Tadex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TADEX (TADEX)

Composition:

Active substance: tadalafil;

One film-coated tablet contains tadalafil 5 mg or 20 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, Opadry II 32K14834 (lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties.

for 5 mg: film-coated tablets, pink in color, round-shaped, with "S60" engraved on one side and smooth on the other;

for 20 mg: film-coated tablets, pink in color, capsule-shaped, with "S55" engraved on one side and smooth on the other.

Pharmacotherapeutic group. Agents for the treatment of erectile dysfunction. Tadalafil.

ATC code G04BE08.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes local release of nitric oxide, inhibition of PDE5 by tadalafil results in increased levels of cGMP in the corpus cavernosum. This leads to relaxation of smooth muscles and increased blood flow into the penile tissue, thereby producing an erection. Tadalafil does not act without sexual stimulation.

The inhibitory effect on cGMP concentrations in the corpus cavernosum is also observed in smooth muscles of the prostate, bladder, and their blood vessels supplying these organs. The resulting vascular relaxation leads to increased blood perfusion and may contribute to the reduction of symptoms of benign prostatic hyperplasia. These vascular effects may be complemented by inhibition of afferent nerves of the bladder and relaxation of smooth muscles of the prostate and bladder.

Pharmacodynamic effects.

In vitro studies have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in the smooth muscles of the corpus cavernosum, vascular and visceral smooth muscles, skeletal muscles, platelets, kidneys, lungs, and cerebellum. The effect of tadalafil on PDE5 is stronger than on other phosphodiesterases. The action of tadalafil on PDE5 is 10,000 times greater than its effect on PDE1, PDE2, and PDE4 enzymes present in the heart, brain, blood vessels, liver, leukocytes, skeletal muscles, and other organs. Tadalafil is 10,000 times more potent against PDE5 than PDE3, an enzyme present in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 plays a role in cardiac muscle contraction. Furthermore, tadalafil is approximately 700 times more potent against PDE5 than PDE6, an enzyme present in the retina responsible for phototransduction. Tadalafil is also 10,000 times more potent against PDE5 than PDE7, PDE8, PDE9, and PDE10.

Clinical efficacy and safety.

Tadalafil administered to healthy volunteers showed no significant difference compared to placebo in systolic and diastolic blood pressure in the supine position (mean maximum decrease 1.6/0.8 mm Hg, respectively), systolic and diastolic blood pressure in the standing position (mean maximum decrease 0.2/4.6 mm Hg, respectively), or significant changes in heart rate.

In a study assessing the effect of tadalafil on vision using the Farnsworth-Munsell 100 Hue color vision test, tadalafil did not impair color discrimination (blue/green). Clinical study data confirm the low affinity of tadalafil for PDE6 compared to PDE5. In all clinical trials, changes in color vision were rarely reported (< 0.1%).

Three clinical studies were conducted in men to evaluate the potential effect of tadalafil on spermatogenesis at doses of 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study), administered once daily. In two of the three studies, a clinically insignificant decrease in sperm count and concentration associated with tadalafil use was observed. These effects were not associated with changes in other parameters such as sperm motility, morphology, or serum follicle-stimulating hormone levels.

Erectile dysfunction.

Tadalafil in doses ranging from 2 mg to 100 mg was evaluated in 16 clinical trials involving 250 patients, including patients with erectile dysfunction of varying severity (mild, moderate, severe), different etiologies, age groups (21 to 86 years), and ethnic backgrounds. In most patients, erectile dysfunction had been present for at least 1 year. In primary efficacy studies, the improvement rate was 81% in the tadalafil group compared to 35% in the placebo group. Additionally, patients with erectile dysfunction of varying severity reported improvement during tadalafil treatment (success rate was 86%, 83%, and 72% in patients with mild, moderate, and severe erectile dysfunction, respectively, compared to 45%, 42%, and 19% in the placebo group). In primary efficacy studies, the success rate was 75% in the tadalafil group compared to 32% in the placebo group.

In a 12-week study involving 186 patients (142 received tadalafil, 44 received placebo) with secondary erectile dysfunction due to spinal cord injury, tadalafil demonstrated significant improvement in erectile function. The average success rate with tadalafil at doses of 10 mg or 20 mg (dose titration, as needed) was 48% in the tadalafil group compared to 17% in the placebo group.

Benign prostatic hyperplasia.

