Pharmacology: Pharmacodynamics: Mechanism of action: Duodart is a combination of two drugs with complementary mechanisms of action to improve symptoms in patients with BPH: dutasteride, a dual 5α-reductase inhibitor (5-ARI) and tamsulosin hydrochloride, an antagonist of α1a-adrenoreceptors.
Dutasteride: Dutasteride inhibits the Type 1 and 2 5α-reductase isoenzymes which are responsible for the conversion of testosterone to 5α-dihydrotestosterone (DHT) and therefore causes a fall in the DHT level in the circulation and in the prostate. DHT is the main androgen responsible for hyperplasia of the glandular prostate tissue.
Dutasteride reduces the size of the prostate, relieves the symptoms, improves urine flow and reduces the risk of acute urinary retention and the need for surgery.
Tamsulosin: Tamsulosin is a selective α1-adrenoreceptor blocker for the symptomatic treatment of functional symptoms of benign prostatic hyperplasia. It binds selectively and competitively to postsynaptic α1-adrenoreceptors (mainly the α1a subtype - approximately 75% of the α1-receptors in the prostate are of the α1a subtype) responsible for contraction of the smooth muscle of the prostate and urethra. Tamsulosin thereby reduces smooth muscle tension in the prostate and urethra. This increases maximum urinary flow rate and reduces urinary tract 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.
Effects on DHT/testosterone: The peak effect of dutasteride in the sense of reduction of DHT is dose-dependent and occurs within 1-2 weeks. After taking dutasteride (0.5 mg/day) for one or two weeks, the mean DHT concentrations in the serum were reduced by 85% and 90% respectively, after one year by 94% and after 2 years by 93%. After discontinuation of treatment the DHT serum concentrations associated with the clinical effects return to the baseline values within about 4 months.
The mean rise in the serum testosterone level was 19% after both one and two years. The testosterone concentrations fluctuated within the normal physiological range.
Safety Pharmacodynamics: Adrenergic alpha-1 receptor blockers can reduce blood pressure by lowering peripheral resistance.
CLINICAL TRIALS: Dutasteride and tamsulosin combination therapy: No efficacy studies have been conducted with Duodart. The following statements reflect the available information on co-administration of dutasteride and tamsulosin. Dutasteride (0.5 mg/day), tamsulosin (0.4 mg/day) and the combination of dutasteride 0.5 mg plus tamsulosin 0.4 mg were evaluated in 4,844 male subjects with enlarged prostate (≥ 30 cm³) in a multicentre, double blind, parallel group study (pivotal trial: CombAT) over 4 years.
The primary efficacy end-point after 4 years was the time until the first occurrence of an acute urinary retention or a BPH-associated surgical intervention. After 4 years of treatment, compared with the tamsulosin monotherapy, the combined treatment led to a significant reduction (by 65.8% [95% Cl - 54.7%-74.1%] of the risk for an acute urinary retention or a BPH-associated surgical intervention (p<0.001)). Compared with dutasteride monotherapy the reduction of the risk was 19.6% (95% Cl - 10.9%-41.7%); here the difference between the two treatment groups was not significant. After 4 years the incidence of acute urinary retention or a BPH-associated surgical intervention was 4.2% for the combination, 11.9% for the tamsulosin monotherapy (p<0.001) and 5.2% for the dutasteride monotherapy.
As secondary end-point, the change compared with the baseline values in the International Prostate System Score (IPSS) was evaluated. Already after 2 years there was a statistically significant mean improvement of the symptom score under the combined therapy, by -6.2 points compared with the baseline values, and the difference compared with the monotherapies was significant compared with dutasteride after 3 months and compared with tamsulosin after 9 months. Under the combined therapy this improvement of the symptomatology could be maintained up to the end of the 4-year treatment period. After 4 years the mean improvement of the symptom score under the combined therapy was by -6.3 points, under the dutasteride monotherapy by -5.3 points (p<0.001) and under the tamsulosin monotherapy by -3.8 points (p<0.001).
After 4 years, the mean increase in maximum flow rate (Qmax) from baseline was 2.4 ml/sec for the combination, 2.0 ml/sec for dutasteride and 0.7 ml/sec for tamsulosin. The mean improvement in BII (BPH Impact Index) from baseline was -2.2 points for the combination, -1.8 for dutasteride and -1.2 for tamsulosin.
Although the combination therapy provided lasting improvement of symptoms over the whole four years of the study compared to dutasteride monotherapy, the greatest benefit of the combination therapy over dutasteride monotherapy was seen in the first 12 months of the treatment, which can be explained by the known rapid onset of action of alpha-receptor blockers.
In the CombAT trial the incidences of investigator-judged drug-related adverse events in the organ system "Reproductive system and breast" during the first year of therapy were higher in the dutasteride + tamsulosin combination therapy group than in the dutasteride and tamsulosin monotherapy groups: impotence (combination: 6%, dutasteride: 5%, tamsulosin: 3%), altered (decreased) libido (combination: 5%, dutasteride: 4%, tamsulosin: 2%), ejaculation disorders (combination: 9%, dutasteride: 1%, tamsulosin: 3%).
Dutasteride monotherapy: For information on dutasteride monotherapy see the prescribing information of Avodart.
Prostate cancer (in particular high-grade tumours): In a 4-year comparison of placebo and Avodart (the REDUCE study) in 8,231 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 (in the case of men 50 to 60 years of age), or 3 ng/mL and 10.0 ng/mL (>60 years of age), 6,706 subjects had prostate needle biopsy (primarily protocol mandated, i.e. not carried out due to symptoms and/or clinical suspicions) 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, 70%).
