Fendazel

SUMMARY OF PRODUCT CHARACTERISTICS
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1. NAME OF THE MEDICINAL PRODUCT

FENDAZEL 1 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 1 mg of finasteride.
Pharmaceutically relevant excipient:
95.55 mg of lactose per tablet.
For the complete list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablets.
7 mm diameter, round biconvex, reddish-brown tablets, engraved with “F1”.

4. CLINICAL INFORMATION

4.1 Therapeutic indications
Finasteride is indicated in men aged 18 to 41 years for the treatment of early stages of androgenetic alopecia. FENDAZEL stabilizes the process of androgenetic alopecia. Efficacy has not been established in bitemporal recession or in the terminal stage of hair loss.

4.2 Posology and method of administration
Posology
The recommended dose is 1 tablet (1 mg) daily. Finasteride may be taken with or without food.
There is no evidence that increasing the dose leads to increased efficacy.
The effectiveness and duration of treatment should be continuously evaluated by the treating physician.
Generally, three to six months of daily treatment are required before stabilization of hair loss becomes evident. Continued use is recommended to maintain benefit. If treatment is discontinued, beneficial effects begin to regress within 6 months and return to baseline levels within 9–12 months.
There are no data regarding concomitant use of finasteride and topical minoxidil in male-pattern hair loss.

Use in renal impairment
No dosage adjustment is required in patients with varying degrees of renal impairment (creatinine clearance as low as 9 mL/min), as pharmacokinetic studies have not indicated any change in finasteride bioavailability.

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

Use in the elderly
No dosage adjustment is required in elderly patients.

Method of administration
Finasteride tablets that are crushed or broken must not be handled by women who are or may become pregnant, due to the possibility of absorption of finasteride and the consequent potential risk to male fetuses (see section 4.6). Finasteride tablets are film-coated to prevent contact with the active ingredient during normal handling, provided they are not broken or crushed.
For oral use only.
The tablet must be swallowed whole and must not be split or crushed (see section 6.6).

4.3 Contraindications
Contraindicated in women: see sections 4.6 "Fertility, pregnancy and lactation" and 5.1 "Pharmacodynamic properties".
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
The use of finasteride is not indicated in women, children, or adolescents.
Finasteride must not be taken by men who are already taking finasteride 5 mg or any other 5α-reductase inhibitor for benign prostatic hyperplasia or for any other condition.

4.4 Special warnings and precautions for use
Paediatric population
Finasteride must not be used in children. There are no data demonstrating the efficacy or safety of finasteride in children under 18 years of age.

Effect on Prostate-Specific Antigen (PSA)
In clinical studies of finasteride in men aged 18 to 41 years, the mean serum prostate-specific antigen (PSA) level decreased from a baseline value of 0.7 ng/mL to 0.5 ng/mL at month 12. If a PSA test is required during finasteride treatment, this reduction in serum concentrations must be taken into account. In men treated with finasteride, the PSA value should be considered doubled before comparison with results from untreated men.

Effects on fertility
See section 4.6 Fertility, pregnancy and lactation.

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

Breast cancer
Breast cancer has been reported in men treated with finasteride during clinical studies and in the post-marketing period.

Physicians should instruct their patients to promptly report any changes in breast tissue such as lumps, pain, gynecomastia, 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 the emergence of psychiatric symptoms, and if such symptoms occur, treatment with finasteride should be discontinued and patients should be advised to seek medical advice. In some patients, sexual dysfunction has been reported, which may contribute to mood alterations, including suicidal ideation. Patients should be informed of the need to consult a physician if they experience sexual dysfunction. Discontinuation of treatment should be considered (see section 4.8).
A patient reminder card highlighting the above is provided in the FENDAZEL packaging.

