1.1  Monotherapy

Dutasteride Capsulesare 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, is 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.

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.

0.5 mg, light yellow colour oblong shaped soft gelatin capsules printed with ‘11’ in black ink containing clear light yellow colour liquid.

Dutasteride Capsules are contraindicated for use in:

·         Pregnancy. In animal reproduction and developmental toxicity studies, dutasteride inhibited development of male fetus external genitalia. Therefore, Dutasteride Capsules may cause fetal harm when administered to a pregnant woman. If Dutasteride Capsules are used during pregnancy or if the patient becomes pregnant while taking Dutasteride Capsules, the patient should be apprised of the potential hazard to the fetus[see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

·         Women of childbearing potential [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

·         Pediatric patients [see Use in Specific Populations (8.4)].

·         Patients with previously demonstrated clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to Dutasteride Capsules or other 5 alpha-reductase inhibitors [see Adverse Reactions (6.2)].

5.1     Effects on Prostate-Specific Antigen (PSA) and the Use of PSA in Prostate   Cancer Detection

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 may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men taking Dutasteride, a new PSA baseline 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 Dutasteride 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 may also affect PSA test results.

To interpret an isolated PSA value in a man treated with Dutasteride, for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men.

The free-to-total PSA (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, no adjustment to its value appears necessary.

Co administration of dutasteride and tamsulosin resulted in similar changes to serum PSA as dutasteride monotherapy.

1.2  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 10.0 ng/mL taking Dutasteride in the 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trials, 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 (1.3), 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 trial-related factors, impacted the results of these trials has not been established.

1.3  Evaluation for Other Urological Diseases

Prior to initiating treatment with Dutasteride, consideration should be given to other urological conditions that may cause similar symptoms. In addition, BPH and prostate cancer may coexist.

1.4  Exposure of Women-Risk to Male Fetus

Dutasteride 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 who could become pregnant comes in contact with leaking Dutasteride capsules, the contact area should be washed immediately with soap and water [see Use in Specific Populations (8.1)].

1.5     Blood Donation

Men being treated with Dutasteride 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.

1.6     Effect on Semen Characteristics

The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, 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 24 weeks 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%), 2 subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, 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.

1.6.1  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 Caucasian. 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 Than the Placebo Group (Randomized, Double-Blind, Placebo-Controlled Trials Pooled) by Time of Onset

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 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 (1.3), 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.

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.

Combination with Alpha-Blocker Therapy (CombAT): Over 4,800 male subjects with BPH were randomly assigned to receive 0.5-mg Dutasteride, 0.4-mg tamsulosin, or combination therapy (0.5-mg Dutasteride 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 Caucasian. 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 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 Dutasteride or Tamsulosin (CombAT) by Time of Onset

a Combination = Dutasteride 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, 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 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 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. 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.

Psychatric disorders: Depressed mood.

Reproductive System and Breast Disorders: Testicular pain and testicular swelling.

7.1 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 Dutasteride to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir) [see Clinical Pharmacology (12.3)].

7.2 Alpha Adrenergic Antagonists

The administration of Dutasteride Capsules in combination with tamsulosin or terazosin has no effect on the steady-state pharmacokinetics of either alpha adrenergic antagonist. The effect of administration of tamsulosin or terazosin on Dutasteride pharmacokinetic parameters has not been evaluated.

7.3 Calcium Channel Antagonists

Co administration 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 dose adjustment is recommended [see Clinical Pharmacology (12.3)].

7.4 Cholestyramine

Administration of a single 5-mg dose of Dutasteride Capsules followed 1 hour later by 12 g of cholestyramine does not affect the relative bioavailability of dutasteride [see Clinical Pharmacology (12.3)].

7.5 Digoxin

Dutasteride Capsules 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 (12.3)].

7.6 Warfarin

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 (12.3)].

In volunteer trials, single doses of dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical trial, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg.

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.

Dutasteride is a synthetic 4-azasteroid compound that is 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.