The use of tadalafil was studied in four 12-week clinical trials involving 1500 patients with symptoms of benign prostatic hyperplasia. In these trials, tadalafil 5 mg demonstrated improvement in patient status according to the International Prostate Symptom Score (IPSS) compared to placebo (IPSS improvement scores with tadalafil 5 mg were –4.8, –5.6, –6.1, and –6.3, compared to –2.2, –3.6, –3.8, and –4.2 with placebo). Improvement in patient status according to the International Prostate Symptom Score (IPSS) was observed as early as 1 week after treatment initiation. In one of the clinical trials, where tamsulosin 0.4 mg was included as an active comparator, IPSS improvement scores with tadalafil 5 mg, tamsulosin, and placebo were –6.3, –5.7, and –4.2, respectively.

In one of these studies, improvement in erectile function and reduction of benign prostatic hyperplasia symptoms were evaluated in patients with both conditions. Improvement in erectile function according to the International Index of Erectile Function and in IPSS scores was 6.5 and –6.1, respectively, with tadalafil 5 mg compared to 1.8 and –3.8 in the placebo group. The average percentage of successful sexual attempts per person in the study was 71.9% in the tadalafil 5 mg group and 48.3% in the placebo group.

Maintenance of the effect of tadalafil was evaluated in an additional open-label study, which showed that improvement in the International Prostate Symptom Score observed over 12 weeks was maintained for an additional year after treatment with tadalafil 5 mg.

Children.

One study was conducted in children with Duchenne muscular dystrophy (DMD), in which no confirmed evidence of efficacy was demonstrated. This study of tadalafil efficacy was a randomized, double-blind, placebo-controlled trial with three parallel groups involving 331 male children aged 7 to 14 years with DMD who were also receiving corticosteroid therapy. The study included a 48-week double-blind period during which patients were assigned to receive daily tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo. Tadalafil did not demonstrate efficacy in the primary endpoint regarding slowing the decline in walking speed, measured by changes in distance in the 6-minute walk test (6MWT). The change in mean distance in the 6MWT, calculated by the least squares method, at week 48 was 51.0 m in the placebo group compared to 64.7 m in the tadalafil 0.3 mg/kg group (p=0.307) and 59.1 m in the tadalafil 0.6 mg/kg group (p=0.538). Confirmed efficacy was also not demonstrated during repeated analyses of the study results. The overall safety results obtained in this study were generally consistent with the known safety profile of tadalafil and adverse events expected in the pediatric DMD population receiving corticosteroid therapy.

Pharmacokinetics.

Absorption. Tadalafil is well absorbed after oral administration. The mean maximum plasma concentration (Cmax) is reached on average 2 hours after administration. The absolute bioavailability of tadalafil after oral administration has not been established.

The rate and extent of tadalafil absorption are not affected by food intake; therefore, Tadex can be taken with or without food. The time of dosing (morning or evening) does not have a clinically significant effect on the rate and extent of absorption.

Distribution. The mean volume of distribution is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is protein-bound. Protein binding is not affected by impaired renal function.

Less than 0.0005% of the administered dose was detected in the semen of healthy volunteers.

Metabolism. Tadalafil is primarily metabolized by cytochrome P450 isoform 3A4 (CYP3A4). The main circulating metabolite is methylcatechol glucuronide. This metabolite has PDE5 activity 13,000 times lower than tadalafil. Therefore, the metabolite is not expected to exhibit clinical activity at observed concentrations.

Elimination. The oral clearance of tadalafil is 2.5 L/hour, and the mean elimination half-life is 17.5 hours in healthy volunteers. Tadalafil is eliminated primarily as inactive metabolites, mainly in feces (approximately 61% of the dose) and to a lesser extent in urine (approximately 36% of the dose).

Linearity/non-linearity of pharmacokinetics. The pharmacokinetics of tadalafil in healthy volunteers is linear with respect to time and dose. In the dose range of 2.5 to 20 mg, the area under the concentration-time curve (AUC) increases proportionally with dose. Steady-state plasma concentrations are achieved within 5 days with once-daily administration.

The pharmacokinetics of the drug is the same in patients with erectile dysfunction and in those without it.

Special patient groups.

Elderly patients. Healthy elderly volunteers (aged 65 years and older) had lower values of tadalafil clearance after oral administration, resulting in a 25% increase in exposure (AUC) compared to healthy volunteers aged 19–45 years. This age effect is not clinically significant and does not require dose adjustment.

