deaths

32

28

Uterine Malignancies*

4

9

Endometrial Adenocarcinoma*

4

0.57

8

1.15

Uterine Sarcoma*

0

0.0

1

0.14

Second primary malignancies (other than endometrial and breast)

30

29

Stroke

2

7

Thromboembolic events (DVT, PE)

5

15

Survival was similar in the placebo and Nolvadex groups. At 5 years from study entry, survival was 97% for both groups.

Reduction in Breast Cancer Incidence in High Risk Women:

The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized, placebo-controlled trial with a primary objective to determine whether 5 years of Nolvadex therapy (20 mg/day) would reduce the incidence of invasive breast cancer in women at high risk for the disease (See INDICATIONS AND USAGE). Secondary objectives included an evaluation of the incidence of ischemic heart disease; the effects on the incidence of bone fractures; and other events that might be associated with the use of Nolvadex, including: endometrial cancer, pulmonary embolus, deep vein thrombosis, stroke, and cataract formation and surgery (See WARNINGS).

The Gail Model was used to calculate predicted breast cancer risk for women who were less than 60 years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors were used: age; number of first-degree female relatives with breast cancer; previous breast biopsies; presence or absence of atypical hyperplasia; nulliparity; age at first live birth; and age at menarche. A 5-year predicted risk of breast cancer of ? 1.67% was required for entry into the trial.

In this trial, 13,388 women of at least 35 years of age were randomized to receive either Nolvadex or placebo for five years. The median duration of treatment was 3.5 years. As of January 31, 1998, follow-up data is available for 13,114 women. Twenty-seven percent of women randomized to placebo (1,782) and 24% of women randomized to Nolvadex (1,596) completed 5 years of therapy. The demographic characteristics of women on the trial with follow-up data are shown in Table 2.

Table 2Demographic Characteristics of Women in the NSABP P-1 Trial

Characteristic

Placebo

Tamoxifen

#

%

#

%

Age (yrs)

35-39

184

3

158

2

40-49

2,394

36

2,411

37

50-59

2,011

31

2,019

31

60-69

1,588

24

1,563

24

?70

393

6

393

6

Age at first live birth (yrs.)

Nulliparous

1,202

18

1,205

18

12-19

915

14

946

15

20-24

2,448

37

2,449

37

25-29

1,399

21

1,367

21

?30

606

9

577

9

Race

White

6,333

96

6,323

96

Black

109

2

103

2

Other

128

2

118

2

Age at menarche

?14

1,243

19

1,170

18

12-13

3,610

55

3,610

55

?11

1,717

26

1,764

27

# of first degree relatives with breast cancer

0

1,584

24

1,525

23

1

3,714

57

3,744

57

2+

1,272

19

1,275

20

Prior Hysterectomy

No

4,173

63.5

4,018

62.4

Yes

2,397

36.5

2,464

37.7

# of previous breast biopsies

0

2,935

45

2,923

45

1

1,833

28

1,850

28

?2

1,802

27

1,771

27

History of atypical hyperplasia in the breast

No

5,958

91

5,969

91

Yes

612

9

575

9

History of LCIS at entry

No

6,165

94

6,135

94

Yes

405

6

409

6

5-year predicated breast cancer risk (%)

?2.00

1,646

25

1,626

25

2.01-3.00

2,028

31

2,057

31

3.01-5.00

1,787

27

1,707

26

?5.01

1,109

17

1,162

18

Total

6,570

100.0

6,544

100.0

Results are shown in Table 3. After a median follow-up of 4.2 years, the incidence of invasive breast cancer was reduced by 44% among women assigned to Nolvadex (86 cases-Nolvadex, 156 cases-placebo; p<0.00001; relative risk (RR)=0.56, 95% CI: 0.43-0.72). A reduction in the incidence of breast cancer was seen in each prospectively specified age group (? 49, 50-59, ? 60), in women with or without LCIS, and in each of the absolute risk levels specified in Table 3. A non-significant decrease in the incidence of ductal carcinoma in situ (DCIS) was seen (23-Nolvadex, 35-placebo; RR=0.66; 95% CI: 0.39-1.11).

There was no statistically significant difference in the number of myocardial infarctions, severe angina, or acute ischemic cardiac events between the two groups (61-Nolvadex, 59-placebo; RR=1.04, 95% CI: 0.73-1.49).

No overall difference in mortality (53 deaths in Nolvadex group vs. 65 deaths in placebo group) was present. No difference in breast cancer-related mortality was observed (4 deaths in Nolvadex group vs. 5 deaths in placebo group).

Although there was a non-significant reduction in the number of hip fractures (9 on Nolvadex, 20 on placebo) in the Nolvadex group, the number of wrist fractures was similar in the two treatment groups (69 on Nolvadex, 74 on placebo). A subgroup analysis of the P-1 trial, suggests a difference in effect in bone mineral density (BMD) related to menopausal status in patients receiving Nolvadex. In postmenopausal women there was no evidence of bone loss of the lumbar spine and hip. Conversely, Nolvadex was associated with significant bone loss of the lumbar spine and hip in premenopausal women.

The risks of Nolvadex therapy include endometrial cancer, DVT, PE, stroke, cataract formation and cataract surgery (See Table 3). In the NSABP P-1 trial, 33 cases of endometrial cancer were observed in the Nolvadex group vs. 14 in the placebo group (RR=2.48, 95% CI: 1.27-4.92). Deep vein thrombosis was observed in 30 women receiving Nolvadex vs. 19 in women receiving placebo (RR=1.59, 95% CI: 0.86-2.98). Eighteen cases of pulmonary embolism were observed in the Nolvadex group vs. 6 in the placebo group (RR=3.01, 95% CI: 1.15-9.27). There were 34 strokes on the Nolvadex arm and 24 on the placebo arm (RR=1.42; 95% CI: 0.82-2.51). Cataract formation in women without cataracts at baseline was observed in 540 women taking Nolvadex vs. 483 women receiving placebo (RR=1.13, 95% CI: 1.00-1.28). Cataract surgery (with or without cataracts at baseline) was performed in 201 women taking Nolvadex vs. 129 women receiving placebo (RR=1.51, 95% CI: 1.21-1.89) (See WARNINGS).

Table 3 summarizes the major outcomes of the NSABP P-1 trial. For each endpoint, the following results are presented: the number of events and rate per 1000 women per year for the placebo and Nolvadex groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between Nolvadex and placebo. Relative risks less than 1.0 indicate a benefit of Nolvadex therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits or risks of Nolvadex therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists.

For most participants, multiple risk factors would have been required for eligibility. This table considers risk factors individually, regardless of other co-existing risk factors, for women who developed breast cancer. The 5-year predicted absolute breast cancer risk accounts for multiple risk factors in an individual and should provide the best estimate of individual benefit (See INDICATIONS AND USAGE).

Table 3Major Outcomes of the NSABP P-1 Trial

# of Events

Rate/1000 Women/Year

95% CI

Type of Event

Placebo

Nolvadex

Placebo

Nolvadex


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Gygel Contraceptive Jelly


1. Name Of The Medicinal Product

GYGEL Contraceptive Jelly

2. Qualitative And Quantitative Composition

The gel contains 2.0% w/w of nonoxinol-9.

3. Pharmaceutical Form

Vaginal gel.

4. Clinical Particulars 4.1 Therapeutic Indications

For use as a spermicidal contraceptive in conjunction with barrier methods of contraception.

4.2 Posology And Method Of Administration

Method of Administration

For vaginal use.

For use by adult females only.

Posology

The gel should be spread over the surface of the diaphragm which will be in contact with the cervix, and on the rim. The diaphragm and spermicide must be allowed to remain undisturbed for at least six to eight hours after coitus. A fresh application of gel or other spermicides, must be made prior to any subsequent acts of coitus within this period of time, without removing the diaphragm. (A vaginal applicator should be used for inserting more jelly.)

Douching is not recommended, but if desired it should be deferred for at least six hours after intercourse.

4.3 Contraindications

Hypersensitivity to nonoxinol-9 or to any component of the preparation.

