- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6. Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- Administrative data
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Adults (including elderly):The recommended dose of Avodart is one capsule (0.5 mg) taken orally once a day. 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. The capsules may be taken with or without food. Although an improvement may be observed at an early stage, it can take up to 6 months before a response to the treatment can be achieved. No dose adjustment is necessary in the elderly.
Renal impairmentThe effect of renal impairment on dutasteride pharmacokinetics has not been studied. No adjustment in dosage is anticipated for patients with renal impairment (see section 5.2).
Hepatic impairmentThe effect of hepatic impairment on dutasteride pharmacokinetics has not been studied so caution should be used in patients with mild to moderate hepatic impairment (see section 4.4 and section 5.2). In patients with severe hepatic impairment, the use of dutasteride is contraindicated (see section 4.3).
Effects of other drugs on the pharmacokinetics of dutasteride
Use together with CYP3A4 and/or P-glycoprotein-inhibitors:Dutasteride is mainly eliminated via metabolism. In vitro studies indicate that this metabolism is catalysed by CYP3A4 and CYP3A5. No formal interaction studies have been performed with potent CYP3A4 inhibitors. However, in a population pharmacokinetic study, dutasteride serum concentrations were on average 1.6 to 1.8 times greater, respectively, in a small number of patients treated concurrently with verapamil or diltiazem (moderate inhibitors of CYP3A4 and inhibitors of P-glycoprotein) than in other patients. Long-term combination of dutasteride with drugs that are potent inhibitors of the enzyme CYP3A4 (e.g. ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally) may increase serum concentrations of dutasteride. Further inhibition of 5-alpha reductase at increased dutasteride exposure, is not likely. However, a reduction of the dutasteride dosing frequency can be considered if side effects are noted. It should be noted that in the case of enzyme inhibition, the long half-life may be further prolonged and it can take more than 6 months of concurrent therapy before a new steady state is reached. Administration of 12g colestyramine one hour after a 5mg single dose of dutasteride did not affect the pharmacokinetics of dutasteride.
Effects of dutasteride on the pharmacokinetics of other drugsDutasteride has no effect on the pharmacokinetics of warfarin or digoxin. This indicates that dutasteride does not inhibit/induce CYP2C9 or the transporter P-glycoprotein. In vitro interaction studies indicate that dutasteride does not inhibit the enzymes CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2D6, CYP2C9, CYP2C19, CYP2B6 or CYP3A4.In vitro, dutasteride is not metabolized by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 and CYP2D6.In a small study (N=24) of two weeks duration in healthy men, dutasteride (0.5 mg daily) had no effect on the pharmacokinetics of tamsulosin or terazosin. There was also no indication of a pharmacodynamic interaction in this study.
FertilityDutasteride has been reported to affect semen characteristics (reduction in sperm count, semen volume, and sperm motility) in healthy men (see section 5.1). The possibility of reduced male fertility cannot be excluded.
PregnancyAs with other 5 alpha reductase inhibitors, dutasteride inhibits the conversion of testosterone to dihydrotestosterone and may, if administered to a woman carrying a male foetus, inhibit the development of the external genitalia of the foetus (see section 4.4). Small amounts of dutasteride have been recovered from the semen in subjects receiving Avodart 0.5 mg day. It is not known whether a male foetus may be adversely affected if his mother is exposed to the semen of a patient being treated with dutasteride (the risk of which is greatest during the first 16 weeks of pregnancy). As with all 5 alpha reductase inhibitors, when the patient's partner is or may potentially be pregnant it is recommended that the patient avoids exposure of his partner to semen by use of a condom.For information on preclinical data, see section 5.3.
LactationIt is not known whether dutasteride is excreted in human milk.
|Organ system||Adverse reaction||Incidence from clinical trial data|
|Incidence during year 1 of treatment (n=2167)||Incidence during year 2 of treatment (n=1744)|
|Reproductive system and breast disorders||Impotence*||6.0%||1.7%|
|Altered (decreased) libido*||3.7%||0.6%|
|Immune system disorders||Allergic reactions including rash, pruritus, urticaria, localised oedema, and angioedema||Incidence estimated from post-marketing data|
|Psychiatric disorders||Depressed mood||Not known|
|Skin and subcutaneous tissue disorders||Alopecia (primarily body hair loss), hypertrichosis||Uncommon|
|Reproductive system and breast disorders||Testicular pain and swelling||Not known|
|System Organ Class||Adverse Reaction||Incidence during treatment period|
|Year 1||Year 2||Year 3||Year 4|
|Nervous system disorders||Dizziness|
|Cardiac disorders||Cardiac failure (composite termb)|
|Reproductive system and breast disorders, Psychiatric disorders, Investigations||Impotencec|
|Altered (decreased) libidoc|
Effects on DHT/Testosterone:Effect of daily doses of Avodart on the reduction on DHT is dose dependant and is observed within 1-2 weeks (85% and 90% reduction, respectively). In patients with BPH treated with dutasteride 0.5 mg/day, the median decrease in serum 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.
