These highlights do not include all the information needed to use JALYN safely and effectively. See full prescribing information for JALYN.JALYN (dutasteride and tamsulosin hydrochloride) CapsulesInitial U.S. Approval: 2010

JALYN™ (dutasteride and tamsulosin hydrochloride) Capsules are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate.

The recommended dosage of JALYN 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 JALYN capsule may result in irritation of the oropharyngeal mucosa.

JALYN should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole) [see Warnings and Precautions (5.2), Drug Interactions (7.1), Clinical Pharmacology (12.3)] .

Renal Impairment: No dosage adjustment is necessary for patients with moderate to severe renal impairment (10≤ CL <30 mL/min/1.73 m). However, there are no data of JALYN or its individual components in patients with end-stage renal disease [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Hepatic Impairment: No dosage recommendation can be made due to the absence of data in patients with hepatic impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

Elderly: No dosage adjustment is necessary [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

JALYN Capsules, containing 0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride, are oblong, hard-shell capsules with a brown body and an orange cap imprinted with “GS 7CZ” in black ink.

JALYN is contraindicated for use in:

As with other alpha-adrenergic antagonists, orthostatic hypotension (postural hypotension, dizziness, and vertigo) may occur in patients treated with tamsulosin-containing products, including JALYN, and can result in syncope. Patients starting treatment with JALYN should be cautioned to avoid situations where syncope could result in an injury [see Adverse Reactions (6.1)].

Strong Inhibitors of CYP3A4: Tamsulosin-containing products, including JALYN, should not be coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole) as this can significantly decrease tamsulosin metabolism and increase tamsulosin exposure [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

  Inhibitors of CYP2D6 and Moderate Inhibitors of CYP3A4: Tamsulosin-containing products, including JALYN, should be used with caution when coadministered with moderate inhibitors of CYP3A4 (e.g., erythromycin), when coadministered with strong (e.g., paroxetine) or moderate (e.g., terbinafine) inhibitors of CYP2D6, 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 JALYN, are coadministered with cimetidine [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Other Alpha-adrenergic Antagonists: Tamsulosin-containing products, including JALYN, should not be coadministered with other alpha-adrenergic antagonists because of the increased risk of symptomatic hypotension [see Drug Interactions (7.2), Clinical Pharmacology (12.3)].

Phosphodiesterase -5 Inhibitors (PDE-5 Inhibitors): Caution is advised when alpha-adrenergic antagonist-containing products, including JALYN, are coadministered with PDE-5 inhibitors. Alpha-adrenergic blockers and PDE-5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these 2 drug classes can potentially cause symptomatic hypotension [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].

Warfarin: Caution should be exercised with concomitant administration of warfarin and tamsulosin-containing products, including JALYN [see Drug Interactions (7.4), Clinical Pharmacology (12.3)].

JALYN Capsules should not be handled by a woman who is pregnant or who may become pregnant. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a woman who is pregnant or may become pregnant comes in contact with a leaking capsule, the contact area should be washed immediately with soap and water [see Use in Specific Populations (8.1)].

Lower urinary tract symptoms of BPH can be indicative of other urological diseases, including prostate cancer. Patients should be assessed to rule out prostate cancer and other urological diseases prior to treatment with JALYN and periodically thereafter. Patients with a large residual urinary volume and/or severely diminished urinary flow may not be good candidates for 5α-reductase inhibitor therapy and should be carefully monitored for obstructive uropathy.

Coadministration of dutasteride with tamsulosin resulted in similar changes to total prostate-specific antigen (PSA) as with dutasteride monotherapy.

Dutasteride: Dutasteride reduces total serum PSA concentration by approximately 40% following 3 months of treatment and by approximately 50% following 6, 12, and 24 months of treatment. This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. Therefore, for interpretation of serial PSAs in a man taking a dutasteride-containing product, including JALYN, a new baseline PSA concentration should be established after 3 to 6 months of treatment, and this new value should be used to assess potentially cancer-related changes in PSA. To interpret an isolated PSA value in a man treated with a dutasteride-containing product, including JALYN, for 6 months or more, the PSA value should be doubled for comparison with normal values in untreated men. Any confirmed increases in PSA levels from nadir while on dutasteride-containing products, including JALYN, may signal the presence of prostate cancer and should be carefully eva luated, even if those values are still within the normal range for men not taking a 5α-reductase inhibitor.

