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英文药名：JALYN (dutasteride and tamsulosin hydrochloride)Capsules 中文药名：度他雄胺/盐酸坦洛新复方胶囊 生产厂家：葛兰素史克 1 INDICATIONS AND USAGE 1.1 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. 1.2 Limitations of Use Dutasteride-containing products, including JALYN, are not approved for the prevention of prostate cancer. 2 DOSAGE AND ADMINISTRATION The recommended dosage of JALYN is 1capsule (0.5mg dutasteride and 0.4mg tamsulosin hydrochloride) taken once daily approximately 30minutes 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. 3 DOSAGE FORMS AND STRENGTHS JALYN Capsules, containing 0.5mg dutasteride and 0.4mg tamsulosin hydrochloride, are oblong, hard-shell capsules with a brown body and an orange cap imprinted with “GS7CZ” in black ink. 4 CONTRAINDICATIONS JALYN is contraindicated for use in:
5 WARNINGS AND PRECAUTIONS 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 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)]. 5.2 Drug-Drug Interactions Strong Inhibitors of CYP3A4: 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 (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), 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. 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 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 (7.4), 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 studies, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6months 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 3months 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 eva luated, 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 3months 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. 5.4 Increased Risk of High-grade Prostate Cancer In men aged 50 to 75years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5ng/mL and 10.0ng/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%) [see Indications and Usage (1.2), Adverse Reactions (6.1)]. 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. 5.5 eva luation for Other Urological Diseases 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. 5.6 Exposure of Women—Risk to Male Fetus JALYN Capsules should not be handled by a woman who is pregnant or who could become pregnant. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a woman who is pregnant or could 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)]. 5.7 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. 5.8 Blood Donation Men being treated with a dutasteride-containing product, including JALYN, should not donate blood until at least 6months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient. 5.9 Intraoperative Floppy Iris Syndrome 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 (2days to 9months). Advise patients considering cataract surgery to tell their ophthalmologist that they take or have taken JALYN Capsules. 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 viscoelastic substances. The benefit of stopping alpha adrenergic antagonist therapy prior to cataract surgery has not been established. 5.10 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. 5.11 Effect on Semen Characteristics Dutasteride: The effects of dutasteride 0.5mg/day on semen characteristics were eva luated in normal volunteers aged 18 to 52 (n=27 dutasteride, n=23 placebo) throughout 52weeks of treatment and 24weeks of post-treatment follow-up. At 52weeks, 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 24weeks 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%), 2subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52weeks, 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. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 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 with rates in the clinical trial of another drug and may not reflect the rates observed in practice.
In the CombAT study, over 4,800male subjects with BPH were randomly assigned to receive 0.5mg dutasteride, 0.4mg tamsulosin hydrochloride, or coadministration therapy (0.5mg dutasteride and 0.4mg tamsulosin hydrochloride) administered once daily in a 4-year double-blind study. Overall, 1,623subjects received monotherapy with dutasteride; 1,611subjects received monotherapy with tamsulosin; and 1,610subjects received coadministration therapy. The population was aged 49 to 88years (mean age: 66years) and 88% were Caucasian. Table1 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 Coadministration = AVODART 0.5mg once daily plus tamsulosin 0.4mg 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 Includes erectile dysfunction and disturbance in sexual arousal. d Includes libido decreased, libido disorder, loss of libido, sexual dysfunction, and male sexual dysfunction. e Includes breast enlargement, gynecomastia, breast swelling, breast pain, breast tenderness, nipple pain, and nipple swelling. Cardiac Failure: In CombAT, after 4years 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 eva luating 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 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 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 study. 