Dutasteride and tamsulosin hydrochloride
Capsule · Oral
Uses
Dutasteride and tamsulosin hydrochloride capsules are a combination of dutasteride, a 5 alpha-reductase inhibitor, and tamsulosin, an alpha adrenergic antagonist, indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate. ( 1.1 ) Limitations of Use: Dutasteride-containing products, including dutasteride and tamsulosin hydrochloride capsules, are not approved for the prevention of prostate cancer. ( 1.2 ) 1.1 Benign Prostatic Hyperplasia (BPH) Treatment Dutasteride and tamsulosin hydrochloride capsules are indicated for the treatment of symptomatic BPH in men with an enlarged prostate. 1.2 Limitations of Use Dutasteride-containing products, including dutasteride and tamsulosin hydrochloride capsules, are not approved for the prevention of prostate cancer.
Dosage and administration
Take one capsule daily approximately 30 minutes after the same meal each day. ( 2 ) Swallow capsule whole. ( 2 ) The recommended dosage of dutasteride and tamsulosin hydrochloride capsules is 1 capsule (0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride) taken once daily approximately 30 minutes after the same meal each day. The capsules should be swallowed whole and not chewed or opened. Contact with the contents of the dutasteride and tamsulosin hydrochloride capsule may result in irritation of the oropharyngeal mucosa.
Dosage forms and strengths
0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride. ( 3 ) Dutasteride and tamsulosin hydrochloride Capsules, containing 0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride, hard shell, with an opaque yellow cap printed '640' with black ink and opaque white body.
Contraindications
Pregnancy. Dutasteride use is contraindicated in females who are pregnant. ( 4 5.6 , 8.1 ) Patients with previously demonstrated, clinically significant hypersensitivity (e.g. serious skin reactions, angioedema, urticaria, pruritus, respiratory symptoms) to dutasteride, other 5 alpha-reductase inhibitors, tamsulosin, or any component of dutasteride and tamsulosin hydrochloride capsules. ( 4 ) Dutasteride and tamsulosin hydrochloride capsules are contraindicated for use in: Pregnancy. Dutasteride use is contraindicated in females who are pregnant. In animal reproduction and developmental toxicity studies, dutasteride inhibited development of male fetus external genitalia. Therefore, dutasteride and tamsulosin hydrochloride capsules may cause fetal harm when administered to a pregnant female. [see Warnings and Precautions ( 5.6 ), Use in Specific Populations ( 8.1 )] . Patients with previously demonstrated, clinically significant hypersensitivity (e.g. serious skin reactions, angioedema, urticaria, pruritus, respiratory symptoms) to dutasteride, other 5 alpha-reductase inhibitors, tamsulosin, or any other component of dutasteride and tamsulosin hydrochloride capsules [see Adverse Reactions ( 6.2 )] .
Warnings and precautions
Orthostatic hypotension and/or syncope can occur. Advise patients of symptoms related to postural hypotension and to avoid situations where injury could result if syncope occurs. ( 5.1 ) Do not use dutasteride and tamsulosin hydrochloride capsules with other alpha adrenergic antagonists, as this may increase the risk of hypotension. ( 5.2 ) Dutasteride and tamsulosin hydrochloride capsules reduce serum prostate-specific antigen (PSA) concentration by approximately 50%. However, any confirmed increase in PSA while on dutasteride and tamsulosin hydrochloride capsules may signal the presence of prostate cancer and should be evaluated, even if those values are still within the normal range for untreated men. ( 5.3 ) Do not use dutasteride and tamsulosin hydrochloride capsules with strong inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole). Use caution in combination with moderate CYP3A4 inhibitors (e.g., erythromycin) or strong (e.g., paroxetine) or moderate CYP2D6 inhibitors, a combination of both CYP3A4 and CYP2D6 inhibitors, or known poor metabolizers of CYP2D6. Concomitant use with known inhibitors can cause a marked increase in drug exposure. ( 5.2 , 7.1 , 12.3 ) Exercise caution with concomitant use of phosphodiesterase-5 (PDE-5) inhibitors, as this may