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Pharmacology: Pharmacodynamics: Dutasteride is a dual inhibitor of 5α-reductase. It inhibits both type 1 and type 2, 5α-reductase isoenzymes, which are responsible for the conversion of testosterone to 5α-dihydrotestosterone (DHT). DHT is the androgen primarily responsible for hyperplasia of glandular prostatic tissue.
Effects on DHT/Testosterone: The maximum effect of daily doses of Avodart on the reduction of DHT is dose-dependent and is observed within 1-2 weeks. After 1 week and 2 weeks of daily dosing of Avodart 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively.
In benign prostatic hyperplasia (BPH) patients treated with 0.5 mg of dutasteride daily, the median decrease in DHT was 94% at 1 year and 93% at 2 years and the median increase in serum testosterone was 19% at both 1 and 2 years. This is an expected consequence of 5α-reductase inhibition and did not result in any known adverse events.
Clinical Studies: Avodart Monotherapy: Dutasteride 0.5 mg/day or placebo was evaluated in 4325 male subjects with enlarged prostates (>30 cc) in 3 primary efficacy 2-year multicenter, placebo-controlled, double-blind studies.
In men with BPH, Avodart treats and prevents disease progression by reducing the risk of both acute urinary retention (AUR) and the need for surgical intervention (SI) and by providing statistically significant improvement of lower urinary tract symptoms (LUTS), maximum urinary flow rate (Qmax) and prostate volume relative to placebo. These improvements in LUTS, Qmax and prostate volume were seen in the course of 24 months, and LUTS and Qmax continued to improve for a further 2 years in open-label extension studies. In addition, reductions in prostate volume were sustained for a further 2 years in open-label extension studies.
Avodart and Tamsulosin Combination Therapy: Avodart 0.5 mg/day, tamsulosin 0.4 mg/day or the combination of Avodart 0.5 mg plus tamsulosin 0.4 mg was evaluated in 4844 male subjects with enlarged prostates ≥30 cc) in a multicenter, double blind, parallel group study over 2 years. The primary efficacy endpoint at 2 years of treatment was the level of improvement from baseline in the international prostate symptom score (IPSS).
After 2 years of treatment, combination therapy showed a statistically significant adjusted mean improvement in symptom scores from baseline of -6.2 units. The adjusted mean improvements in symptom scores observed with the individual therapies were -4.9 units for Avodart and -4.3 units for tamsulosin. The adjusted mean improvement in flow rate from baseline was 2.4 mL/sec for the combination, 1.9 mL/sec for Avodart and 0.9 mL/sec for tamsulosin. The adjusted mean improvement in BPH Impact Index (BII) from baseline was -2.1 units for the combination, -1.7 for Avodart and -1.5 for tamsulosin.
The reduction in total prostate volume and transition zone volume after 2 years of treatment was statistically significant for combination therapy compared to tamsulosin monotherapy alone.
The primary efficacy endpoint at 4 years of treatment was time to first event of AUR or BPH-related surgery. After 4 years of treatment, combination therapy statistically significantly reduced the risk of AUR or BPH-related surgery (65.8% reduction in risk p<0.001 [95% CI 54.7% to 74.1%]) compared to tamsulosin monotherapy. The incidence of AUR or BPH-related surgery by Year 4 was 4.2% for combination therapy and 11.9% for tamsulosin (p<0.001). Compared to Avodart monotherapy, combination therapy reduced the risk of AUR or BPH-related surgery by 19.6%; the difference between treatment groups was not significant (p=0.18 [95% CI ‑10.9% to 41.7%]). The incidence of AUR or BPH-related surgery by Year 4 was 4.2% for combination therapy and 5.2% for Avodart.