Excipients
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
This medicine contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction
Finasteride is metabolized primarily by the cytochrome P450 3A4 system, but does not influence it. Although the risk that finasteride may affect the pharmacokinetics of other drugs is considered small, inhibitors and inducers of cytochrome P450 3A4 are likely to affect plasma concentrations of finasteride. However, based on the established safety margins, any increase due to concomitant use of such inhibitors is unlikely to be of clinical relevance.
Interaction studies have been conducted only in adults.
Compounds tested in humans include phenazone, digoxin, glibenclamide, propranolol, theophylline, and warfarin, and no interactions were observed.
Although no specific interaction studies have been performed, doses of finasteride of 1 mg or higher have been used concomitantly in clinical trials 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
The use of finasteride is contraindicated in women due to the risk during pregnancy.
Due to the ability of finasteride to inhibit the conversion of testosterone to dihydrotestosterone (DHT) in certain tissues, these drugs, including finasteride, may cause abnormalities of the external genitalia of a male fetus when administered to pregnant women (see section 6.6 "Special precautions for disposal and handling").

Lactation
It is not known whether finasteride is excreted in human milk.
The use of finasteride is contraindicated during breastfeeding.

Fertility
There are no long-term data in humans, and no specific studies have been conducted in men with infertility. Male patients planning fatherhood were initially excluded from clinical trials. Although animal studies have not shown significant adverse effects on fertility, spontaneous reports of infertility and/or poor semen quality have been received during the post-marketing phase. In some of these reports, patients had other risk factors that could have contributed to infertility. Normalization or improvement in semen quality has been reported after discontinuation of finasteride therapy.

4.7 Effects on ability to drive and use machines
FENDAZEL does not affect or has negligible effect on the ability to drive vehicles and use machinery.

4.8 Undesirable effects
Adverse reactions reported during clinical studies and/or post-marketing use are listed in the table below.
The frequency of adverse reactions is defined 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 (frequency cannot be estimated from the available data).
The frequency of adverse reactions reported during post-marketing use cannot be determined as they derive from spontaneous reports.

* Incidence 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 studies (Protocols 087, 089, and 092) was not
different between finasteride and placebo.
Additionally, the following adverse effects have been reported in post-marketing use:
persistent sexual dysfunction (decreased libido, erectile dysfunction, and ejaculation disorders)
after discontinuation of finasteride treatment; male breast cancer (see section 4.4).
Sexual adverse effects related to the drug were more common in men treated with
finasteride than in those treated with placebo, with respective frequencies of 3.8% vs. 2.1%
during the first 12 months. The incidence of these effects decreased to 0.6% in men treated with
finasteride over the subsequent 4 years. Approximately 1% of men in each treatment group
discontinued therapy due to drug-related sexual adverse experiences during the first 12 months, and the incidence subsequently decreased.
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Diagnostic investigations:
When evaluating laboratory results for PSA, it should be taken into account that PSA levels generally decrease in patients treated with finasteride. In most patients, a rapid decline in PSA has been observed within the first months of therapy, after which PSA levels stabilize at a new baseline. The post-treatment baseline approximates half the pre-treatment value. Therefore, in patients treated with finasteride for six months or more, PSA values should be doubled to allow comparison with normal reference ranges in untreated men.
For details and clinical interpretations, see section 4.4.
No other differences were observed between patients treated with placebo or finasteride in standard diagnostic tests.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions occurring after marketing authorization of the medicinal product is important, as it allows continued monitoring of the benefit-risk balance of the medicinal product.
Healthcare professionals are required to report any suspected adverse reactions via the national reporting system at www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
4.9 Overdose
In clinical studies, single doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg per day for three months (n=71) did not cause dose-related adverse effects.
There are no recommendations for specific treatment of finasteride overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Dermatologicals
ATC code: D11AX10

Mechanism of action
Finasteride is a 4-azasteroid compound that inhibits human type 2 5α-reductase (present in hair follicles) with over 100-fold greater selectivity than human type 1 5α-reductase, and blocks the peripheral conversion of testosterone to the androgen dihydrotestosterone (DHT). In men experiencing male-pattern hair loss, the bald scalp shows miniaturized hair follicles and increased levels of DHT. Finasteride inhibits the process responsible for the miniaturization of hair follicles in the scalp, potentially making the hair loss process reversible.

