Pinap

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PINAP (PINUP)

Composition:

Active substance: tadalafil;

1 tablet contains 2.5 mg or 5 mg or 10 mg or 20 mg of tadalafil;

Excipients:

Tablet core: lactose monohydrate, sodium croscarmellose, sodium lauryl sulfate, hydroxypropylcellulose, polysorbate 80, magnesium stearate;

Tablet coating:

for 2.5 mg tablets: ready-to-use mixture [hypromellose, lactose monohydrate, titanium dioxide (E 171), triacetin, talc, yellow iron oxide (E 172), red iron oxide (E 172)];

for 5 mg tablets: ready-to-use mixture [hypromellose, lactose monohydrate, titanium dioxide (E 171), triacetin, talc, yellow iron oxide (E 172)];

for 10 mg tablets: ready-to-use mixture [hypromellose, lactose monohydrate, titanium dioxide (E 171), triacetin, talc, yellow iron oxide (E 172), black iron oxide (E 172)];

for 20 mg tablets: ready-to-use mixture [hypromellose, lactose monohydrate, titanium dioxide (E 171), triacetin, talc, yellow iron oxide (E 172)].

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets in the shape of a capsule, biconvex;

2.5 mg tablets: yellow-orange, with the inscription "T 2" on one side;

5 mg tablets: yellow, with the inscription "T 5" on one side;

10 mg tablets: yellow, with the inscription "T 10" on one side;

20 mg tablets: yellow, with the inscription "T 20" on one side.

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, when used to treat erectile dysfunction, does not exhibit its effect in the absence of sexual stimulation.

The inhibitory effect on cGMP concentration in the corpus cavernosum is also observed in smooth muscles of the prostate, bladder, and their blood vessels supplying these organs. The resulting vascular relaxation increases blood perfusion and may contribute to alleviating 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 in 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 exceeds its effect on PDE1, PDE2, and PDE4 enzymes—present in the heart, brain, blood vessels, liver, and other organs—by 10,000 times. Tadalafil is approximately 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 about 700 times more potent against PDE5 than against PDE6, an enzyme present in the retina responsible for phototransduction. Tadalafil is also 10,000 times more potent against PDE5 than against PDE7, PDE8, PDE9, and PDE10.

Clinical efficacy and safety.

In healthy volunteers, tadalafil administration did not show significant differences compared to placebo in systolic and diastolic blood pressure in the supine position (mean maximum decrease 1.6/0.8 mmHg, respectively), systolic and diastolic blood pressure in the standing position (mean maximum decrease 0.2/4.6 mmHg, respectively), or in significant changes in heart rate.

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

Three clinical 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 parameters such as sperm motility, morphology, or blood levels of follicle-stimulating hormone.

Erectile dysfunction.

Three clinical trials involving 1054 patients were conducted to determine the onset of tadalafil's effect, demonstrating statistically significant improvement in erectile function, efficacy lasting up to 36 hours, and an effect observed as early as 16 minutes after dosing compared to placebo (on-demand tadalafil use).

In a 12-week study involving 186 patients (142 receiving tadalafil, 44 receiving placebo) with erectile dysfunction secondary to spinal cord injury, tadalafil significantly improved erectile function. The mean percentage of successful attempts with tadalafil 10 mg or 20 mg (dose adjustment, on-demand use) was 48% compared to 17% in the placebo group.

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

Benign prostatic hyperplasia.

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

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

Maintenance of tadalafil's effect was evaluated in an additional open-label study, which demonstrated that the improvement in IPSS observed over 12 weeks was maintained for up to 1 year after treatment with tadalafil 5 mg.

Children.

One study was conducted in children with Duchenne muscular dystrophy (DMD), which did not demonstrate confirmed efficacy. This study of tadalafil's efficacy was a randomized, double-blind, placebo-controlled trial with three parallel groups involving 331 boys aged 7 to 14 years with DMD who were also receiving corticosteroid therapy. The study included a 48-week double-blind period during which patients were assigned to receive tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo daily. Tadalafil did not demonstrate efficacy on the primary endpoint of slowing the decline in walking speed, measured by changes in distance in the 6-minute walk test (6MWT). The change in mean distance in the 6MWT, calculated using the least squares method, at week 48 was 51.0 m in the placebo group compared to 64.7 m in the tadalafil 0.3 mg/kg group (p=0.307) and 59.1 m in the tadalafil 0.6 mg/kg group (p=0.538). Confirmed efficacy was also not observed during repeated analyses of this study. Overall safety results from this study were generally consistent with the known safety profile of tadalafil and the adverse events expected in the pediatric DMD population receiving corticosteroid therapy.

