Jalyn

Benign Prostatic Hyperplasia (BPH) Treatment

JALYN (dutasteride and tamsulosin hydrochloride) capsules are indicated for the treatment of symptomatic BPH in men with an enlarged prostate.

Limitations of Use

Dutasteride-containing products, including JALYN, are not approved for the prevention of prostate cancer.

Pregnancy

Risk Summary

JALYN is contraindicated for use in pregnancy because it may cause harm to the male fetus [see Contraindications ]. JALYN is not indicated for use in females.

Dutasteride, a component of JALYN, 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 ].

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. Decreased anogenital distance was observed at 0.05 times the MRHD and greater (0.05 mg/kg/day and greater), with a lack of a no-effect level, based on average blood levels in men as an estimation of AUC. Hypospadias and nipple development were observed at 2.5 mg/kg/day or greater (14 times the MRHD or greater, with a no-effect level at 0.05 mg/kg/day). Doses of 2.5 mg/kg/day and greater also resulted in prolonged gestation in the parental females, an increase in time to balano-preputial separation in male offspring, a decrease in time to vaginal patency for female offspring, and a decrease in prostate and seminal vesicle weights in male offspring. Increased stillbirths and decreased neonatal viability in offspring were noted at 30 mg/kg/day (102 times the MRHD in the presence of maternal toxicity [decreased body weights]).

         Tamsulosin: Administration of tamsulosin hydrochloride to pregnant female rats during the period of organogenesis (Gestation Days 7 to 17) at dose levels up to approximately 50 times the human therapeutic AUC exposure (300 mg/kg/day) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits during the period of organogenesis (Gestation Days 6 to 18) at dose levels up to 50 mg/kg/day produced no evidence of fetal harm.

Lactation

Risk Summary

JALYN is not indicated for use in females.

Females and Males of Reproductive Potential

Infertility

Dutasteride:Males: The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated 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 timepoints 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 these effects on semen characteristics for an individual patient’s fertility is not known [see Warnings and Precautions ].

Tamsulosin:Males: Abnormal ejaculation including ejaculation failure, ejaculation disorder, retrograde ejaculation, and decreased ejaculation has been associated with tamsulosin hydrochloride. Studies in rats revealed significantly reduced fertility in males, considered to be due to impairment of ejaculation, which was reversible [see Nonclinical Toxicology ].

Pediatric Use

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

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 ].

Renal Impairment

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≤ CLcr <30 mL/min/1.73 m2), no dosage adjustment is necessary for JALYN in patients with moderate-to-severe renal impairment. However, patients with end-stage renal disease (CLcr<10 mL/min/1.73 m2) have not been studied [see Clinical Pharmacology ].

Hepatic Impairment

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 trial 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 ].

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 ].

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 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 ].

Drug-Drug Interactions

Strong Inhibitors of Cytochrome P450 (CYP) 3A4

Tamsulosin-containing products, including JALYN, should not be coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole) as this can significantly increase tamsulosin exposure [see Drug Interactions , Clinical Pharmacology ].

Moderate Inhibitors of CYP3A4, Inhibitors of CYP2D6, or a Combination of Both CYP3A4 and CYP2D6 Inhibitors

Tamsulosin-containing products, including JALYN, 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 , Clinical Pharmacology ].

Cimetidine

Caution is advised when tamsulosin-containing products, including JALYN, are coadministered with cimetidine [see Drug Interactions , Clinical Pharmacology ].

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.

Phosphodiesterase-5 (PDE-5) Inhibitors

Caution is advised when alpha-adrenergic–antagonist-containing products, including 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.

Warfarin

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

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 JALYN, 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 JALYN, a new baseline PSA should be established at least 3 months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on a dutasteride-containing treatment, including JALYN, may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5-alpha-reductase inhibitor. Noncompliance with JALYN may also affect PSA test results.

To interpret an isolated PSA value in a man treated with JALYN, for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men.

The free-to-total PSA ratio (percent free PSA) remains constant, 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.

Increased Risk of High-Grade Prostate Cancer

In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL taking dutasteride in the 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, there was an increased incidence of Gleason score 8 to 10 prostate cancer compared with men taking placebo (dutasteride 1.0% versus placebo 0.5%) [see Indications and Usage , Adverse Reactions ]. In a 7-year placebo-controlled clinical trial with another 5-alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8 to 10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).

5-alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5-alpha-reductase inhibitors to reduce prostate volume or trial-related factors impacted the results of these trials has not been established.

Evaluation for Other Urological Diseases

Prior to initiating treatment with JALYN, consideration should be given to other urological conditions that may cause similar symptoms. In addition, BPH and prostate cancer may coexist.

Transdermal Exposure of JALYN in Pregnant Females—Risk to Male Fetus

JALYN capsules should not be handled by females who are pregnant or may be pregnant. Dutasteride can be absorbed through the skin and could result in unintended fetal exposure and potential risk to a male fetus. If a female who is or may be pregnant comes in contact with a leaking capsule, the contact area should be washed immediately with soap and water [see Use in Specific Populations ]. Dutasteride can be absorbed through the skin based on animal studies [see Nonclinical Toxicology ].

Priapism

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 should be advised about the seriousness of the condition.

Blood Donation

Men being treated with a dutasteride-containing product, 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

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract and glaucoma surgery in some patients on or previously 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 patients had been 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 modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances.

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

Sulfa Allergy

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.

Effect on Semen Characteristics

Dutasteride

The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in healthy men throughout 52 weeks of treatment and 24 weeks of post‑treatment follow‑up. At 52 weeks, compared with placebo, dutasteride treatment resulted in mean reduction in total sperm count, semen volume, and sperm motility; the effects on total sperm count were not reversible after 24 weeks of follow-up. Sperm concentration and sperm morphology were unaffected and mean values for all semen parameters remained within the normal range at all timepoints. The clinical significance of the effect of dutasteride on semen characteristics for an individual patient’s fertility is not known [see Use in Specific Populations ].

Tamsulosin

The effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated.