Proscar - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Finasteride

Proscar 5 mg film-coated tablets

Indications Why is Proscar used? What is it for?

Proscar contains the active substance finasteride which belongs to a group of medicines called 5α-reductase inhibitors, which work by reducing the size of the prostate gland in men.

Proscar is indicated for the treatment and control of benign prostatic hyperplasia (BPH), also known as prostatic hypertrophy, characterized by benign enlargement of the prostate. Proscar improves urinary flow and symptoms associated with BPH.

Contraindications When Proscar should not be used

DO NOT take Proscar

  • if you are allergic to finasteride or any of the other ingredients of this medicine
  • whether it is a woman or a child;
  • if you are pregnant or suspect you are pregnant (see section "Pregnancy and breast-feeding").

Precautions for use What you need to know before taking Proscar

Talk to your doctor or pharmacist before taking Proscar.

Although BPH is neither a malignant tumor nor can it become one, nevertheless the two conditions can coexist. Only your doctor can assess the symptoms, the possible causes and the correct treatment for you.

Tell your doctor:

  • if you have or have had any medical problems or illnesses or allergies;
  • if you have difficulty emptying your bladder completely or a severe reduction in urine flow.

Tell your doctor if you have been taking finasteride for 6 months or more and if you need to have blood tests to determine your PSA (an indicator of the possible presence of prostate cancer), as finasteride can alter the results of this test.

Children and adolescents

Proscar is not indicated for pediatric use as safety and efficacy in children have not been established.

Interactions Which drugs or foods can change the effect of Proscar

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

No interactions of clinical importance have been identified between Proscar and other medicinal products. In particular, NO significant interactions were found with the following medicines:

  • propranolol (used to treat high blood pressure and angina pectoris);
  • digoxin (used to treat heart rhythm problems);
  • glibenclamide (used to lower blood sugar levels);
  • warfarin (used to prevent blood clots);
  • theophylline (used to treat asthma);
  • phenazone (used to treat inflammation).

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

If your sexual partner is pregnant or suspects pregnancy, you must avoid exposing her to your sperm as this may contain a small amount of the medicine.

If a woman is pregnant or thinks she is pregnant, she should not take Proscar (see section "Do not take Proscar"). You should also not touch Proscar tablets if they are crumbled or broken, as the active ingredient in the tablets could be absorbed and interfere with the normal development of a male baby.

Whole Proscar tablets have a coating that prevents contact with the active ingredient during normal manual contact, as long as the tablets have not been crumbled or broken.

Feeding time

It is not known whether finasteride is excreted in human milk; in any case if you are a woman you should not take Proscar.

Driving and using machines

There are no known effects on the ability to drive or use machines.

Proscar contains lactose

Proscar contains lactose, a milk sugar. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Proscar: Posology

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

The recommended dose is one 5 mg tablet per day, which can be taken with or without meals.

Your doctor may prescribe Proscar together with another medicine, doxazosin, which is used to improve the control of prostatic hypertrophy.

Although improvement is often noticed after a short time, treatment may need to be continued for at least six months. Your doctor will tell you how long to take Proscar.

Use in patients with renal insufficiency

If you have reduced kidney function (renal insufficiency) it is not necessary to change the dose of Proscar.

Use in elderly patients

If you are elderly it is not necessary to adjust the dose of Proscar, although in patients over 70 years of age finasteride is eliminated to a lesser extent.

Overdose What to do if you have taken too much Proscar

If you take more Proscar than you should

In case of accidental ingestion of an overdose of Proscar, notify your doctor immediately or go to the nearest hospital. There were no side effects in patients who took high doses of Proscar for up to three months.

If you forget to take Proscar

Do not take a double dose to make up for a forgotten dose.

If you stop taking Proscar

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Proscar

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Impotence and decreased sexual desire are the most frequent adverse reactions. These adverse reactions occur early in therapy and resolve during the course of therapy in most patients.

