Prosterid

Overdose

In clinical studies, single doses of Prosterid up to 400 mg and multiple doses of Prosterid up to 80 mg/day for three months (n=71) did not result in dose related side effects. No specific treatment of overdose with Prosterid Tablets 1mg is recommended.

No specific treatment of overdosage with 'Prosterid' is recommended. Patients have received single doses of 'Prosterid' up to 400 mg and multiple doses of 'Prosterid' up to 80 mg/day for up to three months without any adverse effects.

In clinical studies, single doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for three months (n=71) did not result in dose-related undesirable effects.

No specific treatment of overdosage with 'Prosterid' is recommended.

Prosterid price

Contraindications

Prosterid should not be used in children / adolescents.

Hypersensitivity to Prosterid or to any of the excipients listed in 6.1.

'Prosterid' is not indicated for use in women or children.

'Prosterid' is contraindicated in the following:

- Hypersensitivity to any component of this product

- Pregnancy - Use in women when they are or may potentially be pregnant (see 4.6 Pregnancy and lactation, Exposure to finasteride - risk to male foetus).

Contraindicated in women: see 4.6 'Fertility, pregnancy and lactation' and 5.1 'Pharmacodynamic properties'.

'Prosterid' is not indicated for use in women or children and adolescents.

'Prosterid' should not be taken by men who are taking 'Proscar' (finasteride 5 mg) or any other 5α-reductase inhibitor for benign prostatic hyperplasia or any other condition.

Incompatibilities

Not applicable.

None reported.

Not applicable.

Undesirable effects

The adverse reactions during clinical trials and / or post-marketing use are listed in the table below.

The frequencies of undesirable effects are following: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to ≤1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

The frequency of adverse reactions reported during post- marketing use cannot be determined as they are derived from spontaneous reports.

$ incidences presented as difference from placebo in clinical studies at Month 12

Drug-related sexual undesirable effects were more common in the Prosterid-treated men than the placebo-treated men, with frequencies during the first 12 months of 3.8% vs 2.1%, respectively. The incidence of these effects decreased to 0.6% in Prosterid-treated men over the following four years. Approximately 1% of men in each treatment group discontinued due to drug related sexual adverse experiences in the first 12 months, and the incidence declined thereafter.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard.

The most frequent adverse reactions are impotence and decreased libido. These adverse reactions occur early in the course of therapy and resolve with continued treatment in the majority of patients.

The adverse reactions reported during clinical trials and/or post-marketing use are listed in the table below.

Frequency of adverse reactions is determined as follows:

Very common (>1/10), Common (>1/100 to <1/10), Uncommon (>1/1,000 to <1/100), Rare (>1/10,000 to <1/1,000), Very rare (<1/10,000), not known (cannot be estimated from the available data). The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports.

In addition, the following has been reported in clinical trials and post-marketing use: male breast cancer (see 4.4 Special warnings and precautions for use).

Medical Therapy of Prostatic Symptoms (MTOPS)

The MTOPS study compared finasteride 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), combination therapy of finasteride 5 mg/day and doxazosin 4 or 8 mg/day (n=786), and placebo (n=737). In this study, the safety and tolerability profile of the combination therapy was generally consistent with the profiles of the individual components. The incidence of ejaculation disorder in patients receiving combination therapy was comparable to the sum of incidences of this adverse experience for the two monotherapies.

Other Long-Term Data

In a 7 year placebo-controlled trial that enrolled 18,882 healthy men, of whom 9060 had prostate needle biopsy data available for analysis, prostate cancer was detected in 803 (18.4%) men receiving 'Prosterid' and 1147 (24.4%) men receiving placebo. In the 'Prosterid' group, 280 (6.4%) men had prostate cancer with Gleason scores of 7-10 detected on needle biopsy vs 237 (5.1%) men in the placebo group. Additional analyses suggest that the increase in the prevalence of high-grade prostate cancer observed in the 'Prosterid' group may be explained by a detection bias due to the effect of 'Prosterid' on prostate volume. Of the total cases of prostate cancer diagnosed in this study, approximately 98% were classified as intracapsular (stage T1 or T2). The relationship between long-term use of 'Prosterid' and tumours with Gleason scores of 7-10 is unknown.

Laboratory Test Findings

). In most patients, a rapid decrease in PSA is seen within the first months of therapy, after which time PSA levels stabilise to a new baseline. The post-treatment baseline approximates half of the pre-treatment value. Therefore, in typical patients treated with 'Prosterid' for six months or more, PSA values should be doubled for comparison to normal ranges in untreated men.

For clinical interpretation see 'Special warnings and precautions for use', Effects on prostate-specific antigen (PSA) and prostate cancer detection.

No other difference was observed in patients treated with placebo or 'Prosterid' in standard laboratory tests.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

The adverse reactions during clinical trials and/or post-marketing use are listed in the table below.

