PENESTER

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PENESTER® (PENESTER®)

Composition:

Active ingredient: finasteride;

1 tablet contains 5 mg of finasteride;

Excipients: lactose monohydrate, corn starch, povidone 30, sodium starch glycolate (type A), sodium docusate, magnesium stearate, hypromellose 2910/5, macrogol 6000, talc, titanium dioxide (E 171), simethicone emulsion SE4, iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical characteristics: yellow, round, biconvex, film-coated tablets, 7.1 mm in diameter.

Pharmacotherapeutic group. Drugs used in benign prostatic hyperplasia. ATC code G04C B01.

Pharmacological Properties

Pharmacodynamics

Finasteride is a specific inhibitor of type II 5-alpha-reductase, an intracellular enzyme that converts testosterone into the more potent androgen dihydrotestosterone (DHT). In benign prostatic hyperplasia (BPH), prostate enlargement is dependent on the conversion of testosterone to DHT within prostate tissue. Finasteride effectively reduces both circulating and intraprostatic DHT levels. Finasteride has no affinity for androgen receptors.

In clinical studies involving patients with moderate to severe symptoms of benign prostatic hyperplasia (BPH), enlarged prostate on digital rectal examination, and low residual urine volume, finasteride reduced the incidence of acute urinary retention from 7 per 100 to 3 per 100 over four years and the need for surgical intervention (transurethral resection of the prostate or prostatectomy) from 10 per 100 to 5 per 100. This reduction was accompanied by a 2-point improvement on the symptom score scale QUASI-AUA (range 0–34), a significant regression of prostate volume by approximately 20%, and a significant increase in urinary flow rate.

The MTOPS (Medical Therapy of Prostatic Symptoms) study was a 4–6-year trial involving 3047 men with symptomatic BPH who were randomized to receive finasteride 5 mg/day, doxazosin 4 or 8 mg/day, 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 an increase of 4 or more points from baseline on symptom score scale, episode of acute urinary retention, BPH-related renal insufficiency, recurrent urinary tract infection or urosepsis, or urinary incontinence). Compared with placebo, treatment with finasteride, doxazosin, or the combination significantly reduced 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 progression events (274 of 351) were confirmed by an increase of ≥ 4 points on the symptom score scale; under treatment, the risk of symptom progression was reduced by 30% (95% confidence interval 6–48%), 46% (95% confidence interval 25–60%), and 64% (95% confidence interval 48–75%) in the finasteride, doxazosin, and combination groups, respectively, compared to placebo. Acute urinary retention occurred in 41 of 351 progression events; under treatment, the risk of 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 showed a statistically significant difference compared to the placebo group.

Pharmacokinetics

In men, after a single oral dose of carbon-14 labeled finasteride, 39% of the administered dose was excreted in the urine as metabolites (a small amount of unchanged finasteride was likely also excreted in urine). 57% of the administered dose was eliminated in feces. Two metabolites of finasteride have been shown to have less inhibitory activity against 5-alpha-reductase. The oral bioavailability of finasteride is approximately 80%. Food intake does not affect the bioavailability of the drug. Maximum plasma concentration of finasteride is reached approximately 2 hours after oral administration. Absorption from the gastrointestinal tract is complete within 6–8 hours after administration. The mean elimination half-life of finasteride in plasma is 6 hours. Plasma protein binding is 93%. Systemic clearance is approximately 165 mL/min, and volume of distribution is 76.1 L.

In elderly men, the elimination rate of finasteride is slightly reduced. In men aged 70 years and older, the elimination half-life of finasteride is approximately 8 hours, compared to 6 hours in men aged 18 to 60 years. However, this does not warrant dose reduction in elderly patients.

In patients with chronic renal impairment (creatinine clearance from 9 to 55 mL/min), no differences were observed in the elimination rate of a single dose of carbon-14 labeled finasteride compared to healthy volunteers. Plasma protein binding in these patient groups was also unchanged. This is explained by the fact that in patients with renal impairment, the fraction of finasteride metabolites normally excreted in urine is instead eliminated in feces. This is confirmed by increased levels of finasteride metabolites in feces and decreased concentrations in urine in these patients. Therefore, dose adjustment of finasteride is not required in patients with renal impairment who are not undergoing hemodialysis.

Pharmacokinetic data in patients with hepatic insufficiency are not available.

Finasteride crosses the blood-brain barrier. A small amount of finasteride has been detected in semen.

Clinical characteristics.

Indications.

Treatment and control of benign prostatic hyperplasia (BPH) in patients with an enlarged prostate gland, aimed at:

• reducing the size (regression) of the enlarged gland, improving urinary flow, and alleviating symptoms associated with BPH;
• reducing the risk of acute urinary retention and the need for surgical intervention, including transurethral resection of the prostate and prostatectomy.

