Tadalafil genheim

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Tadalafil Geneym (TadalafilGeneym)

Composition:

Active ingredient: tadalafil;

One tablet contains 20 mg of tadalafil;

Excipients: lactose monohydrate; microcrystalline cellulose (PH 101); sodium croscarmellose; hypromellose (3 cps); sorbitan stearate; dichloromethane; isopropyl alcohol; microcrystalline cellulose (PH 102); magnesium stearate;

film coating: Opadry II 32K520009 yellow (hypromellose (15 cps) (E 464); lactose monohydrate; titanium dioxide (E 171); iron oxide yellow (E 172); triacetin; talc).

Medicinal form. Film-coated tablets.

Main physicochemical characteristics: yellow, biconvex, film-coated, capsule-shaped tablets with beveled edges, embossed with "T 20" on one side and flat on the other side.

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

ATC code G04BE08.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes local release of nitric oxide, inhibition of PDE5 by tadalafil results in increased levels of cGMP in the corpus cavernosum. This leads to relaxation of smooth muscles and increased blood flow into penile tissues, thereby producing an erection. Tadalafil does not act 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 of the prostate and urinary 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 exceeds its effect on PDE1, PDE2, PDE4, and PDE7 enzymes by 10,000-fold; these enzymes 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 myocardial 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 studies involving 1504 patients were conducted to determine the onset time of tadalafil's effect, which 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.

In a study assessing the effect of tadalafil on vision using the Farnsworth-Munsell 100 Hue color vision test, tadalafil administered to healthy volunteers showed no clinically significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximum decrease: 1.6/0.8 mm Hg, respectively), standing systolic and diastolic blood pressure (mean maximum decrease: 0.2/4.6 mm Hg, respectively), or in clinically significant changes in heart rate.

Tadalafil does not impair color discrimination (blue/green), which is explained by its low affinity for PDE6 compared to PDE5. Additionally, no effects of tadalafil on visual acuity, electroretinogram, intraocular pressure, or pupil size were observed.

Three clinical studies were conducted in men to evaluate the potential effect of tadalafil at doses of 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study), administered once daily, on spermatogenesis. 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 in doses ranging from 2 mg to 100 mg was evaluated in 16 clinical studies involving 3250 patients, including patients with erectile dysfunction of varying severity (mild, moderate, severe), of 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. Moreover, patients with erectile dysfunction of varying severity reported improvement during tadalafil treatment (success rate: 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 showed significant improvement in erectile function. The average success rate with tadalafil 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 trial with three parallel groups involving 331 male children aged 7 to 14 years with DMD who were also receiving corticosteroid therapy. The study included a 48-week double-blind period during which patients were assigned to receive daily tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo. Tadalafil did not demonstrate efficacy 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 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, Tadalafil Geneim can be taken regardless of meals. 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 renal impairment.

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

Metabolism. Tadalafil is primarily metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme. The major circulating metabolite is methylcatechol glucuronide, which has 13,000-fold lower activity against PDE5 than tadalafil. Therefore, this 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 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. The pharmacokinetics of tadalafil in healthy volunteers is linear over time and dose. Within 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 populations

Elderly. Healthy elderly volunteers (aged 65 years and older) had lower oral clearance values 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.

Renal impairment. In clinical pharmacology studies using single doses of tadalafil (5–20 mg), 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 on hemodialysis, the maximum plasma concentration (Cmax) was 41% higher than in healthy volunteers.

The effect of hemodialysis on tadalafil elimination is negligible.

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

Patients with diabetes mellitus. AUC of tadalafil 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.

Tadalafil Geneim is not indicated for use in women.

Contraindications.

Hypersensitivity to tadalafil or to any other component 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 effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, tadalafil is contraindicated in patients receiving organic nitrates in any dosage form.

Tadalafil Geneim 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 disorders.

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

− patients who have had myocardial infarction within the previous 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 previous 6 months;

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

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

Tadalafil Geneim is contraindicated in patients who have experienced sudden vision loss in one eye due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this was associated with prior use of PDE5 inhibitors.

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 at doses of 10 mg and 20 mg; 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 (200 mg daily) increases the AUC of tadalafil (10 mg) by 2-fold and Cmax by 15% compared to tadalafil alone. Ketoconazole (400 mg daily) increases the 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 AUC of tadalafil (20 mg) by 2-fold without altering Cmax. Although specific interactions have not been studied, other protease inhibitors such as saquinavir and other CYP3A4 inhibitors such as erythromycin, clarithromycin, itraconazole, and grapefruit juice should be used with caution, as they are expected to increase plasma concentrations of tadalafil when co-administered. This may lead to an increased frequency of 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). 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 tadalafil plasma concentrations.