Frequency of adverse reactions is determined as follows:

Very Common (> 1/10); Common (> 1/100, < 1/10); Uncommon (> 1/1,000, < 1/100); Rare (>1/10,000, < 1/1,000); Very rare (< 1/10,000); not known (cannot be estimated from the available data).

The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports.

* Incidences presented as difference from placebo in clinical studies at Month 12.

†This adverse reaction was identified through post-marketing surveillance but the incidence in randomized controlled Phase III clinical trials (Protocols 087, 089, and 092) was not different between finasteride and placebo.

Side effects, which usually have been mild, generally have not required discontinuation of therapy.

Finasteride for male pattern hair loss has been evaluated for safety in clinical studies involving more than 3,200 men. In three 12-month, placebo-controlled, double-blind, multicentre studies of comparable design, the overall safety profiles of 'Prosterid' and placebo were similar. Discontinuation of therapy due to any clinical adverse experience occurred in 1.7% of 945 men treated with 'Prosterid' and 2.1% of 934 men treated with placebo.

In these studies, the following drug-related adverse experiences were reported in >1% of men treated with 'Prosterid': decreased libido ('Prosterid', 1.8% vs. placebo, 1.3%) and erectile dysfunction (1.3%, 0.7%). In addition, decreased volume of ejaculate was reported in 0.8% of men treated with 'Prosterid' and 0.4% of men treated with placebo. Resolution of these side effects occurred in men who discontinued therapy with 'Prosterid' and in many who continued therapy. The effect of 'Prosterid' on ejaculate volume was measured in a separate study and was not different from that seen with placebo.

By the fifth year of treatment with 'Prosterid', the proportion of patients reporting each of the above side effects decreased to <0.3%.

Finasteride has also been studied for prostate cancer risk reduction at 5 times the dosage recommended for male pattern hair loss. In a 7-year placebo-controlled trial that enrolled 18,882 healthy men, of whom 9060 had prostate needle biopsy data available for analysis, prostate cancer was detected in 803 (18.4%) men receiving finasteride 5 mg and 1147 (24.4%) men receiving placebo. In the finasteride 5 mg group, 280 (6.4%) men had prostate cancer with Gleason scores of 7-10 detected on needle biopsy vs. 237 (5.1%) men in placebo group. Of the total cases of prostate cancer diagnosed in this study, approximately 98% were classified as intracapsular (stage T1 or T2). The relationship between long-term use of finasteride 5 mg and tumours with Gleason scores of 7-10 is unknown.

In addition, the following have been reported in post-marketing use: persistence of sexual dysfunction (decreased libido, erectile dysfunction and ejaculation disorder) after discontinuation of treatment with 'Prosterid'; male breast cancer (see 4.4 Special warnings and precautions for use).

Drug-related sexual undesirable effects were more common in the finasteride 1 mg-treated men than the placebo-treated men, with frequencies during the first 12 months of 3.8% vs 2.1%, respectively. The incidence of these effects decreased to 0.6% in finasteride 1 mg-treated men over the following four years. Approximately 1% of men in each treatment group discontinued due to drug related sexual adverse experiences in the first 12 months, and the incidence declined thereafter.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, at www.mhra.gov.uk/yellowcard.

Preclinical safety data

Studies in women

Lack of efficacy was demonstrated in post-menopausal women with androgenetic alopecia who were treated with Prosterid 1 mg tablets in a 12-month, placebo-controlled study (n=137). These women did not show any improvement in hair count, patient self-assessment, investigator assessment, or ratings based on standardized photographs, compared with the placebo group.

Absorption

Relative to an intravenous reference dose, the oral bioavailability of Prosterid is approximately 80%. The bioavailability is not affected by food. Maximum Prosterid plasma concentrations are reached approximately two hours after dosing and the absorption is complete after six to eight hours.

Distribution

Protein binding is approximately 93%. The volume of distribution of Prosterid is approximately 76 liters.

At steady state following dosing with 1 mg/day, maximum Prosterid plasma concentration averaged 9.2 ng/ml and was reached 1 to 2 hours post dose; AUC (0-24 hr) was 53 ng-hr/ml.

Prosterid has been recovered in the cerebrospinal fluid (CSF), but the drug does not appear to concentrate preferentially to the CSF. A small amount of Prosterid has also been detected in the seminal fluid of subjects receiving the drug.

Biotransformation

Prosterid is metabolized primarily via but does not affect the cytochrome P450 3A4 system. Following an oral dose of 14C-Prosterid in man, two metabolites of Prosterid were identified that possess only a small fraction of the 5α-reductase inhibitory activity of Prosterid.

Elimination

Following an oral dose of 14C-Prosterid in man, 39% of the dose was excreted in the urine in the form of metabolites (virtually no unchanged drug was excreted in the urine) and 57% of total dose was excreted in the faeces.

Plasma clearance is approximately 165 ml/min.