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 75years with a serum PSA of 2.5ng/mL to 10ng/mL and a negative prostate biopsy within the previous 6months. Subjects were randomized to receive placebo (N=4,126) or 0.5-mg daily doses of dutasteride (N=4,105) for up to 4years. The mean age was 63years and 91% were Caucasian. Subjects underwent protocol-mandated scheduled prostate biopsies at 2 and 4 years of treatment or had “for-cause biopsies” at non-scheduled times if clinically indicated. There was a higher incidence of Gleason score 8-10 prostate cancer in men receiving dutasteride (1.0%) compared with men on placebo (0.5%) [see Indications and Usage (1.2), Warnings and Precautions (5.4)]. 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%). No clinical benefit has been demonstrated in patients with prostate cancer treated with dutasteride. Reproductive and Breast Disorders: In the 3pivotal placebo-controlled BPH trials with dutasteride, each 4years 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 3trials, there was 1 case of breast cancer in the dutasteride group and 1case 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: According to the tamsulosin prescribing information, in two 13-week treatment trials with tamsulosin monotherapy, adverse reactions occurring in at least 2% of subjects receiving 0.4mg 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 0.4mg 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)]. 6.2 Postmarketing Experience 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. Neoplasms: Male breast cancer. Tamsulosin: Immune System Disorders: Hypersensitivity reactions, including rash, urticaria, pruritus, angioedema, and respiratory problems. Cardiac Disorders: Palpitations, dyspnea, atrial fibrillation, arrhythmia, and tachycardia. Skin Disorders: Skin desquamation, including Stevens-Johnson syndrome. 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 (5.9)]. 7 DRUG INTERACTIONS There have been no drug interaction studies using JALYN. The following sections reflect information available for the individual components. 7.1 Cytochrome P450 3A Inhibitors 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 JALYN, 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 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 Cmax 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 0.4mg is coadministered with strong CYP3A4 inhibitors in CYP2D6 PMs, tamsulosin 0.4mg 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 eva luated. However, there is a potential for significant increase in tamsulosin exposure when tamsulosin 0.4mg 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 0.5mg/day for 3weeks 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)]. 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 0.5mg/day for 3weeks [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 Cmax 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 1hour later by a 12-g dose of cholestyramine does not affect the relative bioavailability of dutasteride [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X. 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 5 alpha-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 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 [see Warnings and Precautions (5.6)]. Dutasteride is secreted into semen. The highest measured semen concentration of dutasteride in treated men was 14ng/mL. Assuming exposure of a 50-kg woman to 5mL of semen and 100% absorption, the woman’s dutasteride concentration would be about 0.0175ng/mL. This concentration is more than 100times 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 10times less than the maximum recommended human dose (MRHD) of 0.5mg daily resulted in abnormalities of male genitalia in the fetus (decreased anogenital distance at 0.05mg/kg/day), nipple development, hypospadias, and distended preputial glands in male offspring (at all doses of 0.05, 2.5, 12.5, and 30mg/kg/day). An increase in stillborn pups was observed at 111times the MRHD, and reduced fetal body weight was observed at doses of about 15times the MRHD (animal dose of 2.5mg/kg/day). Increased incidences of skeletal variations considered to be delays in ossification associated with reduced body weight were observed at doses at about 56times the MRHD (animal dose of 12.5mg/kg/day). In a rabbit embryo-fetal study, doses 28- to 93-fold the MRHD (animal doses of 30, 100, and 200mg/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 30mg/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 30mg/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 2.5mg/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 30mg/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 12.5mg/kg/day. Increased stillbirths were noted at 30mg/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 2,010ng/day (12monkeys/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 (14ng/mL), these doses represent 0.8 to 16times the potential maximum exposure of a 50-kg human female to 5mL 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 186times 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: Administration of tamsulosin to pregnant female rats at dose levels up to approximately 50times the human therapeutic AUC exposure (animal dose of 300mg/kg/day) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits at dose levels up to 50mg/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. 8.3 Nursing Mothers 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. 8.4 Pediatric Use JALYN is contraindicated for use in pediatric patients. Safety and effectiveness of JALYN in pediatric patients have not been established. 