increase the risk of hypotension. ( 5.2 ) Drugs that contain dutasteride, including dutasteride and tamsulosin hydrochloride capsules, may increase the risk of high-grade prostate cancer. ( 5.4 , 6.1 ) Prior to initiating treatment with dutasteride and tamsulosin hydrochloride capsules, consideration should be given to other urological conditions that may cause similar symptoms. ( 5.5 ) Females who are pregnant or may be pregnant should not handle dutasteride and tamsulosin hydrochloride capsules due to potential risk to a male fetus. ( 5.6 , 8.1 ) Advise patients about the possibility and seriousness of priapism. ( 5.7 ) Patients should not donate blood until 6 months after their last dose of dutasteride and tamsulosin hydrochloride capsules. ( 5.8 ) Intraoperative Floppy Iris Syndrome has been observed during cataract and glaucoma surgery after alpha-adrenergic antagonist exposure. Advise patients considering cataract or glaucoma surgery to tell their ophthalmologist that they take or have taken dutasteride and tamsulosin hydrochloride capsules. ( 5.9 ) Exercise caution with concomitant use of warfarin. ( 5.2 , 7.2 , 12.3 ) 5.1 Orthostatic Hypotension As with other alpha adrenergic antagonists, orthostatic hypotension (postural hypotension, dizziness, and vertigo) may occur in patients treated with tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules, and can result in syncope. Patients starting treatment with dutasteride and tamsulosin hydrochloride capsules should be cautioned to avoid situations where syncope could result in an injury [see Adverse Reactions ( 6.1 )] . 5.2 Drug-Drug Interactions Strong Inhibitors of Cytochrome P450 (CYP)3A4 Tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules, should not be coadministered with strong CYP3A4 inhibitors (e.g. ketoconazole) as this can significantly increase tamsulosin exposure [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]. Moderate Inhibitors of CYP3A4, Inhibitors of CYP2D6, or a Combination of Both CYP3A4 and CYP2D6 Inhibitors Tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules, should be used with caution when coadministered with moderate inhibitors of CYP3A4 (e.g. erythromycin), strong (e.g. paroxetine) or moderate (e.g. terbinafine) inhibitors of CYP2D6, a combination of both CYP3A4 and CYP2D6 inhibitors, or in patients known to be poor metabolizers of CYP2D6, as there is a potential for significant increase in tamsulosin exposure [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . Cimetidine Caution is advised when tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules, are coadministered with cimetidine [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] . Other Alpha Adrenergic Antagonists Tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules, should not be coadministered with other alpha adrenergic antagonists because of the increased risk of symptomatic hypotension. Phosphodiesterase-5 (PDE-5) Inhibitors Caution is advised when alpha adrenergic antagonist-containing products, including dutasteride and tamsulosin hydrochloride capsules, are coadministered with PDE-5 inhibitors. Alpha adrenergic antagonists and PDE-5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these 2 drug classes can potentially cause symptomatic hypotension. Warfarin Caution should be exercised with concomitant administration of warfarin and tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules [see Drug Interactions ( 7.2 ), Clinical Pharmacology ( 12.3 )] . 5.3 Effects on Prostate-Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection Coadministration of dutasteride with tamsulosin resulted in similar changes to serum PSA as with dutasteride monotherapy. In clinical trials, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in patients with symptomatic BPH, although it may vary in individuals. Dutasteride containing treatment, including dutasteride and tamsulosin hydrochloride capsules, may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men treated with a dutasteride-containing product, including dutasteride and tamsulosin hydrochloride capsules, a new baseline PSA should be established at least 3 months after starting treatment and PSA monitored periodically thereafter.
