Tamsulosin Hydrochloride: Package Insert and Label Information (Page 3 of 4)

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 USP 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 USP 0.4 mg once daily, 491 received tamsulosin hydrochloride capsules USP 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 USP 0.4 mg once daily, or tamsulosin hydrochloride capsules USP 0.8 mg once daily. Patients in tamsulosin hydrochloride capsules USP 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 USP 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 USP 0.4 mg and 0.8 mg once-daily groups compared to placebo in Study 1, and for the tamsulosin hydrochloride capsules USP 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 Score Peak 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.
Study 1†
Tamsulosin hydrochloride capsules USP 19.9 ± 4.9 -9.6* ± 6.7 9.57 ± 2.51 1.78* ± 3.35
0.8 mg once daily n=247 n=237 n=247 n=247
Tamsulosin hydrochloride capsules USP 19.8 ± 5.0 -8.3* ± 6.5 9.46 ± 2.49 1.75* ± 3.57
0.4 mg once daily n=254 n=246 n=254 n=254
Placebo 19.6 ± 4.9 -5.5 ± 6.6 9.75 ± 2.54 0.52 ± 3.39
n=254 n=246 n=254 n=253
Study 2‡
Tamsulosin hydrochloride capsules USP 18.2 ± 5.6 -5.8* ± 6.4 9.96 ± 3.16 1.79* ± 3.36
0.8 mg once daily n=244 n=238 n=244 n=237
Tamsulosin hydrochloride capsules USP 17.9 ± 5.8 -5.1* ± 6.4 9.94 ± 3.14 1.52 ± 3.64
0.4 mg once daily n=248 n=244 n=248 n=244
Placebo 19.2 ± 6.0 -3.6 ± 5.7 9.95 ± 3.12 0.93 ± 3.28
n=239 n=235 n=239 n=235

Week 13: For patients not completing the 13-week study, the last observation was carried forward.

Mean total AUA Symptom Scores for both tamsulosin hydrochloride capsules USP 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 (0-35) Study 1

[ab8b786d-figure-03]

* 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

[ab8b786d-figure-04]

* 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

[ab8b786d-figure-05]

* 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 for the first week.

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

[ab8b786d-figure-06]

* 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 supplied in high density polyethylene bottles containing 100 or 500 hard gelatin capsules with an olive green opaque cap and an orange opaque body. The cap is imprinted with the code “TSL 0.4” in black ink.

Tamsulosin hydrochloride capsules USP, 100 capsules (NDC 0228-2996-11).

Tamsulosin hydrochloride capsules USP, 500 capsules (NDC 0228-2996-50).

Store at 25°C (77°F). Excursions permitted to 15° — 30°C (59° — 86°F) [See USP Controlled Room Temperature].

Keep tamsulosin hydrochloride capsules USP 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 USP, 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 capsules USP, 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 USP 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 USP 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 USP [see WARNINGS AND PRECAUTIONS (5.5)].

Administration

Advise the patient that tamsulosin hydrochloride capsules USP should not be crushed, chewed, or opened [see DOSAGE AND ADMINISTRATION (2)].

FDA-approved Patient Labeling

Patient labeling is provided as a tear-off leaflet at the end of this prescribing information.

Manufactured by:
Rottendorf Pharma GmbH
Ennigerloh, Germany
Made in Germany

or

Synthon Hispania, S.L.
Barcelona, Spain
Made in Spain

Distributed by:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA

Revised — May 2015

PI-5017-7 (PPI-5018-7)

40-9209

PATIENT INFORMATION

Tamsulosin hydrochloride capsules USP,

0.4 mg

Read the Patient Information that comes with tamsulosin hydrochloride capsules USP before you start taking it and each time you refill your prescription. The information may have changed. This leaflet does not take the place of discussions with your doctor about your medical condition or your treatment.

What are tamsulosin hydrochloride capsules USP?

Tamsulosin hydrochloride capsules USP are a prescription alpha-blocker medicine used to treat the signs and symptoms of benign prostatic hyperplasia (BPH), a condition your doctor may refer to as an enlarged prostate.

Tamsulosin hydrochloride capsules USP are not for women.
Tamsulosin hydrochloride capsules USP are not for children.

Who should not take tamsulosin hydrochloride capsules USP?

Do not take tamsulosin hydrochloride capsules USP if you are allergic to any of its ingredients. See the end of this leaflet for a complete list of ingredients in tamsulosin hydrochloride capsules USP.

What should I tell my doctor before using tamsulosin hydrochloride capsules USP?

Before taking tamsulosin hydrochloride capsules USP, tell your doctor about all your medical conditions, including:

any kidney or liver problems.
any history of low blood pressure.
any allergies to sulfa or any other medicines.
if you are planning to have cataract or glaucoma surgery.

Tell your doctor about all the medicines you take, including:

any prescription medicines, including blood pressure medicines.
any non-prescription medicines, including vitamins and herbal supplements.

Some of your other medicines may affect the way tamsulosin hydrochloride capsules USP work. Especially tell your doctor if you take a medicine for high blood pressure. You should not take tamsulosin hydrochloride capsules USP if you are already taking certain blood pressure medicines.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I take tamsulosin hydrochloride capsules USP?

