"SAN DIEGO â€” Long-term testosterone replacement therapy is associated with a decreased â€” not increased â€” risk for cardiovascular disease in men, according to a large population-based cohort study.
This finding "answers the controversy""...
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 evaluated in a multicenter, randomized, double-blind, parallel group trial (the Combination with Alpha-Blocker Therapy, or CombAT, trial). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trial of another drug and may not reflect the rates observed in practice.
- The most common adverse reactions reported in subjects receiving coadministered dutasteride and tamsulosin were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving coadministration therapy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy.
- Trial withdrawal due to adverse reactions occurred in 6% of subjects receiving coadministered dutasteride and tamsulosin and in 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%).
In the CombAT trial, over 4,800 male subjects with BPH were randomly assigned to receive 0.5 mg dutasteride, 0.4 mg tamsulosin hydrochloride, or coadministration therapy (0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride) administered once daily in a 4-year double-blind trial. Overall, 1,623 subjects received monotherapy with dutasteride; 1,611 subjects received monotherapy with tamsulosin; and 1,610 subjects received coadministration therapy. The population was aged 49 to 88 years (mean age: 66 years) and 88% were white. Table 1 summarizes adverse reactions reported in at least 1% of subjects receiving coadministration therapy and at a higher incidence than subjects receiving either dutasteride or tamsulosin as monotherapy.
Table 1: Adverse Reactions
Reported over a 48-Month Period in ≥ 1%
of Subjects and More Frequently in the Coadministration Therapy Group than the
Dutasteride or Tamsulosin Monotherapy Group (CombAT) by Time of Onset
|Adverse Reaction||Adverse Reaction Time of Onset|
|Year 1||Year 2||Year 3||Year 4|
|Months 0-6||Months 7-12|
|Coadministrationa||(n = 1,610)||(n = 1,527)||(n = 1,428)||(n = 1,283)||(n = 1,200)|
|Dutasteride||(n = 1,623)||(n = 1,548)||(n = 1,464)||(n = 1,325)||(n = 1,200)|
|Tamsulosin||(n = 1,611)||(n = 1,545)||(n = 1,468)||(n = 1,281)||(n = 1,112)|
|Dutasteride||0.5%||0.3%||0.1%||< 0.1%||< 0.1%|
|a Coadministration = AVODART® 0.5 mg once
daily plus tamsulosin 0.4 mg once daily.
b Includes anorgasmia, retrograde ejaculation, semen volume decreased, orgasmic sensation decreased, orgasm abnormal, ejaculation delayed, ejaculation disorder, ejaculation failure, and premature ejaculation.
c These sexual adverse reactions are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown.
d Includes erectile dysfunction and disturbance in sexual arousal.
e Includes libido decreased, libido disorder, loss of libido, sexual dysfunction, and male sexual dysfunction.
f Includes breast enlargement, gynecomastia, breast swelling, breast pain, breast tenderness, nipple pain, and nipple swelling.
In CombAT, after 4 years of treatment, the incidence of the composite term cardiac failure in the coadministration group (12/1,610; 0.7%) was higher than in either monotherapy group: dutasteride, 2/1,623 (0.1%) and tamsulosin, 9/1,611 (0.6%). Composite cardiac failure was also examined in a separate 4-year placebo-controlled trial evaluating dutasteride in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking dutasteride was 0.6% (26/4,105) compared with 0.4% (15/4,126) in subjects on placebo. A majority of subjects with cardiac failure in both trials had comorbidities associated with an increased risk of cardiac failure. Therefore, the clinical significance of the numerical imbalances in cardiac failure is unknown. No causal relationship between dutasteride alone or coadministered with tamsulosin and cardiac failure has been established. No imbalance was observed in the incidence of overall cardiovascular adverse events in either trial.
Additional information regarding adverse reactions in placebo-controlled trials with dutasteride or tamsulosin monotherapy follows.
Long-term Treatment (Up to 4 Years): High-grade Prostate Cancer: The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/mL to 10 ng/mL and a negative prostate biopsy within the previous 6 months. Subjects were randomized to receive placebo (n = 4,126) or 0.5-mg daily doses of dutasteride (n = 4,105) for up to 4 years. The mean age was 63 years and 91% were white. 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 to 10 prostate cancer in men receiving dutasteride (1.0%) compared with men on placebo (0.5%) [see INDICATIONS AND USAGE, WARNINGS AND PRECAUTIONS]. In a 7-year placebo-controlled clinical trial with another 5-alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8 to 10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).
No clinical benefit has been demonstrated in patients with prostate cancer treated with dutasteride.
Reproductive and Breast Disorders
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.
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 0.4 mg tamsulosin hydrochloride and at an incidence higher than in subjects receiving placebo were: infection, asthenia, back pain, chest pain, somnolence, insomnia, rhinitis, pharyngitis, cough increased, sinusitis, and diarrhea.