Side effects
The most common adverse reactions, reported in ≥1% of subjects treated with coadministered dutasteride and tamsulosin are ejaculation disorders, impotence, decreased libido, dizziness, and breast disorders. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The clinical efficacy and safety of coadministered dutasteride and tamsulosin, which are individual components of dutasteride and tamsulosin hydrochloride capsules, have been evaluated in a multicenter, randomized, double-blind, parallel group trial (the Combination with Alpha-Blocker Therapy, or CombAT, trial). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trial of another drug and may not reflect the rates observed in practice. The most common adverse reactions reported in subjects receiving coadministered dutasteride and tamsulosin were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving coadministration therapy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy. Trial withdrawal due to adverse reactions occurred in 6% of subjects receiving coadministered dutasteride and tamsulosin and in 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%). In the CombAT trial, over 4,800 male subjects with BPH were randomly assigned to receive 0.5 mg dutasteride, 0.4 mg tamsulosin hydrochloride, or coadministration therapy (0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride) administered once daily in a 4-year double-blind trial. Overall, 1,623 subjects received monotherapy with dutasteride; 1,611 subjects received monotherapy with tamsulosin; and 1,610 subjects received coadministration therapy. The population was aged 49 to 88 years (mean age: 66 years) and 88% were white. Table 1 summarizes adverse reactions reported in at least 1% of subjects receiving coadministration therapy and at a higher incidence than subjects receiving either dutasteride or tamsulosin as monotherapy. Table 1 Adverse Reactions Reported over a 48-Month Period in ≥1% of Subjects and More Frequently in the Coadministration Therapy Group than the Dutasteride or Tamsulosin Monotherapy Group (CombAT) by Time of Onset a Coadministration = AVODART® 0.5 mg once daily plus tamsulosin 0.4 mg once daily. b Includes anorgasmia, retrograde ejaculation, semen volume decreased, orgasmic sensation decreased, orgasm abnormal, ejaculation delayed, ejaculation disorder, ejaculation failure, and premature ejaculation. c These sexual adverse reactions are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown. d Includes erectile dysfunction and disturbance in sexual arousal. e Includes libido decreased, libido disorder, loss of libido, sexual dysfunction, and male sexual dysfunction. f Includes breast enlargement, gynecomastia, breast swelling, breast pain, breast tenderness, nipple pain, and nipple swelling. Adverse Reaction Time of Onset Year 1 Adverse Reaction Months 0 to 6 Months 7 to 12 Year 2 Year 3 Year 4 Coadministration a Dutasteride Tamsulosin (n = 1,610) (n = 1,623) (n = 1,611) (n = 1,527) (n = 1,548) (n = 1,545) (n = 1,428) (n = 1,464) (n = 1,468) (n = 1,283) (n = 1,325) (n = 1,281) (n = 1,200) (n = 1,200) (n = 1,112) Ejaculation disorders b,c Coadministration Dutasteride Tamsulosin 7.8% 1% 2.2% 1.6% 0.5% 0.5% 1 % 0.5% 0.5% 0.5% 0.2% 0.2% <0.1% 0.3% 0.3% Impotence c,d Coadministration Dutasteride Tamsulosin 5.4% 4% 2.6% 1.1% 1.1% 0.8% 1.8% 1.6% 1% 0.9% 0.6% 0.6% 0.4% 0.3% 1.1% Decreased libido c,e Coadministration Dutasteride Tamsulosin 4.5% 3.1% 2 % 0.9% 0.7% 0.6% 0.8% 1% 0.7% 0.2% 0.2% 0.2% 0% 0% <0.1% Breast disorders f Coadministration Dutasteride Tamsulosin 1.1% 0.9% 0.4% 1.1% 0.9% 0.4% 0.8% 1.2% 0.4% 0.9% 0.5% 0.2% 0.6% 0.7% 0% Dizziness Coadministration Dutasteride Tamsulosin 1.1% 0.5% 0.9% 0.4% 0.3% 0.5% 0.1% 0.1% 0.4% <0.1% <0.1% <0.1% 0.2% <0.1% 0% Cardiac Failure In CombAT, after 4 years of treatment, the incidence of the composite term cardiac failure in the coadministration group (12/1,610; 0.7%) was higher than in either monotherapy group: dutasteride, 2/1,623 (0.1%) and tamsulosin, 9/1,611 (0.6%). Composite cardiac failure was also examined in a separate 4-year placebo-controlled trial evaluating dutasteride in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking dutasteride was 0.6% (26/4,105) compared with 0.4% (15/4,126) in subjects on placebo. A majority of subjects with cardiac failure in both trials had comorbidities associated with an increased risk of cardiac failure. Therefore, the clinical significance of the numerical imbalances in cardiac failure is unknown. No causal relationship between dutasteride alone or coadministered with tamsulosin and cardiac failure has been established. No imbalance was observed in the incidence of overall cardiovascular adverse events in either trial. Additional information regarding adverse reactions in placebo-controlled trials with dutasteride or tamsulosin monotherapy follows: Dutasteride Long-term Treatment (Up to 4 Years): High-Grade Prostate Cancer: The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/mL to 10 ng/mL and a negative prostate biopsy within the previous 6 months.
