Pharmacology: Pharmacodynamics: DUODART is a combination of two drugs with complementary mechanisms of action to improve symptoms in patients with BPH: dutasteride, a dual 5 α-reductase inhibitor (5 ARI) and tamsulosin hydrochloride, an antagonist of α1a-adrenoreceptors.
The pharmacodynamics of DUODART as a fixed dose combination would not be expected to be different from those of dutasteride and tamsulosin co-administered as separate components.
Dutasteride: Dutasteride is a dual inhibitor of 5 alpha-reductase. It inhibits both type 1 and type 2, 5 alpha-reductase isoenzymes, which are responsible for the conversion of testosterone to 5 alpha-dihydrotestosterone (DHT). DHT is the androgen primarily responsible for hyperplasia of glandular prostatic tissue.
Dutasteride lowers DHT levels, reduces prostate volume, improves lower urinary tract symptoms and urine flow and reduces the risk of AUR and BPH-related surgery.
The maximum effect of daily doses of dutasteride on the reduction on DHT is dose-dependent and is observed within 1-2 weeks. After 1 week and 2 weeks of daily dosing of dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively.
In 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 5 alpha-reductase inhibition and did not result in any known adverse events.
Tamsulosin: Tamsulosin inhibits α1a adrenergic receptors in the stromal prostatic smooth muscle and bladder neck. Approximately 75% of the α1-receptors in the prostate are of the α1a subtype.
Tamsulosin increases maximum urinary flow rate by reducing smooth muscle tension in the prostate and urethra, thereby relieving obstruction. It also improves the complex of irritative and obstructive symptoms in which bladder instability and tension of the smooth muscles of the lower urinary tract play an important role. Alpha-1 adrenergic blockers can reduce blood pressure by lowering peripheral resistance.
Clinical Studies: The following statements reflect the information available on dutasteride and tamsulosin administered separately or as co-administration therapy.
AVODART 0.5mg/day, tamsulosin 0.4mg/day or the co-administration of AVODART 0.5mg plus tamsulosin 0.4mg was evaluated in 4844 male subjects with enlarged prostates (greater than or equal to 30cc) in a multi-centre, double blind, parallel group study over 4 years.
The primary efficacy endpoint at 2 years of treatment was the level of improvement from baseline in the international prostate symptom score (IPSS). The combination of dutasteride and tamsulosin provides superior improvement in symptoms than either component alone. After 2 years of treatment, co-administration 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. These improvements in flow rate and BII were statistically significant for co-administration therapy compared to both monotherapies.
The reduction in total prostate volume and transition zone volume after 2 years of treatment was statistically significant for co-administration 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 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. 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, 2.0 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=0.050 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.
Dutasteride: Dutasteride 0.5 mg/day or placebo was evaluated in 4325 male subjects with enlarged prostates (greater than 30 cc) in three primary efficacy 2-year multi-centre, placebo controlled, double-blind studies.
In men with BPH, dutasteride 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 through to 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.
Cardiac failure: In a 4-year comparison of AVODART coadministered with tamsulosin and AVODART 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 first 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.
In a 4-year chemoprevention, comparison study of placebo and dutasteride in 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL (the REDUCE study), there was a higher incidence of the composite term cardiac failure in subjects taking AVODART (30/4105, 0.7%) versus placebo (16/4126, 0.4%) for a relative risk estimate for time to first cardiac failure event of 1.91 [95% CI 1.04, 3.50]. In a post-hoc analysis of concomitant alpha blocker use, there was a higher incidence of the composite term cardiac failure in subjects taking AVODART and an alpha blocker concomitantly (12/1152, 1.0%), compared to subjects not taking dutasteride and an alpha blocker concomitantly: AVODART and no alpha blocker (18/2953, 0.6%), placebo and an alpha blocker (1/1399, <0.1%), placebo and no alpha blocker (15/2727, 0.6%). No causal relationship between dutasteride (alone or in combination with an alpha blocker) and cardiac failure has been established (see Precautions).
