Cardura

1 INDICATIONS AND USAGE CARDURA ® XL is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). CARDURA XL is not indicated for the treatment of hypertension. CARDURA XL is an alpha 1 adrenergic antagonist indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia. ( 1 ) CARDURA XL is not indicated for the treatment of hypertension. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended starting dose (initial therapy or switching from immediate-release): 4 mg once daily with breakfast ( 2.1 , 2.2 ) Dose range: 4 to 8 mg once daily ( 2.1 ) 2.1 General Dosing Information The initial dose of CARDURA XL, 4 mg given once daily, should be administered with breakfast. Depending on the patient’s symptomatic response and tolerability, the dose may be increased to 8 mg, the maximum recommended dose. The recommended titration interval is 3-4 weeks. If CARDURA XL administration is discontinued for several days, therapy should be restarted using the 4 mg once daily dose. Tablets should be swallowed whole, and must not be chewed, divided, cut, or crushed. 2.2 Patients Switching from CARDURA to CARDURA XL If switching from CARDURA immediate-release (IR) to CARDURA XL, therapy should be initiated with the lowest dose (4 mg once daily). Prior to starting therapy with CARDURA XL, the final evening dose of CARDURA should not be taken. 2.3 Concomitant Administration with PDE-5 Inhibitors Concomitant administration of CARDURA XL with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension; therefore, PDE-5 inhibitor therapy should be initiated at the lowest dose in patients taking CARDURA XL.

3 DOSAGE FORMS AND STRENGTHS White, round, film-coated tablets containing doxazosin mesylate equivalent to 4 mg and 8 mg doxazosin (free base). 4 mg and 8 mg tablets ( 3 )

4 CONTRAINDICATIONS CARDURA XL is contraindicated in patients with a known hypersensitivity to doxazosin, other quinazolines (e.g., prazosin, terazosin), or any of the inert ingredients. Allergic reactions to doxazosin and other quinazolines have included skin rash, urticaria, pruritus, angioedema, and respiratory symptoms [see Adverse Reactions (6.2) ] . Patients with known sensitivity to doxazosin, other quinazolines, or any of the inert ingredients ( 4 )

6 ADVERSE REACTIONS The most commonly reported adverse reactions from clinical trials are asthenia, headache, 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 clinical practice. The incidence of adverse reactions was derived from two controlled efficacy and safety trials involving 1473 BPH patients. In Study 1, CARDURA XL (n = 317) was compared to doxazosin IR tablets (n = 322) and to placebo (n = 156). In Study 2, CARDURA XL (n = 350) was compared just to doxazosin IR tablets (n = 330). In both of these studies, CARDURA XL was initiated at a dose of 4 mg, which could be increased by the investigator to 8 mg after seven weeks if an adequate response was not seen [see Clinical Studies (14.1) ] . Similarly, doxazosin IR was begun at a dose of 1 mg, which was increased in all patients to 2 mg after 1 week, followed by the option to increase to 4 mg after 4 weeks, and 8 mg after 7 weeks. The most commonly reported adverse reactions leading to discontinuation in the CARDURA XL group were dizziness, dyspnea, asthenia, headache, hypotension, postural hypotension, and somnolence. The rates of discontinuation for adverse reactions were 6%, 7% and 3% in the CARDURA XL, doxazosin IR, and placebo groups, respectively. Table 1 lists the incidence rates of adverse reactions derived from all reported adverse events in the two controlled studies (Studies 1 and 2) combined, at a rate greater than placebo and in 1% or more of patients treated with CARDURA XL. TABLE 1 Adverse Reactions, Derived from All Adverse Events Exceeding Placebo Rate and Occurring in ≥ 1% of BPH Patients Treated with CARDURA XL Body System CARDURA XL (N = 666) Doxazosin IR (N = 651) Placebo (N = 156) BODY AS A WHOLE Abdominal Pain 1.8% 2.3% 0.6% Asthenia 3.9% 6.9% 1.3% Headache 6.0% 5.1% 4.5% CARDIOVASCULAR Hypotension 1.7% 1.8% 0.0% Postural Hypotension 1.2% 2.2% 0.6% DIGESTIVE Dyspepsia 1.4% 1.2% 0.0% Nausea 1.2% 2.3% 0.6% MUSCULOSKELETAL Myalgia 1.4% 0.5% 0.0% NERVOUS Dizziness 5.3% 9.1% 1.9% Somnolence 1.5% 1.2% 0.0% Vertigo 1.5% 4.1% 0.6% RESPIRATORY Dyspnea 1.2% 1.2% 0.0% Respiratory Tract Infection 4.8% 4.5% 1.9% UROGENITAL Urinary Tract Infection 1.4% 0.8% 0.6% Additional adverse events reported with CARDURA XL, reported by less than 1% of patients, and those of clinical interest include: Cardiovascular System: angina pectoris, syncope, tachycardia, chest pain, palpitations; Digestive System: diarrhea; Musculoskeletal System: arthralgia; Nervous System: libido decreased; Urogenital System: impotence, dysuria. In general, the adverse events reported in the open-label safety extension, in approximately 295 BPH patients treated for up to 37 weeks, were similar in type and frequency to the events described above in the controlled trials. 6.2 Postmarketing Experience The following adverse events have been identified during post-approval use of doxazosin. 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. Autonomic Nervous System: priapism; Cardiovascular System: cerebrovascular accidents, dizziness postural, myocardial infarction; Central and Peripheral Nervous System: hypoesthesia, paresthesia; Endocrine System: gynecomastia; Gastrointestinal System: gastrointestinal obstruction, vomiting; General Body System: fatigue, hot flushes, malaise; Heart Rate/Rhythm: bradycardia, cardiac arrhythmias; Hematopoietic: leukopenia, purpura, thrombocytopenia; Liver/Biliary System: abnormal liver function tests, hepatitis, hepati …

