QVAR

DESCRIPTION

DESCRIPTION SECTION

The active component of QVAR 40 mcg Inhalation Aerosol and QVAR 80 mcg Inhalation Aerosol is beclomethasone dipropionate, USP, an anti-inflammatory corticosteroid having the chemical name 9-chloro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate. Beclomethasone dipropionate (BDP) is a diester of beclomethasone, a synthetic corticosteroid chemically related to dexamethasone. Beclomethasone differs from dexamethasone in having a chlorine at the 9-alpha carbon in place of a fluorine, and in having a 16 beta-methyl group instead of a 16 alpha-methyl group. Beclomethasone dipropionate is a white to creamy white, odorless powder with a molecular formula of C 28 H 37 ClO 7 and a molecular weight of 521.1. Its chemical structure is: QVAR is a pressurized, metered-dose aerosol intended for oral inhalation only. Each unit contains a solution of beclomethasone dipropionate in propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol. QVAR 40 mcg delivers 40 mcg of beclomethasone dipropionate from the actuator and 50 mcg from the valve. QVAR 80 mcg delivers 80 mcg of beclomethasone dipropionate from the actuator and 100 mcg from the valve. Both products deliver 50 microliters (59 milligrams) of solution formulation from the valve with each actuation. The 40 mcg and the 80 mcg canisters provide either 100 inhalations or 120 inhalations. QVAR should be "primed" or actuated twice prior to taking the first dose from a new canister, or when the inhaler has not been used for more than ten days. Avoid spraying in the eyes or face while priming QVAR. This product does not contain chlorofluorocarbons (CFCs).

CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

Airway inflammation is known to be an important component in the pathogenesis of asthma. Inflammation occurs in both large and small airways. Corticosteroids have multiple anti-inflammatory effects, inhibiting both inflammatory cells (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and release of inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines). These anti-inflammatory actions of corticosteroids such as beclomethasone dipropionate contribute to their efficacy in asthma. Beclomethasone dipropionate is a prodrug that is rapidly activated by hydrolysis to the active monoester, 17 monopropionate (17-BMP). Beclomethasone 17 monopropionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 13 times that of dexamethasone, 6 times that of triamcinolone acetonide, 1.5 times that of budesonide and 25 times that of beclomethasone dipropionate. The clinical significance of these findings is unknown. Studies in patients with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of QVAR.

CLINICAL TRIALS

CLINICAL STUDIES SECTION

Blinded, randomized, parallel, placebo-controlled and active-controlled clinical studies were conducted in 940 adult asthma patients to assess the efficacy and safety of QVAR in the treatment of asthma. Fixed doses ranging from 40 mcg to 160 mcg twice daily were compared to placebo, and doses ranging from 40 mcg to 320 mcg twice daily were compared with doses of 42 mcg to 336 mcg twice daily of an active CFC-BDP comparator. These studies provided information about appropriate dosing through a range of asthma severity. A blinded, randomized, parallel, placebo-controlled study was conducted in 353 pediatric patients (age 5-12 years) to assess the efficacy and safety of HFA beclomethasone dipropionate in the treatment of asthma. Fixed doses of 40 mcg and 80 mcg twice daily were compared with placebo in this study. In these adult and pediatric efficacy trials, at the doses studied, measures of pulmonary function [forced expiratory volume in 1 second (FEV 1 ) and morning peak expiratory flow (AM PEF)] and asthma symptoms were significantly improved with QVAR treatment when compared to placebo. In controlled clinical trials with adult patients not adequately controlled with beta-agonist alone, QVAR was effective at improving asthma control at doses as low as 40 mcg twice daily (80 mcg/day). Comparable asthma control was achieved at lower daily doses of QVAR than with CFC-BDP. Treatment with increasing doses of both QVAR and CFC-BDP generally resulted in increased improvement in FEV 1 . In this trial the improvement in FEV 1 across doses was greater for QVAR than for CFC-BDP, indicating a shift in the dose response curve for QVAR.

INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

QVAR is indicated in the maintenance treatment of asthma as prophylactic therapy in patients 5 years of age and older. QVAR is also indicated for asthma patients who require systemic corticosteroid administration, where adding QVAR may reduce or eliminate the need for the systemic corticosteroids. Beclomethasone dipropionate is NOT indicated for the relief of acute bronchospasm.

CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

QVAR is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. Hypersensitivity to any of the ingredients of this preparation contraindicates its use.

WARNINGS

WARNINGS SECTION

Particular care is needed in patients who are transferred from systemically active corticosteroids to QVAR because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infections (particularly gastroenteritis) or other conditions with severe electrolyte loss. Although QVAR may provide control of asthmatic symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid that is necessary for coping with these emergencies. During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physician for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack. Transfer of patients from systemic steroid therapy to QVAR may unmask allergic conditions previously suppressed by the systemic steroid therapy, e.g., rhinitis, conjunctivitis, and eczema. Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. It is not known how the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection. Nor is the contribution of the underlying disease and/or prior corticosteroid treatment known. If exposed to chickenpox, prophylaxis with varicella-zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. QVAR is not a bronchodilator and is not indicated for rapid relief of bronchospasm. As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing. If bronchospasm occurs following dosing with QVAR, it should be treated immediately with a short acting inhaled bronchodilator. Treatment with QVAR should be discontinued and alternate therapy instituted. Patients should be instructed to contact their physician immediately when episodes of asthma, which are not responsive to bronchodilators, occur during the course of treatment with QVAR. During such episodes, patients may require therapy with oral corticosteroids.

