Finasteride 1 Mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Finasteride 1 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 1 mg finasteride.
Excipient with known effect:
Each film-coated tablet contains 101.50 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Brown coloured, octagonal, biconvex, film-coated tablets debossed with ‘J’ on one side and ‘81’ on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Early stages of androgenetic alopecia in men. Finasteride stabilizes the process of androgenetic alopecia in men 18-41 years of age. Efficacy in bitemporal recession and end-stage hair loss has not been established.
4.2 Posology and method of administration
1 tablet (1 mg) daily 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 6 months and return to baseline by 9 to 12 months.
No dosage adjustment is required in patients with renal insufficiency.
No data are available on the concomitant use of finasteride and topical minoxidil in male patern hair loss.
Children and adolescents
The safety and efficacy of finasteride in children and adolescents aged less than 18 years have not been established. No data are available.
4.3 Contraindications
Contra-indicated in women: see sections 4.6 and 5.1.
Hypersensitivity to finasteride or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Finasteride should not be used in children. There are no data demonstrating efficacy or safety of finasteride in children under the age of 18.
In clinical studies with finasteride 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 finasteride should be considered before evaluating this test result.
Long-term data on fertility in humans are lacking, and specific studies in subfertile men have not been conducted. The male patients who were planning to father a child were initially excluded from clinical trials. Although animal studies did not show relevant negative effects on fertility, spontaneous reports of infertility and/or poor seminal quality were received post-marketing. In some of these reports, patients had other risk factors that might have contributed to infertility. Normalisation or improvement of seminal quality has been reported after discontinuation of finasteride.
The effect of hepatic insufficiency on the pharmacokinetics of finasteride has not been studied.
Breast cancer has been reported in men taking finasteride 1 mg during the postmarketing period. Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps, pain, gynaecomastia or nipple discharge.
This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Finasteride is metabolised via, but does not affect, the cytochrome P450 3A4 system. Although the risk for finasteride to affect the pharmacokinetics of other drugs is estimated to be small, it is probable that inhibitors and inducers of cytochrome P450 3A4 will affect the plasma concentration of finasteride. However, based on established safety margins, any increase due to concomitant use of such inhibitors is unlikely to be of clinical significance.
4.6 Fertility, pregnancy and lactation
Pregnancy
Finasteride is contraindicated for use in women due to the risk in pregnancy. Because of the ability of finasteride to inhibit conversion of testosterone to dihydrotestosterone (DHT) finasteride may cause abnormalities of the external genitalia of a male fetus when administered to a pregnant woman (see 6.6 Instructions for use/handling).
Lactation
It is not known whether finasteride is excreted in human milk.
4.7 Effects on ability to drive and use machines
There are no data to suggest finasteride affects the ability to drive or use machines.
4.8 Undesirable effects
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 Finasteride and placebo were similar. Discontinuation of therapy due to any clinical adverse experience occurred in 1.7% of 945 men treated with Finasteride 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 Finasteride: decreased libido (Finasteride, 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 Finasteride and 0.4% of men treated with placebo. Resolution of these side effects occurred in men who discontinued therapy with Finasteride and in many who continued therapy. The effect of Finasteride 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 Finasteride, 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.
The adverse reactions considered at least possibly related to treatment are listed below by body system organ class and absolute frequency.
Frequencies are defined as 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).
|
Immune system disorders |
Not known |
Hypersensitivity reactions, including rash, pruritus, urticaria and swelling of the lips and face |
|
Cardiac disorders |
Not known |
Palpitation |
|
Psychiatric disorder |
Uncommon* |
Decreased libido |
|
Uncommon |
Depressed moodf | |
|
Hepatobiliary disorders |
Not known |
Increased hepatic enzymes |
|
Reproductive system and breast disorders |
Uncommon* |
Erectile dysfunction, ejaculation disorder (including decreased volume of ejaculate) |
|
Not known |
Breast tenderness and enlargement, testicular pain, infertility** ** see section 4.4 |
* Incidences presented as difference from placebo in clinical studies at Month 12.
f 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.
Drug-related undesirable effects were more common in the finasteride-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-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.
In addition, the following have been reported in post-marketing use: persistence of erectile dysfunction after discontinuation of treatment with finasteride, male breast cancer (see section 4.4).
4.9 Overdose
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 overdose with finasteride is recommended.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other dermatological preparations, other dermatologicals ATC code: D11AX10
Finasteride is a 4-azasteroid which inhibits human type II 5a-reductase (present within the hair follicles) with greater than 100-fold selectivity over human type I 5 a-reductase, and blocks the peripheral conversion of testosterone to the androgen dihydrotestosterone (DHT).
In men with male pattern hair loss, the balding scalp contains miniaturised hair follicles and increased amounts of DHT. Finasteride inhibits a process responsible for miniaturisation of the scalp hair follicles, which can lead to reversal of the balding process.
