Finasteride 5mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Finasteride 5 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 5.0 mg finasteride.
Excipients: Each film-coated tablet contains 102.63 mg lactose monohydrate. For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablets.
White or almost white, rounded triangle shaped, slightly biconvex film-coated tablets, with an imprinted mark "RG" on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Finasteride 5 mg tablets are indicated for the treatment and control of benign prostatic hyperplasia (BPH) in patients with an enlarged prostate to:
- cause regression of the enlarged prostate, improve urinary flow and improve the symptoms associated with BPH
- reduce the incidence of acute urinary retention and the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy.
4.2 Posology and method of administration
The recommended adult dose is one 5 mg tablet daily, with or without food.
Finasteride tablets are taken orally.
The tablet must be swallowed whole and should not be crushed or broken.
Finasteride can be administered alone or in combination with the alpha-blocker doxazosin (see section 5.1 'Pharmacodynamic properties').
The recommended duration of treatment is a minimum of six months to achieve clinical efficacy, but finasteride may also be continued at unchanged doses (as maintenance therapy).
No dosage adjustment is needed in patients with renal insufficiency (creatinine clearance as low as 9 ml/min) or in patients over 70 years of age.
There are no data available in patients with hepatic insufficiency.
Finasteride is contraindicated in adolescents and children under the age of 18 years.
4.3 Contraindications
Finasteride is not indicated for use in women or children.
Finasteride is contraindicated in the following:
• Hypersensitivity to the active substance or to any of the excipients
• Pregnancy - Use in women when they are or may potentially be pregnant (see 4.6 Pregnancy and lactation, Exposure to finasteride - risk to male fetus).
4.4 Special warnings and precautions for use
General
Finasteride is intended exclusively for men.
Before starting finasteride therapy, any other condition which may cause difficulties in passing urine (such as prostatic carcinoma, stricture of the urethra, neurological disorders) should be excluded.
Patients with high residual volume or severely decreased urinary flow rate should be carefully monitored for obstructive uropathy.
It is recommended to perform laboratory tests, liver and kidney function tests, blood count and urinary sediment tests before starting finasteride therapy and every six months during treatment. Namely, a large amount of finasteride is metabolised in the liver.
Effects on PSA and prostate cancer detection
No clinical benefit has yet been demonstrated in patients with prostate cancer treated with finasteride. Patients with BPH and elevated serum prostate specific antigen (PSA) were monitored in controlled clinical studies with serial PSAs and prostate biopsies. In these BPH studies, finasteride did not appear to alter the rate of prostate cancer detection, and the overall incidence of prostate cancer was not significantly different in patients treated with finasteride or placebo.
Digital rectal examination, as well as other evaluations for prostate cancer, should be carried out on
patients with BPH prior to initiating therapy with finasteride and periodically thereafter. Serum PSA is also used for prostate cancer detection. Generally, when PSA assays are performed a baseline PSA>10 ng/ml (Hybritech) prompts further evaluation and consideration of biopsy; for PSA levels between 4 and 10 ng/ml, further evaluation is advisable. There is considerable overlap in PSA levels among men with and without prostate cancer. Therefore, in men with BPH, PSA values within the normal reference range do not rule out prostate cancer regardless of treatment with finasteride. A baseline PSA <4 ng/ml does not exclude prostate cancer.
Finasteride causes a decrease in serum PSA concentrations by approximately 50% in patients with BPH even in the presence of prostate cancer. This decrease in serum PSA levels in patients with BPH treated with finasteride should be considered when evaluating PSA data and does not rule out concomitant prostate cancer. This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. Analysis of PSA data from over 3000 patients in the 4-year, double-blind, placebo-controlled finasteride Long-Term Efficacy and Safety Study (PLESS) confirmed that in typical patients treated with finasteride for six months or more, PSA values should be doubled for comparison with normal ranges in untreated men. This adjustment preserves the sensitivity and specificity of the PSA assay and maintains its ability to detect prostate cancer.
Any sustained increase in PSA levels of patients treated with finasteride should be carefully evaluated, including consideration of non-compliance to therapy with finasteride. Percent free PSA (free to total PSA ratio) is not significantly decreased by finasteride and remains constant even under the influence of finasteride. When percent free PSA is used as an aid in the detection of prostate cancer, no adjustment is necessary.
Drug/laboratory test interactions Effect on levels of PSA
Serum PSA concentration is correlated with patient age and prostatic volume, and prostatic volume is correlated with patient age. When PSA laboratory determinations are evaluated, consideration should be given to the fact that PSA levels decrease in patients treated with finasteride. In most patients, a rapid decrease in PSA is seen within the first months of therapy, after which time PSA levels stabilize to a new baseline. The post-treatment baseline approximates half of the pretreatment 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 clinical interpretation, see 4.4 Special warnings and precautions for use, Effects on PSA and prostate cancer detection.
Breast cancer in men
Breast cancer has been reported in men taking finasteride 5 mg during clinical trials and 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.
Pediatric use
Finasteride is not indicated for use in children.
Safety and effectiveness in children have not been established.
