Tornetis, tablets 100 mg

Sildenafil is a powerful selective inhibitor of cGMP-specific phosphodiesterase type 5 (FDE-5). The realization of the physiological mechanism of erection is associated with the release of nitric oxide (NO) in the corpora cavernosa during sexual stimulation. This in turn leads to an increase in the level of cGMP, the subsequent relaxation of the smooth muscle tissue of the cavernous body and an increase in blood flow.

Sildenafil has no direct relaxant effect on the isolated human cavernous body, but it enhances the effect of nitric oxide (NO) by inhibiting FDE5, which is responsible for the breakdown of cGMP.

Sildenafil is selective against FDE-5 in vitro, its activity against FDE-5 exceeds activity against other known phosphodiesterase isoenzymes: FDE-6 – 10 times; FDE-1 – more than 80 times; FDE-2, FDE-4, FDE-7-FDE-11 – more than 700 times. Sildenafil is 4,000 times more selective against FDE-5 compared to FDE-3, which is very important because FDE-3 is one of the key enzymes in regulation of myocardial contractility.

The indispensable condition for effectiveness of sildenafil is sexual stimulation.

The use of sildenafil in doses up to 100 mg did not result in clinically significant ECG changes in healthy volunteers. The maximum decrease in BP in the supine position after sildenafil administration at a dose of 100 mg was 8.3 mm Hg, and BP was 5.3 mm Hg. A more pronounced but also transient effect on BP was observed in patients taking nitrates.

In some patients, 1 h after taking sildenafil at a dose of 100 mg, the Farnsworth-Munsel 100 test revealed a mild and transient impairment in the ability to distinguish shades of color (blue/green). These changes were absent 2 h after drug administration.

The impairment of color vision is thought to be caused by inhibition of FDE-6, which is involved in the transmission of light in the retina. Sildenafil has no effect on visual acuity, contrast perception, electroretinogram, intraocular pressure or pupil diameter.

Indications

Treatment of erectile dysfunction characterized by the inability to achieve or maintain a penile erection sufficient for satisfactory intercourse. Sildenafil is effective only with sexual stimulation.

Active ingredient

Composition

Active ingredient:

microcrystalline cellulose 275.7 mg,

calcium hydrophosphate anhydrous 104.4 mg,

How to take, the dosage

Ingestion, about 1 h before planned sexual activity. The single dose for adults is 50 mg once daily. Depending on efficacy and tolerability, the dose may be increased to 100 mg or decreased to 25 mg. The maximum single dose is 100 mg once daily.

In patients with severe renal impairment (CKI less than 30 ml/min) it is recommended to reduce the dose of Tornetis to 25 mg.

Because sildenafil excretion is reduced in patients with hepatic impairment, the recommended dose of Tornetis is 25 mg.

Tornetis dose adjustment is not necessary in elderly patients.

In co-administration with CYP3A4 isoenzyme inhibitors (erythromycin, saquinavir, ketoconazole, itraconazole) the starting dose of Tornetis should be 25 mg.

To minimize the risk of postural hypotension in patients taking alpha-adrenoblockers, Tornetis should be started only after hemodynamic stabilization has been achieved in these patients. A reduction in the starting dose of Tornetis should be considered.

Interaction

The effect of other drugs on sildenafil metabolism
Metabolism of sildenafil occurs mainly in the liver under the action of CYP3A4 isoenzymes (main pathway) and CYP2C9, therefore inhibitors of these isoenzymes may decrease sildenafil clearance, and inducers, respectively, increase sildenafil clearance.

Concomitant use of CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine) has been shown to decrease sildenafil clearance.

Cimetidine (800 mg), which is a non-specific CYP3A4 inhibitor, when taken simultaneously with sildenafil (50 mg) causes an increase in plasma concentration of sildenafil by 56%.

Single administration of sildenafil at a dose of 100 mg concomitantly with erythromycin, a specific CYP3A4 inhibitor (when taking erythromycin 2 times/day at 500 mg for 5 days), while achieving constant levels of erythromycin in the blood results in an increase in sildenafil AUC by 182%.

When simultaneously using sildenafil (once in a dose of 100 mg) and saquinavir, which is both an HIV protease inhibitor and CYP3A4 inhibitor (when taking saquinavir 3 times/day in a dose of 1200 mg), against reaching constant levels of saquinavir in blood, Cmax of sildenafil in blood was increased by 140%, and AUC was increased by 210%. Sildenafil has no effect on the pharmacokinetic parameters of saquinavir.

Powerful CYP3A4 isoenzyme inhibitors such as ketoconazole or itraconazole may cause more pronounced changes in the pharmacokinetics of sildenafil.

Concomitant use of sildenafil (single dose of 100 mg) and ritonavir, which is an HIV protease inhibitor and a potent inhibitor of cytochrome P450 system isoenzymes (when taking ritonavir at 500 mg twice daily), against reaching constant levels of ritonavir in blood, Cmax of sildenafil increased by 300% (4 times) and AUC by 1000% (11 times). After 24 h the plasma concentration of sildenafil was approximately 200 ng/ml (5 ng/ml with a single sildenafil administration).

Grapefruit juice, a weak CYP3A4 inhibitor, can moderately increase plasma concentrations of sildenafil.

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

The CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide-like diuretics, ACE inhibitors and calcium antagonists have no effect on sildenafil pharmacokinetic parameters.

Concomitant administration of azithromycin (500 mg/day for 3 days) has no effect on AUC, Cmax, Tmax, rate constant and T1/2 of sildenafil or its main circulating metabolite.
Nicorandil is a hybrid of nitrate and potassium channel activator. Because of its nitrate component, it can have serious interactions with sildenafil.

The effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of the cytochrome P450 system isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 μM).

It is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates, both with long-term use and when used for acute indications. Therefore, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

The concomitant use of the alpha-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics had an average additional decrease of systolic/diastolic BP in the supine position of 7/7 mm Hg, 9/5 mmHg and 8/4 mmHg, respectively, and in the standing position were 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively.

Rare cases of symptomatic postural hypotension, manifested as dizziness (without syncope), have been reported in these patients. In some sensitive patients receiving alpha-adrenoblockers, concomitant use of sildenafil may lead to symptomatic hypotension.

There is no evidence of significant interaction of sildenafil (50 mg) with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by CYP2C9.

Sildenafil at a dose of 100 mg has no effect on the pharmacokinetic parameters of HIV protease inhibitors at their constant blood concentrations, such as saquinavir and ritonavir, which are simultaneously substrates of CYP3A4.

Sildenafil (50 mg) does not cause an additional increase in bleeding time with acetylsalicylic acid (150 mg). Sildenafil (50 mg) does not increase the hypotensive effect of ethanol in healthy volunteers at maximum blood ethanol levels averaging 80 mg/dL.

In patients with arterial hypertension, there is no evidence of interaction between sildenafil (100 mg) and amlodipine. The mean additional decrease of BP in the supine position is: systolic – by 8 mmHg, diastolic – by 7 mmHg.

The use of sildenafil in combination with antihypertensive agents causes no additional side effects.

Special Instructions

In order to diagnose erectile dysfunction, determine its possible causes and choose an appropriate treatment, a complete medical history and a thorough physical examination must be taken.

Sexual activity poses some risk if you have heart disease, so your doctor should refer you for a cardiovascular exam before starting any therapy for erectile dysfunction.

The use of sildenafil is contraindicated in patients with heart failure, unstable angina pectoris, myocardial infarction or stroke within the last 6 months, hypotension (BP < 90/50 mm Hg).

Sildenafil has a systemic vasodilatory effect leading to a transient decrease in blood pressure, which is not clinically significant and has no consequences in most patients.

However, before prescribing Tornetis®, the physician should carefully evaluate the risk of possible adverse effects of vasodilatation in patients with related conditions, especially with sexual activity.

The increased susceptibility to vasodilators is seen in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy) and also with rare multiple systemic atrophy syndrome manifested by severe autonomic nervous system impairment of blood pressure regulation.

Because co-administration of sildenafil and alpha-adrenoblockers may lead to symptomatic hypotension in some sensitive patients, sildenafil should be used with caution in patients taking alpha-adrenoblockers.

In order to minimize the risk of postural hypotension in patients taking alpha-adrenoblockers, sildenafil should be started only after hemodynamic stabilization has been achieved in these patients.

It should be considered whether to reduce the initial dose of sildenafil. In addition, the physician should inform patients as to what action should be taken if symptoms of postural hypotension occur.

Sildenafil enhances the anti-aggregation effect of sodium nitroprusside (a nitric oxide donor) on human platelets in vitro. There is no information about the safety of sildenafil in patients with internal bleeding or active peptic ulcer of the stomach, so it should be used with caution.

In some post-marketing and clinical studies using all FDE5 inhibitors, including sildenafil, a sudden reduction or loss of hearing in patients has been reported. However, most of these patients had risk factors for this pathology, and no correlation was found between the use of FDE5 inhibitors and sudden hearing loss or reduction.

The patient should be cautioned to discontinue sildenafil therapy and consult a physician immediately if there is a sudden reduction or loss of hearing.

The safety and effectiveness of sildenafil with other treatments for erectile dysfunction has not been studied, so such combinations are not recommended.

Special precautions for disposal of unused medication

There is no need for special precautions for disposal of unused medication.

Influence on driving and operating ability

There is no evidence of adverse effects of Tornetis at recommended doses on driving or operating ability.

However, since the drug may cause decreased blood pressure, chromatopsia, and blurred vision, careful consideration should be given to the individual effect of the drug in the above situations, especially at the start of treatment and when changing the dosing regimen.

Contraindications

Side effects

Nervous system: very common – headache; common – dizziness; infrequent – somnolence, hypoesthesia; rare – stroke, fainting; frequency unknown – transient ischemic attack, seizures, including recurrent ones.

Cardiovascular system: often – “hot flashes”; infrequent – palpitations, tachycardia; rare – increase or decrease of BP, myocardial infarction, atrial fibrillation; frequency unknown – ventricular arrhythmia, unstable angina, sudden death.

An organ of vision: often – visual impairment, impaired color vision; infrequent – conjunctival damage, impaired lacrimation; frequency unknown – anterior ischemic optical neuropathy, retinal vascular occlusion, visual field defects.

Hearing organ: infrequent – vertigo, tinnitus; rarely – deafness.

Respiratory system: often – nasal congestion; rarely – nasal bleeding.

Gastrointestinal disorders: frequent – dyspepsia; infrequent – vomiting, nausea, dry mouth.

Allergic reactions: infrequent – skin rash; frequency unknown – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

Genital organs: frequency unknown – priapism, prolonged erection.

Others: rare – chest pain, fatigue.

Overdose

Symptoms: headache, blood rushes to the face, dizziness, dyspepsia, nasal congestion, visual disturbances.

In studies in healthy volunteers, adverse events at a single dose of up to 800 mg were comparable to those with sildenafil at lower doses, but were more frequent.

Treatment: In case of overdose, standard symptomatic measures should be taken. Dialysis does not accelerate excretion of the drug, since sildenafil is firmly bound to plasma proteins and is not excreted in the urine.

Pregnancy use

Similarities