The elimination rate of Prosterid decreases somewhat with age. Mean terminal half-life is approximately 5-6 hours in men 18-60 years of age and 8 hours in men more than 70 years of age. These findings are of no clinical significance and hence, a reduction in dosage in the elderly is not warranted.

Characteristics in patients

No adjustment in dosage is necessary in non-dialyzed patients with renal impairment.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and carcinogenic potential. Reproduction toxicology studies in male rats have demonstrated reduced prostate and seminal vesicular weights, reduced secretion from accessory genital glands and reduced fertility index (caused by the primary pharmacological effect of Prosterid). The clinical relevance of these findings is unclear.

As with other 5-alpha-reductase inhibitors, femininisation of male rat foetuses has been seen with administration of Prosterid in the gestation period. Intravenous administration of Prosterid to pregnant rhesus monkeys at doses up to 800 ng/day during the entire period of embryonic and foetal development resulted in no abnormalities in male foetuses. This dose is about 60-120 times higher than the estimated amount in semen of a man who have taken 5 mg Prosterid, and to which a woman could be exposed via semen. The reproductive toxicity is believed to be mediated via the intended inhibition of 5α-reductase. Taken into account the species enzyme difference in sensitivity to Prosterid inhibition the margin of pharmacological exposure would be about 4 times. In confirmation of the relevance of the Rhesus model for human foetal development, oral administration of Prosterid 2 mg/kg/day (the systemic exposure (AUC) of monkeys was below or in the range of that of men who have taken 5 mg Prosterid, or approximately 1 to 2 million times the estimated mount of Prosterid in semen) to pregnant monkeys resulted in external genital abnormalities in male foetuses. No other abnormalities were observed in male foetuses and no Prosterid-related abnormalities were observed in female foetuses at any dose.”

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and carcinogenic potential. Reproduction toxicology studies in male rats have demonstrated reduced prostate and seminal vesicular weights, reduced secretion from accessory genital glands and reduced fertility index (caused by the primary pharmacological effect of finasteride). The clinical relevance of these findings is unclear.

As with other 5-alpha-reductase inhibitors, femininisation of male rat foetuses has been seen with administration of finasteride in the gestation period. Intravenous administration of finasteride to pregnant rhesus monkeys at doses up to 800 ng/day during the entire period of embryonic and foetal development resulted in no abnormalities in male foetuses. This dose is about 60-120 times higher than the estimated amount in semen of a man who have taken 5 mg finasteride, and to which a woman could be exposed via semen. In confirmation of the relevance of the Rhesus model for human foetal development, oral administration of finasteride 2 mg/kg/day (the systemic exposure (AUC) of monkeys was slightly higher (3x) than that of men who have taken 5 mg finasteride, or approximately 1-2 million times the estimated amount of finasteride in semen) to pregnant monkeys resulted in external genital abnormalities in male foetuses. No other abnormalities were observed in male foetuses and no finasteride-related abnormalities were observed in female foetuses at any dose.”

In general, the findings in laboratory animal studies with oral finasteride were related to the pharmacological effects of 5α-reductase inhibition.

Intravenous administration of finasteride to pregnant rhesus monkeys at doses as high as 800 ng/day during the entire period of embryonic and foetal development resulted in no abnormalities in male foetuses. This represents at least 750 times the highest estimated exposure of pregnant women to finasteride from semen. In confirmation of the relevance of the Rhesus model for human foetal development, oral administration of finasteride 2 mg/kg/day (100 times the recommended human dose or approximately 12 million times the highest estimated exposure to finasteride from semen) to pregnant monkeys resulted in external genital abnormalities in male foetuses. No other abnormalities were observed in male foetuses and no finasteride-related abnormalities were observed in female foetuses at any dose.

Therapeutic indications

Prosterid 1 mg is indicated for treatment of the first stage of the hair loss (androgenetic alopecia) in males. Prosterid 1 mg stabilizes the process of the androgenetic alopecia in the 18-41 year old males. Its effectiveness in bitemporary recession nor in the loss of hair has not been determined.

Prosterid is not indicated for use in women or children and adolescents.

'Prosterid' is indicated for the treatment and control of benign prostatic hyperplasia (BPH) in patients with an enlarged prostate to:

- cause regression of the enlarged prostate, improve urinary flow and improve the symptoms associated with BPH

- reduce the incidence of acute urinary retention and the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy.

'Prosterid' is indicated for the treatment of men with male pattern hair loss (androgenetic alopecia) to increase hair growth and prevent further hair loss.

'Prosterid' is not indicated for use in women or children and adolescents.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Other dermatologicals

ATC-Code: D11 AX10

Mechanism of action

Prosterid is a 4-azasteroid, which inhibits human Type 2 5α-reductase (present within the hair follicles) with greater than 100-fold selectivity over human Type 1 5α-reductase, and blocks the peripheral conversion of testosterone to the androgen dihydrotestosterone (DHT). In men with male pattern hair loss, the balding scalp contains miniaturized hair follicles and increased amounts of DHT. Prosterid inhibits a process responsible for miniaturization of the scalp hair follicles, which can lead to reversal of the balding process.