8.5 Geriatric Use Of 1,610male subjects treated with coadministered dutasteride and tamsulosin in the CombAT trial, 58% of enrolled subjects were aged 65years and older and 13% of enrolled subjects were aged 75years 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)]. 8.6 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 <30mL/min/1.73m2), no dosage adjustment is necessary for JALYN in patients with moderate-to-severe renal impairment. However, patients with end-stage renal disease (CLcr<10mL/min/1.73m2) have not been studied [see Clinical Pharmacology (12.3)]. 8.7 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 study where 60subjects received 5mg (10times the therapeutic dose) daily for 24weeks, no additional adverse events were observed compared with those observed at the therapeutic dose of 0.5mg [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)]. 10 OVERDOSAGE 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 40mg (80times the therapeutic dose) for 7days have been administered without significant safety concerns. In a clinical study, daily doses of 5mg (10times the therapeutic dose) were administered to 60subjects for 6months with no additional adverse effects to those seen at therapeutic doses of 0.5mg. 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. 11 DESCRIPTION JALYN (dutasteride and tamsulosin hydrochloride) Capsules contain dutasteride (a selective inhibitor of both the type1 and type2 isoforms of steroid 5 alpha-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone (DHT) and tamsulosin (an antagonist of alpha1A-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 “GS7CZ” 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 C27H30F6N2O2, 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 (44mg/mL), methanol (64mg/mL), and polyethylene glycol 400 (3mg/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 C20H28N2O5S•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. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action JALYN is a combination of 2drugs 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 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 5 alpha-reductase, which exists as 2isoforms, type1 and type2. The type2 isoenzyme is primarily active in the reproductive tissues, while the type1 isoenzyme is also responsible for testosterone conversion in the skin and liver. Dutasteride is a competitive and specific inhibitor of both type1 and type2 5 alpha-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 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 3discrete 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. 12.2 Pharmacodynamics Dutasteride:Effect on 5 Alpha-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 2weeks. After 1and 2weeks of daily dosing with dutasteride 0.5mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. In patients with BPH treated with dutasteride 0.5mg/day for 4years, the median decrease in serum DHT was 94% at 1year, 93% at 2years, and 95% at both 3 and 4years. The median increase in serum testosterone was 19% at both 1 and 2years, 26% at 3years, and 22% at 4years, but the mean and median levels remained within the physiologic range. In patients with BPH treated with 5mg/day of dutasteride or placebo for up to 12weeks 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 5,793pg/g, respectively, P<0.001). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group compared with placebo (2,073 and 93pg/g, respectively, P<0.001). Adult males with genetically inherited type2 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. Effects on Other Hormones: In healthy volunteers, 52weeks of treatment with dutasteride 0.5mg/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 8weeks (97.1ng/dL, P<0.003) and thyroid-stimulating hormone at 52weeks (0.4mcIU/mL, P<0.05). The median percentage changes from baseline within the dutasteride group were 17.9% for testosterone at 8weeks and 12.4% for thyroid-stimulating hormone at 52weeks. After stopping dutasteride for 24weeks, 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 6months and 19% at both 12 and 24months. Other Effects: Plasma lipid panel and bone mineral density were eva luated following 52weeks of dutasteride 0.5mg 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. 12.3 Pharmacokinetics 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 Table2 below.
Dutasteride: Following administration of a single 0.5-mg dose of a soft gelatin capsule, time to peak absolute bioavailability in 5healthy 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 Cmax was 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 500L). 