Megalis

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

Composition:

Active substance: tadalafil;

1 tablet contains 20 mg of tadalafil;

Excipients: sodium croscarmellose, microcrystalline cellulose PH 101, lactose monohydrate, colloidal silicon dioxide, povidone, sodium lauryl sulfate, sodium citrate dihydrate, sodium stearyl fumarate;

coating: Instacoat universal Yellow (A05G10382);

coating composition: hypromellose, triacetin, talc, titanium dioxide (E 171), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: biconvex, film-coated, almond-shaped tablets, yellow in color, with "L 64" engraved on one side and smooth on the other.

Pharmacotherapeutic group. Agents for the treatment of erectile dysfunction.

ATC code G04BE08.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes local release of nitric oxide, inhibition of PDE5 by tadalafil results in increased levels of cGMP in the corpus cavernosum. This leads to relaxation of smooth muscles and increased blood flow into penile tissues, thereby producing an erection. Tadalafil does not exert 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, urinary bladder, and their blood vessels supplying these organs. The resulting vasodilation 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 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 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 and responsible for phototransduction. Tadalafil is also 10,000 times more potent against PDE5 than against PDE7, PDE8, PDE9, and PDE10.

Clinical Efficacy and Safety

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

Three clinical trials involving 1504 patients were conducted to determine the onset time of tadalafil's effect, demonstrating statistically significant improvement in erectile function, efficacy lasting up to 36 hours, and 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 discrimination test, it was established that tadalafil does not impair color discrimination (blue/green). The clinical trial data confirm the low affinity of tadalafil for PDE6 compared to PDE5. During all clinical trials, changes in color vision were rarely reported (<0.1%).

Three clinical 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 related to changes in other characteristics such as sperm motility, morphology, or serum follicle-stimulating hormone levels.

Tadalafil at doses ranging from 2 mg to 100 mg was evaluated in 16 clinical trials involving 3250 patients, including 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. Furthermore, improvement was observed in patients with erectile dysfunction of varying severity during tadalafil treatment (success rate was 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 patients received tadalafil, 44 received placebo) with secondary erectile dysfunction due to spinal cord injury, tadalafil demonstrated significant improvement in erectile function, with an average success rate of 48% in the tadalafil group compared to 17% in the placebo group.

Children

One study was conducted in children with Duchenne muscular dystrophy (DMD), which did not demonstrate confirmed efficacy. This tadalafil efficacy study was randomized, double-blind, placebo-controlled, involving three parallel groups of 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 at 0.3 mg/kg, 0.6 mg/kg, or placebo. Tadalafil did not demonstrate efficacy in the primary endpoint of slowing the decline in walking speed, measured by the 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 0.3 mg/kg tadalafil group (p=0.307) and 59.1 m in the 0.6 mg/kg tadalafil group (p=0.538). Confirmed efficacy was also not observed 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 oral bioavailability of tadalafil has not been determined. The rate and extent of tadalafil absorption are not affected by food intake; therefore, the drug can be administered regardless of food intake. The time of dose administration (morning or evening) has no clinically significant effect on the rate and extent of absorption.

Distribution. The mean volume of distribution is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil 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 (CYP) 3A4 isoenzyme. The major circulating metabolite is methylcatechol glucuronide. This metabolite has 13,000 times less activity against PDE5 than tadalafil. Therefore, the metabolite is not expected to have clinical activity at observed concentrations.

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

Linearity/Non-linearity of Pharmacokinetics. The pharmacokinetics of tadalafil in healthy volunteers is time- and dose-proportional. Within the dose range of 2.5 mg to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentration is achieved within 5 days with once-daily administration.

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

Special Populations

Elderly Individuals. Healthy elderly volunteers (aged 65 years and older) had lower values of oral tadalafil clearance, resulting in a 25% increase in AUC compared to healthy volunteers aged 19–45 years. This age 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 AUC was nearly doubled in patients with mild (creatinine clearance 51–80 mL/min) or moderate (creatinine clearance 31–50 mL/min) renal impairment, as well as in patients with end-stage renal disease on dialysis. In patients undergoing hemodialysis, AUC was 41% higher than in healthy volunteers.

The effect of hemodialysis on tadalafil elimination is negligible.

Hepatic Impairment. Tadalafil AUC in patients with mild to moderate hepatic impairment (Child-Pugh classes A and B) is comparable to AUC 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 tadalafil once daily in patients with hepatic impairment. Physicians should carefully assess individual benefit/risk when prescribing tadalafil once daily.

Patients with Diabetes Mellitus. Tadalafil AUC in diabetic patients 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.

Megalys is not indicated for use in women.

Contraindications.

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

During clinical studies, tadalafil demonstrated the ability 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 taking organic nitrates in any dosage form (see section "Interaction with other medicinal products and other forms of interaction").

