Cardura

1 INDICATIONS AND USAGE CARDURA is an alpha 1 adrenergic antagonist indicated for: • Signs and symptoms of Benign Prostatic Hyperplasia (BPH) ( 1.1 ) • Treatment of Hypertension ( 1.2 ) 1.1 Benign Prostatic Hyperplasia (BPH) CARDURA is indicated for the treatment of the signs and symptoms of BPH. 1.2 Hypertension CARDURA is 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 higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. CARDURA may be used alone or in combination with other antihypertensives.

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 of 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 CARDURA, monitor blood pressure for at least 6 hours following administration. If CARDURA 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 CARDURA 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 CARDURA 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.

3 DOSAGE FORMS AND STRENGTHS Tablets: 1 mg (white), 2 mg (yellow or white), 4 mg (orange or white) or 8 mg (green or white). Each tablet contains doxazosin mesylate equivalent to 1 mg, 2 mg, 4 mg or 8 mg doxazosin (free base). • Tablets: 1 mg, 2 mg, 4 mg, 8 mg.

4 CONTRAINDICATIONS The use of CARDURA is contraindicated in patients with a hypersensitivity to doxazosin, other quinazolines (e.g., prazosin, terazosin), or any of its components. • Hypersensitivity to doxazosin, other quinazolines, or any other ingredient in CARDURA. ( 4 )

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 Viatris at 1-877-446-3679 (1-877-4-INFO-RX) 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 CARDURA 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 CARDURA vs. placebo are summarized in Table 1. Table 1. Adverse Reactions Occurring More than 1% More Frequently in BPH Patients Treated with CARDURA Versus Placebo BODY SYSTEM CARDURA N=665 Placebo N=300 NERVOUS SYSTEM DISORDERS Dizziness Includes vertigo 15.6% 9.0% Somnolence 3.0% 1.0% 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 8.0% 1.7% Oedema 2.7% 0.7% Other adverse reactions occurring less than 1% more frequently in BPH patients treated with CARDURA vs. placebo but plausibly related to CARDURA include: palpitations. Hypertension CARDURA has been administered to approximately 4000 hypertensive patients in clinical trials, of whom 1679 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 CARDURA 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 CARDURA Versus Placebo BODY SYSTEM CARDURA 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 CARDURA vs. placebo but plausibly related to CARDURA use include vertigo, hypotension, hot flushes, epistaxis and oedema. CARDURA 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 CARDURA. In cases where follow-up was available, WBC and neutrophil counts returned to normal after discontinuation of CARDURA. 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 CARDURA. 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 exp …

7 DRUG INTERACTIONS • Strong cytochrome P450 (CYP) 3A inhibitors may increase exposure to doxazosin and increased risk of hypotension. ( 7.1 ) • Concomitant administration of CARDURA 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 CARDURA is used concomitantly with strong CYP3A inhibitors [see Clinical Pharmacology (12.3) ] . 7.2 Phosphodiesterase-5 (PDE-5) Inhibitors Concomitant administration of CARDURA 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) ] .

Drug Interactions There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin (e.g., cimetidine). Cimetidine: In healthy volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a four-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin, and a slight but not significant increase in mean C max and mean half-life of doxazosin. In vitro data in human plasma indicate that CARDURA has no effect on protein binding of digoxin, warfarin, phenytoin, or indomethacin.

8 USE IN SPECIFIC POPULATIONS • Hepatic Impairment: Monitor for hypotension. ( 8.6 , 12.3 ) 8.1 Pregnancy Risk Summary The limited available data with CARDURA in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. However, untreated hypertension during pregnancy can result in increased maternal risks [see Clinical Considerations ] . In animal reproduction studies, no adverse developmental effects were observed when doxazosin was orally administered to pregnant rabbits and rats during the period of organogenesis at doses of up to 41 and 20 mg/kg, respectively (exposures in rabbits and rats were 10 and 4 times, respectively, the human AUC exposures with a 12 mg/day therapeutic dose). A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival [see Data ] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Data Animal Data Radioactivity was found to cross the placenta following oral administration of labelled doxazosin to pregnant rats. Studies in pregnant rabbits and rats at daily oral doses of up to 41 and 20 mg/kg, respectively (plasma drug concentrations of 10 and 4 times, respectively, the human AUC exposures with a 12 mg/day therapeutic dose), have revealed no evidence of adverse developmental effects. A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival. In peri- and postnatal studies in rats, postnatal development at maternal doses of 40 or 50 mg/kg/day of doxazosin (about 8 times human AUC exposure with a 12 mg/day therapeutic dose) was delayed, as evidenced by slower body weight gain and slightly later appearance of anatomical features and reflexes. 8.2 Lactation Risk Summary There is limited information on the presence of CARDURA in human milk [see Data ]. There is no information on the effects of CARDURA on the breastfeed infant or the effects on milk production. Data A single case study reports that CARDURA is present in human milk, which resulted in an infant dose of less than 1% of the maternal weight-adjusted dosage and a milk/plasma ratio of 0.1. However, these data are insufficient to confirm the presence of CARDURA in human milk. 8.4 Pediatric Use The safety and effectiveness of CARDURA have not been established in children. 8.5 Geriatric Use Benign Prostatic Hyperplasia (BPH) The safety and effectiveness profile of CARDURA was similar in the elderly (age ≥ 65 years) and younger (age < 65 years) patients. Hypertension Clinical studies of CARDURA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment CARDURA is extensively metabolized in the liver. Hepatic impairment is expected to increase exposure to doxazosin. Use of CARDURA in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. Monitor blood pressure and for symptoms of hypotension in patients with lesser degrees of hepatic impairment (Child …

