FINASTERIDE 5 MG TABLETS - summary of medicine characteristics

Finasteride 5 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 5 mg of finasteride.

Excipients:

Each tablet contains 90.95 mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablets. Blue, round biconvex 7 mm film-coated tablet with “F5” marking on one side.

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.

Finasteride 5 mg tablets should be administered in patients with an enlarged prostate (prostate volume above ca. 40 ml).

4.2 Posology and method of administration

Dosage in Adults: 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 six months may be necessary in order to determine objectively whether a satisfactory response to the treatment has been achieved. Dosage in Children: Finasteride is contraindicated in children (see section 4.3). 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 haemodialysis.

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 foetus).

4.4 Special warnings and precautions for use

General

Patients with large residual urine volume and/or severely diminished urinary flow should be carefully monitored for obstructive uropathy.

Consultation of an urologist should be considered in patients treated with finasteride.

Obstruction due to trilobular growth pattern of the prostate should be excluded before starting treatment with finasteride.

Effects on prostate-specific antigen (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.

Serum PSA concentration is correlated with patient age and prostatic volume, and prostatic volume is correlated with patient age. Digital rectal examination, and, if necessary, determination of prostate-specific antigen (PSA) in serum should be carried out on patients prior to initiating therapy with finasteride and periodically during treatment to rule out prostate cancer. 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. 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 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 should be carefully evaluated, including consideration of non-compliance to finasteride therapy.

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 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 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 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 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.

4.5 Interaction with other medicinal products and other forms of interaction

No clinically important drug interactions have been identified. Finasteride is metabolized primarily via, but does not affect, 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 include propranolol, digoxin, glibenclamide, warfarin, theophylline, and antipyrine 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, betablockers, calcium channel blockers, cardiac nitrates, diuretics, H2 antagonists, HMGCoA reductase inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs) including aspirin and paracetamol, quinolones and benzodiazepines without evidence of clinically significant adverse interactions.

4.6 Pregnancy and lactation

Finasteride is not indicated in women (see section 4.3).

Pregnancy: Finasteride is contraindicated in women during pregnancy. 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).

Exposure to finasteride risk to male foetus

Women who are pregnant or may become pregnant should not handle crushed or broken finasteride tablets 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.

Lactation: Finasteride 5 mg film coated 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 known data to show that finasteride influences the ability to drive and the capacity to operate machinery.

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 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.

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 events without regard to drug relationship were: finasteride 8.3%, doxazosin 5.3%, combination 15.0%, placebo 3.9%. Besides adverse reactions related to “Nervous system disorders” were observed with a greater frequency in patients receiving the combination (see tablet below).

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 and 1147 (24.4%) men receiving placebo. In the finasteride 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 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.

Serum PSA concentration is correlated with patient group 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 details and clinical interpretation See section 4.4 (Paragraph 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

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

Pharmacodynamic group: Testosterone – 5 alpha reductase inhibitors, ATC code: G04C B01.

Finasteride is a synthetic 4-azasteroid, a specifc 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 stand of treatment. Differences from Placebo have been documented at four and seven months, respectively.

All efficacy parameters have been maintained over a 3-year follow-up period. Effect 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.

5.2 Pharmacokinetic properties

Absorption:

The bioavailability of finasteride is approximately 80%. Peak plasma concentrations are reached approximately two hours after drug intake, and absorption is complete within 68 hours.

Distribution:

Binding to plasma proteins is approx. 93%.

Clearance and volume of distribution are approx. 165 ml/min (70–279 ml/min) and 76 l (44–96 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 8–1 0 ng/ml, which remains stable over time.

Biotransformation:

Finasteride is metabolised in the liver. Finasteride does not significantly affect the cytochrome P 450 enzyme system. Two metabolites with low 5a-reductase-inhibiting effects have been identified.

Elimination:

The plasma half-life averages 6 hours (4–12 hours) (in men >70 years of age, 8 hours, range 6–15 hours). After administration of radioactively labelled finasteride, approx. 39% (32–46%) of the given dose is excreted in the urine in the form of metabolites. Virtually no unchanged finasteride is recovered in the urine. Approximately 57% (51–64%) of the total dose is excreted in the faeces. In patients with impaired renal function (creatinine clearance as low as 9 ml/min), no changes in the elimination of finasteride have been seen (See section 4.2). Finasteride has been found to cross the bloodbrain barrier. Small amounts of finasteride have been recovered in the seminal fluid of treated patients. In 2 studies of healthy subjects (n=69) receiving finasteride 5 mg/day for 6–24 weeks, finasteride concentrations in semen ranged from undetectable (<0.1 ng/ml) to 10.54 ng/ml. In an earlier study using a less sensitive assay, finasteride concentrations in the semen of 16 subjects receiving finasteride 5 mg/day ranged from undetectable (<1.0 ng/ml) to 21 ng/ml. Thus, based on a 5-ml ejaculate volume, the amount of finasteride in semen was estimated to be 50– to 100-fold less than the dose of finasteride (5 pg) that had no effect on circulating DHT levels in men (see also section 5.3.).

In patients with chronic renal impairment, whose creatinine clearance ranged from 955 ml/min, the disposition of a single dose of 14Cfinasteride 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 nondialysed patients with renal impairment is not necessary.

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, 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 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 (3×) than that of men who have taken 5 mg finasteride, or approximately 1 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

Cellulose microcrystalline

Pregelatinised starch

Lauroyl macrogoglycerides

Sodium starch glycolate (Type A)

Magnesium stearate

Film coating

Hypromellose 6 cps.

Titanium dioxide (E171)

Indigo carmine lake (E132)

Macrogol 6000

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months

6.4 Special precautions for storage

There are no special storage instructions.

6.5 Nature and contents of container

1. Al/PVC Blister, pack sizes: 12, 28, 30 and 56 Tablets

2. Al/Al Blister, pack sizes: 12, 28, 30 and 56 Tablets

3. HDPE container and a white LDPE cap, pack sizes: 50, 75 and 100 Tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Waymade PLC

Trading as Sovereign Medical

Sovereign House

Miles Gray Road

Basildon

Essex.

SS14 3FR

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 06464/2430

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

20/11/2007