Penester^® (Tablets) Instructions for Use

Marketing Authorization Holder

Zentiva, k.s. (Czech Republic)

Manufactured By

Zentiva, k.s. (Czech Republic)

Contact Information

SANOFI

ATC Code

G04CB01 (Finasteride)

Active Substance

Finasteride (Rec.INN registered by WHO)

Dosage Form

Penester®

Film-coated tablets, 5 mg: 30, 60, or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light yellow in color, round, biconvex.

Excipients : lactose monohydrate, corn starch, povidone K30, sodium carboxymethyl starch (type A), sodium docusate, magnesium stearate.

Film coating composition hypromellose 2910/5, macrogol 6000, talc, titanium dioxide, simethicone emulsion SE4, yellow iron oxide dye.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
15 pcs. – blisters (2) – cardboard packs.
15 pcs. – blisters (4) – cardboard packs.
15 pcs. – blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Drug for the treatment of benign prostatic hyperplasia. 5α-reductase inhibitor

Pharmacotherapeutic Group

Drugs used in urology; drugs for the treatment of benign prostatic hyperplasia; testosterone-5-alpha-reductase inhibitors

Pharmacological Action

Finasteride is a synthetic 4-azasteroid compound. It is a specific competitive inhibitor of type II 5α-reductase, an intracellular enzyme that converts testosterone to the active androgen dihydrotestosterone (DHT). In benign prostatic hyperplasia (BPH), prostate enlargement depends on the conversion of testosterone to DHT in the prostate. Finasteride is highly effective in reducing DHT concentrations in both blood plasma and prostate tissue. Suppression of DHT formation is accompanied by a reduction in prostate size, an increase in maximum urinary flow rate, and a reduction in the severity of symptoms associated with prostatic hyperplasia.

Finasteride has no affinity for androgen receptors.

According to the results of a clinical study (PLESS), which included patients with moderate or severe symptoms of BPH and prostate enlargement, Finasteride reduced the incidence of acute urinary retention from 7/100 to 3/100 over a 4-year period, and the need for surgical intervention (transurethral resection of the prostate (TURP) or prostatectomy) — from 10/100 to 5/100. These changes were also associated with improvement in BPH symptoms (a 2-point reduction on the quasi-AUA symptom scale), a sustained reduction in prostate volume of approximately 20%, and a stable increase in urinary flow rate.

The MTOPS (Medical Therapy Of Prostate Symptoms) study lasting from 4 to 6 years, in which 3047 men with BPH symptoms were randomized to receive: Finasteride 5 mg/day; doxazosin 4 mg/day or 8 mg/day; a combination of finasteride 5 mg/day and doxazosin 4 mg/day or 8 mg/day; or placebo. Treatment led to a significant reduction in the risk of clinical progression of BPH, which with finasteride use was 34% (p=0.002), with doxazosin – 39% (p<0.001) and with combination therapy - 67% (p<0.001) relative to placebo. In most cases, BPH progression (274 out of 351) manifested as worsening of BPH symptoms by ≥4 points on the IPSS (International Prostate Symptom Score), with the risk of worsening symptoms, assessed by a score, reduced by 30% (95% CI: 6-48%) among patients receiving Finasteride, by 46% (95% CI: 25-60%) among those receiving doxazosin, and by 64% (95% CI: 48-75%) among those receiving combination therapy relative to the placebo group. Among patients receiving Finasteride, the risk of acute urinary retention was reduced by 67% (p=0.011), in the doxazosin group by 31% (p=0.296), and in the combination therapy group by 79% (p=0.001) relative to the placebo group. A significant difference from placebo was observed only in the groups of patients receiving Finasteride and combination therapy.

Pharmacokinetics

Absorption

C_max of finasteride in blood plasma is reached approximately 2 hours after oral administration. Absorption of finasteride from the gastrointestinal tract is complete within 6-8 hours after oral administration. The bioavailability of finasteride upon oral administration is approximately 80% of the intravenous reference dose and does not depend on food intake.

Distribution

Binding to plasma proteins is approximately 93%. Plasma clearance is about 165 ml/min, apparent V_d – 76 L.