Patients with absent vaginal sensation e.g. paraplegics and quadriplegics.

4.4 Special Warnings And Precautions For Use

Spermicidal intravaginal preparations are intended for use in conjunction with barrier methods of contraception such as condoms, diaphragms and caps.

Where avoidance of pregnancy is important, the choice of contraceptive method should be made in consultation with a doctor or a family planning clinic.

This product does not protect against HIV (AIDS) or other sexually transmitted diseases (STDs). A latex condom should be used to protect against the spread of STDs. High frequency use of nonoxinol-9 has been reported to cause epithelial damage and increase the risk of HIV infection. Therefore women at risk of HIV/STD infection and who have multiple daily acts of intercourse should be advised to choose another method of contraception. Sexually active women should consider their individual HIV/STD infection risk when choosing a method of contraception.

If vaginal or penile irritation occurs, discontinue use. If symptoms worsen or continue for more than 48 hours, medical advice should be sought.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

There is no evidence from animal and human studies that nonoxinol-9 is teratogenic. Human epidemiological studies have not shown any firm evidence of adverse effects on the foetus, however some studies have shown that nonoxinol-9 may be embryotoxic in animals. This product should not be used if pregnancy is suspected or confirmed. Animal studies have detected nonoxinol-9 in milk after intravaginal administration. Use by lactating women has not been studied.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Nonoxinol-9 has been reported to cause epithelial damage and increase the risk of HIV infection.

It may cause hypersensitivity and application site reactions such as irritation, pain, discomfort, burning sensation, itching, dryness, rash and redness of the vulva, vagina or penis.

4.9 Overdose

If taken orally, the surfactant properties of this preparation may cause gastric irritation. General supportive therapy should be carried out. Hepatic and renal function should be monitored if medically indicated.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

The standard in vitro test (Sander-Cramer) evaluating the effect of nonoxinol-9 on animal sperm motility has shown the compound to be a potent spermicide.

The site of action of nonoxinol-9 has been determined as the sperm cell membrane. The lipoprotein membrane is disrupted, increasing permeability, with subsequent loss of cell components and decreased motility. A similar effect on vaginal epithelial and bacterial cells is also found.

5.2 Pharmacokinetic Properties

The intravaginal absorption and excretion of radiolabelled (14C) nonoxinol-9 has been studied in non-pregnant rats and rabbits and in pregnant rats. No appreciable difference was found in the extent or rate of absorption in pregnant and non-pregnant animals. Plasma levels peaked at about one hour and recovery from urine as unchanged nonoxinol-9 accounted for approximately 15-25% and faeces approximately 70% of the administered dose as unchanged nonoxinol-9. Less than 0.3% was found in the milk of lactating rats. No metabolites were detected in any of the samples analysed.

5.3 Preclinical Safety Data

No relevant information additional to that contained elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Methyl parahydroxybenzoate (E 218)

Sorbitol solution (E 420)

Lactic acid

Povidone K30

Propylene glycol

Sodium carboxymethylcellulose

Sorbic acid (E 200)

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Do not store above 25?C.

6.5 Nature And Contents Of Container

Epoxy resin lined aluminium tubes with polyethylene caps. Available in 30 and 81 gram packs; an applicator is available separately if required.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data 7. Marketing Authorisation Holder

Marlborough Pharmaceuticals Ltd

35A High Street

Marlborough

Wilts

SN8 1LW

UK

8. Marketing Authorisation Number(S)

PL 23138/0010

9. Date Of First Authorisation/Renewal Of The Authorisation

12 September 1995/17 July 1996

10. Date Of Revision Of The Text

9th September 2009

11 LEGAL CATEGORY

GSL


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Calcipotriene Ointment



Calcipotriene Ointment, 0.005%

FOR TOPICAL DERMATOLOGIC USE ONLY.

Not for Ophthalmic, Oral or Intravaginal Use.

Rx Only

Calcipotriene Ointment Description

Calcipotriene Ointment, 0.005% contains the compound calcipotriene, a synthetic vitamin D3 derivative for topical dermatological use.

Chemically, calcipotriene is (5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola- 5,7,10(19),22-tetraene-1?,3?,24-triol-, with the empirical formula C27H40O3, a molecular weight of 412.6, and the following structural formula:

Calcipotriene is a white or off-white crystalline substance. Calcipotriene Ointment contains calcipotriene 50 ?g/g in an ointment base of disodium phosphate dihydrate, edetate disodium, mineral oil, petrolatum, propylene glycol, ?-tocopherol, steareth-2 and purified water.

Calcipotriene Ointment - Clinical Pharmacology

In humans, the natural supply of vitamin D depends mainly on exposure to the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol to vitamin D3 (cholecalciferol) in the skin. Calcipotriene is a synthetic analog of vitamin D3.

Clinical studies with radiolabelled ointment indicate that approximately 6% (± 3%, SD) of the applied dose of calcipotriene is absorbed systemically when the ointment is applied topically to psoriasis plaques or 5% (± 2.6%, SD) when applied to normal skin, and much of the absorbed active is converted to inactive metabolites within 24 hours of application.

Vitamin D and its metabolites are transported in the blood, bound to specific plasma proteins. The active form of the vitamin, 1,25-dihyroxy vitamin D3 (calcitriol), is known to be recycled via the liver and excreted in the bile. Calcipotriene metabolism following systemic uptake is rapid, and occurs via a similar pathway to the natural hormone. The primary metabolites are much less potent than the parent compound.

There is evidence that maternal 1,25-dihydroxy vitamin D3 (calcitriol) may enter the fetal circulation, but it is not known whether it is excreted in human milk. The systemic disposition of calcipotriene is expected to be similar to that of the naturally occurring vitamin.

Clinical Studies

Adequate and well-controlled trials of patients treated with Calcipotriene Ointment have demonstrated improvement usually beginning after two weeks of therapy. This improvement continued in patients using calcipotriene once daily and twice daily. After 8 weeks of once daily calcipotriene, 56.7% of patients showed at least marked improvements (6.4% showed complete clearing). After 8 weeks of twice daily calcipotriene, 70.0% of patients showed at least marked improvement (11.3% showed complete clearing).

Subtracting percentages of patients using placebo (vehicle only) from percentages of patients using calcipotriene who had at least marked improvements after 8 weeks yields 39.9% for once daily and 49.6% for twice daily. This adjustment for placebo effect indicated that what might appear to be differences between once and twice daily use may reflect differences in the studies independent from the frequency of dosing. Although there was a numerical difference in comparison across studies, twice daily dosing has not been shown to be superior in efficacy to once daily dosing.

Over 400 patients have been treated in open label clinical studies of calcipotriene for periods of up to one year. In half of these studies, patients who previously had not responded well to calcipotriene were excluded. The adverse events in these extended studies included skin irritation in approximately 25% of patients and worsening of psoriasis in approximately 10% of patients. In one of these open label studies, half of the patients no longer required calcipotriene by 16 weeks of treatment, because of satisfactory therapeutic results.

Indications and Usage for Calcipotriene Ointment

Calcipotriene Ointment, 0.005%, is indicated for the treatment of plaque psoriasis in adults. The safety and effectiveness of topical calcipotriene in dermatoses other than psoriasis have not been established.

Contraindications

Calcipotriene is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. It should not be used by patients with demonstrated hypercalcemia or evidence of vitamin D toxicity. Calcipotriene should not be used on the face.

Precautions General

Use of calcipotriene may cause irritation of lesions and surrounding uninvolved skin. If irritation develops, calcipotriene should be discontinued.

For external use only. Keep out of the reach of children. Always wash hands thoroughly after use.

Transient, rapidly reversible elevation of serum calcium has occurred with use of calcipotriene. If elevation in serum calcium outside the normal range should occur, discontinue treatment until normal calcium levels are restored.

