Mechanism Of Action
Dutasteride inhibits the conversion of testosterone to dihydrotestosterone (DHT). DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5 alpha-reductase, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver.
Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5 alpha-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor.
Effect On 5 Alpha-Dihydrotestosterone And Testosterone
The maximum effect of daily doses of dutasteride on the reduction of DHT is dose dependent and is observed within 1 to 2 weeks. After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. In patients with BPH treated with dutasteride 0.5 mg/day for 4 years, the median decrease in serum DHT was 94% at 1 year, 93% at 2 years, and 95% at both 3 and 4 years. The median increase in serum testosterone was 19% at both 1 and 2 years, 26% at 3 years, and 22% at 4 years, but the mean and median levels remained within the physiologic range.
In patients with BPH treated with 5 mg/day of dutasteride or placebo for up to 12 weeks prior to transurethral resection of the prostate, mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group compared with placebo (784 and 5,793 pg/g, respectively, P<0.001). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group compared with placebo (2,073 and 93 pg/g, respectively, P<0.001).
Adult males with genetically inherited type 2 5 alpha-reductase deficiency also have decreased DHT levels. These 5 alpha-reductase deficient males have a small prostate gland throughout life and do not develop BPH. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5 alpha-reductase-deficiency have been observed in these individuals.
Effects On Other Hormones
In healthy volunteers, 52 weeks of treatment with dutasteride 0.5 mg/day (n = 26) resulted in no clinically significant change compared with placebo (n = 23) in sex hormone-binding globulin, estradiol, luteinizing hormone, follicle-stimulating hormone, thyroxine (free T4), and dehydroepiandrosterone. Statistically significant, baseline-adjusted mean increases compared with placebo were observed for total testosterone at 8 weeks (97.1 ng/dL, P<0.003) and thyroid-stimulating hormone at 52 weeks (0.4 mcIU/mL, P<0.05). The median percentage changes from baseline within the dutasteride group were 17.9% for testosterone at 8 weeks and 12.4% for thyroid-stimulating hormone at 52 weeks. After stopping dutasteride for 24 weeks, the mean levels of testosterone and thyroidstimulating hormone had returned to baseline in the group of subjects with available data at the visit. In subjects with BPH treated with dutasteride in a large randomized, double-blind, placebo-controlled trial, there was a median percent increase in luteinizing hormone of 12% at 6 months and 19% at both 12 and 24 months.
Plasma lipid panel and bone mineral density were evaluated following 52 weeks of dutasteride 0.5 mg once daily in healthy volunteers. There was no change in bone mineral density as measured by dual energy x-ray absorptiometry compared with either placebo or baseline. In addition, the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins, and triglycerides) was unaffected by dutasteride. No clinically significant changes in adrenal hormone responses to adrenocorticotropic hormone (ACTH) stimulation were observed in a subset population (n = 13) of the 1-year healthy volunteer trial.
Following administration of a single 0.5-mg dose of a soft gelatin capsule, time to peak serum concentrations (Tmax) of dutasteride occurs within 2 to 3 hours. Absolute bioavailability in 5 healthy subjects is approximately 60% (range: 40% to 94%). When the drug is administered with food, the maximum serum concentrations were reduced by 10% to 15%. This reduction is of no clinical significance.
Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid glycoprotein (96.6%).
In a trial of healthy subjects (n = 26) receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at 6 months. On average, at 12 months 11.5% of serum dutasteride concentrations partitioned into semen.
Metabolism And Elimination
Dutasteride is extensively metabolized in humans. In vitro studies showed that dutasteride is metabolized by the CYP3A4 and CYP3A5 isoenzymes. Both of these isoenzymes produced the 4′- hydroxydutasteride, 6-hydroxydutasteride, and the 6,4′-dihydroxydutasteride metabolites. In addition, the 15-hydroxydutasteride metabolite was formed by CYP3A4. Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In human serum following dosing to steady state, unchanged dutasteride, 3 major metabolites (4′-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and 2 minor metabolites (6,4′-dihydroxydutasteride and 15-hydroxydutasteride), as assessed by mass spectrometric response, have been detected. The absolute stereochemistry of the hydroxyl additions in the 6 and 15 positions is not known. In vitro, the 4′-hydroxydutasteride and 1,2-dihydrodutasteride metabolites are much less potent than dutasteride against both isoforms of human 5 alpha-reductase. The activity of 6β- hydroxydutasteride is comparable to that of dutasteride.
Dutasteride and its metabolites were excreted mainly in feces. As a percent of dose, there was approximately 5% unchanged dutasteride (1% to 15%) and 40% as dutasteride-related metabolites (2% to 90%). Only trace amounts of unchanged dutasteride were found in urine (<1%). Therefore, on average, the dose unaccounted for approximated 55% (range: 5% to 97%).