PRECAUTIONS

PRECAUTIONS SECTION

ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

The following reporting rates of common adverse experiences are based upon four clinical trials in which 1196 Patients (671 female and 525 male adults previously treated with as-needed bronchodilators and/or inhaled corticosteroids) were treated with QVAR (doses of 40, 80, 160, or 320 mcg twice daily) or CFC-BDP (doses of 42, 168, or 336 mcg twice daily) or placebo. The table below includes all events reported by patients taking QVAR (whether considered drug related or not) that occurred at a rate over 3% for either QVAR or CFC-BDP. In considering these data, difference in average duration of exposure and clinical trial design should be taken into account. Adverse Events Reported by at Least 3% of the Patients for Either QVAR or CFC-BDP by Treatment and Daily Dose Adverse Events QVAR CFC-BDP Placebo (N=289) % Total (N=624) % 80-160 mcg (N=233) % 320 mcg (N=335) % 640 mcg (N=56) % Total (N=283) % 84 mcg (N=59) % 336 mcg (N=55) % 672 mcg (N=169) % HEADACHE 9 12 15 8 25 15 14 11 17 PHARYNGITIS 4 8 6 5 27 10 12 9 10 UPPER RESP TRACT INFECTION 11 9 7 11 5 12 3 9 17 RHINITIS 9 6 8 3 7 11 15 9 10 INCREASED ASTHMA SYMPTOMS 18 3 2 4 0 8 14 5 7 ORAL SYMPTOMS INHALATION ROUTE 2 3 3 3 2 6 7 5 5 SINUSITIS 2 3 3 3 0 4 7 2 4 PAIN

OVERDOSAGE

OVERDOSAGE SECTION

There were no deaths over 15 days following the oral administration of a single dose of 3000 mg/kg in mice, 2000 mg/kg in rats, and 1000 mg/kg in rabbits. The doses in mice, rats, and rabbits were 19,000, 25,000, and 25,000 times, respectively, the maximum recommended daily inhalation in adults or 36,000, 48,000, and 48,000 times, respectively the maximum recommended daily inhalation dose in children on a mg/m 2 basis.

DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

Patients should prime QVAR by actuating into the air twice before using for the first time or if QVAR has not been used for over ten days. Avoid spraying in the eyes or face when priming QVAR. QVAR is a solution aerosol, which does not require shaking. Consistent dose delivery is achieved, whether using the 40 or 80 mcg strengths, due to proportionality of the two products (i.e., two actuations of 40 mcg strength should provide a dose comparable to one actuation of the 80 mcg strength). QVAR should be administered by the oral inhaled route in patients 5 years of age and older. Use of QVAR with a spacer device in children less than 5 years of age is not recommended (see PRECAUTIONS, Pediatric Use ). The onset and degree of symptom relief will vary in individual patients. Improvement in asthma symptoms should be expected within the first or second week of starting treatment, but maximum benefit should not be expected until 3-4 weeks of therapy. For patients who do not respond adequately to the starting dose after 3-4 weeks of therapy, higher doses may provide additional asthma control. The safety and efficacy of QVAR when administered in excess of recommended doses has not been established. Table 2: Recommended Dosing for Adults and Adolescents Patient's Previous Therapy Recommended Starting Dose Highest Recommended Dose Bronchodilators Alone 40 to 80 mcg twice daily 320 mcg twice daily Inhaled Corticosteroids 40 to 160 mcg twice daily 320 mcg twice daily Table 3: Recommended Dosing for Children 5 to 11 Years Patient's Previous Therapy Recommended Starting Dose Highest Recommended Dose Bronchodilators Alone 40 mcg twice daily 80 mcg twice daily Inhaled Corticosteroids 40 mcg twice daily 80 mcg twice daily As with any inhaled corticosteroid, physicians are advised to titrate the dose of QVAR downward over time to the lowest level that maintains proper asthma control. This is particularly important in children since a controlled study has shown that QVAR has the potential to affect growth in children. Patients should be instructed on the proper use of their inhaler.

HOW SUPPLIED

HOW SUPPLIED SECTION

QVAR is supplied in two strengths: QVAR 40 mcg is supplied either in a 7.3 g canister containing 100 actuations with a beige plastic actuator and gray dust cap, and Patient's Instructions; box of one; 100 Actuations – NDC 59310-175-40 or in an 8.7 g canister containing 120 actuations with a beige plastic actuator and gray dust cap, and Patient's Instructions; box of one; 120 Actuations – NDC 59310-202-40 QVAR 80 mcg is supplied either in a 7.3 g canister containing 100 actuations with a dark mauve plastic actuator and gray dust cap, and Patient's Instructions; box of one; 100 Actuations – NDC 59310-177-80 or in an 8.7 g canister containing 120 actuations with a dark mauve plastic actuator and gray dust cap, and Patient's Instructions; box of one; 120 Actuations – NDC 59310-204-80 The correct amount of medication in each inhalation cannot be assured after 100 actuations from the 7.3 g canister or 120 actuations from the 8.7 g canister even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations have been used.

