Cialis®

I N S T R U C T I O N for medical use of the medicinal product C I A L I S® (CIALIS®)

Composition:

Active substance: tadalafil;

1 tablet contains 20 mg of tadalafil;

Excipients: lactose monohydrate, hydroxypropylcellulose, sodium croscarmellose, sodium lauryl sulfate, microcrystalline cellulose, magnesium stearate; tablet coating: mixture of colorants yellow 32K12884 (lactose monohydrate, hypromellose HPMC 2910, titanium dioxide (E 171), triacetin, iron oxide yellow (E 172)); talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, yellow in color and almond-shaped, with embossing «C20».

Pharmacotherapeutic group. Agents for 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 penile tissues, resulting in erection. Tadalafil has no effect in the absence of sexual stimulation.

The inhibitory effect on cGMP concentrations in the corpus cavernosum is also observed in the smooth muscles of the prostate, 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 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 significantly stronger than on other phosphodiesterases. The activity of tadalafil against PDE5 is 10,000 times greater than its effect on PDE1, PDE2, PDE4, and PDE7, which are present in the heart, brain, blood vessels, liver, leukocytes, skeletal muscles, and other organs. Tadalafil is approximately 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 myocardial contraction. Additionally, tadalafil is about 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

Three clinical trials involving 1504 patients were conducted to determine the onset time of tadalafil's effect, demonstrating statistically significant improvement in erectile function, efficacy lasting up to 36 hours, and effect onset as early as 16 minutes after dosing compared to placebo.

In healthy volunteers, tadalafil showed no significant difference compared to placebo in 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 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 tadalafil's low affinity for PDE6 compared to PDE5. Rarely (<0.1%) during clinical trials, changes in color vision were reported.

Three clinical trials were conducted in men to evaluate the potential impact of Cialis**®** 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 related to changes in other parameters such as sperm motility, morphology, or serum follicle-stimulating hormone levels.

Tadalafil at doses ranging from 2 mg to 100 mg was evaluated in 16 clinical trials involving 3250 patients, including those 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 Cialis® group compared to 35% in the placebo group. Furthermore, patients with erectile dysfunction of varying severity reported improvement during treatment with Cialis**®** (success rates of 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 Cialis® group compared to 32% in the placebo group.

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

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, three-parallel-group trial involving 331 boys 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 subsequent analyses of this study. 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 within 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, Cialis**®** 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 tissue distribution of Cialis**®**. 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 semen in healthy volunteers.

Metabolism. Tadalafil is primarily metabolized by cytochrome P450 3A4 (CYP3A4) isoenzyme. The major circulating metabolite is methylcatechol glucuronide, which has 13,000 times lower activity against PDE5 than tadalafil. Therefore, the metabolite is not expected to have 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 predominantly 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. Tadalafil pharmacokinetics in healthy volunteers are linear and time- and dose-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.

Pharmacokinetics of the drug are similar in patients with erectile dysfunction and those without.

Special patient populations

Elderly individuals. Healthy elderly volunteers (aged 65 years or older) had lower oral clearance of tadalafil, resulting in a 25% increase in exposure (AUC) compared to healthy volunteers aged 19–45 years. This age-related 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), tadalafil exposure (AUC) 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, the maximum plasma concentration (Cmax) was 41% higher than in healthy volunteers. The effect of hemodialysis on tadalafil elimination is negligible.

Hepatic impairment. Tadalafil exposure (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. Safety data for administering Cialis**®** to patients with severe hepatic impairment (Child-Pugh class C) are limited. When prescribing Cialis**®**, physicians should carefully assess individual benefit-risk ratios. There are no data on use of doses higher than 0.10 mg in patients with hepatic impairment.

Patients with diabetes mellitus. Tadalafil exposure (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 drug is effective in the presence of sexual stimulation.

Cialis**®** is not indicated for use in women.

Contraindications.

Hypersensitivity to tadalafil or to any other component of the medicinal product.

In 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 receiving organic nitrates in any dosage form.

Cialis**®** should not be used in men with cardiovascular diseases for whom sexual activity is inadvisable. Physicians should consider the potential cardiovascular risk associated with sexual activity in patients with pre-existing cardiovascular disorders.

The following groups of patients with cardiovascular diseases were not included in clinical studies; therefore, tadalafil use 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.

Cialis**®** is contraindicated in patients who have experienced vision loss in one eye due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether it was associated with previous 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 types of interactions.

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 Cialis**®** (10 mg).

Effect of other medicinal products on tadalafil

Cytochrome CYP450 inhibitors

Tadalafil is predominantly metabolized by CYP3A4. The selective CYP3A4 inhibitor ketoconazole (200 mg daily) increases tadalafil (10 mg) exposure (AUC) by 2-fold and Cmax by 15% compared to tadalafil alone. Ketoconazole (400 mg daily) increases tadalafil (20 mg) exposure (AUC) by 4-fold and Cmax by 22%. Ritonavir, a protease inhibitor (200 mg twice daily) that inhibits CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increases tadalafil (20 mg) exposure (AUC) 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 co-administered. As a result, the frequency of adverse reactions may increase.