Renal impairment. In clinical pharmacology studies using single doses of tadalafil (5–20 mg), the AUC of tadalafil was nearly doubled in patients with mild (creatinine clearance 51–80 mL/min) or moderate (creatinine clearance 31–50 mL/min) renal impairment, as well as in patients with end-stage renal disease on dialysis. In patients undergoing hemodialysis, Cmax was 41% higher than in healthy volunteers.

The effect of hemodialysis on tadalafil elimination is negligible.

Hepatic impairment. Exposure to tadalafil (AUC) in patients with mild to moderate hepatic impairment (Child-Pugh classes A and B) is comparable to that in healthy volunteers when a 10 mg dose is administered. Data on the safety of tadalafil administration in patients with severe hepatic impairment (Child-Pugh class C) are limited. There are no data on the use of tadalafil once daily in patients with hepatic impairment. The physician should carefully assess the individual benefit/risk ratio when prescribing Tadex once daily.

Patients with diabetes mellitus. Exposure to tadalafil (AUC) in patients with diabetes mellitus was approximately 19% lower than AUC values in healthy volunteers. This difference in exposure does not require dose adjustment.

Clinical characteristics.

Indications.

For 5 mg dosage. Treatment of erectile dysfunction in adult men. The drug is effective for the treatment of erectile dysfunction in the presence of sexual stimulation.

Treatment of symptoms of benign prostatic hyperplasia in adult men.

For 20 mg dosage. Treatment of erectile dysfunction in adult men. The drug is effective in the presence of sexual stimulation.

Tadex is not indicated for use in women.

Contraindications.

Hypersensitivity to tadalafil or to any other component of the drug.

Tadalafil is known to potentiate the hypotensive effect of nitrates. This is considered to be a consequence of the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, tadalafil is contraindicated in patients taking organic nitrates in any dosage form (see section "Interaction with other medicinal products and other forms of interaction").

Tadex should not be administered to men with cardiovascular diseases for whom sexual activity is inadvisable. Physicians should consider the potential cardiovascular risk of sexual activity in patients with pre-existing cardiovascular disorders.

The following groups of patients with cardiovascular diseases were not included in clinical trials; therefore, the use of tadalafil is contraindicated in these patients:

− patients who have had a myocardial infarction within the last 90 days;

− patients with unstable angina or angina occurring during sexual intercourse;

− patients with heart failure classified as NYHA class 2 or higher within the last 6 months;

− patients with uncontrolled arrhythmias, hypotension (< 90/50 mm Hg), or uncontrolled hypertension;

− patients who have had a stroke within the last 6 months.

Tadex is contraindicated in patients with loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether it was associated with prior use of PDE5 inhibitors (see section "Special precautions for use").

Concomitant use of PDE5 inhibitors, including tadalafil, with guanylate cyclase stimulators such as riociguat is contraindicated, as it may potentially lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Interaction studies were conducted for 10 mg and 20 mg dosages; data are provided below.

Clinically significant interaction with higher doses cannot be excluded if observed with lower doses of tadalafil (10 mg).

Effect of other medicinal products on tadalafil.

Cytochrome CYP450 inhibitors.

Tadalafil is primarily metabolized by CYP3A4. The selective CYP3A4 inhibitor ketoconazole (200 mg daily) increases the area under the concentration-time curve (AUC) of tadalafil (10 mg) by 2-fold and Cmax by 15% compared to tadalafil alone. Ketoconazole (400 mg daily) increases the area under the concentration-time curve (AUC) of tadalafil (20 mg) by 4-fold and Cmax by 22%. Ritonavir, a protease inhibitor (200 mg twice daily) that inhibits CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increases the area under the concentration-time curve (AUC) of tadalafil (20 mg) by 2-fold, without altering Cmax. Although specific interactions have not been studied, other protease inhibitors such as saquinavir and other CYP3A4 inhibitors such as erythromycin, clarithromycin, itraconazole, and grapefruit juice should be used with caution, as they are expected to increase plasma concentrations of tadalafil when co-administered (see section "Special precautions for use"). As a result, the frequency of adverse reactions may increase (see section "Adverse reactions").

Transporters.

The effect of transporters, such as P-glycoprotein, on tadalafil distribution is unknown. Therefore, there is a possibility of drug interaction mediated by inhibition of transporters.

Cytochrome CYP450 inducers.