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 0.5mg/day for 12months, semen dutasteride concentrations averaged 3.4ng/mL (range: 0.4 to 14ng/mL) at 12months and, similar to serum, achieved steady-state concentrations at 6months. On average, at 12months 11.5% of serum dutasteride concentrations partitioned into semen. Tamsulosin: The mean steady-state apparent volume of distribution of tamsulosin after intravenous administration to 10healthy male adults was 16L, 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 600ng/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, 3major metabolites (4′-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and 2minor 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 15positions 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 5weeks at steady state. The average steady-state serum dutasteride concentration was 40ng/mL following 0.5mg/day for 1year. Following daily dosing, dutasteride serum concentrations achieve 65% of steady-state concentration after 1month and approximately 90% after 3months. Due to the long half-life of dutasteride, serum concentrations remain detectable (greater than 0.1ng/mL) for up to 4 to 6months after discontinuation of treatment. Tamsulosin: On administration of the radiolabeled dose of tamsulosin to 4healthy volunteers, 97% of the administered radioactivity was recovered, with urine (76%) representing the primary route of excretion compared to feces (21%) over 168hours. Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin in plasma ranges from 5 to 7hours. Because of absorption rate-controlled pharmacokinetics with tamsulosin hydrochloride capsules, the apparent half-life of tamsulosin is approximately 9 to 13hours in healthy volunteers and 14 to 15hours in the target population. Tamsulosin undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88L/hr). Specific Populations:Pediatric: The pharmacokinetics of dutasteride and tamsulosin administered together have not been investigated in subjects younger than 18years. Geriatric: 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 36healthy male subjects aged between 24 and 87years following administration of a single 5-mgdose of dutasteride. In this single-dose study, dutasteride half-life increased with age (approximately 170hours in men aged 20 to 49years, approximately 260hours in men aged 50 to 69years, and approximately 300hours in men older than 70years). 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 75years compared to subjects aged 20 to 32years. 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 (5.6)]. 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 6subjects with mild-moderate (30≤CLcr <70 mL/min/1.73m2) or moderate-severe (10≤CLcr <30mL/min/1.73m2) renal impairment and 6normal subjects (CLcr>90mL/min/1.73m2). While a change in the overall plasma concentration of tamsulosin was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in tamsulosin dosing. However, patients with end-stage renal disease (CLcr<10mL/min/1.73m2) have not been studied. 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. Tamsulosin: The pharmacokinetics of tamsulosin have been compared in 8subjects with moderate hepatic impairment (Child-Pugh classification: GradesA and B) and 8normal subjects. While a change in the overall plasma concentration of tamsulosin was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin does not change significantly with only a modest (32%) change in intrinsic clearance of unbound tamsulosin. Therefore, patients with moderate hepatic impairment do not require an adjustment in tamsulosin dosage. Tamsulosin has not been studied in patients with severe hepatic impairment. Drug Interactions: There have been no drug interaction studies using JALYN. The following text reflects information available for the individual components. Cytochrome P450 Inhibitors:Dutasteride: No clinical drug interaction studies have been performed to eva luate the impact of CYP3A enzyme inhibitors on dutasteride pharmacokinetics. However, based on in vitro data, blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4/5 such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, troleandomycin, and ciprofloxacin. 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 1,000ng/mL, 25times greater than steady-state serum concentrations in humans. Tamsulosin:Strong and Moderate Inhibitors of CYP3A4 or CYP2D6: The effects of ketoconazole (a strong inhibitor of CYP3A4) at 400mg once daily for 5days on the pharmacokinetics of a single tamsulosin hydrochloride capsule 0.4mg dose was investigated in 24 healthy volunteers (age range: 23 to 47years). Concomitant treatment with ketoconazole resulted in increases in the Cmax and AUC of tamsulosin by factors of 2.2 and 2.8, respectively. The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of tamsulosin have not been eva luated. The effects of paroxetine (a strong inhibitor of CYP2D6) at 20mg once daily for 9days on the pharmacokinetics of a single tamsulosin capsule 0.4mg dose was investigated in 24healthy volunteers (age range: 23 to 47years). Concomitant treatment with paroxetine resulted in increases in the Cmax 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 0.4mg is coadministered with strong CYP3A4 inhibitors in CYP2D6 PMs, tamsulosin 0.4mg 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 eva luated. The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin capsules 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. Cimetidine: The effects of cimetidine at the highest recommended dose (400mg every 6hours for 6days) on the pharmacokinetics of a single tamsulosin capsule 0.4mg dose was investigated in 10healthy volunteers (age range: 21 to 38years). 