Finasteride 5 Mg Film-Coated Tablet
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Finasteride 5 mg Film-coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One film-coated tablet contains 5 mg of finasteride.
Excipient(s) with known effect: lactose monohydrate 83.80 mg For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Blue colour, round shaped film coated tablets with a dimension of 6.6 x 6.8 mm, debossed with ‘H’ on one side and ‘37’ on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Finasteride 5 mg tablets are indicated for the treatment and control of benign prostatic hyperplasia (BPH) 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 reduce need for surgery including transurethral resection of the prostate (TURP) and prostatectomy.
4.2 Posology and method of administration
For oral use only.
The recommended dosage is one 5 mg tablet daily with or without food. The tablet should be swallowed whole and must not be divided or crushed (See section 6.6). Even though improvement can be seen within a short time, treatment for at least 6 months may be necessary in order to determine objectively whether a satisfactory response to treatment has been achieved.
Dosage in the elderly
Dosage adjustments are not necessary although pharmacokinetic studies have shown that the elimination rate of finasteride is slightly decreased in patients over the age of 70.
Dosage in hepatic insufficiency
There are no data available in patients with hepatic insufficiency (See section 4.4).
Dosage in renal insufficiency
Dosage adjustments are not necessary in patients with varying degrees of renal insufficiency (starting from creatinine clearance as low as 9 ml/min) as in pharmacokinetic studies renal insufficiency was not found to affect the elimination of finasteride. Finasteride has not been studied in patients on hemodialysis.
4.3 Contraindications
Finasteride is not indicated for use in women or children.
Finasteride is contraindicated in the following:
• Hypersensitivity to any component of this product
• 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
To avoid obstructive complications it is important that patients with large residual urine and/or heavily decreased urinary flow are carefully controlled. The possibility of surgery should be an option.
Effects on PSA and prostate cancer detection
No clinical benefit has yet been demonstrated in patients with prostate cancer treated with Finsateride 5 mg. 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 5 mg 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 5 mg or placebo.
Digital rectal examination, as well as other evaluations for prostate cancer, are recommended prior to initiating therapy with Finasteride 5 mg and periodically thereafter. Serum PSA is also used for prostate cancer detection. Generally, 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 5 mg. A baseline PSA <4 ng/mL does not exclude prostate cancer.
Finasteride 5 mg 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 5 mg 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. In patients treated with Finasteride 5 mg 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 5mg should be carefully evaluated, including consideration of non-compliance to therapy with Finasteride 5 mg.
Percent free PSA (free to total PSA ratio) is not significantly decreased by Finasteride 5 mg. The ratio of free to total PSA remains constant even under the influence of Finasteride 5 mg. When percent free PSA is used as an aid in the detection of prostate cancer, no adjustment to its value 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 5 mg. 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 5 mg 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 has been reported in men taking finasteride 5 mg 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.
Pediatric use
Finasteride 5 mg is not indicated for use in children.
Safety and effectiveness in children have not been established.
Lactose
The tablet contains lactose monohydrate. Patients with any of the following genetic deficiencies should not take this drug: galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.
Hepatic Insufficiency
The effect of hepatic insufficiency on the pharmacokinetics of finasteride has not been studied.
4.5 Interaction with other medicinal products and other forms of interaction
No drug interactions of clinical importance have been identified. Finasteride is metabolized primarily via, but does not appear to affect significantly, 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 propranolol, digoxin, glibenclamide, warfarin, theophylline, and phenazone and no clinically meaningful interactions were found.
4.6 Fertility, pregnancy and lactation
Pregnancy
Finasteride is contra indicated in women when they are or may potentially be pregnant (see section 4.3).
Because of the ability of 5a-Reductase-inhibitors to inhibit conversion of testosterone to dihydrotestosterone, these drugs, including finasteride, might 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).
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. When the patient's sexual partner is or may potentially be pregnant, the patient is recommended to minimise exposure of his partner to semen.
Breast feeding
Finasteride 5 mg tablets are not indicated 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 available information indicating that finasteride would have an influence on the ability to drive or use machines.
4.8 Undesirable effects
The most common adverse effects are impotence and reduced libido. These effects usually occur at the beginning of the treatment and in the majority of a transient nature on continued treatment.
