TAMSULOSIN HYDROCHLORIDE- tamsulosin hydrochloride capsule

United States - English - NLM (National Library of Medicine)

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Active ingredient:
tamsulosin hydrochloride (UNII: 11SV1951MR) (tamsulosin - UNII:G3P28OML5I)
Available from:
Synthon Pharmaceuticals, Inc.
INN (International Name):
tamsulosin hydrochloride
Composition:
tamsulosin hydrochloride 0.4 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Tamsulosin hydrochloride capsules, USP are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) [see Clinical Studies (14) ]. Tamsulosin hydrochloride capsules, USP are not indicated for the treatment of hypertension. Tamsulosin hydrochloride capsules, USP are contraindicated in patients known to be hypersensitive to tamsulosin hydrochloride or any component of tamsulosin hydrochloride capsules, USP. Reactions have included skin rash, urticaria, pruritus, angioedema and respiratory symptoms [see Adverse Reactions (6.2) ]. Teratogenic Effects, Pregnancy Category B. Administration of tamsulosin hydrochloride to pregnant female rats at dose levels up to approximately 50 times the human therapeutic AUC exposure (300 mg/kg/day) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits at dose levels up to 50 mg/kg/day produced no evidence of fetal harm. Tamsulosin hydrochloride capsules, USP are not indicated for use in women.
Product summary:
Tamsulosin hydrochloride capsules, USP 0.4 mg are supplied in high density polyethylene bottles containing 100 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). 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.
Authorization status:
Abbreviated New Drug Application
Authorization number:
63672-0021-0

TAMSULOSIN HYDROCHLORIDE- tamsulosin hydrochloride capsule

Synthon Pharmaceuticals, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use tamsulosin hydrochloride capsules, USP

safely and effectively. See full prescribing information for tamsulosin hydrochloride capsules, USP.

Tamsulosin hydrochloride capsules, USP 0.4 mg

Initial U.S. Approval: 1997

RECENT MAJOR CHANGES

Dosage and Administration (2)

4/2009

Contraindications (4)

12/2009

Warnings and Precautions

12/2009

Drug Interactions (5.2)

12/2009

Screening for Prostate Cancer (5.4)

12/2009

INDICATIONS AND USAGE

Tamsulosin hydrochloride capsules, USP are an alpha adrenoceptor antagonist indicated for treatment of the signs and

symptoms of benign prostatic hyperplasia (1)

Tamsulosin hydrochloride capsules, USP are not indicated for the treatment of hypertension (1)

DOSAGE AND ADMINISTRATION

0.4 mg once daily taken approximately one-half hour following the same meal each day (2)

Can be increased to 0.8 mg once daily for patients who fail to respond to the 0.4 mg dose after 2 to 4 weeks of dosing

If discontinued or interrupted for several days, therapy should start again with the 0.4 mg once-daily dose (2)

DOSAGE FORMS AND STRENGTHS

Capsules: 0.4 mg (3)

CONTRAINDICATIONS

Contraindicated in patients known to be hypersensitive to tamsulosin hydrochloride or any component of tamsulosin

hydrochloride capsules, USP (4, 6.2)

WARNINGS AND PRECAUTIONS

Advise patients about the possibility of symptoms related to postural hypotension and to avoid situations where injury

could result should syncope occur (5.1)

Should not be used in combination with strong inhibitors of CYP3A4 (5.2, 7.1). Use with caution in combination with

moderate inhibitors of CYP3A4, with strong or moderate inhibitors of CYP2D6, in patients known to be CYP2D6 poor

metabolizers, or in combination with other cytochrome P450 inhibitors. (5.2, 7.1, 12.3)

Should not be used in combination with other alpha adrenergic blocking agents (5.2, 7.2, 12.3)

Exercise caution with concomitant administration of warfarin (5.2, 7.4, 12.3)

Advise patients about the possibility and seriousness of priapism (5.3)

Intraoperative Floppy Iris Syndrome has been observed during cataract surgery in some patients. Advise patients

considering cataract surgery to tell their ophthalmologist that they have taken tamsulosin hydrochloride capsules, USP.

(5.5)

Advise patients to be screened for the presence of prostate cancer prior to treatment and at regular intervals

afterwards (5.4)

ADVERSE REACTIONS

The most common adverse events (≥2% of patients and at a higher incidence than placebo) with the 0.4 mg dose or 0.8

mg dose were headache, dizziness, rhinitis, infection, abnormal ejaculation, asthenia, back pain, diarrhea, pharyngitis,

chest pain, cough increased, somnolence, nausea, sinusitis, insomnia, libido decreased, tooth disorder, and blurred

vision (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Actavis Elizabeth LLC at 1-800-432-8534 or FDA at 1-

800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Tamsulosin hydrochloride capsules, USP 0.4 mg should not be used with strong inhibitors of CYP3A4 (e.g.,

ketoconazole). Tamsulosin hydrochloride capsules, USP should be used with caution in combination with

moderate inhibitors of CYP3A4 (e.g., erythomycin), in combination with strong (e.g.,paroxetine) or

moderate (e.g.,terbinafine) inhibitors of CYP2D6, or in patients known to be CYP2D6 poor metabolizers,

particularly at a dose higher than 0.4 mg (e.g., 0.8 mg) (5.2, 7.1, 12.3)

Concomitant use of PDE5 inhibitors with tamsulosin can potentially cause symptomatic hypotension (5.2,