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%). Alpha Adrenergic Antagonists:Dutasteride: In a single-sequence, crossover study in healthy volunteers, the administration of tamsulosin or terazosin in combination with dutasteride had no effect on the steady-state pharmacokinetics of either alpha-adrenergic antagonist. Although the effect of administration of tamsulosin or terazosin on dutasteride pharmacokinetic parameters was not eva luated, the percent change in DHT concentrations was similar for dutasteride, alone or in combination with tamsulosin or terazosin. Warfarin: Dutasteride: In a study of 23healthy volunteers, 3weeks of treatment with dutasteride 0.5mg/day did not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time when administered with warfarin. Tamsulosin: A definitive drug-drug interaction study between tamsulosin and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and tamsulosin. Nifedipine, Atenolol, Enalapril:Tamsulosin: In 3studies in hypertensive subjects (age range: 47to 79years) whose blood pressure was controlled with stable doses of nifedipine extended-release, atenolol, or enalapril for at least 3months, tamsulosin hydrochloride capsules 0.4mg for 7days followed by tamsulosin hydrochloride capsules 0.8mg for another 7days (n=8 per study) resulted in no clinically significant effects on blood pressure and pulse rate compared with placebo (n=4 per study). Therefore, dosage adjustments are not necessary when tamsulosin is administered concomitantly with nifedipine extended-release, atenolol, or enalapril. Digoxin and Theophylline:Dutasteride: In a study of 20healthy volunteers, dutasteride did not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5mg/day for 3weeks. Tamsulosin: In 2 studies in healthy volunteers (n=10 per study; age range: 19 to 39years) receiving tamsulosin capsules 0.4mg/day for 2days, followed by tamsulosin capsules 0.8mg/day for 5 to 8days, single intravenous doses of digoxin 0.5mg or theophylline 5mg/kg resulted in no change in the pharmacokinetics of digoxin or theophylline. Therefore, dosage adjustments are not necessary when a tamsulosin capsule is administered concomitantly with digoxin or theophylline. Furosemide:Tamsulosin: The pharmacokinetic and pharmacodynamic interaction between tamsulosin hydrochloride capsules 0.8mg/day (steady-state) and furosemide 20mg intravenously (single dose) was eva luated in 10healthy volunteers (age range: 21to 40years). Tamsulosin had no effect on the pharmacodynamics (excretion of electrolytes) of furosemide. While furosemide produced an 11% to 12% reduction in tamsulosin Cmax and AUC, these changes are expected to be clinically insignificant and do not require dose adjustment for tamsulosin. Calcium Channel Antagonists:Dutasteride: In a population pharmacokinetics analysis, a decrease in clearance of dutasteride was noted when coadministered with the CYP3A4 inhibitors verapamil (-37%, n=6) and diltiazem (-44%, n=5). In contrast, no decrease in clearance was seen when amlodipine, another calcium channel antagonist that is not a CYP3A4 inhibitor, was coadministered with dutasteride (+7%, n=4). The decrease in clearance and subsequent increase in exposure to dutasteride in the presence of verapamil and diltiazem is not considered to be clinically significant. No dosage adjustment is recommended. Cholestyramine:Dutasteride: Administration of a single 5-mg dose of dutasteride followed 1hour later by 12g cholestyramine did not affect the relative bioavailability of dutasteride in 12normal volunteers. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No non-clinical studies have been conducted with JALYN. The following information is based on studies performed with dutasteride or tamsulosin. Carcinogenesis: Dutasteride: A 2-year carcinogenicity study was conducted in B6C3F1 mice at doses of 3, 35, 250, and 500mg/kg/day for males and 3, 35, and 250mg/kg/day for females; an increased incidence of benign hepatocellular adenomas was noted at 250mg/kg/day (290-fold the MRHD of a 0.5-mg daily dose) in female mice only. Two of the 3major human metabolites have been detected in mice. The exposure to these metabolites in mice is either lower than in humans or is not known. In a 2-year carcinogenicity study in Han Wistar rats, at doses of 1.5, 7.5, and 53mg/kg/day in males and 0.8, 6.3, and 15mg/kg/day in females, there was an increase in Leydig cell adenomas in the testes at 135-fold the MRHD (53mg/kg/day and greater). An increased incidence of Leydig cell hyperplasia was present at 52-fold the MRHD (male rat doses of 7.5mg/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 1to 3times the expected clinical exposure. Tamsulosin: In a rat carcinogenicity assay, no increases in tumor incidence was observed in rats administered up to 3times the MRHD of 0.8mg/day (based on AUC of animal doses up to 43mg/kg/day in males and up to 52mg/kg/day in females), with the exception of a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses of 5.4mg/kg or greater. In a carcinogenicity assay, mice were administered up to 8times the MRHD of tamsulosin (oral doses up to 127mg/kg/day in males and 158mg/kg/day in females). There were no significant tumor findings in male mice. Female mice treated for 2years with the 2highest doses of 45 and 158mg/kg/day had statistically significant increases in the incidence of mammary gland fibroadenomas (P<0.0001) and adenocarcinomas. 