Effect of tadalafil on other medicinal products

Nitrates. During clinical studies, tadalafil (5 mg, 10 mg, 20 mg) was found to potentiate the hypotensive effects of nitrates. Therefore, the use of Tadalafil Geneim is contraindicated in patients receiving organic nitrates in any form. If nitrates are medically necessary in a life-threatening situation 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 should be performed under medical supervision with appropriate hemodynamic monitoring.

Antihypertensive agents (including calcium channel blockers)

When tadalafil (5 mg once daily or a single 20 mg dose) was co-administered with the α-adrenoreceptor blocker doxazosin (4–8 mg daily), a significant potentiation of the hypotensive effect of doxazosin was observed. 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 in patients receiving treatment with any α-adrenoreceptor blockers, particularly in elderly individuals. Treatment should be initiated at the lowest dose, with gradual dose escalation.

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), ACE inhibitors (enalapril), β-adrenoreceptor blockers (metoprolol), thiazide diuretics (bendroflumethiazide), and angiotensin II receptor blockers (alone or in combination with thiazide diuretics, calcium channel blockers, β-blockers, and/or α-blockers). Tadalafil (10 mg, except for interaction studies with angiotensin II receptor blockers and amlodipine, where 20 mg 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 4) 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 did not lead to hypotensive symptoms. In patients receiving concomitant antihypertensive therapy, tadalafil 20 mg may cause blood pressure reduction, which (except when combined with α-adrenoreceptor blockers) is minimal and clinically insignificant. Analysis of Phase III clinical trial data did not reveal differences in adverse reactions between patients treated with tadalafil alone and those receiving concomitant antihypertensive therapy. Nevertheless, appropriate advice regarding possible blood pressure reduction should be provided to patients receiving antihypertensive agents and Tadalafil Geneim.

Riociguat

Preclinical studies revealed an additive hypotensive effect when PDE5 inhibitors were used concomitantly with riociguat. Clinical studies showed 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 relief of symptoms of benign prostatic hyperplasia, no new adverse reactions were reported. 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 in 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. This effect should be considered when tadalafil and theophylline are used concomitantly, although it is minor and not clinically significant.

Ethynylestradiol and terbutaline

Tadalafil increases the bioavailability of oral formulations containing ethynylestradiol. This increased bioavailability may be expected when used concomitantly with terbutaline (orally), although the clinical consequences of this combination are unknown.

Alcohol

Alcohol (mean maximum concentration of 0.08%) did not affect the concomitant use of tadalafil (10 mg or 20 mg). No changes in tadalafil concentration were observed during the 3 hours following simultaneous intake of alcohol and tadalafil. Alcohol was administered to achieve maximum alcohol absorption (rapid intake on an empty stomach within 2 hours after administration). Administration of tadalafil (20 mg) did not result in 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) combined 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 AUC of S-warfarin or R-warfarin (CYP2C9 substrates) and did not affect warfarin-induced prothrombin time.

Acetylsalicylic acid

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 initiating treatment with Tadalafil Geneim

Prior to using the medicinal product, the physician should determine the underlying cause of erectile dysfunction and prescribe an appropriate treatment regimen.

Before initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, as there is a certain degree of cardiovascular risk associated with sexual activity. Tadalafil exerts a vasodilatory effect, which may lead to a mild and transient decrease in blood pressure and may potentiate the hypotensive effect of nitrates.

It is unknown whether tadalafil is effective in patients who have undergone pelvic surgery or nerve-sparing radical prostatectomy.

Cardiovascular system

Serious adverse events related to the cardiovascular system, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, cerebrovascular disorders, transient ischemic attack, chest pain, palpitations, and tachycardia, have been reported in post-marketing surveillance and/or during 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 these risk factors, the use of tadalafil, sexual activity, or a combination of these or other factors.

Tadalafil Geneim should be prescribed with caution to patients taking α1-blockers, as concomitant use of these agents in some patients may lead to 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. 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. In most cases, symptoms of CSCR resolved spontaneously after discontinuation of tadalafil. Since this risk may be increased in all patients using tadalafil, physicians should inform patients about the necessity to immediately discontinue tadalafil and seek medical help in case of sudden vision loss, visual acuity disturbances, and/or visual distortion (see section "Contraindications").

Worsening or sudden hearing loss

Cases of sudden hearing loss following tadalafil administration have been reported. Regardless of the presence of other risk factors (such as age, diabetes, arterial 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.

Renal and hepatic impairment

Daily administration of Tadalafil Geneim is not recommended in patients with severe renal impairment due to increased exposure (AUC) of tadalafil, limited clinical experience, and poor clearance during dialysis.

Clinical data on the safety of a single dose of tadalafil in patients with severe hepatic impairment (Child-Pugh class C) are limited.

When prescribing Tadalafil Geneim to such patients, physicians should carefully assess the individual benefit-risk ratio of therapy.