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 Finasteride 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 Finasteride 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 Finasteride 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 Finasteride 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 Finasteride 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 Finasteride 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 Finasteride led to improvements in anagen hair counts, while men in the placebo group lost anagen hair. At 48 weeks, men treated with Finasteride ' 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 Finasteride, compared to placebo. These data provide direct evidence that treatment with Finasteride 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 finasteride 1 mg for 12 months.
5.2 Pharmacokinetic properties
Bioavailability
The oral bioavailability of finasteride is approximately 80% and is not affected by food. Maximum finasteride plasma concentrations are reached approximately 2 hours after dosing and the absorption is complete after 6 to 8 hours.
Distribution
Protein binding is approximately 93%. The volume of distribution is approximately 76 litres (44-96 l).
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 postdose; AUC (0-24 hr) was 53 ng x hr/ml.
Finasteride has been recovered in the cerebrospinal fluid (CSF), but the drug does not appear to concentrate preferentially to the CSF. A very small amount of finasteride has also been detected in the seminal fluid of subjects receiving the drug. Studies in rhesus monkeys showed that this amount is not considered to constitute a risk to the developing male fetus (see sections 4.6 and 5.3).
Biotransformation
Finasteride is metabolised primarily via but does not affect the cytochrome P450 3A4 system. Following an oral dose of 14C-finasteride in man, two metabolites of the drug were identified that possess only a small fraction of the 5a-reductase inhibitory activity of finasteride.
Elimination
Following an oral dose of 14C-finasteride in man, approximately 39% (32-46%) of the dose was excreted in the urine in the form of metabolites. Virtually no unchanged drug was excreted in the urine and 57% (51-64%) of total dose was excreted in the faeces.
Plasma clearance is approximately 165 ml/min (70-279 ml/min).
The elimination rate of finasteride decreases somewhat with age. Mean terminal plasma half-life is approximately 5-6 hours (3-14 hours) (in men more than 70 years of age 8 hours (6-15 hours)). These findings are of no clinical significance and hence, a reduction in dosage in the elderly is not warranted.
Hepatic insufficiency
The effect of hepatic insufficiency on the pharmacokinetics of finasteride has not been studied.
Renal insufficiency
In patients with chronic renal impairment, with creatinine clearances ranging from 955 ml/min, area under the curve, maximum plasma concentrations, half-life, and protein binding of unchanged finasteride after a single dose of 14C-finasteride were similar to values obtained in health volunteers.
5.3 Preclinical safety data
Mutagenicitv/carcinogenicitv
Studies on genotoxicity and carcinogenicity have not revealed any hazards for humans.
Reproduction-disturbing effect including fertility
The effects on embryonic and fetal development have been studied in rats, rabbits and rhesus monkeys. In rats treated with 5-5,000 times the clinical dose, a dose-related occurrence of hypospadias has been observed in male fetuses. In rhesus monkeys, treatment with oral doses of 2 mg/kg/day has also resulted in external genital abnormalities.
Intravenous doses of up to 800 ng/day in rhesus monkeys have not shown any effects on male fetuses. This represents at least 750 times the highest estimated exposure of pregnant women to finasteride from semen of men taking 1 mg/day (see section 5.2).
In the rabbit study, the fetuses were not exposed to finasteride during the period critical for genital development.
Neither ejaculation volume, sperm count nor fertility were affected in the rabbit after treatment with 80 mg/kg/day, a dose that in other studies is shown to have pronounced weight-lowering effects on accessory sexual glands. In rats treated for 6 and 12 weeks with 80 mg/kg/day (approximately 500 times the clinical exposure) no effect on fertility was observed. After 24-30 weeks' treatment some reduced fertility and pronounced weight reduction of prostate and seminal vesicle were seen. All changes were reversible within a 6-week period. The reduced fertility has been shown to be due to impaired seminal plug formation, an effect that has no relevance to man. The development of the newborns and their reproduction capacity at the age of sexual maturation were without remark. After insemination of female rats with epididymis sperms from rats treated for 36 weeks with 80 mg/kg/day no effect was seen on a number of fertility parameters.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose monohydrate Cellulose, microcrystalline Sodium starch glycolate Starch pregelatinised [maize starch]
Docusate sodium Magnesium stearate
Tablet coat: Hypromellose Hydroxy propyl cellulose Talc
Titanium dioxide (E171) Red iron oxide (E172) Yellow iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Finasteride film-coated tablets are available in white opaque PVC/PE/PVdC -Aluminium foil blister pack and HDPE bottle with polypropylene cap containing silica gel as desiccant.
Package size:
Blister pack: 28, 56, 84, & 98 film-coated tablets HDPE bottle pack: 30 & 1000 film-coated tablets
Not all pack sizes may be marketed
6.6 Special precautions for disposal
Crushed or broken tablets of Finasteride should not be handled by women when they are or may potentially be pregnant (see 4.6 'Pregnancy and lactation'). Finasteride tablets are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets are not broken or crushed.
7 MARKETING AUTHORISATION HOLDER
Milpharm Limited
Ares Block, Odyssey Business Park
West End Road
Ruislip HA4 6QD
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 16363/0390
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
18/02/2014
10 DATE OF REVISION OF THE TEXT
09/07/2015