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: Dutasteride was tested for genotoxicity in a bacterial mutagenesis assay (Ames test), a chromosomal aberration assay in CHO cells, and a micronucleus assay in rats. The results did not indicate any genotoxic potential of the parent drug. Two major human metabolites were also negative in either the Ames test or an abbreviated Ames test. Tamsulosin: Tamsulosin produced no evidence of mutagenic potential in vitro in the Ames reverse mutation test, mouse lymphoma thymidine kinase assay, unscheduled DNA repair synthesis assay, and chromosomal aberration assays in CHO cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay. Impairment of Fertility: Dutasteride: Treatment of sexually mature male rats with dutasteride at 0.1- to 110-fold the MRHD (animal doses of 0.05, 10, 50, and 500mg/kg/day for up to 31weeks) resulted in dose- and time-dependent decreases in fertility; reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500mg/kg/day); reduced weights of the epididymis, prostate, and seminal vesicles; and microscopic changes in the male reproductive organs. The fertility effects were reversed by recovery week 6 at all doses, and sperm counts were normal at the end of a 14-week recovery period. The 5 alpha-reductase–related changes consisted of cytoplasmic vacuolation of tubular epithelium in the epididymides and decreased cytoplasmic content of epithelium, consistent with decreased secretory activity in the prostate and seminal vesicles. The microscopic changes were no longer present at recovery week 14 in the low-dose group and were partly recovered in the remaining treatment groups. Low levels of dutasteride (0.6 to 17ng/mL) were detected in the serum of untreated female rats mated to males dosed at 10, 50, or 500mg/kg/day for 29 to 30weeks. In a fertility study in female rats, oral administration of dutasteride at doses of 0.05, 2.5, 12.5, and 30mg/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 2.5mg/kg/day or greater). Fetal body weights were also reduced at less than 0.02-fold the MRHD in rats (0.5mg/kg/day). Tamsulosin: Studies in rats revealed significantly reduced fertility in males at approximately 50times the MRHD based on AUC (single or multiple daily doses of 300mg/kg/day of tamsulosin hydrochloride). The mechanism of decreased fertility in male rats is considered to be an effect of the compound on the vaginal plug formation possibly due to changes of semen content or impairment of ejaculation. The effects on fertility were reversible showing improvement by 3days after a single dose and 4weeks after multiple dosing. Effects on fertility in males were completely reversed within nine weeks of discontinuation of multiple dosing. Multiple doses of 0.2 and 16times the MRHD (animal doses of 10 and 100mg/kg/day tamsulosin hydrochloride) did not significantly alter fertility in male rats. Effects of tamsulosin on sperm counts or sperm function have not been eva luated. Studies in female rats revealed significant reductions in fertility after single or multiple dosing with 300mg/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 100mg/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. 13.2 Animal Toxicology and/or Pharmacology Central Nervous System Toxicology Studies:Dutasteride: In rats and dogs, repeated oral administration of dutasteride resulted in some animals showing signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes at exposures 425- and 315-fold the expected clinical exposure (of parent drug), respectively. 14 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 0.5mg/day and tamsulosin hydrochloride 0.4mg/day (n=1,610) compared with dutasteride alone (n=1,623) or tamsulosin alone (n=1,611). Subjects were at least 50years of age with a serum PSA ≥1.5ng/mL and <10ng/mL and BPH diagnosed by medical history and physical examination, including enlarged prostate (≥30cc) and BPH symptoms that were moderate to severe according to the International Prostate Symptom Score (IPSS). Eighty-eight percent (88%) of the enrolled study population was Caucasian. Approximately 52% of subjects had previous exposure to 5 alpha-reductase inhibitor or alpha adrenergic antagonist treatment. Of the 4,844subjects randomly assigned to receive treatment, 69% of subjects in the coadministration group, 67% in the dutasteride group, and 61% in the tamsulosin group completed 4years of double-blind treatment. Effect on Symptom Score: Symptoms were quantified using the first 7questions of the International Prostate Symptom Score (IPSS). The baseline score was approximately 16.4units for each treatment group. Coadministration therapy was statistically superior to each of the monotherapy treatments in decreasing symptom score at Month24, the primary time point for this endpoint. At Month24, the mean changes from baseline (±SD) in IPSS total symptom scores were -6.2 (±7.14) for the coadministration group, -4.9 (±6.81) for dutasteride, and -4.3 (±7.01) for tamsulosin, with a mean difference between coadministration and dutasteride of -1.3units (P<0.001; [95% CI: -1.69, -0.86]), and between coadministration and tamsulosin of -1.8units (P<0.001; [95% CI: -2.23, -1.40]). A significant difference was seen by Month9 and continued through Month48. At Month 48 the mean changes from baseline (±SD) in IPSS total symptom scores were -6.3 (±7.40) for coadministration, -5.3 (±7.14) for dutasteride, and -3.8 (±7.74) for tamsulosin, with a mean difference between coadministration and dutasteride of -0.96units (P<0.001; [95% CI: -1.40, -0.52]), and between coadministration and tamsulosin of -2.5units (P<0.001; [95% CI: -2.96, -2.07]). See Figure1.
