kwin-ue-PRIS-tin, dal-foe-PRIS-tin

Intravenous route(Powder for Solution)

Quinupristin/dalfopristin has been approved for marketing in the United States for vancomycin-resistant Enterococcus faecium (VREF) bacteremia under FDA's accelerated approval regulations that allow marketing of products for use in life-threatening conditions when other therapies are not available. Approval of this indication is based upon quinupristin/dalfopristin’s ability to clear VREF from the bloodstream, with clearance of bacteremia considered to be a surrogate endpoint. There are no results from well-controlled clinical studies that confirm the validity of this surrogate marker .

Commonly used brand name(s)

In the U.S.

Synercid

Available Dosage Forms:

Powder for Solution

Therapeutic Class: Antibiotic

Chemical Class: Streptogramin

Uses For quinupristin and dalfopristin

Quinupristin and dalfopristin injection is used to treat infections of the skin and the blood. It may also be used for other conditions as determined by your doctor. It is given by injection and is used mainly for serious infection for which other medicine may not work.

Quinupristin and dalfopristin belong to the family of medicine called antibiotics. Antibiotics are medicines used in the treatment of infections caused by bacteria. They work by killing bacteria or preventing their growth. Quinupristin and dalfopristin will not work for colds, flu, or other virus infections.

quinupristin and dalfopristin is available only with your doctor's prescription.

Before Using quinupristin and dalfopristin

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

Allergies

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

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of quinupristin and dalfopristin injection in children younger than 16 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of quinupristin and dalfopristin injection in the elderly.

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

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

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving quinupristin and dalfopristin, 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 quinupristin and dalfopristin with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

Cisapride Pimozide

Using quinupristin and dalfopristin 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.

Astemizole Atorvastatin Cerivastatin Fluvastatin Haloperidol Lovastatin Pravastatin Simvastatin Terfenadine

Using quinupristin and dalfopristin with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Amlodipine Carbamazepine Cyclosporine Delavirdine Diazepam Diltiazem Disopyramide Docetaxel Felodipine Indinavir Isradipine Lacidipine Lidocaine Manidipine Methylprednisolone Midazolam Nevirapine Nicardipine Nifedipine Nilvadipine Nimodipine Nisoldipine Nitrendipine Paclitaxel Quinidine Ritonavir Tacrolimus Verapamil Vinblastine Vincamine Vincristine Vincristine Liposome Vindesine 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 quinupristin and dalfopristin. Make sure you tell your doctor if you have any other medical problems, especially:

Colitis (inflammation of the colon) or Diarrhea, severe—Use with caution. May make these conditions worse. Liver disease—Liver disease may increase blood levels of quinupristin and dalfopristin, increasing the chance of side effects. Proper Use of quinupristin and dalfopristin

A nurse or other trained health professional will give you quinupristin and dalfopristin in a hospital. quinupristin and dalfopristin is given through a needle placed in one of your veins. The medicine must be injected slowly, so your IV tube will need to stay in place for 60 minutes.

To help clear up your infection completely, quinupristin and dalfopristin must be given for the full time of treatment, even if you begin to feel better after a few days. Also, it works best when there is a constant amount in the blood. To help keep the amount constant, quinupristin and dalfopristin must be given on a regular schedule.

Precautions While Using quinupristin and dalfopristin

Your doctor will check your progress closely while you are receiving quinupristin and dalfopristin. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it. Blood tests may be needed to check for unwanted effects.

If your symptoms do not improve or if they become worse, call your doctor.

quinupristin and dalfopristin may cause diarrhea, and in some cases it can be severe. It may occur 2 months or more after you stop receiving quinupristin and dalfopristin. Do not take any medicine to treat diarrhea without first checking with your doctor. If you have any questions or if mild diarrhea continues or gets worse, check with your doctor.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

quinupristin and dalfopristin Side Effects

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

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

More common Swelling, redness, or pain at the injection site Less common Changes in skin color dry, red, hot, or irritated skin joint pain muscle pain pain redness, burning sensation, or pain under the skin usually in the injection site swelling of the foot or leg tenderness Rare Agitation anxiety back, leg, or stomach pains black, tarry stools bleeding gums bloating or swelling of the face, arms, hands, lower legs, or feet blood in the urine bloody, black, or tarry stools blue lips, fingernails, or skin blurred vision bone pain burning, tingling, numbness, or pain in the hands, arms, feet, or legs chest pain or discomfort chest pain, possibly moving to the left arm, neck, or shoulder chills coma confusion constipation convulsions or seizures cough or hoarseness darkened urine decreased urine output difficult, fast, or labored breathing difficult or painful urination difficulty with moving difficulty with swallowing dizziness dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position drowsiness extremely shallow or slow breathing fainting fast, slow, irregular, pounding, or racing heartbeat or pulse feeling of warmth or heat flushing or redness of the skin, especially on the face and neck general body swelling general tiredness and weakness hallucinations headache high fever hives inability to speak increased thirst indigestion irritability itching light-colored stools loss of appetite loss of bladder control loss of consciousness loss of strength or energy lower back or side pain muscle pain or cramps muscle stiffness or weakness nausea or vomiting no blood pressure or pulse nosebleeds not breathing pain in the joints pains in the stomach, side, or abdomen, possibly radiating to the back pale skin problems with bleeding or clotting puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue rapid weight gain redness, burning sensation, or pain in the vagina sensation of pins and needles severe bloody diarrhea severe or sudden headache shakiness in the legs, arms, hands, or feet shortness of breath skin rash skin rash with red patches slurred speech sore throat sores on the skin sores, ulcers, or white spots on the lips or in the mouth stabbing pain stiff neck stopping of the heart sweating swelling of the face, ankles, or hands swollen glands temporary blindness tightness in the chest tingling of the hands or feet total body jerking trembling or shaking of the hands or feet troubled breathing unconsciousness unexplained bleeding or bruising unusual tiredness or weakness unusual weight gain or loss upper right abdominal or stomach pain vomiting vomiting of blood or material that looks like coffee grounds weakness in the arm or leg on one side of the body, sudden and severe wheezing worsening of the underlying disease yellowing of the eyes or skin Incidence not known Large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs

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:

Rare Acid or sour stomach ankle, knee, or great toe joint pain belching cold sweats cool, pale skin cramps in the legs depression excessive muscle tone heartburn hives or welts increased hunger itching of the vagina or genital area joint stiffness or swelling lower back or side pain muscle tension or tightness nightmares pain during sexual intercourse redness of the skin shakiness sleeplessness stomach discomfort, upset, or pain sweating swelling or inflammation of the mouth thick, white vaginal discharge with no odor or with a mild odor trouble sleeping unable to sleep white patches in the mouth, tongue, or throat

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

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

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

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

More quinupristin and dalfopristin Intravenous resources Quinupristin and dalfopristin Intravenous Use in Pregnancy & Breastfeeding Quinupristin and dalfopristin Intravenous Drug Interactions Quinupristin and dalfopristin Intravenous Support Group 0 Reviews for Quinupristin and dalfopristin Intravenous - Add your own review/rating Compare quinupristin and dalfopristin Intravenous with other medications Bacteremia Methicillin-Resistant Staphylococcus Aureus Infection Skin Infection



quinapril hydrochloride and hydrochlorothiazide



Pronunciation: koe-LES-teer-a-meen



Pronunciation: klor-fen-IHR-ah-meen/sue-do-eh-FED-rin



Generic Name: quinidine (KWIH nih deen)



Class: Class Ia Antiarrhythmics



Pronunciation: KWIN-ih-deen



1. Name Of The Medicinal Product QUINOCORT™ CREAM 2. Qualitative And Quantitative Composition

Potassium Hydroxyquinoline Sulphate BP

0.5%

Hydrocortisone BP

1.0%

3. Pharmaceutical Form

Quinocort Cream is a faintly yellow vanishing cream. It is intended for topical use only.

4. Clinical Particulars 4.1 Therapeutic Indications

The treatment of infected eczema, intertrigo and other steroid-responsive dermatoses where anti-infective cover is appropriate.

4.2 Posology And Method Of Administration

Route of administration: For topical use only.

Adults, children and the elderly

By gentle massage over all the affected area two to three times daily.

4.3 Contraindications

Patients with known sensitivity or intolerance to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Contact with eyes and other mucosal surfaces should be avoided. Caution should be exercised when using this preparation in infants. Long term continuous topical therapy should be avoided in infants - adrenal suppression can occur even without occlusion.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not applicable.

4.6 Pregnancy And Lactation

In pregnant animals administration of corticosteroids can cause abnormalities of foetal development. The relevance of this finding in human beings has not been established. However, topical steroids should not be used extensively in pregnancy i.e. in large amounts for long periods.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Not applicable.

4.9 Overdose

Not applicable.

5. Pharmacological Properties

Hydrocortisone provides anti-inflammatory action yet is the least potent topical corticosteroid available. Potassium hydroxyquinoline sulphate provides broad spectrum antibacterial and anticandidal activity. The combination facilitates treatment of steroid-responsive dermatoses where complication by infection with bacteria or yeasts is evident suspected, or a possibility.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Lactic Acid BP, White Soft Paraffin BP, Edetic Acid BP, Sodium Acid Phosphate BP, Maize Starch BP, cetyl stearyl alcohol, sodium cetyl stearyl sulphate, PEG 40 castor oil, Chlorocresol BP, Purified Water BP.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Two years.

6.4 Special Precautions For Storage

Quinocort Cream should be stored in a cool, dry place avoiding extremes of temperature i.e. not less than 5°C and not more than 30°C.

6.5 Nature And Contents Of Container

Quinocort Cream is available in heat sealed low density polyethylene tubes with flush fitting cap containing 30 g of product. Each tube is cartoned and contains a patient information leaflet.

6.6 Special Precautions For Disposal And Other Handling

For topical use only.

8. Marketing Authorisation Number(S)

0291/0014.

10. Date Of Revision Of The Text

May 1995.

Legal category

POM.



Generic Name: cholestyramine (Oral route)

koe-le-STYE-ra-meen

Commonly used brand name(s)

In the U.S.

Prevalite Questran Questran Light

In Canada

Novo-Cholamine Novo-Cholamine Light

Available Dosage Forms:

Powder for Suspension Tablet

Therapeutic Class: Antihyperlipidemic

Pharmacologic Class: Bile Acid Sequestrant

Uses For Questran Light

Cholestyramine is used to lower high cholesterol levels in the blood. This may help prevent medical problems caused by cholesterol clogging the blood vessels. Cholestyramine is also used to remove substances called bile acids from your body. With some liver problems, there is too much bile acid in your body and this can cause severe itching.

Cholestyramine works by attaching to certain substances in the intestine. Since cholestyramine is not absorbed into the body, these substances also pass out of the body without being absorbed.

Cholestyramine may also be used for other conditions as determined by your doctor.

Cholestyramine is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, cholestyramine is used in certain patients with the following medical conditions:

Digitalis glycoside overdose Excess oxalate in the urine Before Using Questran Light

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

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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

This medicine has been tested in a limited number of children. In effective doses, the medicine has not been shown to cause different side effects or problems than it does in adults.

Geriatric

Side effects may be more likely to occur in patients over 60 years of age, who are usually more sensitive to the effects of cholestyramine.

Pregnancy Pregnancy Category Explanation All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. Breast Feeding

Studies suggest that this medication may alter milk production or composition. If an alternative to this medication is not prescribed, you should monitor the infant for side effects and adequate milk intake.

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 this medicine, 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 this medicine 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.

Mycophenolate Mofetil Mycophenolic Acid

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Amiodarone Anisindione Cephalexin Cerivastatin Deferasirox Diclofenac Dicumarol Digitoxin Digoxin Ezetimibe Furosemide Hydrochlorothiazide Leflunomide Levothyroxine Meloxicam Metronidazole Phenprocoumon Valproic Acid Warfarin Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

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

Bleeding problems or Constipation or Gallstones or Heart or blood vessel disease or Hemorrhoids or Stomach ulcer or other stomach problems or Underactive thyroid—Cholestyramine may make these conditions worse Kidney disease—There is an increased risk of developing electrolyte problems (problems in the blood) Phenylketonuria—Phenylalanine in aspartame is included in the sugar-free brand of cholestyramine and should be avoided. Aspartame can cause problems in people with phenylketonuria. Therefore, it is best if you avoid using the sugar-free product. Proper Use of cholestyramine

This section provides information on the proper use of a number of products that contain cholestyramine. It may not be specific to Questran Light. Please read with care.

Take this medicine exactly as directed by your doctor. Try not to miss any doses and do not take more medicine than your doctor ordered.

This medicine should never be taken in its dry form, since it could cause you to choke. Instead, always mix as follows:

Place the medicine in 2 ounces of any beverage and mix thoroughly. Then add an additional 2 to 4 ounces of beverage and again mix thoroughly (it will not dissolve) before drinking. After drinking all the liquid containing the medicine, rinse the glass with a little more liquid and drink that also, to make sure you get all the medicine. You may also mix this medicine with milk in hot or regular breakfast cereals, or in thin soups such as tomato or chicken noodle soup. Or you may add it to some pulpy fruits such as crushed pineapple, pears, peaches, or fruit cocktail.

For patients taking this medicine for high cholesterol :

Importance of diet—Before prescribing medicine for your condition, your doctor will probably try to control your condition by prescribing a personal diet for you. Such a diet may be low in fats, sugars, and/or cholesterol. Many people are able to control their condition by carefully following their doctor's orders for proper diet and exercise. Medicine is prescribed only when additional help is needed. Follow carefully the special diet your doctor gave you, since the medicine is effective only when a schedule of diet and exercise is properly followed. Also, this medicine is less effective if you are greatly overweight. It may be very important for you to go on a reducing diet. However, check with your doctor before going on any diet. Remember that this medicine will not cure your cholesterol problem but it will help control it. Therefore, you must continue to take it as directed if you expect to lower your cholesterol level. Dosing

The dose of this medicine 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 this medicine. 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 oral dosage form (powder for oral suspension): For high cholesterol or pruritus (itching) related to biliary obstruction: Adults—At first, 4 grams one or two times a day before meals. Then, your doctor may increase your dose to 8 to 24 grams a day. This is divided into two to six doses. Children—At first, 4 grams a day. This is divided into two doses and taken before meals. Then, your doctor may increase your dose to 8 to 24 grams a day. This is divided into two or more doses. 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

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Questran Light

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.