The CYP3A4 inducer rifampicin reduces the AUC of tadalafil by 88% compared to the AUC when tadalafil (10 mg) is taken alone. Such a reduction in concentration may lead to decreased efficacy of tadalafil. Concomitant use of other CYP3A4 inducers such as phenobarbital, phenytoin, and carbamazepine may also reduce plasma concentrations of tadalafil.

Effect of tadalafil on other medicinal products.

Nitrates. In clinical studies, tadalafil (5 mg, 10 mg, 20 mg) was shown to potentiate the hypotensive effects of nitrates. Therefore, the use of Tadex in patients receiving treatment with organic nitrates in any form is contraindicated (see section "Contraindications").

If nitrates are medically necessary for a patient receiving tadalafil at any dose (2.5–20 mg) due to a life-threatening condition, at least 48 hours must elapse after the last dose of tadalafil before administering nitrates. In such cases, nitrate administration must be performed under close medical supervision with appropriate hemodynamic monitoring.

Antihypertensive agents (including calcium channel blockers).

When tadalafil (5 mg once daily or a single 20 mg dose) was co-administered with the α-adrenergic blocker doxazosin (4–8 mg daily), a significant potentiation of the hypotensive effect of the latter was observed. This effect lasted up to 12 hours and could manifest as individual symptoms, including dizziness. This combination is not recommended for use (see section "Special precautions for use").

In interaction studies involving a limited number of healthy volunteers, the above effects were not reported with concomitant use of alfuzosin or tamsulosin. Tadalafil should be prescribed with caution to patients receiving treatment with any α-adrenergic blockers, especially elderly individuals. Treatment should be initiated with the lowest dose, with gradual dose escalation. Clinical pharmacodynamic studies evaluated the potential of tadalafil to potentiate the hypotensive effects of major antihypertensive agents. Major drug classes were studied: calcium channel blockers (amlodipine), angiotensin-converting enzyme inhibitors (enalapril), β-adrenergic blockers (metoprolol), thiazide diuretics (bendroflumethiazide), and angiotensin II receptor blockers (alone and in combination with thiazide diuretics, calcium channel blockers, β-adrenergic blockers, and/or α-adrenergic blockers). Tadalafil (10 mg dose, except for interaction studies with angiotensin II receptor blockers and amlodipine, where the 20 mg dose was studied) did not show significant interaction with the above-mentioned drug classes. In another clinical pharmacology study, concomitant use of tadalafil (20 mg) with multiple antihypertensive agents (up to four) was investigated. In patients taking multiple antihypertensive drugs, blood pressure changes depended on the level of blood pressure control. Thus, in patients with well-controlled hypertension, the reduction in blood pressure was minimal and comparable to that in healthy volunteers. In patients with poorly controlled arterial hypertension, a greater reduction in blood pressure was observed, although in most patients this reduction did not lead to hypotensive symptoms. In patients receiving concomitant therapy with antihypertensive agents, administration of tadalafil at a dose of 20 mg may lead to a reduction in blood pressure, which (except in the case of concomitant use with α-adrenergic blockers) is generally minimal and clinically insignificant. Analysis of phase III clinical trial data did not reveal differences in adverse reactions between patients receiving tadalafil with concomitant antihypertensive therapy and those receiving tadalafil alone. Nevertheless, appropriate recommendations regarding possible reduction in blood pressure should be provided to patients treated with hypotensive agents and Tadex.

Riociguat.

Preclinical studies revealed an additive hypotensive effect when PDE5 inhibitors were used concomitantly with riociguat. In clinical studies, riociguat was shown to enhance the hypotensive action of PDE5 inhibitors. There was no evidence of beneficial clinical effect of this combination in the studied population. Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated (see section "Contraindications").

5-α-reductase inhibitors.

In a clinical study comparing concomitant use of tadalafil 5 mg and finasteride 5 mg versus placebo and finasteride 5 mg for relief of symptoms of benign prostatic hyperplasia, no new adverse reactions were identified. However, since drug interaction studies to evaluate the effects of tadalafil and 5-α-reductase inhibitors have not been conducted, tadalafil should be prescribed with caution to patients receiving treatment with 5-α-reductase inhibitors.

CYP1A2 substrates (e.g., theophylline).

