Tadalafil

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

Composition:

Active ingredient: tadalafil;

1 tablet contains 10 mg or 20 mg of tadalafil;

Excipients: lactose monohydrate, copovidone, colloidal anhydrous silicon dioxide, polyethylene glycol castor oil hydrogenated; microcrystalline cellulose, sodium croscarmellose, magnesium stearate; film coating: Opadry II White 32K580001 (hypromellose HPMC 2910, lactose monohydrate, titanium dioxide (E 171), triacetin, talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg tablets: white, capsule-shaped, biconvex, film-coated tablets with the imprint "T16" on one side and "H" on the other;

20 mg tablets: white, capsule-shaped, biconvex, film-coated tablets with the imprint "T15" on one side and "H" 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 the penile tissue, thereby producing an erection. Tadalafil does not act without 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 blood to the aforementioned 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 in 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 on PDE5 is 10,000 times greater than its effect on PDE1, PDE2, and PDE4 enzymes 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.

Pharmacokinetics.

Absorption. Tadalafil is well absorbed after oral administration. The mean maximum plasma concentration (Cmax) is reached on average within 2 hours after administration. The absolute bioavailability of tadalafil after oral administration has not been established.

The rate and extent of tadalafil absorption are not affected by food intake; therefore, Tadalafil can be taken with or without food. The time of dosing (morning or evening) does not have a 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 isoform 3A4 (CYP3A4). The main 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 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 (about 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 to 20 mg, the area under the concentration-time curve (AUC) increases proportionally with dose. Steady-state plasma concentrations are achieved within 5 days with daily administration once daily.

The pharmacokinetics of the drug is the same in patients with erectile dysfunction and in those without it.

Special patient groups.

Elderly patients. Healthy elderly volunteers (aged 65 years and older) had lower values of tadalafil clearance after oral administration, 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), tadalafil 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, Cmax 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. Data on the safety of tadalafil use in patients with severe hepatic impairment (Child–Pugh class C) are limited. When prescribing Tadalafil, the physician should carefully assess the individual benefit-risk ratio. There are no data on the use of doses higher than 10 mg in patients with hepatic impairment.

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

Clinical characteristics.

Indications.

Treatment of erectile dysfunction in adult men.

The medicinal product is effective in the presence of sexual stimulation.

The medicinal product is not indicated for use in women.

Contraindications.

Hypersensitivity to tadalafil or to any of the excipients.

Tadalafil has been shown to potentiate the hypotensive effects of nitrates. This is considered to be the result 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").

The medicinal product should not be used in men with cardiovascular conditions for whom sexual activity is inadvisable. Physicians should consider the potential cardiac risk associated with sexual activity in patients with cardiovascular disease.

The use of tadalafil is contraindicated in the following patient groups with cardiovascular disease:

• patients who have had a 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 that occurred 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.

The medicinal product 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 prior exposure to 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 (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Clinically significant interaction at higher doses cannot be excluded if such interaction was observed at lower doses (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 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 for use"). As a result, the frequency of adverse reactions may increase (see section "Adverse reactions").

Transporters.

The effect of transporters, such as P-glycoprotein, on the distribution of tadalafil is unknown. Therefore, there is a possibility of 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 plasma concentrations of tadalafil.

Effect of tadalafil on other medicinal products.

Nitrates.

In clinical studies, tadalafil (5 mg, 10 mg, 20 mg) was shown to potentiate the hypotensive effects of nitrates. Therefore, the use of the medicinal product in patients receiving treatment with organic nitrates in any form is contraindicated (see section "Contraindications"). If nitrates are medically necessary in a patient receiving tadalafil at any dose (2.5–20 mg) due to a life-threatening condition, at least 48 hours must elapse after the last dose of tadalafil before administering nitrates. In such cases, nitrates should be administered under medical supervision with appropriate hemodynamic monitoring.

Antihypertensive agents (including calcium channel blockers).

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

The aforementioned effects were not reported with concomitant use of alfuzosin or tamsulosin. Tadalafil should be prescribed with caution in patients receiving treatment with alpha-adrenergic blockers, especially elderly patients. Treatment should be initiated at the lowest dose and gradually increased.