Common side effects (may affect up to 1 in 10 people)

  • decrease in semen volume
  • impotence
  • decreased sexual desire

Uncommon side effects (may affect up to 1 in 100 people)

  • rash
  • ejaculation disorders
  • tension in the breast area
  • breast enlargement

Undesirable effects with frequency not known (frequency cannot be estimated from the available data)

  • irregular heartbeat
  • hypersensitivity reactions such as itching, hives and swelling (angioedema) of different parts of the body including the lips, tongue, throat and face
  • increased liver enzymes
  • pain in the testicles
  • erectile dysfunction, which may continue after stopping finasteride
  • male infertility and / or poor semen quality, which normalizes or improves after stopping finasteride
  • breast cancer in men
  • depression
  • persistent reduction in sex drive after stopping treatment
  • persistent ejaculation problems after stopping treatment.

Diagnostic tests:

if you are having blood tests to determine your PSA (an indicator of the possible presence of prostate cancer), be aware that finasteride can alter the results of this test.

Report any changes in breast tissue (mammary gland) such as swelling, pain, enlargement of breast tissue in males or nipple discharge immediately to your doctor, as these may be signs of a serious condition such as breast cancer.

Stop taking Proscar and contact your doctor immediately if you get any of the following symptoms of angioedema:

  • swelling of the face, tongue or throat
  • difficulty swallowing
  • urticaria
  • difficulty in breathing

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avversei. By reporting side effects you can help provide more information on safety. of this medicine.

Expiry and Retention

This medicine does not require any special storage conditions.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the package after "EXP". The expiry date refers to the last day of that month.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

What Proscar contains

  • The active ingredient is finasteride. Each tablet contains 5 mg of finasteride.
  • The other ingredients are lactose monohydrate, pregelatinised starch, sodium carboxymethyl starch, yellow iron oxide, sodium dioctyl sulfosuccinate, microcrystalline cellulose, magnesium stearate, hypromellose, hydroxypropyl cellulose, titanium dioxide, talc, E 132 indigo carmine on aluminum hydrate.

Description of what Proscar looks like and contents of the pack

5 mg film-coated tablets (packs of 15 and 30 tablets).

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information about Proscar can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

PROSCAR 5 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains: Finasteride 5 mg.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablets.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

PROSCAR is indicated in the treatment and control of benign prostatic hyperplasia, also called prostatic hypertrophy, as it induces the regression of prostatic enlargement, improves urinary flow and the symptoms associated with benign prostatic hyperplasia.

04.2 Posology and method of administration

The recommended dosage is one 5 mg tablet per day, with or without meals.

PROSCAR can be administered alone or with the alpha blocker doxazosin (see 5.1 Pharmacodynamic properties, Clinical studies).

Although early improvement may be observed, a therapeutic action of at least six months may be necessary to establish whether a favorable response has been obtained.

Dosage in renal insufficiency

In patients with varying degrees of renal insufficiency (reduction of clearance of creatinine up to 9 ml / min) no dosage adjustments are required, since pharmacokinetic studies have not indicated any changes in the distribution of finasteride.

Dosage in the elderly

Although pharmacokinetic studies have indicated that finasteride elimination decreases slightly in patients over 70 years of age, no dosage adjustment is required.

04.3 Contraindications

PROSCAR is not intended for use in women or children.

PROSCAR is contraindicated in case of:

• Hypersensitivity to the active substance or to any of the excipients.

• Pregnancy - Use in women who are or potentially may be pregnant (see 4.6 Pregnancy and lactation, Finasteride exposure - risk to the male fetus).

04.4 Special warnings and appropriate precautions for use

General

To avoid obstructive complications it is important that patients with considerable residual urine and / or severely reduced urine flow are closely monitored. The possibility of surgery should be considered.

Effects on PSA and prostate cancer detection

No clinical benefit has yet been demonstrated in prostate cancer patients treated with PROSCAR. Patients with BPH and elevated prostate specific antigen (PSA) were monitored in controlled clinical trials with periodic PSA dosing 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.