Drug interactions
There have been no drug interaction trials using dutasteride and tamsulosin hydrochloride capsules. The following sections reflect information available for the individual components. 7.1 Cytochrome P450 Inhibition Dutasteride: Dutasteride is extensively metabolized in humans by the CYP3A4 and CYP3A5 isoenzymes. The effect of potent CYP3A4 inhibitors on dutasteride has not been studied. Because of the potential for drug-drug interactions, use caution when prescribing a dutasteride-containing product, including dutasteride and tamsulosin hydrochloride capsules, to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir) [see Clinical Pharmacology ( 12.3 )] . Tamsulosin: Strong and Moderate Inhibitors of CYP3A4 or CYP2D6: Tamsulosin is extensively metabolized, mainly by CYP3A4 or CYP2D6. Concomitant treatment with ketoconazole (a strong inhibitor of CYP3A4) resulted in increases in the Cmax and area under the concentration-time curve (AUC) of tamsulosin by factors of 2.2 and 2.8, respectively. Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in increases in the C max and AUC of tamsulosin by factors of 1.3 and 1.6, respectively. A similar increase in exposure is expected in poor metabolizers (PM) of CYP2D6 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 0.4 mg is coadministered with strong CYP3A4 inhibitors in CYP2D6 PMs, tamsulosin 0.4 mg capsules should not be used in combination with strong inhibitors of CYP3A4 (e.g. ketoconazole). The effects of coadministration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when tamsulosin 0.4 mg is coadministered with a combination of both CYP3A4 and CYP2D6 inhibitors [see Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 )] . Cimetidine: Treatment with cimetidine resulted in a moderate increase in tamsulosin hydrochloride AUC (44%) [see Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 )] . 7.2 Warfarin Dutasteride: Concomitant administration of dutasteride 0.5 mg/day for 3 weeks with warfarin does not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time [see Clinical Pharmacology ( 12.3 )] . Tamsulosin: A definitive drug-drug interaction trial 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-containing products, including dutasteride and tamsulosin hydrochloride capsules [see Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 )] . 7.3 Nifedipine, Atenolol, Enalapril Tamsulosin : Dosage adjustments are not necessary when tamsulosin is administered concomitantly with nifedipine, atenolol, or enalapril [see Clinical Pharmacology ( 12.3 )] . 7.4 Digoxin and Theophylline Dutasteride: Dutasteride does not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks [see Clinical Pharmacology ( 12.3 )] . Tamsulosin: Dosage adjustments are not necessary when tamsulosin is administered concomitantly with digoxin or theophylline [see Clinical Pharmacology ( 12.3 )] . 7.5 Furosemide Tamsulosin: Tamsulosin had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin hydrochloride C max and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the dose of tamsulosin [see Clinical Pharmacology ( 12.3 )] . 7.6 Calcium Channel Antagonists Dutasteride: Coadministration of verapamil or diltiazem decreases dutasteride clearance and leads to increased exposure to dutasteride. The change in dutasteride exposure is not considered to be clinically significant. No dosage adjustment of dutasteride is recommended [see Clinical Pharmacology ( 12.3 )] . 7.7 Cholestyramine Dutasteride: Administration of a single 5 mg dose of dutasteride followed 1 hour later by a 12 g dose of cholestyramine does not affect the relative bioavailability of dutasteride [see Clinical Pharmacology ( 12.3 )] .
Use in specific populations
8.1 Pregnancy Risk Summary Dutasteride and tamsulosin hydrochloride capsules are contraindicated for use in pregnancy because it may cause harm to the male fetus [see Contraindications (4)]. Dutasteride and tamsulosin hydrochloride capsules are not indicated for use in females. Dutasteride, a component of dutasteride and tamsulosin hydrochloride capsules, is a 5-alpha-reductase inhibitor that prevents conversion of testosterone to dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. Abnormalities in the genitalia of male fetuses is an expected physiological consequence of inhibition of this conversion. These results are similar to observations in male infants with genetic 5-alpha-reductase deficiency. In animal reproduction studies, dutasteride inhibited normal development of external genitalia in male offspring when given to rats or rabbits during organogenesis at less than the maximum recommended human dose (MRHD) of 0.5 mg daily, in the absence of maternal toxicity. At 15 times the MRHD, prolonged pregnancy, decreased reproductive organ weights, and delayed puberty in male offspring were observed in rats, with no-effect levels less than the MRHD of 0.5 mg daily. Increased placental weights in rabbits were also observed, with no-effect levels less than the MRHD of 0.5 mg daily (see Data). Although dutasteride is secreted into human semen, the drug concentration in the human female partner is approximately 100 times less than concentrations producing abnormalities of male genitalia in animal studies (see Data). In monkeys dosed during organogenesis at blood concentrations comparable to or above levels to which a human female partner is estimated to be exposed, male offspring external genitalia was not adversely affected. No feminization occurred