Tamsulosin Hydrochloride: Package Insert and Label Information (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Rats administered doses up to 43 mg/kg/day in males and 52 mg/kg/day in females had no increases in tumor incidence, with the exception of a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses ≥5.4 mg/kg (P<0.015). The highest doses of tamsulosin hydrochloride evaluated in the rat carcinogenicity study produced systemic exposures (AUC) in rats 3 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day.
Mice were administered doses up to 127 mg/kg/day in males and 158 mg/kg/day in females. There were no significant tumor findings in male mice. Female mice treated for 2 years with the two highest doses of 45 and 158 mg/kg/day had statistically significant increases in the incidence of mammary gland fibroadenomas (P<0.0001) and adenocarcinomas (P<0.0075). The highest dose levels of tamsulosin hydrochloride evaluated in the mice carcinogenicity study produced systemic exposures (AUC) in mice 8 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day.
The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin hydrochloride-induced hyperprolactinemia. It is not known if tamsulosin hydrochloride capsules elevate prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known.
Tamsulosin hydrochloride produced no evidence of mutagenic potential in vitro in the Ames reverse mutation test, mouse lymphoma thymidine kinase assay, unscheduled DNA repair synthesis assay, and chromosomal aberration assays in Chinese hamster ovary cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay.
Studies in rats revealed significantly reduced fertility in males dosed with single or multiple daily doses of 300 mg/kg/day of tamsulosin hydrochloride (AUC exposure in rats about 50 times the human exposure with the maximum therapeutic dose). The mechanism of decreased fertility in male rats is considered to be an effect of the compound on the vaginal plug formation possibly due to changes of semen content or impairment of ejaculation. The effects on fertility were reversible, showing improvement by 3 days after a single dose and 4 weeks after multiple dosing. Effects on fertility in males were completely reversed within nine weeks of discontinuation of multiple dosing. Multiple doses of 10 and 100 mg/kg/day tamsulosin hydrochloride (1/5 and 16 times the anticipated human AUC exposure) did not significantly alter fertility in male rats. Effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated.
Studies in female rats revealed significant reductions in fertility after single or multiple dosing with 300 mg/kg/day of the R-isomer or racemic mixture of tamsulosin hydrochloride, respectively. In female rats, the reductions in fertility after single doses were considered to be associated with impairments in fertilization. Multiple dosing with 10 or 100 mg/kg/day of the racemic mixture did not significantly alter fertility in female rats.

14 CLINICAL STUDIES

Four placebo-controlled clinical studies and one active-controlled clinical study enrolled a total of 2296 patients (1003 received tamsulosin hydrochloride capsules 0.4 mg once daily, 491 received tamsulosin hydrochloride 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, tamsulosin hydrochloride capsules 0.4 mg once daily, or tamsulosin hydrochloride capsules 0.8 mg once daily. Patients in tamsulosin hydrochloride 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 tamsulosin hydrochloride capsules 0.4 mg and 0.8 mg once daily compared to placebo in both U.S. studies (Table 3, Figures 2A and 2B). The changes from baseline to Week 13 in peak urine flow rate were also significantly greater for the tamsulosin hydrochloride capsules 0.4 mg and 0.8 mg once-daily groups compared to placebo in Study 1, and for the tamsulosin hydrochloride capsules 0.8 mg once-daily group in Study 2 (Table 3, 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 3 Mean (±S.D.) Changes from Baseline to Week 13 in Total AUA Symptom Score** and Peak Urine Flow Rate (mL/sec)
Total AUA Symptom ScorePeak Urine Flow Rate
Mean Baseline Value Mean Change Mean Baseline Value Mean Change
* 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.
Study 1
Tamsulosin hydrochloride 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
Tamsulosin hydrochloride capsules 0.4 mg once daily 19.8 ± 5 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
Tamsulosin hydrochloride 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
Tamsulosin hydrochloride 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 n=239 -3.6 ± 5.7 n=235 9.95 ± 3.12 n=239 0.93 ± 3.28 n=235

Mean total AUA Symptom Scores for both tamsulosin hydrochloride capsules 0.4 mg and 0.8 mg once-daily groups showed a rapid decrease starting at 1 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 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 to 35) Study 1
(click image for full-size original)

* 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 to 35) Study 2
(click image for full-size original)

* 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.

Figure 3A Mean Increase in Peak Urine Flow Rate (mL/Sec) Study 1
(click image for full-size original)

* 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 to 8 hours after patients received the first dose of double-blind medication.
Measurements at each visit were scheduled 4 to 8 hours after dosing (approximate peak plasma tamsulosin concentration). Note: Patients in the 0.8 mg treatment groups received 0.4 mg for the first week.

Figure 3B Mean Increase in Peak Urine Flow Rate (mL/Sec) Study 2
(click image for full-size original)

* 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 to 8 hours after dosing (approximate peak plasma tamsulosin concentration).
All other visits were scheduled 24 to 27 hours after dosing (approximate trough tamsulosin concentration).

16 HOW SUPPLIED/STORAGE AND HANDLING

Tamsulosin Hydrochloride Capsules USP, 0.4 mg are olive green opaque/orange opaque size 0 hard gelatin capsules imprinted with D on cap and 53 on body with black edible ink filled with white to off-white beadlets.

NDC 68071-5118-1 BOTTLES OF 100


Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Preserve in tight container. Avoid excessive moisture.
Keep tamsulosin hydrochloride capsules and all medicines out of reach of children.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information)

  • Hypotension

Advise the patient about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when taking tamsulosin hydrochloride capsules, and they should be cautioned about driving, operating machinery, or performing hazardous tasks [see Warnings and Precautions (5.1)] .

  • Drug Interactions

Advise the patient that tamsulosin hydrochloride should not be used in combination with strong inhibitors of CYP3A4 [see Warnings and Precautions (5.2) and Drug Interactions (7.1)] .

  • Priapism

Advise the patient about the possibility of priapism as a result of treatment with tamsulosin hydrochloride capsules and other similar medications. Patients should be informed that this reaction is extremely rare, but if not brought to immediate medical attention, can lead to permanent erectile dysfunction (impotence) [see Warnings and Precautions (5.3)] .

  • Screening for Prostate Cancer

Prostate cancer and BPH frequently co-exist; therefore, screen patients for the presence of prostate cancer prior to treatment with tamsulosin hydrochloride capsules and at regular intervals afterwards [see Warnings and Precautions (5.4)].

  • Intraoperative Floppy Iris Syndrome

Advise the patient when considering cataract or glaucoma surgery to tell their ophthalmologist that they have taken tamsulosin hydrochloride capsules [see Warnings and Precautions (5.5)] .

  • Administration

Advise the patient that tamsulosin hydrochloride capsules should not be crushed, chewed or opened [see Dosage and Administration (2)].

FDA-approved Patient Labeling

Patient labeling is provided at the end of this prescribing information.
Distributed by:
Aurobindo Pharma USA, Inc.
279 Princeton-Hightstown Road
East Windsor, NJ 08520

Manufactured by:
Aurobindo Pharma Limited
Hyderabad-500 038, India

Revised: 03/2019

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