It is recommended that digital rectal scans as well as other evaluations for prostate cancer be performed in patients prior to initiating treatment with PROSCAR and periodically thereafter. Prostate Specific Antigen (PSA) determination in serum is also used for the detection of prostate cancer. Typically a baseline PSA value> 10 ng / ml (Hybritech) suggests further evaluation and suggests considering a biopsy ; for PSA levels between 4 and 10 ng / mL further evaluation is advisable. There is considerable overlap in PSA levels between men with and without prostate cancer. Thus, in men with BPH, PSA values ​​within the normal reference range does not exclude prostate cancer, regardless of treatment with PROSCAR. A baseline PSA value

PROSCAR causes a decrease in serum PSA concentration of approximately 50% in patients with BPH even in the presence of prostate cancer. This decrease in serum PSA levels in PROSCAR-treated BPH patients should be taken into account when evaluating PSA data and does not rule out concomitant prostate cancer.

This reduction, although it may vary in individual patients, is applicable to the full range of PSA values. Analysis of PSA data on more than 3,000 patients in a 4-year, double-blind, placebo-controlled study. on long-term efficacy and safety of PROSCAR (PLESS) confirmed that in typical patients treated with PROSCAR for 6 months or more, PSA values ​​should be doubled when compared to the normal range in untreated men.

This adjustment maintains the sensitivity and specificity of the PSA assay, which maintains its ability to detect prostate cancer.

Any persistent increase in serum PSA levels in patients treated with finasteride should be carefully considered, also taking into consideration the lack of compliance with PROSCAR therapy.

The percentage of free PSA (ratio of free PSA to total PSA) is not significantly decreased by PROSCAR. The ratio of free PSA to total PSA remains constant even during treatment with PROSCAR. When using the percentage value of free PSA as an aid in the diagnosis of prostate cancer it is not necessary to adjust the value in any way.

Drug / laboratory test interactions

Effect on PSA levels

Serum PSA concentration correlates with patient age and prostate volume, and prostate volume correlates with patient age. When evaluating PSA laboratory values, it should be taken into account that PSA levels decrease in patients treated with PROSCAR. A rapid decrease in PSA levels is observed in most patients in the first month of therapy, subsequently PSA levels stabilize to a new baseline. The post-treatment baseline value is approximately half of the pre-treatment value. Therefore, in typical patients treated with PROSCAR for six months or longer, PSA values ​​should be doubled when compared to the normal range 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 PROSCAR in clinical trials and in the post-marketing period. Physicians should instruct their patients to promptly report any changes in breast tissue such as swelling, pain, gynaecomastia or nipple discharge.

Pediatric use

PROSCAR is not intended for pediatric use.

Safety and efficacy 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.

04.5 Interactions with other medicinal products and other forms of interaction

No drug interactions of clinical importance have been identified. Finasteride is metabolised essentially via the cytochrome P450 3A4 system, however it does not appear to significantly interfere with the latter. Although the risk of finasteride modifying the pharmacokinetics of other drugs is believed to be low, inhibitors and inducers are likely of cytochrome P450 3A4 will alter the plasma concentration of finasteride. However, based on established safety margins, any increase due to concomitant use of these inhibitors is unlikely to be of clinical relevance.

PROSCAR does not appear to significantly interfere with the cytochrome P450-bound drug metabolising enzyme system.

The substances studied in humans include propranolol, digoxin, glibenclamide, warfarin, theophylline and phenazone and no clinically significant interactions were found.

04.6 Pregnancy and lactation

Pregnancy

PROSCAR is contraindicated in women who are or potentially may be pregnant (see 4.3 Contraindications).

Due to the ability of Type II 5a-reductase inhibitors to inhibit the conversion of testosterone to dihydrotestosterone, these drugs, including finasteride, when administered to a pregnant woman, can cause malformations of the external genitalia in the case of a male fetus.

Exposure to finasteride / Risk to the male fetus

Women should not come into contact with crumbled or broken PROSCAR tablets when they are or potentially may be pregnant, due to possible absorption of finasteride and the resulting potential risk to a male fetus (see 4.6 Pregnancy and lactation - Pregnancy). PROSCAR tablets have a coating, which prevents contact with the active component during normal manual contact, as long as the tablets have not been crumbled or broken.

Small amounts of finasteride were found in the semen of people taking finasteride 5 mg / day. It is not known whether the male fetus can be exposed to adverse events if the mother is exposed to the semen of a patient being treated with finasteride. When the patient's sexual partner is or may be pregnant, the patient should be advised to minimize exposure of the partner to his own semen.

Feeding time

PROSCAR is not indicated for use in women.

