ARISTA

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

Composition:

Active substance: tadalafil;

One film-coated tablet contains tadalafil 20 mg;

Excipients: lactose monohydrate; sodium croscarmellose; sodium lauryl sulfate; hydroxypropylcellulose; microcrystalline cellulose; magnesium stearate; film coating Opadry II Yellow 31K32498 (lactose monohydrate; hypromellose; titanium dioxide (E 171); iron oxide yellow (E 172); triacetin; iron oxide black (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, capsule-shaped, film-coated tablets.

Pharmacotherapeutic group.
Agents for the treatment of erectile dysfunction. 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 penile tissues, thereby producing an erection. Tadalafil has no effect in the absence of sexual stimulation.

The inhibitory effect on cGMP concentration in the corpus cavernosum is also observed in smooth muscles of the prostate, urinary bladder, and their blood vessels supplying these organs. The resulting vascular relaxation increases blood perfusion and may contribute to the reduction of symptoms of benign prostatic hyperplasia. These vascular effects may be complemented by inhibition of afferent nerve activity in the urinary bladder and relaxation of smooth muscles in 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 activity of tadalafil against PDE5 is 10,000 times greater than its effect on PDE1, PDE2, and PDE4, which are present in the heart, brain, blood vessels, liver, leukocytes, skeletal muscles, and other organs. Tadalafil is 10,000 times more potent against PDE5 than against 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 against PDE6, an enzyme present in the retina and responsible for phototransduction. Tadalafil is also 10,000 times more potent against PDE5 than against PDE7, PDE8, PDE9, and PDE10.

Clinical efficacy and safety.

In clinical trials, tadalafil demonstrated statistically significant improvement in erectile function, efficacy lasting up to 36 hours, and onset of effect as early as 16 minutes after dosing compared to placebo (with on-demand use of tadalafil).

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

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 trial data confirm the low affinity of tadalafil for PDE6 compared to PDE5. During 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.

The effect of tadalafil at doses ranging from 2 mg to 100 mg was evaluated in 16 clinical trials involving 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 one year. In primary efficacy studies, the improvement rate was 81% in the tadalafil group compared to 35% in the placebo group. Additionally, improvement was observed in patients with erectile dysfunction of all severity levels during tadalafil treatment (success rates were 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 study involving patients with secondary erectile dysfunction due to spinal cord injury, tadalafil significantly improved erectile function, with an average success rate of 48% in the group receiving 10 mg or 20 mg (dose titration, on-demand use) compared to 17% in the placebo group.

Special patient groups.

Pediatric population.

One study was conducted in children with Duchenne muscular dystrophy (DMD), in which no confirmed evidence of efficacy was demonstrated. This tadalafil efficacy study was randomized, double-blind, placebo-controlled, with three parallel groups involving male children aged 7 to 14 years with DMD who were concurrently receiving corticosteroid therapy. The study included a 48-week double-blind period during which patients were assigned to daily tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo. Tadalafil did not demonstrate efficacy on the primary endpoint of slowing the decline in walking speed, measured by change in distance in the 6-minute walk test (6MWT). The least squares mean change in 6MWT distance 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 in repeated analyses of this study. The overall safety results from 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 dosing. The absolute bioavailability of tadalafil after oral administration has not been determined.

The rate and extent of tadalafil absorption are not affected by food intake; therefore, it can be taken with or without food. The time of dosing (morning or evening) has no 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 is bound to plasma proteins. Protein binding is not affected by renal impairment. Less than 0.0005% of the administered dose was detected in the semen of healthy volunteers.

Metabolism.

Tadalafil is primarily metabolized by cytochrome P450 3A4 (CYP3A4) isoenzyme. The major circulating metabolite is methylcatechol glucuronide. This metabolite has 13,000 times less activity against PDE5 than tadalafil. Therefore, the metabolite is not expected to have clinical activity at observed concentrations.

Excretion.