Do not take any other medicine unless prescribed by your doctor since cholestyramine may change the effect of other medicines.

Do not stop taking this medicine without first checking with your doctor. When you stop taking this medicine, your blood cholesterol levels may increase again. Your doctor may want you to follow a special diet to help prevent this from happening.

Questran Light Side Effects

In some animal studies, cholestyramine was found to cause tumors. It is not known whether cholestyramine causes tumors in humans.

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:

Rare Black, tarry stools stomach pain (severe) with nausea and vomiting

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

More common Constipation Rare Loss of weight (sudden)

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 Heartburn or indigestion nausea or vomiting stomach pain Less common Belching bloating diarrhea dizziness headache

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.

See also: Questran Light side effects (in more detail)

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

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

More Questran Light resources Questran Light Side Effects (in more detail) Questran Light Use in Pregnancy & Breastfeeding Questran Light Drug Interactions Questran Light Support Group 1 Review for Questran Light - Add your own review/rating Questran Light Concise Consumer Information (Cerner Multum) Cholestyramine Prescribing Information (FDA) Cholestyramine Powder MedFacts Consumer Leaflet (Wolters Kluwer) Cholestyramine Professional Patient Advice (Wolters Kluwer) Cholestyramine Light Prescribing Information (FDA) Cholestyramine Resin Monograph (AHFS DI) Prevalite Prescribing Information (FDA) Questran Prescribing Information (FDA) Compare Questran Light with other medications Crohn's Disease Hyperlipoproteinemia Hyperlipoproteinemia Type IIa, Elevated LDL Hyperlipoproteinemia Type IIb, Elevated LDL VLDL Irritable Bowel Syndrome Pruritus of Partial Biliary Obstruction



Pronunciation: kap-SAY-sin



1. Name Of The Medicinal Product

Quinapril/Hydrochlorothiazide 10/12.5 mg film-coated tablets

2. Qualitative And Quantitative Composition

10/12.5 mg:

Each film-coated tablet contains 10 mg of quinapril equivalent to 10.83 mg of quinapril hydrochloride and 12.5 mg hydrochlorothiazide.

Excipient: Each film-coated tablet contains 18.45 mg of lactose (as lactose monohydrate).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

10mg/12.5mg:

Pink coloured, scored, oval shaped, biconvex, film-coated tablets debossed with 'D' on scored side and '18' on other side.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical Particulars 4.1 Therapeutic Indications

Quinapril/Hydrochlorothiazide is indicated as substitution therapy only in adult patients with essential hypertension already adequately controlled with quinapril and hydrochlorothiazide given concurrently.

4.2 Posology And Method Of Administration

Posology

Patients receiving quinapril and hydrochlorothiazide from separate tablets may be switched to combination tablets of Quinapril/Hydrochlorothiazide containing the same component doses.

Adults:

The recommended dose of Quinapril/Hydrochlorothiazide is one tablet per day.

Renal impairment

Due to hydrochlorothiazide component, Quinapril/Hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see sections 4.3, 4.4 and 5.2).

Elderly patients (>65 years old)

The dose should be kept as low as possible commensurate with achievement of adequate blood pressure control.

Children and adolescents (less than 18 years of age)

Quinapril/Hydrochlorothiazide is not recommended for use in children and adolescents due to lack of data on safety and efficacy.

Method of administration

For oral use.

To be taken with or without food. The dose should always time of day to help increase compliance.

4.3 Contraindications

• Quinapril/HCTZ is contraindicated in women who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraceptive measures (see Sections 4.4 and 4.6).

• Quinapril/HCTZ is contraindicated in patients with hypersensitivity to any of the ingredients including patients with a history of angioedema related to previous treatment with ACE inhibitors.

• Quinapril/HCTZ is contraindicated in patients with hereditary/idiopathic angioneurotic oedema.

• Quinapril/HCTZ should not be used in patients with ventricular outflow obstruction.

• Quinapril/HCTZ is contraindicated in patients with anuria or with severe renal dysfunction.

• Quinapril/HCTZ is contraindicated in patients with hypersensitivity to other sulphonamide-derived drugs.

4.4 Special Warnings And Precautions For Use

Quinapril/HCTZ should be used with caution in selected patients with aortic stenosis.

Sensitivity reactions:

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma, e.g. purpura, photosensitivity, urticaria, necrotising angiitis, respiratory distress including pneumonitis and pulmonary oedema, anaphylactic reactions.

Hypotension:

Quinapril/HCTZ can cause symptomatic hypotension, usually not more frequently than either drug as monotherapy. Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving quinapril, hypotension is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has severe renin-dependent hypertension (see Section 4.5).

Quinapril/HCTZ should be used cautiously in patients receiving concomitant therapy with other antihypertensive agents. The thiazide component of quinapril/HCTZ may potentiate the action of other antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. The antihypertensive effects of the thiazide component may also be enhanced in postsympathectomized patients.

If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses; however, lower doses of quinapril or of any concomitant diuretic therapy should be considered if this event occurs.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy for hypertension may cause an excessive drop in blood pressure, which may be associated with oliguria, azotemia, and in rare instances, with acute renal failure and death in such patients. Quinapril/HCTZ therapy should be started under close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dosage is increased.

Heart Failure/Heart Disease:

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the rennin-angiotensin- aldosterone system, treatment with quinapril, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.

Cough:

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Renal Disease:

Quinapril/HCTZ should be used with caution in patients with renal disease. In severe renal disease thiazides may precipitate azotemia and in moderate renal impairment (creatinine clearance 10-20ml/min) thiazides are generally ineffective in such patients, and the effects of repeated dosing may be cumulative.

There is insufficient experience in patients with severe renal impairment (creatinine clearance <10 ml/min).

The half-life of quinaprilat is prolonged as creatinine clearance falls. Patients with a creatinine clearance of <60 mL/min require a lower initial dosage of quinapril (see Section 4.2). These patients' dosage should be titrated upwards based upon therapeutic response, and renal function should be closely monitored although initial studies do not indicate that quinapril produces further deterioration in renal function.

In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.

Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases (>1.25 times the upper limit of normal) in blood urea and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic and has been observed in 4% and 3% respectively of patients on monotherapy. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of a diuretic and/or quinapril may be required.

Impaired Hepatic Function:

Quinapril/HCTZ should be used with caution in patients with impaired hepatic function or progressive liver disease since minor alterations of fluid and electrolyte balance may result from thiazide treatment and may precipitate hepatic coma. Quinapril is rapidly deesterified to quinaprilat, (quinapril diacid, the principal metabolite), which, in human and animal studies, is a potent angiotensin-converting enzyme inhibitor. The metabolism of quinapril is normally dependent upon hepatic esterase. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril.

Rarely, ACE inhibitors have been associated with a syndrome beginning as a cholestatic jaundice and progressing to a fulminant hepatic necrosis (in some cases fatal). Patients who during ACE inhibitor therapy experience jaundice or clearly elevated hepatic enzymes should discontinue quinapril/HCTZ and receive appropriate medical follow-up.

Immune-mediated drug reactions/ Anaphylactoid reactions:

Desensitisation: Patients receiving ACE inhibitors during desensitizing treatment with hymenoptera venom have sustained life-threatening anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld, but they have reappeared upon inadvertent rechallenge.

Stevens-Johnson syndrome and exacerbations or activation of systemic lupus erythematosus have been reported with thiazides.

Angioedema:

Angioedema has been reported in patients treated with angiotensin-converting enzyme inhibitors. If laryngeal stridor or angioedema of the face, tongue, or glottis occur, treatment should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Angioedema associated with laryngeal involvement may be fatal. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, appropriate therapy e.g., subcutaneous adrenaline solution 1:1000 (0.3 to 0.5 ml) should be promptly administered.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see Section 4.3).

Intestinal angioedema:

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Ethnic Differences:

Black patients receiving ACE inhibitor therapy have been reported to have a higher incidence of angioedema compared to non-black patients. It should also be noted that in controlled clinical trials, ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks.

Haemodialysis and LDL Apheresis:

Patients haemodialysed using high-flux polyacrylonitrile ('AN69') membranes are highly likely to experience anaphylactoid reactions if they are treated with ACE inhibitors. This combination should therefore be avoided, either by use of alternative antihypertensive drugs or alternative membranes for haemodialysis. Similar reactions have been observed during low density lipoprotein apheresis with dextran-sulphate. This method should therefore not be used in patients treated with ACE inhibitors.

Derangements of Serum Electrolytes:

Patients receiving quinapril/HCTZ should be observed for clinical signs of thiazide induced fluid or electrolyte imbalance. In such patients periodic determination of serum electrolytes (sodium and potassium in particular) should be performed. Because quinapril reduces the production of aldosterone, its combination with hydrochlorothiazide may minimise diuretic induced hypokalaemia.

The opposite effects of quinapril and hydrochlorothiazide on serum potassium will approximately balance each other in many patients so that no net effect upon serum potassium will be seen. In other patients, one or the other effect may be dominant and some patients may still require potassium supplements. Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Hypokalemia:

Conversely, treatment with thiazide diuretics has been associated with hypokalaemia, hyponatremia, and hypochloremic alkalosis. These disturbances have sometimes been manifest as one or more of the following: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, confusion, seizures and vomiting. Hypokalaemia can also sensitize or exaggerate the response of the heart to the toxic effects of digitalis. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or adrenocorticotrophic hormone (ACTH) (see Section 4.5).

Hyperkalaemia:

Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician (see Section 4.5).

Hypoglycaemia and Diabetes:

In diabetic patients ACE inhibitors may enhance insulin sensitivity and have been associated with hypoglycaemia in patients treated with oral antidiabetic agents or insulin. Glycaemic control should be closely monitored (see Section 4.5).

Neutropenia/Agranulocytosis:

ACE inhibitors have been rarely associated with agranulocytosis and bone marrow depression in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a connective disease with the concomitant use of immunosuppressive or other agents which may be associated with neutropenia/agranulocytosis. Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) as this could be a sign of neutropenia (see Section 4.5).

Agranulocytosis has been rarely reported during treatment with quinapril. As with other ACE inhibitors, monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered.

Surgery/Anaesthesia:

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, quinapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Pregnancy:

Quinapril/HCTZ is contraindicated in pregnancy. Quinapril/HCTZ should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards to the fetus (see Sections 4.3 and 4.6).

Lactose:

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/galactose malabsorption should not use this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Tetracycline and other drugs that interact with magnesium:

Because of the presence of magnesium carbonate in the formulation, quinapril has been shown in healthy volunteers to reduce the absorption of tetracycline in concomitant administration by 28-37%. It is recommended that concomitant administration with tetracycline be avoided. This interaction should be considered if coprescribing quinapril and tetracycline.

Agents increasing serum potassium:

Quinapril/HCTZ contains a thiazide diuretic, which tends to increase the urinary excretion of potassium but it also contains an ACE inhibitor, which tends to conserve potassium by lowering aldosterone levels. It is not advisable to routinely add potassium sparing diuretics or potassium supplements as this may result in elevated serum potassium.

Other diuretics:

Quinapril/HCTZ contains a diuretic. Concomitant use of another diuretic may have an additive effect. Also, patients on diuretics, especially those who are volume and/or salt depleted, may experience an excessive reduction of blood pressure on initiation of therapy, or with increased dosage of an ACE inhibitor.

Other antihypertensive drugs:

There may be an additive effect or potentiation when quinapril/HCTZ is combined with other antihypertensive drugs such as nitrates or vasodilators.

Surgery/anaesthesia:

Although no data are available to indicate there is an interaction between quinapril and anaesthetic agents that produces hypotension, caution should be exercised when patients undergo major surgery or anaesthesia since ACE inhibitors have been shown to block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion (see Section 4.4).

Thiazides may decrease the arterial response to noradrenaline. In emergency surgery pre-anaesthetic and anaesthetic agents should be administered in reduced doses. Thiazides may increase the response to tubocurarine.

Lithium:

Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy due to the sodium-losing effect of these agents. With quinapril/HCTZ, the risk of lithium toxicity may be increased. Quinapril/HCTZ should be administered with caution and frequent monitoring of serum lithium levels is recommended.

Corticosteroids, ACTH:

Intensified electrolyte depletion, particularly hypokalaemia has been observed.

Non-steroidal anti-inflammatory drugs:

In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium sparing, and thiazide diuretics and may reduce the antihypertensive effect of ACE inhibitors. Therefore, when quinapril/HCTZ and nonsteroidal anti-inflammatory agents are used concomitantly the patients should be observed closely to determine if the desired effect of quinapril/HCTZ is obtained. Furthermore, it has been described that NSAIDs and ACE inhibitors exert an additive effect on the increase in serum potassium, whereas renal function may decrease. These effects are in principle reversible and occur especially in patients with compromised renal function.

Allopurinol, cytostatic and immunosuppressive agents, systemic corticosteroids or procainamide:

Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia.

Alcohol, barbiturates or narcotics:

Potentiation of orthostatic hypotension may occur.

Drugs associated with torsades de pointes:

Due to the potential risk of hypokalemia, caution should be used when hydrochlorothiazide is co administered with medicines such as digitalis glycosides or agents associated with torsades de pointes.

Antacids:

Antacids may decrease the bioavailability of quinapril/HCTZ .

