Doxazosin

1 INDICATIONS AND USAGE Doxazosin tablets are an alpha 1 adrenergic antagonist indicated for: • Signs and symptoms of Benign Prostatic Hyperplasia (BPH) • Treatment of HypertensionTreatment of Hypertension 1.1 Benign Prostatic Hyperplasia (BPH) Doxazosin tablets are indicated for the treatment of the signs and symptoms of BPH. 1.2 Hypertension Doxazosin tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including this drug. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at highe

2 DOSAGE AND ADMINISTRATION • For the treatment of BPH: Initiate therapy at 1 mg once daily. Dose may be titrated at 1 to 2 week intervals, up to 8 mg once daily.( 2.2 ) • For the treatment hypertension: Initiate therapy at 1 mg once daily. Dose may be titrated as needed, up to 16 mg once daily. ( 2.3 ) 2.1 Dosing Information Following the initial dose and with each dose increase of doxazosin tablets, monitor blood pressure for at least 6 hours following administration. If doxazosin tablets administration is discontinued for several days, therapy should be restarted using the initial dosing regimen. 2.2 Benign Prostatic Hyperplasia The recommended initial dosage of doxazosin tablets is 1 mg given once daily either in the morning or evening. Depending on the individual patient’s urodynamics and BPH symptomatology, the dose may be titrated at 1 to 2 week intervals to 2 mg, and thereafter to 4 mg and 8 mg once daily. The maximum recommended dose for BPH is 8 mg once daily. Routinely monitor blood pressure in these patients. 2.3 Hypertension The initial dosage of doxazosin tablets is 1 mg given once daily. Daily dosage may be doubled up 16 mg once daily, as needed, to achieve the desired reduction in blood pressure.

6 ADVERSE REACTIONS The most commonly reported adverse reactions from clinical trials are Fatigue, malaise, hypotension, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Benign Prostatic Hyperplasia (BPH) The incidence of adverse events has been ascertained from worldwide clinical trials in 965 BPH patients. The incidence rates presented below (Table 2) are based on combined data from seven placebo-controlled trials involving once-daily administration of doxazosin tablets in doses of 1 to 16 mg in hypertensives and 0.5 to 8 mg in normotensives. Adverse reactions occurring more than 1% more frequently in BPH patients treated with doxazosin tablets vs placebo are summarized in Table 1. Table 1. Adverse Reactions Occurring more than 1% More Frequently in BPH Patients Treated with Doxazosin Tablets Versus Placebo BODY SYSTEM Doxazosin Tablets N=665 Placebo N=300 NERVOUS SYSTEM DISORDERS Dizziness † 15.6% 9% Somnolence 3% 1% CARDIAC DISORDERS Hypotension 1.7% 0% RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Dyspnoea 2.6% 0.3% GASTROINTESTINAL DISORDERS Dry Mouth 1.4% 0.3% GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue 8% 1.7% Oedema 2.7% 0.7% †Includes vertigo Other adverse reactions occurring less than 1% more frequently in BPH patients treated with doxazosin tablets vs placebo but plausibly related to doxazosin tablets include: palpitations. Hypertension Doxazosin tablets has been administered to approximately 4,000 hypertensive patients in clinical trials, of whom 1,679 were included in the hypertension clinical development program. In placebo-controlled studies, adverse events occurred in 49% and 40% of patients in the doxazosin and placebo groups, respectively, and led to discontinuation in 2% of patients in each group. Adverse reactions occurring more than 1% more frequently in hypertensive patients treated with doxazosin tablets vs placebo are summarized in Table 1. Postural effects and edema appeared to be dose-related. The prevalence rates presented below are based on combined data from placebo-controlled studies involving once-daily administration of doxazosin at doses ranging from 1 to 16 mg. Table 2. Adverse Reactions Occurring more than 1% More Frequently in Hypertensive Patients Treated with Doxazosin Tablets versus Placebo BODY SYSTEM Doxazosin Tablets N=339 Placebo N=336 NERVOUS SYSTEM DISORDERS Dizziness 19% 9% Somnolence 5% 1% RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Rhinitis 3% 1% RENAL AND URINARY DISORDERS Polyuria 2% 0% REPRODUCTIVE SYSTEM AND BREAST DISORDERS GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue / Malaise 12% 6% Other adverse reactions occurring less than 1% more frequently in hypertensive patients treated with doxazosin tablets vs placebo but plausibly related to doxazosin tablets use include vertigo, hypotension, hot flushes, epistaxis and oedema. Doxazosin tablets has been associated with decreases in white blood cell counts Laboratory changes observed in clinical studies Leukopenia/Neutropenia: Decreases in mean white blood cell (WBC) and mean neutrophil count were observed in controlled clinical trials of hypertensive patients receiving doxazosin tablets. In cases where follow-up was available, WBC and neutrophil counts returned to normal after discontinuation of doxazosin tablets. No patients became symptomatic as a result of the low WBC or neutrophil counts. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of doxazosin tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In post-marketing experience, the following additional adverse reactions have been reported: Blood and Lymphatic System Disorders: leukopenia, thrombocytopenia; Immune System Disorders: allergic reaction; Nervous System Disorders: hypoesthesia; Eye Disorders: Intraoperative Floppy Iris Syndrome [see Warnings and Precautions ( 5.2 )]; Cardiac Disorders: bradycardia; Respiratory, Thoracic and Mediastinal Disorders: bronchospasm aggravated; Gastrointestinal Disorders: vomiting; Hepatobiliary Disorders: cholestasis, hepatitis cholestatic; Skin and Subcutaneous Tissue Disorders: urticaria; Musculoskeletal and Connective Tissue Disorders: muscle cramps, muscle weakness; Renal and Urinary Disorders: hematuria, micturition disorder, micturition frequency, nocturia; Reproductive System and Breast Disorders: gynecomastia, priapism.

7 DRUG INTERACTIONS • Strong cytochrome P450 (CYP) 3A inhibitors may increase exposure to doxazosin and increased risk of hypotension. ( 7.1 ) • Concomitant administration of doxazosin tablets with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension. ( 7.2 ) 7.1 CYP 3A Inhibitors In vitro studies suggest that doxazosin is a substrate of CYP 3A4. Strong CYP3A inhibitors may increase exposure to doxazosin. Monitor blood pressure and for symptoms of hypotension when doxazosin tablets are used concomitantly with strong CYP3A inhibitors [ see Clinical Pharmacology ( 12.3 ) ]. 7.2 Phosphodiesterase-5 (PDE-5) Inhibitors Concomitant administration of doxazosin tablets with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension. Monitor blood pressure and for symptoms of hypotension [ see Warnings and Precautions ( 5.1 ) ].