TAMSULOSIN HYDROCHLORIDE- tamsulosin hydrochloride_capsule

The symptoms associated with benign prostatic hyperplasia (BPH) 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 alpha1 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 1 1 1 1A 1B 1D 1A Tamsulosin hydrochloride capsules are not intended for use as an antihypertensive drug. Urologic pharmacodynamic effects have been evaluated in neurologically impaired pediatric patients and in adults with BPH [see Use in Specific Populations ( 8. 4 14 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 Effect of Food max max Figure 1 Mean Plasma Tamsulosin Hydrochloride Concentrations Following Single-Dose Administration of Tamsulosin Hydrochloride Capsules 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 a tamsulosin hydrochloride capsule is taken with a light breakfast or a high-fat breakfast (Table 2). Table 2 Mean (+/- S. ) Pharmacokinetic Parameters Following Tamsulosin Hydrochloride Capsules 0. 4 mg Once Daily or 0. 8 mg Once Daily with a Light Breakfast, High-Fat Breakfast or Fasted Pharmacokinetic 0. 4 mg QD to healthy 0. 8 mg QD to healthy volunteers; n=22 Light Fasted Light High-Fat Fasted min 4. 6 C max min 3. 0 T 1/2 - - - - 14. 9 AUC tau 151 +/- 81. 5 199 +/- 94. 1 440 +/- 195 449 +/- 217 557 +/- 257 C min max max 1/2 tau Distribution Tamsulosin hydrochloride is extensively bound to human plasma proteins (94% to 99%), primarily alpha1 acid glycoprotein (AAG), with linear binding over a wide concentration range (20 to 600 ng/mL). The results of two-way in vitro Metabolism [see Warnings and Precautions ( 5. 2 Drug Interactions ( 7. 1 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 Excretion Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin hydrochloride in plasma ranged from 5 to 7 hours. Because of absorption rate-controlled pharmacokinetics with tamsulosin hydrochloride capsules, 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. Specific Populations Pediatric Use [see Use in Specific Populations ( 8. 4 Geriatric (Age) Use [see Use in Specific Populations ( 8. 5 Renal Impairment cr 2 cr 2 2 cr 2 [see Use in Specific Populations ( 8. 6 Hepatic Impairment [see Use in Specific Populations ( 8. 7 Drug Interactions Cytochrome P450 Inhibition Strong and Moderate Inhibitors of CYP3A4 or CYP2D6 [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 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 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 max [see Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 1 The effects of concomitant administration of a moderate CYP2D6 inhibitor (e. , terbinafine) on the pharmacokinetics of tamsulosin hydrochloride have not been evaluated [see Warnings and Precautions ( 5. 1 The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin hydrochloride capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when tamsulosin hydrochloride 0. 4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors [see Warnings and Precautions ( 5. 1 Cimetidine [see Warnings and Precautions ( 5. 1 Other Alpha Adrenergic Blocking Agents [see Warnings and Precautions ( 5. 2 PDE5 Inhibitors [see Warnings and Precautions ( 5. 3 Warfarin [see Warnings and Precautions ( 5. 4 Nifedipine, Atenolol, Enalapril [see Drug Interactions ( 7. 5 Digoxin and Theophylline [see Drug Interactions ( 7. 6 Furosemide max [see Drug Interactions ( 7.

Tamsulosin hydrochloride capsules are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) [see Clinical Studies ( 14 Tamsulosin hydrochloride is an alpha 1 1 1.

Tamsulosin hydrochloride capsules 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 should not be crushed, chewed or opened. [see Warnings and Precautions ( 5. 4 mg once daily taken approximately one-half hour following the same meal each day.

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 Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 or www. gov/medwatch. 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. and European placebo-controlled clinical trials in which daily doses of 0. 8 mg tamsulosin hydrochloride capsules were used. These studies evaluated safety in 1783 patients treated with tamsulosin hydrochloride capsules and 798 patients administered placebo. Table 1 summarizes the treatment-emergent adverse events that occurred in >=2% of patients receiving either tamsulosin hydrochloride capsules 0. 8 mg and at an incidence numerically higher than that in the placebo group during two 13-week U. trials (US92-03A and US93-01) conducted in 1487 men. Table 1 Treatment-Emergent 1 BODY SYSTEM/ ADVERSE EVENT Tamsulosin Hydrochloride CAPSULES GROUPS PLACEBO 0. 8 mg n=502 n=492 n=493 BODY AS WHOLE 2 3 1 2 3 Signs and Symptoms of Orthostasis 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 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 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). Because orthostasis was detected more frequently in tamsulosin hydrochloride capsule-treated patients than in placebo recipients, there is a potential risk of syncope [see Warnings and Precautions ( 5. 1 Abnormal Ejaculation Laboratory Tests The following adverse reactions have been identified during post-approval use of tamsulosin hydrochloride capsules. 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. 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.