Take tamsulosin hydrochloride capsules USP exactly as prescribed by your doctor.
Do not crush, chew, or open tamsulosin hydrochloride capsules USP.
Take tamsulosin hydrochloride capsules USP one time each day, about 30 minutes after the same meal each day. For example, you may take tamsulosin hydrochloride capsules USP 30 minutes after dinner each day.
If you miss a dose of tamsulosin hydrochloride capsules USP, take it as soon as you remember. If you miss your dose for the whole day, continue with your next dose on your regular schedule. Do not take two doses at the same time.
If you stop or forget to take tamsulosin hydrochloride capsules USP for several days, talk with your doctor before starting again.
If you take more tamsulosin hydrochloride capsules USP than prescribed, call your doctor right away.

What are the possible side effects of tamsulosin hydrochloride capsules USP?

Possible side effects of tamsulosin hydrochloride capsules USP may include:

Decreased blood pressure when changing positions. Tamsulosin hydrochloride capsules USP may cause a sudden drop in blood pressure upon standing, especially after the first dose or when changing doses.

Symptoms may include:

fainting
dizziness
lightheadedness

Change positions slowly from lying down to sitting up or from a sitting to a standing position until you learn how you react to tamsulosin hydrochloride capsules USP. If you begin to feel dizzy, sit or lie down until you feel better. If the symptoms are severe or do not improve, call your doctor.

Allergic reactions. Make your doctor aware of any allergic reactions you may experience while taking tamsulosin hydrochloride capsules USP.

Allergic reactions may include:

rash
itching
hives

Rare and more serious allergic reactions may also occur. Get medical help right away if you have any of the following reactions:

swelling of face, tongue, or throat
difficulty breathing
blistering of the skin

A painful erection that will not go away. Tamsulosin hydrochloride capsules USP can cause a painful erection (priapism), which cannot be relieved by having sex. If this happens, get medical help right away. If priapism is not treated, you may not be able to get an erection in the future.

Eye problems during cataract or glaucoma surgery. During cataract or glaucoma surgery, a condition called intraoperative floppy iris syndrome (IFIS) can happen if you take or have taken tamsulosin hydrochloride capsules USP. If you need to have cataract or glaucoma surgery, be sure to tell your surgeon if you take or have taken tamsulosin hydrochloride capsules USP.

Common side effects of tamsulosin hydrochloride capsules USP may include:

runny nose
dizziness
decreased semen

These are not all the possible side effects with tamsulosin hydrochloride capsules USP. Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088, or by visiting www.fda.gov/medwatch.

What should I avoid while taking tamsulosin hydrochloride capsules USP?

Avoid driving, operating machinery, or other dangerous activities, until you know how tamsulosin hydrochloride capsules USP affect you. Tamsulosin hydrochloride capsules USP may cause a sudden drop in blood pressure upon standing, especially after the first dose or when changing doses. See “What are the possible side effects of tamsulosin hydrochloride capsules USP?”

How do I store tamsulosin hydrochloride capsules USP?

Store tamsulosin hydrochloride capsules USP at Room Temperature [77°F (25°C)]. Short-term exposure to higher or lower temperatures [from 59°F (15°C) to 86°F (30°C )] is acceptable. Ask your doctor or pharmacist if you have any questions about storing your capsules.

Keep tamsulosin hydrochloride capsules USP and all medicines out of the reach of children.

General information

This medicine was prescribed for you by your doctor for your condition. Do not use it for another condition. Do not give tamsulosin hydrochloride capsules USP to other people, even if they have the same symptoms that you have. It may harm them.

While taking tamsulosin hydrochloride capsules USP, you must have regular checkups. Follow your doctor’s advice about when to have these checkups.

BPH can occur with other more serious conditions, including prostate cancer. Therefore, ask your doctor about screening for prostate cancer prior to treatment with tamsulosin hydrochloride capsules USP and at regular intervals afterwards.

This patient information leaflet summarizes the most important information about tamsulosin hydrochloride capsules USP. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about tamsulosin hydrochloride capsules USP that is written for health professionals. For more information call Actavis at 1-800-432-8534.

What are the ingredients in tamsulosin hydrochloride capsules USP?

Active Ingredient: tamsulosin hydrochloride

Inactive Ingredients: methacrylic acid copolymer, microcrystalline cellulose, purified water, talc, triethyl citrate, black iron oxide, FD&C Blue No. 2, gelatin, red iron oxide, titanium dioxide, yellow iron oxide and trace amounts of antifoam DC 1510, industrial methylated spirit, lecithin, n-butyl alcohol, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, ammonium, potassium hydroxide and shellac.

Manufactured by:
Rottendorf Pharma GmbH
Ennigerloh, Germany
Made in Germany

or

Synthon Hispania, S.L.
Barcelona, Spain
Made in Spain

Distributed by:
Actavis Pharma, Inc. Parsippany, NJ 07054 USA

PPI-5018-7

40-9209

Revised — May 2015

(PPI-41-1188/0515)

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