Information for Patients

Patients using calcipotriene should receive the following information and instructions:

1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the face or eyes. As with any topical medication, patients should wash hands after application. 2. This medication should not be used for any disorder other than that for which it was prescribed. 3. Patients should report to their physician any signs of local adverse reactions. 4. Patients that apply calcipotriene to exposed portions of the body should avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.) Carcinogenesis, Mutagenesis, Impairment of Fertility

When calcipotriene was applied topically to mice for up to 24 months at dosages of 3, 10 and 30 ?g/kg/day (corresponding to 9, 30 and 90 ?g/m2/day), no significant changes in tumor incidence were observed when compared to control. In a study in which albino hairless mice were exposed to both UVR and topically applied calcipotriene, a reduction in the time required for UVR to indicate the formation of skin tumors was observed (statistically significant in males only), suggesting that calcipotriene may enhance the effect of UVR to induce skin tumors. Patients that apply calcipotriene to exposed portions of the body should avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.). Physicians may wish to limit or avoid use of phototherapy in patients that use calcipotriene.

Calcipotriene did not elicit any mutagenic effects in an Ames mutagenicity assay, a mouse lymphoma TK locus assay, a human lymphocyte chromosome aberration assay, or in a micronucleus assay conducted in mice.

Studies in rats at doses up to 54 ?g/kg/day (324 ?g/m2/day) of calcipotriene indicated no impairment of fertility or general reproductive performance.

Pregnancy Teratogenic Effects: Pregnancy Category C

Studies of teratogenicity were done by the oral route where bioavailability is expected to be approximately 40-60% of the administered dose. In rabbits, increased maternal and fetal toxicity were noted at a dosage of 12 ?g/kg/day (132 ?g/m2/day); a dosage of 36 ?g/kg/day (396 ?g/m2/day) resulted in a significant increase in the incidence of incomplete ossification of the pubic bones and forelimb phalanges of fetuses. In a rat study, a dosage of 54 ?g/kg/day (318 ?g/m2/day) resulted in a significantly increased incidence of skeletal abnormalities (enlarged fontanelles and extra ribs). The enlarged fontanelles are most likely due to calcipotriene’s effect upon calcium metabolism. The estimated maternal and fetal no-effect exposure levels in the rat (43.2 ?g/m2/day) and rabbit (17.6 ?g/m2/day) studies are approximately equal to the expected human systemic exposure level (18.5 ?g/m2/day) from dermal application. There are no adequate and well-controlled studies in pregnant women. Therefore, Calcipotriene Ointment should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether calcipotriene is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Calcipotriene Ointment, 0.005% is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of calcipotriene in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at greater risk than adults of systemic adverse effects when they are treated with topical medication.

Geriatric Use

Of the total number of patients in clinical studies of Calcipotriene Ointment, approximately 12% were 65 or older, while approximately 4% were 75 and over. The results of an analysis of severity of skin-related adverse events showed a statistically significant difference for subjects over 65 years (more severe) compared to those under 65 years (less severe).

Adverse Reactions

In controlled clinical trials, the most frequent adverse reactions reported for calcipotriene were burning, itching and skin irritation, which occurred in approximately 10-15% of patients. Erythema, dry skin, peeling, rash, dermatitis, worsening of psoriasis including development of facial/scalp psoriasis were reported in 1 to 10% of patients. Other experiences reported in less than 1% of patients included skin atrophy, hyperpigmentation, hypercalcemia, and folliculitis. Once daily dosing has not been shown to be superior in safety to twice daily dosing.

Overdosage

Topically applied calcipotriene can be absorbed in sufficient amounts to produce systemic effects. Elevated serum calcium has been observed with excessive use of Calcipotriene Ointment.

Calcipotriene Ointment Dosage and Administration

Apply a thin layer of Calcipotriene Ointment once or twice daily and rub in gently and completely.

How is Calcipotriene Ointment Supplied

Calcipotriene Ointment, 0.005% is available in:

60 gram aluminum tube NDC (51672-4154-3)

STORAGE

Store at controlled room temperature 15°C-25°C (59°F-77°F). Do not freeze.

Manufactured by:

Glenmark Generics Ltd.
Colvale-Bardez, Goa 403 513, India

Distributed by:

Taro Pharmaceuticals U.S.A., Inc.
Hawthorne, NY 10532

June 2010

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
CALCIPOTRIENE 
calcipotriene  ointment Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 51672-4154 Route of Administration TOPICAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CALCIPOTRIENE (CALCIPOTRIENE) CALCIPOTRIENE 50 ug  in 1 g Inactive Ingredients Ingredient Name Strength SODIUM PHOSPHATE, DIBASIC, DIHYDRATE   EDETATE DISODIUM   MINERAL OIL   PETROLATUM   PROPYLENE GLYCOL   ALPHA-TOCOPHEROL   STEARETH-2   WATER   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 51672-4154-3 60 g In 1 CARTON None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090633 08/26/2010
Labeler - Taro Pharmaceuticals USA, Inc. (145186370) Establishment Name Address ID/FEI Operations Glenmark Generics Limited 677318665 ANALYSIS, MANUFACTURE Revised: 08/2010Taro Pharmaceuticals USA, Inc. More Calcipotriene Ointment resources Calcipotriene Ointment Side Effects (in more detail) Calcipotriene Ointment Use in Pregnancy & Breastfeeding Calcipotriene Ointment Drug Interactions Calcipotriene Ointment Support Group 10 Reviews for Calcipotriene - Add your own review/rating Compare Calcipotriene Ointment with other medications Psoriasis
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Hycamtin


Generic Name: topotecan (TOE poe TEE kan)
Brand Names: Hycamtin

What is Hycamtin (topotecan)?

Topotecan is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Topotecan is used to treat ovarian cancer, small cell lung cancer, and certain types of cervical cancer.

Topotecan may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Hycamtin (topotecan)? Do not use topotecan if you are pregnant. It could harm the unborn baby.

Topotecan can lower blood cells that help your body fight infections. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. Your blood may need to be tested often. Visit your doctor regularly.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while using topotecan, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you. Call your doctor at once if you have fever, chills, body aches, flu symptoms, pale skin, easy bruising or bleeding, severe diarrhea with fever or stomach pain, unusual weakness, white patches or sores inside your mouth or on your lips, or other signs of infection. What should I discuss with my healthcare provider before using Hycamtin (topotecan)? You should not use topotecan if you have:

severe bone marrow depression; or

if you are pregnant or breast-feeding.

To make sure you can safely use topotecan, tell your doctor if you have any of these other conditions:

kidney disease;

lung disease or lung cancer; or

if you have had a chest x-ray or radiation treatment of your chest area.

FDA pregnancy category D. Do not use topotecan if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment. It is not known whether topotecan passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using topotecan. How should I use Hycamtin (topotecan)?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Topotecan is usually given once daily for 5 days in a row. This treatment is then repeated every 21 days, usually for at least 4 treatments. It may take several weeks for your body to respond to the medication.

Topotecan capsules are taken by mouth. You may need to take two different colored capsules at one time. Make sure you know the difference between capsules because one contains 4 times as much topotecan as the other, even though they may look the same in size.

Take the topotecan capsule with a full glass (8 ounces) of water. You may take the medicine with or without food.

If you vomit after taking a topotecan capsule, do not take another dose that same day. Call your doctor for instructions.

Do not crush or break a topotecan capsule, or use a capsule that has been accidentally broken. The medicine from a broken capsule can be dangerous if it gets in your eyes or on your skin. If this occurs, wash your skin with soap and water or rinse the eyes for at least 15 minutes with plain water. Ask your doctor or pharmacist how to safely handle and dispose of a broken tablet or capsule. Store topotecan capsules in the refrigerator and protect them from light.

Topotecan injection is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. Topotecan must be given slowly, and the IV infusion can take up to 30 minutes to complete.

Tell your doctor right away if any of this medicine gets on your skin during the injection. If this does happen, the exposed skin should be rinsed thoroughly with soap and warm water.

Topotecan can lower blood cells that help your body fight infections. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. Your blood may need to be tested often. Visit your doctor regularly.

What happens if I miss a dose?

