Jalyn Information
Jalyn () Dosage And Administration
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 () Dosage Forms And Strengths
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 () Contraindications
Jalyn () is contraindicated for use in:
Jalyn () Warnings And Precautions
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, or in patients known to be poor metabolizers of CYP2D6, as there is a potential for significant increase in tamsulosin exposure .
Other Alpha Adrenergic Antagonists:
Phosphodiesterase-5 Inhibitors (PDE-5 Inhibitors):
Coadministration of dutasteride with tamsulosin resulted in similar changes to serum PSA as with dutasteride monotherapy.
In clinical studies, 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.
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 8-10 prostate cancer compared with men taking placebo (dutasteride 1.0% versus placebo 0.5%) . In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8-10 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 study-related factors, impacted the results of these studies has not been established.
Dutasteride:
Tamsulosin:
Jalyn () Adverse Reactions
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 evaluated 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 with 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 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. 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 Caucasian. Table 1 summarizes adverse reactions reported in at least 1% of subjects receiving coadminstration therapy and at a higher incidence than subjects receiving either dutasteride or tamsulosin as monotherapy.
a
b
c
d
e
Cardiac Failure:
Additional information regarding adverse reactions in placebo-controlled trials with dutasteride or tamsulosin monotherapy follows:
Dutasteride:
No clinical benefit has been demonstrated in patients with prostate cancer treated with dutasteride.
In the 3 pivotal placebo-controlled BPH trials with dutasteride, each 4 years in duration, there was no evidence of increased sexual adverse reactions (impotence, decreased libido, and ejaculation disorder) or breast disorders with increased duration of treatment. Among these 3 trials, there was 1 case of breast cancer in the dutasteride group and 1 case in the placebo group. No cases of breast cancer were reported in any treatment group in the 4-year CombAT trial or the 4-year REDUCE trial.
The relationship between long-term use of dutasteride and male breast neoplasia is currently unknown.
Tamsulosin:
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:
Neoplasms:
Tamsulosin:
Immune System Disorders:
Cardiac Disorders:
Skin Disorders:
Gastrointestinal Disorders:
Reproductive System and Breast Disorders:
Vascular Disorders:
Jalyn () Drug Interactions
There have been no drug interaction studies using Jalyn () . The following sections reflect information available for the individual components.
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. 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. 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 .
Tamsulosin:
[see Clinical Pharmacology (12.3)]
Tamsulosin:
[see Clinical Pharmacology (12.3)]
max
Dutasteride:
[see Clinical Pharmacology (12.3)]
Dutasteride:
[see Clinical Pharmacology (12.3)]
Jalyn () Use In Specific Populations
Pregnancy Category X. There are no adequate and well-controlled studies in pregnant women with Jalyn () or its individual components.
Dutasteride:
Abnormalities in the genitalia of male fetuses is an expected physiological consequence of inhibition of the conversion of testosterone to DHT by 5 alpha-reductase inhibitors. These results are similar to observations in male infants with genetic 5 alpha-reductase deficiency. Dutasteride is absorbed through the skin. To avoid potential fetal exposure, women who are pregnant or could become pregnant should not handle dutasteride-containing capsules, including Jalyn () Capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water Dutasteride is secreted into 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 0.0175 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.
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), 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 evaluation 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 the potential maximum exposure of a 50-kg human female to 5 mL semen daily from a dutasteride-treated man, assuming 100% absorption. (These calculations are based on blood levels of parent drug which are achieved at 32 to 186 times the daily doses administered to pregnant monkeys on a ng/kg basis). 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:
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.
Jalyn () Overdosage
No data are available with regard to overdosage with Jalyn () . The following text reflects information available for the individual components.
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.
Jalyn () Description
Jalyn () (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 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 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.
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 () Clinical Pharmacology
Jalyn () is 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 alpha-adrenoreceptors.
Dutasteride:
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:
1
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.
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,
Adult males with genetically inherited type 2 5 alpha-reductase deficiency also have decreased DHT levels. These 5 alpha-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 5 alpha-reductase deficiency have been observed in these individuals.
Other Effects:
The pharmacokinetics of dutasteride and tamsulosin from Jalyn () are comparable to the pharmacokinetics of dutasteride and tamsulosin when administered separately.
Absorption:
Dutasteride:
Tamsulosin:
Effect of Food:
max
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:
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.
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.
Tamsulosin:
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).
Geriatric:
Dutasteride:
Tamsulosin:
Tamsulosin:
Dutasteride:
Tamsulosin:
Hepatic Impairment:
Dutasteride:
Tamsulosin:
Drug Interactions:
Dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1,000 ng/mL, 25 times greater than steady-state serum concentrations in humans.
max
The effects of paroxetine (a strong inhibitor of CYP2D6) at 20 mg once daily for 9 days on the pharmacokinetics of a single tamsulosin capsule 0.4 mg dose was investigated in 24 healthy volunteers (age range: 23 to 47 years). Concomitant treatment with paroxetine resulted in increases in the C 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). A fraction of the population (about 7% of Caucasians and 2% of African-Americans) are CYP2D6 PMs. 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 concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of tamsulosin have not been evaluated.