Dutasteride is 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 (44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it is insoluble in water.

Each Dutasteride Capsule, administered orally, contains 0.5 mg of dutasteride dissolved in a mixture of mono and di-glycerides of caprylic/capric acid and butylated hydroxytoluene. The inactive excipients in the capsule shell are colour iron oxide yellow, gelatin, glycerin, non crystallizing Sorbitol solution, titanium dioxide and purified water. The soft gelatin capsules are printed with edible black ink Opacode Black (S-1-17823).(Containing- Isopropyl alcohol, Black iron oxide, N-butyl alcohol, Propylene glycol, and Ammonium hydroxide).

14.1 Monotherapy

Dutasteride 0.5 mg/day (n = 2,167) or placebo (n = 2,158) was evaluated in male subjects with BPH in three 2-year multicenter, placebo-controlled, double-blind trials, each with 2-year open-label extensions (n = 2,340). More than 90% of the trial population was Caucasian. Subjects were at least 50 years of age with a serum PSA ≥1.5 ng/mL and <10 ng/mL and BPH diagnosed by medical history and physical examination, including enlarged prostate (≥30 cc) and BPH symptoms that were moderate to severe according to the American Urological Association Symptom Index (AUA-SI). Most of the 4,325 subjects randomly assigned to receive either dutasteride or placebo completed 2 years of double-blind treatment (70% and 67%, respectively). Most of the 2,340 subjects in the trial extensions completed 2 additional years of open-label treatment (71%).

Effect on Symptom Scores: Symptoms were quantified using the AUA-SI, a questionnaire that evaluates urinary symptoms (incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia) by rating on a 0 to 5 scale for a total possible score of 35, with higher numerical total symptom scores representing greater severity of symptoms. The baseline AUA-SI score across the 3 trials was approximately 17 units in both treatment groups.

Subjects receiving dutasteride achieved statistically significant improvement in symptoms versus placebo by Month 3 in 1 trial and by Month 12 in the other 2 pivotal trials. At Month 12, the mean decrease from baseline in AUA-SI total symptom scores across the 3 trials pooled was -3.3 units for dutasteride and -2.0 units for placebo with a mean difference between the 2 treatment groups of -1.3 (range: -1.1 to -1.5 units in each of the 3 trials, P<0.001) and was consistent across the 3 trials. At Month 24, the mean decrease from baseline was -3.8 units for dutasteride and -1.7 units for placebo with a mean difference of -2.1 (range: -1.9 to -2.2 units in each of the 3 trials, P<0.001). See Figure 1. The improvement in BPH symptoms seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension trials.

These trials were prospectively designed to evaluate effects on symptoms based on prostate size at baseline. In men with prostate volumes ≥40 cc, the mean decrease was -3.8 units for dutasteride and -1.6 units for placebo, with a mean difference between the 2 treatment groups of -2.2 at Month 24. In men with prostate volumes <40 cc, the mean decrease was -3.7 units for dutasteride and -2.2 units for placebo, with a mean difference between the 2 treatment groups of -1.5 at Month 24.

Figure 1. AUA-SI Scorea Change From Baseline (Randomized, Double-Blind, Placebo-Controlled Trials Pooled)

                                      aAUA-SI score ranges from 0 to 35.

Effect on Acute Urinary Retention and the Need for BPH-Related Surgery: Efficacy was also assessed after 2 years of treatment by the incidence of AUR requiring catheterization and BPH-related urological surgical intervention. Compared with placebo, Dutasteride was associated with a statistically significantly lower incidence of AUR (1.8% for Dutasteride versus 4.2% for placebo, P<0.001; 57% reduction in risk, [95% CI: 38% to 71%]) and with a statistically significantly lower incidence of surgery (2.2% for Dutasteride versus 4.1% for placebo, P<0.001; 48% reduction in risk, [95% CI: 26% to 63%]). See Figures 2 and 3.

