Finasteride 1mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Finasteride 1 mg film-coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Active substance: finasteride
One film-coated tablet contains 1mg finasteride
Excipient(s) with known effect: lactose monohydrate 101.58 mg/tablet
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Film-coated tablets
Brown, round, biconvex film-coated tablets.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Finasteride 1mg is indicated for the treatment of the first stage of hair loss -(androgenetic alopecia) in men. In men aged 18-41 years Finasteride 1 mg film-coated Tablets stabilises the process of androgenetic alopecia. Efficacy in bi-temporal recession and hair loss in the end stage has not been established.
4.2 Posology and method of administration
Oral use
The recommended dosage is one 1mg tablet per day with or without food. The tablets should be swallowed whole and must not be divided or crushed (See section 6.6).
There is no evidence that a higher dose increases efficacy.
The efficacy and continuation of the treatment should continuously be assessed by the treating physician. Generally, Finasteride 1 mg film-coated Tablets must be taken once daily for 3-6 months before evidence of stabilisation of hair loss can be expected. Continuous use is recommended for a sustained beneficial effect. If the treatment is stopped, the beneficial effect begins to disappear after 6 months, and has completely disappeared after 9-12 months.
Dosage in renal insufficiencyThe dosage does not need to be adjusted in patients with renal insufficiency.
Dosage in hepatic insufficiency
There are no data available in patients with hepatic insufficiency
Paediatric population
There is no relevant use of Finasteride 1mg film-coated tablets in the paediatric population.
4.3 Contraindications
Finasteride should not be used in children / adolescents.
Contraindicated in women and children (see section 4.4, 4.6, and 5.1). Should not be taken by men who are taking Finasteride 5 mg Tablets or any other 5 a-
reductase inhibitor for benign prostatic hyperplasia or any other condition.
Hypersensitivity to finasteride or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Finasteride 1 mg film-coated Tablets should not be used in children/adolescents (< 18 years). There are no data demonstrating efficacy or safety of finasteride in children under the age of 18.
In clinical studies with Finasteride 1 mg film-coated Tablets in men 18 - 41 years of age, the mean value for 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 Finasteride 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.
Long-term data on fertility in humans are lacking, and no 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. Patients who are planning to father a child should consider to stop treatment (see also section 4.6).
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 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.
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 medicine.
4.5 Interaction with other medicinal products and other forms of interaction
No drug interactions of clinical importance have been identified. Finasteride is metabolised predominantly via, but does not affect, the P450-3A4 system. Although the risk of finasteride to affect the pharmacokinetics of other drugs is estimated to be small, it is probable that inhibitors and inducers of cytochrome P450 3A4 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. Compounds which have been tested in man have included antipyrine, digoxin, glibenclamide, propranolol, theophylline and warfarin and no interactions were found.
Due to lacking data for the concomitant use of finasteride and topical minoxidil in male pattern hair loss the combination is not recommended.
4.6 Fertility, pregnancy and lactation
Pregnancy:
Finasteride is contraindicated in women due to the risk in pregnancy (see section 4.3). Because of the ability of type II 5a-reductase inhibitors to inhibit conversion of testosterone to dihydrotestosterone (DHT) in some tissues, these drugs, including finasteride may cause abnormalities of the external genitalia of a male foetus when administered to a pregnant woman (see section 5.3. and section 6.6).
Exposure to Finasteride: risk to male foetus
Women who are pregnant or may become pregnant should not handle finasteride tablets especially if crushed or broken because of the possibility of absorption of finasteride and the subsequent potential risk to a male foetus (see section 6.6).
Small amounts of finasteride have been recovered from the semen in subjects receiving finasteride 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 finasteride. When the patient’s sexual partner is or may potentially be pregnant, the patient is recommended to minimise exposure of his partner to semen (e. g. by using condoms).
Lactation:
Finasteride 1 mg are not indicated for use in women. It is not known whether finasteride is excreted in human breast milk.
4.7 Effects on ability to drive and use machines
There are no data to suggest that finasteride affects the ability to drive or use machines.
4.8 Undesirable effects
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, <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.
|
Immune system disorders |
Not known: Hypersensitivity reactions, including rash, pruritus, urticaria and swelling of the lips and face. |
|
Cardiac disorder |
Not known: Palpitation |
|
Psychiatric disorders |
* Uncommon : Decreased libido Uncommon: Mood alterations with depressive symptoms |
|
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 (gynecomastia), Testicular pain, infertility |
* Incidences presented as difference from placebo in clinical studies at Month 12. ** See Section 4.4.
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 finasterde 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.
In addition, the following has been reported in post-marketing use: persistence of erectile dysfunction after discontinuation of treatment with finasteride; male breast cancer (see section 4.4 Special warnings and precautions for use).