The terminal elimination half-life of dutasteride is approximately 5 weeks at steady state. The average steady-state serum dutasteride concentration was 40 ng/mL following 0.5 mg/day for 1 year. Following daily dosing, dutasteride serum concentrations achieve 65% of steady-state concentration after 1 month and approximately 90% after 3 months. Due to the long half-life of dutasteride, serum concentrations remain detectable (greater than 0.1 ng/mL) for up to 4 to 6 months after discontinuation of treatment.
Dutasteride pharmacokinetics have not been investigated in subjects younger than 18 years.
No dose adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were evaluated in 36 healthy male subjects aged between 24 and 87 years following administration of a single 5-mg dose of dutasteride. In this single-dose trial, dutasteride half-life increased with age (approximately 170 hours in men aged 20 to 49 years, approximately 260 hours in men aged 50 to 69 years, and approximately 300 hours in men older than 70 years). Of 2,167 men treated with dutasteride in the 3 pivotal trials, 60% were age 65 and over and 15% were age 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients.
AVODART is contraindicated in pregnancy and women of childbearing potential and is not indicated for use in other women [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. The pharmacokinetics of dutasteride in women have not been studied.
The effect of race on dutasteride pharmacokinetics has not been studied.
The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5-mg dose of dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment.
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.
Cytochrome P450 Inhibitors
No clinical drug interaction trials have been performed to evaluate the impact of CYP3A enzyme inhibitors on dutasteride pharmacokinetics. However, based on in vitro data, blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4/5 such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, troleandomycin, and ciprofloxacin.
Dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1,000 ng/mL, 25 times greater than steady-state serum concentrations in humans.
In a single-sequence, crossover trial in healthy volunteers, the administration of tamsulosin or terazosin in combination with AVODART had no effect on the steadystate pharmacokinetics of either alpha-adrenergic antagonist. Although the effect of administration of tamsulosin or terazosin on dutasteride pharmacokinetic parameters was not evaluated, the percent change in DHT concentrations was similar for AVODART alone compared with the combination treatment.
Calcium Channel Antagonists
In a population pharmacokinetics analysis, a decrease in clearance of dutasteride was noted when coadministered with the CYP3A4 inhibitors verapamil (-37%, n = 6) and diltiazem (-44%, n = 5). In contrast, no decrease in clearance was seen when amlodipine, another calcium channel antagonist that is not a CYP3A4 inhibitor, was coadministered with dutasteride (+7%, n = 4).
The decrease in clearance and subsequent increase in exposure to dutasteride in the presence of verapamil and diltiazem is not considered to be clinically significant. No dose adjustment is recommended.
Administration of a single 5-mg dose of AVODART followed 1 hour later by 12 g cholestyramine did not affect the relative bioavailability of dutasteride in 12 normal volunteers.
In a trial of 20 healthy volunteers, AVODART did not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks.
In a trial of 23 healthy volunteers, 3 weeks of treatment with AVODART 0.5 mg/day did not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time when administered with warfarin.
Other Concomitant Therapy
Although specific interaction trials were not performed with other compounds, approximately 90% of the subjects in the 3 randomized, double-blind, placebo-controlled safety and efficacy trials receiving AVODART were taking other medications concomitantly. No clinically significant adverse interactions could be attributed to the combination of AVODART and concurrent therapy when AVODART was coadministered with anti-hyperlipidemics, angiotensinconverting enzyme (ACE) inhibitors, beta-adrenergic blocking agents, calcium channel blockers, corticosteroids, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), phosphodiesterase Type V inhibitors, and quinolone antibiotics.
Animal Toxicology And/Or Pharmacology
Central Nervous System Toxicology Studies
In rats and dogs, repeated oral administration of dutasteride resulted in some animals showing signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes at exposures 425- and 315-fold the expected clinical exposure (of parent drug), respectively.
AVODART 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 white. 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 doubleblind 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 avodart 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)
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, AVODART was associated with a statistically significantly lower incidence of AUR (1.8% for AVODART 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 AVODART 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 (AVODART versus placebo) were noted at the earliest posttreatment 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, Placebocontrolled 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 AVODART 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 AVODART (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 AVODART arrests the disease process of BPH in men with an enlarged prostate.
Combination With Alpha-Blocker Therapy (CombAT)
The efficacy of combination therapy (AVODART 0.5 mg/day plus tamsulosin 0.4 mg/day, n = 1,610) was compared with AVODART 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 white. 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 AVODART, 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 AVODART, and -4.3 (±7.01) for tamsulosin, with a mean difference between combination and AVODART 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 AVODART, and -3.8 (±7.74) for tamsulosin, with a mean difference between combination and AVODART 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 AVODART and tamsulosin did not provide benefit over monotherapy with AVODART 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 AVODART, and 0.9 (±4.57) mL/sec for tamsulosin, with a mean difference between combination and AVODART 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 AVODART was no longer statistically significant at Month 48.
Figure 7. 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 AVODART, and 0% (±31.14) for tamsulosin, with a mean difference between combination and AVODART 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 AVODART, and +4.6% (±35.45) for tamsulosin.
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