Finasteride 1 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Finasteride 1 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 1 mg finasteride.
Excipient with known effect:
95.55mg Lactose per tablet.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated Tablet.
Round biconvex, reddish brown tablets 7mm in diameter, marked “F1”
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Finasteride is indicated for the treatment of the early stages of androgenetic alopecia in men.
Finasteride is not indicated for use in women or children and adolescents.
4.2 Posology and method of administration
Method of administration
For oral use only
The tablet should be swallowed whole and must not be divided or crushed (see section 6.6).
Posology
Androgenetic alopecia
The recommended dosage is 1 mg daily. Finasteride 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.
No data are available on the concomitant use of Finasteride and topical minoxidil in male pattern hair loss.
Use in renal insufficiency
No adjustment in dosage is required in patients with varying degrees of renal insufficiency (creatinine clearances as low as 9 ml/min), as pharmacokinetic studies did not indicate any change in the disposition of finasteride.
Dosage in hepatic insufficiency
There are no data available in patients with hepatic insufficiency (see section 4.4).
Use in the elderly
No dosage adjustment is required in elderly patients.
4.3 Contraindications
Contraindicated in women: see 4.6 'Pregnancy and lactation' and 5.1 ‘Pharmacodynamic properties’.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Finasteride is not indicated for use in women or children and adolescents.
Finasteride should not be taken by men who are taking finasteride 5mg or any other 5a-reductase inhibitor for benign prostatic hyperplasia or any other condition.
4.4 Special warnings and precautions for use
Paediatric population
Finasteride should not be used in children. There are no data demonstrating efficacy or safety of finasteride in children under the age of 18.
Clinical trial data is limited to patients with ages from 18 to 49 years, and limited data is available for patients older than 49 years.
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. This decrease in serum PSA concentrations needs to be considered if, during treatment with Finasteride, a patient requires a PSA assay. Doubling the PSA value in men taking Finasteride should be considered before making a comparison with the results from untreated men.
The effect of hepatic insufficiency on the pharmacokinetics of finasteride has not been studied. Caution is advised in patients with decreased hepatic function as the plasma-levels of finasteride may be increased in such patients.
Since finasteride inhibits the conversion of testosterone to dihydrotestosterone, it can inhibit the development of the external genitalia of the foetus if it is given to a woman carrying a male foetus (see section 5.3 and 6.6).
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.
Breast cancer has been reported in men taking finasteride 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.
Excipients
Patients with rare hereditary problems of fructose intolerance, galactose intolerance, the Lapp lactase deficiency, galactosaemia or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
Finasteride is metabolised primarily 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. Compounds which have been tested in man have included antipyrine, digoxin, glibenclamide, propranolol, theophylline and warfarin and no interactions were found.
Although specific interaction studies were not performed, in clinical studies finasteride doses of 1 mg or more were used concomitantly with ACE inhibitors, paracetamol, alpha blockers, benzodiazepines, beta blockers, calcium-channel blockers, cardiac nitrates, diuretics, H2 antagonists, HMG-CoA reductase inhibitors, prostaglandin synthetase inhibitors (NSAIDs), and quinolones, without evidence of clinically significant adverse interactions.
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 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 6.6 ‘Special precautions for disposal and other handling’).
Exposure to finasteride: risk to male foetus
A small amount of finasteride, less than 0.001% of the 1 mg dose per ejaculation, has been detected in the seminal fluid of men taking finasteride. Studies in Rhesus monkeys have indicated that this amount is unlikely to constitute a risk to the developing male foetus (see Section 5.3).
During continual collection of adverse experiences, post-marketing reports of exposure to finasteride during pregnancy via semen of men taking 1 mg or higher doses have been received for eight live male births, and one retrospectively-reported case concerned an infant with simple hypospadias. Causality cannot be assessed on the basis of this single retrospective report and hypospadias is a relatively common congenital anomaly with an incidence ranging from 0.8 to 8 per 1000 live male births. In addition, a further nine live male births occurred during clinical trials following exposure to finasteride via semen, during pregnancy, and no congenital anomalies have been reported.