in male offspring of untreated female rats mated to treated male rats even though detectable blood levels of dutasteride were observed in the female rats [see Nonclinical Toxicology ( 13.1 )]. No adverse developmental effects were observed in animal studies in which tamsulosin hydrochloride was administered to rats or rabbits during the period of organogenesis (see Data). Data Human Data: Dutasteride: The highest measured semen concentration of dutasteride in treated men was 14 ng/mL. Although dutasteride is detected in semen, assuming exposure of a 50-kg female to 5 mL of semen and 100% absorption, the female's expected dutasteride blood concentration through semen would be about 0.0175 ng/mL. This concentration is approximately 100 times less than blood concentrations producing abnormalities of male genitalia in animal studies. Dutasteride is highly protein bound in human semen (greater than 96%), which may reduce the amount of dutasteride available for vaginal absorption. Animal Data: Dutasteride: In an embryo-fetal development study in rats, oral administration of dutasteride at 10 times less than the MRHD of 0.5 mg daily (based on average blood levels in men) resulted in feminization of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day with a lack of a no-effect level) in the absence of maternal toxicity. In addition, nipple development, hypospadias, and distended preputial glands occurred in fetuses of dams treated at doses of 2.5 mg/kg/day or greater (approximately 15 times the MRHD). Reduced fetal body weight and associated delayed ossification in the presence of maternal toxicity (decreased body weight gain) were observed at maternal exposure approximately 15 times the MRHD (dose of 2.5 mg/kg/day or greater). An increase in stillborn pups was observed in dams treated at 30 mg/kg/day (approximately 111 times the MRHD), with a no-effect level of 12.5 mg/kg/day. In a rabbit embryo-fetal development study, doses 28 times the MRHD (doses of 30 mg/kg/day or greater), based on average blood levels in men, were administered orally on Gestation Days 7 to 29 (during organogenesis and the late period of external genitalia development). Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus as well as fused skull bones and increased placental weights at all doses in the absence of maternal toxicity. A second embryo-fetal development study in rabbits dosed throughout pregnancy (organogenesis and later period of external genitalia development [Gestation Days 6 to 29]) at 0.3 times the MRHD (doses of 0.05 mg/kg/day or greater, with no no-effect level), also produced evidence of feminization of the genitalia in male fetuses and increased placental weights at all doses in the absence of maternal toxicity. In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously during organogenesis (Gestation Days 20 to 100) to a dutasteride blood level comparable to or above the estimated dutasteride exposure of a human female partner. Dutasteride was administered on Gestation Days 20 to 100 (during organogenesis) at doses of 400, 780, 1, 325, or 2,010 ng/day (12 monkeys/group). No feminization of male external genitalia of monkey offspring was observed. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed at the highest dose tested. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses in the monkey represent up to 16 times the potential maximum exposure of a 50-kg human female to 5 mL of semen daily from a dutasteride-treated male, assuming 100% absorption. The dose levels (on a ng/kg basis) administered to monkeys in this study are 32 to 186 times the nominal (ng/kg) dose to which a female would potentially be exposed via the semen. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites. In an oral pre- and post-natal development study in rats, feminization of the male genitalia was observed.
Pregnancy
8.1 Pregnancy Risk Summary Dutasteride and tamsulosin hydrochloride capsules are contraindicated for use in pregnancy because it may cause harm to the male fetus [see Contraindications (4)]. Dutasteride and tamsulosin hydrochloride capsules are not indicated for use in females. Dutasteride, a component of dutasteride and tamsulosin hydrochloride capsules, is a 5-alpha-reductase inhibitor that prevents conversion of testosterone to dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. Abnormalities in the genitalia of male fetuses is an expected physiological consequence of inhibition of this conversion. These results are similar to observations in male infants with genetic 5-alpha-reductase deficiency. In animal reproduction studies, dutasteride inhibited normal development of external genitalia in male offspring when given to rats or rabbits during organogenesis at less than the maximum recommended human dose (MRHD) of 0.5 mg daily, in the absence of maternal toxicity. At 15 times the MRHD, prolonged pregnancy, decreased reproductive organ weights, and delayed puberty in male offspring were observed in rats, with no-effect levels less than the MRHD of 0.5 mg daily. Increased placental weights in rabbits were also observed, with no-effect levels less than the MRHD of 0.5 mg daily (see Data). Although dutasteride is secreted into human semen, the drug concentration in the human female partner is approximately 100 times less than concentrations producing abnormalities of male genitalia in animal studies (see Data). In monkeys dosed during organogenesis at blood concentrations comparable to or above levels