The free-to-total PSA ratio (percent free PSA) remains constant at Month 12, even under the influence of dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving JALYN, no adjustment to its value appears necessary.

Tamsulosin: Treatment with tamsulosin for up to 24 months had no significant effect on PSA.

Priapism (persistent painful penile erection unrelated to sexual activity) has been associated (probably less than 1 in 50,000) with the use of alpha-adrenergic antagonists, including tamsulosin, which is a component of JALYN. Because this condition can lead to permanent impotence if not properly treated, patients must be advised about the seriousness of the condition.

Men being treated with any dutasteride-containing products, including JALYN, should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient.

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-adrenergic antagonists, including tamsulosin, which is a component of JALYN. Most reports were in patients taking the alpha-adrenergic antagonist when IFIS occurred, but in some cases, the alpha-adrenergic antagonist had been stopped prior to surgery. In most of these cases, the alpha-adrenergic antagonist had been stopped recently prior to surgery (2 to 14 days), but in a few cases IFIS was reported after the patient had been taken off the alpha-adrenergic antagonist 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 modification to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or visoelastic substances. The benefit of stopping alpha-adrenergic antagonist therapy prior to cataract surgery has not been established.

In patients with sulfa allergy, allergic reaction to tamsulosin has been rarely reported. If a patient reports a serious or life-threatening sulfa allergy, caution is warranted when administering tamsulosin-containing products, including JALYN.

Dutasteride: The effects of dutasteride 0.5 mg/day on semen characteristics were eva luated in normal volunteers aged 18 to 52 years (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reductions from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all time-points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), 2 subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride’s effect on semen characteristics for an individual patient’s fertility is not known.

Tamsulosin: The effects of tamsulosin hydrochloride on sperm counts or sperm function have not been eva luated.

There have been no clinical trials conducted with JALYN; however, the clinical efficacy and safety of coadministered dutasteride and tamsulosin, which are individual components of JALYN, have been eva luated in a multicenter, randomized, double-blind, parallel group study (the Combination with Alpha-Blocker Therapy, or CombAT, study). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

In the CombAT study, over 4,800 male subjects with BPH were randomly assigned to receive either 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 study. Adverse reaction information over the first 2 years of treatment is presented below; information for years 2 to 4 is not yet available. During the first 2 years, 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% Caucasian. Table 1 presents clinical adverse reactions considered by the investigator to be possibly drug-related for which the incidence was ≥1% in any treatment group.

Cardiac Failure: In CombAT, after 4 years of treatment, the incidence of the composite term cardiac failure in the co-administration group (12/1,610; 0.7%) was higher than in either monotherapy group: AVODART, 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 eva luating AVODART in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking AVODART was 0.6% (26/4,105) compared to 0.4% (15/4,126) in subjects on placebo. A majority of subjects with cardiac failure in both studies had co-morbidities 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 AVODART, alone or co-administered with tamsulosin, and cardiac failure has been established. No imbalance was observed in the incidence of overall cardiovascular adverse events in either study.

Additional information regarding adverse reactions in controlled trials with dutasteride and tamsulosin monotherapy follows:

Dutasteride: There is no evidence of increased sexual adverse reactions (impotence, decreased libido, and ejaculation disorders) or breast disorders with increased duration of dutasteride monotherapy (up to 4 years). The relationship between long-term use of dutasteride and male breast neoplasia is currently unknown.

Tamsulosin: According to the tamsulosin prescribing information, in two 13-week treatment trials with tamsulosin monotherapy, treatment-emergent adverse reactions occurring in ≥2% of subjects receiving 0.4 mg tamsulosin hydrochloride and at an incidence higher than in subjects receiving placebo were: infection, asthenia, back pain, chest pain, somnolence, insomnia, rhinitis, pharyngitis, cough increased, sinusitis, and diarrhea.