Prostate cancer and high grade tumours: In a 4-year comparison of placebo and AVODART in 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL (the REDUCE study), 6,706 subjects had prostate needle biopsy data available for analysis to determine Gleason Scores. There were 1517 subjects diagnosed with prostate cancer in the study. The majority of biopsy-detectable prostate cancers in both treatment groups were diagnosed as low grade (Gleason 5-6). There was no difference in the incidence of Gleason 7-10 cancers (p=0.81).
There was a higher incidence of Gleason 8-10 prostate cancers in the AVODART group (n=29, 0.9%) compared to the placebo group (n=19, 0.6%) (p=0.15). In Years 1-2, the number of subjects with Gleason 8-10 cancers was similar in the AVODART group (n=17, 0.5%) and the placebo group (n=18, 0.5%). In Years 3-4, more Gleason 8-10 cancers were diagnosed in the AVODART group (n=12, 0.5%) compared with the placebo group (n=1, <0.1%) (p=0.0035). There are no data available on the effect of dutasteride beyond 4 years in men at risk of developing prostate cancer. The percentage of subjects diagnosed with Gleason 8-10 cancers was consistent across study time periods (Years 1-2 and Years 3-4) in the AVODART group (0.5% in each time period), while in the placebo group, the percentage of subjects diagnosed with Gleason 8-10 cancers was lower during Years 3-4 than in Years 1-2 (<0.1% versus 0.5%, respectively). In a 4 year BPH study (CombAT) where there were no protocol-mandated biopsies and all diagnoses of prostate cancer were based on for-cause biopsies, the rates of Gleason 8-10 cancer were (n=8, 0.5%) for AVODART, (n=11, 0.7%) for tamsulosin and (n=5, 0.3%) for combination therapy (see Precautions).
The results of an epidemiological, population-based study (n=174,895) in community practice settings show that the use of 5-ARIs to treat BPH/LUTS is not associated with an increased risk of prostate cancer mortality (hazard ratio adjusted for competing risks: 0.85, 95% CI 0.72, 1.01) when compared with the use of alpha-blockers. Similar results were reported in an epidemiological study (n=13,892) of men with prostate cancer in the UK (adjusted hazard ratio for prostate cancer mortality for 5-ARI users versus non-users: 0.86; 95% CI 0.69, 1.06). A prospective cohort study, the Health Professional's Follow-up Study (n=38,058), also found that 5-ARI use was not associated with fatal prostate cancer (adjusted HR: 0.99; 95% CI 0.58, 1.69).
Effects on prostate specific antigen (PSA) and prostate cancer detection: In the REDUCE study, patients with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL, AVODART treatment caused a decrease in mean serum PSA by approximately 50% after six months of treatment with a large variability (standard deviation of 30%) among patients. The PSA suppression observed at six months was similar in men who did or who did not develop biopsy-detectable prostate cancer during the study (see Precautions).
Incidence of breast cancer: In BPH monotherapy clinical trials, providing 3374 patient years of exposure to AVODART, there were 2 cases of male 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. In subsequent clinical trials in BPH and 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL providing 17489 patient years exposure to AVODART and 5027 patient years exposure to AVODART and tamsulosin combination, there were no reported breast cancer cases in any of the treatment groups.
Two case control, epidemiological studies, one conducted in a US (n=339 breast cancer cases and n=6,780 controls) and the other in a UK (n=398 breast cancer cases and n=3,930 controls) healthcare database, showed no increase in the risk of developing male breast cancer with the use of 5 ARIs (see Precautions). Results from the first study did not identify a positive association for male breast cancer (relative risk for ≥ 1 year of use before breast cancer diagnosis compared with < 1 year of use: 0.70: 95% CI 0.34, 1.45). In the second study, the estimated odds ratio for breast cancer associated with the use of 5-ARIs compared with non-use was 1.08: 95% CI 0.62, 1.87).
The relationship between long term use of AVODART and male breast cancer has not been established.