SPL UNCLASSIFIED SECTION

SPL UNCLASSIFIED SECTION

Rx only U.S. Patent Nos. 5605674, 5683677, 5695743, 5776432 Mktd by: Teva Respiratory, LLC– Horsham, PA 19044 Developed and Manufactured by: 3M Drug Delivery Systems Northridge, CA 91324 OR 3M Health Care, Ltd. Loughborough, UK September, 2010 © 2010 Teva Respiratory, LLC 639300 QVAR® is a registered trademark of IVAX LLC, a member of the TEVA Group. Rev. 09/10 OptiChamber is a registered trademark of Respironics Healthscan, Inc. and AeroChamber Plus is a registered trademark of Trudell Medical International Trudell Partnership Holdings Limited and Packard Medical Supply Centre Ltd.

PATIENT'S INSTRUCTIONS

SPL PATIENT PACKAGE INSERT SECTION

QVAR ® (beclomethasone dipropionate HFA) INHALATION AEROSOL Attention Pharmacist: Detach "PATIENT'S INSTRUCTIONS for Use" from package insert and dispense with the product. PATIENT'S INSTRUCTIONS It is important that you read these instructions before using QVAR. Correct and regular use of the inhaler will prevent or lessen the severity of asthma attacks. 1. Remove the plastic cap (see Figure 1 ) and be sure there are no foreign objects in the mouthpiece. Figure 1 2. As with all aerosol medications, it is recommended to prime the QVAR inhaler before using for the very first time after purchase, and in cases where the inhaler has not been used for more than ten days. Prime by releasing two actuations into the air, away from your eyes and face. Be sure the canister is firmly seated in the plastic mouthpiece adapter before each use. 3. BREATHE OUT AS FULLY AS YOU COMFORTABLY CAN. Hold the inhaler as shown in Figure 2. Close your lips around the mouthpiece, keeping your tongue below it. Figure 2 4. WHILE BREATHING IN DEEPLY AND SLOWLY, PRESS DOWN ON THE CAN WITH YOUR FINGER. When you have finished breathing in, hold your breath as long as you comfortably can (i.e., 5 - 10 seconds). 5. TAKE YOUR FINGER OFF THE CAN and remove the inhaler from your mouth. Breathe out gently. 6. If your physician has told you to take more than one inhalation per treatment repeat steps 3 through 5. 7. You should rinse your mouth with water after treatment. 8. For normal hygiene, the mouthpiece of your inhaler should be cleaned weekly with a clean, dry tissue or cloth. DO NOT WASH OR PUT ANY PART OF YOUR INHALER IN WATER. 9. DISCARD THE CANISTER AFTER the date calculated by your physician or pharmacist. The correct amount of medication in each inhalation cannot be assured after 100 actuations from the 7.3 g canister or 120 actuations from the 8.7 g canister even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations have been used. Before the discard date you should consult your physician to determine whether a refill is needed. It is advisable to keep track of the number of doses taken from the canister to better predict when a refill is necessary. Just as you should not take extra doses without consulting your physician, you also should not stop taking QVAR without consulting your physician. IMPORTANT QVAR is preventive therapy for asthma and must be used regularly and at the times your physician has prescribed. DO NOT CONFUSE QVAR WITH OTHER ASTHMA MEDICATION. QVAR WILL NOT PROVIDE IMMEDIATE RELIEF IF YOU ARE HAVING AN ASTHMA ATTACK. Your physician will decide whether other medication is needed should you require immediate relief. If you also use another medicine by inhalation, you should consult your physician for instructions on when to use it in relation to using QVAR. If this is the first time you will be using QVAR, it may take from 1 to 4 weeks before you feel the full benefits. QVAR Inhalation Aerosol canister should only be used with the QVAR Inhalation Aerosol mouthpiece and the mouthpiece should not be used with any other inhalation drug product. DOSAGE Use only as directed by your physician. CONTENTS UNDER PRESSURE Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 49°C (120°F) may cause bursting. Never throw container into fire or incinerator. Keep out of reach of children. Avoid spraying in eyes. Store at 25°C (77°F). For optimal results, the canister should be at room temperature when used. Store QVAR Inhalation Aerosol when not being used, so that the product rests on the concave end of the canister with the plastic actuator on top. Mktd by: Teva Respiratory, LLC Horsham, PA 19044 Developed and Manufactured by: 3M Drug Delivery Systems Northridge, CA 91324 OR 3M Health Care, Ltd. Loughborough, UK © 2010 Teva Respiratory, LLC QVAR® is a registered trademark of IVAX LLC, a member of the TEVA Group. 639300 Rev. 09/10

PACKAGE LABEL - QVAR 40 MCG METERED INHALATION 7.3 G

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL