Flomax

[Tamsulosin]

Drug-Drug Interactions

Nifedipine, Atenolol, Enalapril:

In three studies in hypertensive subjects (age range 47-79 years) whose blood pressure was controlled with stable doses of Procardia XL ® , atenolol, or enalapril for at least three months, FLOMAX capsules 0.4 mg for seven days followed by FLOMAX capsules 0.8 mg for another seven days (n= 8 per study) resulted in no clinically significant effects on blood pressure and pulse rate compared to placebo (n= 4 per study). Therefore, dosage adjustments are not necessary when FLOMAX capsules are administered concomitantly with Procardia XL ® , atenolol, or enalapril.

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Warfarin

A definitive drug-drug interaction study between tamsulosin HCI and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and FLOMAX capsules.
Digoxin and Theophylline: In two studies in healthy volunteers (n= 10 per study; age range 19-39 years) receiving FLOMAX capsules 0.4 mg/ day for two days, followed by FLOMAX capsules 0.8 mg/ day for five to eight days, single intravenous doses of digoxin 0. 5 mg or theophylline 5 mg/ kg resulted in no change in the pharmacokinetics of digoxin or theophylline. Therefore, dosage adjustments are not necessary when a FLOMAX capsule is administered concomitantly with digoxin or theophylline.

Furosemide

The pharmacokinetic and pharmacodynamic interaction between FLOMAX capsules 0.8 mg/ day (steady-state) and furosemide 20 mg intravenously (single dose) was evaluated in ten healthy volunteers (age range 21-40 years). FLOMAX capsules had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin HCI Cmax and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the FLOMAX capsules dosage.

Cimetidine

The effects of cimetidine at the highest recommended dose (400 mg every six hours for six days) on the pharmacokinetics of a single FLOMAX capsule 0.4 mg dose was investigated in ten healthy volunteers (age range 21-38 years). Treatment with cimetidine resulted in a significant decrease (26%) in the clearance of tamsulosin HCI which resulted in a moderate increase in tamsulosin HCI AUC (44%). Therefore, FLOMAX capsules should be used with caution in combination with cimetidine, particularly at doses higher than 0.4 mg.

Clinical Studies Four placebo-controlled clinical studies and one active-controlled clinical study enrolled a total of 2296 patients (1003 received FLOMAX capsules 0.4 mg once daily, 491 received FLOMAX capsules 0.8 mg once daily, and 802 were control patients) in the U. S. and Europe.

In the two U. S. placebo-controlled, double-blind, 13-week, multicenter studies [Study 1 (US92-03A) and Study 2 (US93-01)], 1486 men with the signs and symptoms of BPH were enrolled. In both studies, patients were randomized to either placebo, FLOMAX capsules 0.4 mg once daily, or FLOMAX capsules 0.8 mg once daily. Patients in FLOMAX capsules 0.8 mg once daily treatment groups received a dose of 0.4 mg once daily for one week before increasing to the 0.8 mg once daily dose.

The primary efficacy assessments included:

1) total American Urological Association (AUA) Symptom Score questionnaire, which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms, where a decrease in score is consistent with improvement in symptoms; and

2) peak urine flow rate, where an increased peak urine flow rate value over baseline is consistent with decreased urinary obstruction.
Mean changes from baseline to week 13 in total AUA Symptom Score were significantly greater for groups treated with FLOMAX capsules 0.4 mg and 0.8 mg once daily compared to placebo in both U. S. studies (Table 2, Figures 2A and 2B).

The changes from baseline to week 13 in peak urine flow rate were also significantly greater for the FLOMAX capsules 0.4 mg and 0.8 mg once daily groups compared to placebo in Study 1, and for the FLOMAX capsules 0.8 mg once daily group in Study 2 (Table 2, Figures 3A and 3B). Overall there were no significant differences in improvement observed in total AUA Symptom Scores or peak urine flow rates between the 0.4 mg and the 0.8 mg dose groups with the exception that the 0.8 mg dose in Study 1 had a significantly greater improvement in total AUA Symptom Score compared to the 0.4 mg dose.