Antidiabetic drugs (oral hypoglycaemic agents and insulin):

In diabetic patients ACE inhibitors may enhance insulin sensitivity and have been associated with hypoglycaemia in patients treated with oral antidiabetic agents or insulin. Glycaemic control should be closely monitored (see Section 4.4).

4.6 Pregnancy And Lactation

Pregnancy:

Quinapril/HCTZ is contraindicated in pregnancy (see Section 4.3). ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, quinapril/HCTZ should be discontinued.

Infants exposed to ACE inhibitors during pregnancy may be at increased risk for malformations of the cardiovascular system and central nervous system. There have also been reports of prematurity, hypotension, renal system disorders (including renal failure), skull hypoplasia, oligohydramnios, limb contractures, craniofacial deformities, hypoplastic lung development, intrauterine growth retardation, patent ductus arteriosus, fetal death and/or death in the newborn in association with the maternal use of ACE inhibitors.

Patients and physicians should be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants who may have been exposed in utero to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalaemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion.

Thiazides cross the placental barrier and appear in cord blood. Nonteratogenic effects to the fetus may include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.

There are no adequate and well-controlled studies of quinapril/HCTZ in pregnant women.

Lactation:

ACE inhibitors, including quinapril, are secreted in human milk to a limited extent. Thiazides appear in human milk. Because of the potential for serious reactions in nursing infants, a decision should be made whether to discontinue quinapril/HCTZ or discontinue nursing, taking into account the importance of the drug to the mother.

4.7 Effects On Ability To Drive And Use Machines

The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired.

4.8 Undesirable Effects

The following undesirable effects have been observed and reported during treatment with quinapril/HCTZ with the following frequencies: very common (

System Organ Class

Frequency

Undesirable effects

Blood and the lymphatic system disorders

Not known

Agranulocytosis##, haemolytic anemia#, neutropenia##, thrombocytopenia#

Immune system disorders

Not known

Anaphylactoid reaction#

Metabolism and nutrition disorders

Common

Hyperkalaemia##

Psychiatric disorders

Common

Insomnia#

Uncommon

Confusion#, depression#, nervousness#

 

Nervous system disorders

Common

Dizziness#, headache#, somnolence#

Uncommon

Paraesthesia#, Transient ischaemic attacks#

 

Rare

Balance disorder

 

Not known

Cerebral haemorrhage#

 

Eye disorders

Uncommon

Amblyopia#

Very Rare

Blurred vision#

 

Ear and labyrinth disorders

Uncommon

Tinnitus#, vertigo#

Cardiac disorders

Common

Myocardial infarction#

Uncommon

Angina pectoris##, tachycardia#, palpitations#

 

Not known

Arrhythmia

 

Vascular disorders

Common

Vasodilation#

Uncommon

Hypotension#, syncope#

 

Not known

Postural hypotension#

 

Respiratory, thoracic and mediastinal disorders

Common

Bronchitis, cough#, pharyngitis#, rhinitis#, upper respiratory tract infection

Uncommon

Dyspnoea#, sinusitis

 

Rare

Eosiniphilic pneumonitis##, angioneurotic oedema#

 

Not known

Bronchospasm#

 

Gastrointestinal disorders

Common

Abdominal pain#, diarrhoea#, dyspepsia#, nausea#, vomiting#

Uncommon

Flatulence#, dry mouth or throat#, altered taste#

 

Rare

Constipation, glossitis

 

Very Rare

Ileus#, intestinal angioedema

 

Not known

Pancreatitis#

 

Hepato-biliary disorders

Not known

Hepatitis#, cholestatic icterus#

Skin and subcutaneous tissue disorders

Uncommon

Alopecia#, photosensitivity# pruritus#, rash#, angioedema##, increased perspiration##

Rare

Skin changes may be associated with fever, muscle and joint pain (myalgias, arthralgias, arthritis), vascular inflammation (vasculitis), psoriasis-like efflorescence#

 

Very Rare

Urticaria#

 

Not known

Toxic epidermal necrolysis#, erythema multiforme#, exfoliative dermatitis#, pemphigus#, purpura, Stevens-Johnson syndrome#, inflammations of serous tissues and certain changes in laboratory values (eosinophilia# and/or elevated ANA titers#, elevated ESR)

 

Musculoskeletal, connective tissue and bone disorders

Common

Back pain#, myalgia#, hyperuricaemia#, gout#

Uncommon

Arthralgia#

 

Renal and urinary disorders

Uncommon

Renal dysfunction#, proteinuria, urinary tract infection

Not known

Interstitial nephritis

 

Reproductive system and breast disorders

Uncommon

Impotence#

General disorders and administration site conditions

Common

Asthenia#, Chest pain#, fatigue#

Uncommon

Fever#, generalised oedema#,#, peripheral oedema#

 

Investigations

Common

Increased serum creatinine#, increased blood urea nitrogen#*

Not known

Increases in cholesterol# and triglyceride levels#.

Decreases in hematocrit# and WCC# as well as elevation in liver enzymes and serum bilirubin.

In patients with a congenital G-6-PDH deficiency, individual cases of haemolytic anaemia# have been reported

 

Infections and infestations

Uncommon

Viral infection

Endocrine disorders

Uncommon

Insulin requirements in diabetic patients may be altered by thiazides and latent diabetes mellitus may occur#

* Such increases are more likely to occur in patients receiving concomitant diuretic therapy than those on monotherapy with quinapril. These observed increases will often reverse on continued therapy.

# Adverse reactions associated with quinapril component, frequencies observed when taking quinapril/HCTZ.

## Adverse reactions associated with quinapril component, frequencies observed in quinapril, adverse reactions not associated with quinapril/HCTZ component.

Clinical Laboratory Test Findings:

Serum Electrolytes: (See section 4.4).

Serum Uric Acid, Glucose, Magnesium, PBI, Parathyroid Function tests and Calcium: (See section 4.4).

Haematology test: (See section 4.4).

4.9 Overdose

No data are available for quinapril/HCTZ with respect to overdosage in humans.

The most likely clinical manifestation would be symptoms attributable to quinapril monotherapy overdosage such as severe hypotension, which would usually be treated by infusion of intravenous normal saline.

The most common signs and symptoms observed for HCTZ monotherapy overdosage are those caused by electrolyte depletion (hypokalaemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalaemia may accentuate cardiac arrythmias.

No specific information is available on the treatment of overdosage with quinapril/HCTZ.

Haemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Treatment is symptomatic and supportive consistent with established medical care.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Quinapril and diuretics, ATC code: C09BA06

Quinapril/Hydrochlorothiazide is a fixed combination of the ACE inhibitor, quinapril, and a diuretic, hydrochlorothiazide. Concomitant administration of these agents reduces blood pressure to a greater degree than either component alone, given as monotherapy. Quinapril may, like other ACE inhibitors, counteract the loss of potassium that is inherent with hydrochlorothiazide.

Quinapril is a prodrug, which is hydrolysed to the active metabolite quinaprilat, a potent longacting inhibitor of angiotensin converting enzyme (ACE) in plasma and tissue. ACE catalyses the conversion of angiotensin-I to angiotensin-II, which is a potent vasoconstrictor. Inhibition of ACE results in decreased concentrations of angiotensin-II and reduced aldosterone secretion. Bradykinin metabolism is probably also inhibited. In clinical studies quinapril has been found to be lipid neutral and has no negative effect on glucose metabolism. Quinapril reduces the total peripheral and renal arterial resistance.

In general there are no clinically relevant changes in renal blood flow or glomerular filtrationrate. Quinaprilat results in a reduction of prone, sitting and standing blood pressure. The peak effect is achieved after 2-4 hours at recommended doses. Achievement of maximum blood pressure lowering effect may require 2-4 weeks of therapy in some patients. A decrease in left ventricular hypertrophy was observed with quinapril in experimental models of hypertension in animals. Morbidity/mortality data is lacking.

Hydrochlorothiazide is a thiazide diuretic and an antihypertensive agent that increases renin activity in plasma. Hydrochlorothiazide decreases the renal reabsorption of electrolytes in distal tubuli and increases the excretion of sodium, chloride, potassium, magnesium, bicarbonate and water. The excretion of calcium may be reduced. Concomitant administration of quinapril and hydrochlorothiazide produces a stronger hypotensive effect than that of either of the agents, given alone as monotherapy.

5.2 Pharmacokinetic Properties

Quinapril

The bioavailability of the active metabolite, quinaprilat, is 30-40% of the given oral dose of quinapril. Peak plasma concentrations are reached after approximately 2 hours. The absorption of quinapril is not affected by concurrent food intake, but an extremely high fat content in the food may reduce uptake. Approximately 97% of the active substance is bound to plasma proteins. With repeat dosing quinaprilat has a half life of 3 hours. Steady state is reached in 2-3 days. Quinaprilat is mainly excreted unchanged by the kidneys. The clearance is 220 ml/min.

In patients with renal dysfunction the half-life of quinaprilat is prolonged and the plasma quinaprilat concentrations are elevated. In patients with severely impaired hepatic function the concentrations of quinaprilat are reduced due to inhibited hydrolysis of quinapril.

After a single oral dose of 20 mg of quinapril in six breast-feeding women, Milk/Plasma ratio for quinapril was 0.12. Quinapril was not detected in milk after 4 hours after the dose. Quinalaprilat milk levels were undetectable (<5 µg/L) at all time points. It is estimated that a breastfed infant would receive about 1.6% of the maternal weight-adjusted dosage of quinapril.

Hydrochlorothiazide

The bioavailability is 60-80%. The diuretic effect is evident within 2 hours of administration, with a maximum effect after ca 4 hours. The effect is maintained for 6-12 hours. Hydrochlorothiazide is excreted unchanged through the kidneys. The mean plasma half-life is in the range of 5-15 hours.

The half-life of Hydrochlorothiazide is prolonged in patients with impaired renal function.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic potential. No studies regarding genotoxicity or carcinogenicity of the combination (quinapril/hydrochlorothiazide) have been carried out. Reproductive toxicity studies in rats suggest that quinapril and/or hydrochlorothiazide has no negative effects on fertility and reproductive performance, and is not teratogenic. ACE inhibitors, as a class, have been shown to be fetotoxic (causing injury and/or death to the fetus) when given in the second or third trimester.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Tablet core:

Lactose monohydrate

Magnesium carbonate heavy

Crospovidone (Type A)

Povidone (K30)

Magnesium stearate

Tablet coat: (Opadry pink)

Hypromellose

Titanium dioxide (E171)

Hydroxypropyl cellulose

Macrogol 400

Iron oxide red (E172)

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Store below 25?C.

6.5 Nature And Contents Of Container

Blister packs Polyamide/Al/PV/Al blister: 7, 10, 14, 20, 28, 30, 42, 50, 56, 60, 84, 90, 98, 100, 156, 250 and 500 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Milpharm Limited

Ares, Odyssey Business Park

West End Road, South Ruislip HA4 6QD

United Kingdom

8. Marketing Authorisation Number(S)

PL 16363/0256

9. Date Of First Authorisation/Renewal Of The Authorisation

15/06/2010

10. Date Of Revision Of The Text

05/02/2011

11 DOSIMETRY

(IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

(IF APPLICABLE)



1. Name Of The Medicinal Product

Qvar Easi-Breathe 100 micrograms per actuation pressurised inhalation solution

2. Qualitative And Quantitative Composition

Beclometasone Dipropionate 100 micrograms per metered (ex-valve) dose.

(The dose delivered from the mouthpiece is an average 75 micrograms).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Pressurised inhalation, solution.

A colourless solution in a pressurised aluminium canister fitted with a metering valve and an actuator.

Qvar Easi-Breathe contains a propellant, which does not contain any chlorofluorocarbons (CFCs).

4. Clinical Particulars 4.1 Therapeutic Indications

Prophylactic management of mild, moderate or severe asthma.

4.2 Posology And Method Of Administration

Qvar Easi-Breathe is for inhalation use only.

Patients should be instructed in the proper use of their inhaler, including rinsing out their mouth with water after use. Patients should be advised that Qvar may have a different taste and feel than a CFC inhaler.

NOTE: The recommended total daily dose of Qvar Easi-Breathe is lower than that for current beclometasone dipropionate CFC containing products and should be adjusted to the needs of the individual patient.

ADULT STARTING AND MAINTENANCE DOSE:

It is important to gain control of asthma symptoms and optimise pulmonary function as soon as possible. When patients' symptoms remain under satisfactory control, the dose should be titrated to the lowest dose at which effective control of asthma is maintained.

To be effective inhaled Qvar Easi-Breathe must be used on a regular basis even when patients are asymptomatic.

THERAPY IN NEW PATIENTS SHOULD BE INITIATED AT THE FOLLOWING DOSAGES

Mild asthma:

100 to 200 micrograms per day in two divided doses.

Moderate asthma:

200 to 400 micrograms per day in two divided doses.

Severe asthma:

400 to 800 micrograms per day in two divided doses.

TRANSFERRING PATIENTS TO QVAR EASI-BREATHE FROM A CFC-CONTAINING INHALER

The general approach to switching patients to Qvar Easi-Breathe involves two steps as detailed below. Specific guidance on switching well-controlled and poorly-controlled (symptomatic) patients is given below the table.

Step 1: Consider the dose of CFC containing beclometasone dipropionate product appropriate to the patient's current condition.

Step 2: Convert the CFC containing beclometasone dipropionate dose to the Qvar Easi-Breathe dose according to the table below.

Total Daily Dose (mcg/day)

               

CFC BDP*

200-250

300

400-500

600-750

800-1000

1100

1200-1500

1600-2000

QVAR EASI-BREATHE

100

150

200

300

400

500

600

800

*CFC-BDP = CFC beclometasone dipropionate

1. Dosing in well-controlled patients with asthma

Patients with well-controlled asthma using beclometasone dipropionate CFC containing product should be switched to Qvar Easi-Breathe at a dose in accordance with the table above.