There was a higher incidence of Gleason 8-10 prostate cancers in the dutasteride 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 dutasteride 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 dutasteride 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 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 dutasteride 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). There was no significant difference between dutasteride and placebo in the incidence of Gleason 7-10 cancers.
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 0.5% (n=8) for dutasteride, 0.7% (n=11) for tamsulosin and 0.3% (n=5) for combination therapy.
No statement can be made yet on a possible causal relationship between dutasteride and high-grade prostate cancer, the clinical significance of the observed imbalance is unknown.
Pharmacokinetics: Bioequivalence was demonstrated between Duodart and concomitant dosing with separate dutasteride and tamsulosin capsules.
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 Duodart in the fed state compared to the fasted state. Food had no effect on the AUC of tamsulosin. The bioavailability of dutasteride is not affected by concomitant intake of food.
Absorption: Dutasteride: After oral administration the peak serum concentration of dutasteride is attained within 1-3 hours. Absolute bioavailability compared with a 2-hour intravenous infusion is approx. 60%.
Tamsulosin: Tamsulosin hydrochloride is absorbed from the intestine and is almost completely available. After a single dose following a meal, tamsulosin plasma concentrations reach their peak after 6 hours.
Tamsulosin hydrochloride has linear absorption kinetics, with achievement of steady state concentrations by about 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 30 minutes after the same meal each day.
Tamsulosin plasma levels exhibit considerable inter-individual variability with both single and multiple dosing.
Distribution: Dutasteride: Dutasteride has a large volume of distribution (300-500 l) and is highly plasma protein bound (> 99.5%; to albumin and α1-acid glycoprotein). The steady-state serum concentration (Css) of approx. 40 ng/ml at a dose of 0.5 mg dutasteride a day is achieved after 6 months. After 1 and 3 months the dutasteride serum levels reach 65% and about 90% respectively of the steady-state concentration. The steady-state concentration is also reached in seminal fluid after 6 months.
After administration for 12 months the dutasteride concentration in seminal fluid was on average 3.4 ng/ml (range 0.4-14 ng/ml), i.e. on average 11.5% of the serum level.
Tamsulosin: The volume of distribution of tamsulosin hydrochloride is low (approx. 0.2l/kg). Tamsulosin hydrochloride is extensively bound to human plasma proteins (94% to 99%), primarily alpha-1 acid glycoprotein (AAG).
Metabolism: Dutasteride: Dutasteride undergoes extensive metabolism. It is mainly hydroxylated and dehydrogenated to inactive metabolites. There are 4 major metabolites and 6 subsidiary metabolites. Hydroxylation takes place in vitro via CYP3A4.
Tamsulosin: Tamsulosin hydrochloride is extensively metabolised slowly by cytochrome P450 enzymes in the liver. In vitro results indicate that CYP3A4 and CYP2D6, and to a minor extent some other CYP isoenzymes, are involved in the metabolism of tamsulosin. However, the majority is present in the plasma in the form of the unchanged active ingredient. None of the metabolites is more active or more toxic than the parent substance. The metabolites of tamsulosin hydrochloride undergo extensive conjugation to glucuronide or sulphate prior to renal excretion.
Elimination: Dutasteride: 5.4% of the dose administered is excreted as unchanged dutasteride in the faeces, and the rest in the form of metabolites. Only traces of the unchanged substance (less than 0.1% of the dose) can be detected in the urine.
Dutasteride clearance is low. The elimination half-life is 3-5 weeks.
Tamsulosin: Following oral administration of tamsulosin in the form of modified release capsules, the apparent elimination half life in the fed state after a single dose is approximately 10 hours and in the steady state is approximately 13 hours. Approximately 10% of the substance is excreted unchanged in urine.
Kinetics of special patient populations: No pharmacokinetic studies have been conducted with Duodart on special patient populations. The following statements reflect the information available on the individual components.
Elderly: Dutasteride: In the age groups >50-65 years and >70 years there were no statistically significant differences in pharmacokinetics.
Tamsulosin: Findings indicate that overall exposure is approx. 40% increased in patients aged 55-75 years compared with young males.
Renal Impairment: Dutasteride: The effects of renal impairment on the pharmacokinetics of dutasteride have not been investigated. As less than 0.1% of the dose is excreted in the urine, no effect on the serum levels is to be expected.
Tamsulosin: No clinically relevant changes in the pharmacokinetics of tamsulosin were observed in patients with mild to moderate (30 ≤ CLcr < 70 mL/min/1.73m2) or moderate to severe (10 ≤ CLcr < 30 mL/min/1.73m2) renal impairment compared with subjects with normal renal function. However, patients with terminal renal disease (CLcr < 10 mL/min/1.73m2) have not been studied.
Hepatic impairment: Dutasteride: The effects of hepatic impairment on the pharmacokinetics of dutasteride have not been investigated (see Precautions).
Tamsulosin: In patients with mild to moderate hepatic dysfunction (Child-Pugh classification: Grades A and B), no clinically relevant changes in the pharmacokinetics of tamsulosin hydrochloride were observed. Tamsulosin hydrochloride has not been studied in patients with severe hepatic dysfunction (Child-Pugh C).
Toxicology: Preclinical data: No preclinical studies have 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.
Mutagenicity and carcinogenicity: 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 an increased incidence of benign interstitial cell tumours in the testes was recorded after exposure equivalent to 158 times the clinical exposure. This is probably attributable to the pharmacological effects of high doses of dutasteride and is therefore presumably clinically irrelevant. In a carcinogenicity study in mice no clinically relevant effects on the tumour profile were found.
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.
Reproduction Toxicity: Dutasteride: In male rats and dogs effects on accessory reproductive organs were observed with dutasteride and in male rats also reversible loss of fertility. These effects are regarded as clinically irrelevant as they did not affect the development, concentration or motility of the sperm.
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.