The oral clearance of tadalafil is 2.5 L/h, and the mean elimination half-life is 17.5 hours in healthy subjects. Tadalafil is eliminated predominantly as inactive metabolites, mainly via the intestine (approximately 61% of the dose) and to a lesser extent via the kidneys (approximately 36% of the dose).

Tadalafil pharmacokinetics in healthy volunteers are linear and time-proportional. Over the dose range of 2.5 mg to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentrations are achieved within 5 days with once-daily dosing.

Tadalafil pharmacokinetics are similar in patients with erectile dysfunction and in those without.

Special patient groups.

Elderly patients.

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

Patients with renal impairment.

In clinical pharmacology studies using single doses of tadalafil (5–20 mg), tadalafil AUC 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.

Patients with hepatic impairment.

Tadalafil AUC in patients with mild to moderate hepatic impairment (Child-Pugh classes A and B) is comparable to exposure in healthy volunteers at a 10 mg dose. Safety data for tadalafil use in patients with severe hepatic impairment (Child-Pugh class C) are limited. If the medicinal product is used, the physician should carefully evaluate the individual benefit/risk ratio. There are no data on use at doses above 10 mg in patients with hepatic impairment.

Patients with diabetes mellitus.

Tadalafil AUC in patients with diabetes mellitus was approximately 19% lower than in healthy volunteers. This difference in exposure does not require dose adjustment.

Clinical characteristics.

Indications.

Treatment of erectile dysfunction in adult men.

The medicinal product is effective in the presence of sexual stimulation.

The medicinal product is not indicated for use in women.

Contraindications.

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

During clinical studies, tadalafil was found to potentiate the hypotensive effect of nitrates. This is considered to be a consequence of the combined effect of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, tadalafil is contraindicated in patients taking organic nitrates in any dosage form.

The medicinal product should not be used in men with cardiovascular disorders for whom sexual activity is inadvisable. Physicians should consider the potential cardiovascular risk associated with sexual activity in patients with pre-existing cardiovascular disease.

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

• patients who have had 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.

The medicinal product is contraindicated in patients who have experienced unilateral vision loss due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this was associated with prior use of PDE5 inhibitors or not.

Concomitant use of PDE5 inhibitors, including tadalafil, with guanylate cyclase stimulators such as riociguat is contraindicated, as this may potentially lead to symptomatic hypotension.

Interaction with other medicinal products and other forms of interaction.

Interaction studies were conducted with 10 mg and 20 mg doses; data are provided below. Clinically significant interactions with higher doses cannot be excluded if such interactions were observed with lower doses of tadalafil (10 mg).

Effect of other medicinal products on tadalafil.

Cytochrome CYP450 inhibitors.

Tadalafil is predominantly metabolized by CYP3A4. The selective CYP3A4 inhibitor ketoconazole (at a dose of 200 mg daily) increases the AUC of tadalafil (10 mg dose) by 2-fold and Cmax by 15% compared to tadalafil alone. Ketoconazole (at a dose of 400 mg daily) increases the AUC of tadalafil (20 mg dose) by 4-fold and Cmax by 22%. Ritonavir, a protease inhibitor (200 mg twice daily) that inhibits CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increases the AUC of tadalafil (20 mg dose) by 2-fold without changing 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 used concomitantly. 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 potential for drug interactions mediated by transporter inhibition.

Cytochrome CYP450 inducers.

The CYP3A4 inducer rifampicin reduces the AUC of tadalafil by 88% compared to tadalafil alone (10 mg dose). This 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 doses) was found to potentiate the hypotensive effects of nitrates. Therefore, the use of tadalafil in patients receiving treatment with organic nitrates in any form is contraindicated (see section "Contraindications"). In a clinical study involving patients who received tadalafil 20 mg daily for 7 days and sublingual nitroglycerin 0.4 mg (at varying time intervals), this interaction lasted more than 24 hours and was not observed after 48 hours following the last dose of tadalafil. If nitrates are medically necessary for a patient receiving tadalafil at any dose (2.5–20 mg), at least 48 hours must elapse after the last dose of tadalafil before administering nitrates. In such cases, nitrate administration must be performed under medical supervision with appropriate hemodynamic monitoring.

