Tamsulosin Hydrochloride: Package Insert and Label Information

TAMSULOSIN HYDROCHLORIDE- tamsulosin hydrochloride capsule
RedPharm Drug, Inc.

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. Tamsulosin hydrochloride capsules USP should not be crushed, chewed, or opened.

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)].

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 should be cautioned to avoid situations in which injury could result should syncope occur.

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 co-administered 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 alpha1 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.

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.

5.5 Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract and glaucoma surgery in some patients on or previously treated with alpha1 blockers, including tamsulosin hydrochloride capsules USP [see ADVERSE REACTIONS (6.2)].

Most reports were in patients taking the alpha1 blocker when IFIS occurred, but in some cases, the alpha1 blocker had been stopped prior to surgery. In most of these cases, the alpha1 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 alpha1 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 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.

IFIS may increase the risk of eye complications during and after the operation. The benefit of stopping alpha1 blocker therapy prior to cataract or glaucoma surgery has not been established. The initiation of therapy with tamsulosin in patients for whom cataract or glaucoma surgery a is scheduled is not recommended.

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-Emergent1 Adverse Events Occurring in ≥2% of Tamsulosin Hydrochloride Capsules USP or Placebo Patients in Two U.S. Short-Term Placebo-Controlled Clinical Studies
TAMSULOSIN HYDROCHLORIDE CAPSULES USP GROUPS
BODY SYSTEM/ 0.4 mg 0.8 mg PLACEBO
ADVERSE EVENT n=502 n=492 n=493
BODY AS WHOLE
1 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.
2 Coding preferred terms also include cold, common cold, head cold, flu, and flu-like symptoms.
3 Coding preferred terms also include nasal congestion, stuffy nose, runny nose, sinus congestion, and hay fever.
Headache 97 (19.3%) 104 (21.1%) 99 (20.1%)
Infection2 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
Rhinitis3 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 mmHg during the orthostatic test; (3) an increase in pulse rate of ≥20 bpm upon standing with a standing pulse rate ≥100 bpm during the orthostatic test; and (4) the presence of clinical symptoms (faintness, lightheadedness/lightheaded, dizziness, spinning sensation, vertigo, or postural hypotension) upon standing during the orthostatic test.

Following the first dose of double-blind medication in Study 1, a positive orthostatic test result at 4 hours post-dose was observed in 7% of patients (37 of 498) who received 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.

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 dyspnea, palpitations, hypotension, atrial fibrillation, arrhythmia, tachycardia, skin desquamation including reports of Stevens-Johnson syndrome, erythema multiforme, dermatitis exfoliative, constipation, vomiting, dry mouth, visual impairment, and epistaxis have been received during the postmarketing period.

During cataract and glaucoma surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha1 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 Cmax 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 Cmax 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 co-administered 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 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 co-administration 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 co-administered 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 co-administered 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 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 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 Cmax and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the tamsulosin hydrochloride capsules USP dosage [see CLINICAL PHARMACOLOGY (12.3)].

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