Signs and Symptoms of Orthostasis: According to the tamsulosin prescribing information, in clinical studies with tamsulosin monotherapy, a positive orthostatic test result was observed in 16% (81/502) of subjects receiving 0.4 mg tamsulosin hydrochloride vs. 11% (54/493) of subjects receiving placebo. Because orthostasis was detected more frequently in the tamsulosin-treated subjects than in placebo recipients, there is a potential risk of syncope [see Warnings and Precaution (5.1)].

The following adverse reactions have been identified during post-approval use of the individual components of JALYN. 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. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to drug exposure.

Dutasteride:

Immune System Disorders: Hypersensitivity reactions, including rash, pruritus, urticaria, localized edema, serious skin reactions, and angioedema.

Tamsulosin:

Immune System Disorders: Hypersensitivity reactions, including rash, urticaria, pruritus, angioedema, and respiratory problems.

Cardiac Disorders: Palpitations.

Skin Disorders: Skin desquamation.

Gastrointestinal Disorders: Constipation, vomiting.

Reproductive System and Breast Disorders: Priapism.

Vascular Disorders: Hypotension.

Ophthalmologic Disorders: During cataract surgery, a variant of small pupil syndrome known as Intraoperative floppy iris syndrome (IFIS) associated with alpha-adrenergic antagonist therapy [see Warnings and Precautions (5.8)].

There have been no drug interaction studies using JALYN. The following sections reflect information available for the individual components.

Dutasteride: Dutasteride is extensively metabolized in humans by the CYP3A4 and CYP3A5 isoenzymes. The effect of strong CYP3A4 inhibitors on dutasteride has not been studied [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 C and AUC of tamsulosin by factors of 2.2 and 2.8, respectively [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)] . The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of tamsulosin have not been eva luated [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)]. Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in increases in the C and AUC of tamsulosin by factors of 1.3 and 1.6, respectively [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)]. 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) [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)]. The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of tamsulosin have not been eva luated [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)]. The effects of coadministration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin have not been eva luated. 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 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), Clinical Pharmacology (12.3)].

Tamsulosin-containing products, including JALYN, should not be used in combination with other alpha-adrenergic antagonists. The pharmacokinetic and pharmacodynamic interactions between tamsulosin and other alpha-adrenergic antagonists have not been determined. However, interactions may be expected [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

Caution is advised when alpha-adrenergic antagonists, including tamsulosin-containing products such as JALYN, 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 [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

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 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-containing products, including JALYN [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

Tamsulosin: Dosage adjustments are not necessary when tamsulosin is administered concomitantly with nifedipine, atenolol, or enalapril [see Clinical Pharmacology (12.3)].

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)].

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 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)].

Dutasteride: Coadministration of verapamil or diltiazem decreases dutasteride clearance and leads to increased exposure to dutasteride. However, the change in dutasteride exposure is not considered to be clinically significant. No dosage adjustment of dutasteride is recommended [see Clinical Pharmacology (12.3)].

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)].

Pregnancy Category X [see Contraindications (4)]. There are no adequate and well-controlled studies in pregnant women with JALYN or its individual components.

Dutasteride: Dutasteride is contraindicated for use in women of childbearing potential and during pregnancy. Dutasteride is a 5α-reductase inhibitor that prevents conversion of testosterone to dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. In animal reproduction and developmental toxicity studies, dutasteride inhibited normal development of external genitalia in male fetuses. Therefore, dutasteride may cause fetal harm when administered to a pregnant woman. If dutasteride is used during pregnancy or if the patient becomes pregnant while taking dutasteride, the patient should be apprised of the potential hazard to the fetus.

Abnormalities in the genitalia of male fetuses is an expected physiological consequence of inhibition of the conversion of testosterone to DHT by 5α-reductase inhibitors. These results are similar to observations in male infants with genetic 5α-reductase deficiency. Dutasteride is absorbed through the skin. To avoid potential fetal exposure, women who are pregnant or may become pregnant should not handle dutasteride-containing capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water. Dutasteride is secreted into male semen. The highest measured semen concentration of dutasteride in treated men was 14 ng/mL. Assuming exposure of a 50-kg woman to 5 mL of semen and 100% absorption, the woman’s dutasteride concentration would be about 0.175 ng/mL. This concentration is more than 100 times less than 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 [see Warnings and Precautions (5.3)].

