Cialis

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CIALIS®

Composition:

Active substance: tadalafil;

1 tablet contains 2.5 mg or 5 mg of tadalafil;

Excipients:

Tablet core: lactose monohydrate, sodium croscarmellose, hydroxypropylcellulose, microcrystalline cellulose, sodium lauryl sulfate, magnesium stearate;

Tablet coating:

for 2.5 mg tablets: yellow color mixture 32K12891 [lactose monohydrate, hypromellose, triacetin, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172)], talc;

for 5 mg tablets: yellow color mixture Y-30-12863-A [lactose monohydrate, hypromellose, triacetin, titanium dioxide (E 171), iron oxide yellow (E 172)], talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated, almond-shaped tablets; 2.5 mg tablets: light orange-yellow color, with the inscription "C 2 ½" on one side; 5 mg tablets: yellow color, with the inscription "C 5".

Pharmacotherapeutic group. Agents for the treatment of erectile dysfunction. ATC code G04BE08.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes local release of nitric oxide, inhibition of PDE5 by tadalafil results in increased levels of cGMP in the corpus cavernosum. This leads to relaxation of smooth muscles and increased blood flow into penile tissue, thereby producing an erection. Tadalafil does not exhibit its effect in the treatment of erectile dysfunction 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. These vascular effects may be complemented by inhibition of afferent nerves of the bladder and relaxation of smooth muscles of the prostate and bladder.

Pharmacodynamic effects

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

Clinical efficacy and safety

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

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

Three clinical studies were conducted in men to evaluate the potential impact of Cialis® on spermatogenesis at doses of 10 mg (one 6-month study) and 20 mg (one 6-month study 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.

Erectile dysfunction

Three clinical studies involving 1054 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 an effect observed as early as 16 minutes after dosing compared to placebo (as-needed use of Cialis®).

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

Tadalafil at doses of 2.5 mg, 5 mg, and 10 mg once daily was evaluated in three clinical studies involving 853 patients of various ages (21 to 82 years) and ethnic groups with erectile dysfunction of varying severity (mild, moderate, severe) and etiology. In two primary efficacy studies in the overall population, the mean success rate was 57% and 67% with Cialis® 5 mg and 50% with Cialis® 2.5 mg, compared to 31% and 37% in the placebo group. In studies involving patients with erectile dysfunction secondary to diabetes, the mean success rate was 41% and 46% with Cialis® 5 mg and 2.5 mg, respectively, compared to 28% in the placebo group. Most patients in these studies had previously used PDE5 inhibitors on an as-needed basis. In a subsequent study, 217 patients who had not previously used PDE5 inhibitors received Cialis® 5 mg once daily or placebo. The mean success rate was 68% in the Cialis® group compared to 52% in the placebo group.

Benign prostatic hyperplasia

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

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

Maintenance of the effect of Cialis® was evaluated in an additional open-label study, which demonstrated that improvement in the International Prostate Symptom Score observed during 12 weeks was maintained for up to 1 year after treatment with Cialis® 5 mg.

Children

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

Pharmacokinetics

Absorption Tadalafil is well absorbed after oral administration. The mean maximum plasma concentration (Cmax) is reached on average 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 independent of food intake; therefore, Cialis 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 Cialis® 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 activity 13,000 times lower than tadalafil. Therefore, the metabolite is not expected to have clinical activity at observed concentrations.

Elimination The mean oral clearance of tadalafil is 2.5 L/h, and the mean elimination half-life is 17.5 hours in healthy subjects. Tadalafil is eliminated predominantly as inactive metabolites, mainly 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 are 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 administration.

The pharmacokinetics of the drug are similar in patients with erectile dysfunction and in those without it.

Special populations

Elderly individuals Healthy elderly volunteers (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. Data on the safety of Cialis® administration in patients with severe hepatic impairment (Child-Pugh class C) are limited. There are no data on the use of Cialis® once daily in patients with hepatic impairment. The physician should carefully assess the individual benefit/risk ratio when prescribing Cialis® once daily.

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

Clinical characteristics.

Indications.

For the 2.5 mg dosage: Treatment of erectile dysfunction in adult men. The drug is effective in the presence of sexual stimulation.

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

Treatment of the symptoms of benign prostatic hyperplasia (BPH) in adult men.

Cialis® is not indicated for use in women.

Contraindications.

