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Finasteride 1 Mg Film-Coated Tablets

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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 1 mg finasteride

Excipient: lactose monohydrate 95.55 mg

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Film-coated tablet.

Reddish brown, round biconvex, 7 mm film-coated tablet with "F1" marking on one 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

For oral use only.

The recommended dosage is 1 tablet (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 stabilization of hair loss can be expected. Continued 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.

Dosage in hepatic insufficiency

There are no data available in patients with hepatic insufficiency (see section 4.4).

4.3 Contraindications

Contra-indicated in women and children (see 4.4, 4.6 and 6.6).

Should not be taken by men who are taking Finasteride 5 mg Tablets or any other 5a-reductase inhibitor for benign prostatic hyperplasia or any other condition.

Hypersensitivity to finasteride or to any of the excipients.

4.4. Special warnings and precautions for use

Finasteride must not be used in adolescents (<18 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. 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. Male patients who are

planning to father a child should consider stopping treatment (see also section 4.6).

There is no experience in patients with liver insufficiency. Caution is advised in patients with decreased hepatic function as the plasma-levels of finasteride may be increased in such patients.

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 does not appear to affect the cytochrome P450-linked drug metabolizing enzyme system. 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 Pregnancy and lactation

Use during pregnancy:

Finasteride is contraindicated in women (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).

Exposure to Finasteride: risk to male foetus

Women who are pregnant or may become pregnant must 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).

Finasteride tablets have a film coating which prevents contact with the active ingredient provided that the tablets have not been broken or crushed.

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 is contraindicated for use in women. It is not known whether finasteride is excreted in breast milk.

4.7 Effects on ability to drive and use machines

There is no information to suggest that Finasteride affects the ability to drive or use machines.

4.8 Undesirable effects

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.
Hepatobiliary disorders:	Not known: Increased hepatic enzymes.

Reproductive system and breast	Uncommon*: Erectile dysfunction,
disorders:	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.

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.

Persistence of erectile dysfunction after discontinuation of treatment with Finasteride has been reported in post-marketing use.

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: Testosteron-5a-reductase-inhibitors ATC-code D11AX10.

Finasteride is a 4-azasteroid, which inhibits human Type 2 5a-reductase (present within the hair follicles) with greater than 100-fold selectivity over human Type 1 5a-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. Finasteride inhibits a process responsible for miniaturization of the scalp hair follicles, which can lead to reversal of the balding process.

Studies in men:

The efficacy of Finasteride 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 Finasteride was continued for 5 years, during which time patients improved compared to both baseline and placebo beginning at 3 to 6 months. While hair improvement measures compared to baseline in men treated with Finasteride were generally greatest at 1-2 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 Finasteride did not increase further after 2 years, the difference between treatment groups continued to increase throughout the 5 years of the studies. Treatment with Finasteride 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 Finasteride 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 selfassessment demonstrated significant increases in hair density, decreases in hair loss, and improvement in appearance of hair after treatment over 5 years with Finasteride (see Table below).

Percent of Patients Improved

as Assessed by Each of

the 4 Measures

Year 1 *

Year 2**

Year 5**

FINASTERIDE

placebo

FINASTERIDE

placebo

FINASTERIDE

placebo

Hair Count

(N=672)

(N=47)

(N=219)

(N=15)

Global

Photographic

Assessment

(N=720)

(N=709)

(N=508) 66

(N=55)

(N=279)

(N=16)

Investigator

Assessment

(N=748)

(N=747)

(N=535)

(N=60)

(N=271)

(N=13)

Patient SelfAssessment: Satisfaction with appearance of hair overall

(N=750)

(N=747)

(N=535)

(N=60)

(N=284)

(N=15)

* Randomization 1:1 FINASTERIDE to placebo ** Randomization 9:1 FINASTERIDE 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 (finasteride 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, finasteride 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. Effects on sperm count, motility or morphology were less than significant. 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 postmenopausal women with androgenetic alopecia who were treated with Finasteride 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..

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 liters (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

finasteride. Studies in rhesus monkeys showed that this amount is not considered to constitute a risk to the developing male foetus (see 4.6, and 5.3).

Biotransformation:

Finasteride is metabolized primarily via but does not affect the cytochrome P450 3A4 system. Following an oral dose of ¹⁴C-finasteride in man, two metabolites of finasteride 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% (3246%) 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 feces.

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 9-55 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 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, feminisation 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 1 - 2 million times the estimated mount 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose monohydrate,

Microcrystalline cellulose,

Pregelatinised maize Starch,

Lauroyl Macrogolglycerides,

Sodium starch glycolate (type A),

Magnesium stearate (E572)

Film coating:

Hypromellose Titanium dioxide (E 171)

Iron Oxide yellow (E172)

Iron oxide red (E172)

Macrogol 6000

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

HDPE container and LDPE screw cap:

Use within 4 months after first opening of the plastic container.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

DE/H/1289/01/DC:

Blister (Aluminium/PVC; Aluminium/Aluminium)

Pack sizes:

7, 10, 14, 15, 20, 28, 30, 50, 56, 60, 84, 90, 98, 100, 180 tablets Unit dose blister:

Pack sizes:

28x1, 30x1, 50x1, 98x1, 100x1 tablets

HDPE container and LDPE screw cap Pack sizes:

100, 250, 500 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

4.6). The tablets have a film coating that prevents contact with the active ingredient provided that the tablets have not been broken or crushed.

7 MARKETING AUTHORISATION HOLDER

Ratiopharm GmbH, Graf-Arco-Str.3, 89079 Ulm, Germany

8 MARKETING AUTHORISATION NUMBER(S)

PL 15773/0681

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/07/2009

10 DATE OF REVISION OF THE TEXT

25/08/2010