Effect on Prostate Volume:Significant reductions in prostate volume have been detected as early as one month after initiation of treatment and reductions continued through Month 24 (p<0.001). Avodart led to a mean reduction of total prostate volume of 23.6% (from 54.9 ml at baseline to 42.1 ml) at Month 12 compared with a mean reduction of 0.5% (from 54.0 ml to 53.7 ml) in the placebo group. Significant (p<0.001) reductions also occurred in prostate transitional zone volume as early as one month continuing through Month 24, with a mean reduction in prostate transitional zone volume of 17.8% (from 26.8 ml at baseline to 21.4 ml) in the Avodart group compared to a mean increase of 7.9% (from 26.8ml to 27.5 ml) in the placebo group at Month 12. The reduction of the prostate volume seen during the first 2 years of double-blind treatment was maintained during an additional 2 years of open-label extension studies. Reduction of the size of the prostate leads to improvement of symptoms and a decreased risk for AUR and BPH-related surgery.
CLINICAL STUDIESAvodart 0.5 mg/day or placebo was evaluated in 4325 male subjects with moderate to severe symptoms of BPH who had prostates ≥30 ml and a PSA value within the range 1.5 - 10 ng/mL in three primary efficacy 2-year multicenter, multinational, placebo-controlled, double-blind studies. The studies then continued with an open-label extension to 4 years with all patients remaining in the study receiving dutasteride at the same 0.5mg dose. 37% of initially placebo-randomized patients and 40% of dutasteride-randomized patients remained in the study at 4 years. The majority (71%) of the 2,340 subjects in the open-label extensions completed the 2 additional years of open-label treatment. The most important clinical efficacy parameters were American Urological Association Symptom Index (AUA-SI), maximum urinary flow (Qmax) and the incidence of acute urinary retention and BPH-related surgery.AUA-SI is a seven-item questionnaire about BPH-related symptoms with a maximum score of 35. At baseline the average score was approx. 17. After six months, one and two years treatment the placebo group had an average improvement of 2.5, 2.5 and 2.3 points respectively while the Avodart group improved 3.2, 3.8 and 4.5 points respectively. The differences between the groups were statistically significant. The improvement in AUA-SI seen during the first 2 years of double-blind treatment was maintained during an additional 2 years of open-label extension studies.Qmax (maximum urine flow):Mean baseline Qmax for the studies was approx 10 ml/sec (normal Qmax ≥15 ml/sec). After one and two years treatment the flow in the placebo group had improved by 0.8 and 0.9 ml/sec respectively and 1.7 and 2.0 ml/sec respectively in the Avodart group. The difference between the groups was statistically significant from Month 1 to Month 24. The increase in maximum urinary flow rate seen during the first 2 years of double blind treatment continued throughout an additional 2 years of open-label extension studies.
Acute Urinary Retention and Surgical InterventionAfter two years of treatment, the incidence of AUR was 4.2% in the placebo group against 1.8% in the Avodart group (57% risk reduction). This difference is statistically significant and means that 42 patients (95% CI 30-73) need to be treated for two years to avoid one case of AUR.The incidence of BPH-related surgery after two years was 4.1% in the placebo group and 2.2% in the Avodart group (48% risk reduction). This difference is statistically significant and means that 51 patients (95% CI 33-109) need to be treated for two years to avoid one surgical intervention.
Hair distributionThe effect of dutasteride on hair distribution was not formally studied during the phase III programme, however, 5 alpha-reductase inhibitors could reduce hair loss and may induce hair growth in subjects with male pattern hair loss (male androgenetic alopecia).
Thyroid function:Thyroid function was evaluated in a one year study in healthy men. Free thyroxine levels were stable on dutasteride treatment but TSH levels were mildly increased (by 0.4 MCIU/mL) compared to placebo at the end of one year's treatment. However, as TSH levels were variable, median TSH ranges (1.4-1.9 MCIU/mL) remained within normal limits (0.5 - 5/6 MCIU/mL), free thyroxine levels were stable within the normal range and similar for both placebo and dutasteride treatment, the changes in TSH were not considered clinically significant. In all the clinical studies, there has been no evidence that dutasteride adversely affects thyroid function.
Breast neoplasia:In the 2 year clinical trials, providing 3374 patient years of exposure to dutasteride, and at the time of registration in the 2 year open label extension, there were 2 cases of breast cancer reported in dutasteride-treated patients and 1 case in a patient who received placebo. In the 4 year CombAT and REDUCE clinical trials providing 17489 patient years exposure to dutasteride and 5027 patient years exposure to dutasteride and tamsulosin combination there were no additional cases in any of the treatment groups. Currently it is not clear if there is a causal relationship between the occurrence of male breast cancer and long term use of dutasteride.