to which a human female partner is estimated to be exposed, male offspring external genitalia was not adversely affected. No feminization occurred in male offspring of untreated female rats mated to treated male rats even though detectable blood levels of dutasteride were observed in the female rats [see Nonclinical Toxicology ( 13.1 )]. No adverse developmental effects were observed in animal studies in which tamsulosin hydrochloride was administered to rats or rabbits during the period of organogenesis (see Data). Data Human Data: Dutasteride: The highest measured semen concentration of dutasteride in treated men was 14 ng/mL. Although dutasteride is detected in semen, assuming exposure of a 50-kg female to 5 mL of semen and 100% absorption, the female's expected dutasteride blood concentration through semen would be about 0.0175 ng/mL. This concentration is approximately 100 times less than blood concentrations producing abnormalities of male genitalia in animal studies. Dutasteride is highly protein bound in human semen (greater than 96%), which may reduce the amount of dutasteride available for vaginal absorption. Animal Data: Dutasteride: In an embryo-fetal development study in rats, oral administration of dutasteride at 10 times less than the MRHD of 0.5 mg daily (based on average blood levels in men) resulted in feminization of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day with a lack of a no-effect level) in the absence of maternal toxicity. In addition, nipple development, hypospadias, and distended preputial glands occurred in fetuses of dams treated at doses of 2.5 mg/kg/day or greater (approximately 15 times the MRHD). Reduced fetal body weight and associated delayed ossification in the presence of maternal toxicity (decreased body weight gain) were observed at maternal exposure approximately 15 times the MRHD (dose of 2.5 mg/kg/day or greater). An increase in stillborn pups was observed in dams treated at 30 mg/kg/day (approximately 111 times the MRHD), with a no-effect level of 12.5 mg/kg/day. In a rabbit embryo-fetal development study, doses 28 times the MRHD (doses of 30 mg/kg/day or greater), based on average blood levels in men, were administered orally on Gestation Days 7 to 29 (during organogenesis and the late period of external genitalia development). Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus as well as fused skull bones and increased placental weights at all doses in the absence of maternal toxicity. A second embryo-fetal development study in rabbits dosed throughout pregnancy (organogenesis and later period of external genitalia development [Gestation Days 6 to 29]) at 0.3 times the MRHD (doses of 0.05 mg/kg/day or greater, with no no-effect level), also produced evidence of feminization of the genitalia in male fetuses and increased placental weights at all doses in the absence of maternal toxicity. In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously during organogenesis (Gestation Days 20 to 100) to a dutasteride blood level comparable to or above the estimated dutasteride exposure of a human female partner. Dutasteride was administered on Gestation Days 20 to 100 (during organogenesis) at doses of 400, 780, 1, 325, or 2,010 ng/day (12 monkeys/group). No feminization of male external genitalia of monkey offspring was observed. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed at the highest dose tested. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses in the monkey represent up to 16 times the potential maximum exposure of a 50-kg human female to 5 mL of semen daily from a dutasteride-treated male, assuming 100% absorption. The dose levels (on a ng/kg basis) administered to monkeys in this study are 32 to 186 times the nominal (ng/kg) dose to which a female would potentially be exposed via the semen. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites. In an oral pre- and post-natal development study in rats, feminization of the male genitalia was observed.
Pediatric use
8.4 Pediatric Use Dutasteride and tamsulosin hydrochloride capsules are not indicated for use in pediatric patients. Safety and effectiveness of dutasteride and tamsulosin hydrochloride capsules in pediatric patients have not been established.
Geriatric use
8.5 Geriatric Use Of 1,610 male subjects treated with coadministered dutasteride and tamsulosin in the CombAT trial, 58% of enrolled subjects were aged 65 years and older and 13% of enrolled subjects were aged 75 years and older. No overall differences in safety or efficacy were observed between these subjects and younger subjects but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology ( 12.3 )] .
Overdosage
No data are available with regard to overdosage with dutasteride and tamsulosin hydrochloride capsules. The following text reflects information available for the individual components. Dutasteride: In volunteer trials, single doses of dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical trial, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg. There is no specific antidote for dutasteride. Therefore, in cases of suspected overdosage symptomatic and supportive treatment should be given as appropriate, taking the long half-life of dutasteride into consideration. Tamsulosin: Should overdosage of tamsulosin lead to hypotension [see Warnings and Precautions ( 5.1 ), 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 is 94% to 99% protein bound; therefore, dialysis is unlikely to be of benefit.