7 DRUG INTERACTIONS Caution should be exercised when concomitantly administering CARDURA XL with a strong cytochrome P450 (CYP) 3A4 inhibitor. ( 7.1 ) Concomitant administration of CARDURA XL with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension. ( 7.3 ) 7.1 CYP 3A4 Inhibitors No in vivo drug interaction studies were conducted with CARDURA XL. In vitro studies suggest that doxazosin is a substrate of CYP 3A4. Caution should be exercised when concomitantly administering CARDURA XL with a strong CYP 3A4 inhibitor, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole [see Clinical Pharmacology (12.3) ] . 7.2 Antihypertensive Medications Pharmacodynamic interactions between CARDURA XL and antihypertensive medications or other vasodilating agents have not been determined. 7.3 PDE-5 Inhibitors Concomitant administration of CARDURA XL with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension [see Dosage and Administration (2.3) ] .

8 USE IN SPECIFIC POPULATIONS Geriatric: Hypotension with CARDURA XL is more prevalent in patients 70 years or older. ( 8.5 ) Hepatic Impairment: CARDURA XL is not recommended for patients with severe hepatic impairment and should be administered with caution to patients with mild or moderate hepatic impairment. ( 8.6 , 12.3 ) 8.1 Pregnancy Risk Summary CARDURA XL is not indicated for use in females and is not indicated for the treatment of hypertension. The limited available data with CARDURA XL in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. No adverse developmental outcomes were observed in animal reproduction studies with oral administration of doxazosin to pregnant rats and rabbits at doses of up to 10 and 4 times, respectively, the 12 mg/day recommended dose. Postnatal development was delayed in rats at a dose of 8 times the 12 mg/day recommended dose [see Data ] . Data Animal Data Radioactivity was found to cross the placenta following oral administration of labeled 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), during organogenesis 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 CARDURA XL is not indicated for use in females and is not indicated for the treatment of hypertension. Doxazosin is present in human milk. There is no information on the effects of CARDURA XL on the breastfeed infant or the effects on milk production. 8.4 Pediatric Use The safety and effectiveness of CARDURA XL in pediatric patients have not been established. 8.5 Geriatric Use The incidence of hypotension with CARDURA XL use appears to be age related and more prevalent in patients 70 years or older. At steady state, increases of 27% in maximum plasma concentrations (C max ) and 34% in the area under the concentration-time curve (AUC) were seen in the elderly (> 65 years old) compared to the young [see Clinical Pharmacology (12.3) ] . Of the 666 patients with BPH who received CARDURA XL in the two controlled clinical efficacy and safety studies, 325 patients (49%) were 65 years of age or older. One hundred thirty-six patients treated with CARDURA XL (20%) were > 70 years of age. In these two studies, the cumulative incidence of hypotension appeared to be age related. The reason for an increased incidence of hypotension in patients older than 70 years of age may be related to a modest increase in systemic exposure to doxazosin [see Clinical Pharmacology (12.3) ] , to an increased propensity to orthostasis in the elderly, or to an enhanced sensitivity to vasodilatory agents in the elderly. The incidence of hypotension reported as an adverse reaction was higher in patients 70 years of age and older (4/136; 2.9%) as compared to patients 65 years old) compared to the young [see Use in Specific Populations (8.5) ] . Hepatic Impairment Administration of a single 2 mg dose of doxazosin IR to patients with mild hepatic impairment (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin compared to patients without hepatic impairment. No studies have been performed to assess the effect of hepatic impairment on the pharmacokinetics of CARDURA XL. Use in patients with severe hepatic impairment is not recommended. CARDURA XL should be administered with caution to patients with evidence of mild or moderately impaired hepatic function or to patients receiving drugs kn …