Figure 2. Percent of Subjects Developing Acute Urinary Retention Over a 24-Month Period (Randomized, Double-Blind, Placebo-Controlled Trials Pooled)

Figure 3. Percent of Subjects Having Surgery for Benign Prostatic Hyperplasia Over a 24-Month Period (Randomized, Double-Blind, Placebo-Controlled Trials Pooled)

Effect on Prostate Volume: A prostate volume of at least 30 cc measured by transrectal ultrasound was required for trial entry. The mean prostate volume at trial entry was approximately 54 cc.

Statistically significant differences (Dutasteride versus placebo) were noted at the earliest post-treatment prostate volume measurement in each trial (Month 1, Month 3, or Month 6) and continued through Month 24. At Month 12, the mean percent change in prostate volume across the 3 trials pooled was -24.7% for dutasteride and -3.4% for placebo; the mean difference (dutasteride minus placebo) was -21.3% (range: -21.0% to -21.6% in each of the 3 trials, P<0.001). At Month 24, the mean percent change in prostate volume across the 3 trials pooled was -26.7% for dutasteride and -2.2% for placebo with a mean difference of -24.5% (range: -24.0% to -25.1% in each of the 3 trials, P<0.001). See Figure 4. The reduction in prostate volume seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension trials.

Figure 4. Prostate Volume Percent Change From Baseline (Randomized, Double-Blind, Placebo-Controlled Trials Pooled)

Effect on Maximum Urine Flow Rate: A mean peak urine flow rate (Qmax) of ≤15 mL/sec was required for trial entry. Qmax was approximately 10 mL/sec at baseline across the 3 pivotal trials.

Differences between the 2 groups were statistically significant from baseline at Month 3 in all 3 trials and were maintained through Month 12. At Month 12, the mean increase in Qmax across the 3 trials pooled was 1.6 mL/sec for Dutasteride and 0.7 mL/sec for placebo; the mean difference (dutasteride minus placebo) was 0.8 mL/sec (range: 0.7 to 1.0 mL/sec in each of the 3 trials, P<0.001). At Month 24, the mean increase in Qmax was 1.8 mL/sec for dutasteride and 0.7 mL/sec for placebo, with a mean difference of 1.1 mL/sec (range: 1.0 to 1.2 mL/sec in each of the 3 trials, P<0.001). See Figure 5. The increase in maximum urine flow rate seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open-label extension trials.

Figure 5. Qmax Change From Baseline (Randomized, Double-Blind, Placebo-Controlled Trials Pooled)

Summary of Clinical Trials: Data from 3 large, well-controlled efficacy trials demonstrate that treatment with Dutasteride (0.5 mg once daily) reduces the risk of both AUR and BPH-related surgical intervention relative to placebo, improves BPH-related symptoms, decreases prostate volume, and increases maximum urinary flow rates. These data suggest that Dutasteride arrests the disease process of BPH in men with an enlarged prostate.

14.2 Combination With Alpha-Blocker Therapy (CombAT)

The efficacy of combination therapy (Dutasteride 0.5 mg/day plus tamsulosin 0.4 mg/day, n = 1,610) was compared with Dutasteride alone (n = 1,623) or tamsulosin alone (n = 1,611) in a 4-year multicenter, randomized, double-blind trial. Trial entry criteria were similar to the double-blind, placebo-controlled monotherapy efficacy trials described above in section 14.1. Eighty-eight percent (88%) of the enrolled trial population was Caucasian. Approximately 52% of subjects had previous exposure to 5 alpha-reductase inhibitor or alpha adrenergic antagonist treatment. Of the 4,844 subjects randomly assigned to receive treatment, 69% of subjects in the combination group, 67% in the group receiving Dutasteride, and 61% in the tamsulosin group completed 4 years of double-blind treatment.