Clinical efficacy

Studies in men:

The efficacy of Prosterid 1mg tablets was demonstrated in three studies in 1879 men 18 to 41 years of age with mild to moderate, but not complete, vertex hair loss and frontal/mid-area hair loss. In these studies, hair growth was assessed using four separate measures including hair count, ratings of photographs of the head by an expert panel of dermatologists, investigator assessment, and patient self-assessment. In the two studies in men with vertex hair loss, treatment with Prosterid 1mg tablets was continued for 5 years, during which time patients improved compared to baseline in men treated with Prosterid 1mg tablets were generally greatest at 2 years and gradually declined thereafter (e.g., hair count in a representative 5.1 cm2 area was increased 88 hairs from baseline at 2 years and 38 hairs from baseline at 5 years), hair loss in the placebo group progressively worsened compared to baseline (decrease of 50 hairs at 2 years and 239 hairs at 5 years). Thus, although improvement compared to baseline in men treated with Prosterid 1mg tablets did not increase further after 2 years, the difference between treatment groups continued to increase throughout the 5 years of the studies. Treatment with Prosterid 1mg tablets for 5 years resulted in stabilization of hair loss in 90% of men based on photographic assessment and in 93% based on investigator assessment.

In addition, increased hair growth was observed in 65% of men treated with Prosterid 1mg tablets based on hair counts, in 48% based on photographic assessment, and in 77% based on investigator assessment. In contrast, in the placebo group, gradual hair loss over time was observed in 100% of men based on hair counts, in 75% based on photographic assessment, and in 38% based on investigator assessment. In addition, patient self-assessment demonstrated significant increases in hair density, decreases in hair loss, and improvement in appearance of hair after treatment over 5 years with Prosterid 1mg tablets (see Table below).

Percent of Patients Improved as Assessed by Each of the 4 Measures

†Randomization 1:1 Prosterid 1MG TABLETS to placebo

††Randomization 9:1 Prosterid 1MG TABLETS to placebo

In a 12-month study, in men with frontal/mid-area hair loss, hair counts were obtained in a representative 1 cm2 area (approximately 1/5 the size of the area sampled in the vertex studies). Hair counts, adjusted to a 5.1 cm2 area, increased by 49 hairs (5%) compared to baseline and by 59 hairs (6%) compared to placebo. This study also demonstrated significant improvements in patient self-assessment, investigator assessment, and ratings of photographs of the head by an expert panel of dermatologists. Two studies of 12 and 24 weeks duration showed that a dose 5-fold the recommended dose (Prosterid 5 mg daily) produced a median decrease in ejaculate volume of approximately 0.5 mL (-25%) compared with placebo. This decrease was reversible after discontinuation of treatment. In a study of 48 weeks of duration, Prosterid 1 mg daily produced a median decrease in ejaculate volume of 0.3 mL (-11%) compared with a 0.2 mL (-8%) decrease for placebo. No effect was observed on sperm count, motility or morphology. Longer-term data are not available. It has not been feasible to undertake clinical studies, which directly elucidate possible negative effects on fertility. However, such effects are judged as very unlikely (see also 5.3 Preclinical safety data).

Studies in women

Lack of efficacy was demonstrated in post-menopausal women with androgenetic alopecia who were treated with Prosterid 1 mg tablets in a 12-month, placebo-controlled study (n=137). These women did not show any improvement in hair count, patient self-assessment, investigator assessment, or ratings based on standardized photographs, compared with the placebo group.

Finasteride is a competitive inhibitor of human 5 α-reductase, an intracellular enzyme which metabolises testosterone into the more potent androgen, dihydrotestosterone (DHT). In benign prostatic hyperplasia (BPH), enlargement of the prostate gland is dependent upon the conversion of testosterone to DHT within the prostate. 'Prosterid' is highly effective in reducing circulating and intraprostatic DHT. Finasteride has no affinity for the androgen receptor.

In clinical studies of patients with moderate to severe symptoms of BPH, an enlarged prostate on digital rectal examination and low residual urinary volumes, 'Prosterid' reduced the incidence of acute retention of urine from 7/100 to 3/100 over four years and the need for surgery (TURP or prostatectomy) from 10/100 to 5/100. These reductions were associated with a 2-point improvement in QUASI-AUA symptom score (range 0-34), a sustained regression in prostate volume of approximately 20% and a sustained increase in urinary flow rate.