Megalys should not be used in men with cardiovascular disorders 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 disorders 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 class 2 or higher according to the New York Heart Association classification within the last 6 months;

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

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

Megalys 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 this was associated with prior use of PDE5 inhibitors or not.

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

Interaction with other medicinal products and other forms of interaction.

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

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 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 changing Cmax. Although specific interactions have not been studied, other protease inhibitors such as saquinavir and other CYP3A4 inhibitors such as erythromycin, clarithromycin, itraconazole, and grapefruit juice should be used with caution, as they are expected to increase plasma concentrations of tadalafil when co-administered. As a result, the frequency of adverse reactions may increase.

Transporters

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

Cytochrome CYP450 inducers

The CYP3A4 inducer rifampicin reduces the AUC of tadalafil by 88 % compared to the AUC when tadalafil (10 mg) is taken alone. 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) demonstrated the ability to potentiate the hypotensive effects of nitrates. Therefore, the use of Megalys in patients receiving treatment with organic nitrates in any form is contraindicated. If nitrates are medically necessary for a patient taking Megalys due to a life-threatening condition, at least 48 hours must elapse after the last dose of Megalys before administering nitrates. In such cases, nitrates should be administered under strict medical supervision with appropriate hemodynamic monitoring.

Antihypertensive agents (including calcium channel blockers)

When tadalafil (5 mg once daily or a single dose of 20 mg) 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 for use.

In interaction studies involving a limited number of healthy volunteers, the above effects were not reported with concomitant use of the drug with 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 with the lowest dose and gradually increased.

In clinical pharmacodynamic studies, the potential of tadalafil to potentiate the hypotensive effects of antihypertensive agents was evaluated. Major classes of drugs were studied: calcium channel blockers (amlodipine), angiotensin-converting enzyme inhibitors (enalapril), β-adrenoreceptor 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-adrenoreceptor blockers, and/or α-adrenoreceptor blockers). Tadalafil (10 mg, except for interaction studies with angiotensin II receptor blockers and amlodipine, where the effect of a 20 mg dose 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 drugs, changes in blood pressure 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 uncontrolled 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 lead to 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 receiving tadalafil with concomitant antihypertensive therapy and those receiving tadalafil alone. Nevertheless, appropriate recommendations regarding the potential reduction in blood pressure should be provided to patients receiving antihypertensive agents and Megalys.

Riociguat

In preclinical studies, an additive hypotensive effect was observed with concomitant use of PDE5 inhibitors and riociguat. In clinical studies, riociguat was found to potentiate the hypotensive action of PDE5 inhibitors. There was no evidence of a favorable clinical effect of this combination in the studied population. Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated.

5-α-reductase inhibitors

In a clinical study comparing concomitant use of tadalafil 5 mg and finasteride 5 mg versus placebo and finasteride 5 mg for the 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 when tadalafil (10 mg) was administered with 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 an increase in bioavailability may be expected with concomitant use of terbutaline (oral), although the clinical consequences of this combination are unknown.

Alcohol

Alcohol (maximum average concentration of 0.08 %) did not affect the concomitant use of tadalafil (10 mg or 20 mg). No changes in tadalafil concentration were observed over the next three hours after simultaneous intake of alcohol with tadalafil. Alcohol was administered to achieve maximum alcohol absorption (on an empty stomach after overnight fasting and without food intake for 2 hours after alcohol administration). Administration of tadalafil (20 mg) did not lead to a statistically significant reduction in mean blood pressure values 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 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 prothrombin time induced by warfarin.

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 of tadalafil with antidiabetic medicinal products have not been conducted.

Special precautions for use.

Before initiating treatment with the medicinal product, the physician should take a medical history and perform a physical examination of the patient, identify potential underlying causes of erectile dysfunction and benign prostatic hyperplasia, and prescribe an appropriate treatment regimen.

Prior to 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 slight and transient reduction in blood pressure (see section "Pharmacological properties") and potentiate the hypotensive effect of nitrates (see section "Contraindications").

Before initiating tadalafil therapy for symptoms of benign prostatic hyperplasia, the patient should be examined to exclude possible prostate carcinoma and carefully assessed for cardiovascular status (see section "Contraindications").

Evaluation of erectile dysfunction should include identification of potential underlying causes and their appropriate treatment following adequate medical assessment. It is unknown whether MEGALIS is effective in patients who have undergone pelvic surgery or nerve-sparing radical prostatectomy.

Cardiovascular system

During the post-marketing period and/or in clinical trials, serious adverse events related to the cardiovascular system 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 tadalafil, 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 MEGALIS is initiated, consideration should be given to the clinical need for adjusting the dose of antihypertensive therapy.

MEGALIS should be used 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"). Concomitant use of tadalafil and doxazosin is not recommended.

