DUTASTERIDE: 3,973 Adverse Event Reports & Safety Profile

Dutasteride and tamsulosin hydrochloride capsules contain dutasteride (a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5 alpha-reductase, an intracellular enzyme that converts testosterone to DHT and tamsulosin (an antagonist of alpha 1A -adrenoceptors in the prostate). Each dutasteride and tamsulosin hydrochloride capsule contains the following: One dutasteride oblong, opaque, yellow gelatin capsule, containing 0.5 mg of dutasteride dissolved in a mixture of butylated hydroxytoluene and mono-and di-glycerides of caprylic/capric acid. The inactive ingredients in the soft-gelatin capsule shell are ferric oxide (yellow), gelatin (from certified BSE-free bovine sources), glycerin, titanium dioxide, lecithin, medium chain triglycerides, propylene glycol, iron oxide black, polyvinyl acetate phthalate, macrogol, and ammonium hydroxide. Tamsulosin hydrochloride white to off-white pellets, containing 0.4 mg tamsulosin hydrochloride and the inactive ingredients: methacrylic acid copolymer, sugar sphere, ethylcellulose, polyethylene glycol, triethyl citrate and talc. The above components are encapsulated in a hard-shell capsule made with the inactive ingredients of hypromellose, FD&C Blue #1, titanium dioxide, shellac, iron oxide black, propylene glycol, FD&C blue #2, FD&C red #40, D&C yellow #10. Blue opaque cap imprinted with “C280” and white opaque body imprinted with “0.5/0.4” in black ink containing white to off white spherical shaped pellets and one oblong, opaque yellow softgel capsule printed with “C300” 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 C 27 H 30 F 6 N 2 O 2 , 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 (44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/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 C 20 H 28 N 2 O 5 S•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. Dutasteride-Structural-Formula.jpg Tamsulosin-Structural-Formula.jpg

AND USAGE Dutasteride capsules is a 5 alpha-reductase inhibitor indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: (1.1)

• improve symptoms,
• reduce the risk of acute urinary retention, and
• reduce the risk of the need for BPH-related surgery. Dutasteride capsules in combination with the alpha adrenergic antagonist, tamsulosin, are indicated for the treatment of symptomatic BPH in men with an enlarged prostate. (1.2) Limitations of Use: Dutasteride capsules are not approved for the prevention of prostate cancer. (1.3)

1.1 Monotherapy Dutasteride capsules are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

• improve symptoms,
• reduce the risk of acute urinary retention (AUR), and
• reduce the risk of the need for BPH-related surgery.

1.2 Combination With Alpha Adrenergic Antagonist Dutasteride capsules in combination with the alpha adrenergic antagonist, tamsulosin, are indicated for the treatment of symptomatic BPH in men with an enlarged prostate.

1.3 Limitations of Use Dutasteride capsules are not approved for the prevention of prostate cancer.

2 DOSAGE & ADMINISTRATION The capsules should be swallowed whole and not chewed or opened, as contact with the capsule contents may result in irritation of the oropharyngeal mucosa.

Dutasteride

Capsules may be administered with or without food.

2.1 Monotherapy The recommended dose of Dutasteride Capsules is 1 capsule (0.5 mg) taken once daily.

2.2 Combination With Alpha-adrenergic Antagonist The recommended dose of Dutasteride Capsules is 1 capsule (0.5 mg) taken once daily and tamsulosin 0.4 mg taken once daily. Monotherapy: 0.5 mg once daily. (2.1) Combination with tamsulosin: 0.5 mg once daily and tamsulosin 0.4 mg once daily. (2.2) Dosing considerations: Swallow whole. May take with or without food. (2)

Dutasteride is contraindicated for use in:

• Pregnancy. In animal reproduction and developmental toxicity studies, dutasteride inhibited development of male fetus external genitalia. 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 [see Warnings and Precautions (5.4), Use in Specific Populations ( Error! Hyperlink reference not valid. )] .
• Women of childbearing potential [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( Error! Hyperlink reference not valid. )] .
• Pediatric patients [see Use in Specific Populations ( 8.4 )] .
• Patients with previously demonstrated clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride or other 5 alpha-reductase inhibitors [see Adverse Reactions ( 6.2 )] .
• Pregnancy and women of childbearing potential. ( 4 , 5.4 , 8.1 )
• Pediatric patients. ( 4 )
• Patients with previously demonstrated, clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride or other 5 alpha-reductase inhibitors. ( 4 )