Contraindications.

Hypersensitivity to finasteride or to any of the excipients of the medicinal product.

Finasteride is contraindicated in women and children.

Pregnancy: use in women who are or may potentially be pregnant (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

No clinically significant interactions with other drugs have been identified. Finasteride does not exert a noticeable effect on the enzyme system metabolizing drugs associated with cytochrome P450. Although the risk that finasteride affects the pharmacokinetics of other medicinal products is considered low, there is a possibility that inhibitors and inducers of cytochrome P450 3A4 may influence the plasma concentration of finasteride. However, given the established safety profile, any increase in finasteride concentration due to concomitant use of cytochrome P450 3A4 inhibitors is unlikely to have clinical significance. Compounds tested in volunteers include propranolol, digoxin, glyburide, warfarin, theophylline, and antipyrine; no clinically relevant interactions were observed.

Concomitant therapy. Although specific interaction studies have not been conducted, in clinical trials finasteride has been used concomitantly with angiotensin-converting enzyme inhibitors, alpha-blockers, beta-blockers, calcium channel blockers, nitrates, diuretics, H2-receptor antagonists, HMG-CoA reductase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and paracetamol, quinolones, and benzodiazepines. No clinically significant adverse interactions have been observed.

Special precautions for use.

General measures.

Patients with a large residual urine volume and/or significantly reduced urinary flow should be closely monitored due to the potential risk of developing obstructive uropathy. Surgical intervention should be considered as an alternative option.

Effect on prostate-specific antigen (PSA) and diagnosis of prostate cancer.

To date, a beneficial clinical effect of finasteride treatment in patients with prostate cancer has not been demonstrated. Patients with benign prostatic hyperplasia (BPH) and elevated PSA levels were monitored in controlled clinical studies during which PSA levels were measured repeatedly and prostate biopsies were performed. In these studies, finasteride treatment did not affect the frequency of prostate cancer detection. The overall incidence of prostate cancer was not significantly different between patients receiving finasteride and those receiving placebo.

Before initiating treatment and periodically during finasteride therapy, patients should be evaluated by digital rectal examination and other appropriate methods to rule out the presence of prostate cancer. Serum PSA measurement is also used to detect prostate cancer. In general, a baseline PSA level above 10 ng/mL warrants thorough evaluation, including biopsy if necessary. When PSA levels are between 4–10 ng/mL, further evaluation is recommended. There is considerable overlap in PSA levels between men with and without prostate cancer. Therefore, normal PSA values do not exclude the presence of prostate cancer in men with BPH, regardless of finasteride treatment. A baseline PSA level below 4 ng/mL does not exclude the presence of prostate cancer.

Finasteride reduces serum PSA levels by approximately 50% in patients with BPH, even in the presence of prostate cancer. This reduction must be taken into account when interpreting PSA values, as this decrease does not rule out concomitant prostate cancer. For correct interpretation, in most patients receiving finasteride for 6 months or longer, PSA values should be doubled compared to normal values in untreated individuals. This adjustment maintains the sensitivity and specificity of PSA testing and preserves its ability to detect prostate cancer.

Any persistent increase in PSA levels in a patient receiving 5 mg finasteride therapy requires thorough evaluation to determine the underlying cause, including non-adherence to the prescribed finasteride regimen.

Effect of the drug on laboratory parameters

Effect on PSA levels

Serum PSA levels correlate with patient age and prostate volume, with prostate volume itself correlating with age. When evaluating laboratory PSA results, it is important to consider that PSA levels decrease during finasteride treatment. In most patients, a rapid decline in PSA occurs during the first few months of treatment, after which PSA stabilizes at a new level approximately half the baseline value. Therefore, in typical patients receiving finasteride for 6 months or longer, PSA values should be doubled compared to normal values in untreated individuals.

Finasteride does not significantly alter the percentage of free PSA (ratio of free to total PSA). The ratio of free to total PSA remains constant even under the influence of finasteride. When using the percentage of free PSA for prostate cancer diagnosis, correction of its value is not required.

Breast cancer in men

Cases of breast cancer in men have been reported during clinical trials and in the post-marketing period in men taking finasteride 5 mg. Physicians should instruct their patients to promptly report any changes in breast tissue, including lumps, pain, gynecomastia, or nipple discharge.

Mood changes and depression

Cases of mood changes, including depressive mood, depression, and, less frequently, suicidal ideation, have been reported in patients receiving finasteride 5 mg. Patients should be monitored for the emergence of psychiatric symptoms, and if such symptoms occur, they should be advised to seek medical help.

