4.1. Therapeutic indications

'Proscar' 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

The recommended adult dose is one 5 mg tablet daily, with or without food.

Proscar' can be administered alone or in combination with the alpha-blocker doxazosin (see section 5.1 'Pharmacodynamic properties').

Although early improvement in symptoms may be seen, treatment for at least six months may be necessary to assess whether a beneficial response has been achieved. Thereafter, treatment should be continued long term.

No dosage adjustment is required in the elderly or in patients with varying degrees of renal insufficiency (creatinine clearances as low as 9 ml/min).

There are no data available in patients with hepatic insufficiency.

Proscar' is contra-indicated in children.

4.3. Contraindications

'Proscar' is not indicated for use in women or children.

'Proscar' 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

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 'Proscar'. 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, 'Proscar' 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 'Proscar' or placebo.

Digital rectal examination, as well as other evaluations for prostate cancer, are recommended prior to initiating therapy with 'Proscar' 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 'Proscar'. A baseline PSA <4 ng/mL does not exclude prostate cancer.

Proscar' 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 'Proscar' 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 'Proscar' 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 'Proscar'.

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 'Proscar'. 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 'Proscar' 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 'Proscar'. The ratio of free to total PSA remains constant even under the influence of 'Proscar'. 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.

Mood alterations and depression

Mood alterations including depressed mood, depression and, less frequently, suicidal ideation have been reported in patients treated with finasteride 5 mg. Patients should be monitored for psychiatric symptoms and if these occur, the patient should be advised to seek medical advice.

Pediatric use

Proscar' 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 medicine: problems of 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.

Sodium

This medicinal product contains less than 1 mmol (23 mg) sodium per dosage unit, that is to say essentially 'sodium-free'.

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. Pregnancy and lactation

Pregnancy: 'Proscar' is contra-indicated in women when they are or may potentially be pregnant (see 4.3 Contraindications).

Because of the ability of Type II 5 α-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 μg/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 α-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 α-reductase. It is for these reasons that 'Proscar' 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 'Proscar' 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'). 'Proscar' 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: 'Proscar' 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 'Proscar' 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 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, anxiety, suicidal ideation

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, haematospermia, 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 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.

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 'Proscar' and 1147 (24.4%) men receiving placebo. In the 'Proscar' 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 'Proscar' group may be explained by a detection bias due to the effect of 'Proscar' 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 'Proscar' 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 'Proscar' (see section 4.4 Special warnings and precautions for use). 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 'Proscar' 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 'Proscar' in standard laboratory tests.

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 website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No specific treatment of overdosage with 'Proscar' is recommended. Patients have received single doses of 'Proscar' up to 400 mg and multiple doses of 'Proscar' up to 80 mg/day for up to three months without any adverse effects.