Fokusin^® Combi (Capsule kit) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

Manufactured By

Zentiva, k.s. (Czech Republic)

Or

Saneca Pharmaceuticals, a.s. (Slovakia)

ATC Codes

G04CA02 (Tamsulosin)

G04CB01 (Finasteride)

Active Substances

Tamsulosin (Rec.INN registered by WHO)

Finasteride (Rec.INN registered by WHO)

Dosage Form

Fokusin® Combi

Set of 30 modified-release capsules 0.4 mg and 30 film-coated tablets 5 mg.

Dosage Form, Packaging, and Composition

Set of modified-release capsules and film-coated tablets

Modified-release capsules are hard gelatin, size No. 1; the body and cap are dark blue, transparent; the capsule contents are white or almost white micropellets.

Excipients: methacrylic acid and ethyl acrylate copolymer [1:1] [30% dispersion] – 74.9 mg (in solid form), microcrystalline cellulose – 257.1 mg, dibutyl sebacate – 8.4 mg, polysorbate 80 – 0.5 mg, colloidal silicon dioxide – 3.7 mg, talc – 0.3 mg.

Capsule shell composition: dye azorubine – 0.2%, dye patent blue – 0.12%, gelatin – up to 100%.

10 pcs. – PVC/PVDH/Al blisters (3) – cardboard packs.

Film-coated tablets are light yellow, round, biconvex.

Excipients: lactose monohydrate – 77.45 mg, corn starch – 40 mg, povidone K30 – 3.25 mg, sodium carboxymethyl starch (type A) – 2.6 mg, sodium docusate – 0.4 mg, magnesium stearate – 1.3 mg.

Film coating composition: hypromellose 2910/5 – 3.15 mg, macrogol 6000 – 0.3 mg, talc – 0.3 mg, titanium dioxide – 0.2 mg, simethicone emulsion SE4 – 0.03 mg, iron oxide yellow dye – 0.02 mg.

10 pcs. – PVC/PVDH/Al blisters (3) – cardboard packs.
15 pcs. – PVC/PVDH/Al blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Drug for the treatment and control of symptoms of benign prostatic hyperplasia. Combination of a 5α-reductase inhibitor with an alpha₁-adrenergic blocker

Pharmacotherapeutic Groups

• Alpha1-adrenergic blocker
• 5-alpha-reductase inhibitor

Pharmacological Action

A combined drug with alpha-adrenergic blocking and antiandrogenic action.

Fokusin^® Combi is intended for the treatment and control of symptoms of benign prostatic hyperplasia (BPH) when combination therapy with tamsulosin and finasteride is necessary.

Fokusin^® Combi can only be used with an enlarged prostate (prostate volume greater than 40 cm³). With such prostate enlargement, combination therapy alleviates BPH symptoms and slows the clinical progression of the disease more effectively than monotherapy with finasteride or an α₁-adrenergic receptor blocker.

Tamsulosin selectively and competitively blocks postsynaptic α_1A-adrenergic receptors of the smooth muscle of the prostate, bladder neck, and prostatic part of the urethra, as well as α_1D-adrenergic receptors of the bladder. This effect leads to a decrease in the tone of the smooth muscle of the prostate, bladder neck, and prostatic part of the urethra, improvement in detrusor function, and reduction in symptoms of obstruction and irritation associated with benign prostatic hyperplasia.

Typically, the therapeutic effect develops 2 weeks after starting the drug, although some patients note a decrease in symptom severity after the first dose.

The ability of tamsulosin to act on α_1A-adrenergic receptors is 20 times greater than its ability to act on α_1B-adrenergic receptors of vascular smooth muscle. Due to this high selectivity, the drug does not cause any clinically significant decrease in systemic blood pressure in either patients with arterial hypertension or patients with normal blood pressure.

Finasteride is a synthetic 4-azasteroid compound, a specific inhibitor of type II 5α-reductase, an intracellular enzyme that converts testosterone to the more active androgen, dihydrotestosterone (DHT). In BPH, its enlargement depends on the conversion of testosterone to DHT in the prostate.

Finasteride is highly effective in reducing DHT concentration both in the blood and in prostate tissue. Suppression of DHT formation is accompanied by a decrease 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.

In patients with BPH who received Finasteride at a dose of 5 mg/day for 4 years (the MTOPS study), a decrease in blood DHT concentration of approximately 70% was observed, which was associated with a reduction in prostate volume of approximately 20%. In addition, the PSA concentration decreased by approximately 50% compared to its baseline concentration, suggesting a reduction in the growth of prostate epithelial cells. The decrease in DHT concentration and the reduction in the severity of prostatic hyperplasia, accompanied by a decrease in PSA concentration, persisted for up to 4 years. In these studies, plasma testosterone levels increased by approximately 10-20%, remaining within physiological values.

