Sinegra^® (Tablets) Instructions for Use

Marketing Authorization Holder

Nobel Ilac Sanayii And Ticaret, A.S. (Turkey)

ATC Code

G04BE03 (Sildenafil)

Active Substance

Sildenafil

Dosage Forms

	Sinegra®	Film-coated tablets, 50 mg: 1, 4 or 12 pcs.
		Film-coated tablets, 100 mg: 1, 4 or 12 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets are blue, square, biconvex, with a score on both sides; the core is white on the cross-section.

Excipients: microcrystalline cellulose PH102 – 175.26 mg, anhydrous calcium hydrogen phosphate – 35 mg, colloidal silicon dioxide (aerosil 200) – 1.5 mg, magnesium stearate – 6 mg, croscarmellose sodium – 12 mg.

Film coating composition: Opadry I blue 85F20578 – 12.5 mg (polyvinyl alcohol – 40%, polyethylene glycol – 20.2%, titanium dioxide (E171) – 18.97%, talc – 14.8%, indigo carmine (E132) – 6.02%, iron oxide yellow (E172) – 0.01%).

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

Film-coated tablets are blue, square, biconvex, with a double score on one side; the core is white on the cross-section.

Excipients: microcrystalline cellulose PH102 – 350.52 mg, anhydrous calcium hydrogen phosphate – 70 mg, colloidal silicon dioxide (aerosil 200) – 3 mg, magnesium stearate – 12 mg, croscarmellose sodium – 24 mg.

Film coating composition: Opadry I blue 85F20578 – 25 mg (polyvinyl alcohol – 40%, polyethylene glycol – 20.2%, titanium dioxide (E171) – 18.97%, talc – 14.8%, indigo carmine (E132) – 6.02%, iron oxide yellow (E172) – 0.01%).

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

Clinical-Pharmacological Group

Erectile dysfunction treatment drug. PDE5 inhibitor

Pharmacotherapeutic Group

Drugs used in urology; drugs for the treatment of erectile dysfunction

Pharmacological Action

It is a potent selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific PDE5.

The realization of the physiological mechanism of erection is associated with the release of NO in the corpus cavernosum during sexual stimulation. This, in turn, leads to an increase in cGMP levels, subsequent relaxation of the smooth muscle tissue of the corpus cavernosum, and increased blood flow.

Sildenafil does not have a direct relaxing effect on the isolated human corpus cavernosum but enhances the effect of NO by inhibiting PDE5, which is responsible for the breakdown of cGMP.

Sildenafil is selective for PDE5 in vitro; its activity against PDE5 exceeds its activity against other known phosphodiesterase isoenzymes: PDE6 – by 10 times; PDE1 – by more than 80 times; PDE2, PDE4, PDE7-PDE11 – by more than 700 times. Sildenafil is 4000 times more selective for PDE5 compared to PDE3, which is of utmost importance since PDE3 is one of the key enzymes regulating myocardial contractility.

A prerequisite for the effectiveness of sildenafil is sexual stimulation.

Pharmacokinetics

The pharmacokinetics of sildenafil in the recommended dose range are linear.

After oral administration, Sildenafil is rapidly absorbed. The absolute bioavailability averages about 40% (from 25% to 63%). In vitro, Sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human PDE5 activity by 50%. After a single dose of sildenafil 100 mg, the mean C_max of free sildenafil in the plasma of men is about 18 ng/ml (38 nM). C_max after oral administration of sildenafil on an empty stomach is achieved on average within 60 min (from 30 min to 120 min). When taken with a high-fat meal, the rate of absorption decreases: C_max decreases on average by 29%, and T_max increases by 60 min, but the extent of absorption does not change significantly (AUC decreases by 11%).

The V_d of sildenafil at steady state averages 105 L. The binding of sildenafil and its main circulating N-desmethyl metabolite to plasma proteins is about 96% and does not depend on the total concentration of the drug. Less than 0.0002% of the sildenafil dose (average 188 ng) was found in semen 90 minutes after taking the drug.

Sildenafil is metabolized mainly in the liver by the cytochrome isoenzyme CYP3A4 (major pathway) and the cytochrome isoenzyme CYP2C9 (minor pathway). The main circulating active metabolite, formed as a result of N-demethylation of sildenafil, undergoes further metabolism. The selectivity of this metabolite for PDE is comparable to that of sildenafil, and its activity against PDE5 in vitro is about 50% of the activity of sildenafil. The plasma concentration of the metabolite in healthy volunteers was about 40% of the concentration of sildenafil. The N-desmethyl metabolite undergoes further metabolism; T_1/2 is about 4 h.