Effect on Symptom Score: Symptoms were quantified using the first 7 questions of the International Prostate Symptom Score (IPSS) (identical to the AUA-SI). The baseline score was approximately 16.4 units for each treatment group. Combination therapy was statistically superior to each of the monotherapy treatments in decreasing symptom score at Month 24, the primary time point for this endpoint. At Month 24 the mean changes from baseline (±SD) in IPSS total symptom scores were -6.2 (±7.14) for combination, -4.9 (±6.81) for Dutasteride, and -4.3 (±7.01) for tamsulosin, with a mean difference between combination and Dutasteride of -1.3 units (P<0.001; [95% CI: -1.69, -0.86]), and between combination and tamsulosin of -1.8 units (P<0.001; [95% CI: -2.23, -1.40]). A significant difference was seen by Month 9 and continued through Month 48. At Month 48 the mean changes from baseline (±SD) in IPSS total symptom scores were -6.3 (±7.40) for combination, -5.3 (±7.14) for Dutasteride, and -3.8 (±7.74) for tamsulosin, with a mean difference between combination and Dutasteride of -0.96 units (P<0.001; [95% CI: -1.40, -0.52]), and between combination and tamsulosin of -2.5 units (P<0.001; [95% CI: -2.96, -2.07]). See Figure 6.

Figure 6. International Prostate Symptom Score Change From Baseline Over a 48-Month Period (Randomized, Double-Blind, Parallel Group Trial [CombAT Trial])

Effect on Acute Urinary Retention or the Need for BPH-Related Surgery: After 4 years of treatment, combination therapy with Dutasteride and tamsulosin did not provide benefit over monotherapy with Dutasteride in reducing the incidence of AUR or BPH-related surgery.

Effect on Maximum Urine Flow Rate: The baseline Qmax was approximately 10.7 mL/sec for each treatment group. Combination therapy was statistically superior to each of the monotherapy treatments in increasing Qmax at Month 24, the primary time point for this endpoint. At Month 24, the mean increases from baseline (±SD) in Qmax were 2.4 (±5.26) mL/sec for combination, 1.9 (±5.10) mL/sec for Dutasteride, and 0.9 (±4.57) mL/sec for tamsulosin, with a mean difference between combination and Dutasteride of 0.5 mL/sec (P = 0.003; [95% CI: 0.17, 0.84]), and between combination and tamsulosin of 1.5 mL/sec (P<0.001; [95% CI: 1.19, 1.86]). This difference was seen by Month 6 and continued through Month 24. See Figure 7.

The additional improvement in Qmax of combination therapy over monotherapy with Dutasteride was no longer statistically significant at Month 48.

Figure7. Qmax Change From Baseline Over a 24-Month Period (Randomized, Double-Blind, Parallel Group Trial [CombAT Trial])

Effect on Prostate Volume: The mean prostate volume at trial entry was approximately 55 cc. At Month 24, the primary time point for this endpoint, the mean percent changes from baseline (±SD) in prostate volume were -26.9% (±22.57) for combination therapy,

-28.0% (±24.88) for Dutasteride, and 0% (±31.14) for tamsulosin, with a mean difference between combination and Dutasteride of 1.1% (P = NS; [95% CI: -0.6, 2.8]), and between combination and tamsulosin of -26.9% (P<0.001; [95% CI: -28.9, -24.9]). Similar changes were seen at Month 48: -27.3% (±24.91) for combination therapy, -28.0% (±25.74) for Dutasteride Capsules, and +4.6% (±35.45) for tamsulosin.

Dutasteride Capsules 0.5 mg are light yellow, oblong shaped soft gelatin capsules printed with ‘11’ in black ink containing clear light yellow liquid, packaged in bottles of 30 (NDC 25000-011-03) and 90 (NDC 25000-011-07) with child-resistant closures. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Dutasteride is absorbed through the skin. Dutasteride 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 (5.4)].

See FDA-approved patient labeling (Patient Information).