7.3, 12.3)

USE IN SPECIFIC POPULATIONS

Pediatric Use: Not indicated for use in pediatric populations (8.4, 12.3)

Geriatric Use: No overall differences in efficacy or safety vs. younger patients, but greater sensitivity of some older

adults cannot be ruled out (8.5, 12.3)

Renal Impairment: Has not been studied in patients with end stage renal disease (8.6, 12.3)

Hepatic Impairment: Has not been studied in patients with severe hepatic impairment (8.7, 12.3)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 5/2010

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Orthostasis

5.2 Drug Interactions

5.3 Priapism

5.4 Screening for Prostate Cancer

5.5 Intraoperative Floppy Iris Syndrome

5.6 Sulfa Allergy

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Cytochrome P450 Inhibition

7.2 Other Alpha Adrenergic Blocking Agents

7.3 PDE5 Inhibitors

7.4 Warfarin

7.5 Nifedipine, Atenolol, Enalapril

7.6 Digoxin and Theophylline

7.7 Furosemide

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Hypotension

17.2 Priapism

17.3 Screening for Prostate Cancer

17.4 Intraoperative Floppy Iris Syndrome

17.5 Administration

17.6 FDA-approved Patient Labeling

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Tamsulosin hydrochloride capsules, USP are indicated for the treatment of the signs and symptoms of

benign prostatic hyperplasia (BPH) [see Clinical Studies (14)]. Tamsulosin hydrochloride capsules, USP

are not indicated for the treatment of hypertension.

2 DOSAGE AND ADMINISTRATION

Tamsulosin hydrochloride capsules, USP 0.4 mg once daily is recommended as the dose for the

treatment of the signs and symptoms of BPH. It should be administered approximately one-half hour

following the same meal each day.

For those patients who fail to respond to the 0.4 mg dose after 2 to 4 weeks of dosing, the dose of

tamsulosin hydrochloride capsules, USP can be increased to 0.8 mg once daily. Tamsulosin

hydrochloride capsules, USP 0.4 mg should not be used in combination with strong inhibitors of

CYP3A4 (e.g., ketoconazole) [see Warnings and Precautions (5.2)].

If tamsulosin hydrochloride capsules, USP administration is discontinued or interrupted for several

days at either the 0.4 mg or 0.8 mg dose, therapy should be started again with the 0.4 mg once-daily

dose.

3 DOSAGE FORMS AND STRENGTHS

Capsule: 0.4 mg, olive green opaque cap and an orange opaque body. The cap is imprinted with the

code "TSL 0.4" in black ink.

4 CONTRAINDICATIONS

Tamsulosin hydrochloride capsules, USP are contraindicated in patients known to be hypersensitive to

tamsulosin hydrochloride or any component of tamsulosin hydrochloride capsules, USP. Reactions

have included skin rash, urticaria, pruritus, angioedema and respiratory symptoms [see Adverse Reactions

(6.2)].

Sections or subsections omitted from the full prescribing information are not listed.

5 WARNINGS AND PRECAUTIONS

5.1 Orthostasis

The signs and symptoms of orthostasis (postural hypotension, dizziness and vertigo) were detected

more frequently in tamsulosin hydrochloride capsules, USP-treated patients than in placebo recipients.

As with other alpha adrenergic blocking agents there is a potential risk of syncope [see Adverse

Reactions (6.1)]. Patients beginning treatment with tamsulosin hydrochloride capsules, USP capsules

should be cautioned to avoid situations where injury could result should syncope occur [see Patient

Counseling Information (17.1)].

5.2 Drug Interactions

Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6. Tamsulosin hydrochloride

capsules, USP 0.4 mg should not be used in combination with strong inhibitors of CYP3A4 (e.g.,

ketoconazole) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Tamsulosin hydrochloride

capsules, USP should be used with caution in combination with moderate inhibitors of CYP3A4 (e.g.,

erythromycin), in combination with strong (e.g., paroxetine) or moderate (e.g., terbinafine) inhibitors of

CYP2D6, in patients known to be CYP2D6 poor metabolizers particularly at a dose higher than 0.4 mg

(e.g., 0.8 mg) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Tamsulosin hydrochloride capsules, USP should be used with caution in combination with cimetidine,

particularly at a dose higher than 0.4 mg (e.g., 0.8 mg) [see Drug Interactions (7.1) and Clinical

Pharmacology (12.3)].

Tamsulosin hydrochloride capsules, USP should not be used in combination with other alpha

adrenergic blocking agents [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Caution is advised when alpha adrenergic blocking agents including tamsulosin hydrochloride capsules,

USP are coadministered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both

vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially

cause symptomatic hypotension [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

Caution should be exercised with concomitant administration of warfarin and tamsulosin hydrochloride

capsules, USP [See Drug Interactions (7.4) and Clinical Pharmacology (12.3)].

5.3 Priapism

Rarely (probably less than 1 in 50,000 patients), tamsulosin, like other alpha antagonists, has been

associated with priapism (persistent painful penile erection unrelated to sexual activity). Because this

condition can lead to permanent impotence if not properly treated, patients must be advised about the

seriousness of the condition [see Patient Counseling Information (17.2)].

5.4 Screening for Prostate Cancer

Prostate cancer and BPH frequently co-exist; therefore, patients should be screened for the presence of

prostate cancer prior to treatment with tamsulosin hydrochloride capsules, USP and at regular intervals

afterwards [see Patient Counseling Information (17.3)].