Pharmacokinetics.

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

The rate and extent of tadalafil absorption are not affected by food intake; therefore, Pinap 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 3A4 (CYP3A4) 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/h, and the mean elimination half-life is 17.5 hours in healthy subjects. Tadalafil is eliminated predominantly as inactive metabolites, mainly in feces (approximately 61% of the dose) and to a lesser extent in urine (approximately 36% of the dose).

Linearity/non-linearity of pharmacokinetics. Tadalafil pharmacokinetics in healthy volunteers are linear and time-proportional. Within the dose range of 2.5 mg to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentrations are achieved within 5 days with once-daily dosing.

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

Special population groups.

Elderly. Healthy elderly volunteers (aged 65 years and older) had lower oral clearance of tadalafil, resulting in a 25% increase in exposure (AUC) compared to healthy volunteers aged 19–45 years. This age-related effect is not clinically significant and does not require dose adjustment.

Renal impairment. In clinical pharmacology studies using single doses of tadalafil (5–20 mg), tadalafil exposure (AUC) nearly doubled in patients with mild (creatinine clearance 51–80 mL/min) or moderate (creatinine clearance 31–50 mL/min) renal impairment, as well as in patients with end-stage renal disease on dialysis. In patients undergoing hemodialysis, the maximum plasma concentration (Cmax) was 41% higher than in healthy volunteers.

The effect of hemodialysis on tadalafil elimination is negligible.

Hepatic impairment. Tadalafil exposure (AUC) in patients with mild to moderate hepatic impairment (Child-Pugh classes A and B) is comparable to that in healthy volunteers when a 10 mg dose is administered. Data on the safety of tadalafil administration 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 Pinap once daily.

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

Clinical characteristics.

Indications.

For 2.5 mg, 10 mg, 20 mg dosage. Treatment of erectile dysfunction in adult men. The drug is effective in the presence of sexual stimulation.

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

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

Pynap is not indicated for use in women.

Contraindications.

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

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

Pynap should not be used in men with cardiovascular diseases for whom sexual activity is undesirable. Physicians should consider the potential cardiovascular risk of sexual activity in patients with a history of cardiovascular disease.

The following groups of patients with cardiovascular diseases were not included in clinical trials; therefore, the use of tadalafil is contraindicated in these patients:

− patients who have had myocardial infarction within the last 90 days;

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

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

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

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

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

Interaction studies were conducted for 10 mg and 20 mg dosages; data are provided below. Regarding interaction studies conducted only with 10 mg tadalafil, clinically significant interactions with higher doses cannot be excluded.

Effect of other medicinal products on tadalafil.

Cytochrome CYP450 inhibitors.

Tadalafil is primarily metabolized by CYP3A4. The selective CYP3A4 inhibitor ketoconazole (200 mg daily) increases the area under the concentration-time curve (AUC) of tadalafil (10 mg) by 2-fold and Cmax by 15% compared to tadalafil alone. Ketoconazole (400 mg daily) increases the 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 tadalafil distribution 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 tadalafil alone (10 mg). This reduction in concentration may lead to decreased 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 tadalafil plasma concentrations.

Effect of tadalafil on other medicinal products.

Nitrates. During clinical studies, tadalafil (5 mg, 10 mg, 20 mg) demonstrated the property of enhancing the hypotensive effects of nitrates. Therefore, the use of Pynap is contraindicated in patients receiving treatment with organic nitrates in any form (see section "Contraindications"). Based on a clinical study involving 150 patients who received tadalafil 20 mg daily for 7 days and sublingual nitroglycerin 0.4 mg (at varying time intervals), this interaction lasted longer than 24 hours and was not observed after 48 hours following the last dose of tadalafil. Therefore, if nitrates are medically necessary for a patient prescribed Pynap at any dosage (2.5–20 mg), at least 48 hours must elapse after the last dose of Pynap before administering nitrates. In such cases, nitrate administration must be performed under strict medical supervision with appropriate hemodynamic monitoring.

Antihypertensive agents (including calcium channel blockers).

Significant potentiation of the hypotensive effect of the α-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 (see section "Special precautions for use").

In interaction studies involving a limited number of healthy volunteers, the above effects were not reported with concomitant use of alfuzosin or tamsulosin. Tadalafil should be prescribed with caution to patients receiving treatment with any α-adrenergic blockers, particularly elderly individuals. Treatment should be initiated at the lowest dose, with gradual dose escalation.

