Razatas (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi (France)

Manufactured By

Mitsubishi Tanabe Pharma Factory Ltd. (Japan)

Quality Control Release

MENARINI-VON HEYDEN, GmbH (Germany)

ATC Code

G04BE10 (Avanafil)

Active Substance

Avanafil (Rec.INN registered by WHO)

Dosage Forms

	Razatas	Tablets 50 mg: 4, 8 or 12 pcs.
		Tablets 100 mg: 2, 4, 8 or 12 pcs.
		Tablets 200 mg: 4, 8 or 12 pcs.

Dosage Form, Packaging, and Composition

Tablets light yellow in color, oval, biconvex, with an engraving “50” on one side.

Excipients: mannitol – 16 mg, fumaric acid – 20 mg, hypromellose – 2.5 mg, low-substituted hypromellose – 6.25 mg, calcium carbonate – 1.5 mg, magnesium stearate – 1.25 mg, yellow iron oxide dye – 0.0975 mg.

4 pcs. – blisters (1) – cardboard packs.
4 pcs. – blisters (2) – cardboard packs.
4 pcs. – blisters (3) – cardboard packs.

Tablets light yellow in color, oval, biconvex, with an engraving “100” on one side.

Excipients: mannitol – 32 mg, fumaric acid – 40 mg, hypromellose – 5 mg, low-substituted hypromellose – 12.5 mg, calcium carbonate – 3 mg, magnesium stearate – 2.5 mg, yellow iron oxide dye – 0.195 mg.

2 pcs. – blisters (1) – cardboard packs.
4 pcs. – blisters (1) – cardboard packs.
4 pcs. – blisters (2) – cardboard packs.
4 pcs. – blisters (3) – cardboard packs.

Tablets light yellow in color, oval, biconvex, with an engraving “200” on one side.

Excipients: mannitol – 64 mg, fumaric acid – 80 mg, hypromellose – 10 mg, low-substituted hypromellose – 25 mg, calcium carbonate – 6 mg, magnesium stearate – 5 mg, yellow iron oxide dye – 0.39 mg.

4 pcs. – blisters (1) – cardboard packs.
4 pcs. – blisters (2) – cardboard packs.
4 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Erectile dysfunction treatment drug. PDE5 inhibitor

Pharmacotherapeutic Group

Erectile dysfunction treatment agent – PDE5 inhibitor

Pharmacological Action

It is an inhibitor of type 5 phosphodiesterase (PDE5). It has specificity for cyclic guanosine monophosphate (cGMP). After sexual stimulation leads to local release of nitric oxide, inhibition of PDE5 by avanafil causes an increase in cGMP concentration in the corpus cavernosum of the penis. This leads to relaxation of smooth muscles and increased blood flow into the penile tissues, thus causing an erection. The effect of avanafil does not develop in the absence of sexual stimulation.

In vitro studies have shown that Avanafil has high selectivity for PDE5. It has a more pronounced effect on PDE5 than on other known phosphodiesterases (more than 100 times stronger than on PDE6; more than 1000 times stronger than on PDE4, PDE8 and PDE10; more than 5000 times stronger than on PDE2 and PDE7; more than 10000 times stronger than on PDE1, PDE3, PDE9 and PDE11).

Avanafil is more than 100 times more potent against PDE5 than against PDE6, which is found in the retina and is responsible for light signal transmission. It is also important that Avanafil exhibits approximately 20,000 times greater selectivity for PDE5 than for PDE3 (an enzyme found in the heart and blood vessels, which is involved in the control of myocardial contractility).

In a study with penile plethysmography (RigiScan) in some men, Avanafil (at a dose of 200 mg) caused an erection of sufficient strength for penetration (60% rigidity according to RigiScan assessment) as early as 20 minutes after administration. The overall response to avanafil in these subjects was statistically significant compared to placebo in the time interval from 20 to 40 minutes.

Pharmacokinetics

After oral administration, Avanafil is rapidly absorbed. C_max in blood plasma is reached within 0.5-0.75 hours after administration. When avanafil is taken with fatty food, the absorption rate decreases, the average delay in T_max is 1.25 hours, and the average reduction in C_max is 39%. No effect on the extent of exposure (AUC) was noted. It is believed that small changes in C_max of avanafil have minimal clinical significance.