It is not known whether finasteride is excreted in human milk.

04.7 Effects on ability to drive and use machines

There are no data suggesting that PROSCAR affects the ability to drive or use machines.

04.8 Undesirable effects

Impotence and decreased libido are the most frequent adverse reactions. These adverse reactions occur early in therapy and resolve during the course of therapy in most patients.

The table below lists adverse reactions reported in clinical trials and / or post-marketing use.

The frequency of adverse reactions is defined as follows:

Very common (≥1 / 10), Common (≥1 / 100,

The frequency or causal relationship of adverse reactions reported during post-marketing use with finasteride at lower doses cannot be determined as they are derived from spontaneous reports.


System and organ classification Frequency: adverse reaction Diagnostic tests Common: decrease in the volume of the ejaculate. Cardiac pathologies Not known: palpitation. Skin and subcutaneous tissue disorders Uncommon: rash. Disorders of the immune system Not known: hypersensitivity reactions such as itching, hives and angioedema (including swelling of the lips, tongue, throat and face). Hepatobiliary disorders Not known: increase in liver enzymes. Diseases of the reproductive system and breast Common: impotence. Uncommon: ejaculation disorders, breast tenderness, breast enlargement. Not known: testicular pain, erectile dysfunction which continued after discontinuation of treatment, male infertility and / or poor semen quality. Normalization or improvement in semen quality has been reported after discontinuation of finasteride. Breast cancer in humans (see 4.4 Special warnings and precautions for use). Psychiatric disorders Common: decreased libido. Not known: depression, persistent sexual dysfunction *.

(*) Persistent sexual dysfunction (decreased libido, erectile dysfunction and ejaculation disorders) has been reported during post-marketing use after discontinuation of PROSCAR treatment.

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 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 of the combination therapy. The incidence of ejaculation disorders in patients treated with the combination was comparable to the sum of the incidences of this adverse experience for the two monotherapies.

Other long-term data

In a 7-year placebo-controlled clinical trial that enrolled 18,882 healthy men, 9,060 of whom with needle biopsy data available for analysis, prostate cancer was detected in 803 (18.4%) of the men treated with PROSCAR and in 1,147 (24.4%) of the men treated with placebo. In the PROSCAR group, 280 (6.4%) men had prostate cancer with a Gleason score of 7-10 detected at needle biopsyvs 237 (5.1%) men in the placebo group. Further analyzes suggest that the increased prevalence of high grade prostate cancer observed in the PROSCAR group may be explained by a bias in identification due to the effect of PROSCAR on prostate volume. Of the total prostate cancer cases diagnosed in this study, approximately 98% were classified as intracapsular (clinical stage T1 or T2) at diagnosis. The clinical relevance of the Gleason 7-10 score data is unknown. .

Lab test

When measuring PSA levels it should be noted that PSA levels are decreased during treatment with PROSCAR (see 4.4 Special warnings and precautions for use).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose

Patients received single doses of PROSCAR up to 400 mg and multiple doses of PROSCAR up to 80 mg / day for three months with no adverse effects.

In case of overdose with PROSCAR no specific treatment is recommended.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Testosterone 5 alpha reductase inhibitors

ATC code: G04CB01

Finasteride is described chemically: N- (1,1-dimethylethyl) -3-oxo-4-aza-5alpha-androst-1-ene-17 beta carboxamide. It is a white crystalline substance freely soluble in chloroform and lower alcohols, but practically insoluble in water.

Finasteride is a competitive inhibitor of Type II 5-a-reductase, with which it slowly forms a stable enzyme complex. Type II 5-a-reductase is an intracellular enzyme that metabolizes testosterone into a more potent androgen, dihydrotestosterone (DHT). The turnover of this complex is extremely slow (t½ ≈ 30 days). In vitro and in vivo, finasteride has been shown to be a specific inhibitor for Type II 5a-reductase and has no affinity for androgen receptors.

The development and enlargement of the prostate gland, and subsequently of BPH, depends on the potent androgen DHT. Testosterone, secreted by the testes and adrenal glands, is rapidly converted into DHT by Type II 5a-reductase especially in the prostate gland, liver and in the skin where it is preferentially bound to the cell nuclei of those tissues.