Call your doctor for instructions if you miss any of your topotecan doses.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose can cause bone marrow depression (fever, chills, body aches, flu symptoms, sores or white patches in your mouth, or other signs of infection).

What should I avoid while using Hycamtin (topotecan)?

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while using topotecan, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you. Live vaccines include measles, mumps, rubella (MMR), oral polio, typhoid, chickenpox (varicella), BCG (Bacillus Calmette and Gu?rin), and nasal flu vaccine. Topotecan may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Hycamtin (topotecan) side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

wheezing, feeling short of breath, chest pain, dry cough;

fever, chills, flu symptoms, mouth and throat ulcers, rapid and shallow breathing, fainting;

pale skin, feeling light-headed, rapid heart rate, trouble concentrating;

easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

diarrhea with fever and stomach cramps;

pain or burning when you urinate; or

skin changes or severe irritation where the needle is placed.

Less serious side effects may include:

nausea, diarrhea, vomiting;

tired feeling; or

temporary hair loss.

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.

What other drugs will affect Hycamtin (topotecan)?

Tell your doctor about all other cancer medicines you use, especially:

filgrastim (Neupogen), pegfilgrastim (Neulasta), or sargramostim (Leukine); or

cisplatin (Platinol), carboplatin (Paraplatin), or oxaliplatin (Eloxatin).

This list is not complete and other drugs may interact with topotecan. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Hycamtin resources Hycamtin Side Effects (in more detail) Hycamtin Use in Pregnancy & Breastfeeding Hycamtin Drug Interactions Hycamtin Support Group 0 Reviews for Hycamtin - Add your own review/rating Hycamtin Prescribing Information (FDA) Hycamtin MedFacts Consumer Leaflet (Wolters Kluwer) Hycamtin Monograph (AHFS DI) Hycamtin Advanced Consumer (Micromedex) - Includes Dosage Information Topotecan Prescribing Information (FDA) Compare Hycamtin with other medications Cancer Cervical Cancer Ovarian Cancer Small Cell Lung Cancer Where can I get more information? Your doctor or pharmacist can provide more information about topotecan.

See also: Hycamtin side effects (in more detail)


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Nicorette 10 mg Patch


1. Name Of The Medicinal Product

Nicorette 10mg Patch or Boots NicAssist 10 mg Patch

2. Qualitative And Quantitative Composition

Nicotine, 10mg released over 16 hours use. Each patch is 20 sq.cm, containing nicotine 0.83mg/sq.cm.

For excipients see section 6.1

3. Pharmaceutical Form

Transdermal Patch

4. Clinical Particulars 4.1 Therapeutic Indications

Nicorette Patch is indicated for the relief of nicotine withdrawal symptoms as an aid to smoking cessation in adults and children over 12 years of age. It is also indicated in pregnant and lactating women (see section 4.6).

If possible, Nicorette Patch should be used in conjunction with a behavioural support programme.

4.2 Posology And Method Of Administration

The patient should make every effort to stop smoking completely during treatment with Nicorette Patch.

Behavioural therapy, advice and support will normally improve the success rate.

Nicorette Patch should be applied to clean, dry intact areas of hairless skin, for example on the hip, upper arm, or chest. These areas should be varied each day and the same site should not be used on consecutive days.

There is no clinically significant difference in bioavailability of nicotine when the patch is applied to either the hip, upper arm or chest.

Adults (over 18 years of age)

The daily dose is one patch delivering 15mg, 10mg or 5mg nicotine as appropriate, with application limited to 16 hours in a 24 hour period in each case.

Daily treatment commences with one 15mg (30cm2) patch, applied on waking (usually in the morning) and removed 16 hours later (usually at bedtime).

After removal, used patches should be disposed of carefully (see warnings).

Treatment should continue at this dose for an initial period of 8 weeks. Patients who have successfully abstained from smoking during this 8 week period should be supported through a further 4 week weaning period, using the lower strength patches. Downward titration of dose is achieved by applying one 10mg (20cm2) patch daily for 2 weeks followed by one 5mg (10cm2) patch daily for a further 2 weeks.

Adults who use NRT beyond 9 months are recommended to seek additional help and advice from a healthcare professional.

Adolescents (12 to 18 years)

The dose and method of use are as for adults however as data are limited in this age group, the recommended treatment duration is 12 weeks. If longer treatment is required, advice from a healthcare professional should be sought.

4.3 Contraindications

Nicorette Patches should not be administered to patients with known hypersensitivity to nicotine or any component of the patch.

4.4 Special Warnings And Precautions For Use

Any risks that may be associated with NRT are substantially outweighed by the well established dangers of continued smoking.

Underlying cardiovascular disease: In stable cardiovascular disease Nicorette Patch presents a lesser hazard than continuing to smoke. However dependent smokers currently hospitalised as a result of myocardial infarction, severe dysrhythmia or CVA and who are considered to be haemodynamically unstable should be encouraged to stop smoking with non-pharmacological interventions. If this fails, Nicorette Patch may be considered, but as data on safety in this patient group are limited, initiation should only be under medical supervision.

Diabetes mellitus: Patients with diabetes mellitus should be advised to monitor their blood sugar levels more closely than usual when NRT is initiated as catecholamines released by nicotine can affect carbohydrate metabolism.

Renal or hepatic impairment: Nicorette Patch should be used with caution in patients with moderate to severe hepatic impairment and/or severe renal impairment as the clearance of nicotine or its metabolites may be decreased with the potential for increased adverse effects.

Danger in small children: Doses of nicotine tolerated by adult and adolescent smokers can produce severe toxicity in small children that may be fatal. Products containing nicotine should not be left where they may be misused, handled or ingested by children. After removal, the patch should be folded in half, adhesive side innermost, and placed inside the opened sachet, or in a piece of aluminium foil. The used patch should then be disposed of carefully, away from the reach of children or animals.

Phaeochromocytoma and uncontrolled hyperthyroidism: As nicotine causes release of catecholamines, Nicorette Patch should be used with caution in patients with uncontrolled hyperthyroidism or phaeochromocytoma.

Transferred dependence: Transferred dependence is rare and is both less harmful and easier to break than smoking dependence.

Stopping smoking: Polycyclic aromatic hydrocarbons in tobacco smoke induce the metabolism of drugs metabolised by CYP 1A2 (and possibly by CYP 1A1). When a smoker stops smoking, this may result in slower metabolism and a consequent rise in blood levels of such drugs. This is of potential clinical importance for products with a narrow therapeutic window, e.g. theophylline, clozapine and ropinirole.

Generalised dermatological disorders :Patients with chronic generalised dermatological disorders such as psoriasis, chronic dermatitis or urticaria should not use Nicorette Patch.

Erythema may occur. If it is severe or persistent, treatment should be discontinued.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically relevant interactions between nicotine replacement therapy and other drugs has definitely been established. However nicotine may possibly enhance the haemodynamic effects of adenosine i.e. increase in blood pressure and heart rate and also increase pain response (angina-pectoris type chest pain) provoked by adenosine administration.

4.6 Pregnancy And Lactation

Pregnancy

NRT is not contraindicated in pregnancy. The decision to use NRT should be made on a risk-benefit assessment as early on in the pregnancy as possible with the aim of discontinuing use as soon as possible.

Smoking during pregnancy is associated with risks such as intra-uterine growth retardation, premature birth or stillbirth. Stopping smoking is the single most effective intervention for improving the health of both pregnant smoker and her baby. The earlier abstinence is achieved the better.

Ideally smoking cessation during pregnancy should be achieved without NRT. However for women unable to quit on their own, NRT may be recommended to assist a quit attempt.

Nicotine passes to the fetus affecting breathing movements and has a dose-dependent effect on placental/fetal circulation. However the risk of using NRT to the fetus is lower than that expected with tobacco smoking, due to lower maximal plasma nicotine concentration and no additional exposure to polycyclic hydrocarbons and carbon monoxide.

Intermittent dosing products may be preferable as these usually provide a lower daily dose of nicotine than patches. However, patches may be preferred if the women is suffering from nausea during pregnancy. If patches are used they should be removed before going to bed.