The total clearance of sildenafil is 41 L/h, and the terminal T_1/2 is 3-5 h. After oral administration, as well as after IV administration, Sildenafil is excreted as metabolites, mainly via the intestines (about 80% of the oral dose) and, to a lesser extent, by the kidneys (about 13% of the oral dose).

Indications

Treatment of erectile dysfunction characterized by the inability to achieve or maintain a penile erection sufficient for satisfactory sexual intercourse.

Sildenafil is effective only with sexual stimulation.

ICD codes

Dosage Regimen

Take orally approximately one hour before sexual activity.

Initiate therapy at the recommended dose of 50 mg.

Adjust the dose based on individual efficacy and tolerability.

Increase the dose to a maximum of 100 mg if the 50 mg dose is insufficient.

Decrease the dose to 25 mg if the 50 mg dose is not well tolerated.

Do not exceed the maximum recommended single dose of 100 mg.

Limit administration to a maximum of once per day.

Administer with or without food; note that a high-fat meal may delay the onset of effect.

For elderly patients, no initial dose adjustment is required.

For patients with mild to moderate hepatic impairment or severe renal impairment (creatinine clearance less than 30 ml/min), consider a starting dose of 25 mg.

Concomitant use with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) necessitates a maximum dose of 25 mg within a 48-hour period.

Discontinue use and seek medical attention if an erection lasts longer than four hours.

Adverse Reactions

Immune system disorders uncommon – hypersensitivity reactions (including skin rash), allergic reactions.

Blood and lymphatic system disorders uncommon – anemia, leukopenia.

Metabolism and nutrition disorders uncommon – feeling of thirst, edema, gout, uncontrolled diabetes mellitus, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.

Eye disorders common – blurred vision, visual impairment, cyanopsia; uncommon – eye pain, photophobia, photopsia, chromatopsia, eye redness/scleral injection, altered perception of light brightness, mydriasis, conjunctivitis, ocular hemorrhage, cataract, lacrimal disorder; rare – eyelid and periorbital edema, feeling of dryness in the eyes, seeing halos around lights, eye fatigue, xanthopsia, erythropsia, conjunctival hyperemia, eye irritation, eye discomfort; frequency unknown – non-arteritic anterior ischemic optic neuropathy, retinal vein occlusion, visual field defect, diplopia*, temporary vision loss or decreased visual acuity, increased intraocular pressure, retinal edema, retinal vascular disease, vitreous detachment/vitreous traction.

Ear and labyrinth disorders uncommon – sudden hearing loss or impairment, tinnitus, ringing in the ears, ear pain.

Nervous system disorders very common – headache; common – dizziness; uncommon – drowsiness, migraine, ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depressive symptoms, insomnia, unusual dreams, hyperreflexia, hypoesthesia; rare – convulsions, recurrent seizures, syncope, cerebrovascular accident, transient ischemic attack.

Cardiac disorders common – flushing; uncommon – tachycardia, palpitations, decreased or increased blood pressure, increased heart rate, unstable angina, AV block, myocardial infarction, cerebral vascular thrombosis, cardiac arrest, heart failure, abnormal ECG readings, cardiomyopathy; rare – atrial fibrillation, sudden cardiac death, ventricular arrhythmia.

Respiratory, thoracic and mediastinal disorders common – nasal congestion; uncommon – epistaxis, rhinitis, asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased sputum volume, increased cough; rare – throat tightness, dryness of the nasal mucosa, swelling of the nasal mucosa.

Gastrointestinal disorders common – nausea, dyspepsia; uncommon – gastroesophageal reflux disease, vomiting, abdominal pain, dry mouth, glossitis, gingivitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal liver function tests, rectal bleeding; rare – oral mucosa hypoesthesia.

Musculoskeletal and connective tissue disorders common – back pain; uncommon – myalgia, limb pain, arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

Renal and urinary disorders uncommon – cystitis, nocturia, urinary incontinence, hematuria.

Reproductive system and breast disorders uncommon – breast enlargement, ejaculation disorder, genital edema, anorgasmia, hematospermia, penile tissue damage; rare – prolonged erection and/or priapism, penile bleeding.

Skin and subcutaneous tissue disorders uncommon – skin rash, urticaria, herpes simplex, pruritus, increased sweating, skin ulceration, contact dermatitis, exfoliative dermatitis; frequency unknown – Stevens-Johnson syndrome, toxic epidermal necrolysis.