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.
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 3 months (n = 71) did not result in dose-related undesirable effects.
No specific treatment for an overdose of Finasteride 1 mg film-coated Tablets is recommended.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other dermatologicals, ATC code: D11AX10
Finasteride is a 4-azasteroid, which inhibits human type 2 5a-reductase (present in the hair follicles) with a more than 100-fold selectivity compared with human type 1 5a-reductase, and blocks the peripheral conversion of testosterone to the androgenic dihydrotestosterone (DHT). In men with male pattern hair loss, the balding scalp
contains miniaturised hair follicles and increased concentrations of DHT. Finasteride inhibits the process responsible for miniaturisation of the scalp hair follicles, which can lead to reversal of the balding process.
Studies in men:
The efficacy of Finasteride has been demonstrated in three studies in 1879 men between 18 and 41 years old with mild to moderate, but not complete, hair loss on the crown and hair loss on the frontal/mid-area of the head. In these studies the hair growth was assessed on the basis of 4 different parameters, namely hair count, assessment of photographs of the head by a panel of expert dermatologists, assessment by the investigator and assessment by the patient himself.
In two studies in men with vertex hair loss, the treatment with Finasteride was continued for 5 years; in this period, an improvement occurred compared with baseline and placebo, beginning after 3 to 6 months.
Although the improvement in hair growth compared to baseline in the men treated with Finasteride was generally greatest after 2 years and then gradually decreased (the increase in hair count in a representative area of 5.1 cm2 two years after the start of treatment was 88 hairs compared with 38 hairs 5 years after the start of treatment), the hair loss in the placebo group was progressively poorer in comparison to baseline (decrease of 50 hairs after 2 years and 239 hairs after five years). Thus, although the improvement in comparison to baseline did not continue further after 2 years in the men treated with Finasteride, the difference between the treatment groups during the 5-year studies continued to increase. Treatment with Finasteride for 5 years resulted in stabilisation of the hair loss in 90 % of the men on the basis of photographic assessment and in 93 % on the basis of assessment by the investigator. In addition, increased hair growth was observed in 65 % of the men treated with Finasteride on the basis of hair count, in 48 % on the basis of photographic assessment, and in 77 % on the basis of assessment by the investigator. In contrast, in the placebo group a gradual hair loss over time was observed in 100 % of the men on the basis of hair count, in 75 % on the basis of photographic assessment, and in 38 % on the basis of assessment by the investigator. In addition, assessment by the patients themselves gave a significant increase in hair density, reduction in hair loss, and improvement in the appearance of the hair after 5 years of treatment with Finasteride (see the Table below).
Percentage of patients with improvement, assessed on the basis of each of the 4 criteria
|
Year 1T |
Year 2n |
Year 5TT | ||||
|
Finasteride |
placebo |
Finasteride |
placebo |
Finasteride |
placebo | |
|
Hair count |
(N=679) 86 |
(N=672) 42 |
(N=433) 83 |
(N=47) 28 |
(N=219) 65 |
(N=15) 0 |
|
Photos of the head |
(N=720) 48 |
(N=709) 7 |
(N=508) 66 |
(N=55) 7 |
(N=279) 48 |
(N=16) 6 |
|
Assessment by the investigator |
(N=748) 65 |
(N=747) 37 |
(N=535) 80 |
(N=60) 47 |
(N=271) 77 |
(N=13) 15 |
|
Assessment by the patient | ||||||
|
himself: |
(N=750) |
(N=747) |
(N=535) |
(N=60) |
(N=284) |
(N=15) |
|
satisfaction with the general appearance of the hair |
39 |
22 |
51 |
25 |
63 |
20 |
f Randomisation 1:1 Finasteride: placebo ff Randomisation 9:1 Finasteride: placebo
In a study lasting 12 months in men with hair loss on the frontal/mid-area of the head, hair counts were performed in a representative area of 1 cm2 (approximately 1/5 of the area on which counts were performed in the vertex studies). The hair count, corrected for an area of 5.1 cm2, increased by 49 hairs (5 %) compared with baseline, and by 59 hairs (6 %) compared with placebo. This study also showed a significant improvement in self-assessment by the patient, in assessment by the investigator, and in the scores on the basis of photos of the head by a panel of expert dermatologists.
Two studies of 12 and 24 weeks showed that a dose of 5 times the recommended dosage (finasteride 5 mg/day) resulted in a median decrease in the volume of the ejaculate of about 0.5 ml (-25 %) compared with placebo. This decrease was reversible after the discontinuation of treatment. In a study lasting 48 weeks, finasteride 1 mg/day resulted in a median decrease in ejaculate volume of 0.3 ml (-11 %) compared with 0.2 ml (-8 %) for placebo. No effect on the number, motility and morphology of the spermatozoa was observed. There are no longer-term data available. It was not possible to carry out clinical trials that might directly reveal a possible negative effect on fertility. However, such effects are considered extremely unlikely (see also section 5.3 Preclinical safety data).