5.5 Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients

treated with alpha blockers, including tamsulosin hydrochloride capsules, USP [see Adverse Reactions

(6.2)]. Most reports were in patients taking the alpha blocker when IFIS occurred, but in some cases,

the alpha blocker had been stopped prior to surgery. In most of these cases, the alpha blocker had

been stopped recently prior to surgery (2 to 14 days), but in a few cases, IFIS was reported after the

patient had been off the alpha blocker for a longer period (5 weeks to 9 months). IFIS is a variant of

small pupil syndrome and is characterized by the combination of a flaccid iris that billows in response

to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation

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 ophthalmologist should be prepared for possible modifications to their surgical

technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. The benefit

of stopping alpha blocker therapy prior to cataract surgery has not been established.

5.6 Sulfa Allergy

In patients with sulfa allergy, allergic reaction to tamsulosin hydrochloride capsules, USP has been

rarely reported. If a patient reports a serious or life-threatening sulfa allergy, caution is warranted when

administering tamsulosin hydrochloride capsules, USP.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reactions rates

observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of

another drug and may not reflect the rates observed in practice.

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 tamsulosin

hydrochloride capsules, USP were used. These studies evaluated safety in 1783 patients treated with

tamsulosin hydrochloride capsules, USP and 798 patients administered placebo. Table 1 summarizes the

treatment-emergent adverse events that occurred in ≥2% of patients receiving either tamsulosin

hydrochloride capsules, USP 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 1 Treatment-Emergent Adverse Events Occurring in ≥2% of

Tamsulosin Hydrochloride Capsules, USP or Placebo Patients in Two

U.S. Short-Term Placebo-Controlled Clinical Studies

BODY SYSTEM/

ADVERSE EVENT

TAMSULOSIN

HYDROCHLORIDE

CAPSULES, USP GROUPS

PLACEBO

0.4 mg

n=502

0.8 mg

n=492

n=493

BODY AS WHOLE

Headache

97 (19.3%)

104 (21.1%)

99 (20.1%)

Infection

45 (9.0%)

53 (10.8%)

37 (7.5%)

Asthenia

39 (7.8%)

42 (8.5%)

27 (5.5%)

Back pain

35 (7.0%)

41 (8.3%)

27 (5.5%)

Chest pain

20 (4.0%)

20 (4.1%)

18 (3.7%)

NERVOUS SYSTEM

Dizziness

75 (14.9%)

84 (17.1%)

50 (10.1%)

Somnolence

15 (3.0%)

21 (4.3%)

8 (1.6%)

Insomnia

12 (2.4%)

7 (1.4%)

3 (0.6%)

Libido decreased

5 (1.0%)

10 (2.0%)

6 (1.2%)

RESPIRATORY SYSTEM

Rhinitis

66 (13.1%)

88 (17.9%)

41 (8.3%)

Pharyngitis

29 (5.8%)

25 (5.1%)

23 (4.7%)

Cough increased

17 (3.4%)

22 (4.5%)

12 (2.4%)

Sinusitis

11 (2.2%)

18 (3.7%)

8 (1.6%)

*

DIGESTIVE SYSTEM

Diarrhea

31 (6.2%)

21 (4.3%)

22 (4.5%)

Nausea

13 (2.6%)

19 (3.9%)

16 (3.2%)

Tooth disorder

6 (1.2%)

10 (2.0%)

7 (1.4%)

UROGENITAL SYSTEM

Abnormal ejaculation

42 (8.4%)

89 (18.1%)

1 (0.2%)

SPECIAL SENSES

Blurred vision

1 (0.2%)

10 (2.0%)

2 (0.4%)

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 mm Hg 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 tamsulosin hydrochloride

capsules, USP 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 tamsulosin hydrochloride capsules, USP 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 tamsulosin hydrochloride capsules, USP 0.4 mg once-

daily group, 92 of the 491 patients (19%) in the tamsulosin hydrochloride capsules, USP 0.8 mg once-

daily group and 54 of the 493 patients (11%) in the placebo group.

A treatment-emergent adverse event was defined as any event satisfying one of the

following criteria:

The adverse event occurred for the first time after initial dosing with double-blind

study medication.

The adverse event was present prior to or at the time of initial dosing with

double-blind study medication and subsequently increased in severity during

double-blind treatment; or

The adverse event was present prior to or at the time of initial dosing with

double-blind study medication, disappeared completely, and then reappeared

during double-blind treatment.

Coding preferred terms also include cold, common cold, head cold, flu, and flu-like

symptoms.

Coding preferred terms also include nasal congestion, stuffy nose, runny nose, sinus

congestion, and hay fever.

Because orthostasis was detected more frequently in tamsulosin hydrochloride capsules, USP -treated

patients than in placebo recipients, there is a potential risk of syncope [see Warnings and Precautions

(5.1)].

Abnormal Ejaculation

Abnormal ejaculation includes ejaculation failure, ejaculation disorder, retrograde ejaculation and

ejaculation decrease. As shown in Table 1, abnormal ejaculation was associated with tamsulosin

hydrochloride capsules, USP administration and was dose-related in the U.S. studies. Withdrawal from

these clinical studies of tamsulosin hydrochloride capsules, USP 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.