The pharmacokinetics of avanafil in the recommended dose range is dose-proportional. It is eliminated primarily through metabolism occurring in the liver, mainly with the participation of the CYP3A4 isoenzyme. Concurrent use of strong CYP3A4 inhibitors (e.g., ketoconazole and ritonavir) is accompanied by an increase in avanafil plasma exposure.

The binding of avanafil to plasma proteins is approximately 99% and does not depend on the concentration of the active substance, age, liver and kidney function. When avanafil was taken at a dose of 200 mg twice daily for 7 days, no accumulation of the drug in the blood plasma occurred. Based on data from measuring avanafil concentration in the semen of healthy volunteers 45-90 minutes after taking avanafil, less than 0.0002% of the administered dose may appear in the semen.

It is metabolized primarily by the hepatic microsomal isoenzymes CYP3A4 (main pathway) and CYP2C9 (additional pathway). The concentration of the main circulating metabolites M4 and M16 in blood plasma was 23% and 29% of the parent substance concentration, respectively. The selectivity of metabolite M4 for PDE was similar to the characteristics of avanafil, and its in vitro inhibitory activity against PDE5 was 18% of the activity of avanafil. Thus, metabolite M4 provides about 4% of the total pharmacological activity of the drug. Metabolite M16 has no activity against PDE5.

Avanafil is excreted as metabolites, mainly in feces (about 63%), to a lesser extent in urine (about 21%).

The terminal T_1/2 of avanafil is about 6-17 hours.

Indications

Treatment of erectile dysfunction in adult men.

ICD codes

Dosage Regimen

Sexual stimulation is necessary for the effect to develop.

For oral administration. The recommended dose is 100 mg taken as needed, approximately 15-30 minutes before sexual activity.

Depending on individual efficacy and tolerability, the dose can be increased to a maximum of 200 mg or reduced to 50 mg. The maximum recommended frequency of use is once daily.

In patients with mild or moderate hepatic impairment (Child-Pugh class A or B), treatment should be started with the minimum effective dose and adjusted based on tolerability.

Adverse Reactions

Immune system disorders: rarely – seasonal allergy.

Metabolism and nutrition disorders rarely – gout, weight gain, increased body temperature.

Psychiatric disorders: rarely – insomnia, premature ejaculation, inappropriate affect.

Nervous system disorders: frequently – headache; infrequently – dizziness, drowsiness, sinus headache; rarely – psychomotor hyperactivity.

Eye disorders infrequently – blurred vision.

Cardiac and vascular disorders frequently – flushing; infrequently – palpitations, hot flushes, ECG changes, increased heart rate; rarely – increased blood pressure, heart murmur on auscultation, angina pectoris, tachycardia, arterial hypertension.

Respiratory, thoracic and mediastinal disorders frequently – nasal congestion; infrequently – edema of the paranasal sinus mucosa, exertional dyspnea; rarely – rhinorrhea, edema of the upper respiratory tract mucosa.

Gastrointestinal disorders: infrequently – dyspepsia, nausea, vomiting, stomach discomfort, increased liver enzyme activity, increased blood bilirubin concentration; rarely – dry mouth, gastritis, lower abdominal pain, diarrhea.

Skin and subcutaneous tissue disorders rarely – skin rash.

Musculoskeletal and connective tissue disorders: infrequently – back pain, muscle tightness; rarely – flank pain, myalgia, muscle spasms.

Renal and urinary disorders rarely – pollakiuria, presence of blood in urine, increased PSA level, increased blood creatinine concentration.

Reproductive system and breast disorders rarely – spontaneous erection, genital itching, penile disorders, increased PSA level.

General disorders and administration site conditions infrequently – increased fatigue.

Contraindications

Hypersensitivity to avanafil, concurrent use with organic nitrates or nitric oxide donors (e.g., amyl nitrite) in any form, myocardial infarction, stroke, or life-threatening episodes of arrhythmia within the last 6 months, resting arterial hypotension (BP <90/50 mm Hg) or arterial hypertension (BP >170/100 mm Hg), unstable angina, angina associated with sexual intercourse, congestive heart failure of functional class II and higher according to NYHA, severe hepatic impairment (Child-Pugh class C), severe renal impairment (CrCl <30 ml/min), loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy, regardless of whether this episode was associated with prior use of PDE5 inhibitors, confirmed hereditary degenerative retinal diseases, concurrent use with guanylate cyclase stimulators, such as riociguat (potential risk of symptomatic hypotension), concurrent use of strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, and telithromycin).