A single 5 mg dose of finasteride caused a rapid decrease in serum DHT concentration, with the maximum effect observed after 8 hours. While plasma levels of finasteride vary over the course of 24 hours, serum levels of DHT during this period remain constant, which means that plasma drug concentrations do not correlate directly with those of DHT. In patients with BPH, administration of finasteride for 4 years at a dose of 5 mg / day has been shown to reduce circulating concentrations of DHT by about 70%, and was associated with a median reduction in prostate volume of about 20%. In addition, PSA was reduced by about 50% from baseline, suggesting a reduction in prostate growth. prostate epithelial cells. In studies up to 4 years, suppression of DHT levels and regression of the hyperplastic prostate associated with decreased d and PSA levels. In these studies, circulating testosterone levels increased by approximately 10-20%, still remaining within physiological values.

When PROSCAR was administered for 7-10 days to patients waiting to undergo prostatectomy, the drug caused an approximately 80% decrease in intraprostatic DHT. Intraprostatic testosterone concentrations were increased up to 10-fold beyond levels. pre-treatment.

In healthy volunteers treated with PROSCAR for 14 days, the DHT values ​​returned to pre-treatment levels in about 2 weeks when therapy was stopped. In patients treated for 3 months, the prostate volume, which decreased by about 20%, returned to close to baseline after about 3 months after discontinuation of therapy.

Finasteride had no effect, compared to placebo, on circulating levels of cortisol, estradiol, prolactin, thyrotropic hormone or thyroxine. No clinically significant effects were observed on plasma lipid profile (e.g., total cholesterol, low density lipoprotein, high density lipoprotein and triglycerides) or bone mineral density.

In patients treated for 12 months, an increase of about 15% of the luteinizing hormone (LH) and of about 9% of the follicle-stimulating hormone (FSH) was observed; however these levels remained well within physiological values. Levels of LH and FSH following stimulation with gonadotropin-releasing hormone (GnRH) were not altered, indicating that pituitary-gonadal axis control was not affected. Following treatment with PROSCAR for 24 weeks of healthy male volunteers to evaluate semen parameters, there was no clinically significant effect on sperm concentration, motility, morphology, or sperm pH. A median decrease in ejaculate volume of 0.6 ml was observed, with a concomitant reduction in the total sperm per ejaculate. These parameters remained within the normal range. range and were reversible upon discontinuation of therapy.

Finasteride has been shown to inhibit the metabolism of steroids C19 and C21 thus showing an inhibitory effect on both hepatic and peripheral activity of Type II 5a-reductase.

Clinical studies

PROSCAR Long-Term Efficacy and Safety Study (PLESS)

PLESS is a 4-year, double-blind, randomized, placebo-controlled, multicenter study conducted to evaluate the effect of PROSCAR therapy on BPH symptoms and related urological events (surgery and acute urinary retention). [RUA]) involving 3,040 patients (45-78 years) with moderate-to-severe symptoms of BPH and enlarged prostate on digital rectal examination. The study was completed by 1,883 patients (finasteride n = 1,000; placebo n = 883).

In the PLESS study, surgery or acute urinary retention occurred in 13.2% of patients taking placebo compared to 6.6% of patients taking PROSCAR (51% risk reduction). PROSCAR reduced the risk of surgery by 55% (10.1% for placebo vs 4.6% for PROSCAR) and urinary retention of 57% (6.6% for placebo vs 2.8% for PROSCAR).

PROSCAR improved the symptom score by 3.3 points compared to 1.3 points in the placebo group (p

Medical Therapy Of Prostatic Symptoms (MTOPS)

MTOPS is a four to six year study in which 3,047 men with symptomatic BPH were randomized to treatment with finasteride 5 mg / day, doxazosin 4 or 8 mg / day, combination of finasteride 5 mg / day and doxazosin 4 o 8 mg / day, or placebo. Compared to placebo, treatment with finasteride, doxazosin, or combination therapy resulted in a significant reduction in the risk of clinical progression of BPH (defined by the onset of: increase in symptom score from baseline of ≥ 4 points, urinary retention, BPH-related renal failure, recurrent urinary or urosepsis infections, incontinence) of 34, 39, and 67%, respectively.