Medical therapy of prostatic symptoms

The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a 4- to 6-year study in 3047 men with symptomatic BPH who were randomised to receive finasteride 5 mg/day, doxazosin 4 or 8 mg/day*, the combination of finasteride 5 mg/day and doxazosin 4 or 8 mg/day*, or placebo. The primary endpoint was time to clinical progression of BPH, defined as a >4 point confirmed increase from baseline in symptom score, acute urinary retention, BPH-related renal insufficiency, recurrent urinary tract infections or urosepsis, or incontinence. Compared to placebo, treatment with finasteride, doxazosin, or combination therapy resulted in a significant reduction in the risk of clinical progression of BPH by 34 (p=0.002), 39 (p<0.001), and 67% (p<0.001), respectively. The majority of the events (274 out of 351) that constituted BPH progression were confirmed >4 point increases in symptom score; the risk of symptom score progression was reduced by 30 (95% CI 6 to 48%), 46 (95% CI 25 to 60%), and 64% (95% CI 48 to 75%) in the finasteride, doxazosin, and combination groups, respectively, compared to placebo. Acute urinary retention accounted for 41 of the 351 events of BPH progression; the risk of developing acute urinary retention was reduced by 67 (p=0.011), 31 (p=0.296), and 79% (p=0.001) in the finasteride, doxazosin, and combination groups, respectively, compared to placebo. Only the finasteride and combination therapy groups were significantly different from placebo.

* Titrated from 1 mg to 4 or 8 mg as tolerated over a 3-week period

Pharmacotherapeutic group: 5α-reductase inhibitor. ATC code D11AX10

Mechanism of action

Finasteride is a competitive and specific inhibitor of type II 5α-reductase. Finasteride has no affinity for the androgen receptor and has no androgenic, anti-androgenic, oestrogenic, anti-oestrogenic, or progestational effects. Inhibition of this enzyme blocks the peripheral conversion of testosterone to the androgen DHT, resulting in significant decreases in serum and tissue DHT concentrations. Finasteride produces a rapid reduction in serum DHT concentration, reaching significant suppression within 24 hours of dosing.

Hair follicles contain type II 5α-reductase. In men with male pattern hair loss, the balding scalp contains miniaturised hair follicles and increased amounts of DHT. Administration of finasteride decreases scalp and serum DHT concentrations in these men. Men with a genetic deficiency of type II 5α-reductase do not suffer from male pattern hair loss. Finasteride inhibits a process responsible for miniaturisation of the scalp hair follicles, which can lead to reversal of the balding process.

Clinical efficacy and safety

Studies in men

Clinical studies were conducted in 1879 men aged 18 to 41 with mild to moderate, but not complete, vertex hair loss and/or frontal/mid-area hair loss. In the two studies in men with vertex hair loss (n=1553), 290 men completed 5 years of treatment with Prosterid vs. 16 patients on placebo. In these two studies, efficacy was assessed by the following methods: (i) hair count in a representative 5.1cm2 area of scalp, (ii) patient self assessment questionnaire, (iii) investigator assessment using a seven point scale, and (iv) photographic assessment of standardised paired photographs by a blinded expert panel of dermatologists using a seven point scale.

In these 5- year studies men treated with 'Prosterid' improved compared to both baseline and placebo beginning as early as 3 months, as determined by both the patient and investigator assessments of efficacy. With regard to hair count, the primary endpoint in these studies, increases compared to baseline were demonstrated starting at 6 months (the earliest time point assessed) through to the end of the study. In men treated with 'Prosterid' these increases were greatest at 2 years and gradually declined thereafter to the end of 5 years; whereas hair loss in the placebo group progressively worsened compared to baseline over the entire 5 year period. In 'Prosterid' treated patients, a mean increase from baseline of 88 hairs [p <0.01; 95% CI (77.9, 97.80; n=433] in the representative 5.1 cm2 area was observed at 2 years and an increase from baseline of 38 hairs [p <0.01; 95% CI (20.8, 55.6); n=219] was observed at 5 years, compared with a decrease from baseline of 50 hairs [p <0.01; 95% CI (-80.5, -20.6);n=47] at 2 years and a decrease from baseline of 239 hairs [p <0.01; 95% CI (-304.4, -173.4); n=15] at 5 years in patients who received placebo. Standardised photographic assessment of efficacy demonstrated that 48% of men treated with finasteride for 5 years were rated as improved, and an additional 42% were rated as unchanged. This is in comparison to 25% of men treated with placebo for 5 years who were rated as improved or unchanged. These data demonstrate that treatment with 'Prosterid' for 5 years resulted in a stabilisation of the hair loss that occurred in men treated with placebo.

An additional 48-week, placebo-controlled study designed to assess the effect of 'Prosterid' on the phases of the hair-growth cycle (growing phase [anagen] and resting phase [telogen]) in vertex baldness enrolled 212 men with androgenetic alopecia. At baseline and 48 weeks, total, anagen and telogen hair counts were obtained in a 1-cm2 target area of the scalp. Treatment with 'Prosterid' led to improvements in anagen hair counts, while men in the placebo group lost anagen hair. At 48 weeks, men treated with 'Prosterid' showed net increases in total and anagen hair counts of 17 hairs and 27 hairs, respectively, compared to placebo. This increase in anagen hair count, compared to total hair count, led to a net improvement in the anagen-to-telogen ratio of 47% at 48 weeks for men treated with 'Prosterid', compared to placebo. These data provide direct evidence that treatment with 'Prosterid' promotes the conversion of hair follicles into the actively growing phase.

