Tadalafil

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

Composition:

Active substance: tadalafil;

1 tablet contains 5 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: white, round, biconvex film-coated tablets with "T17" imprinted on one side and "H" on the other.

Pharmacotherapeutic group. Drugs 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 the 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 has no effect in the absence of sexual stimulation.

The inhibitory effect on cGMP concentration in the corpus cavernosum is also observed in the 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 nerve activity in 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, which are present in the heart, brain, blood vessels, liver, leukocytes, skeletal muscles, and other organs. Tadalafil is 10,000 times more potent against PDE5 than against PDE3, an enzyme present in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 plays a role in 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 dosing. The absolute bioavailability of tadalafil after oral administration has not been determined.

The rate and extent of tadalafil absorption are not affected by food intake; therefore, Tadafil can be taken regardless of meals. 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 renal impairment.

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 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 (approximately 36% of the dose).

Linearity/non-linearity of pharmacokinetics. The pharmacokinetics of tadalafil in healthy volunteers is linear over time and dose. Within the dose range of 2.5 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 once-daily dosing.

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

Special patient populations

Elderly patients. Healthy elderly volunteers (aged 65 years and older) had lower oral clearance values of tadalafil, resulting in a 25% increase in AUC compared to healthy volunteers aged 19–45 years. This age-related effect is not considered 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 hemodialysis. In patients on 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 that in healthy volunteers when a 10 mg dose is administered. Safety data for tadalafil use in patients with severe hepatic impairment (Child–Pugh class C) are limited. There are no available data on once-daily tadalafil administration in patients with hepatic impairment. The physician should carefully assess the individual benefit/risk ratio when prescribing Tadafil at a once-daily dose.

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 drug is effective for the treatment of erectile dysfunction in the presence of sexual stimulation.

Treatment of symptoms of benign prostatic hyperplasia in adult men.

The drug is not indicated for use in women.

Contraindications.

Hypersensitivity to tadalafil or to any other component of the drug.

Tadalafil is known to potentiate the hypotensive effect of nitrates. This is considered to be a consequence of the combined effect of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, tadalafil is contraindicated in patients receiving organic nitrates in any dosage form (see section "Interaction with other medicinal products and other forms of interaction").

The drug should not be used in men with cardiovascular diseases for whom sexual activity is undesirable. Physicians should consider the potential cardiovascular risk associated with sexual activity in patients with cardiovascular diseases.

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

• 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 that occurred within the last 6 months;
• Patients with uncontrolled arrhythmia, arterial hypotension (< 90/50 mm Hg), or uncontrolled hypertension;
• Patients who have had a stroke within the last 6 months.

The drug 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 use of PDE5 inhibitors or not (see section "Special precautions for use").

Concomitant use of PDE5 inhibitors, including tadalafil, with guanylate cyclase stimulators such as riociguat is contraindicated, as this may potentially lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

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 metabolized primarily 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 interaction mediated by inhibition of transporters.

Cytochrome CYP450 inducers

The CYP3A4 inducer rifampicin reduces the AUC of tadalafil by 88% compared to tadalafil alone (10 mg). It can be assumed that such a reduction in concentration leads to decreased efficacy of tadalafil; the degree 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

In clinical studies, tadalafil (5 mg, 10 mg, 20 mg) was shown to potentiate the hypotensive effects of nitrates. Therefore, the use of the drug is contraindicated in patients receiving treatment with organic nitrates in any form (see section "Contraindications"). If nitrates are medically necessary for a patient receiving tadalafil at any dose (2.5–20 mg), at least 48 hours must elapse after the last dose of tadalafil before administering nitrates. In such cases, 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 20 mg dose). 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 above effects were not reported with concomitant use of alfuzosin or tamsulosin. Tadalafil should be prescribed with caution to 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 drugs were studied: calcium channel blockers (amlodipine), ACE inhibitors (enalapril), beta-blockers (metoprolol), thiazide diuretics (bendroflumethiazide), and angiotensin II receptor blockers (alone and 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 20 mg dose was studied) did not show significant interaction with the above-mentioned drug classes. In another clinical pharmacology study, concomitant use of tadalafil (20 mg dose) with multiple antihypertensive agents (up to four) was evaluated. In patients taking multiple antihypertensive drugs, blood pressure changes depended on the level of blood pressure control. Thus, in patients with well-controlled hypertension, blood pressure reduction was minimal and comparable to that in healthy volunteers. In patients with poorly controlled hypertension, more pronounced blood pressure reduction was observed, although in most patients, this reduction was not accompanied by hypotensive symptoms. In patients receiving concomitant antihypertensive therapy, the use of tadalafil at a dose of 20 mg may lead to blood pressure reduction, which (except when used concomitantly with alpha-adrenergic 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 possible blood pressure reduction should be provided to patients receiving antihypertensive drugs and tadalafil.

Riociguat

Preclinical studies revealed an additive hypotensive effect when PDE5 inhibitors were used concomitantly with riociguat. Clinical studies showed that riociguat potentiates the hypotensive action of PDE5 inhibitors. There was no evidence of beneficial clinical effect of this combination in the studied population. Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated (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 identified. However, since drug interaction studies to evaluate the effects of tadalafil and 5-alpha-reductase inhibitors have not been conducted, tadalafil should be prescribed with caution to patients receiving 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 when tadalafil and theophylline are used concomitantly, despite its lack of clinical significance.