Pregnancy
Pregnant women and women of childbearing potential, specifically those who intend to get pregnant and those, in whom pregnancy cannot be excluded, should not touch broken or crushed tablets and should avoid contact with the seminal fluid of treated men throughout the treatment period and for two months after termination of the treatment. Finasteride is classified as a pregnancy category X compound. (see Section 4.6).
Lactose
The tablet 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 clinically important drug interactions have been identified. Finasteride does not appear to significantly affect the cytochrome P450 linked drug metabolising enzyme system.
Compounds which have been tested in man include propranolol, digoxin, glyburide (glibenclamide), warfarin, theophylline, and antipyrine (phenazone) and no clinically meaningful interactions were found.
Other concomitant therapy: Although specific interaction studies were not performed in clinical studies, finasteride was used concomitantly with ACE inhibitors, alpha-blockers, beta-blockers, calcium channel blockers, cardiac nitrates, diuretics, H2 antagonists, HMG-CoA reductase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin and paracetamol, quinolones and benzodiazepines without evidence of clinically significant adverse interactions.
Drug-lab modifications
Finasteride decreases the prostate-specific antigen (PSA) values in the serum.
4.6 Pregnancy and lactation
Finasteride is contra-indicated in women who are or may potentially be pregnant.
Because of the ability of Type II 5 a-reductase inhibitors to inhibit conversion of testosterone to dihydrotestosterone, these drugs, including finasteride, may cause abnormalities of the external genitalia of a male foetus when administered to a pregnant woman.
In animal developmental studies, dose-dependent development of hypospadias were observed in the male offspring of pregnant rats given finasteride at doses ranging from 100 frg/kg/day to 100 mg/kg/day, at an incidence of 3.6% to 100%.
Additionally, pregnant rats produced male offspring with decreased prostatic and seminal vesicular weights, delayed preputial separation, transient nipple development and decreased anogenital distance, when given finasteride at doses below the recommended human dose. The critical period during which these effects can be induced has been defined in rats as days 16-17 of gestation.
The changes described above are expected pharmacological effects of Type II 5 a-reductase inhibitors. Many of the changes, such as hypospadias, observed in male rats exposed in utero to finasteride are similar to those reported in male infants with a genetic deficiency of Type II 5 a-reductase. It is for these reasons that finasteride is contra-indicated in women who are or may potentially be pregnant.
No effects were seen in female offspring exposed in utero to any dose of finasteride.
Exposure to finasteride risk to male foetus:
Women should not handle crushed or broken tablets of finasteride 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 (see 'Pregnancy'). Finasteride tablets are coated and will prevent contact with the active ingredient during normal handling, 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. 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.
Lactation:
Finasteride is not indicated for use in women. 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 that finasteride influences the ability to drive and use machines.
4.8 Undesirable effects
The most frequent adverse reactions are impotence and decreased libido. These adverse reactions occur early in the course of therapy and resolve with continued treatment in the majority of patients.
The adverse reactions during clinical trials and post-marketing are listed in the table below.
Frequency of adverse reactions is determining as follows:
Very common (>1/10); Common (>1/100, <1/10); Uncommon (>1/1000, <1/100); Rare (>1/10,000, <1/1000); 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.
Investigations
Common: decreased volume of ejaculate
Cardiac disorders Unknown: palpitation
Skin and subcutaneous tissue disorders
Uncommon: rash
Unknown: pruritus, urticaria
Immune system disorders
Unknown: hypersensitivity reactions, including swelling of the lips and
face
Hepatobiliary disorders
Unknown: increased hepatic enzymes
Reproductive system and breast disorders Common: impotence
Uncommon: ejaculation disorder, breast tenderness, breast enlargement Unknown: testicular pain
Psychiatric disorders Uncommon: decreased libido
In addition, the following has been reported in clinical trials and postmarketing use: male breast cancer (see 4.4 Special warnings and precautions for use).
Medical therapy of prostatic symptoms (MTOPS)
The MTOPS study compared finasteride 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), combination therapy of finasteride 5 mg/day and doxazosin 4 or 8 mg/day (n=786), and placebo (n=737). In this study, the safety and tolerability profile of the combination therapy was generally consistent with the profiles of the individual components. The incidence of ejaculation disorder events without regard to drug relationship were: finasteride 8.3%, doxazosin 5.3%, combination 15.0%, placebo 3.9%.
Other long-term data
In a 7 year placebo-controlled trial that enrolled 18,882 healthy men, of 9,060 had prostate needle biopsy data available for analysis, prostate cancer was detected in 803 (18.4%) men receiving finasteride and 1,147 (24.4%) men receiving placebo. In the finasteride group, 280 (6.4%) of men had prostate cancer with Gleason scores of 7-10 detected on needle biopsy vs 237 (5.1%) men in the placebo group. Additional analyses suggest that the increase in the prevalence of high-grade prostate cancer observed in the finasteride group may be explained by a detection bias due to the effect of finasteride on prostate volume. Of the total cases of prostate cancer diagnosed in this study, approximately 98% were classified as intracapsular (stage T1 or T2). The relationship between longterm use of finasteride and tumours with Gleason scores of 7-10 is unknown.