Laboratory Tests

No laboratory test interactions with tamsulosin hydrochloride capsules, USP are known. Treatment with

tamsulosin hydrochloride capsules, USP for up to 12 months had no significant effect on prostate-

specific antigen (PSA).

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of tamsulosin

hydrochloride capsules, USP. 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 tamsulosin hydrochloride capsules, USP.

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 blocker therapy [see Warnings and

Precautions (5.5)].

7 DRUG INTERACTIONS

7.1 Cytochrome P450 Inhibition

Strong and Moderate Inhibitors of CYP3A4 or CYP2D6

Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6.

Concomitant treatment with ketoconazole (a strong inhibitor of CYP3A4) resulted in an increase in the

and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively [see Warnings and Precautions (5.2)

and Clinical Pharmacology (12.3)]. The effects of concomitant administration of a moderate CYP3A4

inhibitor (e.g., erythromycin) on the pharmacokinetics of tamsulosin hydrochloride capsules, USP have

not been evaluated [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in an increase in the

and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively [see Warnings and Precautions (5.2)

and Clinical Pharmacology (12.3)]. A similar increase in exposure is expected in CYP2D6 poor

metabolizers (PM) as compared to extensive metabolizers (EM). Since CYP2D6 PMs cannot be readily

identified and the potential for significant increase in tamsulosin exposure exists when tamsulosin

hydrochloride capsules, USP 0.4 mg are coadministered with strong CYP3A4 inhibitors in CYP2D6

PMs, tamsulosin hydrochloride capsules, USP 0.4 mg should not be used in combination with strong

PMs, tamsulosin hydrochloride capsules, USP 0.4 mg should not be used in combination with strong

inhibitors of CYP3A4 (e.g., ketoconazole) [see Warnings and Precautions (5.2) and Clinical

Pharmacology (12.3)].

The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the

pharmacokinetics of tamsulosin hydrochloride capsules, USP have not been evaluated [see Warnings and

Precautions (5.2) and Clinical Pharmacology (12.3)].

The effects of coadministration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin

hydrochloride capsules, USP have not been evaluated. However, there is a potential for significant

increase in tamsulosin exposure when tamsulosin hydrochloride capsules, USP 0.4 mg are

coadministered with a combination of both CYP3A4 and CYP2D6 inhibitors [see Warnings and

Precautions (5.2) and Clinical Pharmacology (12.3)].

Cimetidine

Treatment with cimetidine resulted in a significant decrease (26%) in the clearance of tamsulosin

hydrochloride, which resulted in a moderate increase in tamsulosin hydrochloride AUC (44%) [see

Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

7.2 Other Alpha Adrenergic Blocking Agents

The pharmacokinetic and pharmacodynamic interactions between tamsulosin hydrochloride capsules,

USP and other alpha adrenergic blocking agents have not been determined; however, interactions

between tamsulosin hydrochloride capsules, USP and other alpha adrenergic blocking agents may be

expected [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

7.3 PDE5 Inhibitors

Caution is advised when alpha adrenergic blocking agents including tamsulosin hydrochloride capsules,

USP are coadministered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both

vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially

cause symptomatic hypotension [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

7.4 Warfarin

A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin was not

conducted. Results from limited in vitro and in vivo studies are inconclusive. Caution should be

exercised with concomitant administration of warfarin and tamsulosin hydrochloride capsules, USP [see

Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

7.5 Nifedipine, Atenolol, Enalapril

Dosage adjustments are not necessary when tamsulosin hydrochloride capsules, USP are administered

concomitantly with nifedipine, atenolol, or enalapril [see Warnings and Precautions (5.2) and Clinical

Pharmacology (12.3)].

7.6 Digoxin and Theophylline

Dosage adjustments are not necessary when tamsulosin hydrochloride capsules, USP are administered

concomitantly with digoxin or theophylline [see Warnings and Precautions (5.2) and Clinical

Pharmacology (12.3)].

7.7 Furosemide

Tamsulosin hydrochloride capsules, USP had no effect on the pharmacodynamics (excretion of

electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin

hydrochloride C

and AUC, these changes are expected to be clinically insignificant and do not

require adjustment of the tamsulosin hydrochloride capsules, USP dosage [see Warnings and

Precautions (5.2) and Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects, Pregnancy Category B.

Administration of tamsulosin hydrochloride to pregnant female rats at dose levels up to approximately

50 times the human therapeutic AUC exposure (300 mg/kg/day) revealed no evidence of harm to the

fetus. Administration of tamsulosin hydrochloride to pregnant rabbits at dose levels up to 50 mg/kg/day

produced no evidence of fetal harm. Tamsulosin hydrochloride capsules, USP are not indicated for use

in women.

8.3 Nursing Mothers

Tamsulosin hydrochloride capsules, USP are not indicated for use in women.

8.4 Pediatric Use

Tamsulosin hydrochloride capsules, USP are not indicated for use in pediatric populations.

A description of the data from pediatric studies of tamsulosin hydrochloride capsules, USP is contained

in the approved labeling of Boehringer Ingelheim's Flomax

capsules. However, due to Boehringer

Ingelheim's marketing exclusivity rights, a description of these pediatric studies is not contained in the

approved labeling for tamsulosin hydrochloride capsules, USP.