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 to <1/10), Uncommon (>1/1,000 to <1/100), Rare (>1/10,000 to <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.
|
System Organ Class |
Frequency: adverse reaction |
|
Immune system disorders |
Unknown: hypersensitivity reactions including swelling of the lips and face |
|
Psychiatric disorders |
Common: decreased libido Unknown: depression |
|
Cardiac disorders |
Unknown: palpitation |
|
Hepatobiliary disorders |
Unknown: increased hepatic enzymes |
|
Skin and subcutaneous tissue disorders |
Uncommon: rash Unknown: pruritus, urticaria |
|
Reproductive system and breast disorders |
Common: impotence Uncommon: ejaculation disorder, breast tenderness, breast enlargement. Unknown: testicular pain, erectile dysfunction which may continue after discontinuation of treatment; male infertility and/or poor seminal quality. Normalization or improvement of seminal quality has been reported after discontinuation of finasteride. |
|
Investigations |
Common: decreased volume of ejaculate |
In addition, the following has been reported in clinical trials and post-marketing 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 in patients receiving combination therapy was comparable to the sum of incidences of this adverse experience for the two monotherapies
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 and 1147 (24.4%) men receiving placebo. In the finasteride group, 280 (6.4%) men had prostate cancer with Gleason scores of 710 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 (clinical stage T1 or T2) at diagnosis. The clinical significance of the Gleason 7-10 data is unknown.
Laboratory test findings:
When PSA laboratory determinations are evaluated, consideration should be given to the fact that PSA levels are decreased in patients treated with Finasteride 5 mg. (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
Patients have received single doses of finasteride up to 400 mg and multiple doses up to 80 mg/day without adverse effects. There is no specific recommended treatment of overdose of finasteride.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Testosteron-5a-reductase-inhibitors. ATC-Code: G 04 CB 01
Finasteride is a synthetic 4-azasteroid, a specific competitive inhibitor of the intracellular enzyme Type-II-5a-reductase. The enzyme converts testosterone into the
more potent androgen dihydrotestosterone (DHT). The prostate gland and, consequently, also the hyperplasic prostate tissue are dependent on the conversion, of testosterone to DHT for their normal function and growth. Finasteride has no affinity for the androgen receptor.
Clinical studies show a rapid reduction of the Serum DHT levels of 70%, which leads to a reduction on prostate volume. After 3 months, a reduction of approx. 20% in the volume of the gland occurs, and the shrinking continues and reaches approx. 27% after 3 years. Marked reduction takes place in the periurethral Zone immediately surrounding the Urethra. Urodynamic measurements have also confirmed a significant reduction of detrusor pressure as a result of the reduced obstruction.
Significant improvements in maximum urinary flow rate and symptoms have been obtained after a few weeks, compared with the start of treatment. Differences from Placebo have been documented at 4 and 7 months, respectively.
All efficacy parameters have been maintained over a 3-year follow-up period.
Effects of four years treatment with finasteride on incidence of acute urine retention, need for surgery, symptom-Score and prostate volume:
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 QUASJ-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. 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
In this study the safety and tolerability profile of combined treatment was broadly similar to the profile of each of the drugs taken separately. However, undesirable effects concerning the "nervous system" and "uro-genital system" organ classes were observed more frequently when the two drugs were used in combination (see section 4.8).
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
The oral LD50 of finasteride in male and female mice is approximately 500 mg/kg. The oral LD50 of finasteride in female and male rats is approximately 400 and 1000 mg/kg, respectively.
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 to120 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. 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 slightly higher (3x) than that of men who have taken 5 mg finasteride, or approximately 1 to 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose monohydrate Microcrystalline cellulose Starch pregelatinized (1500)
Sodium starch glycolate (type A)
Docusate Sodium Magnesium Stearate
Film -Coating:
Hypromellose (E464)
Titanium dioxide (E171)
Indigo carmine aluminium lake (E132) Talc
Iron oxide yellow (E172)
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 Pack: Pack-Aluminium-PVC/PE/PVdC
Pack sizes 15, 28, 30, 50, 60, 90, 98 or 100 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
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 4.6).
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Bluefish Pharmaceuticals AB Torsgatan 11 111 23 Stockholm Sweden
8 MARKETING AUTHORISATION NUMBER(S)
PL 31774/0029