TABLE 2 MEAN (± S. D.) CHANGES FROM BASELINE TO WEEK 13 IN TOTAL AUA SYMPTOM SCORE ** AND PEAK URINE FLOW RATE (ML/ SEC)
Total AUA Symptom Score Peak Urine Flow Rate Mean Baseline
Value Mean Change Mean Baseline Value Mean Change Study 1 *
FLOMAX capsules 0.8 mg once daily 19.9 ± 4.9 n= 247 -9.6* ± 6.7 n= 237 9.57 ± 2.51 n= 247 1.78* ± 3.35 n= 247
FLOMAX capsules 0.4 mg once daily 19.8 ± 5.0 n= 254 -8.3* ± 6.5 n= 246 9.46 ± 2.49 n= 254 1.75* ± 3.57 n= 254
Placebo 19.6 ± 4.9 n= 254 -5.5 ± 6.6 n= 246 9.75 ± 2.54 n= 254 0.52 ± 3.39 n= 253

Study 2 * FLOMAX capsules
0.8 mg once daily 18.2 ± 5.6 n= 244 -5.8* ± 6.4 n= 238 9.96 ± 3.16 n= 244 1.79* ± 3.36 n= 237 FLOMAX capsules

0.4 mg once daily 17.9 ± 5.8 n= 248 -5.1* ± 6.4 n= 244 9.94 ± 3.14 n= 248 1.52 ± 3.64 n= 244 Placebo
19.2 ± 6.0 n= 239 -3.6 ± 5.7 n= 235 9.95 ± 3.12 n= 239 0.93 ± 3.28 n= 235

* Statistically significant difference from placebo (p-value . 0. 050; Bonferroni-Holm multiple test procedure); ** Total AUA Symptom Scores ranged from 0 to 35
* Peak urine flow rate measured 4 to 8 hours post dose at week 13 * Peak urine flow rate measured 24 to 27 hours post dose at week 13
Week 13: For patients not completing the 13 week study the last observation was carried forward.

Mean total AUA Symptom Scores for both FLOMAX capsules 0.4 mg and 0.8 mg once daily groups showed a rapid decrease starting at one week after dosing and remained decreased through 13 weeks in both studies (Figures 2A and 2B).
In Study 1, 400 patients (53% of the originally randomized group) elected to continue in their originally assigned treatment groups in a double-blind, placebo controlled, 40 week extension trial (138 patients on 0.4 mg, 135 patients on 0.8 mg and 127 patients on placebo). Three hundred and twenty-three patients (43% of the originally randomized group) completed one year. Of these, 81% (97 patients) on 0.4 mg, 74% (75 patients) on 0.8 mg and 56% (57 patients) on placebo had a response . 25% above baseline in total AUA Symptom Score at one year.

Figure 2A: Mean Change from Baseline in Total AUA Symptom Score (0-35) Study 1

* indicates significant difference from placebo (p-value . 0. 050). B = Baseline determined approximately one week prior to the initial dose of double-blind medication at Week 0. Subsequent values are observed cases. LOCF= Last observation carried forward for patients not completing the 13-week study.
Note: Patients in the 0.8 mg treatment group received 0. 4 mg for the first week. Note: Total AUA Symptom Scores range from 0 to 35

Figure 2B: Mean Change from Baseline in Total AUA Symptom Score (0-35) Study 2

* indicates significant difference from placebo (p-value . 0. 050). Baseline measurement was taken Week 0. Subsequent values are observed cases.
LOCF= Last observation carried forward for patients not completing the 13-week study. Note: Patients in the 0.8 mg treatment group received 0. 4 mg for the first week.
Note: Total AUA Symptom Scores range from 0 to 35.

* indicates significant difference from placebo (p-value . 0. 050). B = Baseline determined approximately one week prior to the initial dose of double-blind medication at Week 0. Subsequent values are observed cases. LOCF= Last observation carried forward for patients not completing the 13-week study.
Note: The uroflowmetry assessments at week 0 were recorded 4-8 hours after patients received the first dose of double-blind medication. Measurements at each visit were scheduled 4-8 hours after dosing (approximately peak plasma tamsulosin concentration).
Note: Patients in the 0.8 mg treatment groups received 0.4 for the first week.

Figure 3B: Mean Increase in Peak Urine Flow Rate (mL/ Sec) Study 2

* indicates significant difference from placebo (p-value . 0.050). Baseline measurement was taken Week 0. Subsequent values are observed cases.
LOCF= Last observation carried forward for patients not completing the 13-week study. Note: Patients in the 0.8 mg treatment group received 0. 4 mg for the first week.
Note: Week 1 and Week 2 measurements were scheduled 4-8 hours after dosing (approximate peak plasma tamsulosin concentration). All other visits were scheduled 24-27 hours after dosing (approximate trough tamsulosin concentration).

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