12.1 Mechanism of Action 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 BPH symptoms and improve urine flow. Doxazosin mesylate is a selective inhibitor of the alpha 1 -subtype of alpha adrenergic receptors. In the human prostate, doxazosin mesylate antagonizes phenylephrine (alpha 1 agonist)-induced contractions, in vitro , and binds with high affinity to the alpha 1A adrenoceptor.

11 DESCRIPTION CARDURA XL contains doxazosin which is a quinazoline compound with the chemical name 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 XL is an extended-release tablet for oral use and is designed to deliver 4 or 8 mg of doxazosin as the free base. Each 4 and 8 mg tablet contains 5.1 and 10.2 mg doxazosin mesylate (includes a 5% overage) to ensure the labeled dose of 4 and 8 mg doxazosin as the free base (equivalent to 4.9 and 9.8 mg of doxazosin mesylate), is delivered. The inactive ingredients for CARDURA XL are black iron oxide, cellulose acetate, hypromellose, Macrogol ® , magnesium stearate, pharmaceutical glaze, polyethylene oxide, red ferric oxide, sodium chloride and titanium dioxide. CARDURA XL System Components and Performance CARDURA XL is similar in appearance to a conventional tablet. It consists, however, of an osmotically active drug core surrounded by a semipermeable membrane. The core itself is divided into two layers: an “active” layer containing the drug, and a “push” layer containing pharmacologically inert (but osmotically active) components. The membrane surrounding the tablet is permeable to water, but not to drug or osmotic excipients. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and “pushes” against the drug layer, resulting in the release of drug through a small, laser-drilled orifice in the membrane on the drug side of the tablet. CARDURA XL utilizes GITS (Gastrointestinal Therapeutic System) which is designed to provide a controlled rate of delivery of doxazosin into the gastrointestinal lumen which is independent of pH or gastrointestinal (GI) motility. The function of CARDURA XL depends upon the existence of an osmotic gradient between the contents of the bi-layer core and fluid in the GI tract. Drug delivery is essentially constant as long as the osmotic gradient remains constant, and then gradually falls to zero. The biologically inert components of the tablet remain intact during GI transit and are eliminated in the feces as an insoluble shell. Doxazosin Mesylate Structural Formula

10 OVERDOSAGE There is no experience with CARDURA XL overdosage. Overdosage experience with the doxazosin IR is limited. Two adolescents who each intentionally ingested 40 mg doxazosin IR with diclofenac or paracetamol were treated with gastric lavage with activated charcoal and made full recoveries. A two-year-old child who accidentally ingested 4 mg doxazosin IR 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 doxazosin IR and was reported to have been drowsy. A 32-year-old female with chronic renal failure, epilepsy, and depression intentionally ingested 60 mg doxazosin IR (blood level 0.9 μg/mL; normal values in hypertensives = 0.02 μg/mL); death was attributed to a grand mal seizure resulting from hypotension. A 39-year-old female who ingested 70 mg doxazosin IR, alcohol, and Dalmane ® (flurazepam) developed hypotension which responded to fluid therapy. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of fluid, keeping the patient in the supine position, and in certain circumstances, the administration of vasopressors. As doxazosin is highly protein bound, dialysis would not be indicated.

16 HOW SUPPLIED/STORAGE AND HANDLING CARDURA XL (doxazosin) extended-release tablets is available as 4 mg (white, imprinted with CXL 4) and 8 mg (white, imprinted with CXL 8) tablets. Bottle of 30: 4 mg (NDC 58151-078-93) Bottle of 30: 8 mg (NDC 58151-079-93) Storage Recommended Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].