Transporters

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

Cytochrome CYP450 inducers

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

Effect of tadalafil on other medicinal products

Nitrates. In clinical studies, tadalafil (5 mg, 10 mg, 20 mg) was found to potentiate the hypotensive effects of nitrates. Therefore, the use of Cialis**®** is contraindicated in patients receiving treatment with organic nitrates in any form. If nitrates are medically necessary for a patient receiving Cialis**®** at any dose (2.5–20 mg), at least 48 hours must elapse after the last dose of Cialis**®** before administering nitrates. In such cases, nitrates should be administered under medical supervision with appropriate hemodynamic monitoring.

Antihypertensive agents (including calcium channel blockers)

Significant potentiation of the hypotensive effect of the α-adrenoreceptor blocker doxazosin (4–8 mg daily) was observed when co-administered with tadalafil (5 mg once daily or a single 20 mg dose). This effect lasts up to 12 hours and may manifest as individual symptoms, including dizziness. This combination is not recommended.

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 α-adrenoreceptor blockers, especially elderly patients. 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 studied: calcium channel blockers (amlodipine), ACE inhibitors (enalapril), β-blockers (metoprolol), thiazide diuretics (bendroflumethiazide), and angiotensin II receptor blockers (alone and in combination with thiazide diuretics, calcium channel blockers, β-blockers, and/or α-adrenoreceptor blockers). Tadalafil (10 mg dose, except for interaction studies with angiotensin II receptor blockers and amlodipine, where 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 dose) 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, 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 antihypertensive therapy, tadalafil at a dose of 20 mg may cause a reduction in blood pressure, which (except in the case of concomitant use with α-adrenoreceptor 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 therapy and those receiving tadalafil alone. Nevertheless, appropriate advice regarding possible blood pressure reduction should be provided to patients receiving antihypertensive agents and Cialis**®**.

Riociguat

An additive hypotensive effect was observed in preclinical studies with concomitant use of PDE5 inhibitors and riociguat. Clinical studies have shown that riociguat potentiates 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.

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 the treatment of symptoms of benign prostatic hyperplasia, no new adverse reactions were observed. However, since no dedicated drug interaction study has been conducted to evaluate the effects of tadalafil and 5-α-reductase inhibitors, tadalafil should be prescribed with caution to patients receiving 5-α-reductase inhibitors.

CYP1A2 substrates (e.g., theophylline)

In a clinical pharmacology study, no pharmacokinetic interaction was observed between tadalafil (10 mg) and 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, despite its lack of clinical significance.

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 (maximum average concentration 0.08%) did not affect the concomitant use of tadalafil (10 or 20 mg). No changes in tadalafil concentration were observed during the following three hours after simultaneous intake of alcohol and tadalafil. Alcohol was administered to achieve maximum alcohol absorption (rapid intake without food for 2 hours after administration). Tadalafil (20 mg) did not cause statistically significant blood pressure reduction when combined with alcohol (0.7 g/kg), although postural dizziness and orthostatic hypotension were observed in some patients. Tadalafil (20 mg) 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).

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) did not show clinically significant effects on the 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) 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 starting treatment with Cialis®

Before using the medication, the physician should determine the underlying cause of erectile dysfunction and prescribe an appropriate treatment regimen.

Prior to initiating any treatment for erectile dysfunction, physicians must evaluate the cardiovascular status of patients, as there is a certain degree of cardiovascular risk associated with sexual activity. Tadalafil produces vasodilatory effects, which may lead to a slight and transient decrease in blood pressure and may potentiate the hypotensive effect of nitrates.

It is unknown whether Cialis® is effective in patients who have undergone pelvic surgery or radical prostatectomy without nerve-sparing procedures.

Cardiovascular system

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

Cialis® should be prescribed with caution to patients taking α-1-blockers, as in some individuals concomitant use of these medications may lead to symptomatic hypotension. Combined use of tadalafil and doxazosin is not recommended.

Eyes

Cases of visual disturbances, including central serous chorioretinopathy (CSC) and non-arteritic anterior ischemic optic neuropathy (NAION), have been reported during the use of Cialis® and other PDE5 inhibitors. In most cases, symptoms of CSC resolved spontaneously after discontinuation of tadalafil. Regarding NAION, analysis of data from observational studies 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 be increased in all patients taking tadalafil, physicians should inform patients about the necessity to discontinue tadalafil and seek immediate medical attention in case of sudden vision loss, decreased visual acuity, and/or visual distortion (see section "Contraindications").

Worsening or sudden hearing loss

Cases of sudden hearing loss after taking tadalafil have been reported. Regardless of whether other risk factors were present (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 deterioration or hearing loss.

Hepatic impairment

Clinical data on the safety of a single dose of Cialis® in patients with severe hepatic impairment (Child-Pugh class C) are limited. Physicians should carefully assess the individual benefit-risk ratio before prescribing Cialis® to such patients.