REACTIONS The most common adverse reactions, reported in ≥1% of subjects treated with dutasteride capsules and more commonly than in subjects treated with placebo, are impotence, decreased libido, ejaculation disorders, and breast disorders. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Epic Pharma, LLC at 1-888-374-2791 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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. From clinical trials with Dutasteride as monotherapy or in combination with tamsulosin: The most common adverse reactions reported in subjects receiving dutasteride were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), and ejaculation disorders. The most common adverse reactions reported in subjects receiving combination therapy (dutasteride plus tamsulosin) were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving combination therapy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy. Trial withdrawal due to adverse reactions occurred in 4% of subjects receiving dutasteride, and 3% of subjects receiving placebo in placebo-controlled trials with dutasteride. The most common adverse reaction leading to trial withdrawal was impotence (1%). In the clinical trial evaluating the combination therapy, trial withdrawal due to adverse reactions occurred in 6% of subjects receiving combination therapy (dutasteride plus tamsulosin) and 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%).

Monotherapy Over

4,300 male subjects with BPH were randomly assigned to receive placebo or 0.5-mg daily doses of dutasteride in 3 identical 2-year, placebo-controlled, double-blind, Phase 3 treatment trials, each followed by a 2-year open-label extension. During the double-blind treatment period, 2,167 male subjects were exposed to dutasteride, including 1,772 exposed for 1 year and 1,510 exposed for 2 years. When including the open-label extensions, 1,009 male subjects were exposed to dutasteride for 3 years and 812 were exposed for 4 years. The population was aged 47 to 94 years (mean age: 66 years) and greater than 90% were white.

Table

1 summarizes clinical adverse reactions reported in at least 1% of subjects receiving dutasteride and at a higher incidence than subjects receiving placebo.

Table

1.

Adverse Reactions

Reported in ≥1% of Subjects over a 24-Month Period and More Frequently in the Group Receiving Dutasteride Capsules than the Placebo Group (Randomized, Double-blind, Placebo-Controlled Trials Pooled) by Time of Onset Adverse Reaction Adverse Reaction Time of Onset Months 0-6 Months 7-12 Months 13-18 Months 19-24 Dutasteride capsules (n) (n = 2,167) (n = 1,901) (n = 1,725) (n = 1,605) Placebo (n) (n = 2,158) (n = 1,922) (n = 1,714) (n = 1,555)

Impotencea

Dutasteride capsules 4.7% 1.4% 1.0% 0.8% Placebo 1.7% 1.5% 0.5% 0.9% Decreased libido a Dutasteride capsules 3.0% 0.7% 0.3% 0.3% Placebo 1.4% 0.6% 0.2% 0.1% Ejaculation disorders a Dutasteride capsules 1.4% 0.5% 0.5% 0.1% Placebo 0.5% 0.3% 0.1% 0.0% Breast disorders b Dutasteride capsules 0.5% 0.8% 1.1% 0.6% Placebo 0.2% 0.3% 0.3% 0.1% a 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. b Includes breast tenderness and breast enlargement. 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 capsules (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 8-10 prostate cancer in men receiving dutasteride capsules (1.0%) compared with men on placebo (0.5%) [see Indications and Usage (1.3) , Warnings and Precautions (5.2) ]. 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 capsules. Reproductive and Breast Disorders In the 3 pivotal placebo-controlled BPH trials with dutasteride capsules, 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. Combination with Alpha-blocker Therapy (CombAT)

Over

4,800 male subjects with BPH were randomly assigned to receive 0.5-mg dutasteride capsules, 0.4-mg tamsulosin, or combination therapy (0.5-mg dutasteride capsules plus 0.4-mg tamsulosin) administered once daily in a 4-year double-blind trial. Overall, 1,623 subjects received monotherapy with dutasteride capsules; 1,611 subjects received monotherapy with tamsulosin; and 1,610 subjects received combination therapy. The population was aged 49 to 88 years (mean age: 66 years) and 88% were white.

Table

2 summarizes adverse reactions reported in at least 1% of subjects in the combination group and at a higher incidence than subjects receiving monotherapy with dutasteride capsules or tamsulosin.

Table

2.