Description
Dutasteride and tamsulosin hydrochloride capsules contain dutasteride (a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5 alpha-reductase, an intracellular enzyme that converts testosterone to DHT and tamsulosin (an antagonist of alpha1A-adrenoceptors in the prostate). Each dutasteride and tamsulosin hydrochloride capsule contains the following: One dutasteride opaque white colored, oblong shaped soft gelatin capsules containing clear colorless to slightly yellowish oily liquid, containing 0.5 mg dutasteride and the inactive ingredients: butylated hydroxy toluene, gelatin, glycerin, methylparaben, mono and diglycerides of capric acid, propylparaben and titanium dioxide. Tamsulosin hydrochloride white to off-white pellets, containing 0.4 mg tamsulosin hydrochloride and the inactive ingredients: microcrystalline cellulose, methacrylic acid copolymer dispersion, talc and triacetin. The above components are encapsulated in a hard-shell capsule made with the inactive ingredients: carrageenan, hypromellose, iron oxide yellow, potassium chloride, titanium dioxide, and imprinted with black pharmaceutical ink which contains butyl alcohol, ferrosoferic oxide, dehydrated alcohol, isopropyl alcohol, propylene glycol, potassium hydroxide, shellac and strong ammonia solution. Dutasteride: Dutasteride, USP is a synthetic 4-azasteroid compound chemically designated as (5α,17β)-N-{2,5 bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide. The molecular formula of dutasteride is C 27 H 30 F 6 N 2 O 2 , representing a molecular weight of 528.5 with the following structural formula: Dutasteride, USP is white to off-white colored powder. It is soluble in absolute ethanol and methanol and insoluble in water. Tamsulosin: Tamsulosin hydrochloride, USP is a synthetic compound chemically designated as (-)-( R )-5-[2-[[2-( o -Ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide, monohydrochloride. The molecular formula of tamsulosin hydrochloride is C 20 H 28 N 2 O 5 S
• HCl. The molecular weight of tamsulosin hydrochloride is 444.97. Its structural formula is: Tamsulosin hydrochloride, USP is white crystalline powder, odorless or practically odorless. It is slightly soluble in water and anhydrous ethanol, sparingly soluble in methanol, freely soluble in dimethyl sulfoxide and formic acid, practically soluble in ether. Dutasteride and tamsulosin hydrochloride capsules Dutasteride and tamsulosin hydrochloride capsules
Mechanism of action
12.1 Mechanism of Action Dutasteride and tamsulosin hydrochloride capsules are a combination of 2 drugs with different mechanisms of action to improve symptoms in patients with BPH: dutasteride, a 5-alpha-reductase inhibitor, and tamsulosin, an antagonist of alpha1A-adrenoreceptors. Dutasteride: Dutasteride inhibits the conversion of testosterone to DHT. DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5 alpha-reductase, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver. Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5-alpha-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor. Tamsulosin: 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 alpha1-adrenoceptor blocking agent, exhibits selectivity for alpha1-receptors in the human prostate. At least 3 discrete alpha1-adrenoceptor subtypes have been identified: alpha1A, alpha1B, and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1-receptors in human prostate are of the alpha1A subtype. Tamsulosin is not intended for use as an antihypertensive.
How supplied
Dutasteride and tamsulosin hydrochloride capsules, containing 0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride, hard shell, with an opaque yellow cap printed '640' with black ink and opaque white body. They are available as follows: NDC 68382-640-06 in bottle with child-resistant closure of 30 capsules NDC 68382-640-16 in bottle with child-resistant closure of 90 capsules Storage: Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. Capsules may become deformed and/or discolored if kept at high temperatures. Dutasteride is absorbed through the skin. Dutasteride and tamsulosin hydrochloride capsules should not be handled by females who are pregnant or who could become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus [see Warnings and Precautions ( 5.6 )] .
