JALYN (Page 2 of 7)

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

JALYN capsules should not be handled by females who are pregnant or may be pregnant. Dutasteride can be absorbed through the skin and could result in unintended fetal exposure and potential risk to a male fetus. If a female who is or may be pregnant comes in contact with a leaking capsule, the contact area should be washed immediately with soap and water [see Use in Specific Populations (8.1)]. Dutasteride can be absorbed through the skin based on animal studies [see Nonclinical Toxicology (13.2)].

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 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient.

5.9 Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract and glaucoma surgery in some patients on or previously treated with alpha-adrenergic antagonists, including tamsulosin, which is a component of JALYN.

Most reports were in patients taking the alpha-adrenergic antagonist when IFIS occurred, but in some cases, the alpha-adrenergic antagonist had been stopped prior to surgery. In most of these cases, the alpha-adrenergic antagonist had been stopped recently prior to surgery (2 to 14 days), but in a few cases, IFIS was reported after the patients had been off the alpha-adrenergic antagonist for a longer period (5 weeks to 9 months). IFIS is a variant of small pupil syndrome and is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances.

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

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 0.5 mg/day on semen characteristics were evaluated in healthy men throughout 52 weeks of treatment and 24 weeks of post‑treatment follow‑up. At 52 weeks, compared with placebo, dutasteride treatment resulted in mean reduction in total sperm count, semen volume, and sperm motility; the effects on total sperm count were not reversible after 24 weeks of follow-up. Sperm concentration and sperm morphology were unaffected and mean values for all semen parameters remained within the normal range at all timepoints. The clinical significance of the effect of dutasteride on semen characteristics for an individual patient’s fertility is not known [see Use in Specific Populations (8.3)].

Tamsulosin

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

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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
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.

Adverse Reaction

Adverse Reaction Time of Onset

Year 1

Year 2

Year 3

Year 4

Months 06

Months 712

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)

Ejaculation disordersb,c

Coadministration

7.8%

1.6%

1.0%

0.5%

<0.1%

Dutasteride

1.0%

0.5%

0.5%

0.2%

0.3%

Tamsulosin

2.2%

0.5%

0.5%

0.2%

0.3%

Impotencec,d

Coadministration

5.4%

1.1%

1.8%

0.9%

0.4%

Dutasteride

4.0%

1.1%

1.6%

0.6%

0.3%

Tamsulosin

2.6%

0.8%

1.0%

0.6%

1.1%

Decreased libidoc,e

Coadministration

4.5%

0.9%

0.8%

0.2%

0.0%

Dutasteride

3.1%

0.7%

1.0%

0.2%

0.0%

Tamsulosin

2.0%

0.6%

0.7%

0.2%

<0.1%

Breast disordersf

Coadministration

1.1%

1.1%

0.8%

0.9%

0.6%

Dutasteride

0.9%

0.9%

1.2%

0.5%

0.7%

Tamsulosin

0.4%

0.4%

0.4%

0.2%

0.0%

Dizziness

Coadministration

1.1%

0.4%

0.1%

<0.1%

0.2%

Dutasteride

0.5%

0.3%

0.1%

<0.1%

<0.1%

Tamsulosin

0.9%

0.5%

0.4%

<0.1%

0.0%

Cardiac Failure

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.

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 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 (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 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.

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 0.4 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 (5.1)].

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