Tadalafil

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

Composition:

Active substance: tadalafil;

One film-coated tablet contains tadalafil 10 mg or 20 mg;

Excipients: lactose monohydrate, sodium croscarmellose, microcrystalline cellulose PH102, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, coating mixture 03K12429: hypromellose 6 mPa·s, titanium dioxide (E 171), talc, triacetin, iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg: film-coated tablets, from pale yellow to yellow, round-shaped, biconvex, with imprint “45” on one side and smooth on the other.

20 mg: film-coated tablets, from pale yellow to yellow, round-shaped, biconvex, with imprint “47” on one side and smooth on the other.

Pharmacotherapeutic group. Agents for 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, tadalafil's inhibition of PDE5 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, 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 (BPH). 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 stronger than on other phosphodiesterases. Tadalafil's activity 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 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

Three clinical trials involving 1,054 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 onset of effect as early as 16 minutes after dosing compared to placebo. The effect of tadalafil administered to healthy volunteers did not differ significantly from placebo in terms of 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), and 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. During all clinical trials, changes in color vision were rarely reported (< 0.1%).

Three clinical trials were conducted in men to evaluate the potential impact 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 3,250 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 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 12-week study involving 186 patients (142 receiving tadalafil, 44 receiving placebo) with secondary erectile dysfunction due to spinal cord injury, tadalafil significantly improved erectile function. The average success rate with tadalafil (10 mg or 20 mg, dose adjustment, as needed) was 48% compared to 17% in the placebo group.

Children
A single study was conducted in children with Duchenne muscular dystrophy (DMD), which did not demonstrate confirmed efficacy. This study of tadalafil's efficacy was a randomized, double-blind, placebo-controlled, three-arm trial involving 331 boys 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 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. 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 treatment.

Pharmacokinetics

Absorption
Tadalafil is well absorbed after oral administration. The mean peak plasma concentration (Cmax) is reached at approximately 2 hours after dosing. The absolute oral bioavailability of tadalafil has not been determined.

The rate and extent of tadalafil absorption are not affected by food intake; therefore, the medication can be taken with or without food. The time of dosing (morning or evening) had 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 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 isoenzyme 3A4 (CYP3A4). The major circulating metabolite is methylcatechol glucuronide. This metabolite has PDE5 inhibitory activity 13,000 times less than that of tadalafil. Therefore, the metabolite is not expected to have clinical activity at observed concentrations.

Elimination
The oral clearance of tadalafil is 2.5 L/h, and the mean elimination half-life is 17.5 hours in healthy volunteers. Tadalafil is primarily eliminated as inactive metabolites, predominantly 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. In the dose range of 2.5 to 20 mg, the area under the plasma concentration-time curve (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 patients
Healthy elderly volunteers (aged 65 years and 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), AUC of tadalafil 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. Safety data for tadalafil use in patients with severe hepatic impairment (Child-Pugh class C) are limited. There are no data on the use of doses higher than 10 mg in patients with hepatic impairment. Physicians should carefully assess the individual benefit/risk ratio when prescribing tadalafil for once-daily dosing.

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 the treatment of erectile dysfunction in adult men. The medicinal product is effective in the presence of sexual stimulation. Tadalafil is not indicated for use in women.

Contraindications.

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

Tadalafil is known 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 (see section "Interaction with other medicinal products and other forms of interaction").

Tadalafil should not be used in men with cardiovascular diseases for whom sexual activity is undesirable. Physicians should consider the potential cardiovascular risk of sexual activity in patients with cardiovascular disease.

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 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, arterial hypotension (< 90/50 mm Hg), or uncontrolled hypertension;

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

Tadalafil 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 (see section "Special precautions for use").

Concomitant use of PDE5 inhibitors, including tadalafil, with guanylate cyclase stimulators such as riociguat is contraindicated, as this 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.

The interaction studies described below were conducted using doses of 10 mg and 20 mg.

Clinically significant interaction with higher doses cannot be excluded if it was observed with lower doses of the drug (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 the exposure (AUC) of tadalafil (10 mg) by 2-fold and Cmax by 15%. Ketoconazole (400 mg daily) increases the exposure (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 exposure (AUC) of tadalafil (20 mg) 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.