Adverse Reactions

Reported over a 48-Month Period in ≥1% of Subjects and More Frequently in the Coadministration Therapy Group than the Groups Receiving Monotherapy with Dustateride Capsules or Tamsulosin (CombAT) by Time of Onset Adverse Reaction Adverse Reaction Time of Onset Year 1 Months 0-6 Months 7-12 Year 2 Years 3 Year 4 Combination a (n = 1,610) (n = 1,527) (n = 1,428) (n = 1,283) (n = 1,200) Dutasteride capsules (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 disorders b,c Combination 7.8% 1.6% 1.0% 0.5% <0.1% Dutasteride capsules 1.0% 0.5% 0.5% 0.2% 0.3% Tamsulosin 2.2% 0.5% 0.5% 0.2% 0.3% Impotence c,d Combination 5.4% 1.1% 1.8% 0.9% 0.4% Dutasteride capsules 4.0% 1.1% 1.6% 0.6% 0.3% Tamsulosin 2.6% 0.8% 1.0% 0.6% 1.1% Decreased libido c,e Combination 4.5% 0.9% 0.8% 0.2% 0.0% Dutasteride capsules 3.1% 0.7% 1.0% 0.2% 0.0% Tamsulosin 2.0% 0.6% 0.7% 0.2% <0.1% Breast disorders f Combination 1.1% 1.1% 0.8% 0.9% 0.6% Dutasteride capsules 0.9% 0.9% 1.2% 0.5% 0.7% Tamsulosin 0.4% 0.4% 0.4% 0.2% 0.0% Dizziness Combination 1.1% 0.4% 0.1% <0.1% 0.2% Dutasteride capsules 0.5% 0.3% 0.1% <0.1% <0.1% Tamsulosin 0.9% 0.5% 0.4% <0.1% 0.0% a Combination = Dutasteride capsules 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.

Cardiac

Failure: In CombAT, after 4 years of treatment, the incidence of the composite term cardiac failure in the combination therapy group (12/1,610; 0.7%) was higher than in either monotherapy group: dutasteride capsules, 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 capsules in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking dutasteride capsules 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 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 capsules, alone or in combination with tamsulosin, and cardiac failure has been established. No imbalance was observed in the incidence of overall cardiovascular adverse events in either trial

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of dutasteride capsules. 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 dutasteride.

Immune System Disorders

Hypersensitivity reactions, including rash, pruritus, urticaria, localized edema, serious skin reactions, and angioedema.

Neoplasms

Male breast cancer.

Psychiatric Disorders

Depressed mood.

Reproductive

System and Breast Disorders Testicular pain and testicular swelling.

AND PRECAUTIONS Orthostatic hypotension and/or syncope can occur. Advise patients of symptoms related to postural hypotension and to avoid situations where injury could result if syncope occurs. ( 5.1 ) Do not use dutasteride and tamsulosin hydrochloride capsules with other alpha adrenergic antagonists, as this may increase the risk of hypotension. ( 5.2 ) Dutasteride and tamsulosin hydrochloride capsules reduce serum prostate-specific antigen (PSA) concentration by approximately 50%. However, any confirmed increase in PSA while on dutasteride and tamsulosin hydrochloride capsules may signal the presence of prostate cancer and should be evaluated, even if those values are still within the normal range for untreated men. ( 5.3 ) Do not use dutasteride and tamsulosin hydrochloride capsules with strong inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole). Use caution in combination with moderate CYP3A4 inhibitors (e.g., erythromycin) or strong (e.g., paroxetine) or moderate CYP2D6 inhibitors, a combination of both CYP3A4 and CYP2D6 inhibitors, or known poor metabolizers of CYP2D6. Concomitant use with known inhibitors can cause a marked increase in drug exposure. ( 5.2 , 7.1 , 12.3 ) Exercise caution with concomitant use of phosphodiesterase-5 (PDE-5) inhibitors, as this may increase the risk of hypotension. ( 5.2 ) Drugs that contain dutasteride, including dutasteride and tamsulosin hydrochloride capsules, may increase the risk of high-grade prostate cancer. ( 5.4 , 6.1 ) Prior to initiating treatment with dutasteride and tamsulosin hydrochloride capsules, consideration should be given to other urological conditions that may cause similar symptoms. ( 5.5 ) Females who are pregnant or may be pregnant should not handle dutasteride and tamsulosin hydrochloride capsules due to potential risk to a male fetus. ( 5.6 , 8.1 ) Advise patients about the possibility and seriousness of priapism. ( 5.7 ) Patients should not donate blood until 6 months after their last dose of dutasteride and tamsulosin hydrochloride capsules. ( 5.8 )

Intraoperative Floppy Iris

Syndrome has been observed during cataract and glaucoma surgery after alpha-adrenergic antagonist exposure. Advise patients considering cataract or glaucoma surgery to tell their ophthalmologist that they take or have taken dutasteride and tamsulosin hydrochloride capsules. ( 5.9 ) Exercise caution with concomitant use of warfarin. ( 5.2 , 7.2 , 12.3 )

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 dutasteride and tamsulosin hydrochloride capsules, and can result in syncope. Patients starting treatment with dutasteride and tamsulosin hydrochloride capsules should be cautioned to avoid situations where syncope could result in an injury <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

5.2 Drug-Drug Interactions Strong Inhibitors of Cytochrome P450 (CYP)3A4 Tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules, should not be coadministered with strong CYP3A4 inhibitors (e.g. ketoconazole) as this can significantly increase tamsulosin exposure <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]</span>.