With long-term therapy, slow accumulation of finasteride in small amounts is observed. With daily oral administration of finasteride at a dose of 5 mg, its minimum C_ss in blood plasma reaches 8-10 ng/ml and remains stable over time.

In patients who received the drug for 7-10 days, Finasteride was detected in the cerebrospinal fluid. When taking the drug at a dose of 5 mg/day, Finasteride is detected in seminal fluid in small amounts.

Metabolism and Excretion

T_1/2 of finasteride averages 6 hours. In men after a single oral dose of ¹⁴C-labeled finasteride, 39% of the administered dose is excreted by the kidneys as metabolites (unchanged Finasteride is practically not excreted by the kidneys); 57% – through the intestine. In this study, 2 metabolites of finasteride were identified, which have a slight inhibitory effect on 5α-reductase compared to finasteride.

Pharmacokinetics in Special Clinical Cases

In old age, the elimination rate of finasteride is somewhat reduced. With age, T_1/2 increases: in men 18-60 years old, the average T_1/2 is 6 hours, and in men over 70 years old – 8 hours. These changes are not clinically significant, and therefore, dose reduction of the drug in elderly men is not required.

In patients with chronic renal failure (creatinine clearance from 9 to 55 ml/min), the distribution of ¹⁴C-labeled finasteride after a single dose did not differ from that in healthy volunteers. The binding of finasteride to plasma proteins also did not differ in patients with impaired renal function.

In renal failure, the portion of finasteride metabolites that is normally excreted by the kidneys is eliminated through the intestine. This is manifested by an increase in the amount of finasteride metabolites in the stool with a corresponding decrease in their concentration in the urine. In patients with renal failure not requiring hemodialysis, no adjustment of the finasteride dose is required.

Indications

• Treatment of BPH and prevention of urological complications in order to:
  • Reduce the risk of acute urinary retention;
  • Reduce the risk of the need for surgical interventions, including TURP and prostatectomy;
• Treatment to reduce the size of the enlarged prostate, improve urination and reduce the severity of symptoms associated with BPH;
• In combination with doxazosin to reduce the risk of progression of symptoms associated with BPH.

ICD codes

Dosage Regimen

The drug is taken orally at 5 mg once/day, regardless of meals.

The duration of therapy before evaluating its effectiveness should be at least 6 months, so the course of treatment should be sufficiently long.

Finasteride can be used as monotherapy, as well as in combination with doxazosin.

There is insufficient clinical data on the use of the drug in patients with hepatic impairment.

In patients with various stages of renal failure (with a decrease in creatinine clearance to 9 ml/min), no dose adjustment is required, since special studies have not demonstrated any changes in the pharmacokinetic profile of finasteride.

Elderly patients do not require dose adjustment, although pharmacokinetic studies indicate that the elimination of finasteride in patients over 70 years of age is somewhat reduced.

Adverse Reactions

Adverse reactions identified during clinical trials (PLESS study)

Adverse reactions are divided by system-organ classes in accordance with the MedDRA classification. The frequency of adverse reactions was determined according to the following gradation (WHO classification): very common (more than 1/10); common (from more than 1/100 to less than 1/10); uncommon (from more than 1/1000 to less than 1/100); rare (from more than 1/10,000 to less than 1/1000); very rare (less than 1/10,000, including isolated reports).

Psychiatric disorders common – decreased libido.

Skin and subcutaneous tissue disorders uncommon – skin rash.

Reproductive system and breast disorders common – sexual dysfunction; uncommon – ejaculation disorder, decreased ejaculate volume, breast enlargement, breast tenderness.

Within the MTOPS study, the use of finasteride 5 mg/day (n=768), doxazosin 4 mg/day or 8 mg/day (n=756), combination therapy with finasteride 5 mg/day and doxazosin 4 or 8 mg/day (n=786), and placebo (n=737) were compared. According to the results of this study, the safety and tolerability profile of combination therapy generally coincided with the profile of its individual components. The frequency of ejaculation disorders in patients receiving combination therapy was comparable to the sum of the frequency of this adverse event during two types of monotherapy.