In an embryo-fetal development study in female rats, oral administration of dutasteride at doses 10 times less than the maximum recommended human dose (MRHD) of 0.5 mg daily resulted in abnormalities of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day), and nipple development, hypospadias, and distended preputial glands in male offspring (at all doses of 0.05, 2.5, 12.5, and 30 mg/kg/day). An increase in stillborn pups was observed at 111 times the MRHD, and reduced fetal body weight was observed at doses of about 15 times the MRHD (animal dose of 2.5 mg/kg/day). Increased incidences of skeletal variations considered to be delays in ossification associated with reduced body weight were observed at doses at about 56 times the MRHD (animal dose of 12.5 mg/kg/day).

In a rabbit embryo-fetal study, doses 28- to 93-fold the MRHD (animal doses of 30, 100, and 200 mg/kg/day) were administered orally during the period of major organogenesis (gestation days 7 to 29) to encompass the late period of external genitalia development. Histological eva luation of the genital papilla of fetuses revealed evidence of feminization of the male fetus at all doses. A second embryo-fetal study in rabbits at 0.3- to 53-fold the expected clinical exposure (animal doses of 0.05, 0.4, 3.0, and 30 mg/kg/day) also produced evidence of feminization of the genitalia in male fetuses at all doses.

In an oral pre- and post-natal development study in rats, dutasteride doses of 0.05, 2.5, 12.5, or 30 mg/kg/day were administered. Unequivocal evidence of feminization of the genitalia (i.e., decreased anogenital distance, increased incidence of hypospadias, nipple development) of male offspring occurred at 14- to 90-fold the MRHD (animal doses of 2.5 mg/kg/day or greater). At 0.05-fold the expected clinical exposure (animal dose of 0.05 mg/kg/day), evidence of feminization was limited to a small, but statistically significant, decrease in anogenital distance. Animal doses of 2.5 to 30 mg/kg/day resulted in prolonged gestation in the parental females and a decrease in time to vaginal patency for female offspring and a decrease in prostate and seminal vesicle weights in male offspring. Effects on newborn startle response were noted at doses greater than or equal to 12.5 mg/kg/day. Increased stillbirths were noted at 30 mg/kg/day.

In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously to a dutasteride blood level comparable to the dutasteride concentration found in human semen. Dutasteride was administered on gestation days 20 to 100 at doses of 400, 780, 1,325, or 2,010 ng/day (12 monkeys/group). The development of male external genitalia of monkey offspring was not adversely affected. 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 in monkeys. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses represent 0.8 to 16 times based on blood levels of parent drug (32 to 186 times based on a ng/kg daily dose) the potential maximum exposure of a 50-kg human female to 5 mL semen daily from a dutasteride-treated man, assuming 100% absorption. Dutasteride is highly bound to proteins in human semen (greater than 96%), potentially reducing the amount of dutasteride available for vaginal absorption. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites.

Estimates of exposure multiples comparing animal studies to the MRHD for dutasteride are based on clinical serum concentration at steady state.

Tamsulosin: Administration of tamsulosin to pregnant female rats at dose levels up to approximately 50 times the human therapeutic AUC exposure (animal dose of 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. However, because of the effect of dutasteride on the fetus, JALYN is contraindicated for use in pregnant women. Estimates of exposure multiples comparing animal studies to the MRHD for tamsulosin are based on AUC.

JALYN is contraindicated for use in women of childbearing potential, including nursing women. It is not known whether dutasteride or tamsulosin is excreted in human milk.

JALYN is contraindicated for use in pediatric patients. Safety and effectiveness of JALYN in pediatric patients have not been established.

Of 1,610 male subjects treated with coadministered dutasteride and tamsulosin in the CombAT trial, 58% of enrolled subjects were 65 years of age and over and 13% of enrolled subjects were 75 years of age and over. No overall differences in safety or efficacy were observed between these subjects and younger subjects [see Clinical Pharmacology (12.3)].