12.1 Mechanism of Action Benign Prostatic Hyperplasia (BPH) The symptoms associated with benign prostatic hyperplasia (BPH), such as urinary frequency, nocturia, weak stream, hesitancy, and incomplete emptying are related to two components, anatomical (static) and functional (dynamic). The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component of BPH is associated with an increase in smooth muscle tone in the prostate and bladder neck. The degree of tone in this area is mediated by the alpha 1 adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule and bladder neck. Blockade of the alpha 1 receptor decreases urethral resistance and may relieve the obstruction and BPH symptoms and improve urine flow. Hypertension The mechanism of action of CARDURA is selective blockade of the alpha 1 (postjunctional) subtype of adrenergic receptors. Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine (an alpha 1 agonist) and the systolic pressor effect of norepinephrine. Doxazosin and prazosin have similar abilities to antagonize phenylephrine. The antihypertensive effect of CARDURA results from a decrease in systemic vascular resistance. The parent compound doxazosin is primarily responsible for the antihypertensive activity. The low plasma concentrations of known active and inactive metabolites of doxazosin (2-piperazinyl, 6'- and 7'-hydroxy and 6- and 7-O-desmethyl compounds) compared to parent drug indicate that the contribution of even the most potent compound (6'-hydroxy) to the antihypertensive effect of doxazosin in man is probably small. The 6'- and 7'-hydroxy metabolites have demonstrated antioxidant properties at concentrations of 5 μM, in vitro .

11 DESCRIPTION CARDURA ® (doxazosin) is a quinazoline compound that is a selective inhibitor of the alpha 1 subtype of alpha-adrenergic receptors. The chemical name of doxazosin mesylate is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The empirical formula for doxazosin mesylate is C 23 H 25 N 5 O 5 ∙ CH 4 O 3 S and the molecular weight is 547.6. It has the following structure: CARDURA (doxazosin) is freely soluble in dimethylsulfoxide, soluble in dimethylformamide, slightly soluble in methanol, ethanol, and water (0.8% at 25°C), and very slightly soluble in acetone and methylene chloride. CARDURA is available as colored tablets for oral use and contains doxazosin mesylate equivalent to 1 mg (white), 2 mg (yellow or white), 4 mg (orange or white) and 8 mg (green or white) of doxazosin as the free base. The inactive ingredients for all tablets are microcrystalline cellulose, lactose, sodium starch glycolate, magnesium stearate and sodium lauryl sulfate. The 2 mg yellow tablet contains D & C yellow 10 and FD & C yellow 6; the 4 mg orange tablet contains FD & C yellow 6; the 8 mg green tablet contains FD & C blue 2 and D & C yellow 10. Chemical Structure

10 OVERDOSAGE Experience with CARDURA overdosage is limited. Two adolescents, who each intentionally ingested 40 mg CARDURA with diclofenac or acetaminophen, were treated with gastric lavage with activated charcoal and made full recoveries. A two-year-old child who accidently ingested 4 mg CARDURA was treated with gastric lavage and remained normotensive during the five-hour emergency room observation period. A six-month-old child accidentally received a crushed 1 mg tablet of CARDURA and was reported to have been drowsy. A 32-year-old female with chronic renal failure, epilepsy, and depression intentionally ingested 60 mg CARDURA (blood level = 0.9 mcg/mL; normal values in hypertensives = 0.02 mcg/mL); death was attributed to a grand mal seizure resulting from hypotension. A 39-year-old female who ingested 70 mg CARDURA, alcohol, and Dalmane ® (flurazepam) developed hypotension which responded to fluid therapy. The oral LD 50 of doxazosin is greater than 1000 mg/kg in mice and rats. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of fluid. As doxazosin is highly protein bound, dialysis would not be indicated.

16 HOW SUPPLIED/STORAGE AND HANDLING CARDURA (doxazosin) is available as tablets for oral administration. Each tablet contains doxazosin mesylate equivalent to 1 mg (white), 2 mg (yellow or white), 4 mg (orange or white) or 8 mg (green or white) of doxazosin as the free base. NDC and Pack Size Strength Description NDC 0049-2750-66 (Bottle of 100) NDC 0049-2750-41 (Unit dose of 100) 1 mg White, capsule shaped tablet engraved "Cardura" on one side, scored and engraved "1 mg" on the other side. NDC 0049-2410-10 (Bottle of 100) 1 mg White, round tablet engraved "CN1" on one side and "Pfizer" on the other side. NDC 0049-2760-66 (Bottle of 100) NDC 0049-2760-41 (Unit dose of 100) 2 mg Yellow, capsule shaped tablet engraved "Cardura" on one side, scored and engraved "2 mg" on the other side. NDC 0049-2512-10 (Bottle of 100) 2 mg White capsule shaped tablet with break score and engraved "CN2" on one side and "Pfizer" on the other side. NDC 0049-2770-66 (Bottle of 100) NDC 0049-2770-41 (Unit Dose of 100) 4 mg Orange, capsule shaped tablet engraved "Cardura" on one side, scored and engraved "4 mg" on the other side. NDC 0049-2614-10 (Bottle of 100) 4 mg White, diamond shaped tablet with break score and engraved "CN4" on one side and "Pfizer" on the other side. NDC 0049-2780-66 (Bottle of 100) NDC 0049-2780-41 (Unit dose of 100) 8 mg Green, capsule shaped tablet engraved "Cardura" on one side, scored and engraved "8 mg" on the other side. NDC 0049-2716-10 (Bottle of 100) 8 mg White, capsule shaped tablet with break score and engraved "CN8" on one side and "Pfizer" on the other side. Recommended Storage: Store at 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].