Studies in women

Lack of efficacy was demonstrated in post-menopausal women with androgenetic alopecia who were treated with 'Prosterid' in a 12 month, placebo-controlled study (n=137). These women did not show any improvement in hair count, patient self-assessment, investigator assessment, or ratings based on standardised photographs, compared with the placebo group.

Pharmacokinetic properties

Absorption

Relative to an intravenous reference dose, the oral bioavailability of Prosterid is approximately 80%. The bioavailability is not affected by food. Maximum Prosterid plasma concentrations are reached approximately two hours after dosing and the absorption is complete after six to eight hours.

Distribution

Protein binding is approximately 93%. The volume of distribution of Prosterid is approximately 76 liters.

At steady state following dosing with 1 mg/day, maximum Prosterid plasma concentration averaged 9.2 ng/ml and was reached 1 to 2 hours post dose; AUC (0-24 hr) was 53 ng-hr/ml.

Prosterid has been recovered in the cerebrospinal fluid (CSF), but the drug does not appear to concentrate preferentially to the CSF. A small amount of Prosterid has also been detected in the seminal fluid of subjects receiving the drug.

Biotransformation

Prosterid is metabolized primarily via but does not affect the cytochrome P450 3A4 system. Following an oral dose of 14C-Prosterid in man, two metabolites of Prosterid were identified that possess only a small fraction of the 5α-reductase inhibitory activity of Prosterid.

Elimination

Following an oral dose of 14C-Prosterid in man, 39% of the dose was excreted in the urine in the form of metabolites (virtually no unchanged drug was excreted in the urine) and 57% of total dose was excreted in the faeces.

Plasma clearance is approximately 165 ml/min.

The elimination rate of Prosterid decreases somewhat with age. Mean terminal half-life is approximately 5-6 hours in men 18-60 years of age and 8 hours in men more than 70 years of age. These findings are of no clinical significance and hence, a reduction in dosage in the elderly is not warranted.

Characteristics in patients

No adjustment in dosage is necessary in non-dialyzed patients with renal impairment.

After an oral dose of 14C-finasteride in man, 39% of the dose was excreted in the urine in the form of metabolites (virtually no unchanged drug was excreted in the urine), and 57% of total dose was excreted in the faeces. Two metabolites have been identified which possess only a small fraction of the Type II 5 α-reductase activity of finasteride.

The oral bioavailability of finasteride is approximately 80%, relative to an intravenous reference dose, and is unaffected by food. Maximum plasma concentrations are reached approximately two hours after dosing and the absorption is complete within 6-8 hours. Protein binding is approximately 93%. Plasma clearance and the volume of distribution are approximately 165 ml/min and 76 l, respectively.

In the elderly, the elimination rate of finasteride is somewhat decreased. Half-life is prolonged from a mean half-life of approximately six hours in men aged 18-60 years to eight hours in men aged more than 70 years. This is of no clinical significance and does not warrant a reduction in dosage.

In patients with chronic renal impairment, whose creatinine clearance ranged from 9-55 ml/min, the disposition of a single dose of 14C-finasteride was not different from that in healthy volunteers. Protein binding also did not differ in patients with renal impairment. A portion of the metabolites which normally is excreted renally was excreted in the faeces. It therefore appears that faecal excretion increases commensurate to the decrease in urinary excretion of metabolites. Dosage adjustment in non-dialysed patients with renal impairment is not necessary.

There are no data available in patients with hepatic insufficiency.

Finasteride has been found to cross the blood-brain barrier. Small amounts of finasteride have been recovered in the seminal fluid of treated patients.

Absorption

Relative to an intravenous reference dose, the oral bioavailability of finasteride is approximately 80%. The bioavailability is not affected by food. Maximum finasteride plasma concentrations are reached approximately two hours after dosing and the absorption is complete after six to eight hours.

Distribution

Protein binding is approximately 93%. The volume of distribution of finasteride is approximately 76 litres.

At steady state following dosing with 1 mg/day, maximum finasteride plasma concentration averaged 9.2 ng/ml and was reached 1 to 2 hours post-dose; AUC (0-24 hr) was 53 ng-hr/ml.

Finasteride has been recovered in the cerebrospinal fluid (CSF), but the drug does not appear to concentrate preferentially to the CSF. A small amount of finasteride has also been detected in the seminal fluid of subjects receiving the drug.

Biotransformation

Finasteride is metabolised primarily via the cytochrome P450 3A4 enzyme subfamily. Following an oral dose of 14C-finasteride in man, two metabolites of the drug were identified that possess only a small fraction of the 5α-reductase inhibitory activity of finasteride.