For example:

Patients on 2 puffs twice daily of CFC beclometasone dipropionate 200 micrograms would change to 2 puffs twice daily of Qvar Easi-Breathe 100 micrograms.

2. Dosing in poorly-controlled (symptomatic) patients with asthma

Patients with poorly-controlled asthma may be switched from CFC containing beclometasone dipropionate products to Qvar Easi-Breathe at the same microgram for microgram dose up to 800 micrograms daily. Comparative clinical studies have demonstrated that asthma patients achieve equivalent pulmonary function and control of symptoms with Qvar aerosol (an equivalent inhaler) at lower total daily doses than with CFC containing beclometasone dipropionate products.

Alternatively the patient's current CFC containing beclometasone dipropionate dose can be doubled and this dose can be converted to the Qvar Easi-Breathe dose according to the table above.

Patients on budesonide inhalers may be transferred to Qvar Easi-Breathe as described for CFC containing beclometasone dipropionate products.

Patients on fluticasone inhalers may be transferred to the same total daily dose of Qvar Easi-Breathe up to 800 micrograms daily.

Once transferred to Qvar Easi-Breathe the dose should be adjusted to meet the needs of the individual patient.

The maximum recommended dose is 800 micrograms per day in divided doses.

The same total daily dose in micrograms from either Qvar Easi-Breathe 50 (a lower strength) or Qvar Easi-Breathe 100 Inhaler provides the same clinical effect.

Patients should be instructed in the proper use of their inhaler, including rinsing out their mouth with water after use. Patients should be advised that Qvar Easi-Breathe may have a different taste and feel than a CFC inhaler.

CHILDREN

There are no data to date on Qvar Easi-Breathe in children under 12 years of age, hence no definitive dosage recommendation can be made.

SPECIAL PATIENT GROUPS

No special dosage recommendations are made for elderly or patients with hepatic or renal impairment.

INSTRUCTIONS FOR USE

The aerosol spray is inhaled through the mouth into the lungs. The inhaler should be primed by firing two shots into the air before first use or if the inhaler has not been used for a period of two weeks or longer.

After removal of the cap the inhaler mouthpiece should be placed in the mouth with the lips closed around it. The patient should breathe in slowly and deeply through the mouthpiece. They should be advised not to stop breathing when the inhaler delivers the dose into their mouth but carry on until they have taken a deep breath to ensure optimal delivery of the product.

For normal hygiene, the mouthpiece of the inhaler should be cleaned weekly with a clean dry tissue or cloth. The inhaler should not be washed or immersed in water at any time.

Full instructions for use are given in the Patient Information Leaflet, which should be read carefully by the patient before use.

Qvar Easi-Breathe delivers a consistent dose

- whether or not the canister is shaken by the patient

- without the need for the patient to wait between individual actuations

- regardless of storage orientation or periods without use of up to 14 days

- at temperatures as low as -10°C.

4.3 Contraindications

Hypersensitivity to beclometasone dipropionate or to any of the excipients.

4.4 Special Warnings And Precautions For Use

To be effective, Qvar Easi-Breathe must be used by patients on a regular basis, even when patients do not have asthma symptoms. When symptoms are controlled, maintenance Qvar Easi-Breathe therapy should be reduced in a stepwise manner to the minimum effective dose. Inhaled steroid treatment should not be stopped abruptly.

Patients with asthma are at risk of acute attacks and should have regular assessments of their asthma control including pulmonary function tests.

Qvar Easi-Breathe is not indicated for the immediate relief of asthma attacks. Patients therefore need to have relief medication (inhaled short-acting bronchodilator) available for such circumstances.

Qvar Easi-Breathe is not indicated in the management of status asthmaticus.

Severe asthma exacerbations should be managed in the usual way. Subsequently, it may be necessary to increase the dose of Qvar Easi-Breathe up to the maximum daily dose. Systemic steroid treatment may be needed and/or an antibiotic, if there is an infection.

Patients should be advised to seek medical attention for review of maintenance Qvar Easi-Breathe therapy if peak flow falls, symptoms worsen or if the short-acting bronchodilator becomes less effective and increased inhalations are required. This may indicate worsening asthma.

Patients who have received systemic steroids for long periods of time or at high doses, or both, need special care and subsequent management when being transferred to inhaled steroid therapy. Patients should have stable asthma before being given inhaled steroids in addition to the usual maintenance dose of systemic steroid. Withdrawal of systemic steroids should be gradual, starting about seven days after the introduction of Qvar Easi-Breathe therapy. For daily oral doses of prednisolone of 10mg or less, dose reduction in 1mg steps, at intervals of not less than one week is recommended. For patients on daily maintenance doses of oral prednisolone greater than 10mg, larger weekly reductions in the dose might be acceptable. The dose reduction scheme should be chosen to correlate with the magnitude of the maintenance systemic steroid dose.

Most patients can be successfully transferred to inhaled steroids with maintenance of good respiratory function, but special care is necessary for the first few months after the transfer, until the hypothalamic-pituitary-adrenal (HPA) system has sufficiently recovered to enable the patient to cope with stressful emergencies such as trauma, surgery or serious infections. Patients should, therefore, carry a steroid warning card to indicate the possible need to re-instate systemic steroid therapy rapidly during periods of stress or where airways obstruction or mucus significantly compromises the inhaled route of administration. In addition, it may be advisable to provide such patients with a supply of corticosteroid tablets to use in these circumstances. The dose of inhaled steroids should be increased at this time and then gradually reduced to the maintenance level after the systemic steroid has been discontinued. As recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy is slow, adrenocortical function should be monitored regularly.

Patients should be advised that they may feel unwell in a non-specific way during systemic steroid withdrawal despite maintenance of, or even improved respiratory function. Patients should be advised to persevere with their inhaled product and to continue withdrawal of systemic steroids, even if feeling unwell, unless there is evidence of HPA axis suppression.

Discontinuation of systemic steroids may also cause exacerbation of allergic diseases such as atopic eczema and rhinitis. These should be treated as required with topical therapy, including corticosteroids and/or antihistamines.

Beclometasone dipropionate, like other inhaled steroids, is absorbed into the systemic circulation from the lungs. Beclometasone dipropionate and its metabolites may exert detectable suppression of adrenal function. Within the dose range 100-800 micrograms daily, clinical studies with Qvar aerosol (an equivalent inhaler) have demonstrated mean values for adrenal function and responsiveness within the normal range. However, systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma, and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than the recommended doses, may result in clinically significant adrenal suppression. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Like other corticosteroids, caution is necessary in patients with active or latent pulmonary tuberculosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

The potential risk of this product for humans is unknown.

Qvar Easi-Breathe

There is no experience of this product in pregnancy and lactation in humans, therefore the product should only be used if the expected benefits to the mother are thought to outweigh any potential risk to the foetus or neonate.

Beclometasone dipropionate

There is inadequate evidence of safety in human pregnancy.

The use of beclometasone dipropionate in pregnancy requires that the possible benefits of the drug be weighed against the possible hazards. The drug has been in widespread use for many years without apparent ill consequence.

It is probable that beclometasone dipropionate is excreted in milk. However, given the relatively low doses used by the inhalation route, the levels are likely to be low. In mothers breast-feeding their baby the therapeutic benefits of the drug should be weighed against the potential hazards to mother and baby.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

A serious hypersensitivity reaction including oedema of the eye, face, lips and throat (angioedema) has been reported rarely.

As with other inhaled therapy, paradoxical bronchospasm may occur after dosing. Immediate treatment with a short-acting bronchodilator should be initiated, Qvar should be discontinued immediately and an alternate prophylactic treatment introduced.

Systemic effects of inhaled corticosteroids may occur, particularly with high doses prescribed for prolonged periods. These include adrenal suppression, growth retardation in children, decrease in bone mineral density and the occurrence of cataract and glaucoma.

Commonly, when taking Qvar, hoarseness and candidiasis of the throat and mouth may occur. To reduce the risk of hoarseness and candida infection, patients are advised to rinse their mouth after using their inhaler.

Based on the MedDra system organ class and frequencies, adverse events are listed in the table below according to the following frequency estimate: very common (

MedDra – system organ class

Frequency and Symptom

Infections and infestations

Common: Candidiasis in mouth and throat

Immune system disorders

Rare: Allergic reactions, angioedema in eyes, throat, lips and face

Endocrine disorders

Very rare: Adrenal suppression, growth retardation in children

Nervous system disorders

Uncommon: Headache, vertigo, tremor

Eye disorders

Very rare: Cataract, glaucoma

Respiratory, thoracic and mediastinal disorders

Common: Hoarseness, pharyngitis

Uncommon: Cough, increased asthma symptoms

Rare: Paradoxical bronchospasm

Gastrointestinal disorders

Common: Taste disturbances

Uncommon: Nausea

Skin and subcutaneous tissue disorders

Uncommon: Urticaria, rash, pruritus, erythema, purpura

Musculoskeletal and connective tissue disorders

Very rare: Decrease bone mineral density

Psychiatric Disorders

Unknown: Psychomotor hyperactivity, sleep disorders, anxiety, depression, aggression, behavioural changes (predominantly in children)

4.9 Overdose

Acute overdosage is unlikely to cause problems. The only harmful effect that follows inhalation of large amounts of the drug over a short time period is suppression of HPA function. Specific emergency action need not be taken. Treatment with Qvar Easi-Breathe should be continued at the recommended dose to control the asthma; HPA function recovers in a day or two.

If excessive doses of beclometasone dipropionate were taken over a prolonged period a degree of atrophy of the adrenal cortex could occur in addition to HPA suppression. In this event the patient should be treated as steroid dependent and transferred to a suitable maintenance dose of a systemic steroid such as prednisolone. Once the condition is stabilised, the patient should be returned to Qvar Easi-Breathe by the method described above in Section 4.4.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Glucocorticoids, ATC code: R03BA01

Qvar Easi-Breathe contains beclometasone dipropionate in solution in propellant HFA-134a resulting in an extra fine aerosol. The aerosol droplets are on average much smaller than the beclometasone dipropionate particles delivered by CFC-suspension formulations or dry powder formulations of beclometasone dipropionate. The extra fine particle fraction will be 60% ± 20% of the drug particles

Radiolabelled deposition studies in adults with mild asthma have demonstrated that the majority of drug (> 55% ex-actuator) is deposited in the lung and a small amount (< 35% ex-actuator) is deposited in the oropharynx. These studies were performed with Qvar Aerosol. Qvar Aerosol is a 'press and breathe' inhaler, whereas Qvar Easi-Breathe is a breath-activated inhaler.

Inhaled beclometasone dipropionate is now well established in the management of asthma. It is a synthetic glucocorticoid and exerts a topical, anti-inflammatory effect on the lungs, with fewer systemic effects than oral corticosteroids.

Comparative clinical studies of Qvar aerosol have demonstrated that asthma patients achieve equivalent pulmonary function and control of symptoms with Qvar aerosol at lower total daily doses than CFC containing beclometasone dipropionate aerosol inhalers.

Pharmacodynamic studies in patients with mild asthma given Qvar aerosol for 14 days, have shown that there is a linear correlation among urinary free cortisol suppression, dose administered, and serum total-beclometasone levels obtained. At a daily dose of 800 micrograms Qvar aerosol, suppression of urinary free cortisol was comparable with that observed with the same daily dose of CFC containing beclometasone dipropionate, indicating a wider safety margin, as Qvar Easi-Breathe is administered at lower doses than the CFC product.

5.2 Pharmacokinetic Properties

The pharmacokinetic profile of Qvar aerosol (an equivalent inhaler) shows that the peak serum concentration for total- beclometasone (BOH) (total of any beclometasone OH and beclometasone dipropionate or monopropionate hydrolysed to beclometasone OH) or after single and multiple doses is achieved after 30 minutes.

The value at the peak is approximately 2 nanograms/ml after a total daily dose of 800 micrograms and the serum levels after 100, 200 and 400 micrograms are proportional. The principal route of elimination of beclometasone dipropionate and its several metabolites is in the faeces. Between 10% and 15% of an orally administered dose is excreted in the urine, as both conjugated and free metabolites of the drug.

In both single dose and multiple dose pharmacokinetic studies of Qvar aerosol, a dose of 200 micrograms of Qvar aerosol achieved comparable total-BOH levels, as a dose of 400 micrograms of CFC containing beclometasone dipropionate Aerosol. This provided the scientific rationale for investigating lower total daily doses of Qvar aerosol to achieve the same clinical effect.

Pharmacokinetic studies with Qvar Easi-Breathe have not been carried out in any special populations.

5.3 Preclinical Safety Data

In animal studies, propellant HFA-134a has been shown to have no significant pharmacological effects other than at very high exposure concentrations, then narcosis and a relatively weak cardiac sensitising effect were found. The potency of the cardiac sensitisation was less than that of CFC-11 (trichlorofluoromethane).

In studies to detect toxicity, repeated high dose levels of propellant HFA-134a indicated that safety margins based on systemic exposure would be of the order 2200, 1314 and 381 for mouse, rat and dog with respect to humans.

There are no reasons to consider propellant HFA-134a as a potential mutagen, clastogen or carcinogen judged from in vitro and in vivo studies including long-term administration by inhalation in rodents.

Studies of propellant HFA-134a administered to pregnant and lactating rats and rabbits have not revealed any special hazard.

In animals, systemic administration of relatively high doses can cause abnormalities of foetal development including growth retardation and cleft palate. There may therefore be a very small risk of such effects in the human foetus. However, inhalation of beclometasone dipropionate into the lungs avoids the high level of exposure that occurs with administration by systemic routes.

Safety studies with Qvar aerosol (an equivalent inhaler) in rat and dog showed few, if any, adverse effects other than those normally associated with general steroid exposure including lymphoid tissue alterations such as reduction in thymus, adrenal and spleen weights. An inhalation reproductive study Qvar aerosol (an equivalent inhaler) in rats did not exhibit any teratogenic effects.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Propellant HFA-134a (Norflurane)

Ethanol.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 Years.