Antihypertensive agents (including calcium channel blockers).

Significant potentiation of the hypotensive effect of the α-adrenoceptor blocker doxazosin (4–8 mg daily) was observed when co-administered with tadalafil (5 mg once daily or single 20 mg dose). This effect lasts up to 12 hours and may 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 used with caution in patients receiving treatment with α-adrenoceptor blockers, especially elderly individuals. Treatment should be initiated at the lowest dose and gradually increased.

Clinical pharmacodynamic studies evaluated the potential of tadalafil to potentiate the hypotensive effects of major antihypertensive agents. Major drug classes were investigated: calcium channel blockers (amlodipine), angiotensin-converting enzyme inhibitors (enalapril), β-adrenoceptor blockers (metoprolol), thiazide diuretics (bendroflumethiazide), and angiotensin II receptor blockers (alone and in combination with thiazide diuretics, calcium channel blockers, β-adrenoceptor blockers, and/or α-adrenoceptor 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 agents, blood pressure changes depended on the level of blood pressure control. Thus, in patients with well-controlled hypertension, the blood pressure reduction was minimal and comparable to that in healthy volunteers. In patients with poorly controlled hypertension, greater blood pressure reduction was observed, although in most patients this reduction was not accompanied by hypotensive symptoms. In patients receiving concomitant therapy with antihypertensive agents, tadalafil at a dose of 20 mg may cause blood pressure reduction, which (except in the case of concomitant use with α-adrenoceptor blockers) is minimal and clinically insignificant. Analysis of phase 3 clinical trial data did not reveal differences in adverse reactions between patients receiving tadalafil with concomitant antihypertensive agents and those receiving tadalafil alone. Nevertheless, appropriate counseling regarding the potential for blood pressure reduction should be provided to patients receiving antihypertensive agents and tadalafil.

Riociguat.

Preclinical studies revealed an additive hypotensive effect when PDE5 inhibitors were used concomitantly with riociguat. Clinical studies demonstrated that riociguat enhances 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 observed. However, since a dedicated drug interaction study to evaluate the effects of tadalafil and 5-α-reductase inhibitors has not been conducted, tadalafil should be used with caution in patients receiving treatment with 5-α-reductase inhibitors.

CYP1A2 substrates (e.g., theophylline).

In a clinical pharmacology study, no pharmacokinetic interaction was observed between tadalafil (10 mg dose) and theophylline (a non-selective phosphodiesterase inhibitor). The only pharmacodynamic effect was a slight increase in heart rate (3.5 beats/min). The possibility of this effect should be considered when tadalafil and theophylline are used concomitantly, although it is 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, although the clinical consequences of this combination are unknown.

Alcohol.

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

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) did not show clinically significant effects on the AUC of S-warfarin or R-warfarin (CYP2C9 substrates) and had no effect on prothrombin time induced by warfarin.

Acetylsalicylic acid.

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 between tadalafil and antidiabetic medicinal products have not been conducted.

Special precautions for use.

Before prescribing the medicinal product, the physician should collect a medical history and perform a physical examination of the patient, identify potential causes of erectile dysfunction, and prescribe an appropriate treatment course.

Before initiating any treatment for erectile dysfunction, the patient's cardiovascular status should be assessed, since there is a certain degree of cardiovascular risk associated with sexual activity. Tadalafil produces a vasodilatory effect, which may lead to a slight and transient decrease in blood pressure (see section "Pharmacological properties") and potentiation of the hypotensive effect of nitrates (see section "Contraindications").

