Finasteride 5 Mg 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 mg of finasteride.
Excipients with known effect: Each film-coated tablet contains 83.49mg of lactose and 0.006 mg of sunset yellow FCF (E110)
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet (tablet)
Light blue, round, biconvex film-coated tablets, with a 6.5 mm nomial diameter and embossed with ‘BL5’ on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Finasteride is 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
Posology
The recommended dosage is one 5 mg tablet daily with or without food. Even though improvement can be seen within ashort 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 rateof 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 toaffect the elimination of finasteride. Finasteride has not been studied in patients on hemodialysis.
Method of administration For oral use only.
The tablet should be swallowed whole and must not be divided or crushed (See section 6.6).
4.3 Contraindications
• Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1
• Finasteride is not indicated for use in women or children.
• Pregnancy - Use in women when they are or may potentially be pregnant (see 4.6 Pregnancy and lactation, Exposure to finasteride - risk to male foetus).
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 finasteride 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. Analysis of PSA data from over 3000 patients in the 4-year, double-blind, placebo-controlled PROSCAR 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 5mg should be carefully evaluated, including consideration of non-compliance to therapy with finasteride 5 mg.
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.
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.
Breast cancer in men
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.
Paediatric use
Finasteride is not indicated for use in children.
Safety and effectiveness in children have not been established.
Hepatic Insufficiency
The effect of hepatic insufficiency on the pharmacokinetics of finasteride has not been studied.
Important information regarding the ingredients of this medicine
This medicine contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicine also contains Sunset yellow. Sunset yellow may cause allergic reactions, possibly delayed.
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 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 ( see section 5.3 and section 6.6).
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 4.6 Pregnancy and Lactation '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. When the patient's sexual partner is or may potentially be pregnant, the patient is recommended to minimise exposure of his partner to semen.
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 affects the ability to drive or 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 reported during clinical trials and/or post-marketing use with finasteride 5mg and/or finasteride at lower doses 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, tongue, throat and face |
|
Psychiatric disorders |
Common: decreased libido |
|
Unknown: decreased libido that may continue after discontinuation of therapy, 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 |
Common: impotence |
|
disorders |
Uncommon: ejaculation disorder, breast tenderness, breast enlargement. |
|
Unknown: testicular pain, sexual dysfunction (erectile dysfunction and ejaculation disorder) 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 section 4.4 ).
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.
Other Long-Term Data
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 5mg 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 the placebo group. Additional analyses suggest that the increase in the prevalence of high-grade prostate cancer observed in the finasteride 5 mg group may be explained by a detection bias due to the effect of finasteride 5 mg 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 long-term use of finasteride and tumours with Gleason scores of 7-10 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 (see section 4.4). 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 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 section 4.4, 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
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this
4.9 Overdose
No specific treatment of overdosage with finasteride is recommended. Patients have received single doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for up to three months without any adverse effects.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Testosteron-5a-reductase-inhibitors
ATC-Code: G04 CB01
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 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
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
Absorption
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.
Distribution
Finasteride has a plasme elimination half-life of six hours and protein binding is approximately 93%. Plasma clearance and the volume of distribution are approximately 165 ml/min and 76 l, respectively. Accumulation of small amounts of finasteride is seen on repeated administration. After a daily dose of 5 mg the lowest steady-state concentration of finasteride has been calculated to be 8-10 ng/ml, which remains stable over time
Biotransformation
Finasteride is metabolised in the liver and excreted in the urine and faeces as metabolites. Finasteride does not significantly affect the cytochrome P 450 enzyme system. Two metabolites with low 5a-reductase-inhibiting effects have been identified.
Elimination
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.
Finasteride has been recovered in the cerebrospinal fluid (CSF) of patients treated with a 7-10 day course of finasteride, but the medicine does not appear to concentrate preferentially to the CSF. Finasteride has also been recovered in the seminal fluid of subjects receiving 5 mg/day Finasteride. The amount of finasteride in the seminal fluid was 50 to 100 fold less than the dose of finasteride (5 mcg) that had no effect on circulating DHT levels in adult males
Older people
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.
Renal impairment
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.
Hepatic impairment
There are no data available in patients with hepatic insufficiency.
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 60-120 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. 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 1-2 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 Maize starch pregelatinised Docusate sodium Iron oxide yellow (E172)
Sodium starch glycollate Microcrystalline cellulose Colloidal anhydrous silica Magnesium stearate Film-coating
Opadry blue consists of: Hypromellose Hydroxypropyl cellulose Titanium dioxide (E171) Indigotine
Indigo carmine (E132) Sunset yellow FCF (E110) Quinoline yellow (E104)
6.2 Incompatibilities
None
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
PVC/PE/PVDC/Al blister packs of 7, 10, 14, 15, 20, 28, 30, 50, 56, 60, 84, 90, 98, 100 or 120 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
Bristol Laboratories Ltd,
Unit 3, Canalside,
Northbridge Road, Berkhamsted,
Herts, HP4 1EG, UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 17907/0498
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
01/09/2015
10 DATE OF REVISION OF THE TEXT
01/09/2015