Laboratory test findings
Serum PSA concentration is correlated with patient age and prostatic volume, and prostatic volume is correlated with patient age. When PSA laboratory determinations are evaluated, consideration should be given to the fact that PSA levels generally decrease in patients treated with finasteride. In most 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 clinical interpretation see 'Special warnings and precautions for use', 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.
4.9 Overdose
In clinical studies, single 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: Testosterone-5a-reductase inhibitor
Finasteride is a competitive inhibitor of human 5 a-reductase, an intracellular enzyme which metabolises testosterone into the more potent androgen, dihydrotestosterone (DHT). In benign prostatic hyperplasia (BPH), enlargement of the prostate gland is dependent upon the conversion of testosterone to DHT within the prostate.
Finasteride is highly effective in reducing circulating and intraprostatic DHT. Finasteride has no affinity for the androgen receptor.
In clinical studies of patients with moderate to severe symptoms of BPH, an enlarged prostate on digital rectal examination and low residual urinary volumes, Finasteride reduced the incidence of acute retention of urine from 7/100 to 3/100 over four years and the need for surgery (TURP or prostatectomy) from 10/100 to 5/100. These reductions were associated with a 2-point improvement in QUASI-AUA symptom score (range 0-34), a sustained regression in prostate volume of approximately 20% and a sustained increase in urinary flow rate.
Medical therapy of prostatic symptoms
The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a 4- to 6-year study in 3047 men with symptomatic BPH who were randomised to receive finasteride 5 mg/day, doxazosin 4 or 8 mg/day , the combination of finasteride 5 mg/day and doxazosin 4 or 8 mg/day , or placebo. The primary endpoint was time to clinical progression of BPH, defined as a ^ 4 point confirmed increase from baseline in symptom score, acute urinary retention, BPH-related renal insufficiency, recurrent urinary tract infections or urosepsis, or incontinence. Compared to placebo, treatment with finasteride, doxazosin, or combination therapy resulted in a significant reduction in the risk of clinical progression of BPH by 34(p=0.002), 39 (p<0.001), and 67% (p<0.001), respectively. The majority of the events (274 out of 351) that constituted BPH progression were confirmed ^4 point increases in symptom score; the risk of symptom score progression was reduced by 30 (95% CI 6 to 48%), 46 (95% CI 25 to 60%), and 64% (95% CI 48 to 75%) in the finasteride, doxazosin, and combination groups, respectively, compared to placebo. Acute urinary retention accounted for 41 of the 351 events of BPH progression; the risk of developing acute urinary retention was reduced by 67(p=0.011), 31 (p=0.296), and 79% (p=0.001) in the finasteride, doxazosin, and combination groups, respectively, compared to placebo. Only the finasteride and combination therapy groups were significantly different from placebo.
* Titrated from 1 mg to 4 or 8 mg as tolerated over a 3-week period
5.2 Pharmacokinetic properties
After 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. Two metabolites have been identified which possess only a small fraction of the Type II 5 a-reductase activity of finasteride.
The oral bioavailability of finasteride is approximately 80%, relative to an intravenous reference dose, and is unaffected by food. Maximum plasma concentrations are reached approximately two hours after dosing and the absorption is complete within 6-8 hours. Protein binding is approximately 93%. Plasma clearance and the volume of distribution are approximately 165 ml/min and 76 l, respectively.
In the elderly, the elimination rate of finasteride is somewhat decreased. Half-life is prolonged from a mean half-life of approximately six hours in men aged 18-60 years to eight hours in men aged more than 70 years. This is of no clinical significance and does not warrant a reduction in dosage.
In patients with chronic renal impairment, whose creatinine clearance ranged from 955 ml/min, the disposition of a single dose of 14C-finasteride was not different from that in healthy volunteers. Protein binding also did not differ in patients with renal impairment. A portion of the metabolites which normally is excreted renally was excreted in the faeces. It therefore appears that faecal excretion increases commensurate to the decrease in urinary excretion of metabolites. Dosage adjustment in non-dialysed patients with renal impairment is not necessary.
There are no data available in patients with hepatic insufficiency.
Finasteride has been found to cross the blood-brain barrier. Small amounts of finasteride have been recovered in the seminal fluid of treated patients.
5.3 Preclinical safety data
No further information provided.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Magnesium stearate Talc
Sodium starch glycolate (type A)
Pregelatinised starch Microcrystalline cellulose Lactose monohydrate
Tablet coating:
Titanium dioxide (C.I.77891, E171)
Lactose monohydrate Macrogol 6000 Hyprolose Hypromellose
Incompatibilities
6.2
Not applicable.
6.3 Shelf life
5 years
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5 Nature and contents of container
Blister packs of hard aluminium foil and white, hard PVC foil containing 7x, 10x, 14x, 15x, 28x, 30x, 50x, 56x, 90x, 98x, 100x, 105x, 120x tablets.
(Not all pack sizes may be marketed.)
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Gedeon Richter PLC
Gyomroi Ut 19-21
Budapest
1103
Hungary
8 MARKETING AUTHORISATION NUMBER(S)
PL 04854/0042
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 14/11/2006
10
DATE OF REVISION OF THE TEXT
29/07/2010