In clinical pharmacodynamic studies, the potential of tadalafil to potentiate the hypotensive effects of major antihypertensive agents was evaluated. Major classes of antihypertensive agents were studied: calcium channel blockers (amlodipine), ACE inhibitors (enalapril), beta-blockers (metoprolol), thiazide diuretics (bendroflumethiazide), and angiotensin II receptor blockers (alone or in combination with thiazide diuretics, calcium channel blockers, beta-blockers, and/or alpha-adrenergic blockers). Tadalafil (10 mg dose, except for interaction studies with angiotensin II receptor blockers and amlodipine, where the 20 mg dose was studied) did not show significant interaction with the aforementioned classes of medicinal products. In another clinical pharmacology study, concomitant use of tadalafil (20 mg) with multiple antihypertensive agents (up to four) was evaluated. In patients taking multiple antihypertensive agents, the change 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 poorly controlled hypertension, a more pronounced reduction in blood pressure was observed, although in most patients this reduction was not accompanied by hypotensive symptoms. In patients receiving concomitant therapy with antihypertensive agents, administration 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 alpha-adrenergic blockers) is generally minimal and clinically insignificant. Analysis of phase 3 clinical trial data did not reveal differences in adverse reactions between patients receiving tadalafil with concomitant antihypertensive therapy and those receiving tadalafil alone. Nevertheless, appropriate advice regarding the potential reduction in blood pressure should be provided to patients receiving antihypertensive agents and tadalafil.

Riociguat.

In preclinical studies, an additive hypotensive effect was observed with concomitant use of PDE5 inhibitors and riociguat. In clinical studies, riociguat was shown to potentiate the hypotensive effect of PDE5 inhibitors. There was no evidence of beneficial clinical effect of this combination in the studied population. Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated (see section "Contraindications").

5-alpha-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 observed. However, since drug interaction studies to assess the effects of tadalafil and 5-alpha-reductase inhibitors have not been conducted, tadalafil should be prescribed with caution in patients receiving treatment with 5-alpha-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 with concomitant use of tadalafil and theophylline, although it is 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, although the clinical consequences of this combination are unknown.

Alcohol.

Alcohol (mean maximum concentration 0.08 %) did not affect the concomitant use of tadalafil (10 mg or 20 mg). No changes in tadalafil concentration were observed during the subsequent 3 hours after 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 a statistically significant reduction in blood pressure when alcohol was consumed (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 arterial hypotension, and dizziness was observed 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. Tadalafil does not inhibit or induce CYP450 isoenzymes, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9, and CYP2C19.

CYP2C9 substrates (e.g., R-warfarin).

Tadalafil (10 mg and 20 mg) did not show a 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 studies on the interaction of tadalafil with antidiabetic medicinal products have not been conducted.

Special precautions for use.

Before initiating treatment with the medicinal product.

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

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of 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 decrease in blood pressure (see section "Pharmacological properties") and potentiate the hypotensive effect of nitrates (see section "Contraindications").

The evaluation of erectile dysfunction should include identification of potential underlying causes and their appropriate management following adequate medical assessment. It is unknown whether the medicinal product is effective in patients who have undergone pelvic surgery or radical prostatectomy without nerve-sparing.

Cardiovascular system.

During the post-marketing period and/or clinical trials, serious adverse events related to the cardiovascular system have been reported, including myocardial infarction, sudden cardiac death, unstable angina, ventricular arrhythmia, cerebrovascular accidents, transient ischaemic attack, chest pain, palpitations, and tachycardia. Most patients who experienced such adverse reactions had underlying cardiovascular risk factors. However, it is not possible to definitively determine whether the aforementioned events are related to these risk factors, the use of the medicinal product, 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 the medicinal product is initiated, the clinical need for adjusting the dose of antihypertensive therapy should be considered.

The medicinal product should be prescribed with caution in patients taking alpha1-blockers, as in some patients concomitant administration 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 chorioretinopathy (CSC) and non-arteritic anterior ischaemic optic neuropathy (NAION), have been reported during the use of tadalafil and other PDE5 inhibitors. In most cases, symptoms of CSC resolved spontaneously after discontinuation of tadalafil. Observational study data analyses have 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 occur in all patients using tadalafil, physicians should inform patients about the necessity to discontinue tadalafil and seek immediate medical help in case of sudden vision loss (see section "Contraindications").

Worsening or sudden hearing loss.

Cases of sudden hearing loss after administration of tadalafil have been reported. Regardless of the presence of other risk factors (such as age, diabetes, hypertension, or history of hearing loss), patients should be advised to discontinue tadalafil and seek immediate medical attention in case of sudden hearing decrease or hearing loss.

Hepatic impairment.

When prescribing the medicinal product to patients with severe hepatic impairment (Child–Pugh class C), the physician should carefully evaluate the individual benefit/risk ratio of therapy.

