SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Nikitid 5mg film - coated tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5 mg of finasteride For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet

Round, biconvex, blue film - coated tablets, with no defect on coating layer, scored on one side.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Nikitid 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.

Nikitid 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

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

Nikitid can be administered alone or in combination with the alpha-blocker doxazosin.

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.

Renal insufficiency

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

Use in the elderly

No dosage adjustment is required in the elderly.

Hepatic insufficiency

There are no data available in patients with hepatic insufficiency.

Use in children

Nikitid is contra-indicated in children (see section 4.3).

4.3 Contraindications

Nikitid is not indicated for use in women or children.

Nikitid 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 finasteride 5mg. 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 5mg 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 5mg or placebo.

Digital rectal examinations as well as other evaluations for prostate cancer are recommended prior to initiating therapy with finasteride 5mg 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 5mg. A baseline PSA <4 ng/ml does not exclude prostate cancer.

Finasteride 5mg 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 5mg 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 5mg 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 5mg.

Percent free PSA (free to total PSA ratio) is not significantly decreased by finasteride 5mg. The ratio of free to total PSA remains constant even under the influence of finasteride 5mg. When percent free PSA is used as an aid in the detection of prostate cancer, no adjustment to its value is necessary.

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

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 Nikitid. 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 Nikitid 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

Nikitid 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.

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.

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Nikitid is contraindicated for use in women when they are or may potentially be pregnant (see 4.3 Contraindications).

Because of the ability of type II 5a-reductase inhibitors to inhibit conversion of testosterone to dihydrotestosterone, these drugs, including finasteride, may cause abnormalities of the external genitalia of a male fetus when administered to a pregnant woman.

Studies in animals have shown reproductive toxicity (see section 5.3).

Exposure to finasteride - risk to male fetus

Women should not handle crushed or broken tablets of Nikitid 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). Nikitid 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 fetus 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 (e.g. by use of a condom).

Lactation

Nikitid 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 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 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.

Immune system disorders	Unknown: hypersensitivity reactions including swelling of the lips and face
Psychiatric disorders	Common: decreased libido
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
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).

There was no evidence of increased adverse experiences with increased duration of treatment with Nikitid and the incidence of new drug-related sexual adverse experiences decreased with duration of treatment.

Medical Therapy of Prostate 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. 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 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 5mg 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 5mg group may be explained by a detection bias due to the effect of finasteride 5mg 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

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 are decreased in patients treated with finasteride (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 Nikitid 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 PSA and prostate cancer detection.

No other difference was observed in patients treated with placebo or finasteride in standard laboratory tests.

4.9    Overdose

Patients have received single doses of finasteride up to 400 mg and multiple doses up to 80 mg/day for three months without adverse effects.

No specific treatment of overdosage with Nikitid is recommended.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Testosterone-5a - reductase inhibitors

ATC code: G04CB01

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. Nikitid 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 (MTOPS)

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. Halflife 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 9 - 55 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

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.”

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Microcrystalline cellulose Pregelatinized Maize Starch Sodium starch glycollate Iron oxide yellow (E172) Sodium docusate Magnesium stearate

Film-coating:

Hypromellose Titanium Dioxide (E171)

Talc

Propylene Glycol Indigo Carmine (E132) Quinoline Yellow FCF (E104) Sunset Yellow FCF (E110)

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.