Binfine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BINFINE (BINFIN)

Composition:

Active substance: finasteride;

1 tablet contains 5 mg of finasteride;

Excipients: lactose monohydrate; pregelatinized starch; microcrystalline cellulose; sodium starch glycolate; sodium docusate; magnesium stearate; Opadry Blue 03A80928 (hypromellose, titanium dioxide (E 171), talc, indigo carmine aluminum lake (E 132), iron oxide yellow (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, blue, film-coated tablets, with the inscription "H" on one side and "37" on the other.

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 BPH symptoms, enlarged prostate on digital rectal examination, and low residual urine volume, the medicinal product Binfin reduced the incidence of acute urinary retention from 7/100 to 3/100 over 4 years and the need for surgical intervention (transurethral resection of the prostate and prostatectomy) from 10/100 to 5/100. This reduction was accompanied by a 2-point improvement on the symptom assessment scale QUASI-AUA (range 0–34), significant regression of prostate volume—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 mg/day or 8 mg/day), combination therapy with finasteride (5 mg/day) and doxazosin (4 mg/day or 8 mg/day), or placebo. The primary endpoint was time to clinical progression of BPH (defined as an increase of ≥4 points from baseline on the symptom score scale, an 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. Most cases (274 out of 351) of BPH progression 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 out of 351 cases of BPH progression; under treatment, 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 showed a statistically significant difference compared to the placebo group.

Pharmacokinetics.

In men, after a single oral dose of radiolabeled carbon-14C finasteride, 39% of the administered dose was excreted in the urine as metabolites (a negligible amount of unchanged finasteride was likely also excreted in urine). 57% of the administered dose was eliminated in feces. Studies have also shown that two metabolites of finasteride have a weaker inhibitory effect on 5-alpha-reductase. The bioavailability of finasteride after oral administration 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 of the drug from the gastrointestinal tract is complete within 6–8 hours after administration. The mean elimination half-life of finasteride in plasma is approximately 6 hours. Plasma protein binding is 93%. Systemic clearance is approximately 165 ml/min, and the volume of distribution is 76.1 liters.

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

In patients with chronic renal impairment (creatinine clearance from 9 to 55 ml/min), no differences in the elimination rate of a single dose of radiolabeled carbon-14C finasteride were observed 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 is not required for patients with renal impairment who are not undergoing hemodialysis.

Pharmacokinetic data on the drug in patients with hepatic impairment are not available.

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

Clinical characteristics.

Indications.

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

• reducing the size (regression) of the enlarged gland, improving urinary flow, and decreasing 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 component of this medicinal product.

The medicinal product Binfine is not indicated for use in women and children.

Pregnancy or if the patient 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. The medicinal product Binfine does not significantly affect the enzyme system metabolizing drugs related to 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, considering 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 humans include propranolol, digoxin, glyburide, warfarin, theophylline, and antipyrine; no clinically significant interactions were found.

Special precautions for use.

General precautions

Careful monitoring for possible development of obstructive uropathy is necessary in patients with large residual urine volume and/or markedly reduced urinary flow.

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

To date, no beneficial clinical effect of Binfin treatment has been demonstrated in patients with prostate cancer. Patients with benign prostatic hyperplasia (BPH) and elevated PSA levels were observed in controlled clinical trials with multiple PSA measurements and prostate biopsies. In these studies, the use of Binfin did not affect the frequency of prostate cancer detection. The overall incidence of prostate cancer was not significantly different between patients receiving Binfin and those receiving placebo.

Prior to initiating treatment and periodically during therapy with Binfin, patients should be examined by digital rectal examination and other methods to rule out prostate cancer. Serum PSA measurement is also used to detect prostate cancer. In general, if baseline PSA levels exceed 10 ng/mL (Hybritech), thorough evaluation of the patient, including biopsy if necessary, should be performed. For PSA levels between 4 and 10 ng/mL, further patient evaluation is recommended. There is considerable overlap in PSA levels between men with and without prostate cancer. Therefore, normal PSA values in men with BPH do not exclude the presence of prostate cancer, regardless of Binfin use. A baseline PSA level below 4 ng/mL does not exclude the presence of prostate cancer.