Most of the events (274 out of 351) that constituted BPH progression were confirmed increases in symptom score ≥ 4; the risk of progression was reduced by 30, 46 and 64% in the finasteride, doxazosin and combination therapy groups, respectively, compared to placebo. Acute urinary retention accounted for 41 out of 351 BPH progression events; the risk of developing acute urinary retention was reduced by 67, 31, and 79% in the finasteride, doxazosin, and combination therapy groups, respectively, compared to placebo.

Further clinical studies

The urodynamic effects of finasteride in the treatment of bladder outflow obstruction due to BPH were evaluated using invasive techniques in a 24-week, double-blind, placebo-controlled study of 36 patients with moderate to severe symptoms of urinary obstruction. and a maximum flow rate of less than 15 ml / sec. In patients treated with 5 mg of PROSCAR a decrease in obstruction was demonstrated compared to placebo, evidenced by a significant improvement in detrusor pressure and an increase in the mean rate of flow.

In a double-blind, placebo-controlled, one-year study, the effects of finasteride on the volume of the peripheral and periurethral areas of the prostate were evaluated by MRI in 20 men with BPH. Patients treated with PROSCAR, but not those treated with placebo, showed a significant decrease [11.5 ± 3.2 cc (SE)] in gland size in toto, largely attributable to a reduction [6.2 ± 3 cc] in the size of the periurethral area. Since the periurethral zone is responsible for the outflow obstruction, this reduction may explain the favorable clinical response observed in these patients.

In a 7-year placebo-controlled clinical study enrolling 18,882 healthy men ≥ 55 years of age with normal digital rectal findings and PSA ≤ 3.0 ng / mL, 9,060 of whom with needle biopsy data available for analysis, prostate cancer was detected in 803 (18.4%) of the men treated with PROSCAR and in 1,147 (24.4%) of the men treated with placebo. In the PROSCAR group, 280 (6.4%) men had cancer. prostate with a Gleason score of 7-10 detected at needle biopsy vs 237 (5.1%) men in the placebo group. Additional data suggest that the increased prevalence of high-grade prostate cancer observed in the PROSCAR-treated group may be explained by a bias in identification (detection bias) due to the effect of PROSCAR on prostate volume. Of the total prostate cancer cases diagnosed in this study, approximately 98% were classified as intracapsular (clinical stage T1 or T2) at the time of diagnosis. The clinical relevance of the Gleason 7-10 score data is unknown.

This information may be of some relevance to men undergoing PROSCAR treatment for BPH. PROSCAR has no indication for reducing the risk of prostate cancer.

05.2 Pharmacokinetic properties

Absorption

The bioavailability of finasteride is approximately 80% and is unaffected by food. Maximum plasma concentrations of finasteride are reached approximately 2 hours after administration and absorption is complete after 6-8 hours.

Distribution

After daily administration of 5 mg / day, the equilibrium plasma concentration was 8-10 ng / ml and remained stable over time.

Protein binding is approximately 93% even in patients with renal impairment (creatinine clearance 9 to 55 ml / min).

Finasteride has been found in the cerebrospinal fluid (CSF) of patients treated with a 7-10 day course of finasteride but the drug does not appear to preferentially concentrate at the CSF level. Finasteride has also been found in the semen of subjects treated with PROSCAR 5 mg / day. In adult men, the amount of finasteride in semen was 50 to 100 times lower than the dose of finasteride (5 mg) and had no effect on circulating DHT levels (see also 5.3 Preclinical safety data - Developmental and reproductive toxicity).

Biotransformation / Elimination

In humans, following an oral dose of 14C-finasteride, 39% of the dose was excreted in the urine as metabolites (virtually no unchanged drug was excreted in the urine) and 57% of the total dose was excreted with the faeces.

Finasteride exhibits a mean plasma elimination half-life of 6 hours clearance plasma and the volume of distribution of finasteride are approximately 165 ml / min and 76 liters, respectively.

The elimination rate of finasteride is slightly decreased in the elderly. With advancing age the half-life is prolonged from a mean half-life of about 6 hours in men aged 18-60 to 8 hours in men aged 18-60. over 70 years of age This observation has no clinical significance and therefore, a reduction in dosage is not warranted.