8.5 Geriatric Use

Of the total number of subjects (1783) in clinical studies of tamsulosin, 36% were 65 years of age and

over. No overall differences in safety or effectiveness were observed between these subjects and

younger subjects, and the other reported clinical experience has not identified differences in responses

between the elderly and younger patients, but greater sensitivity of some older individuals cannot be

ruled out [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Patients with renal impairment do not require an adjustment in tamsulosin hydrochloride capsules, USP

dosing. However, patients with endstage renal disease (CL <10 mL/min/1.73 m ) have not been studied

[see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Patients with moderate hepatic impairment do not require an adjustment in tamsulosin hydrochloride

capsules, USP dosage. Tamsulosin hydrochloride capsules, USP have not been studied in patients with

severe hepatic impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Should overdosage of tamsulosin hydrochloride capsules, USP lead to hypotension [see Warnings and

Precautions (5.1) and Adverse Reactions (6.1)], support of the cardiovascular system is of first

importance. Restoration of blood pressure and normalization of heart rate may be accomplished by

keeping the patient in the supine position. If this measure is inadequate, then administration of

intravenous fluids should be considered. If necessary, vasopressors should then be used and renal

function should be monitored and supported as needed. Laboratory data indicate that tamsulosin

hydrochloride is 94% to 99% protein bound; therefore, dialysis is unlikely to be of benefit.

11 DESCRIPTION

Tamsulosin hydrochloride is an antagonist of alpha

adrenoceptors in the prostate.

Tamsulosin hydrochloride is (-)-(R)-5-[2-[[2-(o-Ethoxyphenoxy) ethyl]amino]propyl]-2-

methoxybenzenesulfonamide, monohydrochloride. Tamsulosin hydrochloride is a white crystalline

powder that melts with decomposition at approximately 230°C. It is sparingly soluble in water and

methanol, slightly soluble in glacial acetic acid and ethanol, and practically insoluble in ether.

The molecular formula of tamsulosin hydrochloride is C

H N O S HCl. The molecular weight of

tamsulosin hydrochloride is 444.98.

Its structural formula is:

Each tamsulosin hydrochloride capsule, USP for oral administration contains tamsulosin hydrochloride

0.4 mg, and the following 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.

USP Dissolution Test pending.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The symptoms associated with benign prostatic hyperplasia are related to bladder outlet obstruction,

which is comprised of two underlying components: static and dynamic. The static component is related

to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic

stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate

well with the size of the prostate. The dynamic component is a function of an increase in smooth muscle

tone in the prostate and bladder neck leading to constriction of the bladder outlet. Smooth muscle tone is

mediated by the sympathetic nervous stimulation of alpha adrenoceptors, which are abundant in the

prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can

cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine

flow rate and a reduction in symptoms of BPH.

Tamsulosin, an alpha adrenoceptor blocking agent, exhibits selectivity for alpha receptors in the

human prostate. At least three discrete alpha adrenoceptor subtypes have been identified: alpha

alpha

, and alpha

; their distribution differs between human organs and tissue. Approximately 70% of

the alpha receptors in human prostate are of the alpha

subtype.

Tamsulosin hydrochloride capsules, USP are not intended for use as an antihypertensive drug.

12.2 Pharmacodynamics

Urologic pharmacodynamic effects have been evaluated in neurologically impaired pediatric patients

and in adults with BPH [see Use in Specific Populations (8.4) and Clinical Studies (14)]

12.3 Pharmacokinetics

The pharmacokinetics of tamsulosin hydrochloride have been evaluated in adult healthy volunteers and

patients with BPH after single and/or multiple administration with doses ranging from 0.1 mg to 1 mg.

Absorption

Absorption of tamsulosin hydrochloride from tamsulosin hydrochloride capsules, USP 0.4 mg is

essentially complete (>90%) following oral administration under fasting conditions. Tamsulosin

hydrochloride exhibits linear kinetics following single and multiple dosing, with achievement of

steady-state concentrations by the fifth day of once-a-day dosing.

Effect of Food

The time to maximum concentration (T

) is reached by four to five hours under fasting conditions and

by six to seven hours when tamsulosin hydrochloride capsules, USP are administered with food. Taking

tamsulosin hydrochloride capsules, USP under fasted conditions results in a 30% increase in

bioavailability (AUC) and 40% to 70% increase in peak concentrations (C

) compared to fed

conditions (Figure 1).

Figure 1 Mean Plasma Tamsulosin Hydrochloride Concentrations Following Single-Dose

Administration of Tamsulosin Hydrochloride Capsules, USP 0.4 mg Under Fasted and Fed

Conditions (n=8)

The effects of food on the pharmacokinetics of tamsulosin hydrochloride are consistent regardless of

whether tamsulosin hydrochloride capsules, USP are taken with a light breakfast or a high-fat breakfast

(Table 2).