Tamsulosin: Tamsulosin rapidly (from one week) increases maximum urinary flow rate by reducing smooth muscle tension in the prostate and urethra, thereby relieving obstruction. It also improves the complex of irritative and obstructive symptoms in which bladder instability and tension of the smooth muscles of the lower urinary tract play an important role.
Pharmacokinetics: Bioequivalence was demonstrated between dutasteride-tamsulosin and concomitant dosing with separate dutasteride and tamsulosin capsules.
The tamsulosin HCl component of DUODART consists of a multi-unit pelletised preparation which has modified release properties. The individual pellets consist of a drug core and an outer coating layer which reduces the rate of dissolution of the drug.
The single dose bioequivalence study was performed in both the fasted and fed states. A 30% reduction in Cmax was observed for the tamsulosin component of dutasteride-tamsulosin in the fed state compared to the fasted state. Food had no effect on AUC of tamsulosin.
Absorption: Dutasteride: 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 to 3 hours.
Absolute bioavailability in man is approximately 60% relative to a 2 hour intravenous infusion. The bioavailability of dutasteride is not affected by food.
Tamsulosin: Tamsulosin hydrochloride is absorbed from the intestine and is almost completely bioavailable. Tamsulosin hydrochloride exhibits linear kinetics, following single and multiple dosing, with achievement of steady state concentrations by the fifth day of once-a-day dosing. The rate of absorption of tamsulosin hydrochloride is reduced by a recent meal. Uniformity of absorption can be promoted by the patient always taking tamsulosin hydrochloride approximately 30 minutes after the same meal each day.
Distribution: Dutasteride: 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 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 nanograms/mL are achieved after 6 months of dosing 0.5 mg once a day. Similarly to serum, dutasteride concentrations in semen achieved steady state at 6 months. After 52 weeks of therapy, semen dutasteride concentrations averaged 3.4 nanograms/mL (range 0.4 to 14 nanograms/mL). Dutasteride partitioning from serum into semen averaged 11.5%.
Tamsulosin: The mean steady-state apparent volume of distribution of tamsulosin hydrochloride after intravenous administration to ten healthy male adults was 16L, which is suggestive of distribution into extracellular fluids in the body.
Tamsulosin hydrochloride is extensively bound to human plasma proteins (94% to 99%), primarily alpha-1 acid glycoprotein (AAG), with linear binding over a wide concentration range (20 to 600 nanograms/mL).
Biotransformation: Dutasteride: In vitro, dutasteride is metabolised by the human cytochrome P450 isoenzyme CYP3A4 to two minor monohydroxylated metabolites, but it is not metabolised by CYP1A2, CY2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 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 five 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.
Tamsulosin: There is no enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolised by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. In vitro results indicate that CYP3A4 and CYP2D6 are involved in metabolism of tamsulosin as well as some minor participation of other CYP isoenzymes. Inhibition of hepatic drug metabolizing enzymes may lead to increased exposure to tamsulosin. (see Precautions and Interactions) The metabolites of tamsulosin hydrochloride undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.
Elimination: Dutasteride: Dutasteride is extensively metabolised. Following oral dosing of dutasteride 0.5 mg/day to steady state in humans, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as dutasteride in the faeces. The remainder is excreted in the faeces as 4 major metabolites comprising 39%, 21%, 7%, and 7% each of drug-related material and 6 minor metabolites (less than 5% each).
Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are detected in human urine.
At therapeutic concentrations, the terminal half-life of dutasteride is 3 to 5 weeks.
Serum concentrations remain detectable (greater than 0.1 nanograms/mL) for up to 4 to 6 months after discontinuation of treatment.
At low serum concentrations (less than 3 nanograms/mL), dutasteride is cleared rapidly by both the concentration-dependent and concentration-independent elimination pathways. Single doses of 5 mg or less showed evidence of rapid clearance and a short half-life of 3 to 9 days.
At serum concentrations, greater than 3 nanograms/mL, dutasteride is cleared slowly (0.35 to 0.58 L/h) primarily by linear, non-saturable elimination with terminal half-life of 3 to 5 weeks. At therapeutic concentrations, following repeat dosing of 0.5 mg/day, the slower clearance dominates and the total clearance is linear and concentration-independent.