Lactation

NRT is not contraindicated in lactation. Nicotine from smoking and NRT is found in breast milk. However the amount of nicotine the infant is exposed to is relatively small and less hazardous than the second-hand smoke they would otherwise be exposed to.

Using intermittent dose NRT preparations, compared with patches, may minimize the amount of nicotine in the breast milk as the time between administrations of NRT and feeding can be more easily prolonged.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Some symptoms may be related to nicotine withdrawal associated with stopping smoking. These can include; irritability/aggression, dysphoria/depressed mood, anxiety, restlessness, poor concentration, increased appetite/weight gain, urges to smoke (cravings), night-time awakenings/sleep disturbance and decreased heart rate.

Increased frequency of aphthous ulcer may occur after abstinence from smoking. The causality is unclear.

Nicorette Patch may cause adverse reactions similar to those associated with nicotine given by other means, including smoking, and these are mainly dose-dependent. At recommended doses Nicorette Patch has not been found to cause any serious adverse effects. Excessive use of Nicorette Patch by those who have not been in the habit of inhaling tobacco smoke could possibly lead to nausea, faintness or headaches.

About 20% of Nicorette patch users experience mild local skin reactions, during the first weeks of treatment.

Reported adverse events associated with Nicorette 5mg, 10mg and 15mg patch include:

Body System

Incidence*

Reported adverse event

 

Nervous system disorders:

Common:

Dizziness, headache

Cardiac disorders:

Uncommon:

Palpitations

 

 

Very rare:

Reversible atrial fibrillation

Gastrointestinal disorders:

Common:

Gastrointestinal discomfort, nausea, vomiting

Skin and subcutaneous tissue disorders:

Uncommon:

Urticaria

General disorders and administration site disorders:

Very common:

Itching

 

 

Common:

Erythema

*Very common >1/10); common >1/100, <1/10); uncommon >1/1 000, <1/100); rare >1/10 000, <1/1 000); very rare (<1/10 000), including isolated reports.

4.9 Overdose

Symptoms: The minimum lethal dose of nicotine in a non-tolerant man has been estimated to be 40 to 60mg. Symptoms of acute nicotine poisoning include nausea, salivation, abdominal pain, diarrhoea, sweating headache, dizziness, disturbed hearing and marked weakness. In extreme cases, these symptoms may be followed by hypotension, rapid or weak or irregular pulse, breathing difficulties, prostration, circulatory collapse and terminal convulsions.

Management of an overdose: All nicotine intake should stop immediately and the patient should be treated symptomatically. Artificial respiration should be instituted if necessary. Activated charcoal reduces the gastro-intestinal absorption of nicotine.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Nicotine has no therapeutic uses except as replacement therapy for the relief of abstinence symptoms in nicotine-dependent smokers.

Owing to its many actions, the overall effects of nicotine are complex. A wide variety of stimulant and depressant effects are observed that involve the central and peripheral nervous, cardiovascular, endocrine, gastro-intestinal and skeletal motor systems. Nicotine acts on specific binding sites or receptors throughout the nervous system.

5.2 Pharmacokinetic Properties

Taking into account the residual concentration of nicotine in the transdermal system, the nicotine released from the system is efficiently absorbed: a bioavailability of between 80-100% has been reported. There is no clinically significant difference in bioavailability of nicotine when the patch is applied to either the hip, upper arm or chest.

Steady state concentrations of plasma nicotine in volunteers were examined during a study period of six days. Although nicotine was detectable 24 hours after the first dose, the data did not indicate any accumulation.

Tmax of nicotine after application of a 30cm2 nicotine transdermal system has been shown to vary between 6 ± 2 and 9 ± 3 hours: Cmax has been shown to vary between 13 ± 3 and 16 ± 5 ng/ml. No differences in these pharmacokinetic parameters have been observed between males and females.

All Nicorette Patches are labelled by the average amount of nicotine absorbed by the patient over 16 hours.

5.3 Preclinical Safety Data

Preclinical data indicate that nicotine is neither mutagenic nor genotoxic.

There are no other findings derived from preclinical testing of relevance to the prescriber in determining the safety of the product which have not been considered in other relevant sections of this Summary of Product Characteristics.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Medium molecular weight polyisobutylene

Low molecular weight polyisobutylene

Polybutylene

Polyester non- woven

Backing film

Siliconised polyester release liner

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Do not store at above 30oC.

6.5 Nature And Contents Of Container

Heat sealed multilaminate pouch containing one patch. Cartons of 1, 2, 3, 7*, 14 and 28 pouches (*pack presently marketed).

6.6 Special Precautions For Disposal And Other Handling

Cut open the pouch with scissors along the line, as indicated. A clean, dry intact area of skin is selected which is hairless, such as the hip, upper arm or chest. The transparent plastic backing is peeled away and the patch pressed carefully onto the skin. The fingers should be rubbed firmly round the edge to ensure that the patch sticks properly. The patch will normally resist bathing, showering, or swimming, but if it does come off it should be replaced with a new one. Use of skin oils or talc can prevent proper adhesion of the patch.

It is intended that the patch is worn through the waking hours (approximately 16 hours) being applied on waking and removed at bedtime. Nicotine residues in the used patches may present a hazard to children and pets, thus used patches should be folded, sticky sides together, put back in an empty pouch and placed in household rubbish.

7. Marketing Authorisation Holder

Pharmacia Ltd.

Ramsgate Road

Sandwich

Kent CT13 9NJ

UK

8. Marketing Authorisation Number(S)

PL 0032/0293

9. Date Of First Authorisation/Renewal Of The Authorisation

1 May 2001/ 1st January 2002

10. Date Of Revision Of The Text

04 November 2005


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Alinia


nitazoxanide
Dosage Form: tablet, powder, for suspension
Alinia® (nitazoxanide) Tablets
(nitazoxanide) for Oral Suspension DESCRIPTION

Alinia Tablets and Alinia for Oral Suspension contain the active ingredient, nitazoxanide, a synthetic antiprotozoal agent for oral administration. Nitazoxanide is a light yellow crystalline powder. It is poorly soluble in ethanol and practically insoluble in water. Chemically, nitazoxanide is 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide. The molecular formula is C12H9N3O5S and the molecular weight is 307.3. The structural formula is:

Alinia Tablets contain 500 mg of nitazoxanide and the following inactive ingredients: maize starch, pregelatinized corn starch, hydroxypropyl methylcellulose, sucrose, sodium starch glycollate, talc, magnesium stearate, soy lecithin, polyvinyl alcohol, xanthan gum, titanium dioxide, FD&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, and FD&C Blue No. 2 Aluminum Lake.

Alinia for Oral Suspension, after reconstitution, contains 100 mg nitazoxanide per 5 mL and the following inactive ingredients: sodium benzoate, sucrose, xanthan gum, microcrystalline cellulose and carboxymethylcellulose sodium, anhydrous citric acid, sodium citrate dihydrate, acacia gum, sugar syrup, FD&C Red #40 and natural strawberry flavoring.

CLINICAL PHARMACOLOGY

Absorption: Following oral administration of Alinia Tablets or Oral Suspension, maximum plasma concentrations of the active metabolites tizoxanide and tizoxanide glucuronide are observed within 1-4 hours. The parent nitazoxanide is not detected in plasma. Pharmacokinetic parameters of tizoxanide and tizoxanide glucuronide are shown in Tables 1 and 2 below.