In a clinical pharmacology study, no pharmacokinetic interaction was observed when tadalafil (10 mg) was administered with theophylline (a non-selective phosphodiesterase inhibitor). The only pharmacodynamic effect was a slight increase in heart rate. The possibility of this effect should be considered when tadalafil and theophylline are used concomitantly, although it is minor and not clinically significant.

Ethinylestradiol and terbutaline.

Tadalafil increased the bioavailability of oral formulations containing ethinylestradiol. Such an increase in bioavailability may be expected with concomitant use of terbutaline (oral), although the clinical consequences of this combination are unknown.

Alcohol.

Alcohol (mean maximum concentration 0.08%) did not affect the concomitant use of tadalafil (10 or 20 mg). No changes in tadalafil concentration were observed during the subsequent 3 hours after simultaneous intake of alcohol with tadalafil. Alcohol was administered to achieve maximum absorption (on an empty stomach after overnight fasting and without food intake for 2 hours after alcohol administration). Administration of tadalafil (20 mg) did not result in a statistically significant reduction in mean blood pressure values when alcohol was consumed (0.7 g/kg or approximately 180 ml of 40% alcohol (vodka) in an 80 kg man), although postural dizziness and orthostatic hypotension were observed in some patients. Administration of tadalafil with lower doses of alcohol (0.6 g/kg) did not cause hypotension, and dizziness occurred at the same frequency as with alcohol alone. The effect of alcohol on cognitive function was not enhanced by concomitant administration of tadalafil (10 mg).

Medicinal products metabolized by cytochrome P450.

Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medicinal products metabolized by CYP450 isoenzymes. Clinical studies have demonstrated that tadalafil does not inhibit or induce CYP450 isoenzymes, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9, and CYP2C19.

CYP2C9 substrates (e.g., R-warfarin).

Tadalafil (10 mg and 20 mg doses) had no clinically significant effect on exposure (AUC) of S-warfarin or R-warfarin (CYP2C9 substrates), nor did it affect warfarin-induced prothrombin time.

Aspirin.

Tadalafil (10 mg and 20 mg doses) did not potentiate the increase in bleeding time caused by acetylsalicylic acid.

Antidiabetic medicinal products.

Specific interaction studies of tadalafil with antidiabetic medicinal products have not been conducted.

Special precautions for use.

Before initiating treatment with Tadex.

Before prescribing Tadex, the physician should take a medical history and perform a physical examination of the patient, identify potential causes of erectile dysfunction and benign prostatic hyperplasia, and determine an appropriate treatment regimen.

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of patients, as there is a certain degree of cardiovascular risk associated with sexual activity. Tadalafil has a vasodilatory effect that may lead to a slight and transient decrease in blood pressure (see section "Pharmacological properties") and may potentiate the hypotensive effect of nitrates (see section "Contraindications").

Before initiating tadalafil therapy for symptoms of benign prostatic hyperplasia, patients should be evaluated to exclude the possibility of prostate carcinoma and their cardiovascular status should be carefully assessed (see section "Contraindications").

Assessment of erectile dysfunction should include identification of potential underlying causes and appropriate medical evaluation prior to treatment. It is unknown whether Tadex is effective in patients who have undergone pelvic surgery or nerve-sparing radical prostatectomy.

Cardiovascular system.

During the post-marketing period and/or clinical trials, serious adverse events involving the cardiovascular system have been reported, including myocardial infarction, sudden cardiac death, unstable angina, ventricular arrhythmia, cerebrovascular accidents, transient ischemic attack, chest pain, palpitations, and tachycardia. Most patients who experienced such adverse reactions had pre-existing cardiovascular risk factors. However, it is currently not possible to definitively determine whether the aforementioned events are related to these risk factors, the use of Tadex, sexual activity, or a combination of these or other factors.

In patients receiving concomitant antihypertensive therapy, tadalafil may enhance the reduction in blood pressure. If daily treatment with Tadex is initiated, consideration should be given to the clinical need for adjusting the dose of antihypertensive therapy.

Tadex should be prescribed with caution in patients taking α1-blockers, as in some patients, concomitant use of these drugs may lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction"). Combination of tadalafil with doxazosin is not recommended.

Vision.

Cases of visual disturbances and non-arteritic anterior ischemic optic neuropathy (NAION) have been reported during treatment with tadalafil and other PDE5 inhibitors. Analysis of observational study data has shown an increased risk of acute NAION in men with erectile dysfunction following the use of tadalafil or other PDE5 inhibitors. Since this risk may occur in all patients using tadalafil, physicians should inform patients about the necessity to immediately discontinue tadalafil and seek medical help in case of sudden vision loss (see section "Contraindications").