The effect of renal impairment on dutasteride and tamsulosin pharmacokinetics has not been studied using JALYN. Because no dosage adjustment is necessary for dutasteride or tamsulosin in patients with moderate-to-severe renal impairment (10≤ CL <30 mL/min/1.73 m), no dosage adjustment is necessary for JALYN in patients with moderate-to-severe renal impairment. However, patients with end-stage renal disease (CL<10 mL/min/1.73 m) have not been studied [see Clinical Pharmacology (12.3)].

The effect of hepatic impairment on dutasteride and tamsulosin pharmacokinetics has not been studied using JALYN. The following text reflects information available for the individual components.

Dutasteride: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. However, in a clinical study where 60 subjects received 5 mg (10 times the therapeutic dose) daily for 24 weeks, no additional adverse events were observed compared with those observed at the therapeutic dose of 0.5 mg [see Clinical Pharmacology (12.3)].

Tamsulosin: Patients with moderate hepatic impairment do not require an adjustment in tamsulosin dosage. Tamsulosin has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

No data are available with regard to overdosage with JALYN. The following text reflects information available for the individual components.

Dutasteride: In volunteer studies, 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 study, 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.

JALYN (dutasteride and tamsulosin hydrochloride) Capsules contain dutasteride (a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5α-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone (DHT) and tamsulosin (an antagonist of alpha-adrenoceptors in the prostate). Each JALYN Capsule contains the following:

The above components are encapsulated in a hard-shell capsule made with the inactive ingredients of carrageenan, FD&C yellow 6, hypromellose, iron oxide red, potassium chloride, titanium dioxide, and imprinted with “GS 7CZ” in black ink.

Dutasteride: Dutasteride 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 empirical formula of dutasteride is CHFNO, representing a molecular weight of 528.5 with the following structural formula:

Dutasteride is a white to pale yellow powder with a melting point of 242° to 250°C. It is soluble in ethanol (44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it is insoluble in water.

Tamsulosin: Tamsulosin hydrochloride is a synthetic compound chemically designated as (-)-(R)-5-[2-[[2-(o-Ethoxyphenoxy) ethyl]amino]propyl]-2-methoxybenzenesulfonamide, monohydrochloride.

The empirical formula of tamsulosin hydrochloride is CHNOS•HCl. The molecular weight of tamsulosin hydrochloride is 444.97. Its structural formula is:

Tamsulosin hydrochloride is a white or almost white crystalline powder that melts with decomposition at approximately 234°C. It is sparingly soluble in water and slightly soluble in methanol, ethanol, acetone, and ethyl acetate.

JALYN is a combination of 2 drugs with different mechanisms of action to improve symptoms in patients with BPH: dutasteride, a 5α-reductase inhibitor (5 ARI), and tamsulosin, an antagonist of alpha-adrenoreceptors.

Dutasteride: Dutasteride inhibits the conversion of testosterone to dihydrotestosterone (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 5α-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 5α-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been eva luated 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 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 3 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 is not intended for use as an antihypertensive.

Dutasteride: Effect on 5α-Dihydrotestosterone and Testosterone: The maximum effect of daily doses of dutasteride on the reduction of DHT is dose-dependent and is observed within 1 to 2 weeks. After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. In patients with BPH treated with dutasteride 0.5 mg/day for 4 years, the median decrease in serum DHT was 94% at 1 year, 93% at 2 years, and 95% at both 3 and 4 years. The median increase in serum testosterone was 19% at both 1 and 2 years, 26% at 3 years, and 22% at 4 years, but the mean and median levels remained within the physiologic range.

In patients with BPH treated with 5 mg/day of dutasteride or placebo for up to 12 weeks prior to transurethral resection of the prostate, mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group compared with placebo (784 and 5,793 pg/g, respectively, P<0.001). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group compared with placebo (2,073 and 93 pg/g, respectively, P<0.001).

Adult males with genetically inherited type 2 5α-reductase deficiency also have decreased DHT levels. These 5α-reductase deficient males have a small prostate gland throughout life and do not develop BPH. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5α-reductase deficiency have been observed in these individuals.