Table 1. Mean (±SD) plasma pharmacokinetic parameter values following administration of a single dose of one 500 mg Alinia Tablet with food to subjects ?12 years of age

* Tmax is given as a Mean (Range)

Tizoxanide Tizoxanide glucuronide Age Cmax
(?g/mL) Tmax*
(hr) AUC?
(?g•hr/mL) Cmax
(?g/mL) Tmax*
(hr) AUC?
(?g•hr/mL) 12-17 years 9.1 (6.1) 4.0 (1-4) 39.5 (24.2) 7.3 (1.9) 4.0 (2-8) 46.5 (18.2) ?18 years 10.6 (2.0) 3.0 (2-4) 41.9 (6.0) 10.5 (1.4) 4.5 (4-6) 63.0 (12.3) Table 2. Mean (± SD) plasma pharmacokinetic parameter values following administration of a single dose of Alinia for Oral Suspension with food to subjects ?1 year of age

* Tmax is given as a Mean (Range)

Tizoxanide Tizoxanide glucuronide
Age
Dose Cmax (?g/mL) Tmax*
(hr) AUCinf
(?g•hr/mL) Cmax
(?g/mL) Tmax*
(hr) AUCinf
(?g•hr/mL) 1-3 years 100mg 3.11 (2.0) 3.5 (2-4) 11.7 (4.46) 3.64 (1.16) 4.0 (3-4) 19.0 (5.03) 4-11 years 200mg 3.00 (0.99) 2.0 (1-4) 13.5 (3.3) 2.84 (0.97) 4.0 (2-4) 16.9 (5.00) ?18 years 500mg 5.49 (2.06) 2.5 (1-5) 30.2 (12.3) 3.21 (1.05) 4.0 (2.5-6) 22.8 (6.49)

Alinia for Oral Suspension is not bioequivalent to Alinia Tablets. The relative bioavailability of the suspension compared to the tablet was 70%.

Effect of Food: When Alinia Tablets are administered with food, the AUCt of tizoxanide and tizoxanide glucuronide in plasma is increased almost two-fold and the Cmax is increased by almost 50%.

When Alinia for Oral Suspension was administered with food, the AUCt of tizoxanide and tizoxanide glucuronide increased by about 45-50% and the Cmax increased by ?10%.

Alinia Tablets and for Oral Suspension were administered with food in clinical trials and hence they are recommended to be administered with food (see DOSAGE AND ADMINISTRATION).

Multiple dosing: Following oral administration of a single Alinia Tablet every 12 hours for 7 consecutive days, there was no significant accumulation of nitazoxanide metabolites tizoxanide or tizoxanide glucuronide detected in plasma.

Distribution: In plasma, more than 99% of tizoxanide is bound to proteins.

Metabolism: Following oral administration in humans, nitazoxanide is rapidly hydrolyzed to an active metabolite, tizoxanide (desacetyl-nitazoxanide). Tizoxanide then undergoes conjugation, primarily by glucuronidation. In vitro metabolism studies have demonstrated that tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes.

Elimination: Tizoxanide is excreted in the urine, bile and feces, and tizoxanide glucuronide is excreted in urine and bile. Approximately two-thirds of the oral dose of nitazoxanide is excreted in the feces and one-third in the urine.

Special Populations

Patients with Impaired Hepatic and/or Renal Function: The pharmacokinetics of nitazoxanide in patients with impaired hepatic and/or renal function has not been studied.

Geriatric Patients: The pharmacokinetics of nitazoxanide in geriatric patients has not been studied.

Pediatric Patients: The pharmacokinetics of nitazoxanide following administration of Alinia Tablets in pediatric patients less than 12 years of age has not been studied. The pharmacokinetics of nitazoxanide following administration of Alinia for Oral Suspension in pediatric patients less than one year of age has not been studied.

MICROBIOLOGY Mechanism of Action

The antiprotozoal activity of nitazoxanide is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction which is essential to anaerobic energy metabolism. Studies have shown that the PFOR enzyme from Giardia lamblia directly reduces nitazoxanide by transfer of electrons in the absence of ferredoxin. The DNA-derived PFOR protein sequence of Cryptosporidium parvum appears to be similar to that of Giardia lamblia. Interference with the PFOR enzyme-dependent electron transfer reaction may not be the only pathway by which nitazoxanide exhibits antiprotozoal activity.

Activity in vitro

Nitazoxanide and its metabolite, tizoxanide, are active in vitro in inhibiting the growth of (i) sporozoites and oocysts of Cryptosporidium parvum and (ii) trophozoites of Giardia lamblia.

Drug Resistance

A potential for development of resistance by Cryptosporidium parvum or Giardia lamblia to nitazoxanide has not been examined.

Susceptibility Tests:

For protozoa such as Cryptosporidium parvum and Giardia lamblia, standardized tests for use in clinical microbiology laboratories are not available.

INDICATIONS AND USAGE Diarrhea caused by Giardia lamblia or Cryptosporidium parvum:

Alinia for Oral Suspension (patients 1 year of age and older) and Alinia Tablets (patients 12 years and older) are indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum.

Alinia for Oral Suspension and Alinia Tablets have not been shown to be superior to placebo for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients (see CLINICAL STUDIES).

CONTRAINDICATIONS

Alinia Tablets and Alinia for Oral Suspension are contraindicated in patients with a prior hypersensitivity to nitazoxanide or any other ingredient in the formulations.

PRECAUTIONS

General: The pharmacokinetics of nitazoxanide in patients with compromised renal or hepatic function have not been studied. Therefore, nitazoxanide must be administered with caution to patients with hepatic and biliary disease, to patients with renal disease and to patients with combined renal and hepatic disease.

Information for Patients

Alinia Tablets and Alinia for Oral Suspension should be taken with food.

Diabetic patients and caregivers should be aware that the oral suspension contains 1.48 grams of sucrose per 5 mL.

Drug Interactions

Tizoxanide is highly bound to plasma protein (>99.9%). Therefore, caution should be used when administering nitazoxanide concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices, as competition for binding sites may occur (e.g., warfarin). In vitro metabolism studies have demonstrated that tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes. Although no drug-drug interaction studies have been conducted in vivo, it is expected that no significant interaction would occur when nitazoxanide is co-administered with drugs that either are metabolized by or inhibit cytochrome P450 enzymes.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have not been conducted.

Nitazoxanide was not genotoxic in the Chinese hamster ovary (CHO) cell chromosomal aberration assay or the mouse micronucleus assay. Nitazoxanide was genotoxic in one tester strain (TA 100) in the Ames bacterial mutation assay.

Nitazoxanide did not adversely affect male or female fertility in the rat at 2400 mg/kg/day (approximately 20 times the clinical adult dose adjusted for body surface area).

Pregnancy: Teratogenic Effects

Pregnancy Category B: Reproduction studies have been performed at doses up to 3200 mg/kg/day in rats (approximately 26 times the clinical adult dose adjusted for body surface area) and 100 mg/kg/day in rabbits (approximately 2 times the clinical adult dose adjusted for surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to nitazoxanide. There are, however, no adequate and well-controlled studies in pregnant women.

Nursing Mothers

It is not known whether nitazoxanide is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitazoxanide is administered to a nursing woman.

Pediatric Use

A single Alinia Tablet contains a greater amount of nitazoxanide than is recommended for pediatric dosing and should therefore not be used in pediatric patients 11 years or younger. Alinia for Oral Suspension should be used for dosing nitazoxanide in pediatric patients (See DOSAGE AND ADMINISTRATION).

Safety and effectiveness of Alinia for Oral Suspension in pediatric patients less than one year of age have not been studied.

Geriatric Use

Clinical studies of Alinia Tablets and Alinia for Oral Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Alinia Tablets and Alinia for Oral Suspension. As stated in the PRECAUTIONS section, this therapy must be administered with caution to patients with renal and or hepatic impairment.

HIV-Infected or Immunodeficient Patients

Alinia Tablets and Alinia for Oral Suspension have not been studied for the treatment of diarrhea caused by Giardia lamblia in HIV-infected or immunodeficient patients. Alinia Tablets and Alinia for Oral Suspension have not been shown to be superior to placebo for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients (see CLINICAL STUDIES).

Adverse Reactions

Alinia Tablets: In controlled and uncontrolled clinical studies of 1,657 HIV-uninfected patients age 12 years and older who received various dosage regimens of Alinia Tablets, the most common adverse events reported regardless of causality assessment were: abdominal pain (6.6%), diarrhea (4.2%), headache (3.1%) and nausea (3.0%). In placebo-controlled clinical trials using the recommended dose, the rates of occurrence of these events did not differ significantly from those of the placebo. In placebo-controlled trials of HIV-uninfected patients age 12 years and older who received Alinia Tablets for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum, less than 1% of patients discontinued therapy because of an adverse event.