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

During clinical studies, tadalafil was shown 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 who are using organic nitrates in any dosage form (see section "Interaction with other medicinal products and other forms of interaction").

Cialis® should not be used in men with cardiovascular diseases for whom sexual activity is inadvisable. Physicians should consider the potential cardiovascular risk of sexual activity in patients with a history of 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 a myocardial infarction within the last 90 days;

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

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

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

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

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

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.

Interaction studies were conducted with 10 mg and 20 mg dosages; data are provided below. Regarding interaction studies using only Cialis® 10 mg, a clinically significant interaction with higher doses cannot be excluded.

Effect of other medicinal products on tadalafil.

Cytochrome CYP450 inhibitors.

Tadalafil is primarily metabolized by CYP3A4. The selective CYP3A4 inhibitor ketoconazole (200 mg daily) increases the area under the concentration-time curve (AUC) of tadalafil (10 mg) by 2-fold and Cmax by 15% compared to tadalafil alone. Ketoconazole (400 mg daily) increases the area under the concentration-time curve (AUC) of tadalafil (20 mg) by 4-fold and Cmax by 22%. Ritonavir, a protease inhibitor (200 mg twice daily) that inhibits CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increases the 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 (see section "Special precautions"). This may consequently increase the frequency of adverse reactions (see section "Adverse reactions").

Transporters.

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

Cytochrome CYP450 inducers.

The CYP3A4 inducer rifampicin reduces the AUC of tadalafil by 88% compared to tadalafil alone (10 mg). This reduction in concentration may lead to reduced efficacy of tadalafil; the extent of efficacy reduction is unknown. 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. During clinical studies, tadalafil (5 mg, 10 mg, 20 mg) was shown to potentiate the hypotensive effects of nitrates. Therefore, the use of Cialis® in patients receiving treatment with organic nitrates in any form is contraindicated (see section "Contraindications"). In a clinical study involving 150 patients who received tadalafil 20 mg daily for 7 days and sublingual nitroglycerin 0.4 mg (at varying time intervals), this interaction lasted more than 24 hours and was not observed after 48 hours following the last dose of tadalafil. Therefore, 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, nitrate administration must be performed under strict medical supervision with appropriate hemodynamic monitoring.

Antihypertensive agents (including calcium channel blockers).

Significant potentiation of the hypotensive effect of the α-adrenoceptor blocker doxazosin (4–8 mg daily) was observed when co-administered with tadalafil (5 mg once daily or 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 (see section "Special precautions").

In interaction studies involving a limited number of healthy volunteers, the above effects were not reported with alfuzosin or tamsulosin. Tadalafil should be prescribed with caution in patients receiving treatment with any α-adrenoceptor blockers, particularly in 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 antihypertensive agents. Major classes of drugs were studied: calcium channel blockers (amlodipine), angiotensin-converting enzyme inhibitors (enalapril), β-adrenoceptor blockers (metoprolol), thiazide diuretics (bendroflumethiazide), and angiotensin II receptor blockers (various types and doses, alone or in combination with thiazide diuretics, calcium channel blockers, β-adrenoceptor blockers, and/or α-adrenoceptor 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 classes of medicinal products. In another clinical pharmacology study, concomitant use of tadalafil (20 mg) with multiple antihypertensive agents (up to four) was investigated. In patients taking multiple antihypertensive agents, blood pressure changes depended on the level of blood pressure control. Thus, in patients with well-controlled hypertension, blood pressure reduction was minimal and comparable to that in healthy volunteers. In patients with uncontrolled hypertension, blood pressure reduction was greater, 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-adrenoceptor blockers) is generally minor and clinically insignificant. Analysis of phase 3 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 advice regarding the potential for blood pressure reduction should be provided to patients treated with antihypertensive agents and Cialis®.

Riociguat.

Preclinical studies demonstrated an additive hypotensive effect when PDE5 inhibitors were used concomitantly with riociguat. Clinical studies confirmed 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 (see section "Contraindications").

5-α-reductase inhibitors.

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

CYP1A2 substrates (e.g., theophylline).

In a clinical pharmacology study, no pharmacokinetic interaction was observed between tadalafil (10 mg) and theophylline (a non-selective phosphodiesterase inhibitor). The only pharmacodynamic effect was a slight increase in heart rate (3.5 beats/min). The possibility of this effect should be considered when tadalafil and theophylline are used concomitantly, although it is minor and not clinically significant.

