Doxazosin

5 WARNINGS AND PRECAUTIONS Postural hypotension with or without syncope may occur. ( 5.1 ) Risk of Intraoperative Floppy Iris Syndrome during cataract surgery. ( 5.2 ) Screen for the presence of prostate cancer prior to treatment for BPH and at regular intervals afterwards. ( 5.3 ) 5.1 Postural Hypotension Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of doxazosin tablets. However, infrequently, symptomatic postural hypotension has also been reported later than a few hours after dosing. As with other alpha-blockers, there is a potential for syncope, especially after the initial dose or after an increase in dosage strength. Advise patient how to avoid symptoms resulting from postural hypotension and what measures to take should they develop. Concomitant administration of doxazosin tablets with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension. 5.2 Cataract Surgery Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alpha 1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha 1 blocker therapy prior to cataract surgery. 5.3 Prostate Cancer Carcinoma of the prostate causes many of the symptoms associated with BPH and the two disorders frequently co-exist. Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with doxazosin tablets for the treatment of BPH. 5.4 Priapism Alpha1 antagonists, including doxazosin, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). This condition can lead to permanent impotence if not promptly treated.

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.

<table frame="box" rules="all" width="100%"><caption>Table 1. Adverse Reactions Occurring more than 1% More Frequently in BPH Patients Treated with Doxazosin Tablets Versus Placebo</caption><col align="left" valign="top" width="50%"/><col align="center" valign="top" width="25%"/><col align="center" valign="top" width="25%"/><tbody align="center"><tr><td align="left"><content styleCode="bold">BODY SYSTEM</content></td><td><content styleCode="bold">Doxazosin Tablets N=665 </content></td><td><content styleCode="bold">Placebo N=300 </content></td></tr><tr><td align="left" colspan="3"><content styleCode="bold">NERVOUS SYSTEM DISORDERS</content></td></tr><tr><td align="left">Dizziness ^&#x2020;</td><td>15.6%</td><td>9%</td></tr><tr><td align="left">Somnolence</td><td>3%</td><td>1%</td></tr><tr><td align="left" colspan="3"><content styleCode="bold">CARDIAC DISORDERS</content></td></tr><tr><td align="left">Hypotension</td><td>1.7%</td><td>0%</td></tr><tr><td align="left" colspan="3"><content styleCode="bold">RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS</content></td></tr><tr><td align="left">Dyspnoea</td><td>2.6%</td><td>0.3%</td></tr><tr><td align="left" colspan="3"><content styleCode="bold">GASTROINTESTINAL DISORDERS</content></td></tr><tr><td align="left">Dry Mouth</td><td>1.4%</td><td>0.3%</td></tr><tr><td align="left" colspan="3"><content styleCode="bold">GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS</content></td></tr><tr><td align="left">Fatigue</td><td>8%</td><td>1.7%</td></tr><tr><td align="left">Oedema</td><td>2.7%</td><td>0.7%</td></tr></tbody></table>

<table frame="box" rules="all" width="100%"><caption>Table 2. Adverse Reactions Occurring more than 1% More Frequently in Hypertensive Patients Treated with Doxazosin Tablets versus Placebo</caption><col align="left" valign="top" width="50%"/><col align="center" valign="top" width="25%"/><col align="center" valign="top" width="25%"/><tbody align="center"><tr><td align="left"><content styleCode="bold">BODY SYSTEM</content></td><td><content styleCode="bold">Doxazosin Tablets N=339 </content></td><td><content styleCode="bold">Placebo N=336 </content></td></tr><tr><td align="left" colspan="3"><content styleCode="bold">NERVOUS SYSTEM DISORDERS</content></td></tr><tr><td align="left">Dizziness</td><td>19%</td><td>9%</td></tr><tr><td align="left">Somnolence</td><td>5%</td><td>1%</td></tr><tr><td align="left" colspan="3"><content styleCode="bold">RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS</content></td></tr><tr><td align="left">Rhinitis</td><td>3%</td><td>1%</td></tr><tr><td align="left" colspan="3"><content styleCode="bold">RENAL AND URINARY DISORDERS</content></td></tr><tr><td align="left">Polyuria</td><td>2%</td><td>0%</td></tr><tr><td align="left" colspan="3"><content styleCode="bold">REPRODUCTIVE SYSTEM AND BREAST DISORDERS GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS </content></td></tr><tr><td align="left">Fatigue / Malaise</td><td>12%</td><td>6%</td></tr></tbody></table>