With caution in patients with obstruction of left ventricular outflow (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis); in patients with anatomical deformation of the penis (angulation, cavernous body fibrosis, or Peyronie’s disease); in patients with conditions predisposing to priapism (sickle cell anemia, multiple myeloma, or leukemia); in patients with bleeding disorders; in patients with active gastric ulcer; concurrent use with alpha-adrenergic blockers.

Use in Pregnancy and Lactation

Not intended for use in women.

Special Precautions

Before using avanafil, the physician should consider the potential risk of cardiac complications during sexual activity in patients with cardiovascular diseases. Avanafil has vasodilator properties, causing a slight and transient decrease in BP, and thus potentiates the hypotensive effect of nitrates. Patients who have obstruction of left ventricular outflow, for example, with aortic stenosis and idiopathic hypertrophic subaortic stenosis, may have particular sensitivity to the action of vasodilators, including PDE5 inhibitors.

Patients with an erection lasting 4 hours or more (priapism) should be advised to seek immediate medical attention.

Avanafil should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous body fibrosis, or Peyronie’s disease), as well as in patients with conditions that may predispose to priapism (sickle cell anemia, multiple myeloma, or leukemia).

There are reports of visual disturbances and cases of non-arteritic anterior ischemic optic neuropathy associated with the use of other PDE5 inhibitors. In case of sudden visual impairment, the patient should be advised to immediately stop taking avanafil and consult a doctor.

There is no safety information on the use of avanafil in patients with bleeding disorders and active gastric ulcer. Therefore, Avanafil should be prescribed to such patients only after careful consideration of the benefit and risk.

Patients with signs of hemodynamic instability during therapy with alpha-adrenergic blockers alone have an increased risk of developing symptomatic hypotension in case of concurrent use of avanafil. In patients with stable hemodynamic parameters during therapy with alpha-adrenergic blockers, avanafil should be started at the minimum dose of 50 mg. In patients already receiving Avanafil at an optimally selected dose, therapy with alpha-adrenergic blockers should be started at the minimum dose. Stepwise increase in the dose of alpha-adrenergic blockers may be associated with an additional decrease in BP after taking avanafil. The safety of the combined use of avanafil and alpha-adrenergic blockers may be affected by intravascular fluid deficiency and the use of other antihypertensive drugs.

The safety and efficacy of combinations of avanafil with other PDE5 inhibitors or other drugs for the treatment of erectile dysfunction have not been studied. Patients should be advised to avoid taking avanafil in such combinations.

When consuming ethanol (alcohol) in combination with avanafil, the risk of developing symptomatic arterial hypotension may increase. Patients should be made aware that concurrent use of avanafil and ethanol (alcohol) may be accompanied by an increased likelihood of arterial hypotension, dizziness, or fainting. Doctors should give patients recommendations regarding measures in case of postural hypotensive symptoms.

Effect on ability to drive vehicles and operate machinery

Avanafil has a minimal effect on the ability to drive vehicles and engage in other potentially hazardous activities. Since dizziness and visual disturbances have been reported in clinical studies of avanafil, patients should know how they react to taking avanafil before starting to drive or operate machinery.

Drug Interactions

Concurrent use of avanafil and strong inhibitors of the CYP3A4 isoenzyme (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, and telithromycin) is contraindicated.

In patients receiving concomitant therapy with moderate inhibitors of the CYP3A4 isoenzyme (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of avanafil should not exceed 100 mg, and the interval between doses should be at least 48 hours.

It has been shown in healthy individuals that Avanafil, compared to placebo, enhances the hypotensive effect of nitrates. This is thought to be due to the combined action of nitrates and avanafil on the mechanism involving nitric oxide and cGMP. Therefore, the use of avanafil is contraindicated in patients receiving organic nitrates or nitric oxide donor compounds (e.g., amyl nitrite) in any form. In a patient requiring nitrates for a life-threatening condition and who has taken Avanafil no more than 12 hours before, the likelihood of a significant and potentially dangerous decrease in BP increases. Under such circumstances, nitrates should be used only under conditions of careful medical supervision and proper hemodynamic monitoring.