Worsening or sudden hearing loss.

Cases of sudden hearing loss have been reported following the use of tadalafil. Regardless of the presence of other risk factors (such as age, diabetes, hypertension, or history of hearing loss), patients should be informed about the need to discontinue tadalafil and seek medical help in case of sudden hearing loss or worsening of hearing.

Renal and hepatic impairment.

Daily use of Tadex is not recommended in patients with severe renal impairment due to increased tadalafil exposure (AUC), limited clinical experience, and poor ability to clear tadalafil via dialysis.

Clinical data on the use of Tadex for daily administration in patients with severe hepatic impairment (Child–Pugh class C) are limited.

Daily use of the drug for the treatment of erectile dysfunction and benign prostatic hyperplasia has not been evaluated in patients with hepatic insufficiency. Before prescribing Tadex, the physician should carefully assess the individual benefit/risk ratio of therapy.

Priapism and anatomical deformity of the penis.

If a patient experiences an erection lasting 4 hours or longer, he should seek immediate medical help. Without prompt treatment of priapism, damage to penile tissue and permanent loss of erectile function may occur.

Tadex should be prescribed with caution in patients with anatomical deformities of the penis (such as penile angulation, cavernous fibrosis, or Peyronie’s disease) or in patients with conditions that may predispose to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

Concomitant use with CYP3A4 inhibitors.

Tadex should be prescribed with caution in patients taking CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), as co-administration with tadalafil results in increased tadalafil exposure (AUC) (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with other medicinal products for erectile dysfunction.

The safety and efficacy of using Tadex in combination with other PDE5 inhibitors or other erectile dysfunction treatments have not been studied. Therefore, patients should be informed not to take Tadex in such combinations.

Lactose.

The product contains lactose monohydrate and should not be used by patients with rare hereditary forms of galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency.

Sodium.

5 mg dosage: this medicinal product contains less than 0.3 mmol (or 6 mg)/dose of sodium.

20 mg dosage: this medicinal product contains less than 1.1 mmol (or 26 mg)/dose of sodium.

Caution should be exercised when administering to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Tadex is not indicated for use in women.

Fertility. In two clinical studies, no adverse effects on fertility were expected in humans, although decreased sperm concentration was observed in some individual men.

Ability to influence the speed of reactions when driving vehicles or operating machinery.

The effect of Tadex on the ability to drive or operate machinery is minor. Although the frequency of reports of dizziness during placebo-controlled clinical trials and clinical trials with tadalafil was similar, patients should know how Tadex affects them before driving a vehicle or operating machinery.

Method of Administration and Dosage.

For oral use. Tadex tablets should be taken with the recommended content of active ingredient.

Erectile dysfunction in adult men.

The recommended dose is 10 mg* taken prior to anticipated sexual activity, regardless of food intake. For patients who do not achieve the desired effect with tadalafil 10 mg*, a dose of 20 mg may be used.

The drug can be taken 30 minutes before sexual activity. The efficacy of tadalafil lasts up to 36 hours after dose administration.

The maximum recommended frequency of administration is once daily.

Tadalafil 10 mg* and 20 mg are intended for use prior to anticipated sexual activity and are not recommended for daily use.

If frequent use of tadalafil (at least twice a week) is anticipated, a daily regimen with lower doses of Tadex may be more appropriate, based on patient preference and physician decision. For such patients, the recommended dose is 5 mg once daily, taken approximately at the same time each day. The dose may be reduced to 2.5 mg once daily* (using tadalafil preparations with appropriate dosage due to inability to split the tablet), depending on individual tolerance. The appropriateness of long-term daily use should be periodically reviewed.

Benign prostatic hyperplasia in adult men (only 5 mg tadalafil).

For daily use, the recommended dose is 5 mg once daily, taken approximately at the same time each day, regardless of food intake. For treatment of adult men with erectile dysfunction and symptoms of benign prostatic hyperplasia, the recommended dose for daily use is 5 mg once daily, taken approximately at the same time each day. For patients intolerant to tadalafil 5 mg daily in the treatment of benign prostatic hyperplasia, alternative therapy should be considered, as the efficacy of tadalafil 2.5 mg once daily* for treatment of benign prostatic hyperplasia has not been evaluated.

Special patient groups.