Ethinylestradiol and terbutaline.

Tadalafil increased the bioavailability of oral formulations containing ethinylestradiol. Such increased bioavailability may be expected when used concomitantly with terbutaline (oral), 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 three hours following simultaneous intake of alcohol and tadalafil. Alcohol was administered to achieve maximum alcohol absorption (fasting after overnight fasting and no food intake for 2 hours after alcohol administration). Administration of tadalafil (20 mg) did not result in statistically significant reduction in mean blood pressure when combined with alcohol (0.7 g/kg or approximately 180 ml of 40% alcohol (vodka) in an 80 kg man), although postural dizziness and orthostatic hypotension were observed in some patients. Administration of tadalafil with lower doses of alcohol (0.6 g/kg) did not cause hypotension, and dizziness occurred at the same frequency as with alcohol alone. The effect of alcohol on cognitive function was not enhanced by concomitant use of tadalafil (10 mg).

Medicinal products metabolized by cytochrome P-450.

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 exposure (AUC) of S-warfarin or R-warfarin (CYP2C9 substrates), nor did it affect prothrombin time induced by warfarin.

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 initiating treatment with Cialis®.

Prior to administration of the medicinal product, the physician should take a medical history and perform a physical examination to identify potential underlying causes of erectile dysfunction and benign prostatic hyperplasia, and to determine appropriate treatment.

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 has a vasodilatory effect, which may lead to a slight and transient decrease in blood pressure (see section "Pharmacological properties") and may potentiate the hypotensive effect of nitrates (see section "Contraindications").

Prior to initiating tadalafil therapy for symptoms of benign prostatic hyperplasia, the patient should be examined to exclude the possibility of prostate cancer and to carefully assess cardiovascular status (see section "Contraindications").

Evaluation of erectile dysfunction should include identification of potential underlying causes and appropriate medical evaluation before treatment. The efficacy of Cialis® in patients who have undergone pelvic surgery or nerve-sparing radical prostatectomy is unknown.

Cardiovascular system.

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

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

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

Vision.

Cases of visual disturbances, including central serous retinopathy (CSR) and non-arteritic anterior ischemic optic neuropathy (NAION), have been reported during the use of Cialis® and other PDE5 inhibitors. In most cases of CSR, symptoms resolved spontaneously after discontinuation of tadalafil. With regard to 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 of the necessity to immediately discontinue tadalafil and seek medical help 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 following the use 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 warned to discontinue tadalafil and seek medical help immediately in case of sudden hearing deterioration or hearing loss.

Renal and hepatic impairment.

Daily use of Cialis® is not recommended in patients with severe renal impairment due to increased tadalafil exposure (AUC), limited clinical experience, and poor ability to affect its clearance by dialysis.

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

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

Priapism and anatomical deformity of the penis.

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

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

Concomitant use with CYP3A4 inhibitors.

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

Concomitant use with other medicinal products for erectile dysfunction.

The safety and efficacy of using Cialis® in combination with other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied; therefore, patients should be informed not to take Cialis® 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 take this medicinal product.

Sodium.

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

Use during pregnancy or breastfeeding.

Cialis® is not indicated for use in women.

Pregnancy. Data from studies 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 use of Cialis® during pregnancy.

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

Fertility. Effects indicating impaired fertility were observed in dogs. Two clinical studies have shown that such an effect is not expected in humans, although decreased sperm concentration was observed in some individual men (see section "Pharmacological properties").

Ability to influence reaction speed when driving or operating machinery.

The effect of Cialis® on the ability to drive or operate machinery is negligible. Although the frequency of dizziness reported in placebo-controlled clinical trials and in trials with tadalafil was similar, patients should know how Cialis® 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, regardless of food intake. For patients who do not achieve adequate effect with tadalafil 10 mg, a dose of 20 mg may be used.

The medication can be taken 30 minutes prior to sexual activity.

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.

If frequent use of Cialis® (at least twice weekly) is anticipated, a daily regimen with lower doses of Cialis® 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 appropriateness of long-term daily use should be periodically reevaluated.

Benign prostatic hyperplasia in adult men.

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

Special patient populations.

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 (on-demand use of Cialis®). Daily administration of tadalafil 2.5 mg or 5 mg is not recommended for the treatment of patients with severe renal impairment and benign prostatic hyperplasia or erectile dysfunction (see sections "Special precautions for use" and "Pharmacological properties").