Vision

Cases of visual disturbances 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. Since this risk may be elevated 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 (see section "Contraindications").

Sudden hearing loss or hearing impairment

Cases of sudden hearing loss following tadalafil administration have been reported. Regardless of whether other risk factors were present (age, presence of diabetes, hypertension, or history of hearing loss), patients should be warned to discontinue tadalafil and seek medical help immediately in case of sudden hearing impairment or hearing loss.

Renal and hepatic impairment

Daily use of MEGALIS is not recommended in patients with severe renal impairment due to increased tadalafil AUC, limited clinical experience, and poor ability to affect its clearance via dialysis.

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

The daily use of the medicinal product for the treatment of erectile dysfunction as well as for the treatment of benign prostatic hyperplasia has not been evaluated in patients with hepatic insufficiency. Before prescribing MEGALIS, 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. If priapism is not treated promptly, it may lead to penile tissue damage and long-term loss of potency.

MEGALIS should be used with caution in patients with anatomical deformity of the penis (e.g., angulation, cavernous 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

MEGALIS should be used with caution in patients taking CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), as co-administration with tadalafil results in increased tadalafil 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 tadalafil in combination with other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Therefore, patients should be informed not to take MEGALIS 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 syndrome should not take this medicinal product.

Use during pregnancy or breastfeeding.

MEGALIS is not indicated for use in women.

Fertility. Effects indicating potential impairment of fertility were observed in dogs. Two clinical studies indicated 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 affect reaction speed when driving or operating machinery.

The effect of MEGALIS on the ability to drive or operate machinery is negligible. Although the frequency of dizziness was similar in clinical trials with placebo and tadalafil, patients should be aware of how the medicinal product affects them before driving or operating machinery.

Method of Administration and Dosage

For oral use.

The efficacy of tadalafil lasts up to 36 hours after dose administration.

Adult Men

The recommended dose is 10 mg* taken prior to anticipated sexual activity, regardless of food intake. In patients who do not achieve an adequate response with tadalafil 10 mg*, a dose of 20 mg may be used.

The tablet should be taken at least 30 minutes before anticipated sexual activity. The efficacy of tadalafil lasts up to 36 hours after dose administration.

The maximum recommended frequency of dosing is once daily.

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

If frequent use of Megalis (at least twice weekly) is anticipated, a daily regimen with a lower dose of tadalafil may be more appropriate, based on patient preference and physician's decision. For such patients, the recommended dose is 5 mg* daily at approximately the same time each day. The dose may be reduced to 2.5 mg* daily based on individual tolerability. The continued need for long-term daily treatment should be periodically reassessed.

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* when using appropriately dosed tablets.

Men with Hepatic Impairment

The recommended dose of tadalafil is 10 mg* prior to anticipated sexual activity, regardless of food intake. Clinical data on the safety of Megalis in patients with severe hepatic impairment (Child–Pugh class C) are limited; if the medicinal product is prescribed, 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.

Men with Diabetes Mellitus

Dose adjustment is not required.

*Use tadalafil medicinal products at the appropriate dosage strength.

Children

Megalis is not intended for use in children under 18 years of age.

Overdose

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

Treatment. In case of overdose, standard symptomatic and supportive treatment should be administered as necessary. Hemodialysis has an insignificant effect on tadalafil elimination.

Adverse reactions.

Short description of the safety profile

The most commonly reported adverse effects during treatment of erectile dysfunction or benign prostatic hyperplasia were headache, dyspepsia, back pain, and myalgia, with frequency increasing with higher doses of tadalafil. Adverse reactions were generally short-lived and mild to moderate in severity. Most cases of headache with daily tadalafil use occurred within the first 10–30 days after starting 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), using tadalafil as needed and daily dosing for the treatment of erectile dysfunction, and daily dosing for the treatment of benign prostatic hyperplasia.

The adverse reactions listed below are categorized according to the following frequency classification: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), very rare (<1/10000), frequency not known (frequency cannot be estimated from the available data).

1 Most of the patients who experienced such adverse reactions had cardiovascular risk factors in their medical history (see section "Dosage and Administration").

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 ECG abnormalities, primarily sinus bradycardia, was 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. Data on the use of tadalafil in patients aged 65 years and older in clinical trials for the treatment of erectile dysfunction and benign prostatic hyperplasia are limited. In clinical trials of on-demand tadalafil (20 mg dose) for the treatment of erectile dysfunction, diarrhea occurred more frequently in patients aged 65 years and older. 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 aged 75 years and older.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via national reporting systems.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

1, 2, or 4 tablets in a blister; 1 blister per cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

MACLEODS PHARMACEUTICALS LIMITED.

Manufacturer's address and location of its business operations.

Village Thedda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.