Elderly men. Dose adjustment is not required.

Men with renal impairment. Dose adjustment is not required in patients with mild or moderate renal impairment. For patients with severe renal impairment, the maximum recommended dose is 10 mg* when using tablets of appropriate strength. Daily administration of tadalafil 2.5 mg* or 5 mg is not recommended for the treatment of patients with severe renal impairment and benign prostatic hyperplasia or erectile dysfunction (see sections "Special precautions for use" and "Pharmacological properties").

Men with hepatic impairment. For treatment of erectile dysfunction, the recommended dose of tadalafil is 10 mg* prior to anticipated sexual activity, independent of food intake. Clinical data on the safety of tadalafil in patients with severe hepatic impairment (Child-Pugh class C) are limited; if prescribed, the physician should carefully assess the individual benefit/risk ratio. There are no data on the use of tadalafil at doses above 10 mg* in patients with hepatic impairment. There are no data on the use of tadalafil 2.5 mg* or 5 mg once daily in patients with hepatic impairment; therefore, if prescribed, the physician should carefully assess the individual benefit/risk ratio of prescribing Tadex 5 mg once daily.

Men with diabetes mellitus. Dose adjustment is not required.

Children. The drug is not intended for use in children.

Special precautions for disposal. Unused medication or waste should be disposed of in accordance with current regulatory requirements.

*Tadalafil preparations should be used at the appropriate dosage strength.

Children.

The drug is not intended for use in children (under 18 years of age).

Overdose.

Symptoms. In healthy volunteers, single doses of tadalafil up to 500 mg and multiple daily doses up to 100 mg were associated with adverse effects similar to those observed with lower doses of the drug.

Treatment. In case of overdose, standard symptomatic treatment should be applied if necessary. Hemodialysis has negligible effect on tadalafil elimination.

Adverse reactions.

Summary of the medicinal product's safety profile.

The most commonly reported adverse effects during treatment of erectile dysfunction or benign prostatic hyperplasia were headache, dyspepsia, back pain, and myalgia, with incidence increasing with higher doses of the drug. Adverse reactions were generally transient and mild to moderate in severity. Most cases of headache with daily administration of tadalafil at doses of 2.5 mg and 5 mg occurred within the first 10–30 days after initiation of treatment.

Tabulated adverse reaction data.

The table below presents data on adverse reactions from spontaneous reports and placebo-controlled clinical trials (in total, 8022 patients received tadalafil and 4422 patients received placebo), involving on-demand and daily use of tadalafil for treatment of erectile dysfunction and daily use for treatment of benign prostatic hyperplasia.

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 (frequency cannot be estimated from the available data).

1 Most of the patients who experienced such adverse reactions had cardiovascular risk factors. (See section "Special precautions").

2 Adverse reactions from post-marketing surveillance not observed during other clinical trials.

3 More frequently reported when tadalafil was used concomitantly with antihypertensive agents.

Isolated adverse reactions. A slightly higher frequency of ECG abnormalities, primarily sinus bradycardia, was reported in patients receiving tadalafil once daily compared to patients receiving placebo. Most of these ECG abnormalities were not associated with clinical adverse reactions.

Special patient groups. Data on the use of tadalafil in patients aged 65 years and older during clinical trials, both for the treatment of erectile dysfunction and for the treatment of benign prostatic hyperplasia, are limited. In clinical trials of on-demand tadalafil (20 mg dose) for the treatment of erectile dysfunction, diarrhea occurred more frequently in patients aged over 65 years. In clinical trials of tadalafil 5 mg once daily for the treatment of benign prostatic hyperplasia, dizziness and diarrhea were more frequently observed in patients aged 75 years and older.

Shelf life. 3 years.

Storage conditions. Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.

Packaging.

For 5 mg: 14 film-coated tablets in a blister. One blister per cardboard box.

For 20 mg: 1 or 4 film-coated tablets in a blister. One blister per cardboard box.

Prescription status. Prescription only.

Manufacturer. Sunshine Lake Pharma Co., Ltd.

Manufacturer's address and site of operations.
No.1, Norsen Industry Road, Norsen Industry Park of Song Shan Lake, Dongguan, Guangdong 523808, China.

Marketing Authorization Holder. LLC "Decanta".

Address of the Marketing Authorization Holder.
2, Zarichna Street, Building 3, Office 92, Kyiv, Ukraine, 02132. Tel.: +380-98-956-75-00.