Clinical progression was defined as a composite of worsening symptoms, (IPSS), and BPH‑related events of AUR, incontinence, UTI, and renal insufficiency. Combination therapy was associated with a statistically significantly lower rate of clinical progression compared with tamsulosin (p<0.001, 44.1% risk reduction [95 % CI: 33.6% to 53.0%]) after 4 years. The rates of clinical progression for combination therapy, tamsulosin, and Avodart were: 12.6%, 21.5%, and 17.8%, respectively.
The statistically significant adjusted mean improvement in symptom scores (IPSS) from baseline was maintained from year 2 to year 4. At 4 years, the adjusted mean improvements in symptom scores observed were -6.3 units for combination therapy, -5.3 units for Avodart monotherapy and -3.8 units for tamsulosin monotherapy. After 4 years of treatment, the adjusted mean improvement in flow rate (Qmax) from baseline was 2.4 mL/sec for combination therapy, 2 mL/sec for Avodart monotherapy and 0.7 mL/sec for tamsulosin monotherapy. Compared with tamsulosin, the adjusted mean improvement from baseline in Qmax was statistically significantly greater with combination therapy at each 6‑month assessment from Month 6 to Month 48 (p<0.001). Compared with Avodart, the adjusted mean improvement from baseline in Qmax was not statistically significantly different than with combination therapy (p=0.05 at Month 48).
Combination therapy was significantly superior (p<0.001) to tamsulosin monotherapy and to Avodart monotherapy for the improvement in health outcome parameters BII and BPH-related Health Status (BHS) at 4 years. The adjusted mean improvement in BII from baseline was -2.2 units for the combination, -1.8 for Avodart and -1.2 for tamsulosin. The adjusted mean improvement in BHS from baseline was -1.5 units for the combination, -1.3 for Avodart and -1.1 for tamsulosin.
The reduction in total prostate volume and transition zone volume after 4 years of treatment was statistically significant for combination therapy compared to tamsulosin monotherapy alone.
In a 4-year comparison of Avodart co-administered with tamsulosin and dutasteride or tamsulosin monotherapy in men with BPH (the CombAT study), the incidence of the composite term cardiac failure in the combination group (14/1610, 0.9%) was higher than in either monotherapy group: Avodart, 4/1623 (0.2%) and tamsulosin, 10/1611, (0.6%). The relative risk estimate for time to 1st cardiac failure event was 3.57 [95% CI 1.17, 10.8] for combination treatment compared to Avodart monotherapy and 1.36 [95% CI 0.61, 3.07] compared to tamsulosin monotherapy. No causal relationship between Avodart (alone or in combination with an alpha blocker) and cardiac failure has been established (see Precautions).
Incidence Of Breast Cancer: In BPH monotherapy clinical trials, providing 3374 patient years of exposure to Avodart, there were 2 cases of breast cancer reported in Avodart-treated patients, one after 10 weeks and one after 11 months of treatment and 1 case in a patient who received placebo. The relationship between long-term use of dutasteride and male breast cancer is unknown.
Pharmacokinetics: Absorption: Dutasteride is administered orally in solution as a soft gelatin capsule. Following administration of a single 0.5-mg dose, peak serum concentrations of dutasteride occur within 1-3 hrs.
Absolute bioavailability in man is approximately 60% relative to a 2-hr IV infusion. The bioavailability of dutasteride is not affected by food.
Distribution: Pharmacokinetic data following single and repeated oral doses show that dutasteride has a large volume of distribution (300-500 L). Dutasteride is highly bound to plasma proteins (>99.5%).
Following daily dosing, dutasteride serum concentrations achieve 65% of steady-state concentration after 1 month and approximately 90% after 3 months. Steady-state serum concentrations (Css) of approximately 40 ng/mL are achieved after 6 months of dosing 0.5 mg once a day. Similar to serum, dutasteride concentrations in semen achieved steady-state at 6 months. After 52 weeks of therapy, semen dutasteride concentrations averaged 3.4 ng/mL (range 0.4-14 ng/mL). Dutasteride partitioning from serum into semen averaged 11.5%.