Patient information
Advise the patient to read the FDA-approved patient labeling (Patient Information). Orthostatic Hypotension Inform patients about the possible occurrence of symptoms related to orthostatic hypotension, such as dizziness and vertigo, and the potential risk of syncope when taking dutasteride and tamsulosin hydrochloride capsules. Caution patients starting treatment with dutasteride and tamsulosin hydrochloride capsules to avoid situations where injury could result should syncope occur (e.g., driving, operating machinery, performing hazardous tasks). Advise patients to sit or lie down at the first signs of orthostatic hypotension [see Warnings and Precautions ( 5.1 )] . Drug Interactions Advise patients that dutasteride and tamsulosin hydrochloride capsules should not be used in combination with strong inhibitors of CYP3A4 [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.1 )]. PSA Monitoring Inform patients that dutasteride and tamsulosin hydrochloride capsules reduce serum PSA levels by approximately 50% within 3 to 6 months of therapy, although it may vary for each individual. For patients undergoing PSA screening, increases in PSA levels while on treatment with dutasteride and tamsulosin hydrochloride capsules may signal the presence of prostate cancer and should be evaluated by a healthcare provider [see Warnings and Precautions ( 5.3 )] . Increased Risk of High-Grade Prostate Cancer Inform patients that there was an increase in high-grade prostate cancer in men treated with 5alpha-reductase inhibitors (which are indicated for BPH treatment), including dutasteride, which is a component of dutasteride and tamsulosin hydrochloride capsules, compared with those treated with placebo in trials looking at the use of these drugs to reduce the risk of prostate cancer [see Indications and Usage ( 1.2 ), Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.1 )] . Transdermal Exposure of Dutasteride and Tamsulosin Hydrochloride in Pregnant or Potentially Pregnant Females—Risk to Male Fetus Inform patients that dutasteride and tamsulosin hydrochloride capsules should not be handled by females who are pregnant or may potentially be pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus. Dutasteride can be absorbed through the skin and could result in unintended fetal exposure. If a pregnant or potentially pregnant female comes in contact with leaking dutasteride and tamsulosin hydrochloride capsules, the contact area should be washed immediately with soap and water [see Warnings and Precautions ( 5.6 ), Use in Specific Populations ( 8.1 )] . Effects on Semen Parameters Advise men that dutasteride and tamsulosin hydrochloride capsules may affect sperm characteristics but the effect on fertility is unknown [see Warnings and Precautions ( 5.11 ), Use in Specific Populations ( 8.3 )]. Administration Instructions Dutasteride and tamsulosin hydrochloride capsules should be swallowed whole and not chewed, crushed, or opened. Dutasteride and tamsulosin hydrochloride capsules may become deformed and/or discolored if kept at high temperatures. If this occurs, capsules should not be used. Priapism Inform patients about the possibility of priapism as a result of treatment with dutasteride and tamsulosin hydrochloride capsules or other alpha-adrenergic–antagonist-containing medications. Inform patients that this reaction is extremely rare, but can lead to permanent erectile dysfunction if not brought to immediate medical attention [see Warnings and Precautions ( 5.7 )] . Blood Donation Inform men treated with dutasteride and tamsulosin hydrochloride capsules that they should not donate blood until at least 6 months following their last dose to prevent pregnant female from receiving dutasteride through blood transfusion [see Warnings and Precautions ( 5.8 )] . Serum levels of dutasteride are detectable for 4 to 6 months after treatment ends [see Clinical Pharmacology ( 12.3 )] . Intraoperative Floppy Iris Syndrome (IFIS) Advise patients considering cataract or glaucoma surgery to tell their ophthalmologist that they take or have taken dutasteride and tamsulosin hydrochloride capsules, an alpha adrenergic antagonist-containing product [see Warnings and Precautions ( 5.9 )] .
Label text from the FDA structured product label by Zydus Pharmaceuticals USA Inc. (revised Nov 11, 2024). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Dutasteride in 3 products
- Tamsulosin Hydrochloride in 3 products
Dutasteride and tamsulosin hydrochloride NDC products (3)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 59651-063 | Dutasteride .5 mg/1; Tamsulosin Hydrochloride .4 mg/1 Capsule | Aurobindo Pharma Limited | ANDA |
| 70771-1356 | Dutasteride .5 mg/1; Tamsulosin Hydrochloride .4 mg/1 Capsule | Zydus Lifesciences Limited | ANDA |
| 68382-640 | Dutasteride .5 mg/1; Tamsulosin Hydrochloride .4 mg/1 Capsule | Zydus Pharmaceuticals USA Inc. | ANDA |
Frequently asked questions
What is Dutasteride and tamsulosin hydrochloride used for?
Dutasteride and tamsulosin hydrochloride capsules are a combination of dutasteride, a 5 alpha-reductase inhibitor, and tamsulosin, an alpha adrenergic antagonist, indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate. ( 1.1 ) Limitations of Use: Dutasteride-containing products, including dutasteride and tamsulosin hydrochloride capsules,…
What are the side effects of Dutasteride and tamsulosin hydrochloride?
The most common adverse reactions, reported in ≥1% of subjects treated with coadministered dutasteride and tamsulosin are ejaculation disorders, impotence, decreased libido, dizziness, and breast disorders. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The… See the full label for the complete list.
Who makes Dutasteride and tamsulosin hydrochloride?
Dutasteride and tamsulosin hydrochloride is listed by 3 labelers in the FDA NDC directory, including Aurobindo Pharma Limited, Zydus Lifesciences Limited, Zydus Pharmaceuticals USA Inc..