It has been established that long-term use (more than 4 years) of finasteride in patients with BPH with moderate or severe symptoms of the disease reduced the risk of urological complications (acute urinary retention requiring catheterization) and the frequency of surgical intervention (transurethral resection (TUR) of the prostate or prostatectomy) by 51%, and was accompanied by a pronounced and persistent decrease in prostate volume, as well as a persistent increase in maximum urinary flow rate and improvement in symptoms (the PLESS study).

Pharmacokinetics

Tamsulosin

Absorption

After oral administration, Tamsulosin is rapidly and almost completely absorbed from the small intestine, its bioavailability is almost 100%. Food intake reduces drug absorption, so to achieve adequate absorption levels, the drug should be taken daily at the dose specified in the medical instructions, after breakfast.

After a single oral dose of tamsulosin 0.4 mg, C_max in plasma is reached after 6 hours. With multiple doses, steady state is reached by day 5, and the C_max of the drug is approximately 2-3 times higher than with a single dose. Although these indicators were obtained in elderly patients, it is assumed that they are similar in young patients. With single and multiple doses, pronounced individual fluctuations in plasma drug concentration may occur.

Distribution

Plasma protein binding is 99%. The V_d of tamsulosin is insignificant and is approximately 0.2 l/kg.

The pharmacokinetics of tamsulosin are linear.

Metabolism

Tamsulosin does not undergo presystemic metabolism and is slowly biotransformed in the liver to form pharmacologically active metabolites that retain high selectivity for α_1A-adrenergic receptors. Most of the active substance is present in the blood unchanged. In rats, slight induction of hepatic microsomal enzymes caused by tamsulosin was identified. None of the metabolites are more effective or toxic than the main substance.

Excretion

Tamsulosin and its metabolites are predominantly excreted by the kidneys, approximately 9% of the administered drug dose is excreted unchanged. The T_1/2 of the drug from plasma is 10 hours after a single dose of a 0.4 mg capsule, and 13 hours after multiple doses.

Pharmacokinetics in special clinical cases

In case of kidney disease, dose adjustment is not required.

Finasteride

Absorption

C_max of finasteride in plasma is reached approximately 2 hours after oral administration and absorption is completely completed within 6-8 hours. The bioavailability of finasteride when taken orally is approximately 80% of the intravenous reference dose and does not depend on food intake.

Distribution

Plasma protein binding is approximately 93%. Plasma clearance is about 165 ml/min, V_d is 76 L.

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

In patients who received Finasteride for 7-10 days, the drug was detected in the cerebrospinal fluid. When taking finasteride at a dose of 5 mg/day, the drug is also detected in seminal fluid. The concentration of finasteride in seminal fluid ranges from undetectable (<1 ng/ml) to 21 ng/ml, which did not affect the concentration of circulating DHT in adult men.

Metabolism

Finasteride is actively metabolized in the liver through oxidative biotransformation. Two of the five metabolites of finasteride have weak activity and account for 20% of the total inhibition of 5α-reductase.

Excretion

The T_1/2 of finasteride averages 6 hours (4-12 hours). In men after a single oral dose of ¹⁴C-labeled finasteride, 39% of the administered dose is excreted by the kidneys in the form of metabolites (unchanged Finasteride is practically not excreted by the kidneys), 57% is excreted through the intestines.

Pharmacokinetics in special clinical cases

In old age, the rate of finasteride excretion decreases slightly. 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, it is 8 hours. These changes are not clinically significant; 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 excreted through the intestines. 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 on dialysis, no adjustment of the finasteride dose is required.

Pharmacokinetic parameters in patients with impaired liver function have not been sufficiently studied. Since Finasteride is actively metabolized in the liver, the drug should be used with caution in such patients.

Indications

• Treatment and reduction of the risk of progression of symptoms associated with BPH;
• Prevention of urological complications in patients with BPH:
  • Acute urinary retention;
  • Need for surgical interventions (TUR of the prostate and prostatectomy).

ICD codes

Dosage Regimen

The drug Fokusin^® Combi contains Tamsulosin 0.4 mg in modified-release capsules and Finasteride 5 mg in film-coated tablets.

The drug is intended for daily oral administration. The daily dose of the drug Fokusin^® Combi includes 1 modified-release capsule of tamsulosin 0.4 mg and 1 film-coated tablet of finasteride 5 mg.