6.4 Special Precautions For Storage

Do not store above 25°C. Protect from frost and direct sunlight.

The canister contains a pressurised liquid. Do not expose to temperatures higher that 50°C. Do not pierce the canister.

6.5 Nature And Contents Of Container

Pressurised aluminium canister closed with a metering valve containing either 100 or 200 actuations.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Teva UK Limited

Brampton Road

Hampden Park

Eastbourne

East Sussex

BN22 9AG

United Kingdom

8. Marketing Authorisation Number(S)

PL 00289/1376

9. Date Of First Authorisation/Renewal Of The Authorisation

1st July 2010

10. Date Of Revision Of The Text

11/05/2011



Generic Name: quinidine (Oral route, Injection route, Intramuscular route)

KWIN-i-deen

Oral route(Tablet, Extended Release)

Many trials of antiarrhythmic therapy for non-life threatening arrhythmias, has resulted in increased mortality; the risk of active therapy is probably greatest in patients with structural heart disease. In the case of quinidine used to prevent or defer recurrence of atrial flutter/fibrillation, meta-analysis data has shown that the mortality associated with the use of quinidine was more than three times greater than placebo. Another meta-analysis showed that in patients with various non-life-threatening ventricular arrhythmias, the mortality associated with the use of quinidine was consistently greater than that associated with the use of any of a variety of alternative antiarrhythmics .

Oral route(Tablet)

Many trials of antiarrhythmic therapy for non-life threatening arrhythmias, has resulted in increased mortality; the risk of active therapy is probably greatest in patients with structural heart disease. In the case of quinidine used to prevent or defer recurrence of atrial flutter/fibrillation, meta-analysis data has shown that the mortality associated with the use of quinidine was more than three times greater than placebo. Another meta-analysis showed that in patients with various non-life-threatening ventricular arrhythmias, the mortality associated with the use of quinidine was consistently greater than that associated with the use of any of a variety of alternative antiarrhythmics .

Commonly used brand name(s)

In the U.S.

Cardioquin Quinaglute Quinalan Quinidex Extentabs

Available Dosage Forms:

Tablet Tablet, Extended Release Capsule Solution

Therapeutic Class: Antiarrhythmic, Group IA

Chemical Class: Cinchona Alkaloid

Uses For Quinidex Extentabs

Quinidine is used to treat abnormal heart rhythms. It is also used to treat malaria.

Do not confuse this medicine with quinine, which, although related, has different medical uses.

Quinidine is available only with your doctor's prescription.

Before Using Quinidex Extentabs

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

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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

Quinidine has not been widely studied in children; however, it is used in children to treat abnormal heart rhythms and to treat malaria. Children may be able to take higher doses than adults and may have fewer side effects (such as vomiting, loss of appetite, and diarrhea) than 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 no specific information comparing use of quinidine in the elderly with use in other age groups, this medicine is not expected to cause different side effects or problems in older people than it does in younger adults. However, quinidine may remain in the bodies of older adults longer than it does in younger adults, which may increase the risk of side effects and which may require lower doses.

Pregnancy Pregnancy Category Explanation All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, 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 this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

Aurothioglucose Bepridil Cisapride Dronedarone Grepafloxacin Itraconazole Levomethadyl Mesoridazine Nelfinavir Pimozide Posaconazole Ritonavir Saquinavir Sparfloxacin Terfenadine Thioridazine Tipranavir Voriconazole Ziprasidone

Using this medicine 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.

Acetazolamide Ajmaline Alfuzosin Amiodarone Amitriptyline Amoxapine Amprenavir Apomorphine Aprindine Arbutamine Arsenic Trioxide Asenapine Astemizole Atazanavir Atracurium Azithromycin Boceprevir Chloral Hydrate Chloroquine Ciprofloxacin Citalopram Clarithromycin Clomipramine Colchicine Crizotinib Darunavir Dasatinib Decamethonium Delavirdine Desipramine Digitoxin Digoxin Disopyramide Dofetilide Dolasetron Doxepin Droperidol Enflurane Erythromycin Etravirine Flecainide Fluconazole Fosamprenavir Foscarnet Gatifloxacin Gemifloxacin Granisetron Halofantrine Haloperidol Halothane Hydroquinidine Ibutilide Imipramine Infliximab Isoflurane Isradipine Lanreotide Lapatinib Levofloxacin Lidocaine Lidoflazine Lopinavir Lorcainide Lumefantrine Mefloquine Methadone Mexiletine Moxifloxacin Nalidixic Acid Nilotinib Norfloxacin Nortriptyline Octreotide Ofloxacin Ondansetron Paliperidone Pancuronium Pazopanib Pentamidine Perflutren Lipid Microsphere Pirmenol Prajmaline Prilocaine Probucol Procainamide Prochlorperazine Propafenone Protriptyline Quetiapine Quinidine Quinine Ranolazine Salmeterol Sodium Phosphate Sodium Phosphate, Dibasic Sodium Phosphate, Monobasic Solifenacin Sorafenib Sotalol Spiramycin Succinylcholine Sulfamethoxazole Sunitinib Telaprevir Telavancin Telithromycin Tetrabenazine Toremifene Trazodone Trifluoperazine Trimethoprim Trimipramine Tubocurarine Vandetanib Vardenafil Vasopressin Vecuronium Vemurafenib Zolmitriptan

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Abarelix Amiloride Aripiprazole Atenolol Cimetidine Clozapine Dalfopristin Dextromethorphan Dicumarol Fosphenytoin Galantamine Ketoconazole Magaldrate Magnesium Carbonate Magnesium Hydroxide Magnesium Oxide Magnesium Trisilicate Metoprolol Nifedipine Nisoldipine Paroxetine Phenobarbital Phenytoin Propranolol Quinupristin Rifapentine Timolol Tolterodine Tramadol Verapamil 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. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

Grapefruit Juice Other Medical Problems

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

Electrolyte disorders—Quinidine may worsen heart rhythm problems Heart disease or Myasthenia gravis—Quinidine may make these conditions worse Kidney disease or Liver disease—Effects may be increased because of slower removal of quinidine from the body Proper Use of quinidine

This section provides information on the proper use of a number of products that contain quinidine. It may not be specific to Quinidex Extentabs. Please read with care.

Take this medicine exactly as directed. Do not take more of this medicine and do not take it more often than your doctor ordered. Do not miss any doses.

Taking quinidine with food may help lessen stomach upset.

For patients taking the extended-release tablet form of this medicine:

Quinidex Extentabs or Biquin Durules—Swallow the tablets whole; do not break, crush, or chew before swallowing. Note that Biquin Durules may sometimes appear as a whole tablet in the stool; this tablet is just the empty shell that is left after the medicine has been absorbed into the body. Quinaglute Duratabs or Quin-Release—These tablets may be broken in half; however, they should not be crushed or chewed before swallowing. Dosing

The dose of this medicine 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 this medicine. 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 regular (short-acting) oral dosage form (tablets): For abnormal heart rhythm: Adults—200 to 650 milligrams (mg) three or four times a day. Children—30 to 40 mg per kilogram (kg) (13.6 to 18.2 mg per pound) of body weight per day. Your doctor may increase the dose if needed. For long-acting oral dosage form (tablets): For abnormal heart rhythm: Adults—300 to 660 mg every eight to twelve hours. Children—30 to 40 mg per kilogram (kg) (13.6 to 18.2 mg per pound) of body weight per day. Your doctor may increase the dose if needed. For injection dosage form: For abnormal heart rhythm: Adults—190 to 380 mg injected into the muscle every two to four hours. Or, up to 0.25 mg per kg (0.11 mg per pound) of body weight per minute in a solution injected into a vein. Children—Dose must be determined by your doctor. For malaria: Adults—10 mg per kg (4.54 mg per pound) of body weight in a solution injected slowly into a vein over one to two hours. Then, 0.02 mg per kg (0.009 mg per pound) of body weight per minute is given. Or, 24 mg per kg (10.91 mg per pound) of body weight in a solution injected slowly into a vein over a four-hour period. Then, eight hours after the first dose, 12 mg per kg (5.45 mg per pound) of body weight, injected slowly into a vein over a four-hour period, and repeated every eight hours. Children—Dose must be determined by your doctor. 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

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Quinidex Extentabs

It is very important that your doctor check your progress at regular visits to make sure that the quinidine is working properly and does not cause unwanted effects.

Do not stop taking this medicine without first checking with your doctor, to avoid possible worsening of your condition.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking this medicine.

Dizziness or lightheadedness may occur with this medicine, especially when you get up from a lying or sitting position. Getting up slowly may help.

Fainting may occur with this medicine. Do not drive or do anything else that could be dangerous if fainting occurs.

. Check with your doctor immediately if you faint or experience other side effects with this medicine.

Your doctor may want you to carry a medical identification card or bracelet stating that you are using this medicine.

Quinidex Extentabs Side Effects

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

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

Less common Abdominal pain and/or yellow eyes or skin blurred and/or double vision, confusion, delirium, disturbed color perception, headache, noises or ringing in the ear, and/or visual intolerance of light dizziness or lightheadedness fainting fever Rare Chest pain, fever, general discomfort, joint pain, joint swelling, muscle pain, and/or skin rash nosebleeds or bleeding gums unusual tiredness or weakness and/or pale skin

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 loss of appetite muscle weakness nausea or vomiting

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.

See also: Quinidex Extentabs side effects (in more detail)

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

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

More Quinidex Extentabs resources Quinidex Extentabs Side Effects (in more detail) Quinidex Extentabs Use in Pregnancy & Breastfeeding Drug Images Quinidex Extentabs Drug Interactions Quinidex Extentabs Support Group 0 Reviews for Quinidex Extentabs - Add your own review/rating Quinidex Extentabs Concise Consumer Information (Cerner Multum) Quin-G Concise Consumer Information (Cerner Multum) Quinidine Professional Patient Advice (Wolters Kluwer) Quinidine Prescribing Information (FDA) Quinidine Gluconate Monograph (AHFS DI) Compare Quinidex Extentabs with other medications Arrhythmia Malaria



1. Name Of The Medicinal Product

Quinoderm 10% / 0.5% w/w Cream

2. Qualitative And Quantitative Composition

Benzoyl Peroxide, hydrous

10.0% w/w

Potassium Hydroxyquinoline Sulphate

0.5% w/w

Excipients: Also includes cetostearyl alcohol, approx 0.825% w/w

For full list of excipients, see section 6.1

3. Pharmaceutical Form

Quinoderm Cream is a creamy white astringent vanishing cream. It is intended for topical use only.

4. Clinical Particulars 4.1 Therapeutic Indications

Acne vulgaris, acneform eruptions, folliculitis.

4.2 Posology And Method Of Administration

Route of administration

For topical use only.

Adults, children and the elderly

By gentle massage over all the affected area two or three times daily.

4.3 Contraindications

Acne rosacea. Patients with known sensitivity to either of the active ingredients should not use Quinoderm Cream.

4.4 Special Warnings And Precautions For Use

Contact with mouth and eyes should be avoided. Care should be taken to avoid contact with dyed fabrics as this product may adversely affect dye fastness.

In a few isolated cases, overreaction to Quinoderm Cream may occur. To minimise this possibility, select a small area of skin behind the ear, apply the cream and leave for 12 hours. If severe irritation or pronounced redness occurs, do not proceed with treatment.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Benzoyl Peroxide is an oxidising agent. Hence, Quinoderm Cream should not be used at the same time as other topical agents which would react with an oxidising agent.

4.6 Pregnancy And Lactation

Quinoderm Cream is not contra-indicated in pregnancy or lactation.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Skin & Subcutaneous Tissue Disorders

Local irritation or inflammation may result; in such cases use should be interrupted or frequency reduced. Itch or rash may occur in which instance treatment should cease and a Physician or Pharmacist consulted.

4.9 Overdose

Not applicable.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Peroxides, Benzoyl Peroxide

ATC Code: D10AE01

Potassium Hydroxyquinoline Sulphate – not known.

The combination of the mild keratolytic properties of benzoyl peroxide and the antibacterial and antifungal properties of potassium hydroxyquinoline sulphate in a specially formulated bland water-miscible base make this preparation valuable in the treatment of acne vulgaris, acneform eruptions and folliculitis.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Lactic Acid,

White Soft Paraffin,

Edetic Acid,

Sodium Dihydrogen Phosphate Dihydrate ,

Maize Starch,

Cetostearyl Alcohol

Sodium Cetostearyl Sulphate

Macrogol 40 Castor Oil

Purified Water.

6.2 Incompatibilities

Any topical agent that would react with an oxidising agent

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Do not store above 25?C. Do not refrigerate.

6.5 Nature And Contents Of Container

Quinoderm Cream is available in heat sealed low density polyethylene tubes with flush fitting cap containing 25 g, 40g and 50 g of product. Each tube is cartoned and contains a patient information leaflet.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Ferndale Pharmaceuticals Ltd,

12 York Place,

Leeds,

LS1 2DS,

United Kingdom.

8. Marketing Authorisation Number(S)

PL 20685/0022

9. Date Of First Authorisation/Renewal Of The Authorisation

23 April 2004

10. Date Of Revision Of The Text

05 November 2010

11 DOSIMETRY

n/a

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

n/a





1. Name Of The Medicinal Product

Quinoderm 5% / 0.5% w/w Cream

2. Qualitative And Quantitative Composition

Benzoyl Peroxide, hydrous

5.0% w/w

Potassium Hydroxyquinoline Sulphate

0.5% w/w

Excipients: Also includes cetostearyl alcohol, approx 0.825% w/w

For full list of excipients, see section 6.1

3. Pharmaceutical Form

Quinoderm Cream is a creamy white astringent vanishing cream. It is intended for topical use only.