Adverse events occurring in less than 1% of the patients age 12 years and older participating in clinical trials of Alinia Tablets are listed below:

Body as a Whole: asthenia, fever, pain, allergic reaction, pelvic pain, back pain, chills, chills and fever, flu syndrome.

Nervous System: dizziness, somnolence, insomnia, tremor, hypesthesia.

Digestive System: vomiting, dyspepsia, anorexia, flatulence, constipation, dry mouth, thirst.

Urogenital System: discolored urine, dysuria, amenorrhea, metrorrhagia, kidney pain, edema labia.

Metabolic & Nutrition: increased SGPT.

Hemic & Lymphatic Systems: anemia, leukocytosis.

Skin: rash, pruritus.

Special Senses: eye discoloration, ear ache.

Respiratory System: epistaxis, lung disease, pharyngitis.

Cardiovascular System: tachycardia, syncope, hypertension.

Muscular System: myalgia, leg cramps, spontaneous bone fracture.

Alinia for Oral Suspension: In controlled and uncontrolled clinical studies of 613 HIV-uninfected pediatric patients who received Alinia for Oral Suspension, the most frequent adverse events reported regardless of causality assessment were: abdominal pain (7.8%), diarrhea (2.1%), vomiting (1.1%) and headache (1.1%). These were typically mild and transient in nature. In placebo-controlled clinical trials, the rates of occurrence of these events did not differ significantly from those of the placebo. None of the 613 pediatric patients discontinued therapy because of adverse events.

Adverse events occurring in less than 1% of the pediatric patients participating in clinical trials of Alinia for Oral Suspension are listed below:

Digestive System: nausea, anorexia, flatulence, appetite increase, enlarged salivary glands.

Body as a Whole: fever, infection, malaise.

Metabolic & Nutrition: increased creatinine, increased SGPT.

Skin: pruritus, sweat.

Special Senses: eye discoloration (pale yellow).

Respiratory System: rhinitis.

Nervous System: dizziness.

Urogenital System: discolored urine.

The adverse events seen in adult patients treated with Alinia for Oral Suspension were similar to those observed in adult patients treated with Alinia Tablets.

OVERDOSAGE

Information on nitazoxanide overdosage is not available. In acute studies in rodents and dogs, the oral LD50 was higher than 10,000 mg/kg. Single oral doses of up to 4000 mg nitazoxanide have been administered to healthy adult volunteers without significant adverse effects. In the event of overdose, gastric lavage may be appropriate soon after oral administration. Patients should be carefully observed and given symptomatic and supportive treatment.

DOSAGE & ADMINISTRATION

* Alinia Tablets and Alinia for Oral Suspension have not been studied for the treatment of Giardia lamblia in HIV-infected or immunodeficient patients. Alinia Tablets and Alinia for Oral Suspension have not been shown to be superior to placebo for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients (see CLINICAL STUDIES).

Indication Age Dosage Duration Treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum* 1-3 years 5 mL of Alinia for Oral Suspension
(100 mg nitazoxanide) every 12 hours with food
3 days 4-11 years 10 mL of Alinia for Oral Suspension
(200 mg nitazoxanide) every 12 hours with food     ?12 years 1 Alinia Tablet (500 mg nitazoxanide) every 12 hours with food or 25 mL of Alinia for Oral Suspension (500 mg nitazoxanide) every 12 hours with food    

A single Alinia tablet contains a greater amount of nitazoxanide than is recommended for pediatric dosing and should therefore not be used in pediatric patients 11 years or younger.

DIRECTIONS FOR MIXING Alinia FOR ORAL SUSPENSION

Prepare a suspension at time of dispensing as follows: The amount of water required for preparation of the suspension is 48 mL. Tap bottle until all powder flows freely. Add approximately one-half of the total amount of water required for reconstitution and shake vigorously to suspend powder. Add remainder of water and again shake vigorously.

The container should be kept tightly closed, and the suspension should be shaken well before each administration. The suspension may be stored for 7 days, after which any unused portion must be discarded.

HOW SUPPLIED

Alinia Tablets are round, yellow, film-coated tablets debossed with Alinia on one side and 500 on the other side. Each tablet contains 500 mg of nitazoxanide. The tablets are packaged in HDPE bottles of 30 and 60 tablets.

  Bottles of 30            NDC 67546-111-12   Bottles of 60            NDC 67546-111-11

Alinia for Oral Suspension is a pink-colored powder formulation that, when reconstituted as directed, contains 100 mg nitazoxanide/5 mL. The reconstituted suspension has a pink color and strawberry flavor. Alinia for Oral Suspension is available as:

  Bottles of 60 mL       NDC 67546-212-21

Storage and Stability: Store the tablets, unsuspended powder, and the reconstituted oral suspension at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature]

CLINICAL STUDIES Diarrhea caused by Giardia lamblia in adults and adolescents 12 years of age or older:

In a double-blind, controlled study (Study 1) conducted in Peru and Egypt in adults and adolescents with diarrhea caused by Giardia lamblia, a three-day course of treatment with Alinia Tablets administered 500 mg BID was compared with a placebo tablet for 3 days. A third group of patients received open-label Alinia for Oral Suspension administered 500mg/25mL of suspension BID for 3 days. A second double-blind, controlled study (Study 2) conducted in Egypt in adults and adolescents with diarrhea caused by Giardia lamblia compared Alinia Tablets administered 500 mg BID for 3 days to a placebo tablet. For both of these studies, clinical response was evaluated 4 to 7 days following the end of treatment. A clinical response of 'well' was defined as 'no symptoms, no watery stools and no more than 2 soft stools with no hematochezia within the past 24 hours' or 'no symptoms and no unformed stools within the past 48 hours.' The following clinical response rates were obtained:

Adult and Adolescent Patients with Diarrhea Caused by Giardia lamblia Clinical Response Rates* 4 to 7 Days Post-therapy % (Number of Successes/Total)

* Includes all patients randomized with Giardia lamblia as the sole pathogen. Patients failing to complete the studies were treated as failures.

¶ Clinical response rates statistically significantly higher when compared to placebo.

§ The 95% confidence interval of the difference in response rates for the tablet and suspension is (-14%, 17%).

Alinia Tablets Alinia for Oral Suspension Placebo Tablets Study 1 85% (46/54) ¶ § 83% (45/54) ¶ § 44% (12/27) Study 2 100% (8/8) - 30% (3/10)

Some patients with 'well' clinical responses had Giardia lamblia cysts in their stool samples 4 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.

Diarrhea caused by Giardia lamblia in pediatric patients 1 through 11 years of age:

In a randomized, controlled study conducted in Peru in 110 pediatric patients with diarrhea caused by Giardia lamblia, a three-day course of treatment with nitazoxanide (100 mg BID in pediatric patients ages 24-47 months, 200 mg BID in pediatric patients ages 4 through 11 years) was compared to a five-day course of treatment with metronidazole (125 mg BID in pediatric patients ages 2 through 5 years, 250 mg BID in pediatric patients ages 6 through 11 years). Clinical response was evaluated 7 to 10 days following initiation of treatment with a 'well' response defined as 'no symptoms, no watery stools and no more than 2 soft stools with no hematochezia within the past 24 hours' or 'no symptoms and no unformed stools within the past 48 hours.' The following clinical cure rates were obtained:

Pediatric Patients with Diarrhea Caused by Giardia lamblia Clinical Response Rates 7 to 10 Days Following Initiation of Therapy Intent-to-Treat and Per Protocol Analyses % (Number of Successes/Total), [95% Confidence Interval]

† Intent-to-treat analysis includes all patients randomized with patients not completing the study treated as failures.

¶ Per protocol analysis includes only patients who took all of their medication and completed the study. Seven patients in each treatment group missed at least one dose of medication and one in the metronidazole treatment group was lost to follow-up.

§ 95% Confidence Interval on the difference in response rates (nitazoxanide-metronidazole).