Evaluation of erectile dysfunction should include identification of potential underlying causes and their appropriate management following adequate medical evaluation. It is unknown whether tadalafil is effective in patients who have undergone pelvic surgery or radical prostatectomy without nerve-sparing.

Cardiovascular effects.

During clinical trials and post-marketing use of tadalafil, serious adverse events related to the cardiovascular system have been reported, including myocardial infarction, sudden cardiac death, unstable angina, ventricular arrhythmia, cerebrovascular accidents, transient ischemic attacks, 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 these events are related to the risk factors, the use of tadalafil, sexual activity, or a combination of these or other factors.

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

Effects on vision.

Cases of visual disturbances, including central serous chorioretinopathy (CSC) and non-arteritic anterior ischemic optic neuropathy (NAION), have been reported during the use of tadalafil and other PDE5 inhibitors. In most cases of CSC, symptoms resolved spontaneously after discontinuation of tadalafil. 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 increased risk may occur in all patients taking tadalafil, physicians should inform patients of the need to discontinue tadalafil and seek immediate medical attention in case of sudden vision loss (see section "Contraindications").

Effects on hearing.

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 advised to discontinue tadalafil and seek immediate medical attention in case of sudden hearing decrease or hearing loss.

Risk of priapism.

Patients experiencing erections lasting 4 hours or longer should seek immediate medical attention. If priapism is not treated promptly, it may lead to penile tissue damage and long-term loss of potency.

The medicinal product should be used with caution in patients with anatomical penile deformities (such as angulation, cavernosal fibrosis, or Peyronie's disease) or in patients with conditions that may predispose to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

Use in patients with hepatic impairment.

Data on the safety of tadalafil use in patients with severe hepatic impairment (Child–Pugh class C) are limited. When prescribing the medicinal product to such patients, a careful individual assessment of the benefits and risks of therapy should be performed.

Concomitant use with CYP3A4 inhibitors.

The medicinal product should be used with caution in patients taking CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), as concomitant use with tadalafil results in increased tadalafil concentrations (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 tadalafil in combination with other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied; therefore, such combinations are not recommended.

Warnings about excipients.

The medicinal product contains lactose and therefore should not be used in patients with rare hereditary conditions of galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency.

The medicinal product contains less than 1 mmol (23 mg) of sodium per 1 dose, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

The medicinal product is not indicated for use in women.

Fertility.

Two clinical studies have shown that fertility impairment is not expected in humans, although decreased sperm concentration has been observed in some individual men.

Ability to affect reaction speed when driving or operating machinery.

The effect of tadalafil on the ability to drive or operate machinery is minimal. Although the frequency of reports of dizziness during placebo-controlled clinical trials and clinical trials with tadalafil was similar, patients should be aware of their individual response to the medicinal product before driving or operating machinery.

Method of Administration and Dosage.

For oral use. Tadalafil tablets should be taken with the recommended amount of active ingredient.

Adult Men.

The recommended dose is 10 mg taken prior to anticipated sexual activity, regardless of food intake. For patients in whom 10 mg of tadalafil does not produce the desired effect, a dose of 20 mg may be used.

The medicinal product should be taken at least 30 minutes before anticipated sexual activity.

The efficacy of tadalafil lasts up to 36 hours after dosing.

The maximum recommended frequency of administration is once per day.

Tadalafil in doses of 10 mg and 20 mg is intended for use prior to anticipated sexual activity and is not recommended for daily use.

In cases of anticipated frequent use of the medicinal product (at least twice a week), a daily regimen with lower doses of tadalafil may be more appropriate based on patient preference and physician's decision. For such patients, the recommended dose is 5 mg once daily, taken at approximately the same time each day. The dose may be reduced to 2.5 mg once daily based on individual tolerance to the drug. The appropriateness of long-term daily use should be periodically reviewed.

Special Patient Groups.

Elderly Men

No dose adjustment is required.

Men with Renal Impairment

No dose adjustment is required for 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.