Effects on male fertilityThe effects of dutasteride 0.5mg/day on semen characteristics were evaluated in healthy 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 reduction 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 parameters at all time points remained within the normal ranges and did not meet the predefined criteria for a clinically significant change (30%), two 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 possibility of reduced male fertility cannot be excluded.AVODART IN COMBINATION WITH THE ALPHA-BLOCKER TAMSULOSINAvodart 0.5 mg/day (n = 1,623), tamsulosin 0.4 mg/day (n = 1,611) or the combination of Avodart 0.5 mg plus tamsulosin 0.4 mg (n = 1,610) were evaluated in male subjects with moderate to severe symptoms of BPH who had prostates ≥30 ml and a PSA value within the range 1.5 - 10 ng/mL in a multicentre, multinational, randomized double-blind, parallel group study (the CombAT study).. Approximately 53% of subjects had previous exposure to 5-alpha reductase inhibitor or alpha-blocker treatment. The primary efficacy endpoint during the first 2 years of treatment was change in International Prostate Symptom Score (IPSS), an 8-item instrument based on AUA-SI with an additional question on quality of life. Secondary efficacy endpoints at 2 years included maximum urine flow rate (Qmax) and prostate volume. The combination achieved significance for IPSS from Month 3 compared to Avodart and from Month 9 compared to tamsulosin. For Qmax combination achieved significance from Month 6 compared to both Avodart and tamsulosin. 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% (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.Secondary efficacy endpoints after 4 years of treatment included time to clinical progression (defined as a composite of: IPSS deterioration by ≥4 points, BPH-related events of AUR, incontinence, urinary tract infection (UTI), and renal insufficiency) change in International Prostate Symptom Score (IPSS), maximum urine flow rate (Qmax) and prostate volume. Results following 4 years of treatment are presented below:
|AUR or BPH related surgery (%)||Incidence at Month 48||4.2||5.2||11.9a|
|Clinical progression* (%)||Month 48||12.6||17.8b||21.5a|
|IPSS (units)||[Baseline] Month 48 (Change from Baseline)||[16.6] -6.3||[16.4] -5.3b||[16.4] -3.8a|
|Qmax (mL/sec)||[Baseline] Month 48 (Change from Baseline)||[10.9] 2.4||[10.6] 2.0||[10.7] 0.7a|
|Prostate Volume (ml)||[Baseline] Month 48 (% Change from Baseline)||[54.7] -27.3||[54.6] -28.0||[55.8] +4.6a|
|Prostate Transition Zone Volume (ml)#||[Baseline] Month 48 (% Change from Baseline)||[27.7] -17.9||[30.3] -26.5||[30.5] 18.2a|
|BPH Impact Index (BII) (units)||[Baseline] Month 48 (Change from Baseline)||[5.3] -2.2||[5.3] -1.8b||[5.3] -1.2a|
|IPSS Question 8 (BPH-related Health Status) (units)||[Baseline] Month 48 (Change from Baseline)||[3.6] -1.5||[3.6] -1.3b||[3.6] -1.1a|
AbsorptionFollowing oral administration of a single 0.5 mg dutasteride dose, the time to peak serum concentrations of dutasteride is 1 to 3 hours. The absolute bioavailability is approximately 60%. The bioavailability of dutasteride is not affected by food.
DistributionDutasteride has a large volume of distribution (300 to 500 L) and 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 0.5mg once a day. Dutasteride partitioning from serum into semen averaged 11.5%.
EliminationDutasteride is extensively metabolised in vivo. In vitro, dutasteride is metabolised by the cytochrome P450 3A4 and 3A5 to three monohydroxylated metabolites and one dihydroxylated metabolite.Following oral dosing of dutasteride 0.5 mg/day to steady state, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as unchanged 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.The elimination of dutasteride is dose dependent and the process appears to be described by two elimination pathways in parallel, one that is saturable at clinically relevant concentrations and one that is non saturable. At low serum concentrations (less than 3ng/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 therapeutic concentrations, following repeat dosing of 0.5 mg/day, the slower, linear elimination pathway is dominating and the half-life is approx. 3-5 weeks.
ElderlyDutasteride pharmacokinetics were evaluated in 36 healthy male subjects between the ages of 24 and 87 years following administration of a single 5mg dose of dutasteride. No significant influence of age was seen on the exposure of dutasteride but the half-life was shorter in men under 50 years of age. Half-life was not statistically different when comparing the 50-69 year old group to the greater than 70 years old.
Renal impairmentThe 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 clinically significant increase of the dutasteride plasma concentrations is anticipated for patients with renal impairment (see section 4.2).
Hepatic impairmentThe effect on the pharmacokinetics of dutasteride in hepatic impairment has not been studied (see section 4.3). Because dutasteride is eliminated mainly through metabolism the plasma levels of dutasteride are expected to be elevated in these patients and the half-life of dutasteride be prolonged (see section 4.2 and section 4.4).
Capsule contents:mono- and diglycerides of caprylic/capric acidbutylhydroxytoluene (E321).
Capsule shell:gelatinglyceroltitanium dioxide (E171)iron oxide yellow (E172)triglycerides, medium chainlecithin (may contain soya oil).
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