Clinical pharmacodynamic studies evaluated the potential of tadalafil to enhance the hypotensive effects of antihypertensive agents. Major drug classes were investigated: calcium channel blockers (amlodipine), angiotensin-converting enzyme inhibitors (enalapril), β-adrenergic 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-blockers, and/or α-blockers). Tadalafil (10 mg dose, except for interaction studies with angiotensin II receptor blockers and amlodipine, where 20 mg was studied) did not show significant interaction with the above-mentioned drug classes. In another clinical pharmacology study, concomitant use of tadalafil (20 mg) with multiple antihypertensive agents (up to four) was investigated. In patients taking multiple antihypertensive drugs, blood pressure changes depended on the level of blood pressure control. Thus, in patients with well-controlled hypertension, 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 was not accompanied by hypotensive symptoms. In patients receiving concomitant antihypertensive therapy, tadalafil 20 mg may cause a reduction in blood pressure, which (except in the case of concomitant use with α-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 Pynap.

Riociguat.

An additive hypotensive effect was observed in preclinical studies with concomitant use of PDE5 inhibitors and riociguat. Clinical studies demonstrated that riociguat enhances the hypotensive effect of PDE5 inhibitors. There was no evidence of favorable clinical effect of this combination in the studied population. Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated (see section "Contraindications").

5-α-reductase inhibitors.

In a clinical study comparing concomitant use of tadalafil 5 mg and finasteride 5 mg versus placebo and finasteride 5 mg for 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 have not been 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 between tadalafil (10 mg) and theophylline (a non-selective phosphodiesterase inhibitor). The only pharmacodynamic effect was a slight increase in heart rate (3.5 beats/min). The possibility of this effect should be considered when combining tadalafil and theophylline, 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 (orally), although the clinical consequences of this combination are unknown.

Alcohol.

Alcohol (average maximum concentration 0.08%) did not affect the concomitant use of tadalafil (10 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 mean blood pressure when combined with alcohol (0.7 g/kg or approximately 180 ml of 40% alcohol (vodka) in an 80 kg man), although postural dizziness and orthostatic hypotension were observed in some patients. Administration of tadalafil with lower doses of alcohol (0.6 g/kg) did not cause hypotension, and dizziness occurred at the same frequency as with alcohol alone. The effect of alcohol on cognitive function was not enhanced by concomitant use of tadalafil (10 mg).

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

Aspirin.

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

Antidiabetic medicinal products.

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

Special precautions for use.

Before initiating treatment with Pinap.

Before prescribing the medicinal product, the physician should take a medical history and perform a physical examination to identify potential causes of erectile dysfunction and benign prostatic hyperplasia, and initiate appropriate treatment.

Prior to initiating any treatment for erectile dysfunction, physicians should assess the cardiovascular status of their patients, as there is a certain degree of cardiovascular risk associated with sexual activity. Tadalafil has a vasodilatory effect, which may lead to a slight and transient reduction in blood pressure (see section "Pharmacological properties") and may potentiate the hypotensive effect of nitrates (see section "Contraindications").

Before initiating tadalafil therapy for symptoms of benign prostatic hyperplasia, the patient should be evaluated to exclude the possibility of 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. The efficacy of tadalafil in patients who have undergone pelvic surgery or nerve-sparing radical prostatectomy is unknown.

Cardiovascular system.

During the post-marketing period and/or clinical trials, serious cardiovascular events have been reported, including myocardial infarction, sudden cardiac death, unstable angina, ventricular arrhythmia, cerebrovascular accident, transient ischaemic 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 these events are related to underlying 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 Pinap is initiated, the clinical need for adjustment of antihypertensive therapy should be considered.

Pinap should be prescribed with caution in patients taking α1-blockers, as in some patients concomitant use of these agents 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 (CSCR), and non-arteritic anterior ischaemic optic neuropathy (NAION) have been reported during the use of tadalafil and other PDE5 inhibitors. Most cases of CSCR 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 taking tadalafil, physicians should inform patients of the necessity to immediately discontinue tadalafil and seek medical help in case of sudden visual field defect, decreased visual acuity, and/or visual distortion (see section "Contraindications").

Worsening or sudden hearing loss.

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

Renal and hepatic impairment.

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

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

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

Priapism and anatomical deformation of the penis.

If an erection lasts 4 hours or longer, the patient should seek immediate medical help. If priapism is not treated promptly, it may lead to penile tissue damage and permanent loss of potency.

Pinap should be prescribed 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 (such as sickle cell anaemia, multiple myeloma, or leukaemia).

Concomitant use with CYP3A4 inhibitors.