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. Therefore, when the patient’s sexual partner is or may potentially be pregnant, the patient should either avoid exposure of his partner to semen (e.g. by use of a condom) or discontinue finasteride.
Crushed or broken tablets of Finasteride should not be handled by women when they are or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male foetus. Finasteride tablets are coated to prevent contact with the active ingredient during normal handling, provided that the tablets are not broken or crushed.
Breast-feeding
It is not known whether finasteride is excreted in human milk. Finasteride is contraindicated for use in lactation.
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
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 'Propecia' and placebo were similar. Discontinuation of therapy due to any clinical adverse experience occurred in 1.7% of 945 men treated with 'Propecia' 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 'Propecia': decreased libido ('Propecia', 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 'Propecia' and 0.4% of men treated with placebo. Resolution of these side effects occurred in men who discontinued therapy with 'Propecia' and in many who continued therapy. The effect of 'Propecia' 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 'Propecia', 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 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: |
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 dif |
erence 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 sexual 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 sexual dysfunction (decreased libido, erectile dysfunction and ejaculation disorders) after discontinuation of treatment with finasteride; male breast cancer (see 4.4 Special warnings and precautions for use).
Laboratory tests:
When PSA laboratory determinations are evaluated, consideration should be given to the fact that PSA levels generally decrease in patients treated with finasteride. In a majority of the 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 finasteride for six months or more, PSA values should be doubled for comparison to normal ranges in untreated men. For details and clinical interpretation see section 4.4 (paragraph Effects on prostate-specific antigen (PSA) and prostate cancer detection).
No other difference was observed in patients treated with placebo or finasteride 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 national reporting system listed in Appendix V.
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 overdosage with finasteride is recommended.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Dermatologicals ATC-Code: D11AX10
Mechanism of action
Finasteride is a competitive and specific inhibitor of type II 5a-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 5a-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 5a-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.
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 Propecia 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 cm 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 'Propecia' 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 'Propecia' led to improvements in anagen hair counts, while men in the placebo group lost anagen hair. At 48 weeks, men treated with 'Propecia' 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 'Propecia', compared to placebo. These data provide direct evidence that treatment with 'Propecia' 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 in a 12 month, placebo-controlled study (n=137). These women did not show any improvement in hair count, patient selfassessment, investigator assessment, or ratings based on standardised photographs, compared with the placebo group.
5.2 Pharmacokinetic properties
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 postdose; 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 5a-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 halflife 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-dialysed patients with renal impairment.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
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. When finasteride was administered to primates during gestation no femininisation of male foetuses was seen at a blood exposure level well above the expected levels in human semen. It is not likely that exposure of male foetuses to finasteride from semen will cause negative effects.
In general, the findings in laboratory animal studies with oral finasteride were related to the pharmacological effects of 5a-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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet Core
Lactose monohydrate Cellulose, microcrystalline Pregelatinised Starch Lauroyl Macrogolglycerides Sodium starch glycolate - Type A Magnesium stearate
Tablet Coating
Hypromellose 6 cps. Titanium dioxide (E171) Iron oxide yellow E 172 Iron oxide red E 172 Macrogol 6000
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
Blister packs: Aluminium/PVC or Aluminium/Aluminium. Pack size 28 tablets.
Plastic bottles (HDPE) with cap. Pack size 28 tablets.
6.6 Special precautions for disposal and other handling
Women who are pregnant or may become pregnant should not handle crushed or broken finasteride tablets because of the possibility of absorption of finasteride and the subsequent potential risk to a male foetus (see section 4.6).
7 MARKETING AUTHORISATION HOLDER
Caduceus Pharma Limited 6th Floor 94 Wigmore Street
London
W1U 3RF
8 MARKETING AUTHORISATION NUMBER(S)
PL 24668/0030
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
06/06/2008
10 DATE OF REVISION OF THE TEXT
29/10/2015