Studies in women:
No 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. The peak finasteride plasma concentration is reached approximately two hours after administration; 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 (44-96 l). At steady state following administration of 1 mg/day, the mean maximum finasteride plasma concentration was 9.2 ng/ml and was reached 1 to 2 hours after administration; the AUC (0-24 hours) was 53 ng x hours/ml.
Finasteride has been recovered in the cerebrospinal fluid (CSF), but the drug does not appear to concentrate preferentially there. A very small amount of finasteride has also been detected in the seminal fluid of subjects receiving the drug. From studies in rhesus monkeys it appears that this amount is not considered to constitute a risk for the growing male foetus (see section 4.6 pregnancy and lactation and section 5.3 Preclinical safety data).
Biotransformation:
Finasteride is metabolised primarily via the cytochrome P450 3A4 system, but has no effect here. Following an oral dose of 14C-finasteride in man, two metabolites of the drug were identified that represent only a small fraction of the inhibitory activity of finasteride on 5a-reductase.
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 the 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. The mean terminal half-life is approximately 5-6 hours (3-14 hours), and in men more than 70 years of age 8 hours (6-15 hours). These findings are of no clinical significance and therefore a reduction in dosage in the elderly is not necessary.
Hepatic insufficiency:
The effect of hepatic insufficiency on the pharmacokinetics of finasteride has not been studied.
Renal insufficiency:
In patients with a chronic disturbance of renal function with creatinine clearance between 9 55 ml/min the area under the curve, the peak plasma concentrations, the half-life and the protein-binding of unchanged finasteride after a single dose of 14C-finasteride were virtually identical to the values in healthy volunteers.
5.3 Preclinical safety data
“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. The reproductive toxicity is believed to be mediated via the intended inhibition of 5a-reductase. Taken into account the species enzyme difference in sensitivity to finasteride 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 finasteride 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 finasteride, or approximately 77000 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.”
Mutagenicity/carcinogenicity
In genotoxicity and carcinogenicity studies no dangers for humans were revealed.
Negative effect on reproduction, including fertility
The effect on embryonal and foetal development has been studied in rats, rabbits and rhesus monkeys. In rats that were treated with 5-5000x the clinical dose, a dose-dependent occurrence of hypospadia in male foetuses was observed. In rhesus monkeys, treatment with oral doses of 2 mg/kg/day also resulted in abnormalities of the external genitalia. After intravenous doses of up to 800 ng/day in rhesus monkeys no effects on the male foetuses were observed. This represents at least 750 times the highest estimated exposure of pregnant women to finasteride from the semen of men who take 1 mg/day (see section 5.2). In the study in rabbits the foetuses were not exposed to finasteride during the critical period for the development of the genitalia.
In rabbits, after treatment with 80 mg/kg/day, a dose which in other studies was shown to have a clear weight-lowering effect on the gonads, no effect on ejaculate volume, sperm count or fertility was observed. In rats that were treated for 6 and 12 weeks with 80 mg/kg/day (about 500 times the clinical dose), no effect on fertility was observed. After treatment for 24-30 weeks some reduction in fertility and a clear decrease in weight of the prostate and the seminal vesicles was observed. All these changes appeared to be reversible within 6 weeks. The reduced fertility appeared to be the results of disturbed semen plug formation, an effect that is not relevant for humans. The development of the newborns and their ability to reproduce at sexually mature age were normal. After insemination of female rats with spermatozoa from the epididymis of rats that had been treated for 36 weeks with 80 mg/kg/day, no effect on the various fertility parameters was observed.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose monohydrate Microcrystalline cellulose (E460)
Pregelatinised Maize starch Sodium starch glycollate Docusate sodium Magnesium stearate (E470b)
Povidone K30
Coating:
OPADRY OY-S-36500 brown:
Titanium dioxide (E171)
Yellow and red iron oxide (E172).
Talc (E533b)
Hypromellose (E464)
Hydroxypropylcellulose (E463)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package to protect from light.
6.5 Nature and contents of container
PVC/Aluminium blisters packs of 7, 14, 28, 30, 60, 84, 90, 98 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Crushed or broken Finasteride tablets should not be handled by women who are or may be pregnant on account of the possible absorption of finasteride and the resultant potential danger for the male foetus (see section 4.6).
Finasteride tablets are coated, as a result of which contact with the active ingredient during normal handling is prevented provided that the tablets are not broken or crushed.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
04569/0898
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
08/09/2009
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 08/02/2014
10
DATE OF REVISION OF THE TEXT
08/02/2014