Figure 1. International Prostate Symptom Score Change From Baseline Over a 48-Month Period (Randomized, Double-Blind, Parallel-Group Study [CombAT Study])
Effect on Acute Urinary Retention or the Need for BPH-Related Surgery: After 4years of treatment, coadministration therapy with dutasteride and tamsulosin did not provide benefit over dutasteride monotherapy in reducing the incidence of AUR or BPH-related surgery. In separate 2-year randomized, double-blind trials, compared with placebo, dutasteride monotherapy was associated with a statistically significantly lower incidence of AUR (1.8% for dutasteride versus 4.2% for placebo; 57% reduction in risk) and with a statistically significantly lower incidence of BPH-related surgery (2.2% for dutasteride versus. 4.1% for placebo; 48% reduction in risk). Effect on Maximum Urine Flow Rate: The baseline Qmax was approximately 10.7mL/sec for each treatment group. Coadministration therapy was statistically superior to each of the monotherapy treatments in increasing Qmax at Month24, the primary time point for this endpoint. At Month24, the mean increases from baseline (±SD) in Qmax were 2.4(±5.26)mL/sec for coadministration group, 1.9(±5.10)mL/sec for dutasteride, and 0.9(±4.57)mL/sec for tamsulosin, with a mean difference between coadministration and dutasteride of 0.5mL/sec (P=0.003; [95% CI: 0.17, 0.84]), and between coadministration and tamsulosin of 1.5mL/sec (P<0.001; [95% CI: 1.19, 1.86]). This difference was seen by Month6 and continued through Month24. See Figure2. The additional improvement in Qmax of coadministration therapy over dutasteride monotherapy was no longer statistically significant at Month 48.
Figure 2. Q-max Change From Baseline Over a 24-Month Period (Randomized, Double-Blind, Parallel-Group Study [CombAT Study])
Effect on Prostate Volume: The mean prostate volume at study entry was approximately 55cc. At Month24, the primary time point for this endpoint, the mean percent changes from baseline (±SD) in prostate volume were -26.9% (±22.57) for coadministration therapy, -28.0% (±24.88) for dutasteride, and 0% (±31.14) for tamsulosin, with a mean difference between coadministration and dutasteride of 1.1% (P=NS; [95% CI: -0.6, 2.8]), and between coadministration and tamsulosin of -26.9% (P<0.001; [95% CI: -28.9, -24.9]). Similar changes were seen at Month48: -27.3% (±24.91) for coadministration therapy, -28.0% (±25.74) for dutasteride, and +4.6% (±35.45) for tamsulosin. 16 HOW SUPPLIED/STORAGE AND HANDLING JALYN Capsules, containing 0.5mg dutasteride and 0.4mg tamsulosin hydrochloride, are oblong hard-shell capsules with a brown body and an orange cap imprinted with “GS7CZ” 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 [see Warnings and Precautions (5.6)].
2010年6月22日，美国食品及药物管理局（FDA）已经批准由0.5mg度他雄胺和0.4mg坦索罗辛（Jalyn；葛兰素史克）组成的单胶囊药物，用于治疗良性前列腺增生症（BPH），这一处方药物预计可与2010年下半年上市。 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