Avanafil, being a vasodilator, can cause a decrease in BP. When using avanafil in combination with other drugs that lower BP, the occurrence of additive effects may lead to the development of symptomatic arterial hypotension, manifested by dizziness, a feeling of “lightheadedness”, syncope, or presyncope.

Patients with left ventricular outflow obstruction (aortic stenosis, idiopathic hypertrophic subaortic stenosis) and patients with severe autonomic control impairment of BP may be particularly sensitive to the action of vasodilators, including Avanafil.

When studying the hemodynamic interaction of avanafil with doxazosin and tamsulosin, a clinically significant change in BP is possible.

When studying the interaction of enalapril and avanafil, a statistically significant change in the maximum decrease in diastolic pressure in the supine position relative to the baseline value was observed; 4 hours after taking avanafil, BP returned to baseline. Avanafil did not affect the pharmacokinetics of amlodipine, but amlodipine caused an increase in the maximum and total exposure of avanafil by 28% and 60%, respectively.

When consuming ethanol in combination with avanafil, the risk of developing arterial hypotension with clinical symptoms increases.

Avanafil is a substrate of the CYP3A4 isoenzyme and is metabolized primarily by this isoenzyme. Studies have shown that drugs that inhibit the CYP3A4 isoenzyme can increase the exposure of avanafil.

Ketoconazole (at a dose of 400 mg/day), a selective and strong inhibitor of the CYP3A4 isoenzyme, caused an increase in C_max and exposure (AUC) of avanafil (after a single 50 mg dose) by 3 times and 14 times, respectively, and an increase in T_1/2 of avanafil to approximately 9 hours. Ritonavir (at a dose of 600 mg twice daily), a strong inhibitor of the CYP3A4 isoenzyme, which also inhibits the CYP2C9 isoenzyme, caused an increase in C_max and AUC of avanafil (after a single 50 mg dose) by approximately 2 times and 13 times, and an increase in T_1/2 of avanafil to approximately 9 hours. Other strong inhibitors of the CYP3A4 isoenzyme (itraconazole, voriconazole, clarithromycin, nefazodone, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin) are likely to have a similar effect. Therefore, concurrent use of avanafil and strong inhibitors of the CYP3A4 isoenzyme is contraindicated.

Erythromycin (at a dose of 500 mg twice daily), a moderate inhibitor of the CYP3A4 isoenzyme, caused an increase in C_max and AUC of avanafil (after a single 200 mg dose) by approximately 2 times and 3 times, respectively, and an increase in T_1/2 of avanafil to approximately 8 hours. Other moderate inhibitors of the CYP3A4 isoenzyme (amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil) are likely to have a similar effect. Therefore, in patients concurrently taking moderate inhibitors of the CYP3A4 isoenzyme, the maximum recommended dose of avanafil is 100 mg, and the interval between doses should be at least 48 hours.

Although specific interactions have not been studied, other inhibitors of the CYP3A4 isoenzyme, including grapefruit juice, may also increase the exposure of avanafil. Patients should be advised to avoid consuming grapefruit juice for 24 hours before taking avanafil.

Amlodipine (at a dose of 5 mg/day) caused an increase in the C_max and AUC of avanafil (after a single 200 mg dose) by approximately 28% and 60%, respectively. These changes in exposure appear to be clinically insignificant. At the same time, no changes in the plasma concentrations of avanafil or amlodipine occurred after a single dose.

The potential influence of CYP inducers, particularly inducers of the CYP3A4 isoenzyme (bosentan, carbamazepine, efavirenz, phenobarbital, and rifampin), on the pharmacokinetics and efficacy of avanafil has not been studied. The concomitant use of avanafil and CYP450 inducers is not recommended, as it may reduce the efficacy of avanafil.

Preclinical studies have shown the development of an additive hypotensive effect when PDE5 inhibitors are used concomitantly with riociguat. Clinical studies have shown that riociguat enhances the hypotensive effect of PDE5 inhibitors. No evidence of favorable clinical effects was identified in the studied population when using this combination. The concomitant use of riociguat with PDE5 inhibitors, including avanafil, is contraindicated.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.