Transporters.

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

Cytochrome CYP450 inducers.

The CYP3A4 inducer rifampicin reduces the AUC of tadalafil by 88% compared to AUC values when tadalafil (10 mg) is taken alone. 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) was shown to potentiate the hypotensive effects of nitrates. Therefore, the use of tadalafil is contraindicated in patients receiving treatment with organic nitrates in any form.

If nitrates are medically necessary for a patient receiving tadalafil at any dose (2.5–20 mg)\textsuperscript{1}, 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\textsuperscript{1} once daily or a single 20 mg dose) was co-administered with the α-adrenoreceptor 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.

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-adrenoreceptor 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 antihypertensive agents. Major drug classes were studied: calcium channel blockers (amlodipine), angiotensin-converting enzyme inhibitors (enalapril), β-adrenoreceptor blockers (metoprolol), thiazide diuretics (bendroflumethiazide), and angiotensin II receptor blockers (alone and in combination with thiazide diuretics, calcium channel blockers, β-adrenoreceptor blockers, and/or α-adrenoreceptor 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 hypertension, the reduction in blood pressure was greater, although in most patients this reduction did not lead to hypotensive symptoms. In patients receiving concomitant therapy with antihypertensive agents, the use of 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 generally minimal and clinically insignificant. Analysis of phase III clinical trial data did not reveal differences in adverse reactions between patients treated with tadalafil with concomitant antihypertensive therapy and those treated with tadalafil alone. Nevertheless, appropriate recommendations regarding the potential reduction in blood pressure should be provided to patients receiving antihypertensive drugs and tadalafil.

Riociguat.

Preclinical studies revealed an additive hypotensive effect with concomitant use of PDE5 inhibitors and riociguat. In clinical studies, riociguat was shown to potentiate the hypotensive effect 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\textsuperscript{1} 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 drug interaction studies to evaluate the effects of tadalafil and 5-α-reductase inhibitors were not 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 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 the lack of clinical significance.

Ethinylestradiol and terbutaline.

Tadalafil increased the bioavailability of oral medicinal products containing ethinylestradiol. Such an increase in bioavailability can be expected with concomitant use of terbutaline, although the clinical consequences of this combination are unknown.

Alcohol.

Alcohol (mean maximum concentration 0.08%) did not affect the action of tadalafil (10 or 20 mg). No changes in tadalafil concentration were observed over the next 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 alcohol administration). Administration of tadalafil (20 mg) did not result in a statistically significant reduction in blood pressure when combined with alcohol (0.7 g/kg), although postural dizziness and orthostatic hypotension were observed in some patients. Administration of tadalafil (20 mg) with lower doses of alcohol (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) had no clinically significant effect 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.

\textsuperscript{1} Use tadalafil preparations at the appropriate dosage.

Special precautions for use.

Before prescribing the medicinal product Tadalafil.

Before prescribing the medication, the physician should determine the underlying causes of erectile dysfunction and initiate appropriate treatment.

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

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

Cardiovascular system.

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

Tadalafil should be prescribed with caution in patients taking α1-blockers, as in some individuals concomitant use of these drugs may result in symptomatic hypotension. Combined use of tadalafil and doxazosin is not recommended.

Vision.

Cases of visual disturbances, including central serous chorioretinopathy (CSCR) and non-arteritic anterior ischemic optic neuropathy (NAION), have been reported during the use of tadalafil and other PDE5 inhibitors. In most cases of CSCR, symptoms 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 increased risk may occur in all patients taking tadalafil, physicians should inform patients about the necessity to immediately discontinue tadalafil and seek medical help in case of sudden vision loss, visual acuity disturbances, and/or visual distortion (see section "Contraindications").

Worsening or sudden hearing loss.

Cases of sudden hearing loss after administration of 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 tadalafil in patients with severe hepatic impairment (Child-Pugh class C) are limited.

Before prescribing Tadalafil, the physician should carefully assess the individual benefit/risk ratio of therapy.