General disorders and administration site conditions uncommon – feeling hot, facial edema, photosensitivity reaction, shock, asthenia, increased fatigue, pain of various locations, chills, accidental falls, chest pain, accidental injuries; rare – irritability.

Contraindications

Hypersensitivity to sildenafil; use in patients receiving continuous or intermittent nitric oxide donors, organic nitrates or nitrites in any form, since Sildenafil enhances the hypotensive effect of nitrates; children and adolescents under 18 years of age; according to the registered indication, Sildenafil is not intended for use in women; concomitant use of sildenafil with ritonavir, with other means of treating erectile dysfunction is not recommended.

With caution

Anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie’s disease); conditions predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia); diseases accompanied by bleeding; exacerbation of gastric and duodenal ulcer; hereditary pigmentary retinitis; heart failure, unstable angina, myocardial infarction, stroke or life-threatening arrhythmias within the last 6 months, arterial hypertension (BP >170/100 mmHg) or hypotension (BP <90/50 mmHg); in patients with a history of episodes of non-arteritic anterior ischemic optic neuropathy.

Use in Pregnancy and Lactation

According to the registered indication, it is not intended for use in women.

Use in Hepatic Impairment

Since the elimination of sildenafil is impaired in patients with liver damage (in particular, cirrhosis), the dose of Sildenafil should be reduced.

Use in Renal Impairment

In mild to moderate renal impairment (creatinine clearance 30-80 ml/min), dose adjustment is not required; in severe renal impairment (creatinine clearance <30 ml/min), the dose of sildenafil should be reduced.

Pediatric Use

According to the registered indication, Sildenafil is not intended for use in children and adolescents under 18 years of age.

Geriatric Use

Dose adjustment of sildenafil in elderly patients is not required.

Special Precautions

To diagnose erectile dysfunction, determine its possible causes and choose adequate treatment, it is necessary to collect a complete medical history and conduct a thorough physical examination. Erectile dysfunction treatment agents should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie’s disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia).

Drugs intended for the treatment of erectile dysfunction should not be prescribed to men for whom sexual activity is undesirable.

Sexual activity poses a certain risk in the presence of heart disease, so before starting any therapy for erectile dysfunction, the doctor should refer the patient for an examination of the cardiovascular system. Sexual activity is undesirable in patients with heart failure, unstable angina, myocardial infarction or stroke within the last 6 months, life-threatening arrhythmias, arterial hypertension (BP >170/100 mmHg) or hypotension (BP <90/50 mmHg).

During post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as serious cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension) have been reported, which had a temporal relationship with the use of sildenafil. Most of these patients, but not all, had risk factors for cardiovascular complications. Many of these adverse events were observed shortly after sexual activity, and some were noted after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct connection between the noted adverse events and the mentioned or other factors.

Sildenafil has a systemic vasodilating effect, leading to a transient decrease in blood pressure, which is not a clinically significant phenomenon and does not lead to any consequences in most patients. Nevertheless, before starting the use of sildenafil, the doctor should carefully assess the risk of possible adverse manifestations of the vasodilating effect in patients with relevant diseases, especially during sexual activity. Increased susceptibility to vasodilators is observed in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare syndrome of multiple system atrophy, manifested by severe impairment of blood pressure regulation by the autonomic nervous system.

Concomitant use of sildenafil and alpha-blockers can lead to symptomatic arterial hypotension in some sensitive patients; Sildenafil should be used with caution in patients receiving alpha-blockers. To minimize the risk of developing postural hypotension in patients taking alpha-blockers, Sildenafil should be started only after hemodynamic stabilization has been achieved in these patients. The advisability of reducing the initial dose of sildenafil should also be considered. The physician should inform patients about what actions to take in case of symptoms of postural hypotension.

Rare cases of development of non-arteritic anterior ischemic optic neuropathy, as a cause of deterioration or loss of vision, have been noted with the use of all PDE5 inhibitors, including Sildenafil. Most of these patients had risk factors such as optic disc cupping, age over 50 years, diabetes mellitus, arterial hypertension, coronary artery disease, hyperlipidemia and smoking. No causal relationship has been established between the use of PDE5 inhibitors and the development of non-arteritic anterior ischemic optic neuropathy. The physician should inform the patient about the increased risk of developing non-arteritic anterior ischemic optic neuropathy if this condition has already been noted in him. In case of sudden vision loss, patients should immediately receive the necessary medical care. A small number of patients with hereditary retinitis pigmentosa have genetically determined disorders of retinal PDE function. There is no information on the safety of sildenafil use in patients with retinitis pigmentosa, so Sildenafil should be used with caution.