Lactose

The medicinal product contains lactose. Therefore, patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of finasteride has not been studied.

Use during pregnancy or breastfeeding.

Use during pregnancy.

Penester**®** is contraindicated in women.

Effect of finasteride: risk to male fetus.

Women who are or may potentially become pregnant should avoid contact with crushed or damaged finasteride tablets due to the potential for absorption of finasteride and the subsequent risk to a male fetus (see section "Use during pregnancy" above). The tablets are coated, which prevents contact with the active ingredient as long as the tablets remain intact and are not crushed.

Available data indicate that small amounts of finasteride are excreted in semen of patients taking 5 mg daily. It is unknown whether exposure to semen from a finasteride-treated patient may adversely affect a male fetus. If a patient's sexual partner is or may potentially be pregnant, the patient should be advised to avoid exposing his partner to his semen.

Because type II 5-alpha-reductase inhibitors can inhibit the conversion of testosterone to dihydrotestosterone, these agents, including finasteride, may cause abnormalities in the development of external genitalia in a male fetus.

The tablets are coated, which prevents contact with the active ingredient as long as the tablets are not crushed or damaged.

Use during breastfeeding.

Penester**®** is not indicated for use in women. It is unknown whether finasteride is excreted in human breast milk.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product does not affect the ability to drive a vehicle or operate machinery.

Dosage and Administration

The recommended dose is 1 tablet of 5 mg once daily, independent of food intake.

Finasteride may be used as monotherapy or in combination with the alpha-blocker doxazosin.

The duration of treatment is determined individually by a physician. Although symptomatic improvement may be observed earlier, at least six months of continuous treatment are required to assess therapeutic efficacy, after which treatment should be continued. The risk of acute urinary retention decreases during the four months following treatment completion.

Dose adjustment is not required in patients with renal impairment of any severity (including creatinine clearance as low as 0.9 mL/min), as pharmacokinetic studies have shown no changes in finasteride distribution.

There are no data regarding the use of this drug in patients with hepatic impairment.

No dose adjustment is necessary for elderly patients.

Not intended for use in children.

Children

Penesther**®** is contraindicated in children.

The safety and efficacy of this medicinal product in children have not been established.

Overdose

In patients who received finasteride at a single dose of up to 400 mg or at daily doses of up to 80 mg for 3 months, no adverse effects were observed.

There are no specific recommendations for the treatment of finasteride overdose.

Adverse reactions.

The most common adverse reactions are impotence and decreased libido. These adverse reactions occur at the beginning of the treatment course and resolve with continued therapy in most patients.

Adverse reactions reported during clinical trials and/or post-marketing use are listed below in the table.

The frequency of adverse reactions is defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data).

In addition, during clinical trials and in post-marketing use, cases of breast cancer have been reported in men taking finasteride (see section "Special precautions during use").

Drug treatment of prostate symptoms

In the MTOPS study, finasteride 5 mg/day (n = 768), doxazosin 4 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. The safety and tolerability profile of combination therapy was consistent with the profiles of the individual components. The incidence of ejaculation disorders in patients receiving combination therapy was: finasteride – 8.3%, doxazosin – 5.3%, combination therapy – 15%, placebo – 3.9%.

Other data from long-term studies

In a seven-year placebo-controlled study involving 18,882 healthy men, with needle biopsy data of the prostate available for analysis in 9,060 men, prostate cancer was detected in 803 (18.4%) men receiving finasteride and in 1,147 (24.4%) men receiving placebo. In the finasteride treatment group, 280 (6.4%) men had prostate cancer with Gleason scores of 7–10 identified by needle biopsy, compared to 237 (5.1%) men in the placebo group. Additional analyses suggest that the observed increased incidence of high-grade prostate cancer in the finasteride group can be explained by the effect of finasteride on prostate volume. Of the total number of prostate cancer cases diagnosed in this study, approximately 98% were classified as intracapsular (stage T1 or T2) cancer. Information on the relationship between long-term use of finasteride and tumors with Gleason scores of 7–10 is lacking.

Laboratory test data

Serum PSA levels correlate with patient age and prostate volume, with prostate volume itself correlating with patient age. When evaluating laboratory PSA results, it must be taken into account that PSA levels decrease during treatment with finasteride (see section "Special precautions during use").

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Keep out of reach and sight of children.

Packaging.

No. 30 (15x2): 15 tablets in a blister, 2 blisters in a cardboard box.

No. 90 (30x3): 30 tablets in a blister, 3 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Zentiva, k.s.

Manufacturer's address and place of business.

U Kabelovny 130, Dolni Měcholupy, Prague-Dolni Měcholupy, 102 00, Czech Republic.