Cardura XL

CARDURA XL- doxazosin mesylate tablet, multilayer, extended release
Roerig

1 INDICATIONS AND USAGE

CARDURA® XL (doxazosin mesylate extended release tablets) 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.

2 DOSAGE AND ADMINISTRATION

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 4 mg and 8 mg doxazosin mesylate.

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)].

5 WARNINGS AND PRECAUTIONS

5.1 Postural Hypotension

Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of CARDURA XL. 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. Patients should be warned of the possible occurrence of such events and should avoid situations where injury could result should syncope occur. Care should be taken when CARDURA XL is administered to patients with symptomatic hypotension or patients who have had a hypotensive response to other medications.

5.2 Cataract Surgery

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alpha1 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 from stopping alpha1 blocker therapy prior to cataract surgery.

5.3 Gastrointestinal Disorders

As with any other non-deformable material, caution should be used when administering CARDURA XL to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of another drug in this non-deformable extended release formulation. Markedly increased GI retention times, as may occur in patients with chronic constipation, can increase systemic exposure to doxazosin and thereby potentially increase adverse reactions.

5.4 Prostate Cancer

Carcinoma of the prostate causes many of the same 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 CARDURA XL.

5.5 PDE-5 Inhibitors

Concomitant administration of CARDURA XL with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension. Pharmacodynamic interactions between CARDURA XL and antihypertensive medications or other vasodilating agents have not been determined.

5.6 Patients with 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 [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

5.7 Patients with Coronary Insufficiency

Patients with congestive heart failure, angina pectoris, or acute myocardial infarction within the last 6 months were excluded from the Phase 3 studies. If symptoms of angina pectoris should newly appear or worsen, CARDURA XL should be discontinued.

5.8 CYP 3A4 Inhibitors

Caution should be exercised when concomitantly administering CARDURA XL with a strong CYP 3A4 inhibitor, such as atanazavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole.

5.9 Priapism

Rarely (probably less frequently than once in every several thousand patients), alpha-1 antagonists, including doxazosin, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition.

6 ADVERSE REACTIONS

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.

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