Priapism and anatomical deformity of the penis.

Patients who experience an erection 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 permanent loss of erectile function.

The medicinal product should be used with caution in patients with anatomical deformity of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients with conditions that may predispose to priapism (e.g., sickle cell anaemia, multiple myeloma, or leukemia).

Concomitant use with CYP3A4 inhibitors.

The medicinal product 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 the medicinal product in combination with other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied; therefore, such combinations are not recommended.

Lactose.

The medicinal product contains lactose monohydrate; therefore, patients with rare hereditary conditions of galactose intolerance, the glucose-galactose malabsorption syndrome, or Lapp lactase deficiency 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.

The medicinal product 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 shown 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 the medicinal product during pregnancy.

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

Fertility. Impairment of fertility is not expected, although decreased sperm concentration has been observed in some men (see section "Pharmacological properties").

Ability to drive and use machines.

The effect of the medicinal product on the ability to drive and operate machinery is negligible. When driving or operating machinery, the individual response to the medicinal product (possible decrease in blood pressure, dizziness, visual disturbances) should be taken into account, especially at the beginning of treatment and when changing dosage.

Method of Administration and Dosage.

For oral use. The recommended dosage should be taken as tablets containing the appropriate amount of active substance.

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

The medication should be taken at least 30 minutes before anticipated sexual activity.

The efficacy of tadalafil lasts up to 36 hours after dosing.

The maximum recommended frequency of administration is once daily.

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

If frequent use of the medication is anticipated (at least twice weekly), a regimen of daily administration of lower doses may be more appropriate, based on patient preference and physician decision. For such patients, the recommended dose is 5 mg* daily (tadalafil products with corresponding dosage should be used due to the inability to split the tablet), taken approximately at the same time each day. The dose may be reduced to 2.5 mg* daily (tadalafil products with corresponding dosage should be used due to the inability to split the tablet), depending on individual tolerability. The appropriateness of long-term daily use should be periodically reviewed.

Special patient groups.

Elderly men. Dose adjustment is not required.

Men with renal impairment. Dose adjustment is not required in patients with mild or moderate renal impairment. For patients with severe renal impairment, the maximum recommended dose is 10 mg. Daily administration of tadalafil is not recommended in patients with severe renal impairment (see sections "Special precautions for use" and "Pharmacological properties").

Men with hepatic impairment. For the treatment of erectile dysfunction, the recommended dose is 10 mg taken 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; if prescribing, the physician should carefully assess the individual benefit/risk ratio. There are no data on the use of tadalafil at doses above 10 mg in patients with hepatic impairment. There are no data on the use of tadalafil 2.5–5 mg* once daily in patients with hepatic impairment; therefore, if prescribing, the physician should carefully assess the individual benefit/risk ratio of administering tadalafil 2.5–5 mg* once daily (see sections "Special precautions for use" and "Pharmacological properties").

Men with diabetes mellitus. Dose adjustment is not required.

Special precautions for disposal

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

* Use tadalafil products with the appropriate dosage.

Children.

This medicinal product 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 in patients with erectile dysfunction up to 100 mg were associated with adverse effects similar to those observed with lower doses.

Treatment. In case of overdose, standard symptomatic therapy should be applied. Hemodialysis has negligible 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, with frequency increasing with higher doses of the drug. Adverse reactions were transient and mild to moderate in severity. Most cases of headache during daily administration occurred within the first 10–30 days after initiation of treatment.

Tabulated adverse reaction data.

The table below presents data on adverse reactions associated with on-demand and daily use of tadalafil for the treatment of erectile dysfunction.

The following classification is used to assess the frequency of adverse reactions: 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 (cannot be estimated from available data).

(1) Most of the patients who experienced such adverse reactions had cardiovascular risk factors in their medical history (see section "Special Warnings and Precautions for Use").

(2) Adverse reactions reported during post-marketing surveillance that were not observed during placebo-controlled clinical studies.

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

Isolated adverse reactions. A slightly higher frequency of ECG changes, most commonly sinus bradycardia, 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 groups. Data on the use of tadalafil for the treatment of erectile dysfunction in patients aged 65 years and older are limited. When tadalafil was used on-demand for the treatment of erectile dysfunction, diarrhea was reported more frequently in patients aged 65 years and older.

Reporting suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC.

Keep out of reach and sight of children.

Packaging.

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

Prescription category. Prescription-only medicine.

Manufacturer. Hetero Labs Limited.

Manufacturer's address and location of operations.

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.