A 7-year placebo-controlled PCPT study was conducted, which included 18,882 healthy men. Analyzable data from prostate needle biopsies were obtained for 9060 subjects, with prostate cancer detected in 803 (18.4%) men receiving Finasteride at a daily dose of 5 mg, and in 1147 (24.4%) men receiving placebo. According to the results of needle biopsy, prostate cancer with a Gleason score of 710 was diagnosed in 280 (6.4%) men from the group receiving Finasteride at a daily dose of 5 mg, while in the placebo group, cancer with this degree of differentiation was diagnosed in 237 (5.1%) patients. The results of an additional analysis indicated that the increased prevalence of poorly differentiated prostate cancer observed in the group of patients receiving Finasteride at a daily dose of 5 mg could be explained by an assessment bias associated with the effect of therapy with finasteride 5 mg once/day on prostate volume. Of the total number of prostate cancer cases diagnosed in this study, approximately 98% of cases were classified as localized cancer (clinical stage T1 or T2) at the time of diagnosis. The clinical significance of data on tumor process with a degree of differentiation of 7-10 points on the Gleason scale is unknown.

Information obtained from post-registration experience with the drug

The frequency of adverse reactions is unknown, because based on the data obtained, it is not always possible to establish the frequency and causal relationship with the action of finasteride, since reports of these reactions were received voluntarily from a population of unknown size.

Immune system disorders frequency unknown – hypersensitivity reactions, incl. pruritus, urticaria, angioedema (including swelling of the lips, face and larynx).

Hepatobiliary disorders frequency unknown – increased activity of liver transaminases.

Cardiac disorders frequency unknown – palpitations.

Psychiatric disorders frequency unknown – depression, decreased libido that persists after discontinuation of therapy.

Reproductive system and breast disorders frequency unknown – sexual dysfunction (erectile dysfunction and ejaculation disorders) that persists after discontinuation of treatment, testicular pain, male infertility and/or decreased semen quality. After discontinuation of finasteride, semen quality returned to normal or improved.

Laboratory parameters

When evaluating the results of laboratory tests, it must be taken into account that in patients receiving treatment with finasteride, the PSA content in blood plasma decreases. In most patients, a rapid decrease in PSA is observed during the first months of therapy, followed by its stabilization. The baseline PSA value established after therapy with finasteride is approximately half of the corresponding indicator noted before the start of treatment. Thus, in patients receiving treatment with finasteride for 6 months or more, the PSA value should be doubled compared to the normal values of men not receiving treatment. This correction maintains the sensitivity and specificity of the PSA test and the ability to detect prostate cancer. No other differences in standard laboratory parameters were observed between groups of patients receiving Finasteride and placebo.

Contraindications

• Hypersensitivity to finasteride and/or other components of the drug;
• Hereditary lactose intolerance, lactase deficiency or glucose/galactose malabsorption;
• Pregnancy and use of the drug in women with preserved reproductive potential;
• Age under 18 years.

With caution the drug should be prescribed to patients with a large volume of residual urine and/or significantly reduced urinary flow rate (patients should be regularly monitored by a doctor to detect obstructive uropathy), patients with hepatic insufficiency, as well as elderly patients.

Use in Pregnancy and Lactation

The use of the drug Penester^® is contraindicated during pregnancy and in women with preserved reproductive potential. Due to the ability of type II 5α-reductase inhibitors to suppress the conversion of testosterone to dihydrotestosterone, these agents, including Finasteride, when used in pregnant women, can cause abnormalities in the development of the external genitalia in a male fetus.

Finasteride is not indicated for use in women.

There are no data on the excretion of finasteride in breast milk.

Small amounts of finasteride have been found in the semen of patients receiving Finasteride at a dose of 5 mg/day. Although there are no clinical data on the effect of finasteride on the male fetus, women with preserved reproductive potential should avoid contact with the semen of men taking Finasteride.

Women with preserved reproductive potential and pregnant women should avoid contact with damaged finasteride tablets, because the drug’s ability to suppress the conversion of testosterone to DHT may cause impaired development of the genital organs in a male fetus.