Elimination

Following an oral dose of 14C-finasteride in man, 39% of the dose was excreted in the urine in the form of metabolites (virtually no unchanged drug was excreted in the urine) and 57% of total dose was excreted in the faeces.

Plasma clearance is approximately 165 ml/min.

The elimination rate of finasteride decreases somewhat with age. Mean terminal half-life is approximately 5-6 hours in men 18-60 years of age and 8 hours in men more than 70 years of age. These findings are of no clinical significance and hence, a reduction in dosage in the elderly is not warranted.

Renal impairment

No adjustment in dosage is necessary in non-dialysed patients with renal impairment.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Paediatric population

Prosterid must not be used in children / adolescents (< 18 years). There are no data demonstrating efficacy or safety of Prosterid in children under the age of 18.

Effects on Prostate Specific Antigen (PSA)

In clinical studies with Prosterid 1 mg Tablets in men 18-41 years of age, the mean value of serum prostate-specific antigen (PSA) decreased from 0.7 ng/ml at baseline to 0.5 ng/ml at month 12. This decrease in serum PSA concentrations needs to be considered, if during treatment with Prosterid Tablets 1mg, a patient requires a PSA assay. In this case it should be considered to double PSA value before making a comparison with the results from untreated men.

Effects on fertility

See 4.6 Fertility, pregnancy and lactation

Breast cancer has been reported in men taking Prosterid during clinical trials and in the post-marketing period.

Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps, pain, gynaecomastia or nipple discharge.

The effect of hepatic insufficiency on the pharmacokinetics of Prosterid has not been studied.

Excipients

This medicinal product contains lactose-monohydrate. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.

Mood alterations and depression

Mood alterations including depressed mood, depression and, less frequently, suicidal ideation have been reported in patients treated with Prosterid 1 mg. Patients should be monitored for psychiatric symptoms and if these occur, treatment with Prosterid should be discontinued and the patient advised to seek medical advice.

General

To avoid obstructive complications it is important that patients with large residual urine and/or heavily decreased urinary flow are carefully controlled. The possibility of surgery should be an option.

Effects on PSA and prostate cancer detection

No clinical benefit has yet been demonstrated in patients with prostate cancer treated with 'Prosterid'. Patients with BPH and elevated serum prostate specific antigen (PSA) were monitored in controlled clinical studies with serial PSAs and prostate biopsies. In these BPH studies, 'Prosterid' did not appear to alter the rate of prostate cancer detection, and the overall incidence of prostate cancer was not significantly different in patients treated with 'Prosterid' or placebo.

Digital rectal examination, as well as other evaluations for prostate cancer, are recommended prior to initiating therapy with 'Prosterid' and periodically thereafter. Serum PSA is also used for prostate cancer detection. Generally, a baseline PSA >10 ng/mL (Hybritech) prompts further evaluation and consideration of biopsy; for PSA levels between 4 and 10 ng/mL, further evaluation is advisable. There is considerable overlap in PSA levels among men with and without prostate cancer. Therefore, in men with BPH, PSA values within the normal reference range do not rule out prostate cancer, regardless of treatment with 'Prosterid'. A baseline PSA <4 ng/mL does not exclude prostate cancer.

'Prosterid' causes a decrease in serum PSA concentrations by approximately 50% in patients with BPH, even in the presence of prostate cancer. This decrease in serum PSA levels in patients with BPH treated with 'Prosterid' should be considered when evaluating PSA data and does not rule out concomitant prostate cancer. This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. In patients treated with 'Prosterid' for six months or more, PSA values should be doubled for comparison with normal ranges in untreated men. This adjustment preserves the sensitivity and specificity of the PSA assay and maintains its ability to detect prostate cancer.

Any sustained increase in PSA levels of patients treated with finasteride 5mg should be carefully evaluated, including consideration of non-compliance to therapy with 'Prosterid'.

Drug/laboratory test interactions

Effect on levels of PSA

Serum PSA concentration is correlated with patient age and prostatic volume, and prostatic volume is correlated with patient age. When PSA laboratory determinations are evaluated, consideration should be given to the fact that PSA levels decrease in patients treated with 'Prosterid'. In most patients, a rapid decrease in PSA is seen within the first months of therapy, after which time PSA levels stabilise to a new baseline. The post-treatment baseline approximates half of the pre-treatment value. Therefore, in typical patients treated with 'Prosterid' for six months or more, PSA values should be doubled for comparison to normal ranges in untreated men. For clinical interpretation, see 4.4 Special warnings and precautions for use, Effects on PSA and prostate cancer detection.

Percent free PSA (free to total PSA ratio) is not significantly decreased by 'Prosterid'. The ratio of free to total PSA remains constant even under the influence of 'Prosterid'. When percent free PSA is used as an aid in the detection of prostate cancer, no adjustment to its value is necessary.