Effects on Other Hormones: In healthy volunteers, 52 weeks of treatment with dutasteride 0.5 mg/day (n = 26) resulted in no clinically significant change compared with placebo (n = 23) in sex hormone-binding globulin, estradiol, luteinizing hormone, follicle-stimulating hormone, thyroxine (free T4), and dehydroepiandrosterone. Statistically significant, baseline-adjusted mean increases compared with placebo were observed for total testosterone at 8 weeks (97.1 ng/dL, P<0.003) and thyroid-stimulating hormone at 52 weeks (0.4 mcIU/mL, P<0.05). The median percentage changes from baseline within the dutasteride group were 17.9% for testosterone at 8 weeks and 12.4% for thyroid-stimulating hormone at 52 weeks. After stopping dutasteride for 24 weeks, the mean levels of testosterone and thyroid-stimulating hormone had returned to baseline in the group of subjects with available data at the visit. In patients with BPH treated with dutasteride in a large randomized, double-blind, placebo-controlled study, there was a median percent increase in luteinizing hormone of 12% at 6 months and 19% at both 12 and 24 months.

Other Effects: Plasma lipid panel and bone mineral density were eva luated following 52 weeks of dutasteride 0.5 mg once daily in healthy volunteers. There was no change in bone mineral density as measured by dual energy x-ray absorptiometry compared with either placebo or baseline. In addition, the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins, and triglycerides) was unaffected by dutasteride. No clinically significant changes in adrenal hormone responses to ACTH stimulation were observed in a subset population (n = 13) of the 1-year healthy volunteer study.

The pharmacokinetics of dutasteride and tamsulosin from JALYN are comparable to the pharmacokinetics of dutasteride and tamsulosin when administered separately.

Absorption: The pharmacokinetic parameters of dutasteride and tamsulosin observed after administration of JALYN in a single dose, randomized, 3-period partial cross-over study are summarized in Table 2 below.

Dutasteride: Following administration of a single 0.5-mg dose of a soft gelatin capsule, time to peak absolute bioavailability in 5 healthy subjects is approximately 60% (range: 40% to 94%).

Tamsulosin: Absorption of tamsulosin is essentially complete (>90%) following oral administration of 0.4-mg tamsulosin hydrochloride capsules under fasting conditions. Tamsulosin exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-daily dosing.

Effect of Food: Food does not affect the pharmacokinetics of dutasteride following administration of JALYN. However, a mean 30% decrease in tamsulosin Cwas observed when JALYN was administered with food, similar to that seen when tamsulosin monotherapy was administered under fed versus fasting conditions.

Distribution: Dutasteride: Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid glycoprotein (96.6%).

In a study of healthy subjects (n = 26) receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at 6 months. On average, at 12 months 11.5% of serum dutasteride concentrations partitioned into semen.

Tamsulosin: The mean steady-state apparent volume of distribution of tamsulosin after intravenous administration to 10 healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body.

Tamsulosin is extensively bound to human plasma proteins (94% to 99%), primarily alpha-1 acid glycoprotein (AAG), with linear binding over a wide concentration range (20 to 600 ng/mL). The results of 2-way in vitro studies indicate that the binding of tamsulosin to human plasma proteins is not affected by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-hydroxy acid metabolite, warfarin, diazepam, or propranolol. Likewise, tamsulosin had no effect on the extent of binding of these drugs.

Metabolism: Dutasteride: Dutasteride is extensively metabolized in humans. In vitro studies showed that dutasteride is metabolized by the CYP3A4 and CYP3A5 isoenzymes. Both of these isoenzymes produced the 4′-hydroxydutasteride, 6-hydroxydutasteride, and the 6,4′-dihydroxydutasteride metabolites. In addition, the 15-hydroxydutasteride metabolite was formed by CYP3A4. Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In human serum following dosing to steady state, unchanged dutasteride, 3 major metabolites (4′-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and 2 minor metabolites (6,4′-dihydroxydutasteride and 15-hydroxydutasteride), as assessed by mass spectrometric response, have been detected. The absolute stereochemistry of the hydroxyl additions in the 6 and 15 positions is not known. In vitro, the 4′-hydroxydutasteride and 1,2-dihydrodutasteride metabolites are much less potent than dutasteride against both isoforms of human 5α-reductase. The activity of 6β-hydroxydutasteride is comparable to that of dutasteride.