Use in Hepatic Impairment

With caution the drug should be prescribed to patients with hepatic insufficiency.

Use in Renal Impairment

In patients with various stages of renal failure (with a decrease in creatinine clearance to 9 ml/min), no dose adjustment is required, since special studies have not demonstrated any changes in the pharmacokinetic profile of finasteride.

Pediatric Use

Contraindicated under 18 years of age.

Geriatric Use

Should be prescribed with caution to elderly patients.

Special Precautions

General instructions

To avoid obstructive complications, careful monitoring of patients with a large volume of residual urine and/or significantly difficult urination is necessary. The possibility of the need for surgical intervention should be taken into account.

Effect on PSA levels and diagnosis of prostate cancer

To date, no clinical benefits of using finasteride in patients with prostate cancer have been proven. In controlled clinical trials in patients with BPH and elevated plasma PSA levels, PSA levels and prostate biopsy results were monitored. It was found that the use of finasteride apparently does not change the detection rate of prostate cancer and does not affect the frequency of its occurrence in patients taking Finasteride or placebo.

Before starting treatment and periodically during therapy with finasteride, it is recommended to perform a digital rectal examination and use other methods for diagnosing prostate cancer. Determination of PSA in blood plasma is also used to detect prostate cancer. In general, a baseline PSA concentration above 10 ng/ml indicates the need for further examination of the patient and a prostate biopsy. When determining PSA concentration within 4-10 ng/ml, further examination of the patient is necessary. In men with BPH, normal PSA values do not rule out prostate cancer, regardless of finasteride treatment. A baseline PSA concentration below 4 ng/ml also does not rule out prostate cancer.

Finasteride causes a decrease in serum PSA concentration by approximately 50% in patients with BPH, even in the presence of prostate cancer. This fact must be taken into account when assessing PSA levels in patients with BPH receiving treatment with finasteride, because a decrease in PSA concentration does not exclude the presence of concomitant prostate cancer. This decrease is expected for any range of PSA concentration values, although it may vary in individual patients. Analysis of PSA values in more than 3000 patients in the 4-year double-blind placebo-controlled PLESS study confirmed that in patients taking Finasteride for 6 months or more, PSA values should be doubled to compare them with the normal values of this indicator in patients not receiving the drug. This correction maintains the sensitivity and specificity of the PSA test and the ability to detect prostate cancer. Any persistent increase in PSA concentration in patients receiving treatment with finasteride requires careful examination to determine the cause, which may be non-compliance with the drug regimen. Finasteride does not significantly reduce the percentage of free PSA (the ratio of free PSA to total). This indicator remains constant even under the influence of the drug. If the percentage of free PSA is used to diagnose prostate cancer, correction of the values of this indicator is not necessary.

Breast Cancer in Men

During clinical studies and in the post-registration period, cases of breast cancer have been observed in men taking Finasteride.

Physicians should instruct their patients to immediately report any changes in breast tissue, such as lumps, pain, gynecomastia, or nipple discharge.

Effect on Driving and Operating Machinery

No adverse effects of the drug on the ability to drive vehicles and operate machinery have been reported.

Overdose

Patients have received Finasteride in single doses of up to 400 mg, and no adverse reactions were observed with multiple doses of up to 80 mg/day for 3 months.

Overdose of finasteride does not require specific treatment.

Drug Interactions

No clinically significant interaction with other drugs has been identified.

Finasteride is metabolized primarily by the cytochrome P450 isoenzyme CYP3A4 and does not significantly affect the function of this system.

Although the risk of finasteride affecting the pharmacokinetics of other drugs is considered low, there is a possibility that inhibitors or inducers of the cytochrome P450 isoenzyme CYP3A4 will affect the plasma concentration of finasteride.

Nevertheless, given the available safety data, it seems unlikely that an increase in finasteride concentration associated with the concomitant use of such inhibitors will be of clinical significance.

No clinically significant interaction was identified with the combined use of finasteride with propranolol, digoxin, glibenclamide, warfarin, theophylline, and phenazone.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.