Table 2 Mean (± S.D.) Pharmacokinetic Parameters Following Tamsulosin

Hydrochloride Capsules, USP 0.4 mg Once Daily or 0.8 mg Once Daily with a

Light Breakfast, High-Fat Breakfast or Fasted

Pharmacokinetic

Parameter

0.4 mg QD to healthy

volunteers; n=23

(age range 18-32 years)

0.8 mg QD to healthy volunteers;

n=22

(age range 55-75 years)

Light

Breakfas t

Fas ted

Light

Breakfas t

High-Fat

Breakfas t

Fas ted

(ng/mL)

4.0 ± 2.6

3.8 ± 2.5

12.3 ± 6.7

13.5 ± 7.6

13.3 ±

13.3

= observed minimum concentration

= observed maximum tamsulosin hydrochloride plasma concentration

= median time-to-maximum concentration

= observed half-life

AUC = area under the tamsulosin hydrochloride plasma time curve over the

dosing interval

(ng/mL)

10.1 ± 4.8

17.1 ± 17.1

29.8 ± 10.3

29.1 ± 11.0

41.6 ±

15.6

Ratio

3.1 ± 1.0

5.3 ± 2.2

2.7 ± 0.7

2.5 ± 0.8

3.6 ± 1.1

(hours)

(hours)

14.9 ±

AUC (ng·hr/mL)

151 ± 81.5

199 ± 94.1

440 ± 195

449 ± 217

557 ±

Distribution

The mean steady-state apparent volume of distribution of tamsulosin hydrochloride after intravenous

administration to ten healthy male adults was 16 L, which is suggestive of distribution into extracellular

fluids in the body.

Tamsulosin hydrochloride is extensively bound to human plasma proteins (94% to 99%), primarily

alpha acid glycoprotein (AAG), with linear binding over a wide concentration range (20 to 600 ng/mL).

The results of two-way in vitro studies indicate that the binding of tamsulosin hydrochloride to human

plasma proteins is not affected by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-

hydroxy acid metabolite, warfarin, diazepam, propranolol, trichlormethiazide, or chlormadinone.

Likewise, tamsulosin hydrochloride had no effect on the extent of binding of these drugs.

Metabolism

There is no enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer

in humans. Tamsulosin hydrochloride is extensively metabolized by cytochrome P450 enzymes in the

liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic

profile of the metabolites in humans has not been established. Tamsulosin is extensively metabolized,

mainly by CYP3A4 and CYP2D6, as well as via some minor participation of other CYP isoenzymes.

Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to tamsulosin [see

Warnings and Precautions (5.2) and Drug Interactions (7.1)]. The metabolites of tamsulosin

hydrochloride undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.

Incubations with human liver microsomes showed no evidence of clinically significant metabolic

interactions between tamsulosin hydrochloride and amitriptyline, albuterol (beta agonist), glyburide

(glibenclamide) and finasteride (5alpha-reductase inhibitor for treatment of BPH). However, results of

the in vitro testing of the tamsulosin hydrochloride interaction with diclofenac and warfarin were

equivocal.

Excretion

On administration of the radiolabeled dose of tamsulosin hydrochloride to four healthy volunteers, 97%

of the administered radioactivity was recovered, with urine (76%) representing the primary route of

excretion compared to feces (21%) over 168 hours.

Following intravenous or oral administration of an immediate-release formulation, the elimination half-

life of tamsulosin hydrochloride in plasma ranged from five to seven hours. Because of absorption

rate-controlled pharmacokinetics with tamsulosin hydrochloride capsules, USP, the apparent half-life

of tamsulosin hydrochloride is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in

the target population.

Tamsulosin hydrochloride undergoes restrictive clearance in humans, with a relatively low systemic

clearance (2.88 L/h).

Special Populations

Pediatric Use

Tamsulosin hydrochloride capsules, USP are not indicated for use in pediatric populations [see Use in

Specific Populations (8.4)].

Geriatric (Age) Use

Cross-study comparison of tamsulosin hydrochloride capsules, USP overall exposure (AUC) and half-

life indicates that the pharmacokinetic disposition of tamsulosin hydrochloride may be slightly

prolonged in geriatric males compared to young, healthy male volunteers. Intrinsic clearance is

independent of tamsulosin hydrochloride binding to AAG, but diminishes with age, resulting in a 40%

overall higher exposure (AUC) in subjects of age 55 to 75 years compared to subjects of age 20 to 32

years [see Use in Specific Populations (8.5)].

Renal Impairment

The pharmacokinetics of tamsulosin hydrochloride have been compared in 6 subjects with mild-

moderate (30≤CL <70 mL/min/1.73 m ) or moderate-severe (10≤CL <30 mL/min/1.73 m ) renal

impairment and 6 normal subjects (CL >90 mL/min/1.73 m ). While a change in the overall plasma

concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the

unbound (active) concentration of tamsulosin hydrochloride, as well as the intrinsic clearance, remained

relatively constant. Therefore, patients with renal impairment do not require an adjustment in tamsulosin

hydrochloride capsules, USP dosing. However, patients with endstage renal disease (CL <10

mL/min/1.73 m ) have not been studied [see Use in Specific Populations (8.6)].

Hepatic Impairment

The pharmacokinetics of tamsulosin hydrochloride have been compared in 8 subjects with moderate

hepatic impairment (Child-Pugh's classification: Grades A and B) and 8 normal subjects. While a change

in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered

binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride does not change

significantly, with only a modest (32%) change in intrinsic clearance of unbound tamsulosin

hydrochloride. Therefore, patients with moderate hepatic impairment do not require an adjustment in

tamsulosin hydrochloride capsules, USP dosage. Tamsulosin hydrochloride capsules, USP have not

been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].