Clinical efficacy and safety
Studies in men
The efficacy of finasteride has been demonstrated in three studies involving 1879 men aged between 18 and 41 years with mild to moderate, but not complete, vertex hair loss and hair loss in the frontal/intermediate areas. In these studies, hair growth was assessed using four different variables: hair counts, expert dermatologist panel evaluation of photographic reproductions of the scalp, investigator assessment, and patient self-assessment.

In two studies conducted in men with vertex hair loss, treatment with finasteride continued for 5 years. During this period, patients showed improvement from month 3 to month 6 compared to both baseline and placebo. While hair improvement parameters in men treated with finasteride generally reached a maximum at Year 2 and then gradually declined thereafter (e.g., hair count in a representative 5.1 cm² sample area increased by 88 hairs from baseline at 2 years and by 38 hairs from baseline at 5 years), hair loss in the placebo group progressively worsened compared to baseline (a decrease of 50 hairs at 2 years and 239 hairs at 5 years). Therefore, although improvement from baseline in men treated with finasteride did not increase further after Year 2, the difference between treatment groups continued to widen throughout the five-year study period. Treatment with finasteride for 5 years resulted in stabilization of hair loss in 90% of men based on photographic evaluation and in 93% based on investigator assessment. Additionally, increased hair growth was observed in 65% of men treated with finasteride based on hair counts, in 48% based on photographic evaluation, and in 77% based on investigator assessment. In contrast, in the placebo group, progressive hair loss over time was observed in 100% of men based on hair counts, in 75% based on photographic evaluation, and in 38% based on investigator assessment. Furthermore, patient self-assessment showed significant improvements in hair density, reduced hair loss, and improved hair appearance after more than 5 years of treatment with finasteride (see table below).

Percentage of patients improved for each of the 4 assessed parameters

†1:1 randomization finasteride vs placebo
††9:1 randomization finasteride vs placebo
In a 12-month study in men with hair loss in the mid-frontal area, hair counts
were obtained in a representative 1 cm area (approximately 1/5 of the sample area used in vertex studies).
Hair counts in a standardized area of 5.1 cm² increased by 49 hairs (5%) compared to baseline and by 59 hairs (6%) compared to placebo. This study also
demonstrated significant improvement in patient self-assessment, investigator assessment, and expert dermatologist panel grading of photographs of the scalp.
Two studies of 12 and 24 weeks' duration showed that a dose 5 times higher than the recommended dose (finasteride 5 mg/day) resulted in a median reduction in ejaculate volume of approximately 0.5 ml (-25%) compared to placebo. This reduction was reversible after discontinuation of treatment. In a 48-week study, finasteride at a dose of 1 mg/day produced a median reduction in ejaculate volume of 0.3 ml (-11%) compared to a reduction of 0.2 ml (-8%) with placebo. No effects were observed on sperm count, motility, or morphology.
Data for longer periods are not available. Clinical studies to directly clarify possible negative effects on fertility have not been feasible. However, such effects are
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considered very unlikely (see section 5.3 Preclinical safety data).

Studies in women
Lack of efficacy has been demonstrated in postmenopausal women with androgenetic alopecia treated with finasteride for 12 months.

5.2 Pharmacokinetic properties

Absorption
The bioavailability of finasteride after oral administration is approximately 80% and is not affected by food. Maximum plasma concentrations of finasteride are reached approximately 2 hours after dosing, and absorption is complete within six to eight hours.

Distribution
Protein binding is approximately 93%. The volume of distribution of finasteride is approximately 76 liters (44–96 liters).
At steady state following a dosage of 1 mg/day, the maximum plasma concentration of finasteride reaches 9.2 ng/ml, achieved 1 to 2 hours after administration; AUC is 53 ng·h/ml.
Finasteride has been detected in cerebrospinal fluid (CSF), but the drug does not appear to concentrate preferentially in CSF. A small amount of finasteride has also been found in the seminal fluid of subjects taking finasteride.
Studies in Rhesus monkeys have shown that this amount is not considered capable of posing a risk to a developing male fetus (see section 4.6 Fertility, pregnancy and lactation and section 5.3 Preclinical safety data).

Metabolism
Finasteride is primarily metabolized via the cytochrome P450 3A4 system, but does not interfere with the activity of this system. Following an oral dose of radiolabeled C-finasteride in humans, two metabolites of finasteride were identified, each possessing only a small fraction of the 5α-reductase inhibitory activity.