4. Clinical Particulars 4.1 Therapeutic Indications

Acne vulgaris, acneform eruptions, folliculitis.

4.2 Posology And Method Of Administration

Route of administration

For topical use only.

Adults, children and the elderly

By gentle massage over all the affected area two or three times daily.

4.3 Contraindications

Acne rosacea. Patients with known sensitivity to either of the active ingredients should not use Quinoderm Cream.

4.4 Special Warnings And Precautions For Use

Contact with mouth and eyes should be avoided. Care should be taken to avoid contact with dyed fabrics as this product may adversely affect dye fastness.

In a few isolated cases, overreaction to Quinoderm Cream may occur. To minimise this possibility, select a small area of skin behind the ear, apply the cream and leave for 12 hours. If severe irritation or pronounced redness occurs, do not proceed with treatment.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Benzoyl Peroxide is an oxidising agent. Hence, Quinoderm Cream should not be used at the same time as other topical agents which would react with an oxidising agent.

4.6 Pregnancy And Lactation

Quinoderm Cream is not contra-indicated in pregnancy or lactation.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Skin & Subcutaneous Tissue Disorders

Local irritation or inflammation may result; in such cases use should be interrupted or frequency reduced. Itch or rash may occur in which instance treatment should cease and a Physician or Pharmacist consulted.

4.9 Overdose

Not applicable.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Peroxides, Benzoyl Peroxide

ATC Code: D10AE01

Potassium Hydroxyquinoline Sulphate – not known.

The combination of the mild keratolytic properties of benzoyl peroxide and the antibacterial and antifungal properties of potassium hydroxyquinoline sulphate in a specially formulated bland water-miscible base make this preparation valuable in the treatment of acne vulgaris, acneform eruptions and folliculitis.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Lactic Acid,

White Soft Paraffin,

Edetic Acid,

Sodium Dihydrogen Phosphate Dihydrate ,

Maize Starch,

Cetostearyl Alcohol

Sodium Cetostearyl Sulphate

Macrogol 40 Castor Oil

Purified Water.

6.2 Incompatibilities

Any topical agent that would react with an oxidising agent

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Do not store above 25?C. Do not refrigerate.

6.5 Nature And Contents Of Container

Quinoderm Cream is available in heat sealed low density polyethylene tubes with flush fitting cap containing 25 g, and 50 g of product. Each tube is cartoned and contains a patient information leaflet.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Ferndale Pharmaceuticals Ltd,

12 York Place,

Leeds,

LS1 2DS,

United Kingdom.

8. Marketing Authorisation Number(S)

PL 20685/0023

9. Date Of First Authorisation/Renewal Of The Authorisation

09 September 2005

10. Date Of Revision Of The Text

05 November 2010

11 DOSIMETRY

n/a

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

n/a

Recent History:

05/11/2010 Var 0015

Type IB Az – administrative changes to SmPC 2, 4.8, 5.1, 6.1, 6.2, 6.4, 6.5.



Generic Name: diphenhydramine (DYE fen HYE dra meen)



1. Name Of The Medicinal Product

Quinapril/Hydrochlorothiazide 20/12.5 mg film-coated tablets

2. Qualitative And Quantitative Composition

20 /12.5 mg:

Each film-coated tablet contains 20 mg of quinapril equivalent to 21.66 mg of quinapril hydrochloride and 12.5 mg hydrochlorothiazide.

Excipient: Each film-coated tablet contains 35.56 mg of lactose (as lactose monohydrate).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

20mg/12.5mg:

Pink coloured, triangular, biconvex, film-coated tablets debossed with 'D' and '19' on either sides of a scoreline on one side and plain on the other side.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical Particulars 4.1 Therapeutic Indications

Quinapril/Hydrochlorothiazide is indicated as substitution therapy only in adult patients with essential hypertension already adequately controlled with quinapril and hydrochlorothiazide given concurrently.

4.2 Posology And Method Of Administration

Posology

Patients receiving quinapril and hydrochlorothiazide from separate tablets may be switched to a combination tablets of Quinapril/Hydrochlorothiazide containing the same component doses.

Adults:

The recommended dose of Quinapril/Hydrochlorothiazide is one tablet per day.

Renal impairment

Due to hydrochlorothiazide component, Quinapril/Hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see sections 4.3, 4.4 and 5.2).

Elderly patients (>65 years old)

The dose should be kept as low as possible commensurate with achievement of adequate blood pressure control.

Children and adolescents (less than 18 years of age)

Quinapril/Hydrochlorothiazide is not recommended for use in children and adolescents due to lack of data on safety and efficacy.

Method of administration

For oral use.

To be taken with or without food. The dose should always be taken at about the same time of day to help increase compliance.

4.3 Contraindications

• Quinapril/HCTZ is contraindicated in women who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraceptive measures (see Sections 4.4 and 4.6).

• Quinapril/HCTZ is contraindicated in patients with hypersensitivity to any of the ingredients including patients with a history of angioedema related to previous treatment with ACE inhibitors.

• Quinapril/HCTZ is contraindicated in patients with hereditary/idiopathic angioneurotic oedema.

• Quinapril/HCTZ should not be used in patients with ventricular outflow obstruction.

• Quinapril/HCTZ is contraindicated in patients with anuria or with severe renal dysfunction.

• Quinapril/HCTZ is contraindicated in patients with hypersensitivity to other sulphonamide-derived drugs.

4.4 Special Warnings And Precautions For Use

Quinapril/HCTZ should be used with caution in selected patients with aortic stenosis.

Sensitivity reactions:

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma, e.g. purpura, photosensitivity, urticaria, necrotising angiitis, respiratory distress including pneumonitis and pulmonary oedema, anaphylactic reactions.

Hypotension:

Quinapril/HCTZ can cause symptomatic hypotension, usually not more frequently than either drug as monotherapy. Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving quinapril, hypotension is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has severe renin-dependent hypertension (see Section 4.5).

Quinapril/HCTZ should be used cautiously in patients receiving concomitant therapy with other antihypertensive agents. The thiazide component of quinapril/HCTZ may potentiate the action of other antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. The antihypertensive effects of the thiazide component may also be enhanced in postsympathectomized patients.

If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses; however, lower doses of quinapril or of any concomitant diuretic therapy should be considered if this event occurs.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy for hypertension may cause an excessive drop in blood pressure, which may be associated with oliguria, azotemia, and in rare instances, with acute renal failure and death in such patients. Quinapril/HCTZ therapy should be started under close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dosage is increased.

Heart Failure/Heart Disease:

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the rennin-angiotensin- aldosterone system, treatment with quinapril, may be associated with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.

Cough:

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Renal Disease:

Quinapril/HCTZ should be used with caution in patients with renal disease. In severe renal disease thiazides may precipitate azotemia and in moderate renal impairment (creatinine clearance 10-20ml/min) thiazides are generally ineffective in such patients, and the effects of repeated dosing may be cumulative.

There is insufficient experience in patients with severe renal impairment (creatinine clearance <10 ml/min).

The half-life of quinaprilat is prolonged as creatinine clearance falls. Patients with a creatinine clearance of <60 mL/min require a lower initial dosage of quinapril (see Section 4.2). These patients' dosage should be titrated upwards based upon therapeutic response, and renal function should be closely monitored although initial studies do not indicate that quinapril produces further deterioration in renal function.

In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.

Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases (>1.25 times the upper limit of normal) in blood urea and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic and has been observed in 4% and 3% respectively of patients on monotherapy. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of a diuretic and/or quinapril may be required.

Impaired Hepatic Function:

Quinapril/HCTZ should be used with caution in patients with impaired hepatic function or progressive liver disease since minor alterations of fluid and electrolyte balance may result from thiazide treatment and may precipitate hepatic coma. Quinapril is rapidly deesterified to quinaprilat, (quinapril diacid, the principal metabolite), which, in human and animal studies, is a potent angiotensin-converting enzyme inhibitor. The metabolism of quinapril is normally dependent upon hepatic esterase. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril.

Rarely, ACE inhibitors have been associated with a syndrome beginning as a cholestatic jaundice and progressing to a fulminant hepatic necrosis (in some cases fatal). Patients who during ACE inhibitor therapy experience jaundice or clearly elevated hepatic enzymes should discontinue quinapril/HCTZ and receive appropriate medical follow-up.

Immune-mediated drug reactions/ Anaphylactoid reactions:

Desensitisation: Patients receiving ACE inhibitors during desensitizing treatment with hymenoptera venom have sustained life-threatening anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld, but they have reappeared upon inadvertent rechallenge.

Stevens-Johnson syndrome and exacerbations or activation of systemic lupus erythematosus have been reported with thiazides.

Angioedema:

Angioedema has been reported in patients treated with angiotensin-converting enzyme inhibitors. If laryngeal stridor or angioedema of the face, tongue, or glottis occur, treatment should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Angioedema associated with laryngeal involvement may be fatal. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, appropriate therapy e.g., subcutaneous adrenaline solution 1:1000 (0.3 to 0.5 ml) should be promptly administered.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see Section 4.3).

Intestinal angioedema:

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Ethnic Differences:

Black patients receiving ACE inhibitor therapy have been reported to have a higher incidence of angioedema compared to non-black patients. It should also be noted that in controlled clinical trials, ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks.

Haemodialysis and LDL Apheresis:

Patients haemodialysed using high-flux polyacrylonitrile ('AN69') membranes are highly likely to experience anaphylactoid reactions if they are treated with ACE inhibitors. This combination should therefore be avoided, either by use of alternative antihypertensive drugs or alternative membranes for haemodialysis. Similar reactions have been observed during low density lipoprotein apheresis with dextran-sulphate. This method should therefore not be used in patients treated with ACE inhibitors.

Derangements of Serum Electrolytes:

Patients receiving quinapril/HCTZ should be observed for clinical signs of thiazide induced fluid or electrolyte imbalance. In such patients periodic determination of serum electrolytes (sodium and potassium in particular) should be performed. Because quinapril reduces the production of aldosterone, its combination with hydrochlorothiazide may minimise diuretic induced hypokalaemia.

The opposite effects of quinapril and hydrochlorothiazide on serum potassium will approximately balance each other in many patients so that no net effect upon serum potassium will be seen. In other patients, one or the other effect may be dominant and some patients may still require potassium supplements. Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Hypokalemia:

Conversely, treatment with thiazide diuretics has been associated with hypokalaemia, hyponatremia, and hypochloremic alkalosis. These disturbances have sometimes been manifest as one or more of the following: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, confusion, seizures and vomiting. Hypokalaemia can also sensitize or exaggerate the response of the heart to the toxic effects of digitalis. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or adrenocorticotrophic hormone (ACTH) (see Section 4.5).

Hyperkalaemia:

Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician (see Section 4.5).

Hypoglycaemia and Diabetes:

In diabetic patients ACE inhibitors may enhance insulin sensitivity and have been associated with hypoglycaemia in patients treated with oral antidiabetic agents or insulin. Glycaemic control should be closely monitored (see Section 4.5).

Neutropenia/Agranulocytosis:

ACE inhibitors have been rarely associated with agranulocytosis and bone marrow depression in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a connective disease with the concomitant use of immunosuppressive or other agents which may be associated with neutropenia/agranulocytosis. Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) as this could be a sign of neutropenia (see Section 4.5).

Agranulocytosis has been rarely reported during treatment with quinapril. As with other ACE inhibitors, monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered.

Surgery/Anaesthesia:

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, quinapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Pregnancy:

Quinapril/HCTZ is contraindicated in pregnancy. Quinapril/HCTZ should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards to the fetus (see Sections 4.3 and 4.6).

Lactose:

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/galactose malabsorption should not use this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Tetracycline and other drugs that interact with magnesium:

Because of the presence of magnesium carbonate in the formulation, quinapril has been shown in healthy volunteers to reduce the absorption of tetracycline in concomitant administration by 28-37%. It is recommended that concomitant administration with tetracycline be avoided. This interaction should be considered if coprescribing quinapril and tetracycline.

Agents increasing serum potassium:

Quinapril/HCTZ contains a thiazide diuretic, which tends to increase the urinary excretion of potassium but it also contains an ACE inhibitor, which tends to conserve potassium by lowering aldosterone levels. It is not advisable to routinely add potassium sparing diuretics or potassium supplements as this may result in elevated serum potassium.

Other diuretics:

Quinapril/HCTZ contains a diuretic. Concomitant use of another diuretic may have an additive effect. Also, patients on diuretics, especially those who are volume and/or salt depleted, may experience an excessive reduction of blood pressure on initiation of therapy, or with increased dosage of an ACE inhibitor.

Other antihypertensive drugs:

There may be an additive effect or potentiation when quinapril/HCTZ is combined with other antihypertensive drugs such as nitrates or vasodilators.

Surgery/anaesthesia:

Although no data are available to indicate there is an interaction between quinapril and anaesthetic agents that produces hypotension, caution should be exercised when patients undergo major surgery or anaesthesia since ACE inhibitors have been shown to block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion (see Section 4.4).

Thiazides may decrease the arterial response to noradrenaline. In emergency surgery pre-anaesthetic and anaesthetic agents should be administered in reduced doses. Thiazides may increase the response to tubocurarine.

Lithium:

Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy due to the sodium-losing effect of these agents. With quinapril/HCTZ, the risk of lithium toxicity may be increased. Quinapril/HCTZ should be administered with caution and frequent monitoring of serum lithium levels is recommended.

Corticosteroids, ACTH:

Intensified electrolyte depletion, particularly hypokalaemia has been observed.

Non-steroidal anti-inflammatory drugs:

In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium sparing, and thiazide diuretics and may reduce the antihypertensive effect of ACE inhibitors. Therefore, when quinapril/HCTZ and nonsteroidal anti-inflammatory agents are used concomitantly the patients should be observed closely to determine if the desired effect of quinapril/HCTZ is obtained. Furthermore, it has been described that NSAIDs and ACE inhibitors exert an additive effect on the increase in serum potassium, whereas renal function may decrease. These effects are in principle reversible and occur especially in patients with compromised renal function.