Pinap 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 tadalafil in combination with other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Patients should therefore be informed not to take Pinap in such combinations.

Sodium.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially "sodium-free".

Lactose.

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

Use during pregnancy or breastfeeding.

Pinap is not indicated for use in women.

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

Breastfeeding. Available pharmacodynamic/toxicological animal data indicate excretion of tadalafil into milk. A risk to breastfed infants cannot be excluded. Pinap should not be used during breastfeeding.

Fertility. Effects indicating impaired 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 tadalafil on the ability to drive or operate machinery is negligible. Although the frequency of reports of dizziness in clinical trials with placebo and tadalafil was similar, patients should be aware of how Pinap affects them before driving or operating machinery.

Method of Administration and Dosage.

For oral use.

Erectile dysfunction in adult men.

The recommended dose is 10 mg taken prior to anticipated sexual activity, regardless of food intake. For patients who do not achieve an adequate response with 10 mg of Pinap, 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.

Pinap 10 mg and 20 mg are intended to be taken prior to anticipated sexual activity and are not recommended for daily use.

If frequent use of Pinap is anticipated (at least twice weekly), a daily regimen with lower doses of Pinap may be more appropriate, based on patient preference and physician decision. For such patients, the recommended dose is 5 mg once daily at approximately the same time each day. The dose may be reduced to 2.5 mg daily based on individual tolerability. The appropriateness of long-term daily use should be periodically re-evaluated.

Benign prostatic hyperplasia in adult men.

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

Special patient populations.

Elderly men. Dose adjustment is not required.

Men with renal impairment. Dose adjustment is not required in patients with mild or moderate renal impairment. For patients with severe renal impairment, the maximum recommended dose is 10 mg (on-demand use of Pinap). Daily administration of Pinap at doses of 2.5 mg or 5 mg is not recommended for the treatment of patients with severe renal impairment and benign prostatic hyperplasia or erectile dysfunction (see sections "Special precautions for use" and "Pharmacological properties").

Men with hepatic impairment.

For the treatment of erectile dysfunction, the recommended dose of Pinap is 10 mg taken prior to anticipated sexual activity, independent of food intake (on-demand use of Pinap). Clinical data on the safety of tadalafil in patients with severe hepatic impairment (Child–Pugh class C) are limited; if prescribed, the physician should carefully assess the individual benefit/risk ratio. There are no data on the use of tadalafil at 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 should carefully evaluate the individual benefit/risks of such therapy (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 should be disposed of in accordance with current regulatory requirements.

Children.

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

Overdose.

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

Treatment. In case of overdose, standard symptomatic treatment should be initiated as necessary. Hemodialysis has minimal effect on the elimination of tadalafil.

Adverse reactions.

Summary of the medicinal product's safety profile.

The most commonly reported adverse effects during treatment of erectile dysfunction or benign prostatic hyperplasia were headache, dyspepsia, back pain, and myalgia, with incidence rates increasing with higher doses of tadalafil. Adverse reactions were generally transient and mild to moderate in severity. Most cases of headache during daily administration of tadalafil occurred within the first

10–30 days after initiation of treatment.

Tabulated data on adverse reactions.

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

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

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 from post-marketing experience which were not observed during placebo-controlled clinical trials.

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

Isolated 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 over 65 years of age in clinical studies, both for the treatment of erectile dysfunction and for the treatment of benign prostatic hyperplasia, are limited. In clinical studies of on-demand tadalafil (20 mg dose) for the treatment of erectile dysfunction, diarrhea occurred more frequently in patients over 65 years of age. In clinical studies of tadalafil 5 mg once daily for the treatment of benign prostatic hyperplasia, dizziness and diarrhea were reported more frequently in patients over 75 years of age.

Reporting of adverse reactions

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, or their legal representatives are encouraged to 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. 3 years.

Storage conditions. No special storage conditions are required for this medicinal product. Keep out of reach and sight of children.

Packaging.

Dosage of 2.5 mg: 14 tablets per blister, 1 or 2 blisters per cardboard pack.

Dosage of 5 mg: 14 tablets per blister, 1 or 2 blisters per cardboard pack.

Dosage of 10 mg: 4 tablets per blister, 1 or 2 blisters per cardboard pack.

Dosage of 20 mg: 1 tablet per blister, 1 blister per cardboard pack;

or 2 tablets per blister, 1, 2, or 4 blisters per cardboard pack;

or 4 tablets per blister, 1 or 2 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer. Jenepharm S.A.

Manufacturer's address and place of business.

18th Km Marathonomou Avenue, Pallini, 153 51, Greece