Tamsulosin hydrochloride capsules are contraindicated in patients known to be hypersensitive to tamsulosin hydrochloride or any component of tamsulosin hydrochloride capsules. Reactions have included skin rash, urticaria, pruritus, angioedema, and respiratory symptoms [see Adverse Reactions ( 6. 2 Contraindicated in patients known to be hypersensitive to tamsulosin hydrochloride or any component of tamsulosin hydrochloride capsules ( 4 6.

Pediatric Use: Not indicated for use in pediatric populations ( 8. 3 Risk Summary [see Data]. Data Tamsulosin hydrochloride is not indicated for use in women. There are no data on the presence of tamsulosin hydrochloride in human milk, the effects of tamsulosin hydrochloride on the breastfed infant, or the effects of tamsulosin hydrochloride on milk production. Tamsulosin hydrochloride is present in the milk of lactating rats [see Data]. Data Infertility Males see Clinical Trials Experience ( 6. 1 see Nonclinical Toxicology ( 13. 1 Females see Nonclinical Toxicology ( 13. 1 Tamsulosin hydrochloride capsules are not indicated for use in pediatric populations. Efficacy and positive benefit/risk of tamsulosin hydrochloride was not demonstrated in two studies conducted in patients 2 years to 16 years of age with elevated detrusor leak point pressure (>40 cm H 2 2 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 Patients with renal impairment do not require an adjustment in tamsulosin hydrochloride capsules dosing. However, patients with end-stage renal disease (CL cr 2 [see Clinical Pharmacology ( 12. 3 Patients with moderate hepatic impairment do not require an adjustment in tamsulosin hydrochloride capsules dosage. Tamsulosin hydrochloride has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology ( 12.

Tamsulosin hydrochloride capsules 0. 4 mg should not be used with strong inhibitors of CYP3A4 (e. , ketoconazole). Tamsulosin hydrochloride capsules should be used with caution in combination with moderate inhibitors of CYP3A4 (e. , erythromycin), in combination with strong (e. , paroxetine) or moderate (e. , terbinafine) inhibitors of CYP2D6, or in patients known to be CYP2D6 poor metabolizers, particularly at a dose higher than 0. 3 Strong and Moderate Inhibitors of CYP3A4 or CYP2D6 Concomitant treatment with ketoconazole (a strong inhibitor of CYP3A4) resulted in an increase in the C max [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 3) Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in an increase in the C max [see Warnings and Precautions ( 5. 2 ) and Clinical Pharmacology ( 12. The effects of concomitant administration of a moderate CYP2D6 inhibitor (e. , terbinafine) on the pharmacokinetics of tamsulosin hydrochloride capsules have not been evaluated [see Warnings and Precautions ( 5. 3 The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin hydrochloride capsules have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when tamsulosin hydrochloride 0. 4 mg is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors [see Warnings and Precautions ( 5. 3 Cimetidine [see Warnings and Precautions ( 5. 3 The pharmacokinetic and pharmacodynamic interactions between tamsulosin hydrochloride capsules and other alpha adrenergic blocking agents have not been determined; however, interactions between tamsulosin hydrochloride capsules and other alpha adrenergic blocking agents may be expected [see Warnings and Precautions ( 5. 3 Caution is advised when alpha adrenergic blocking agents including tamsulosin hydrochloride 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. 3 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 [see Warnings and Precautions ( 5. 3 Dosage adjustments are not necessary when tamsulosin hydrochloride capsules are administered concomitantly with nifedipine, atenolol, or enalapril [see Clinical Pharmacology ( 12. 3 Dosage adjustments are not necessary when a tamsulosin hydrochloride capsule is administered concomitantly with digoxin or theophylline [see Clinical Pharmacology ( 12. 3 Tamsulosin hydrochloride capsules had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin hydrochloride C max [see Clinical Pharmacology ( 12.