Population Nitazoxanide (3 days) Metronidazole (5 days) 95% CI Diff§ Intent-to-treat analysis† 85% (47/55) 80% (44/55 ) [-9%, 20%] Per protocol analysis¶ 90% (43/48) 83% (39/47 ) [-8%, 21%]

Some patients with 'well' clinical responses had Giardia lamblia cysts in their stool samples 4 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.

Diarrhea caused by Cryptosporidium parvum in adults and adolescents 12 years of age or older:

In a double-blind, controlled study conducted in Egypt in adults and adolescents with diarrhea caused by Cryptosporidium parvum, a three-day course of treatment with Alinia Tablets administered 500 mg BID was compared with a placebo tablet for 3 days. A third group of patients received open-label Alinia for Oral Suspension administered 500mg/25mL of suspension BID for 3 days. Clinical response was evaluated 4 to 7 days following the end of treatment. A clinical response of 'well' was defined as 'no symptoms, no watery stools and no more than 2 soft stools within the past 24 hours' or 'no symptoms and no unformed stools within the past 48 hours.' The following clinical response rates were obtained:

Adult and Adolescent Patients with Diarrhea Caused by Cryptosporidium parvum Clinical Response Rates 4 to 7 Days Post-therapy % (Number of Successes/Total)

* Includes all patients randomized with Cryptosporidium parvum as the sole pathogen. Patients failing to complete the study were treated as failures.

¶ Clinical response rates statistically significantly higher when compared to placebo.

§ The 95% confidence interval of the difference in response rates for the tablet and suspension is (-10%, 28%).

Alinia Tablets Alinia Suspension Placebo Tablets Intent-to-treat analysis* 96% (27/28) ¶ § 87% (27/31) ¶ § 41% (11/27)

In a second double-blind, placebo-controlled study of nitazoxanide tablets conducted in Egypt in adults and adolescents with diarrhea caused by Cryptosporidium parvum as the sole pathogen, clinical and parasitological response rates showed a similar trend to the first study. Clinical response rates, evaluated 2 to 6 days following the end of treatment, were 71% (15/21) in the nitazoxanide group and 42.9% (9/21) in the placebo group.

Some patients with 'well' clinical responses had Cryptosporidium parvum oocysts in their stool samples 4 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.

Diarrhea caused by Cryptosporidium parvum in pediatric patients 1 through 11 years of age:

In two double-blind, controlled studies in pediatric patients with diarrhea caused by Cryptosporidium parvum, a three-day course of treatment with nitazoxanide (100 mg BID in pediatric patients ages 12-47 months, 200 mg BID in pediatric patients ages 4 through 11 years) was compared with a placebo. One study was conducted in Egypt in outpatients ages 1 through 11 years with diarrhea caused by C. parvum. Another study was conducted in Zambia in malnourished pediatric patients admitted to the hospital with diarrhea caused by C. parvum. Clinical response was evaluated 3 to 7 days post-therapy with a 'well' response defined as 'no symptoms, no watery stools and no more than 2 soft stools within the past 24 hours' or 'no symptoms and no unformed stools within the past 48 hours.' The following clinical response rates were obtained:

Pediatric Patients with Diarrhea Caused by Cryptosporidium parvum Clinical Response Rates 3 to 7 Days Post-therapy, Intent-to-Treat Analyses % (Number of Successes/Total)

* Clinical response rates statistically significantly higher compared to placebo.

¶ 60% considered severely underweight, 19% moderately underweight, 17% mild underweight.

Population Nitazoxanide* Placebo Outpatient Study, age 1 - 11 years 88% (21/24) 38% (9/24) Inpatient Study, Malnourished¶,age 12-35 months 56% (14/25) 23% (5/22 )

Some patients with 'well' clinical responses had Cryptosporidium oocysts in their stool samples 3 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.

Diarrhea caused by Cryptosporidium parvum in AIDS patients:

A double-blind, placebo-controlled study did not produce clinical cure rates that were significantly different from the placebo control when conducted in hospitalized, severely malnourished pediatric patients with acquired immune deficiency syndrome (AIDS) in Zambia. In this study, the pediatric patients received a three day course of nitazoxanide suspension (100 mg BID in pediatric patients ages 12-47 months, 200 mg BID in pediatric patients ages 4 through 11 years) and were evaluated for response four days after the end of treatment.

Rx Only
US Patents No. 5,578,621; 6,020,353; 5,968,961; 5,387,598; 6,117,894; 5,965,590.
DATE OF ISSUANCE: October, 2008

ROMARK Laboratories, L.C.
3000 Bayport Drive, Suite 200, Tampa, FL 33607
Telephone: 813-282-8544, Fax: 813-282-1162
E-mail: [email protected]
Web site: www.romark.com

Principal Display Panel

Alinia 500 mg 30 Tablets Bottle Label

NDC 67546-111-12
Alinia®
(nitazoxanide) tablets
500 mg
Rx only
30 TABLETS

Alinia 500 mg 30 Tablets Carton

NDC 67546-111-12
Alinia®
(nitazoxanide) tablets
500 mg
Romark Pharmaceuticals
Rx Only
30 TABLETS

Alinia 500 mg 2 Tablets Sample Blister

NDC 67546-111-37
Alinia® (nitazoxanide)
Two (2) tablets, 500 mg
Rx Only
Sample: NOT FOR SALE
Manufactured for Romark Laboratories, L.C.

Alinia 500 mg 2 Tablets Sample Carton

NDC 67546-111-37
2 TABLETS
Alinia®
(nitazoxanide) tablets
500 mg
Rx Only
Professional Sample
NOT FOR SALE

Alinia 500 mg 2 Tablets Sample Tray

NDC 67546-111-37
Alinia®
(nitazoxanide) tablets
500 mg
Rx Only
5 Boxes x 2 Tablets
Professional Sample
NOT FOR SALE

Alinia 100mg/5mL Suspension Bottle Label

NDC 67546-212-21
Alinia® (nitazoxanide)
For Oral Suspension
100mg/5mL
Reconstitute with 48mL water
SHAKE WELL BEFORE USING
Any unused portion must be discarded
7 days after mixing
60mL reconstituted
Rx only
Romark Laboratories, L.C.

Alinia 100mg/5mL Suspension Carton

NDC 67546-212-21
Alinia® (nitazoxanide)
For Oral Suspension
100mg/5mL
Reconstitute with 48mL water
SHAKE WELL BEFORE USING
Any unused portion must be discarded
7 days after mixing
60mL reconstituted
Rx only
Romark Pharmaceuticals


Alinia 
nitazoxanide  tablet Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 67546-111 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength nitazoxanide (nitazoxanide) nitazoxanide 500 mg Inactive Ingredients Ingredient Name Strength starch, corn   hypromellose   sucrose   sodium starch glycolate type A potato   talc   magnesium stearate   lecithin, soybean   polyvinyl alcohol   xanthan gum   titanium dioxide   D&C Yellow No. 10   FD&C Yellow No. 6   FD&C Blue No. 2   Product Characteristics Color yellow (yellow) Score no score Shape ROUND (ROUND) Size 13mm Flavor Imprint Code Alinia;500 Contains          Packaging # NDC Package Description Multilevel Packaging 1 67546-111-11 60 TABLET In 1 BOTTLE, PLASTIC None 2 67546-111-12 30 TABLET In 1 BOTTLE, PLASTIC None 3 67546-111-37 2 TABLET In 1 BLISTER PACK None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021497 07/21/2004
Alinia 
nitazoxanide  powder, for suspension Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 67546-212 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength nitazoxanide (nitazoxanide) nitazoxanide 100 mg  in 5 mL Inactive Ingredients Ingredient Name Strength sodium benzoate   sucrose   xanthan gum   cellulose, microcrystalline   carboxymethylcellulose sodium   anhydrous citric acid   trisodium citrate dihydrate   acacia   FD&C Red No. 40   Product Characteristics Color      Score      Shape Size Flavor STRAWBERRY (STRAWBERRY) Imprint Code Contains         
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