Priapism and penile anatomical deformity

Patients who experience erections lasting 4 hours or longer should be advised to seek immediate medical attention. If priapism is not treated promptly, it may result in penile tissue damage and long-term loss of erectile function.

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

Concomitant use with CYP3A4 inhibitors

Cialis® should be prescribed with caution to patients taking CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), as co-administration with tadalafil results in increased tadalafil exposure (AUC).

Concomitant use with other medications for erectile dysfunction

The safety and efficacy of Cialis® used in combination with other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied; therefore, patients should be advised not to take Cialis® in such combinations.

Lactose

Cialis® contains lactose. Cialis® should not be administered to patients with rare hereditary conditions of galactose intolerance, glucose-galactose malabsorption syndrome, or lactase deficiency.

Sodium

One tablet of this medication contains less than 1 mmol of sodium (23 mg), i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Cialis® is not indicated for use in women.

Pregnancy. Data on the use of tadalafil in pregnant women are limited. Animal studies have not shown direct or indirect harmful effects on pregnancy, embryonic/fetal development, labor, or postnatal development. As a precautionary measure, it is advisable to avoid using Cialis during pregnancy.

Breastfeeding. Available pharmacodynamic/toxicological data in animals indicate excretion of tadalafil into breast milk. Risk to the breastfed infant cannot be excluded. Cialis should not be used during breastfeeding.

Fertility. Effects indicating impaired fertility were observed in dogs. Two clinical studies have indicated that fertility impairment in humans is not expected, although decreased sperm concentration has been observed in some individual men.

Ability to affect reaction speed when driving or operating machinery.

The effect of Cialis® on the ability to drive or operate machinery is minimal. Although the frequency of dizziness reported in placebo-controlled clinical trials and in tadalafil clinical trials was similar, patients should be aware of how Cialis® affects them before driving or operating machinery.

Method of Administration and Dosage

For oral use. The tablets of the medicinal product Cialis**®** should be taken with the recommended content of the active substance.

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

The medication 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 daily.

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

In cases where frequent use of Cialis**®** is anticipated (at least twice weekly), a regimen of daily administration of lower doses of this medication may be more appropriate, based on patient preference and physician 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 due to individual intolerance. The appropriateness of long-term daily use should be periodically reviewed.

Special patient groups

Elderly men. Dose adjustment is not required.

Men with renal impairment. Dose adjustment is not necessary for patients with mild or moderate renal impairment. For patients with severe renal impairment, the maximum recommended dose is 10 mg using appropriately dosed tablets.

Men with hepatic impairment. The recommended dose of Cialis**®** is 10 mg taken prior to anticipated sexual activity, regardless of food intake.

Clinical safety data for use of Cialis**®** in patients with severe hepatic impairment (Child-Pugh class C) are limited; if prescribed, the physician should carefully assess individual benefit/risks. There are no data on the use of doses higher than 00 mg in patients with hepatic impairment. There are no data on the use of 2.5–5 mg once daily in patients with hepatic impairment; therefore, if prescribing, the physician should carefully assess individual benefit/risks of administering Cialis**®** at a dose of 2.5–5 mg once daily.

Men with diabetes mellitus. Dose adjustment is not required.

Children. The medication 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 medication 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 therapy should be applied as needed. Hemodialysis has minimal effect on tadalafil elimination.

Adverse reactions.

Summary of the drug safety profile

The most commonly reported adverse effects during treatment of erectile dysfunction are headache, dyspepsia, back pain, and myalgia, the incidence of which increased with higher doses of Cialis**®. Adverse reactions were short-term and mild to moderate in severity. Most cases of headache with daily administration of Cialis®** at doses of 2.5 mg and 5 mg occurred within the first 10–30 days after initiation of treatment.

Table of adverse reaction data

The table below presents data on adverse reactions reported from spontaneous reports and observed during placebo-controlled clinical trials (involving 8022 patients receiving Cialis**®** and 4422 patients receiving placebo) with on-demand and daily use of Cialis**®** for the treatment of erectile dysfunction.

Very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000), frequency not known (frequency cannot be estimated from available data).

1 Most of the patients in whom such adverse reactions were observed had cardiovascular risk factors.

2 Adverse reactions reported during post-marketing studies and not observed in placebo-controlled clinical trials.

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

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

Special patient groups. Clinical data on the use of tadalafil for the treatment of erectile dysfunction in patients over 65 years of age are limited. In clinical trials of on-demand tadalafil use for the treatment of erectile dysfunction, diarrhea occurred more frequently in patients over 65 years of age.

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30°C, in a place inaccessible to children.

Packaging. 1 or 2 tablets of 20 mg in blisters, with 1, 2, or 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Primary and secondary packaging, batch release:

Lilly S.A. / Lilly S.A.

Manufacturer's address and location of operations.

Avda de la Industria, 30, 28108, Alcobendas, Madrid, Spain / Avda de la Industria, 30, Alcobendas, Madrid, 28108, Spain.