OVERDOSAGE
Should overdosage of tamsulosin hydrochloride capsules lead to hypotension [ see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )
NONCLINICAL TOXICOLOGY
Rats administered doses up to 43 mg/kg/day in males and 52 mg/kg/day in females had no increases in tumor incidence, with the exception of a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses >=5.4 mg/kg (P<0.015). The highest doses of tamsulosin hydrochloride evaluated in the rat carcinogenicity study produced systemic exposures (AUC) in rats 3 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day. Mice were administered doses up to 127 mg/kg/day in males and 158 mg/kg/day in females. There were no significant tumor findings in male mice. Female mice treated for 2 years with the two highest doses of 45 and 158 mg/kg/day had statistically significant increases in the incidence of mammary gland fibroadenomas (P<0.0001) and adenocarcinomas (P<0.0075). The highest dose levels of tamsulosin hydrochloride evaluated in the mice carcinogenicity study produced systemic exposures (AUC) in mice 8 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day. The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin hydrochloride-induced hyperprolactinemia. It is not known if tamsulosin hydrochloride capsules elevate prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known. Tamsulosin hydrochloride produced no evidence of mutagenic potential in vitro in vivo 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.
CLINICAL STUDIES
Four placebo-controlled clinical studies and one active-controlled clinical study enrolled a total of 2296 patients (1003 received tamsulosin hydrochloride capsules 0. 4 mg once daily, 491 received tamsulosin hydrochloride capsules 0. 8 mg once daily, and 802 were control patients) in the U. In the two U. placebo-controlled, double-blind, 13-week, multicenter studies [Study 1 (US92-03A) and Study 2 (US93-01)], 1486 men with the signs and symptoms of BPH were enrolled. In both studies, patients were randomized to either placebo, tamsulosin hydrochloride capsules 0. 4 mg once daily, or tamsulosin hydrochloride capsules 0. 8 mg once daily. Patients in tamsulosin hydrochloride capsules 0. 8 mg once-daily treatment groups received a dose of 0. 4 mg once daily for one week before increasing to the 0. 8 mg once-daily dose. The primary efficacy assessments included: 1) total American Urological Association (AUA) Symptom Score questionnaire, which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms, where a decrease in score is consistent with improvement in symptoms; and 2) peak urine flow rate, where an increased peak urine flow rate value over baseline is consistent with decreased urinary obstruction. Mean changes from baseline to Week 13 in total AUA Symptom Score were significantly greater for groups treated with tamsulosin hydrochloride capsules 0. 8 mg once daily compared to placebo in both U. studies (Table 3, Figures 2A and 2B). The changes from baseline to Week 13 in peak urine flow rate were also significantly greater for the tamsulosin hydrochloride capsules 0. 8 mg once-daily groups compared to placebo in Study 1, and for the tamsulosin hydrochloride capsules 0. 8 mg once-daily group in Study 2 (Table 3, Figures 3A and 3B). Overall there were no significant differences in improvement observed in total AUA Symptom Scores or peak urine flow rates between the 0. 4 mg and the 0. 8 mg dose groups with the exception that the 0. 8 mg dose in Study 1 had a significantly greater improvement in total AUA Symptom Score compared to the 0. Table 3 Mean (+/-S. ) 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 dagger Tamsulosin hydrochloride capsules 0. 8 mg once daily 19. 35 Tamsulosin hydrochloride capsules 0. 4 mg once daily 19. 57 Placebo 19. 39 Study 2 double dagger Tamsulosin hydrochloride capsules 0. 8 mg once daily 18. 36 Tamsulosin hydrochloride capsules 0. 4 mg once daily 17. 64 Placebo 19. 28 * ** dagger double dagger 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 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 * Figure 2B Mean Change from Baseline in Total AUA Symptom Score (0-35) Study 2 * Figure 3A Mean Increase in Peak Urine Flow Rate (mL/Sec) Study 1 * Figure 3B Mean Increase in Peak Urine Flow Rate (mL/Sec) Study 2 * fig fig fig fig.

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TAMSULOSIN HYDROCHLORIDE- tamsulosin hydrochloride_capsule Product manual source documgent