In patients with chronic renal impairment whose clearance creatinine ranged from 9 to 55 mL / min, single dose distribution of 14C finasteride was not different from that of healthy volunteers. Some of the metabolites that are normally excreted by the kidney was excreted in the faeces. Therefore it appears that faecal excretion increases in proportion to the decrease in urinary excretion of metabolites. No dosage adjustment is necessary in non-dialysis patients with renal impairment.

05.3 Preclinical safety data

Animal toxicology

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and carcinogenic potential.

The oral LD ​​of finasteride in male and female mice is approximately 500 mg / kg. The oral LD ​​of finasteride in male and female rats is approximately 400 and 1,000 mg / kg, respectively.

In a hepatotoxicity test, 40 mg / kg / day of finasteride was administered orally to dogs for 28 days. Venous blood was analyzed for transaminases (SGPT / SGOT). Neither transaminase was elevated, showing that finasteride did not cause liver damage.

Furthermore, no important changes in renal, gastric and respiratory functions in dogs or in the cardiovascular system in dogs and rats were observed with finasteride.

In a study lasting 24 months, no evidence of a carcinogenic effect was observed in rats receiving finasteride doses up to 320 mg / kg / day (3,200 times the recommended human dose of 5 mg / day).

No evidence of mutagenicity was observed in one test in vitro of bacterial mutagenesis, in a test in mammalian cell mutagenesis or in an alkaline elution test in vitro.

Development and Reproduction Toxicity

Reproductive toxicology studies in male rats demonstrated a reduction in the weight of the prostate and seminal vesicles, reduced secretion from accessory genital glands and a reduction in the fertility index (caused by the primary pharmacological effect of finasteride). The clinical relevance of these data is unclear.

As with other 5-alpha reductase inhibitors, feminization of fetuses from male rats was observed with administration of finasteride in the gestation period.

The intrauterine effects of exposure to finasteride during embryo-fetal development were evaluated in the rhesus monkey (gestation period 20 - 100 days), an animal species more similar to humans than the rat and rabbit, although it concerns intrauterine development.

Intravenous administration of finasteride to pregnant rhesus monkeys at doses up to 800 ng / day throughout the entire period of embryonic and fetal development did not result in abnormalities in male fetuses. estimated amount present in the semen of a man who has taken finasteride 5 mg, and to which a woman could be exposed via semen. Confirming the relevance of the rhesus model for the development of the human fetus, oral administration of finasteride 2 mg / kg / day (systemic exposure (AUC) of monkeys was slightly (3x) higher than that of humans who took finasteride 5 mg, or approximately 1 million times the estimated amount of finasteride present in semen) in monkeys in pregnancy it resulted in abnormalities of the external genitalia of male fetuses. No other abnormalities were observed in male fetuses and no finasteride-related abnormalities were observed in female fetuses for any of the dosages used.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Lactose monohydrate, pregelatinized starch, sodium carboxymethyl starch, yellow iron oxide, sodium dioctylsulfosuccinate, microcrystalline cellulose, magnesium stearate, hypromellose, hydroxypropyl cellulose, titanium dioxide, talc, E 132 indigo carmine on hydrated aluminum.

06.2 Incompatibility

Incompatibilities with other medicines are unknown.

06.3 Period of validity

3 years.

06.4 Special precautions for storage

This medicine does not require any special storage conditions.

06.5 Nature of the immediate packaging and contents of the package

The tablets are contained in opaque PVC / PE / PVDC and aluminum blisters. The blister is contained with the package leaflet in a lithographed cardboard box.

15 film-coated tablets of 5 mg

30 film-coated tablets of 5 mg

Not all pack sizes may be marketed.

06.6 Instructions for use and handling

No special instructions.

Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.

07.0 MARKETING AUTHORIZATION HOLDER

MERCK SHARP & DOHME LIMITED

Hertford Road, Hoddesdon

Hertfordshire, United Kingdom

08.0 MARKETING AUTHORIZATION NUMBER

15 film-coated tablets 5 mg 028308017

30 film-coated tablets 5 mg 028308029

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

July 2002

10.0 DATE OF REVISION OF THE TEXT

January 2014

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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