Biotransformation: In vitro, dutasteride is metabolized by the human cytochrome P-450 isoenzyme CYP3A4 to 2 minor monohydroxylated metabolites, but it is not metabolized by CYP1A2, CYP2C9, CYP2C19 or CYP2D6.
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 5 human serum metabolites of dutasteride have been detected in rat serum, however, the stereochemistry of the hydroxyl additions at the 6 and 15 positions in the human and rat metabolites is not known.
Elimination: Dutasteride is extensively metabolized. Following oral dosing of dutasteride 0.5 mg/day to steady-state in humans, 1-15.4% (mean of 5.4%) of the administered dose is excreted as dutasteride in the feces. The remainder is excreted in the feces as 4 major metabolites comprising 39%, 21%, 7% and 7% each of drug-related material and 6 minor metabolites (<5% each).
Only trace amounts of unchanged dutasteride (<0.1% of the dose) are detected in human urine.
At therapeutic concentrations, the terminal t½ of dutasteride is 3-5 weeks.
Serum concentrations remain detectable (>0.1 ng/mL) for up to 4-6 months after discontinuation of treatment.
Linearity/Nonlinearity: Dutasteride pharmacokinetics can be described as first order absorption process and 2 parallel elimination pathways, 1 saturable (concentration-dependent) and 1 non-saturable (concentration-independent).
At low serum concentrations (<3 ng/mL), dutasteride is cleared rapidly by both the concentration-dependent and concentration-independent elimination pathways. Single doses of ≤5 mg showed evidence of rapid clearance and a short t½ of 3-9 days.
At serum concentrations >3 ng/mL, dutasteride is cleared slowly (0.35-0.58 L/hr) primarily by linear, non-saturable elimination with terminal t½ of 3-5 weeks. At therapeutic concentrations, following repeated dosing of 0.5 mg/day, the slower clearance dominates and the total clearance is linear and concentration-independent.
Elderly: Dutasteride pharmacokinetics and pharmacodynamics were evaluated in 36 healthy male subjects between ages of 24 and 87 years following administration of a single 5-mg dose of dutasteride. Exposure of dutasteride, represented by AUC and Cmax values, was not statistically different when comparing age groups. Half-life was not statistically different when comparing the 50-69 year old group to the >70 year old group, which encompasses the age of most men with BPH. No differences in drug effect as measured by DHT reduction were observed between age groups.
Results indicated that no dutasteride dose-adjustment based on age is necessary.
Renal Impairment: The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, <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.
Hepatic Impairment: The effect on the pharmacokinetics of dutasteride in hepatic impairment has not been studied. (See Precautions.).
Toxicology: Preclinical Safety Data: At exposures greatly in excess of those at the clinical dose, reversible and nonspecific CNS-related effects were seen in rats (425-fold) and dogs (315-fold)
Other toxicity findings were consistent with the pharmacological activity of 5α-reductase inhibition. In male rats and dogs, these include effects on accessory reproductive organs and, in male rats, a reversible decrease in fertility. This is considered to have no clinical relevance as there was no effect on sperm development, concentration or motility. Feminization of the external genitalia was noted in male fetuses of female rats and rabbits orally dosed with dutasteride. However, IV administration of dutasteride to pregnant Rhesus monkeys during embryofetal development at doses of up to 2010 ng/animal/day did not produce adverse maternal or fetal toxicity. This dose represents a multiple of at least 186-fold (ng/kg basis) the potential maximum daily dose in a 50-kg woman, resulting from exposure to 5 mL semen (assuming 100% absorption) from a dutasteride-treated man.
Dutasteride was not genotoxic in a wide range of mutagenicity tests.
In a carcinogenicity study in rats, there was an increase in benign interstitial cell tumours in the testis at the high dose (158-fold clinical exposure). However, the endocrine mechanisms believed to be involved in the production of interstitial cell hyperplasia and adenomas in the rat are not relevant to humans. There were no clinically relevant effects on tumour profile in a carcinogenicity study in mice.