Moderate

Inhibitors of CYP3A4, Inhibitors of CYP2D6, or a Combination of Both CYP3A4 and CYP2D6 Inhibitors Tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules, should be used with caution when coadministered with moderate inhibitors of CYP3A4 (e.g. erythromycin), strong (e.g. paroxetine) or moderate (e.g. terbinafine) inhibitors of CYP2D6, a combination of both CYP3A4 and CYP2D6 inhibitors, or in patients known to be poor metabolizers of CYP2D6, as there is a potential for significant increase in tamsulosin exposure [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] .

Cimetidine

Caution is advised when tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules, are coadministered with cimetidine [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] .

Other Alpha Adrenergic Antagonists

Tamsulosin-containing products, including dutasteride and tamsulosin hydrochloride capsules, should not be coadministered with other alpha adrenergic antagonists because of the increased risk of symptomatic hypotension. Phosphodiesterase-5 (PDE-5)

Inhibitors

Caution is advised when alpha adrenergic antagonist-containing products, including dutasteride and tamsulosin hydrochloride capsules, 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 dutasteride and tamsulosin hydrochloride capsules [see Drug Interactions ( 7.2 ), 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 trials, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in patients with symptomatic BPH, although it may vary in individuals. Dutasteride containing treatment, including dutasteride and tamsulosin hydrochloride capsules, 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 dutasteride and tamsulosin hydrochloride capsules, a new baseline PSA should be established at least 3 months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on a dutasteride-containing treatment, including dutasteride and tamsulosin hydrochloride capsules, may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5 alpha-reductase inhibitor. Noncompliance with dutasteride and tamsulosin hydrochloride capsules may also affect PSA test results. To interpret an isolated PSA value in a man treated with dutasteride and tamsulosin hydrochloride capsules, for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men. The free-to-total PSA ratio (percent free PSA) remains constant, even under the influence of dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving dutasteride and tamsulosin hydrochloride capsules, no adjustment to its value appears necessary.

5.4 Increased Risk of High-Grade Prostate Cancer In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10 ng/mL taking dutasteride in the 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, there was an increased incidence of Gleason score 8 to 10 prostate cancer compared with men taking placebo (dutasteride 1% versus placebo 0.5%) <span class="opacity-50 text-xs">[see Indications and Usage ( 1.2 ), Adverse Reactions ( 6.1 )]</span> . In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR ® ), similar results for Gleason score 8 to 10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%). 5 alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5 alpha-reductase inhibitors to reduce prostate volume or trial-related factors impacted the results of these trials has not been established.

5.5 Evaluation for Other Urological Diseases Prior to initiating treatment with dutasteride and tamsulosin hydrochloride capsules, consideration should be given to other urological conditions that may cause similar symptoms. In addition, BPH and prostate cancer may coexist.

5.6 Transdermal Exposure of Dutasteride and Tamsulosin Hydrochloride in Pregnant Females—Risk to Male Fetus Dutasteride and tamsulosin hydrochloride capsules should not be handled by females who are pregnant or may be pregnant. Dutasteride and tamsulosin hydrochloride capsules 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span>. Dutasteride can be absorbed through the skin based on animal studies <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( 13.2 )]</span>.

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 dutasteride and tamsulosin hydrochloride capsules. 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 dutasteride and tamsulosin hydrochloride capsules, 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 dutasteride and tamsulosin hydrochloride capsules. 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&apos;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 dutasteride and tamsulosin hydrochloride.

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.

INTERACTIONS There have been no drug interaction trials using dutasteride and tamsulosin hydrochloride capsules. The following sections reflect information available for the individual components.

7.1 Cytochrome P450 Inhibition 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 dutasteride and tamsulosin hydrochloride capsules, to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir) <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 ) ]</span> .

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 C max and AUC of tamsulosin by factors of 2.2 and 2.8, respectively. Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in increases in the C max and area under the concentration-time curve (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 ( 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 0.5 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 ) ]</span> . Tamsulosin 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 dutasteride and tamsulosin hydrochloride capsules <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 ) ]</span> .

7.3 Nifedipine, Atenolol, Enalapril Tamsulosin Dosage adjustments are not necessary when tamsulosin is administered concomitantly with nifedipine, atenolol, or enalapril <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 ) ]</span> .

7.4 Digoxin and Theophylline Dutasteride Dutasteride does not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

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 C max and AUC, these changes are expected to be clinically insignificant and do not require adjustment of the dose of tamsulosin <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 ) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 ) ]</span> .

7.7 Cholestyramine Dutasteride 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 ) ]</span> .