Drug Interactions

Cytochrome P450 Inhibition

Strong and Moderate Inhibitors of CYP3A4 or CYP2D6

The effects of ketoconazole (a strong inhibitor of CYP3A4) at 400 mg once daily for 5 days on the

pharmacokinetics of a single tamsulosin hydrochloride capsule, USP 0.4 mg dose was investigated in

24 healthy volunteers (age range 23 to 47 years). Concomitant treatment with ketoconazole resulted in an

increase in the C

and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively [see Warnings and

Precautions (5.2) and Clinical Pharmacology (12.3)]. The effects of concomitant administration of a

moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of tamsulosin hydrochloride

capsules, USP have not been evaluated [see Warnings and Precautions (5.2) and Drug Interactions (7.1)].

The effects of paroxetine (a strong inhibitor of CYP2D6) at 20 mg once daily for 9 days on the

pharmacokinetics of a single tamsulosin hydrochloride capsule, USP 0.4 mg dose was investigated in

24 healthy volunteers (age range 23 to 47 years). Concomitant treatment with paroxetine resulted in an

increase in the C

and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively [see Warnings and

Precautions (5.2) and Drug Interactions (7.1)]. A similar increase in exposure is expected in CYP2D6

poor metabolizers (PM) as compared to extensive metabolizers (EM). A fraction of the population

(about 7% of Caucasians and 2% of African Americans) are CYP2D6 PMs. Since CYP2D6 PMs cannot

be readily identified and the potential for significant increase in tamsulosin exposure exists when

tamsulosin hydrochloride capsules, USP 0.4 mg are coadministered with strong CYP3A4 inhibitors in

CYP2D6 PMs, tamsulosin hydrochloride capsules, USP 0.4 mg should not be used in combination with

strong inhibitors of CYP3A4 (e.g., ketoconazole) [see Warnings and Precautions (5.2) and Drug

Interactions (7.1)].

The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the

pharmacokinetics of tamsulosin hydrochloride capsules, USP have not been evaluated [see Warnings and

Precautions (5.2) and Drug Interactions (7.1)].

The effects of coadministration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin

hydrochloride capsules, USP have not been evaluated. However, there is a potential for significant

increase in tamsulosin exposure when tamsulosin hydrochloride capsules, USP 0.4 mg are

coadministered with a combination of both CYP3A4 and CYP2D6 inhibitors [see Warnings and

Precautions (5.2) and Drug Interactions (7.1)].

Cimetidine

The effects of cimetidine at the highest recommended dose (400 mg every 6 hours for 6 days) on the

pharmacokinetics of a single tamsulosin hydrochloride capsule, USP 0.4 mg dose was investigated in

10 healthy volunteers (age range 21 to 38 years). Treatment with cimetidine resulted in a significant

decrease (26%) in the clearance of tamsulosin hydrochloride, which resulted in a moderate increase in

tamsulosin hydrochloride AUC (44%) [see Warnings and Precautions (5.2) and Drug Interactions (7.1)].

Other Alpha Adrenergic Blocking Agents

The pharmacokinetic and pharmacodynamic interactions between tamsulosin hydrochloride capsules,

USP and other alpha adrenergic blocking agents have not been determined; however, interactions

between tamsulosin hydrochloride capsules, USP and other alpha adrenergic blocking agents may be

expected [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].

PDE5 Inhibitors

Caution is advised when alpha adrenergic blocking agents including tamsulosin hydrochloride capsules,

USP are coadministered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both

vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially

cause symptomatic hypotension [see Warnings and Precautions (5.2) and Drug Interactions (7.3)]

Warfarin

A definitive drug-drug interaction study between tamsulosin hydrochloride 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 tamsulosin hydrochloride capsules, USP

[see Warnings and Precautions (5.2) and Drug Interactions (7.4)].

Nifedipine, Atenolol, Enalapril

In three studies in hypertensive subjects (age range 47 to 79 years) whose blood pressure was

controlled with stable doses of nifedipine, atenolol, or enalapril for at least 3 months, tamsulosin

hydrochloride capsules, USP 0.4 mg for 7 days followed by tamsulosin hydrochloride capsules, USP

0.8 mg for another 7 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 tamsulosin hydrochloride capsules, USP are administered concomitantly with nifedipine, atenolol,

when tamsulosin hydrochloride capsules, USP are administered concomitantly with nifedipine, atenolol,

or enalapril [see Drug Interactions (7.5)].

Digoxin and Theophylline

In two studies in healthy volunteers (n=10 per study; age range 19 to 39 years) receiving tamsulosin

hydrochloride capsules, USP 0.4 mg/day for 2 days, followed by tamsulosin hydrochloride capsules,

USP 0.8 mg/day for 5 to 8 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 tamsulosin hydrochloride capsules, USP are administered

concomitantly with digoxin or theophylline [see Drug Interactions (7.6)].

Furosemide

The pharmacokinetic and pharmacodynamic interaction between tamsulosin hydrochloride capsules,

USP 0.8 mg/day (steady-state) and furosemide 20 mg intravenously (single dose) was evaluated in ten

healthy volunteers (age range 21 to 40 years). Tamsulosin hydrochloride capsules, USP had no effect

on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an

11% to 12% reduction in tamsulosin hydrochloride C

and AUC, these changes are expected to be

clinically insignificant and do not require adjustment of the tamsulosin hydrochloride capsules, USP

dosage [see Drug Interactions (7.7)].

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

Study 1

Tamsulosin

hydrochloride

capsules, USP

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, USP

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

19.6 ± 4.9

-5.5 ± 6.6

9.75 ± 2.54

0.52 ± 3.39

*

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

carried forward.

