CARDURA XL Extended-release tablet Ref.[10543] Active ingredients: Doxazosin

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.

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:

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.

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, hepatitis cholestatic, jaundice

Musculoskeletal System: muscle cramps, muscle weakness

Psychiatric: agitation, anorexia, nervousness

Respiratory System: bronchospasm aggravated

Skin Disorders: alopecia, urticaria, skin rash, pruritus

Special Senses: blurred vision, Intraoperative Floppy Iris Syndrome [see Warnings and Precautions (5.2)]

Urinary System: hematuria, micturition disorder, micturition frequency, nocturia, polyuria

There have been rare reports of gastrointestinal irritation and gastrointestinal bleeding with use of another drug in this non-deformable sustained release formulation, although causal relationship to the drug is uncertain.

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 atanazavir, 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)].

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.

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.

The safety and effectiveness of CARDURA XL in pediatric patients have not been established.

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 <70 years of age (7/530; 1.3%).

Since there is no clinical experience in patients with severe hepatic impairment, use in these patients is not recommended. CARDURA XL should be administered with caution to patients with mild or moderate hepatic impairment [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)].