Priapism and penile anatomical deformity.

If a patient experiences an erection lasting 4 hours or longer, immediate medical attention is required. If priapism is not treated promptly, it may lead to penile tissue damage and permanent loss of potency.

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

Concomitant use with CYP3A4 inhibitors.

Tadalafil should be used 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 types of interactions").

Concomitant use with other erectile dysfunction medications.

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

Lactose.

The medicinal product contains lactose monohydrate; therefore, patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not use this product.

One 10 mg tablet contains 123.56 mg of lactose monohydrate; one 20 mg tablet contains 247.12 mg of lactose monohydrate. Use with caution in patients with diabetes mellitus.

Use during pregnancy or breastfeeding.

Tadalafil is not indicated for use in women.

Fertility. In two clinical studies, no impairment of fertility was expected in humans, although decreased sperm concentration was observed in some men (see section "Pharmacological properties").

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 dizziness was similar between placebo and tadalafil groups in clinical trials, patients should be aware of how Tadalafil affects them before driving or operating machinery.

Method of administration and dosing.

For oral use. The medicinal product 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 10 mg of tadalafil does not produce an adequate 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 daily.

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

If frequent use of the medicinal product is anticipated (at least twice per week), a daily regimen with lower doses of tadalafil may be more appropriate, based on patient preference and physician decision. For such patients, the recommended dose of tadalafil is 5 mg once daily at approximately the same time each day. The dose of tadalafil may be reduced to 2.5 mg once daily\textsuperscript{1}, taking into account individual tolerability. 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 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 corresponding strength.

Men with hepatic impairment. The recommended dose of tadalafil is 10 mg prior to anticipated sexual activity, independent of food intake. Clinical data on the safety of the drug 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 higher than 10 mg in patients with hepatic impairment. There are no data on the use of tadalafil at doses of 2.5–5 mg\textsuperscript{1} once daily in patients with hepatic impairment; therefore, if prescribed, the physician should carefully assess the individual benefit/risk ratio of administering tadalafil at a dose of 2.5–5 mg\textsuperscript{1} once daily.

Men with diabetes mellitus. Dose adjustment is not required.

Children. The medicinal product is not intended for use in children.

Special precautions for disposal. Unused medicinal product or waste material must be disposed of in accordance with current regulatory requirements.

\textsuperscript{1} Use tadalafil preparations of corresponding dosage strength.

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

Overdose.

Symptoms. When administered as a single dose up to 500 mg to healthy volunteers, and with multiple dosing of tadalafil up to 100 mg daily in patients, adverse effects were similar to those observed with lower doses of the drug.

Treatment. In case of overdose, standard symptomatic treatment should be applied as necessary. Hemodialysis had no significant effect on tadalafil elimination.

Adverse reactions

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

The table below presents data on adverse reactions from spontaneous reports and placebo-controlled clinical trials (in total, 8022 patients receiving tadalafil and 4422 patients receiving placebo) with the use of tadalafil as needed and with daily use for the treatment of erectile dysfunction.

1 Most of the patients in whom such adverse reactions were observed had cardiovascular risk factors in their medical history (see section "Special warnings and precautions for use").

2 Adverse reactions from post-marketing studies which were not observed during other clinical trials.

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

Individual adverse reactions. A slightly higher frequency of ECG abnormalities, primarily sinus bradycardia, has been 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. Clinical trial data on the use of tadalafil in patients aged over 65 years for the treatment of erectile dysfunction are limited. In clinical trials evaluating on-demand use of tadalafil for the treatment of erectile dysfunction, diarrhea was reported more frequently in patients aged over 65 years.

Shelf life. 3 years.

Storage conditions. Store in the original packaging, protected from light, in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging.

For 10 mg: 4 or 7 film-coated tablets in a blister. One blister pack in a cardboard box.

For 20 mg: 1, 4, or 7 film-coated tablets in a blister. One blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Chilu Pharmaceutical (Hainan) Co., Ltd.

Manufacturer's address and place of business.
No. 273-A, Nanhai Avenue, Nanshin Hi-Tech Zone, Haikou, Hainan 570314, China.