Men with Hepatic Impairment

The recommended dose of tadalafil is 10 mg prior to anticipated sexual activity, regardless of food intake.

Clinical safety data for tadalafil administration 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 at doses of 2.5–5 mg once daily in patients with hepatic impairment; therefore, if prescribed, the physician should carefully assess the individual benefit/risk ratio of administering tadalafil at 2.5–5 mg once daily.

Men with Diabetes Mellitus

No dose adjustment is 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.

Children.

The medicinal product 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 in patients up to 100 mg per day resulted in adverse reactions similar to those observed with lower doses of tadalafil.

Treatment.

In case of overdose, symptomatic and supportive therapy should be administered. Hemodialysis has minimal effect on tadalafil elimination.

Adverse Reactions.

The most commonly reported adverse effects during treatment of erectile dysfunction were headache, dyspepsia, back pain, and myalgia, the frequency of which increased with higher doses of tadalafil. Adverse reactions were generally transient and mild to moderate in severity. Most cases of headache associated with daily tadalafil administration occurred within the first 10–30 days of treatment initiation.

The following classification was used to assess the frequency of adverse reactions: 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), and not known (frequency cannot be estimated from available data).

Immune system disorders:

Uncommon – hypersensitivity reactions; rare – angioedema².

Nervous system disorders:

Common – headache; uncommon – dizziness; rare – cerebrovascular disorders¹ (including hemorrhagic events) and transient ischemic attacks¹, syncope, migraine², seizures, transient global amnesia.

Eye disorders:

Uncommon – blurred vision, eye pain; rare – visual field defects, eyelid edema, conjunctival hyperemia, non-arteritic anterior ischemic optic neuropathy (NAION)², retinal vein occlusion²; not known – central serous chorioretinopathy.

Ear and labyrinth disorders:

Uncommon – tinnitus; rare – sudden hearing loss.

Cardiovascular disorders:

Common – flushing; uncommon – arterial hypotension³, arterial hypertension, tachycardia, palpitations; rare – myocardial infarction, unstable angina², ventricular arrhythmia².

Respiratory, thoracic and mediastinal disorders:

Common – nasal congestion; uncommon – dyspnea, epistaxis.

Gastrointestinal disorders:

Common – dyspepsia; uncommon – abdominal pain, nausea, vomiting, gastroesophageal reflux.

Skin and subcutaneous tissue disorders:

Uncommon – rash; rare – urticaria, Stevens-Johnson syndrome², exfoliative dermatitis², hyperhidrosis (excessive sweating).

Renal and urinary disorders:

Uncommon – hematuria.

Musculoskeletal and connective tissue disorders:

Common – back pain, limb pain, myalgia.

Reproductive system and breast disorders:

Uncommon – prolonged erection; rare – priapism, penile hemorrhage, hematospermia.

General disorders:

Uncommon – chest pain¹, peripheral edema, fatigue; rare – facial edema², sudden cardiac death^1,2.

¹ Most patients who experienced these adverse reactions had underlying cardiovascular risk factors (see section "Special Warnings and Precautions for Use").

² Adverse reactions reported during post-marketing surveillance that were not observed in placebo-controlled clinical trials.

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

Specific adverse reactions.

A slightly higher frequency of ECG changes, most commonly sinus bradycardia, was reported in patients receiving once-daily tadalafil compared to those receiving placebo. Most ECG changes were not associated with clinical adverse reactions.

Special patient groups.

Data on the use of tadalafil in patients aged 65 years and older in clinical trials for erectile dysfunction are limited. In clinical trials evaluating on-demand tadalafil (20 mg dose) for erectile dysfunction, diarrhea occurred more frequently in patients over 65 years of age.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging and keep out of reach of children.

Packaging.

2 or 4 tablets in a blister; 1 or 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLDMEDICIN ILAC SAN. VE TIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder.

LLC "WORLD MEDICINE", Ukraine /
WORLD MEDICINE, LLC, Ukraine.