17.1 PSA Monitoring

Physicians should inform patients that Dutasteride Capsules reduces serum PSA levels by approximately 50% within 3 to 6 months of therapy, although it may vary for each individual. For patients undergoing PSA screening, increases in PSA levels while on treatment with Dutasteride Capsules may signal the presence of prostate cancer and should be evaluated by a healthcare provider [see Warnings and Precautions (5.1)].

17.2 Increased Risk of High-grade Prostate Cancer

Physicians should inform patients that there was an increase in high-grade prostate cancer in men treated with 5 alpha-reductase inhibitors (which are indicated for BPH treatment), including Dutasteride Capsules, compared with those treated with placebo in trials looking at the use of these drugs to reduce the risk of prostate cancer [see Indications and Usage (1.3), Warnings and Precautions (5.2), Adverse Reactions (6.1)].

17.3 Exposure of Women-Risk to Male Fetus

Physicians should inform patients that Dutasteride Capsules should not be handled by a woman who is pregnant or who could become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a pregnant woman or woman of childbearing potential comes in contact with leaking Dutasteride Capsules, the contact area should be washed immediately with soap and water [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

17.4 Blood Donation

Physicians should inform men treated with Dutasteride Capsules that they should not donate blood until at least 6 months following their last dose to prevent pregnant women from receiving dutasteride through blood transfusion [see Warnings and Precautions (5.5)]. Serum levels of dutasteride are detectable for 4 to 6 months after treatment ends [see Clinical Pharmacology (12.3)].

Manufactured for:

Time-Cap Labs, Inc.

7 Michael Avenue

Farmingdale, NY 11735, USA

 

Manufactured by:

Marksans Pharma Ltd.

Plot No.L-82, L-83, Verna Indl. Estate,

Verna, Goa-403 722, India

Iss 03/16

------------------------------------------------------------------------------------------------------------

PATIENT INFORMATION

Dutasteride (doo-TAS-ter-ide) Capsules

Dutasteride Capsules are for use by men only.

Read this patient information before you start taking Dutasteride Capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What are Dutasteride Capsules?

Dutasteride Capsules are a prescription medicine that contains dutasteride. Dutasteride Capsules are used to treat the symptoms of benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

·         Improve symptoms

·         Reduce the risk of acute urinary retention (a complete blockage of urine flow)

·         Reduce the risk of the need for BPH-related surgery

Who should NOT take Dutasteride Capsules?

Do Not Take Dutasteride Capsules if you are:

·         Pregnant or could become pregnant. Dutasteride may harm your unborn baby. Pregnant women should not touch Dutasteride capsules. If a woman who is pregnant with a male baby gets enough Dutasteride in her body by swallowing or touching Dutasteride capsules, the male baby may be born with sex organs that are not normal. If a pregnant woman or woman of childbearing potential comes in contact with leaking Dutasteride capsules, the contact area should be washed immediately with soap and water.

·         A child or a teenager.

·         Allergic to dutasteride or any of the ingredients in Dutasteride capsules. See the end of this leaflet for a complete list of ingredients in Dutasteride capsules.

·         Allergic to other 5 alpha-reductase inhibitors, for example, PROSCAR (finasteride) Tablets.

What should I tell my healthcare provider before taking Dutasteride Capsules?

Before you take Dutasteride Capsules, tell your healthcare provider if you:

·         have liver problems

     Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Dutasteride and other medicines may affect each other, causing side effects. Dutasteride may affect the way other medicines work, and other medicines may affect how Dutasteride works.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take Dutasteride Capsules?

·         Take 1 Dutasteride capsules once a day.

·         Swallow Dutasteride capsules whole. Do not crush, chew, or open Dutasteride capsules because the contents of the capsule may irritate your lips, mouth, or throat.

·         You can take Dutasteride capsules with or without food.

·         If you miss a dose, you may take it later that day. Do not make up the missed dose by taking 2 doses the next day.

What should I avoid while taking Dutasteride Capsules?

·         You should not donate blood while taking Dutasteride capsules or for 6 months after you have stopped Dutasteride capsules. This is important to prevent pregnant women from receiving dutasteride through blood transfusions.