Men with hepatic impairment.

For the treatment of erectile dysfunction, the recommended dose of Cialis® is 10 mg prior to anticipated sexual activity, regardless of food intake (on-demand use of Cialis®). Clinical data on the safety of Cialis® 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 Cialis® at doses higher than 10 mg in patients with hepatic impairment. Daily use of Cialis® for the treatment of patients with benign prostatic hyperplasia or erectile dysfunction has not been evaluated in patients with hepatic impairment; therefore, the physician should carefully assess the individual benefit/risk ratio of such therapy (see sections "Special precautions for use" and "Pharmacological properties").

Men with diabetes. Dose adjustment is not required.

Special precautions for disposal.

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

Children.

There are no data on the use of Cialis® in children for the treatment of erectile dysfunction.

Overdose.

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

Treatment. In case of overdose, standard symptomatic treatment should be applied 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 or benign prostatic hyperplasia were headache, dyspepsia, back pain, and myalgia, the incidence of which increased with higher doses of Cialis®. Adverse reactions were generally short-lived and mild to moderate in severity. Most cases of headache with daily use of Cialis® occurred within the first 10–30 days after initiation of treatment.

Tabulated adverse reaction data.

The table below presents data on adverse reactions from spontaneous reports and placebo-controlled clinical trials (overall, 8022 patients receiving Cialis® and 4422 patients receiving placebo) for both on-demand and daily use of Cialis® in the treatment of erectile dysfunction, as well as daily use for the treatment of benign prostatic hyperplasia.

Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (frequency cannot be estimated from the available data).

Very common (≥ 1/10)	Common (≥ 1/100 to >1/10)	Uncommon (≥ 1/1000 to <1/100)	Rare (≥ 1/10000 to <1/1000)	Frequency not known
Immune system disorders
		Hypersensitivity reactions	Angioneurotic edema2
Nervous system disorders
	Headache	Dizziness	Cerebrovascular events1 (including hemorrhagic events), loss of consciousness, transient ischemic attack1, migraine2, seizures2, transient global amnesia
Eye disorders
		Blurred vision, eye pain	Visual field defects, eyelid edema, conjunctival hyperemia, non-arteritic anterior ischemic optic neuropathy (NAION)2, retinal vein occlusion2	Central serous chorioretinopathy
Ear and labyrinth disorders
		Tinnitus	Sudden hearing loss
Cardiac disorders1
		Tachycardia, palpitations	Myocardial infarction, unstable angina2, ventricular arrhythmia2
Vascular disorders
	Flushing	Hypotension3, hypertension
Respiratory system disorders
	Nasal congestion	Dyspnea, epistaxis
Gastrointestinal disorders
	Dyspepsia	Abdominal pain, vomiting, nausea, gastroesophageal reflux
Skin and subcutaneous tissue disorders
		Rash	Urticaria, Stevens-Johnson syndrome2, exfoliative dermatitis2, hyperhidrosis (excessive sweating)
Musculoskeletal and connective tissue disorders
	Back pain, myalgia, limb pain
Renal and urinary disorders
		Hematuria
Reproductive system disorders
		Prolonged erection	Penile hemorrhage, hematospermia
General disorders and administration site conditions
		Chest pain1, peripheral edema, fatigue	Facial edema2, sudden cardiac death1,2

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 experience that were not observed during placebo-controlled clinical trials.

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

Individual adverse reactions. A slightly higher frequency of electrocardiogram (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 data on the use of tadalafil in patients over 65 years of age are limited, both in the treatment of erectile dysfunction and benign prostatic hyperplasia. During clinical trials of on-demand tadalafil (20 mg dose) for the treatment of erectile dysfunction, diarrhea was reported more frequently in patients over 65 years of age. In clinical trials of tadalafil 5 mg once daily for the treatment of benign prostatic hyperplasia, dizziness and diarrhea were reported more frequently in patients over 75 years of age.

Shelf life. 3 years.

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

Packaging.

Tablets 2.5 mg: 28 tablets (14×2) in blisters, in a cardboard carton.

Tablets 5 mg: 14 tablets or 28 tablets (14×2) in blisters, in a cardboard carton.

Prescription category. Prescription only.

Manufacturer.

Primary and secondary packaging, batch release:

Lilly S.A. / Lilly S.A.

Manufacturer's address and location of its operations.

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