Binfin causes a reduction in serum PSA levels by approximately 50% in patients with BPH, even in the presence of prostate cancer. This decrease in serum PSA must be taken into account when interpreting PSA levels, as this reduction does not rule out concomitant prostate cancer. The reduction is predictable across the entire range of PSA values, although individual variations may occur. In most patients treated with Binfin for 6 months or longer, PSA values should be doubled compared to the reference values in untreated individuals. This adjustment maintains the sensitivity and specificity of PSA testing and preserves its ability to detect prostate cancer.

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

Effect of the drug on laboratory parameters

Effect on PSA levels

Serum PSA levels correlate with patient age and prostate volume, which itself correlates with age. When evaluating laboratory PSA parameters, it should be noted that PSA levels decrease during Binfin 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 Binfin for 6 months or longer, PSA values should be doubled compared to reference values in untreated individuals.

Binfin 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 Binfin. When using the percentage of free PSA for prostate cancer diagnosis, correction of its value is not required.

Breast cancer in men

Cases of male breast cancer 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 5 mg finasteride. Patients should be monitored for the emergence of psychiatric symptoms, and medical help should be sought if such symptoms occur.

Lactose

The drug contains lactose; therefore, Binfin should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Hepatic impairment

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

Use during pregnancy or breastfeeding.

Use during pregnancy

Binfin is contraindicated in pregnant women.

Effect of finasteride – risk to male fetus.

Women who are or may potentially become pregnant should avoid contact with crushed or damaged Binfin tablets due to the potential for finasteride absorption and subsequent risk to a male fetus. Binfin 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 may be excreted in semen of patients taking 5 mg finasteride 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 is advised to avoid exposing her to semen.

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

Use during breastfeeding

Binfin is not indicated for use in women. It is unknown whether finasteride is excreted in human milk.

Ability to affect reaction speed when driving vehicles or operating machinery.

Does not affect the ability to drive vehicles or operate machinery.

Dosage and Administration.

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

The medicinal product Binfen can be used as monotherapy or in combination with the alpha-blocker doxazosin (see section "Pharmacological properties").

The duration of treatment is determined individually by the physician. Although symptom improvement may be observed earlier, at least six months of treatment are required to assess therapeutic efficacy, after which treatment should be continued.

No dose adjustment is required for elderly patients or for patients with renal impairment of any degree (creatinine clearance down to 9 mL/min).

There are no data regarding the use of the medicinal product in patients with hepatic impairment.

Do not use in children.

Children.

The medicinal product Binfen is contraindicated in children.

Safety and efficacy of the medicinal product in children have not been established.

Overdose.

In patients who received the medicinal product Binfen at a single dose of up to 400 mg and the medicinal product Binfen at a daily dose of up to 80 mg for 3 months, no adverse effects were observed.

There are no specific recommendations for the treatment of overdose with this medicinal product.

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 follows: 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, breast cancer in men has been reported in clinical studies and during post-marketing use of finasteride. Patients should inform their physician immediately about any changes in breast tissue, such as lumps, pain, gynecomastia, or nipple discharge.

When comparing the safety profiles of monotherapy with finasteride (5 mg/day) and doxazosin (4 or 8 mg/day) versus combination therapy with finasteride (5 mg/day) and doxazosin (4 or 8 mg/day) and placebo, the safety and tolerability profile of combination therapy was consistent with the safety profiles of the individual components. The incidence of ejaculation disorders in patients receiving combination therapy was comparable to the sum of the adverse reaction incidences observed with the two monotherapies.

There is no available information on the relationship between long-term use of finasteride and Gleason score 7–10 tumors.

Laboratory test data

When evaluating laboratory results for prostate-specific antigen (PSA), it should be noted that PSA levels decrease in patients taking Binfin. In most patients, a rapid decline in PSA occurs during the first few months of therapy, after which PSA levels stabilize at a new baseline. The post-treatment baseline is approximately half the pre-treatment value. Therefore, in most patients treated with Binfin for 6 months or longer, the PSA value should be doubled when comparing to normal reference ranges in untreated men.

In standard laboratory tests, no other differences were observed between patients receiving Binfin and those receiving placebo.

Reporting of suspected adverse reactions

Reporting of adverse reactions following marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep out of the reach of children.

Packaging.

15 film-coated tablets in a blister pack.

2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer’s address and location of operations.

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.