What are the possible side effects of Dutasteride Capsules?

Dutasteride Capsules may cause serious side effects, including:

·         Rare and serious allergic reactions, including:

o        swelling of your face, tongue, or throat

o        serious skin reactions, such as skin peeling

Get medical help right away if you have these serious allergic reactions.

Higher chance of a more serious form of prostate cancer.

The most common side effects of Dutasteride Capsules include:

·         trouble getting or keeping an erection (impotence)*

·         a decrease in sex drive (libido)*

·         ejaculation problems*

·         enlarged or painful breasts. If you notice breast lumps or nipple discharge, you should talk to your healthcare provider.

* Some of these events may continue after you stop taking Dutasteride capsules

Depressed mood has been reported in patients receiving Dutasteride capsules

Dutasteride capsules has been shown to reduce sperm count, semen volume, and sperm movement. However, the effect of Dutasteride capsules on male fertility is not known.

Prostate-Specific Antigen (PSA) Test:Your healthcare provider may check you for other prostate problems, including prostate cancer before you start and while you take Dutasteride. A blood test called PSA (prostate-specific antigen) is sometimes used to see if you might have prostate cancer. Dutasteride will reduce the amount of PSA measured in your blood. Your healthcare provider is aware of this effect and can still use PSA to see if you might have prostate cancer. Increases in your PSA levels while on treatment with Dutasteride (even if the PSA levels are in the normal range) should be evaluated by your healthcare provider.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects with Dutasteride. For more information, ask you healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to Marksans Pharma Ltd. at 1-877-290-4008 and/or FDA at 1-800-FDA-1088.

How should I store Dutasteride Capsules?

·         Store Dutasteride Capsules at room temperature (59°F to 86°F or 15°C to 30°C).

·         Dutasteride Capsules may become deformed and/or discolored if kept at high temperatures.

·         Do not use Dutasteride Capsules if your capsules are deformed, discolored, or leaking.

·         Safely throw away medicine that is no longer needed.

Keep Dutasteride Capsules and all medicines out of the reach of children.

Medicines are sometimes prescribed for purposes other than those listed in a patient leaflet. Do not use Dutasteride Capsules for a condition for which it was not prescribed. Do not give Dutasteride Capsules to other people, even if they have the same symptoms that you have. It may harm them.

This patient information leaflet summarizes the most important information about Dutasteride Capsules. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Dutasteride Capsules that is written for health professionals.

What are the ingredients in Dutasteride Capsules?

Active ingredient:Dutasteride.

Inactive ingredients: mono and diglycerides of caprylic/capric acid, butylated hydroxyl toluene, gelatin, glycerin, noncrystallizing Sorbitol solution, titanium dioxide, colour iron oxide yellow, purified water and edible ink Opacode Black (S-1-17823) [containing Isopropyl alcohol, Black iron oxide, N-butyl alcohol, Propylene glycol and Ammonium hydroxide].

How do Dutasteride Capsules work?

Prostate growth is caused by a hormone in the blood called dihydrotestosterone (DHT). Dutasteride Capsules lowers DHT production in the body, leading to shrinkage of the enlarged prostate in most men. While some men have fewer problems and symptoms after 3 months of treatment with Dutasteride Capsules, a treatment period of at least 6 months is usually necessary to see if Dutasteride Capsules will work for you.

Manufactured for:

Time-Cap Labs, Inc.

7 Michael Avenue

Farmingdale, NY 11735, USA

Manufactured by:

Marksans Pharma Ltd.

Plot No.L-82, L-83,

Verna Indl. Estate,

Verna, Goa-403 722, India

Iss 03/16

NDC # 25000-011-03

Dutasteride Capsules, 0.5 mg

30 counts Bottle Label

Rx only

NDC # 25000-011-07

Dutasteride Capsules, 0.5 mg

90 counts Bottle Label

Rx only