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, USP

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, USP

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

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 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 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

Total AUA Symptom Scores ranged from 0 to 35.

Peak urine flow rate measured 4 to 8 hours post dose at Week 13.

Statistically significant difference from placebo (p-value ≤ 0.050; Bonferroni-Holm

multiple test procedure).

Peak urine flow rate measured 24 to 27 hours post dose at Week 13.

* 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.

Figure 3A Mean Increase in Peak Urine Flow Rate (mL/sec) Study 1

* indicates significant difference from placebo (p-value ≤0.050).

* 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 (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

* 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).

16 HOW SUPPLIED/STORAGE AND HANDLING

Tamsulosin hydrochloride capsules, USP 0.4 mg are supplied in high density polyethylene bottles

containing 100 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).

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

See FDA-Approved Patient Labeling (17.6).

17.1 Hypotension

Patients should be told 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)].

17.2 Priapism

Patients should be advised 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)].

17.3 Screening for Prostate Cancer

Prostate cancer and BPH frequently co-exist; therefore, patients should be screened 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)].

17.4 Intraoperative Floppy Iris Syndrome

Patients considering cataract surgery should be advised to tell their ophthalmologist that they have taken

tamsulosin hydrochloride capsules, USP [see Warnings and Precautions (5.5)].

17.5 Administration

Patients should be advised not to crush or chew the tamsulosin hydrochloride capsules, USP.

17.6 FDA-approved Patient Labeling

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

Procardia XL is a registered trademark of Pfizer

Manufactured for:

Actavis Elizabeth LLC

200 Elmora Avenue

Elizabeth, NJ 07207 USA

Manufactured by:

Rottendorf Pharma GmbH

Ennigerloh, Germany

Made in Germany

Issue Date: 03/2010

PI-5004-0 (PPI-5005-0)

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?

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

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 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.

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.

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 affects 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 [77ºF (25ºC)]. 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

Allergic reactions may include:

rash

itching

hives

Rare and more serious allergic reactions may also include:

swelling of face, tongue, or throat

difficulty breathing

Get medical help right away if you have swelling of the face, tongue or throat, or

difficulty breathing.

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 surgery. During cataract 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 surgery, be sure to tell your

surgeon if you take or have taken tamsulosin hydrochloride capsules, USP.

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 Elizabeth LLC 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 for:

Actavis Elizabeth LLC

200 Elmora Avenue

Elizabeth, NJ 07207 USA

Manufactured by:

Rottendorf Pharma GmbH

Ennigerloh, Germany

Made in Germany

Issue Date: 03/2010

PPI-5005-0

PRINCIPAL DISPLAY PANEL - Bulk Drum Shipping Label

ROTTENDORF PHARMA GMBH

59320 ENNIGERLOH

TAMSULOSIN 0,4MG USA/EU KPS (API 167901)

Ch.-B. : 4224612

RPH - Material - Nr. : 109471

Brutto : (Kg)

9,86

Tara : (Kg)

1,40

Netto : (Kg)

8,46

Stück (TS) :

20,239

Stückgewicht (mg) :

Gebinde - Nr. :

Kunden - Name : SYNTHON HISPANIA S.L.

Kunden - Charge : 10A15GA

Anz. Trockenbeutel pro Geb. : 1

Lagerbedingungen: 15 - 30 °C

Verpackt am : 02.02.2010

Bearbeiter : Ww/OI

Gebinde sind nur zur kurzfristigen Zwischenlagerung geeignet.

TAMSULOSIN HYDROCHLORIDE

tamsulosin hydrochloride capsule

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 36 72-0 0 21

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

ta msulo sin hydro chlo ride (UNII: 11SV19 51MR) (tamsulo sin - UNII:G3P28 OML5I)

tamsulo sin hydro chlo ride

0 .4 mg

Synthon Pharmaceuticals, Inc.

Inactive Ingredients

Ingredient Name

Stre ng th

cellulo se, micro crysta lline (UNII: OP1R32D6 1U)

wa ter (UNII: 0 59 QF0 KO0 R)

ta lc (UNII: 7SEV7J4R1U)

triethyl citra te (UNII: 8 Z9 6 QXD6 UM)

ferro so ferric o xide (UNII: XM0 M8 7F357)

FD&C Blue No . 2 (UNII: L0 6 K8 R7DQK)

g ela tin (UNII: 2G8 6 QN327L)

ferric o xide red (UNII: 1K0 9 F3G6 75)

tita nium dio xide (UNII: 15FIX9 V2JP)

ferric o xide yello w (UNII: EX438 O2MRT)

butyl a lco ho l (UNII: 8 PJ6 1P6 TS3)

a lco ho l (UNII: 3K9 9 58 V9 0 M)

iso pro pyl a lco ho l (UNII: ND2M416 30 2)

pro pylene g lyco l (UNII: 6 DC9 Q16 7V3)

po ta ssium hydro xide (UNII: WZH3C48 M4T)

shella c (UNII: 46 N10 7B71O)

Product Characteristics

Color

ORANGE, GREEN (o live co lo red cap)

S core

no sco re

S hap e

CAPSULE

S iz e

19 mm

Flavor

Imprint Code

TSL;0 ;4

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 36 72-0 0 21-0

20 20 0 in 1 DRUM

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 8 0 1

0 4/27/20 10

Labeler -

Synthon Pharmaceuticals, Inc. (013502302)

Revised: 5/2010

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