Tamsulosin 0.4 mg modified-release capsules should be taken at the same time of day after a meal. The capsules should be swallowed whole, not broken or chewed, as this may disrupt the delayed release of the active substance.

Finasteride 5 mg film-coated tablets should be taken regardless of food at the same time.

Long-term use of the drug Fokusin^® Combi is necessary for the full therapeutic effect. If adverse reactions occur, the patient can be switched to finasteride monotherapy, but if the severity of BPH symptoms increases, it is recommended to return to the combination regimen.

Adverse Reactions

The frequency of adverse reactions is presented in accordance with the MedDRA classification: very common (>10%); common (≥1% and <10%); uncommon (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%); frequency unknown (cannot be estimated from the available data).

Adverse reactions during tamsulosin monotherapy

Nervous system disorders common – dizziness; uncommon – headache; rare – fainting.

Eye disorders frequency unknown – blurred vision, visual impairment.

Cardiac and vascular disorders uncommon – palpitations, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders uncommon – rhinitis; frequency unknown – epistaxis.

Gastrointestinal disorders uncommon – nausea, vomiting, constipation or diarrhea; frequency unknown – dry mouth.

Skin and subcutaneous tissue disorders uncommon – skin rash, itching, urticaria; rare – angioedema; very rare – Stevens-Johnson syndrome; frequency unknown – erythema multiforme, exfoliative dermatitis.

Reproductive system and breast disorders very rare – priapism; frequency unknown – ejaculation disorders, including retrograde ejaculation, absence of ejaculation.

General disorders and administration site conditions uncommon – asthenic syndrome.

During post-registration use of tamsulosin, in addition to the listed adverse reactions, atrial fibrillation, arrhythmia, tachycardia, and dyspnea have been noted (frequency of occurrence unknown).

In the post-registration period, cases of intraoperative floppy iris syndrome (a variant of intraoperative floppy iris syndrome) were also identified, which developed during cataract surgery and was associated with the use of tamsulosin.

Adverse reactions during finasteride monotherapy

Immune system disorders frequency unknown – hypersensitivity reactions, including swelling of the lips, tongue, pharynx, and face.

Psychiatric disorders common – decreased libido; frequency unknown – depression.

Cardiac and vascular disorders frequency unknown – palpitations.

Hepatobiliary disorders frequency unknown – increased activity of liver enzymes.

Skin and subcutaneous tissue disorders uncommon – rash; frequency unknown – urticaria, skin itching.

Reproductive system and breast disorders common – erectile dysfunction; uncommon – ejaculation disorder, breast enlargement and tenderness; frequency unknown – testicular pain, sexual dysfunction (ejaculation disorder and erectile dysfunction) which may persist after treatment is discontinued; male infertility and/or decreased quality of semen, which recovers after discontinuation of treatment.

Effect on the results of laboratory and instrumental studies

In patients taking Finasteride, a decrease in plasma PSA concentration is possible. A decrease in ejaculate volume was often noted.

In addition, during clinical studies and post-registration use, cases of breast cancer in men have been reported.

Adverse reactions during combination therapy

In patients receiving combination therapy (Finasteride and an alpha₁-blocker), the same adverse reactions have been described, occurring with the same frequency as with finasteride monotherapy and alpha₁-blocker monotherapy. The results obtained showed that erectile dysfunction and ejaculation disorder occurred more frequently with combination therapy, whereas disease progression (including increased severity of BPH symptoms or the need for surgical treatment) occurred more frequently with monotherapy.

Contraindications

• Orthostatic hypotension (including history);
• Severe hepatic insufficiency;
• Hereditary lactose intolerance, lactase deficiency or glucose/galactose malabsorption;
• Women;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to the active or auxiliary substances of the drug.

With caution the drug should be prescribed for liver diseases; presence of risk of obstructive uropathy; chronic renal failure (creatinine clearance <10 ml/min); planned cataract surgery; simultaneous use with potent or moderately active inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole, voriconazole).

Use in Pregnancy and Lactation

Fokusin^® Combi should not be taken by women.

During preclinical studies of intrauterine development in rats, the ability of type II 5α-reductase inhibitors (including finasteride) to cause developmental abnormalities of the external genitalia in male fetuses was proven. Many of these disorders, such as hypospadias observed in male rats exposed to finasteride in utero, are similar to disorders noted in male infants with genetically determined type II 5α-reductase deficiency. In this regard, pregnant women and women of reproductive age should avoid contact with crushed or damaged tablets containing Finasteride. To avoid contact with the semen of a man taking Finasteride, it is recommended to use a condom, as the drug penetrates into the semen.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic insufficiency.