In case of sudden hearing deterioration or hearing loss while taking sildenafil, you should immediately consult a doctor.

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There is no data on the safety of sildenafil use in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcers, so Sildenafil should be used with caution in these patients. The frequency of epistaxis in patients with pulmonary hypertension associated with diffuse connective tissue diseases was higher than in patients with primary pulmonary hypertension (Sildenafil 3%, placebo 2.4%). In patients receiving Sildenafil in combination with a vitamin K antagonist, the frequency of epistaxis was higher (8.8%) than in patients not taking a vitamin K antagonist (1.7%).

Effect on ability to drive vehicles and operate machinery

Since sildenafil may cause decreased blood pressure, chromatopsia, blurred vision and other side effects, individual response to the drug in these situations should be carefully considered, especially at the start of treatment and when changing the dosage regimen.

Drug Interactions

Sildenafil metabolism occurs primarily with the participation of the CYP3A4 isoenzyme (the main pathway) and CYP2C9; therefore, inhibitors of these isoenzymes may reduce the clearance of sildenafil, and inducers, respectively, may increase the clearance of sildenafil. A decrease in sildenafil clearance has been observed with the simultaneous use of cytochrome CYP3A4 isoenzyme inhibitors (ketoconazole, erythromycin, cimetidine).

Cimetidine (800 mg), a non-specific inhibitor of the cytochrome CYP3A4 isoenzyme, when taken concomitantly with sildenafil (50 mg), causes a 56% increase in plasma concentration of sildenafil. A single dose of sildenafil 100 mg taken with erythromycin (500 mg twice daily for 5 days), a specific inhibitor of the cytochrome CYP3A4 isoenzyme, against the background of achieving a steady-state erythromycin concentration in the blood, leads to a 182% increase in the AUC of sildenafil.

When sildenafil (a single 100 mg dose) and saquinavir (1200 mg three times daily), an HIV protease inhibitor and cytochrome CYP3A4 isoenzyme inhibitor, were taken concomitantly against the background of achieving a steady-state saquinavir concentration in the blood, the C_max of sildenafil increased by 140%, and the AUC increased by 210%. Sildenafil does not affect the pharmacokinetics of saquinavir.

Stronger inhibitors of the cytochrome CYP3A4 isoenzyme, such as ketoconazole and itraconazole, may cause more pronounced changes in the pharmacokinetics of sildenafil.

Concomitant use of sildenafil (a single 100 mg dose) and ritonavir (500 mg twice daily), an HIV protease inhibitor and a strong cytochrome P450 inhibitor, against the background of achieving a steady-state ritonavir concentration in the blood, leads to an increase in the C_max of sildenafil by 300% (4-fold), and the AUC by 1000% (11-fold). After 24 hours, the plasma concentration of sildenafil is about 200 ng/ml (after a single dose of sildenafil alone – 5 ng/ml), which is consistent with information about the pronounced effect of ritonavir on the pharmacokinetics of various cytochrome P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Concomitant use of sildenafil with ritonavir is not recommended.

If Sildenafil is taken at recommended doses by patients who are simultaneously receiving strong cytochrome CYP3A4 isoenzyme inhibitors, then the C_max of free sildenafil does not exceed 200 nM, and the drug is well tolerated.

A single dose of an antacid (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil.

Inhibitors of the cytochrome CYP2C9 isoenzyme (tolbutamide, warfarin), the cytochrome CYP2D6 isoenzyme (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors, and calcium antagonists do not affect the pharmacokinetics of sildenafil.

Azithromycin (500 mg/day for 3 days) does not affect the AUC, C_max, T_max, elimination rate constant, and T_1/2 of sildenafil or its main circulating metabolite.

Sildenafil is a weak inhibitor of the cytochrome P450 isoenzymes -1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC₅₀>150 µmol). When sildenafil is taken at recommended doses, its C_max is about 1 µmol; therefore, it is unlikely that Sildenafil can affect the clearance of substrates of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates, both during their long-term use and when they are prescribed for acute indications. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

With the simultaneous administration of the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the mean additional reduction in systolic/diastolic blood pressure in the supine position was 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, respectively, and in the standing position – 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. Rare cases of symptomatic postural hypotension have been reported in such patients, manifested as dizziness (without fainting). In some sensitive patients receiving alpha-blockers, the simultaneous use of sildenafil may lead to symptomatic hypotension.

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.