Breast cancer in men

Breast cancer has been reported in men taking finasteride 5 mg during clinical trials and the post-marketing period. Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps, pain, gynaecomastia or nipple discharge.

Mood alterations and depression

Mood alterations including depressed mood, depression and, less frequently, suicidal ideation have been reported in patients treated with finasteride 5 mg. Patients should be monitored for psychiatric symptoms and if these occur, the patient should be advised to seek medical advice.

Pediatric use

'Prosterid' is not indicated for use in children.

Safety and effectiveness in children have not been established.

Lactose

The tablet contains lactose monohydrate. Patients with any of the following genetic deficiencies should not take this drug: galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.

Hepatic Insufficiency

The effect of hepatic insufficiency on the pharmacokinetics of finasteride has not been studied.

Paediatric population

'Prosterid' should not be used in children. There are no data demonstrating efficacy or safety of finasteride in children under the age of 18.

Effects on Prostate Specific Antigen (PSA)

In clinical studies with 'Prosterid' in men 18-41 years of age, the mean value of serum prostate-specific antigen (PSA) decreased from 0.7 ng/ml at baseline to 0.5 ng/ml at month 12. Doubling the PSA level in men taking 'Prosterid' should be considered before evaluating this test result.

Effects on fertility

See 4.6 Fertility, pregnancy and lactation

Hepatic impairment

The effect of hepatic insufficiency on the pharmacokinetics of finasteride has not been studied.

Breast Cancer

Breast cancer has been reported in men taking finasteride 1 mg during the post-marketing period. Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps, pain, gynaecomastia or nipple discharge.

Mood alterations and depression

Mood alterations including depressed mood, depression and, less frequently, suicidal ideation have been reported in patients treated with finasteride 1 mg. Patients should be monitored for psychiatric symptoms and if these occur, treatment with finasteride should be discontinued and the patient advised to seek medical advice.

Lactose intolerance

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effects on ability to drive and use machines

Prosterid 1 mg has no or negligible influence on the ability to drive or use machines.

There are no data to suggest that 'Prosterid' affects the ability to drive or use machines.

Prosterid has no or negligible influence on the ability to drive and use machines.

Dosage (Posology) and method of administration

Posology

For oral use only.

The recommended dosage is one 1 mg tablet daily. Prosterid Accord 1mg may be taken with or without food. The tablet should be swallowed whole and must not be divided or crushed.

There is no evidence that an increase in dosage will result in increased efficacy.

Efficacy and duration of treatment should continuously be assessed by the treating physician. Generally, three to six months of once daily treatment are required before evidence of stabilization of hair loss can be expected. Continuous use is recommended to sustain benefit. If treatment is stopped, the beneficial effects begin to reverse by six months and return to baseline by 9 to 12 months.

Method of administration

For oral use only.

Dosage in renal insufficiency

No dosage adjustment is required in patients with renal insufficiency.

Dosage in hepatic insufficiency

There are no data available in patients with hepatic insufficiency

The recommended adult dose is one 5 mg tablet daily, with or without food.

'Prosterid' can be administered alone or in combination with the alpha-blocker doxazosin (see section 5.1 'Pharmacodynamic properties').

Although early improvement in symptoms may be seen, treatment for at least six months may be necessary to assess whether a beneficial response has been achieved. Thereafter, treatment should be continued long term.

No dosage adjustment is required in the elderly or in patients with varying degrees of renal insufficiency (creatinine clearances as low as 9 ml/min).

There are no data available in patients with hepatic insufficiency.

'Prosterid' is contra-indicated in children.

Posology

The recommended dosage is one 1 mg tablet daily. 'Prosterid' may be taken with or without food.

There is no evidence that an increase in dosage will result in increased efficacy.

Efficacy and duration of treatment should continuously be assessed by the treating physician. Generally, three to six months of once daily treatment are required before evidence of stabilisation of hair loss can be expected. Continuous use is recommended to sustain benefit. If treatment is stopped, the beneficial effects begin to reverse by six months and return to baseline by 9 to 12 months.

Method of administration

). 'Prosterid' tablets are coated to prevent contact with the active ingredient during normal handling, provided that the tablets are not broken or crushed.

Patients with renal impairment

No dosage adjustment is required in patients with renal insufficiency.

No data are available on the concomitant use of 'Prosterid' and topical minoxidil in male pattern hair loss.

Special precautions for disposal and other handling

Women who are pregnant or may become pregnant should not handle Prosterid tablets especially if crushed or broken because of the possibility of absorption of Prosterid and the subsequent potential risk to a male foetus.

Any unused product or waste material should be disposed of in accordance with local requirements.

Women should not handle crushed or broken 'Prosterid' Tablets when they are or may potentially be pregnant (see 'Contra-indications, 'Pregnancy and lactation', Exposure to finasteride - risk to male foetus).

Crushed or broken tablets of 'Prosterid' should not be handled by women when they are or may potentially be pregnant (see 4.6 'Pregnancy and lactation').

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.