Ethinylestradiol and terbutaline

Tadalafil increases the bioavailability of oral formulations containing ethinylestradiol. Such an increase in bioavailability can be expected when used concomitantly with terbutaline (orally), 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 (on an empty stomach after overnight fasting and without food intake for 2 hours after alcohol administration). Administration of tadalafil (20 mg) did not result in statistically significant reduction in 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 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 warfarin-induced prothrombin time.

Acetylsalicylic acid

Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid.

Antidiabetic medicinal products

Specific interaction studies of tadalafil with antidiabetic medicinal products have not been conducted.

Special precautions for use.

Before starting treatment with the medicinal product

Prior to initiating treatment with 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 initiate appropriate treatment.

Before initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of patients, as there is a certain degree of cardiac risk associated with sexual activity. Tadalafil produces 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 possible prostate carcinoma and to carefully assess cardiovascular status (see section "Contraindications").

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 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 disorders, transient ischaemic attack, chest pain, palpitations, and tachycardia. Most patients who experienced such adverse reactions had pre-existing cardiovascular risk factors. However, it is not possible to definitively determine whether the aforementioned events are related to cardiovascular risk factors, 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, consideration should be given to the clinical need for adjusting the dose of antihypertensive therapy.

The medicinal product should be prescribed with caution in patients taking alpha1-blockers, as in some patients concomitant use of these medicinal products 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.

Eyes

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. Analysis of observational study data showed 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 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 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 about the need to discontinue tadalafil and seek immediate medical help in case of sudden hearing loss or deterioration.

Renal and hepatic impairment

Daily use of the medicinal product is not recommended in patients with severe renal impairment due to increased tadalafil AUC, limited clinical experience, and poor ability to influence its clearance by dialysis.

Clinical data on the use of the medicinal product 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 or benign prostatic hyperplasia has not been evaluated in patients with hepatic insufficiency. Before prescribing the medicinal product, the physician should carefully assess the individual benefit-risk ratio of therapy.

Priapism and anatomical deformation 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 long-term loss of erectile function.

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

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 erectile dysfunction treatments have not been studied; therefore, such combinations are not recommended.

Lactose

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

Sodium

One tablet of this medicinal product contains less than 1 mmol 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 revealed any direct or indirect harmful effects on pregnancy, embryonic/foetal development, parturition, or postnatal development. As a precautionary measure, it is advisable to avoid use of the medicinal product during pregnancy.

Breastfeeding period. Available pharmacodynamic/toxicological data in animals indicate excretion of tadalafil into breast milk. Risk to the breastfed infant should not 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").

Effect on ability to drive and use machines.

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

Method of administration and dosage.

For oral use. The recommended dosage is to take tablets containing the appropriate amount of active substance.

Erectile dysfunction in adult men

The recommended dose is 10 mg taken prior to anticipated sexual activity, regardless of food intake. For patients in whom tadalafil 10 mg does not produce the desired effect, a dose of 20 mg may be used. The medication can be taken 30 minutes before 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 the medication is expected (at least twice weekly), a daily regimen with a lower dose may be more appropriate, based on patient preference and physician decision. For such patients, the recommended dose is 5 mg once daily, taken at approximately the same time each day. The dose may be reduced to 2.5 mg* daily (using tadalafil preparations with appropriate dosage due to the inability to split the tablet), depending on individual tolerability. The appropriateness of long-term daily use should be periodically reviewed.

Benign prostatic hyperplasia in adult men

The recommended dose for daily use is 5 mg taken once daily at approximately the same time, regardless of food intake. For the treatment of adult men with both erectile dysfunction and symptoms of benign prostatic hyperplasia, the recommended dose for daily use is 5 mg once daily at approximately the same time. For patients intolerant to tadalafil 5 mg daily when treating 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 groups

Elderly men. Dose adjustment is not required.

Men with renal impairment. Dose adjustment is not required for patients with mild or moderate renal impairment. For patients with severe renal impairment, the maximum recommended dose is 10 mg using tablets of appropriate strength. 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 is 10 mg taken prior to anticipated sexual activity, regardless of food intake.

Clinical data on the safety of tadalafil use in patients with severe hepatic impairment (Child–Pugh class C) are limited; if prescribing the medication, the physician must carefully assess individual benefit/risks. There are no data on the use of doses higher than 10 mg in patients with hepatic impairment.

Daily administration of tadalafil for the treatment of patients with benign prostatic hyperplasia or erectile dysfunction has not been evaluated in patients with hepatic impairment; therefore, the physician must carefully assess individual benefit/risks 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.

* Use tadalafil preparations with appropriate dosage.

Children.

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

Overdose.

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

Treatment. In case of overdose, standard symptomatic therapy should be applied. Hemodialysis had negligible effect on tadalafil elimination.

Adverse reactions.

Summary of the medicinal product 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 the drug. Adverse reactions were generally short-term and mild to moderate in severity. Most cases of headache with daily administration of the drug occurred within the first 10–30 days after initiation of treatment.

Tabulated data on adverse reactions

The table below provides data on adverse reactions observed with on-demand and daily use of tadalafil for the treatment of erectile dysfunction, as well as with daily use for the treatment of benign prostatic hyperplasia.

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 (cannot be estimated from the available data).

(1) Most of the patients who experienced such adverse reactions had a history of cardiovascular risk factors (see section "Special precautions").

(2) Adverse reactions reported during post-marketing surveillance and 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 incidence 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 in patients aged 65 years and older in clinical trials, both for the treatment of erectile dysfunction and for the treatment of benign prostatic hyperplasia, are limited. In clinical trials of on-demand tadalafil 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 of suspected adverse reactions after drug registration is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 1 or 3 blisters per carton.

Prescription category. Prescription only.

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.