Elimination
Following an oral dose of radiolabeled C-finasteride in humans, approximately 39% (32–46%) of the dose is excreted in urine as metabolites (virtually no unchanged drug is excreted in urine), and 57% (51–64%) of the total dose is excreted in feces.
Plasma clearance is approximately 165 ml/min (70–279 ml/min).
The elimination rate of finasteride decreases moderately with age. The mean terminal plasma half-life is approximately 5–6 hours (3–14 hours) [8 hours (6–15 hours) in men over 70 years of age]. These findings are not clinically significant; therefore, dosage adjustment in the elderly is not warranted.

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

Renal impairment
In patients with chronic renal impairment, with creatinine clearance ranging from 9 to 55 ml/min, the area under the curve, maximum plasma concentrations, half-life, and protein binding of unchanged finasteride after a single dose of radiolabeled finasteride were similar to values obtained in healthy volunteers.

5.3 Preclinical safety data

Mutagenicity/carcinogenicity: Genotoxicity and carcinogenicity studies revealed no risk to humans.

Effects on reproductive function including fertility: Embryo- and fetotoxicity studies have been conducted in rats, rabbits, and Rhesus monkeys. In rats treated with 5 to 5,000 times the clinical dose, dose-dependent occurrence of hypospadias was observed in male fetuses. In Rhesus monkeys, oral treatment with doses of 2 mg/kg/day resulted in abnormalities of external genitalia. Intravenous doses up to 800 ng/day in Rhesus monkeys showed no effects on male fetuses. This dose represents at least 750 times the highest estimated exposure to finasteride in pregnant women from exposure to seminal fluid of men taking 1 mg/day (see section 5.2 Pharmacokinetic properties). In the rabbit study, fetuses were not exposed to finasteride during the critical period for genital development.

In rabbits, after treatment with 80 mg/kg/day—a dose that in other studies showed pronounced effects on reducing the weight of accessory sex glands—neither ejaculate volume, sperm count, nor fertility were altered. In rats treated for 6 and 12 weeks with 80 mg/kg/day (approximately 500 times the clinical exposure), no effects on fertility were observed. After 24–30 weeks of treatment, some reduction in fertility and a marked reduction in prostate and seminal vesicle weight were observed. All changes were reversible within 6 weeks. The reduced fertility was shown to be due to impaired seminal clot formation, an effect not relevant to humans. Neonatal development and reproductive capacity at sexual maturity were unremarkable. No effects were observed on multiple fertility parameters after insemination of female rats with epididymal sperm from rats treated for 36 weeks with 80 mg/kg/day.
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6. PHARMACEUTICAL INFORMATION

6.1 List of excipients
Tablet core:
Monohydrate lactose
Microcrystalline cellulose
Pregelatinized starch
Glyceryl macrogol laurate
Sodium starch glycolate – type A
Magnesium stearate.
Tablet coating:
Hypromellose 6 cps
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Red iron oxide (E 172)
Macrogol 6000.

6.2 Incompatibilities
Not applicable.
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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 the container
Blister: Al/PVC or Al/Al. Pack size: 28 tablets.
Plastic bottles (HDPE) with cap. Pack size: 28 tablets.

6.6 Special precautions for disposal and handling
Women who are pregnant or planning to become pregnant must not handle crushed or broken finasteride tablets due to the possibility of absorption of finasteride and the potential risks this may pose to male fetuses (see section 4.6).

7. MARKETING AUTHORISATION HOLDER

Pharmacare S.r.l.
Via Marghera, 29
20149 Milano
Italy

8. MARKETING AUTHORISATION NUMBER(S)

AIC n. 038376012 - 1 mg film-coated tablets, 28 tablets in Al/PVC blisters
AIC n. 038376024 - 1 mg film-coated tablets, 28 tablets in Al/Al blisters
AIC n. 038376036 - 1 mg film-coated tablets, 28 tablets in HDPE bottle

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 01/2009
Date of the most recent renewal: December 2016

10. DATE OF TEXT REVISION

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