Signs and Symptoms of Orthostasis: According to the tamsulosin prescribing information, in clinical trials with tamsulosin monotherapy, a positive orthostatic test result was observed in 16% (81/502) of subjects receiving 0.4 mg tamsulosin hydrochloride versus 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 PRECAUTIONS].
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.
Neoplasms: Male breast cancer.
Psychiatric Disorders: Depressed mood.
Reproductive System and Breast Disorders: Testicular pain and testicular swelling.
Immune System Disorders: Hypersensitivity reactions, including rash, urticaria, pruritus, angioedema, and respiratory problems have been reported with positive rechallenge in some cases.
Gastrointestinal Disorders: Constipation, vomiting, dry mouth.
Reproductive System and Breast Disorders: Priapism.
Vascular Disorders: Hypotension.
Ophthalmologic Disorders: Blurred vision, visual impairment. 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].
Read the Jalyn (dutasteride and tamsulosin hydrochloride capsules) Side Effects Center for a complete guide to possible side effects
There have been no drug interaction trials using JALYN. The following sections reflect information available for the individual components.
Cytochrome P450 3A Inhibitors
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].
Strong and Moderate Inhibitors of CYP3A4 or CYP2D6: Tamsulosin is extensively metabolized, mainly by CYP3A4 or CYP2D6.
Concomitant treatment with ketoconazole (a strong inhibitor of CYP3A4) resulted in increases in the Cmax and area under the concentration-time curve (AUC) of tamsulosin by factors of 2.2 and 2.8, respectively. Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in increases in the 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 0.4 mg is coadministered with strong CYP3A4 inhibitors in CYP2D6 PMs, tamsulosin 0.4 mg capsules should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole). The effects of coadministration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when tamsulosin 0.4 mg is coadministered with a combination of both CYP3A4 and CYP2D6 inhibitors [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].
Concomitant administration of dutasteride 0.5 mg/day for 3 weeks with warfarin does not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time [see CLINICAL PHARMACOLOGY].
A definitive drug-drug interaction trial between tamsulosin hydrochloride and warfarin was not conducted. Results from limited in vitro and in vivo studies are inconclusive. Caution should be exercised with concomitant administration of warfarin and tamsulosin-containing products, including JALYN [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].
Nifedipine, Atenolol, Enalapril
Dosage adjustments are not necessary when tamsulosin is administered concomitantly with nifedipine, atenolol, or enalapril [see CLINICAL PHARMACOLOGY].
Digoxin And Theophylline
Dutasteride does not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks [see CLINICAL PHARMACOLOGY].
Dosage adjustments are not necessary when tamsulosin is administered concomitantly with digoxin or theophylline [see CLINICAL PHARMACOLOGY].
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].
Calcium Channel Antagonists
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].
Administration of a single 5-mg dose of dutasteride followed 1 hour later by a 12-g dose of cholestyramine does not affect the relative bioavailability of dutasteride [see CLINICAL PHARMACOLOGY].
Use In Specific Population
Pregnancy Category X. There are no adequate and well-controlled studies in pregnant women with JALYN or its individual components.
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]. 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.
Administration of tamsulosin to pregnant female rats at dose levels up to approximately 50 times the human therapeutic AUC exposure (animal dose of 300 mg/kg/day) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits at dose levels up to 50 mg/kg/day produced no evidence of fetal harm. However, because of the effect of dutasteride on the fetus, JALYN is contraindicated for use in pregnant women. Estimates of exposure multiples comparing animal studies to the MRHD for tamsulosin are based on AUC.
JALYN is contraindicated for use in women of childbearing potential, including nursing women. It is not known whether dutasteride or tamsulosin is excreted in human milk.
JALYN is contraindicated for use in pediatric patients. Safety and effectiveness of JALYN in pediatric patients have not been established.
Of 1,610 male subjects treated with coadministered dutasteride and tamsulosin in the CombAT trial, 58% of enrolled subjects were aged 65 years and older and 13% of enrolled subjects were aged 75 years and older. No overall differences in safety or efficacy were observed between these subjects and younger subjects but greater sensitivity of some older individuals cannot be ruled out [see CLINICAL PHARMACOLOGY].
The effect of renal impairment on dutasteride and tamsulosin pharmacokinetics has not been studied using JALYN. Because no dosage adjustment is necessary for dutasteride or tamsulosin in patients with moderate-to-severe renal impairment (10 ≤ CLcr < 30 mL/min/1.73 m²), no dosage adjustment is necessary for JALYN in patients with moderate-to-severe renal impairment. However, patients with end-stage renal disease (CLcr < 10 mL/min/1.73 m²) have not been studied [see CLINICAL PHARMACOLOGY].
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.
The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. However, in a clinical trial where 60 subjects received 5 mg (10 times the therapeutic dose) daily for 24 weeks, no additional adverse events were observed compared with those observed at the therapeutic dose of 0.5 mg [see CLINICAL PHARMACOLOGY].
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].
Read the Jalyn Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 2/11/2016
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