The drug should be used with caution in patients with liver diseases.

Use in Renal Impairment

The drug should be used with caution in patients with chronic renal failure (CrCl <10 ml/min).

Pediatric Use

The use of the drug is contraindicated under the age of 18 years (efficacy and safety have not been established).

Special Precautions

Before starting treatment with Fokusin^® Combi, other conditions that present with the same symptoms as BPH should be ruled out in the patient. Before treatment and regularly during treatment, a digital rectal examination of the prostate should be performed and, if necessary, the plasma PSA level should be determined.

Patients with a large volume of residual urine and/or severe difficulty urinating should be examined to identify obstructive uropathy.

Precautions for the use of tamsulosin

As with the use of other α₁-adrenergic receptor blockers, a decrease in blood pressure may be observed during treatment with tamsulosin, which in rare cases may lead to fainting. Tamsulosin should be used with caution in patients predisposed to orthostatic hypotension. At the first signs of orthostatic hypotension (e.g., dizziness, weakness), the patient should be seated or laid down until the symptoms completely disappear.

When treating patients with severe renal impairment (CrCl less than 10 ml/min), caution should be exercised, as the effect of the drug in this population has not been studied.

If angioedema develops, as well as other immunological reactions, such as Stevens-Johnson syndrome, the use of the drug should be stopped immediately. The patient should be under medical supervision until this pathological condition is eliminated. Re-prescription of tamsulosin is not allowed.

Intraoperative floppy iris syndrome (a variant of small pupil syndrome) was observed during cataract surgery in some patients taking Tamsulosin. Intraoperative floppy iris syndrome may increase the incidence of complications during or after surgery. It is not recommended to initiate treatment with tamsulosin in patients scheduled for cataract surgery. Discontinuation of tamsulosin 1-2 weeks before surgery usually reduces the risk of complications; however, the benefit of discontinuing treatment is currently unknown. To prevent the development of intraoperative floppy iris syndrome, the surgeon and ophthalmologist should ascertain in the preoperative period whether the patient has previously taken or is continuing to take Tamsulosin. This will allow appropriate measures to be taken during the planning and course of surgery.

Tamsulosin should not be used in combination with potent inhibitors of the CYP3A4 isoenzyme in patients with the “poor metabolizer” phenotype for the CYP2D6 isoenzyme.

Caution should be exercised when taking tamsulosin with potent and moderate inhibitors of the CYP3A4 isoenzyme.

Precautions for the use of finasteride

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 PSA levels, based on plasma PSA levels and prostate biopsy results, it was found that the use of finasteride did not change the detection rate of prostate cancer and did not affect its incidence in patients taking Finasteride or placebo.

Before starting treatment and periodically during treatment with finasteride, it is recommended to perform a digital rectal examination and use other methods for diagnosing prostate cancer. The plasma PSA level is also determined to detect prostate cancer. In general, a baseline PSA level above 10 ng/ml indicates the need for further examination of the patient and a biopsy. If the PSA level is in the range of 4-10 ng/ml, examination of the patient is recommended. PSA levels in men with and without prostate cancer can significantly overlap, so in men with BPH, normal PSA values do not rule out prostate cancer, regardless of treatment with Finasteride. A baseline PSA level below 4 ng/ml also does not rule out prostate cancer.

Finasteride at a dose of 5 mg/day causes a decrease in plasma 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 the PSA level in patients with BPH receiving treatment with finasteride, because a decrease in PSA concentration does not rule out the presence of concomitant prostate cancer. This decrease can be predicted at any PSA level, although it may vary among patients. An analysis of PSA values in more than 3000 patients in the 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 treatment. This correction preserves the sensitivity and specificity of the PSA test and the ability to detect prostate cancer.

Any persistent increase in plasma PSA concentration in patients receiving treatment with finasteride requires careful examination to determine the cause, which may be non-compliance with the drug regimen.

Plasma PSA concentration correlates with the age of the patients and the volume of the prostate gland, and the prostate volume correlates with the age of the patient. When evaluating laboratory test results, it must be taken into account that in patients receiving treatment with finasteride, 5 mg, the plasma PSA level decreases. In most patients, a rapid decrease in PSA is observed during the first months of therapy, followed by its stabilization at a new baseline level.

Finasteride does not significantly reduce the percentage of free PSA (the ratio of free PSA to total PSA). This indicator is maintained even during treatment. 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

Cases of breast cancer have been noted during clinical trials and post-registration studies of finasteride use. The patient should be informed that any changes in breast tissue (e.g., lumps, pain, gynecomastia, nipple discharge) should be reported to a doctor immediately.