Tamsulosin: There is no enantiomeric bioconversion from tamsulosin [R(-) isomer] to the S(+) isomer in humans. Tamsulosin 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. In vitro studies indicate that CYP3A4 and CYP2D6 are involved in metabolism of tamsulosin as well as some minor participation of other CYP isoenzymes. Inhibition of hepatic drug metabolizing enzymes may lead to increased exposure to tamsulosin [see Drug Interactions (7.2)]. The metabolites of tamsulosin 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 and amitriptyline, albuterol, glyburide, and finasteride. However, results of the in vitro testing of the tamsulosin interaction with diclofenac and warfarin were equivocal.

Excretion: Dutasteride: Dutasteride and its metabolites were excreted mainly in feces. As a percent of dose, there was approximately 5% unchanged dutasteride (approximately 1% to approximately 15%) and 40% as dutasteride-related metabolites (~2% to ~90%). Only trace amounts of unchanged dutasteride were found in urine (<1%). Therefore, on average, the dose unaccounted for approximated 55% (range: 5% to 97%). The terminal elimination half-life of dutasteride is approximately 5 weeks at steady state. The average steady-state serum dutasteride concentration was 40 ng/mL following 0.5 mg/day for 1 year. Following daily dosing, dutasteride serum concentrations achieve 65% of steady-state concentration after 1 month and approximately 90% after 3 months. Due to the long half-life of dutasteride, serum concentrations remain detectable (greater than 0.1 ng/mL) for up to 4 to 6 months after discontinuation of treatment.

Tamsulosin: On administration of the radiolabeled dose of tamsulosin to 4 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 in plasma ranges from 5 to 7 hours. Because of absorption rate-controlled pharmacokinetics with tamsulosin hydrochloride capsules, the apparent half-life of tamsulosin is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population.

Tamsulosin undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/hr).

Specific Populations: Pediatric Patients: The pharmacokinetics of dutasteride and tamsulosin administered together have not been investigated in subjects younger than 18 years.

Geriatric Patients: Dutasteride and tamsulosin pharmacokinetics using JALYN have not been studied in geriatric patients. The following text reflects information for the individual components.

Dutasteride: No dosage adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were eva luated in 36 healthy male subjects aged between 24 and 87 years following administration of a single 5-mg dose of dutasteride. In this single-dose study, dutasteride half-life increased with age (approximately 170 hours in men aged 20 to 49 years, approximately 260 hours in men aged 50 to 69 years, and approximately 300 hours in men older than 70 years).

Tamsulosin: Cross-study comparison of tamsulosin overall exposure (AUC) and half-life indicate that the pharmacokinetic disposition of tamsulosin may be slightly prolonged in geriatric males compared to young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin binding to AAG, but diminishes with age, resulting in a 40% overall higher exposure (AUC) in subjects aged 55 to 75 years compared to subjects aged 20 to 32 years.

Gender: Dutasteride: Dutasteride is contraindicated in pregnancy and women of childbearing potential and is not indicated for use in other women [see Contraindications (4), Warnings and Precautions (5.3)]. The pharmacokinetics of dutasteride in women have not been studied.

Tamsulosin: Tamsulosin is not indicated for use in women. No information is available on the pharmacokinetics of tamsulosin in women.

Race: The effect of race on pharmacokinetics of dutasteride and tamsulosin administered together or separately has not been studied.

Renal Impairment: The effect of renal impairment on dutasteride and tamsulosin pharmacokinetics has not been studied using JALYN. The following text reflects information for the individual components.

Dutasteride: The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5-mg dose of dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment.

Tamsulosin: The pharmacokinetics of tamsulosin 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

Manufacturer

GlaxoSmithKline LLC

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
•  Last Updated: 2nd of March 2011