Allopurinol, cytostatic and immunosuppressive agents, systemic corticosteroids or procainamide:

Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia.

Alcohol, barbiturates or narcotics:

Potentiation of orthostatic hypotension may occur.

Drugs associated with torsades de pointes:

Due to the potential risk of hypokalemia, caution should be used when hydrochlorothiazide is co administered with medicines such as digitalis glycosides or agents associated with torsades de pointes.

Antacids:

Antacids may decrease the bioavailability of quinapril/HCTZ .

Antidiabetic drugs (oral hypoglycaemic agents and insulin):

In diabetic patients ACE inhibitors may enhance insulin sensitivity and have been associated with hypoglycaemia in patients treated with oral antidiabetic agents or insulin. Glycaemic control should be closely monitored (see Section 4.4).

4.6 Pregnancy And Lactation

Pregnancy:

Quinapril/HCTZ is contraindicated in pregnancy (see Section 4.3). ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, quinapril/HCTZ should be discontinued.

Infants exposed to ACE inhibitors during pregnancy may be at increased risk for malformations of the cardiovascular system and central nervous system. There have also been reports of prematurity, hypotension, renal system disorders (including renal failure), skull hypoplasia, oligohydramnios, limb contractures, craniofacial deformities, hypoplastic lung development, intrauterine growth retardation, patent ductus arteriosus, fetal death and/or death in the newborn in association with the maternal use of ACE inhibitors.

Patients and physicians should be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants who may have been exposed in utero to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalaemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion.

Thiazides cross the placental barrier and appear in cord blood. Nonteratogenic effects to the fetus may include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.

There are no adequate and well-controlled studies of quinapril/HCTZ in pregnant women.

Lactation:

ACE inhibitors, including quinapril, are secreted in human milk to a limited extent. Thiazides appear in human milk. Because of the potential for serious reactions in nursing infants, a decision should be made whether to discontinue quinapril/HCTZ or discontinue nursing, taking into account the importance of the drug to the mother.

4.7 Effects On Ability To Drive And Use Machines

The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired.

4.8 Undesirable Effects

The following undesirable effects have been observed and reported during treatment with quinapril/HCTZ with the following frequencies: very common (

System Organ Class

Frequency

Undesirable effects

Blood and the lymphatic system disorders

Not known

Agranulocytosis##, haemolytic anemia#, neutropenia##, thrombocytopenia#

Immune system disorders

Not known

Anaphylactoid reaction#

Metabolism and nutrition disorders

Common

Hyperkalaemia##

Psychiatric disorders

Common

Insomnia#

Uncommon

Confusion#, depression#, nervousness#

 

Nervous system disorders

Common

Dizziness#, headache#, somnolence#

Uncommon

Paraesthesia#, Transient ischaemic attacks#

 

Rare

Balance disorder

 

Not known

Cerebral haemorrhage#

 

Eye disorders

Uncommon

Amblyopia#

Very Rare

Blurred vision#

 

Ear and labyrinth disorders

Uncommon

Tinnitus#, vertigo#

Cardiac disorders

Common

Myocardial infarction#

Uncommon

Angina pectoris##, tachycardia#, palpitations#

 

Not known

Arrhythmia

 

Vascular disorders

Common

Vasodilation#

Uncommon

Hypotension#, syncope#

 

Not known

Postural hypotension#

 

Respiratory, thoracic and mediastinal disorders

Common

Bronchitis, cough#, pharyngitis#, rhinitis#, upper respiratory tract infection

Uncommon

Dyspnoea#, sinusitis

 

Rare

Eosiniphilic pneumonitis##, angioneurotic oedema#

 

Not known

Bronchospasm#

 

Gastrointestinal disorders

Common

Abdominal pain#, diarrhoea#, dyspepsia#, nausea#, vomiting#

Uncommon

Flatulence#, dry mouth or throat#, altered taste#

 

Rare

Constipation, glossitis

 

Very Rare

Ileus#, intestinal angioedema

 

Not known

Pancreatitis#

 

Hepato-biliary disorders

Not known

Hepatitis#, cholestatic icterus#

Skin and subcutaneous tissue disorders

Uncommon

Alopecia#, photosensitivity# pruritus#, rash#, angioedema##, increased perspiration##

Rare

Skin changes may be associated with fever, muscle and joint pain (myalgias, arthralgias, arthritis), vascular inflammation (vasculitis), psoriasis-like efflorescence#

 

Very Rare

Urticaria#

 

Not known

Toxic epidermal necrolysis#, erythema multiforme#, exfoliative dermatitis#, pemphigus#, purpura, Stevens-Johnson syndrome#, inflammations of serous tissues and certain changes in laboratory values (eosinophilia# and/or elevated ANA titers#, elevated ESR)

 

Musculoskeletal, connective tissue and bone disorders

Common

Back pain#, myalgia#, hyperuricaemia#, gout#

Uncommon

Arthralgia#

 

Renal and urinary disorders

Uncommon

Renal dysfunction#, proteinuria, urinary tract infection

Not known

Interstitial nephritis

 

Reproductive system and breast disorders

Uncommon

Impotence#

General disorders and administration site conditions

Common

Asthenia#, Chest pain#, fatigue#

Uncommon

Fever#, generalised oedema#,#, peripheral oedema#

 

Investigations

Common

Increased serum creatinine#, increased blood urea nitrogen#*

Not known

Increases in cholesterol# and triglyceride levels#.

Decreases in hematocrit# and WCC# as well as elevation in liver enzymes and serum bilirubin.

In patients with a congenital G-6-PDH deficiency, individual cases of haemolytic anaemia# have been reported

 

Infections and infestations

Uncommon

Viral infection

Endocrine disorders

Uncommon

Insulin requirements in diabetic patients may be altered by thiazides and latent diabetes mellitus may occur#

* Such increases are more likely to occur in patients receiving concomitant diuretic therapy than those on monotherapy with quinapril. These observed increases will often reverse on continued therapy.

# Adverse reactions associated with quinapril component, frequencies observed when taking quinapril/HCTZ.

## Adverse reactions associated with quinapril component, frequencies observed in quinapril, adverse reactions not associated with quinapril/HCTZ component.

Clinical Laboratory Test Findings:

Serum Electrolytes: (See section 4.4).

Serum Uric Acid, Glucose, Magnesium, PBI, Parathyroid Function tests and Calcium: (See section 4.4).

Haematology test: (See section 4.4).

4.9 Overdose

No data are available for quinapril/HCTZ with respect to overdosage in humans.

The most likely clinical manifestation would be symptoms attributable to quinapril monotherapy overdosage such as severe hypotension, which would usually be treated by infusion of intravenous normal saline.

The most common signs and symptoms observed for HCTZ monotherapy overdosage are those caused by electrolyte depletion (hypokalaemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalaemia may accentuate cardiac arrythmias.

No specific information is available on the treatment of overdosage with quinapril/HCTZ.

Haemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Treatment is symptomatic and supportive consistent with established medical care.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Quinapril and diuretics, ATC code: C09BA06

Quinapril/Hydrochlorothiazide is a fixed combination of the ACE inhibitor, quinapril, and a diuretic, hydrochlorothiazide. Concomitant administration of these agents reduces blood pressure to a greater degree than either component alone, given as monotherapy. Quinapril may, like other ACE inhibitors, counteract the loss of potassium that is inherent with hydrochlorothiazide.

Quinapril is a prodrug, which is hydrolysed to the active metabolite quinaprilat, a potent longacting inhibitor of angiotensin converting enzyme (ACE) in plasma and tissue. ACE catalyses the conversion of angiotensin-I to angiotensin-II, which is a potent vasoconstrictor. Inhibition of ACE results in decreased concentrations of angiotensin-II and reduced aldosterone secretion. Bradykinin metabolism is probably also inhibited. In clinical studies quinapril has been found to be lipid neutral and has no negative effect on glucose metabolism. Quinapril reduces the total peripheral and renal arterial resistance.

In general there are no clinically relevant changes in renal blood flow or glomerular filtrationrate. Quinaprilat results in a reduction of prone, sitting and standing blood pressure. The peak effect is achieved after 2-4 hours at recommended doses. Achievement of maximum blood pressure lowering effect may require 2-4 weeks of therapy in some patients. A decrease in left ventricular hypertrophy was observed with quinapril in experimental models of hypertension in animals. Morbidity/mortality data is lacking.

Hydrochlorothiazide is a thiazide diuretic and an antihypertensive agent that increases renin activity in plasma. Hydrochlorothiazide decreases the renal reabsorption of electrolytes in distal tubuli and increases the excretion of sodium, chloride, potassium, magnesium, bicarbonate and water. The excretion of calcium may be reduced. Concomitant administration of quinapril and hydrochlorothiazide produces a stronger hypotensive effect than that of either of the agents, given alone as monotherapy.

5.2 Pharmacokinetic Properties

Quinapril

The bioavailability of the active metabolite, quinaprilat, is 30-40% of the given oral dose of quinapril. Peak plasma concentrations are reached after approximately 2 hours. The absorption of quinapril is not affected by concurrent food intake, but an extremely high fat content in the food may reduce uptake. Approximately 97% of the active substance is bound to plasma proteins. With repeat dosing quinaprilat has a half life of 3 hours. Steady state is reached in 2-3 days. Quinaprilat is mainly excreted unchanged by the kidneys. The clearance is 220 ml/min.

In patients with renal dysfunction the half-life of quinaprilat is prolonged and the plasma quinaprilat concentrations are elevated. In patients with severely impaired hepatic function the concentrations of quinaprilat are reduced due to inhibited hydrolysis of quinapril.

After a single oral dose of 20 mg of quinapril in six breast-feeding women, Milk/Plasma ratio for quinapril was 0.12. Quinapril was not detected in milk after 4 hours after the dose. Quinalaprilat milk levels were undetectable (<5 µg/L) at all time points. It is estimated that a breastfed infant would receive about 1.6% of the maternal weight-adjusted dosage of quinapril.

Hydrochlorothiazide

The bioavailability is 60-80%. The diuretic effect is evident within 2 hours of administration, with a maximum effect after ca 4 hours. The effect is maintained for 6-12 hours. Hydrochlorothiazide is excreted unchanged through the kidneys. The mean plasma half-life is in the range of 5-15 hours.

The half-life of Hydrochlorothiazide is prolonged in patients with impaired renal function.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic potential. No studies regarding genotoxicity or carcinogenicity of the combination (quinapril/hydrochlorothiazide) have been carried out. Reproductive toxicity studies in rats suggest that quinapril and/or hydrochlorothiazide has no negative effects on fertility and reproductive performance, and is not teratogenic. ACE inhibitors, as a class, have been shown to be fetotoxic (causing injury and/or death to the fetus) when given in the second or third trimester.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Tablet core:

Lactose monohydrate

Magnesium carbonate heavy

Crospovidone (Type A)

Povidone (K30)

Magnesium stearate

Tablet coat: (Opadry pink)

Hypromellose

Titanium dioxide (E171)

Hydroxypropyl cellulose

Macrogol 400

Iron oxide red (E172)

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

Blister packs Polyamide/Al/PV/Al blister: 7, 10, 14, 20, 28, 30, 42, 50, 56, 60, 84, 90, 98, 100, 156, 250 and 500 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Milpharm Limited

Ares, Odyssey Business Park

West End Road, South Ruislip HA4 6QD

United Kingdom

8. Marketing Authorisation Number(S)

PL 16363/0257

9. Date Of First Authorisation/Renewal Of The Authorisation

15/06/2010

10. Date Of Revision Of The Text

05/02/2011



1. Name Of The Medicinal Product

Qvar 50 Aerosol 50 micrograms per actuation pressurised inhalation solution

2. Qualitative And Quantitative Composition

Beclometasone Dipropionate 50 micrograms per metered (ex-valve) dose.

(The dose delivered from the mouthpiece is an average 37.5 micrograms).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Pressurised inhalation, solution.

A colourless solution in a pressurised aluminium canister fitted with a metering valve and an actuator.

Qvar contains a propellant, which does not contain any chlorofluorocarbons (CFCs).

4. Clinical Particulars 4.1 Therapeutic Indications

Prophylactic management of mild, moderate or severe asthma.

4.2 Posology And Method Of Administration

Qvar is for inhalation use only.

Patients should be instructed in the proper use of their inhaler, including rinsing out their mouth with water after use. Patients should be advised that Qvar may have a different taste and feel than a CFC inhaler.

NOTE: The recommended total daily dose of Qvar is lower than that for current beclometasone dipropionate CFC containing products and should be adjusted to the needs of the individual patient.

ADULT STARTING AND MAINTENANCE DOSE:

It is important to gain control of asthma symptoms and optimise pulmonary function as soon as possible. When patients' symptoms remain under satisfactory control, the dose should be titrated to the lowest dose at which effective control of asthma is maintained.

To be effective, inhaled Qvar must be used on a regular basis even when patients are asymptomatic.

THERAPY IN NEW PATIENTS SHOULD BE INITIATED AT THE FOLLOWING DOSAGES

Mild asthma:

100 to 200 micrograms per day in two divided doses.

Moderate asthma:

200 to 400 micrograms per day in two divided doses.

Severe asthma:

400 to 800 micrograms per day in two divided doses.

TRANSFERRING PATIENTS TO QVAR FROM A CFC-CONTAINING INHALER

The general approach to switching patients to Qvar involves two steps as detailed below. Specific guidance on switching well-controlled and poorly-controlled (symptomatic) patients is given below the table.

Step 1: Consider the dose of CFC containing beclometasone dipropionate product appropriate to the patient's current condition.