Use in pediatrics

The use of Fokusin^® Combi in children is contraindicated. The safety and efficacy of tamsulosin and finasteride in children and adolescents under 18 years of age have not been established.

Lactose

Finasteride tablets contain lactose monohydrate. Patients with rare hereditary lactose intolerance, lactase deficiency, or glucose/galactose malabsorption should not take this drug.

Effect on the ability to drive vehicles and machinery

No adverse effects of finasteride on the ability to drive vehicles and machinery have been reported. A similar effect of tamsulosin has not been studied. However, the possibility of dizziness, fainting, and visual disturbances in patients should be taken into account. They should temporarily refrain from driving vehicles and working with machinery with an increased risk of injury.

Overdose

No cases of simultaneous overdose with finasteride and tamsulosin have been described.

Tamsulosin

There are no clinical data on overdose with tamsulosin.

Symptoms theoretically, acute overdose with tamsulosin may cause severe arterial hypotension, which may lead to cardiovascular disorders.

Treatment to restore blood pressure and heart rate, the patient should be placed on their back with their legs elevated. If necessary, plasma-substituting drugs should be used and, depending on the patient’s condition, vasoconstrictor drugs. It is recommended to monitor renal function and carry out general measures aimed at maintaining vital functions. Dialysis is not indicated due to the significant binding of tamsulosin to plasma proteins. If the drug was taken recently, it is advisable to induce vomiting. After taking a large amount of the drug, gastric lavage should be performed and activated charcoal and an osmotic laxative (e.g., sodium sulfate) should be prescribed.

Finasteride

A single dose of finasteride 400 mg and multiple doses of up to 80 mg/day for 3 months were not associated with adverse reactions. In case of overdose, no specific treatment is required.

Drug Interactions

In vitro studies of hepatic microsomal fractions (a model of drug metabolism by the cytochrome P450 enzyme system) determined that Tamsulosin does not enter into pharmacokinetic interaction with finasteride during metabolism in the liver.

Interaction of tamsulosin with other drugs

No drug interaction was found with simultaneous use of tamsulosin with atenolol, enalapril or theophylline.

Concomitant use with cimetidine may cause an increase in the plasma concentration of tamsulosin, while furosemide causes its decrease. However, no dose adjustment of the drug is required, because the concentration of tamsulosin remains within the normal range.

In vitro, diazepam, propranolol, trichlormethiazide, chlormadinone, amitriptyline, diclofenac, glibenclamide, simvastatin and warfarin did not change the free fraction content of tamsulosin in human plasma. Also, Tamsulosin did not change the plasma content of the free fraction of diazepam, trichlormethiazide, propranolol and chlormadinone.

Diclofenac and warfarin may increase the elimination rate of tamsulosin. Concomitant use of tamsulosin and potent inhibitors of the CYP3A4 isoenzyme may cause an increase in the systemic exposure of tamsulosin. Simultaneous administration of tamsulosin with ketoconazole (a potent inhibitor of the CYP3A4 isoenzyme) led to an increase in the AUC and C_max of tamsulosin by 2.8 and 2.2 times, respectively.

Tamsulosin should not be used in combination with potent inhibitors of the CYP3A4 isoenzyme in patients with “poor metabolism” of the CYP2D6 isoenzyme.

Caution should be exercised when using tamsulosin concomitantly with potent or moderately active inhibitors of the CYP3A4 isoenzyme.

Concomitant use of tamsulosin hydrochloride with paroxetine, a potent CYP2D6 inhibitor, led to an increase in the C_max and AUC of tamsulosin by 1.3 and 1.6 times, respectively, but this increase is not clinically significant.

There is a possibility that concomitant use of other alpha₁-adrenergic blockers with tamsulosin may enhance the hypotensive effect.

Interaction of finasteride with other drugs

No clinically significant interaction of finasteride with other drugs has been identified. Finasteride is metabolized primarily by the CYP3A4 isoenzyme of the cytochrome P450 system, without significantly affecting 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 CYP3A4 isoenzyme will affect the plasma concentration of finasteride. However, given the established safety margins, it seems unlikely that an increase in the plasma concentration of finasteride associated with the concomitant use of such inhibitors will be of clinical significance. In clinical studies, the following drugs were tested: propranolol, digoxin, glibenclamide, warfarin, theophylline, phenazone, and no clinically significant interaction with finasteride was found.

Storage Conditions

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

Shelf Life

Shelf life – 2 years. Do not use after the expiration date stated on the packaging.

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.