Tamsulosin: Tamsulosin half-life is 5 to 7 hours. Approximately 10% is excreted unchanged in urine.
Elderly: Dutasteride: Dutasteride pharmacokinetics and pharmacodynamics were evaluated in 36 healthy male subjects between the 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 greater than 70 years 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.
Tamsulosin: Cross-study comparison of tamsulosin hydrochloride overall exposure (AUC) and half-life indicate that the pharmacokinetic disposition of tamsulosin hydrochloride may be slightly prolonged in elderly males compared to young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin hydrochloride binding to AAG, but diminishes with age, resulting in a 40% overall higher exposure (AUC) in subjects of age 55 to 75 years compared to subjects of age 20 to 32 years.
Renal impairment: Dutasteride: 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.
Tamsulosin: The pharmacokinetics of tamsulosin hydrochloride have been compared in 6 subjects with mild-moderate (30 ≤ CLcr < 70 mL/min/1.73m2) or moderate-severe (10 ≤ CLcr < 30 mL/min/1.73m2) renal impairment and 6 normal subjects (CLcr > 90 mL/min/1.73m2). While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in tamsulosin hydrochloride capsules dosing. However, patients with endstage renal disease (CLcr < 10 mL/min/1.73m2) have not been studied.
Hepatic impairment: Dutasteride: The effect on the pharmacokinetics of dutasteride in hepatic impairment has not been studied (see Precautions). Because dutasteride is extensively metabolised, exposure could be higher in hepatically impaired patients.
Tamsulosin: The pharmacokinetics of tamsulosin hydrochloride have been compared in 8 subjects with moderate hepatic dysfunction (Child-Pugh's classification: Grades A and B) and 8 normal subjects. While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride does not change significantly with only a modest (32%) change in intrinsic clearance of unbound tamsulosin hydrochloride. Therefore, patients with moderate hepatic dysfunction do not require an adjustment in tamsulosin hydrochloride dosage. Tamsulosin hydrochloride has not been studied in patients with severe hepatic dysfunction.
Toxicology: Preclinical Safety Data: Non-clinical studies have not been conducted with DUODART. Dutasteride and tamsulosin hydrochloride individually have been extensively evaluated in animal toxicity tests and findings were consistent with the known pharmacological actions of 5 alpha-reductase inhibitors and alpha-adrenergic blockers. The following statements reflect the information available on the individual components.
Carcinogenesis, mutagenesis: Dutasteride and tamsulosin hydrochloride showed no evidence of genotoxicity in a wide range of in vitro and in vivo tests.
Dutasteride: In a carcinogenicity study in rats, dutasteride produced 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.
Tamsulosin: In carcinogenicity studies in rats and mice, tamsulosin hydrochloride produced an increased incidence of proliferative changes of the mammary glands in females. These findings, which are probably mediated by hyperprolactinaemia and only occurred at high dose levels, are regarded as not clinically relevant.
Reproductive toxicology: Dutasteride: Dutasteride produced a reversible decrease in fertility in male rats consistent with the pharmacological activity of 5 alpha-reductase inhibition on accessory reproductive organs. This is considered to have no clinical relevance as there was no effect on sperm development, concentration or motility.
Feminisation of the external genitalia was noted in male fetuses of female rats and rabbits orally dosed with dutasteride. However, intravenous administration of dutasteride to pregnant Rhesus monkeys during embryofetal development at doses of up to 2010 nanograms/animal/day did not produce adverse maternal or fetal toxicity. This dose represents a multiple of at least 186-fold (nanograms/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.
Tamsulosin: High doses of tamsulosin hydrochloride resulted in a reversible reduction in fertility in male rats considered possibly due to changes of semen content or impairment of ejaculation. Effects of tamsulosin on sperm counts or sperm function have not been evaluated.
Administration of tamsulosin hydrochloride to pregnant female rats and rabbits at higher than the therapeutic dose showed no evidence of foetal harm.