Step 2: Convert the CFC containing beclometasone dipropionate dose to the Qvar dose according to the table below.

Total Daily Dose (mcg/day)

               

CFC-BDP*

200-250

300

400-500

600-750

800-1000

1100

1200-1500

1600-2000

QVAR

100

150

200

300

400

500

600

800

*CFC-BDP = CFC beclometasone dipropionate

1. Dosing in well-controlled patients with asthma

Patients with well-controlled asthma using beclometasone dipropionate CFC containing product should be switched to Qvar at a dose in accordance with the table above.

For example:

Patients on 2 puffs twice daily of CFC beclometasone dipropionate 100 micrograms would change to 2 puffs twice daily of Qvar 50 micrograms.

2. Dosing in poorly-controlled (symptomatic) patients with asthma

Patients with poorly-controlled asthma may be switched from CFC containing beclometasone dipropionate products to Qvar at the same microgram for microgram dose up to 800 micrograms daily. Comparative clinical studies have demonstrated that asthma patients achieve equivalent pulmonary function and control of symptoms with Qvar at lower total daily doses than with CFC containing beclometasone dipropionate products.

Alternatively the patient's current CFC containing beclometasone dipropionate dose can be doubled and this dose can be converted to the Qvar dose according to the table above.

Patients on budesonide inhalers may be transferred to Qvar as described for CFC containing beclometasone dipropionate products.

Patients on fluticasone inhalers may be transferred to the same total daily dose of Qvar up to 800 micrograms daily.

Once transferred to Qvar the dose should be adjusted to meet the needs of the individual patient.

The maximum recommended dose is 800 micrograms per day in divided doses.

The same total daily dose in micrograms from either Qvar 50 or Qvar 100 (a higher strength) aerosol provides the same clinical effect.

CHILDREN

There are no data to date on Qvar in children under 12 years of age, hence no definitive dosage recommendation can be made.

SPECIAL PATIENT GROUPS

No special dosage recommendations are made for elderly or patients with hepatic or renal impairment.

INSTRUCTIONS FOR USE

Qvar aerosol is recommended for those patients who have demonstrated consistent good technique with co-ordinating actuation and inhalation.

The patient should read the instruction leaflet before use.

Before first use of the inhaler, or if the inhaler has not been used for two weeks or more, prime the inhaler by releasing two puffs into the air.

Where a spacer is considered necessary for specific patient needs, Qvar aerosol can be used with AeroChamber Plus™ holding chamber, as the extrafine particle fraction is maintained.

Qvar delivers a consistent dose

- whether or not the canister is shaken by the patient

- without the need for the patient to wait between individual actuations

- regardless of storage orientation or periods without use of up to 14 days

- at temperatures as low as -10°C.

4.3 Contraindications

Hypersensitivity to beclometasone dipropionate or to any of the excipients.

4.4 Special Warnings And Precautions For Use

To be effective, Qvar must be used by patients on a regular basis, even when patients do not have asthma symptoms. When symptoms are controlled, maintenance Qvar therapy should be reduced in a stepwise manner to the minimum effective dose. Inhaled steroid treatment should not be stopped abruptly. Patients with asthma are at risk of acute attacks and should have regular assessments of their asthma control including pulmonary function tests.

Qvar is not indicated for the immediate relief of asthma attacks. Patients therefore need to have relief medication (inhaled short-acting bronchodilator) available for such circumstances.

Qvar is not indicated in the management of status asthmaticus.

Severe asthma exacerbations should be managed in the usual way. Subsequently, it may be necessary to increase the dose of Qvar up to the maximum daily dose. Systemic steroid treatment may be needed and/or an antibiotic, if there is an infection.

Patients should be advised to seek medical attention for review of maintenance Qvar therapy if peak flow falls, symptoms worsen or if the short-acting bronchodilator becomes less effective and increased inhalations are required. This may indicate worsening asthma.

Patients who have received systemic steroids for long periods of time or at high doses, or both, need special care and subsequent management when being transferred to inhaled steroid therapy. Patients should have stable asthma before being given inhaled steroids in addition to the usual maintenance dose of systemic steroid. Withdrawal of systemic steroids should be gradual, starting about seven days after the introduction of Qvar therapy. For daily oral doses of prednisolone of 10mg or less, dose reduction in 1mg steps, at intervals of not less than one week is recommended. For patients on daily maintenance doses of oral prednisolone greater than 10mg, larger weekly reductions in the dose might be acceptable. The dose reduction scheme should be chosen to correlate with the magnitude of the maintenance systemic steroid dose.

Most patients can be successfully transferred to inhaled steroids with maintenance of good respiratory function, but special care is necessary for the first few months after the transfer, until the hypothalamic-pituitary-adrenal (HPA) system has sufficiently recovered to enable the patient to cope with stressful emergencies such as trauma, surgery or serious infections. Patients should, therefore, carry a steroid warning card to indicate the possible need to re-instate systemic steroid therapy rapidly during periods of stress or where airways obstruction or mucus significantly compromises the inhaled route of administration. In addition, it may be advisable to provide such patients with a supply of corticosteroid tablets to use in these circumstances. The dose of inhaled steroids should be increased at this time and then gradually reduced to the maintenance level after the systemic steroid has been discontinued. As recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy is slow, adrenocortical function should be monitored regularly.

Patients should be advised that they may feel unwell in a non-specific way during systemic steroid withdrawal despite maintenance of, or even improved respiratory function. Patients should be advised to persevere with their inhaled product and to continue withdrawal of systemic steroids, even if feeling unwell, unless there is evidence of HPA axis suppression.

Discontinuation of systemic steroids may also cause exacerbation of allergic diseases such as atopic eczema and rhinitis. These should be treated as required with topical therapy, including corticosteroids and/or antihistamines.

Beclometasone dipropionate, like other inhaled steroids, is absorbed into the systemic circulation from the lungs. Beclometasone dipropionate and its metabolites may exert detectable suppression of adrenal function. Within the dose range 100-800 micrograms daily, clinical studies with Qvar have demonstrated mean values for adrenal function and responsiveness within the normal range. However, systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma, and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than the recommended doses, may result in clinically significant adrenal suppression. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Like other corticosteroids, caution is necessary in patients with active or latent pulmonary tuberculosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

The potential risk of this product for humans is unknown.

Qvar

There is no experience of this product in pregnancy and lactation in humans, therefore the product should only be used if the expected benefits to the mother are thought to outweigh any potential risk to the foetus or neonate

Beclometasone dipropionate

There is inadequate evidence of safety in human pregnancy.

The use of beclometasone dipropionate in pregnancy requires that the possible benefits of the drug be weighed against the possible hazards. The drug has been in widespread use for many years without apparent ill consequence.

It is probable that beclometasone dipropionate is excreted in milk. However, given the relatively low doses used by the inhalation route, the levels are likely to be low. In mothers breast feeding their baby the therapeutic benefits of the drug should be weighed against the potential hazards to mother and baby.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

A serious hypersensitivity reaction including oedema of the eye, face, lips and throat (angioedema) has been reported rarely.

As with other inhaled therapy, paradoxical bronchospasm may occur after dosing. Immediate treatment with a short-acting bronchodilator should be initiated, Qvar should be discontinued immediately and an alternate prophylactic treatment introduced.

Systemic effects of inhaled corticosteroids may occur, particularly with high doses prescribed for prolonged periods. These include adrenal suppression, growth retardation in children, decrease in bone mineral density and the occurrence of cataract and glaucoma.

Commonly, when taking Qvar, hoarseness and candidiasis of the throat and mouth may occur. To reduce the risk of hoarseness and candida infection, patients are advised to rinse their mouth after using their inhaler.

Based on the MedDra system organ class and frequencies, adverse events are listed in the table below according to the following frequency estimate: very common (

MedDra – system organ class

Frequency and Symptom

Infections and infestations

Common: Candidiasis in mouth and throat

Immune system disorders

Rare: Allergic reactions, angioedema in eyes, throat, lips and face

Endocrine disorders

Very rare: Adrenal suppression, growth retardation in children

Nervous system disorders

Uncommon: Headache, vertigo, tremor

Eye disorders

Very rare: Cataract, glaucoma

Respiratory, thoracic and mediastinal disorders

Common: Hoarseness, pharyngitis

Uncommon: Cough, increased asthma symptoms

Rare: Paradoxical bronchospasm

Gastrointestinal disorders

Common: Taste disturbances

Uncommon: Nausea

Skin and subcutaneous tissue disorders

Uncommon: Urticaria, rash pruritus, erythema, purpura

Musculoskeletal and connective tissue disorders

Very rare: Decrease bone mineral density

Psychiatric Disorders

Unknown: Psychomotor hyperactivity, sleep disorders, anxiety, depression, aggression, behavioural changes (predominantly in children)

4.9 Overdose

Acute overdosage is unlikely to cause problems. The only harmful effect that follows inhalation of large amounts of the drug over a short time period is suppression of HPA function. Specific emergency action need not be taken. Treatment with Qvar should be continued at the recommended dose to control the asthma; HPA function recovers in a day or two.

If excessive doses of beclometasone dipropionate were taken over a prolonged period a degree of atrophy of the adrenal cortex could occur in addition to HPA suppression. In this event the patient should be treated as steroid dependent and transferred to a suitable maintenance dose of a systemic steroid such as prednisolone. Once the condition is stabilised, the patient should be returned to Qvar by the method described above in section 4.4.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Glucocorticoids, ATC Code: R03B A01

Qvar contains beclometasone dipropionate in solution in propellant HFA-134a resulting in an extrafine aerosol. The aerosol droplets are on average much smaller than the beclometasone dipropionate particles delivered by CFC-suspension formulations or dry powder formulations of beclometasone dipropionate. The extrafine particle fraction will be 60% ± 20% of the drug particles

Radio-labelled deposition studies in adults with mild asthma have demonstrated that the majority of drug (>55% ex-actuator) is deposited in the lung and a small amount (< 35% ex-actuator) is deposited in the oropharynx. These delivery characteristics result in equivalent therapeutic effects at lower total daily doses of Qvar, compared with CFC beclometasone dipropionate formulations.

Inhaled beclometasone dipropionate is now well established in the management of asthma. It is a synthetic glucocorticoid and exerts a topical, anti-inflammatory effect on the lungs, with fewer systemic effects than oral corticosteroids.

Comparative clinical studies have demonstrated that asthma patients achieve equivalent pulmonary function and control of symptoms with Qvar at lower total daily doses than CFC containing beclometasone dipropionate aerosol inhalers.

Pharmacodynamic studies in patients with mild asthma given Qvar for 14 days, have shown that there is a linear correlation among urinary free cortisol suppression, dose administered, and serum total-beclometasone levels obtained. At a daily dose of 800 micrograms Qvar, suppression of urinary free cortisol was comparable with that observed with the same daily dose of CFC containing beclometasone dipropionate, indicating a wider safety margin, as Qvar is administered at lower doses than the CFC product.

5.2 Pharmacokinetic Properties

The pharmacokinetic profile of Qvar shows that the peak serum concentration for total- beclometasone (BOH) (total of any beclometasone OH and beclometasone dipropionate or monopropionate hydrolysed to beclometasone OH) after single and multiple doses is achieved after 30 minutes.

The value at the peak is approximately 2 nanograms/ml after a total daily dose of 800 micrograms and the serum levels after 100, 200 and 400 micrograms are proportional. The principal route of elimination of beclometasone dipropionate and its several metabolites is in the faeces. Between 10% and 15% of an orally administered dose is excreted in the urine, as both conjugated and free metabolites of the drug.

In both single dose and multiple dose pharmacokinetic studies, a dose of 200 micrograms of Qvar achieved comparable total-BOH levels, as a dose of 400 micrograms of CFC containing beclometasone dipropionate aerosol. This provided the scientific rationale for investigating lower total daily doses of Qvar to achieve the same clinical effect.

Pharmacokinetic studies with Qvar have not been carried out in any special populations.

5.3 Preclinical Safety Data

In animal studies, propellant HFA-134a has been shown to have no significant pharmacological effects other than at very high exposure concentrations, then narcosis and a relatively weak cardiac sensitising effect were found. The potency of the cardiac sensitisation was less than that of CFC-11 (trichlorofluoromethane).

In studies to detect toxicity, repeated high dose levels of propellant HFA-134a indicated that safety margins based on systemic exposure would be of the order 2200, 1314 and 381 for mouse, rat and dog with respect to humans.

There are no reasons to consider propellant HFA-134a as a potential mutagen, clastogen or carcinogen judged from in vitro and in vivo studies including long-term administration by inhalation in rodents.

Studies of propellant HFA-134a administered to pregnant and lactating rats and rabbits have not revealed any special hazard.

In animals, systemic administration of relatively high doses can cause abnormalities of foetal development including growth retardation and cleft palate. There may therefore be a very small risk of such effects in the human foetus. However, inhalation of beclometasone dipropionate into the lungs avoids the high level of exposure that occurs with administration by systemic routes.

Safety studies with Qvar in rat and dog showed few, if any, adverse effects other than those normally associated with general steroid exposure including lymphoid tissue alterations such as reduction in thymus, adrenal and spleen weights. An inhalation reproductive study with this product in rats did not exhibit any teratogenic effects.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Propellant HFA-134a (Norflurane)

Ethanol.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 25°C. Protect from frost and direct sunlight.

The canister contains a pressurised liquid. Do not expose to temperatures higher that 50°C. Do not pierce the canister.

6.5 Nature And Contents Of Container

Pressurised aluminium canister closed with a metering valve containing either 100 or 200 actuations.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Teva UK Limited

Brampton Road

Hampden Park

Eastbourne

East Sussex

BN22 9AG

United Kingdom

8. Marketing Authorisation Number(S)

PL 00289/1371

9. Date Of First Authorisation/Renewal Of The Authorisation

2nd November 2009

10. Date Of Revision Of The Text

11/05/2011





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