The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin capsules 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.
Cimetidine:
Warfarin: Dutasteride:
Tamsulosin:
Tamsulosin:
max
Jalyn () Nonclinical Toxicology
No non-clinical studies have been conducted with Jalyn () . The following information is based on studies performed with dutasteride or tamsulosin.
Carcinogenesis:
Dutasteride:
In a 2-year carcinogenicity study in Han Wistar rats, at doses of 1.5, 7.5, and 53 mg/kg/day in males and 0.8, 6.3, and 15 mg/kg/day in females, there was an increase in Leydig cell adenomas in the testes at 135-fold the MRHD (53 mg/kg/day and greater). An increased incidence of Leydig cell hyperplasia was present at 52-fold the MRHD (male rat doses of 7.5 mg/kg/day and greater). A positive correlation between proliferative changes in the Leydig cells and an increase in circulating luteinizing hormone levels has been demonstrated with 5 alpha-reductase inhibitors and is consistent with an effect on the hypothalamic-pituitary-testicular axis following 5 alpha-reductase inhibition. At tumorigenic doses, luteinizing hormone levels in rats were increased by 167%. In this study, the major human metabolites were tested for carcinogenicity at approximately 1 to 3 times the expected clinical exposure.
Tamsulosin:
In a carcinogenicity assay, mice were administered up to 8 times the MRHD of tamsulosin (oral doses up to 127 mg/kg/day in males and 158 mg/kg/day in females). There were no significant tumor findings in male mice. Female mice treated for 2 years with the 2 highest doses of 45 and 158 mg/kg/day had statistically significant increases in the incidence of mammary gland fibroadenomas (
The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin-induced hyperprolactinemia. It is not known if tamsulosin elevates prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known.
Mutagenesis:
Dutasteride:
Tamsulosin:
Impairment of Fertility:
Dutasteride:
In a fertility study in female rats, oral administration of dutasteride at doses of 0.05, 2.5, 12.5, and 30 mg/kg/day resulted in reduced litter size, increased embryo resorption and feminization of male fetuses (decreased anogenital distance) at 2- to 10-fold the MRHD (animal doses of 2.5 mg/kg/day or greater). Fetal body weights were also reduced at less than 0.02-fold the MRHD in rats (0.5 mg/kg/day).
Tamsulosin:
Studies in female rats revealed significant reductions in fertility after single or multiple dosing with 300 mg/kg/day of the R-isomer or racemic mixture of tamsulosin hydrochloride, respectively. In female rats, the reductions in fertility after single doses were considered to be associated with impairments in fertilization. Multiple dosing with 10 or 100 mg/kg/day of the racemic mixture did not significantly alter fertility in female rats.
Estimates of exposure multiples comparing animal studies to the MRHD for dutasteride are based on clinical serum concentration at steady state.
Estimates of exposure multiples comparing animal studies to the MRHD for tamsulosin are based on AUC.
Central Nervous System Toxicology Studies:
Dutasteride:
Jalyn () Clinical Studies
The trial supporting the efficacy of Jalyn () was a 4-year multicenter, randomized, double-blind, parallel-group study (CombAT study) investigating the efficacy of the coadministration of dutasteride 0.5 mg/day and tamsulosin hydrochloride 0.4 mg/day (n = 1,610) compared with dutasteride alone (n = 1,623) or tamsulosin alone (n = 1,611). Subjects were at least 50 years of age with a serum PSA ≥1.5 ng/mL and
The additional improvement in Q of coadministration therapy over dutasteride monotherapy was no longer statistically significant at Month 48.
Jalyn () How Supplied/storage And Handling
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. They are available in bottles with child-resistant closures as follows:
Bottle of 30 (NDC 0173-0809-13).
Bottle of 90 (NDC 0173-0809-59).
Store at 25°C (77°F); excursions permitted 15° to 30°C (59° to 86°F). [see USP Controlled Room Temperature]. Capsules may become deformed and/or discolored if kept at high temperatures.
Dutasteride is absorbed through the skin. Jalyn () Capsules should not be handled by women 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 .
Jalyn () Patient Counseling Information
See FDA-approved patient labeling (Patient Information)
Physicians should advise patients considering cataract surgery to tell their ophthalmologist that they take or have taken Jalyn () , an alpha adrenergic antagonist-containing product.
Jalyn () and AVODART are trademarks of GlaxoSmithKline.
The other brands listed are trademarks of their respective owners and are not trademarks of GlaxoSmithKline. The makers of these brands are not affiliated with and do not endorse GlaxoSmithKline or its products.
Jointly Manufactured by
Catalent Pharma Solutions
F-67930 Beinheim, France
D-73614 Schorndorf, Germany
and
Rottendorf Pharma GmbH
D-59320 Ennigerloh, Germany
Distributed byGlaxoSmithKlineResearch Triangle Park, NC 27709
©2011, GlaxoSmithKline. All rights reserved.
2011JLN:PI
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Jalyn ()
Jalyn ()