Priapism and anatomical deformation of the penis

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

Tadalafil Geneim should be prescribed with caution to patients with anatomical deformation of the penis (e.g., Peyronie’s disease, penile angulation, cavernosal fibrosis) or conditions that may predispose to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia).

Concomitant use with CYP3A4 inhibitors

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

Concomitant use with other medicinal products for erectile dysfunction

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

Lactose

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

Sodium

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

Use during pregnancy or breastfeeding.

Tadalafil Geneim is not indicated for use in women.

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

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

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 influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

For oral use.

Erectile Dysfunction in Adult Men

The recommended dose is 10 mg* taken prior to anticipated sexual activity, with or without food. For patients in whom tadalafil 10 mg* does not provide 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 dosing frequency 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 tadalafil is anticipated (at least twice weekly), 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 at approximately the same time each day. The dose may be reduced to 2.5 mg* once daily based on individual tolerability. The continued need for long-term daily treatment should be periodically reassessed.

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*.

Men with Hepatic Impairment

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

Clinical safety data on the use of tadalafil in patients with severe hepatic impairment (Child-Pugh class C) are limited; therefore, when prescribing the drug, the physician must carefully evaluate 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 also no data on the use of tadalafil 2.5–5 mg* once daily in patients with hepatic impairment; therefore, if prescribing the drug, the physician must carefully assess the individual benefit/risks of administering tadalafil 2.5–5 mg* once daily.

*Use tadalafil products at the appropriate dosage strength.

Men with Diabetes Mellitus

Dose adjustment is not required.

Special Warnings on Disposal

Unused medication or waste material must be disposed of in accordance with current regulatory requirements.

Children

This medication is not intended for use in children (under 18 years of age).

Overdose

Symptoms. When administered as a single dose up to 500 mg in healthy volunteers, or multiple doses 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 needed. Hemodialysis has minimal effect on the elimination of tadalafil.

Adverse Reactions.

Summary of the medicinal product's safety profile

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

Below are data on adverse reactions reported from spontaneous reports and observed in placebo-controlled clinical trials (involving 8,022 patients receiving tadalafil and 4,422 patients receiving placebo) for on-demand and daily use of tadalafil in 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).

Immune system disorders:
Uncommon – hypersensitivity reactions; rare – angioedema^2.

Nervous system disorders:
Common – headache; uncommon – dizziness; rare – cerebrovascular disorders^1 (including hemorrhagic events), loss of consciousness, transient ischemic attack^1, migraine^2, seizures^2, transient 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 occlusion^2; frequency not known – central serous chorioretinopathy.

Ear and labyrinth disorders:
Uncommon – tinnitus; rare – sudden hearing loss.

Cardiac disorders^1:
Uncommon – tachycardia, palpitations; rare – myocardial infarction, unstable angina^2, ventricular arrhythmia^2.

Vascular disorders:
Common – flushing; uncommon – arterial hypotension^3, arterial hypertension.

Respiratory, thoracic and mediastinal disorders:
Common – nasal congestion; uncommon – dyspnea, epistaxis.

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

Skin and subcutaneous tissue disorders:
Uncommon – rash; rare – urticaria, Stevens-Johnson syndrome^2, exfoliative dermatitis^2, hyperhidrosis (excessive sweating).

Musculoskeletal, connective tissue and bone disorders:
Common – back pain, myalgia, limb pain.

Renal and urinary disorders:
Uncommon – hematuria.

Reproductive system and breast disorders:
Uncommon – prolonged erection; rare – priapism, penile hemorrhage, hematospermia.

General disorders and administration site conditions:
Uncommon – chest pain^1, peripheral edema, fatigue; rare – facial swelling^2, sudden cardiac death^1,^2.

^1 Most patients who experienced these adverse reactions had underlying cardiovascular risk factors.
^2 Adverse reactions from post-marketing experience not observed during placebo-controlled clinical trials.
^3 More frequently reported when tadalafil was used concomitantly with antihypertensive agents.

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

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

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the 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: http://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging.

2 tablets per blister, 1 blister per carton.

4 tablets per blister, 1 or 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Accord Healthcare Polska Sp. z o.o. Importer’s Address/Accord Healthcare Polska Sp. z o.o. Importer’s Warehouse.

Manufacturer’s location and address of its business premises.

ul. Lutomierska 50, Pabianice, 95-200, Poland / ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing Authorization Holder. Accord Healthcare Polska Sp. z o.o. / Accord Healthcare Polska Sp. z o.o.
Inquiries regarding product quality issues; questions concerning safety of use, improper use of the medicinal product, or complaints are accepted 24/7 via phone: +380993100335 or by email at: [email protected].

Marketing Authorization Holder’s address. 7 Tasmowa St., Warsaw, 02-677, Poland / 7 Tasmowa St., Warsaw, 02-677, Poland.