The incidence of treatment-emergent adverse events has been ascertained from six short-term U.S. and European placebo-controlled clinical trials in which daily doses of 0.1 to 0.8 mg FLOMAX capsules were used. These studies evaluated safety in 1783 patients treated with FLOMAX capsules and 798 patients administered placebo. Table 3 summarizes the treatment-emergent adverse events that occurred in ≥ 2% of patients receiving either FLOMAX capsules 0.4 mg, or 0.8 mg and at an incidence numerically higher than that in the placebo group during two 13-week U.S. trials (US92-03A and US93-01) conducted in 1487 men.

Table 3 : Treatment Emergent¹ Adverse Events Occurring in ≥ 2% of Flomax® (tamsulosin hydrochloride) capsules or Placebo Patients in Two U.S. Short-Term Placebo-Controlled Clinical Studies

Signs and Symptoms of Orthostasis: In the two U.S. studies, symptomatic postural hypotension was reported by 0.2% of patients (1 of 502) in the 0.4 mg group, 0.4% of patients (2 of 492) in the 0.8 mg group, and by no patients in the placebo group. Syncope was reported by 0.2% of patients (1 of 502) in the 0.4 mg group, 0.4% of patients (2 of 492) in the 0.8 mg group and 0.6% of patients (3 of 493) in the placebo group. Dizziness was reported by 15% of patients (75 of 502) in the 0.4 mg group, 17% of patients (84 of 492) in the 0.8 mg group, and 10% of patients (50 of 493) in the placebo group. Vertigo was reported by 0.6% of patients (3 of 502) in the 0.4 mg group, 1% of patients (5 of 492) in the 0.8 mg group and by 0.6% of patients (3 of 493) in the placebo group.

Multiple testing for orthostatic hypotension was conducted in a number of studies. Such a test was considered positive if it met one or more of the following criteria: (1) a decrease in systolic blood pressure of ≥ 20 mmHg upon standing from the supine position during the orthostatic tests; (2) a decrease in diastolic blood pressure ≥ 10 mmHg upon standing, with the standing diastolic blood pressure < 65 mmHg during the orthostatic test; (3) an increase in pulse rate of ≥ 20 bpm upon standing with a standing pulse rate ≥ 100 bpm during the orthostatic test; and (4) the presence of clinical symptoms (faintness, lightheadedness/lightheaded, dizziness, spinning sensation, vertigo, or postural hypotension) upon standing during the orthostatic test.

Following the first dose of double-blind medication in Study 1, a positive orthostatic test result at 4 hours post-dose was observed in 7% of patients (37 of 498) who received Flomax® (tamsulosin hydrochloride) capsules 0.4 mg once daily and in 3% of the patients (8 of 253) who received placebo. At 8 hours post-dose, a positive orthostatic test result was observed for 6% of the patients (31 of 498) who received FLOMAX capsules 0.4 mg once daily and 4% (9 of 250) who received placebo (Note: patients in the 0.8 mg group received 0.4 mg once daily for the first week of Study 1).

In Studies 1 and 2, at least one positive orthostatic test result was observed during the course of these studies for 81 of the 502 patients (16%) in the FLOMAX capsules 0.4 mg once daily group, 92 of the 491 patients (19%) in the FLOMAX capsules 0.8 mg once daily group and 54 of the 493 patients (11%) in the placebo group.

Because orthostasis was detected more frequently in FLOMAX capsule-treated patients than in placebo recipients, there is a potential risk of syncope (see WARNINGS).

Abnormal Ejaculation: Abnormal ejaculation includes ejaculation failure, ejaculation disorder, retrograde ejaculation and ejaculation decrease. As shown in Table 3, abnormal ejaculation was associated with FLOMAX capsules administration and was dose-related in the U.S. studies. Withdrawal from these clinical studies of FLOMAX capsules because of abnormal ejaculation was also dose-dependent with 8 of 492 patients (1.6%) in the 0.8 mg group, and no patients in the 0.4 mg or placebo groups discontinuing treatment due to abnormal ejaculation.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of FLOMAX capsules. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to FLOMAX capsules. Allergic-type reactions such as skin rash, urticaria, pruritus, angioedema and respiratory symptoms have been reported with positive rechallenge in some cases. Priapism has been reported rarely. Infrequent reports of palpitations, hypotension, skin desquamation, constipation and vomiting have been received during the post-marketing period.

During cataract surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha-1 blocker therapy (see PRECAUTIONS, General).

Drug-Drug Interactions: The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha-adrenergic blocking agents have not been determined. However, interactions may be expected and FLOMAX capsules should NOT be used in combination with other alpha-adrenergic blocking agents.

The pharmacokinetic interaction between cimetidine, a mild inhibitor of several CYP enzymes, and FLOMAX capsules was investigated in 10 subjects (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions). The results indicate significant changes in both tamsulosin hydrochloride clearance (26% decrease) and exposure (44% increase in AUC). Therefore, FLOMAX capsules should be used with caution in combination with cimetidine, particularly at doses higher than 0.4 mg.

Additional pharmacokinetic interactions between strong or moderate CYP2D6 or CYP3A4 inhibitors with FLOMAX have not been examined. As FLOMAX is extensively metabolized (mainly by CYP2D6 and CYP3A4) and as concomitant administration with cimetidine caused 44% increase in FLOMAX exposure, concomitant administration of FLOMAX and an inhibitor of CYP2D6 or CYP3A4 may lead to increased FLOMAX plasma exposure. FLOMAX capsules should be used with caution in combination with moderate or strong inhibitors of CYP2D6 (e.g., fluoxetine) or CYP3A4 (e.g., ketoconazole), particularly at doses higher than 0.4 mg.

Results from limited in vitroand in vivo drug-drug interaction studies between tamsulosin hydrochloride and warfarin are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and FLOMAX capsules.

See also Drug-Drug Interactions studies in CLINICAL PHARMACOLOGY, Pharmacokinetics subsection.

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