Tegrum: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TEGRA (TEGRUM)

Composition:

Active substance: sildenafil;

One tablet contains 70.225 mg of sildenafil citrate, equivalent to 50 mg of sildenafil;

One tablet contains 140.450 mg of sildenafil citrate, equivalent to 100 mg of sildenafil;

Excipients: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, hypromellose, anhydrous colloidal silicon dioxide, sodium croscarmellose, magnesium stearate, titanium dioxide (E 171), talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or white with a creamy shade, biconvex tablets with smooth surface, film-coated.

Pharmacotherapeutic group.

Medicinal products used in urology. Agents used for erectile dysfunction. Sildenafil. ATC code G04BE03.

Pharmacological Properties

Pharmacodynamics

Sildenafil is an oral medication indicated for the treatment of erectile dysfunction. During sexual stimulation, the drug restores impaired erectile function by enhancing blood flow to the penis.

The physiological mechanism responsible for erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Released NO activates the enzyme guanylate cyclase, which increases levels of cyclic guanosine monophosphate (cGMP), leading to relaxation of smooth muscle in the corpus cavernosum and promoting blood inflow.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for cGMP degradation. The effects of sildenafil on erection are peripheral in nature. Sildenafil does not exert direct relaxant effects on isolated human corpus cavernosum, but it potently enhances the NO-mediated relaxation of this tissue. When the NO/cGMP pathway is activated during sexual stimulation, sildenafil's inhibition of PDE5 increases cGMP levels in the corpus cavernosum. Thus, sexual stimulation is required for sildenafil to produce the desired pharmacological effect.

In vitro studies have shown that sildenafil is selective for PDE5, which actively participates in the erectile process. The effect of sildenafil on PDE5 is more potent than on other known phosphodiesterases. This effect is 10-fold more potent than its effect on PDE6, which is involved in retinal phototransduction. At maximum recommended doses, sildenafil's selectivity for PDE5 is 80 times greater than for PDE1, 700 times higher than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. Specifically, sildenafil's selectivity for PDE5 is 4000 times greater than for PDE3—an isoform of cAMP-specific phosphodiesterase involved in regulating cardiac contractility.

Pharmacokinetics

Absorption

Sildenafil is rapidly absorbed. Maximum plasma concentrations are reached within 30–120 minutes (median 60 minutes) after oral administration on an empty stomach. The mean absolute bioavailability after oral administration is 41% (range 25–63%). Within the recommended dose range (25–100 mg), the area under the plasma concentration-time curve (AUC) and maximum concentration (Cmax) of sildenafil increase proportionally with dose.

When sildenafil is taken with food, the rate of absorption is reduced, with a mean delay in Tmax to 60 minutes and a mean reduction in Cmax by 29%.

Distribution

The mean steady-state volume of distribution (Vd) is 105 liters, indicating distribution of the drug into body tissues. After a single 100 mg oral dose of sildenafil, the mean peak total plasma concentration of sildenafil is approximately 440 ng/mL (coefficient of variation 40%). Since binding of sildenafil and its major N-desmethyl metabolite to plasma proteins is about 96%, the mean peak plasma concentration of free sildenafil reaches approximately 18 ng/mL (38 nmol). The extent of plasma protein binding is independent of total sildenafil concentrations.

In healthy volunteers who received a single 100 mg dose of sildenafil, less than 0.0002% (mean 188 ng) of the administered dose was detected in semen 90 minutes after dosing.

Metabolism

Sildenafil is metabolized primarily by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite results from N-demethylation of sildenafil. The metabolite's selectivity for PDE5 is comparable to that of sildenafil, and its activity against PDE5 is approximately 50% of the parent compound. Plasma concentrations of this metabolite are about 40% of sildenafil plasma concentrations. The N-desmethyl metabolite undergoes further metabolism, and its elimination half-life is approximately 4 hours.

Elimination

Total clearance of sildenafil is 41 L/h, resulting in an elimination half-life of 3–5 hours. After both oral and intravenous administration, sildenafil is excreted primarily as metabolites in feces (approximately 80% of the oral dose) and to a lesser extent in urine (approximately 13% of the oral dose).

Pharmacokinetics in Special Patient Populations

Elderly Patients

In healthy elderly volunteers (aged 65 years and older), reduced clearance of sildenafil was observed, resulting in approximately 90% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite compared to younger healthy volunteers (18–45 years). Due to age-related differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%.

Renal Impairment

In volunteers with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil remained unchanged after a single 50 mg oral dose. Mean AUC and Cmax of the N-desmethyl metabolite increased by 126% and 73%, respectively, compared to age-matched volunteers with normal renal function. However, due to high inter-individual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance <30 mL/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax by 100% and 88%, respectively, compared to age-matched volunteers with normal renal function. Additionally, AUC and Cmax of the N-desmethyl metabolite increased significantly by 79% and 200%, respectively.

Hepatic Impairment

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh classes A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with normal liver function. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

TEGRUM is recommended for use in men with erectile dysfunction, defined as the inability to achieve or maintain a penile erection sufficient for successful sexual intercourse.

For effective action of TEGREM, sexual stimulation is required.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the NO/cGMP pathway and potentiate the hypotensive effect of nitrites;
Concomitant use of PDE5 inhibitors (including sildenafil) with guanylate cyclase stimulators such as riociguat is contraindicated, as it may lead to symptomatic hypotension (see section "Interaction with other medicinal products and other types of interactions");
Conditions in which sexual activity is not recommended (e.g., severe cardiovascular disorders such as unstable angina or severe heart failure);
Unilateral sudden vision loss due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this condition is associated with prior use of PDE5 inhibitors;
Presence of conditions such as severe hepatic impairment, arterial hypotension (blood pressure below 90/50 mm Hg), recent stroke or myocardial infarction, and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a small number of such patients have genetic disorders of retinal phosphodiesterases), since the safety of sildenafil has not been studied in these patient subgroups.

Interaction with other medicinal products and other types of interactions.

Effects of other medicinal products on sildenafil

In vitro studies

Sildenafil is metabolized primarily by cytochrome P450 isoform 3A4 (major pathway) and isoform 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance, while inducers of these isoenzymes may increase its clearance.

In vivo studies

Population pharmacokinetic analysis of clinical study data demonstrated reduced sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although increased incidence of adverse effects was not observed during concomitant use of sildenafil and CYP3A4 inhibitors, consideration should be given to initiating treatment with a sildenafil dose of 25 mg.

Concomitant administration of the HIV protease inhibitor ritonavir, a very potent inhibitor of P450, at steady-state concentration (500 mg once daily) and sildenafil (single 100 mg dose) resulted in a 300% increase (4-fold) in sildenafil Cmax and a 1000% increase (11-fold) in plasma AUC. After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL when sildenafil was administered alone, indicating a significant effect of ritonavir on a wide range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Due to these pharmacokinetic data, concomitant use of sildenafil and ritonavir is not recommended (see section "Special precautions for use"); under no circumstances should the maximum dose of sildenafil exceed 25 mg within 48 hours.

Concomitant administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a dose providing steady-state concentration (1200 mg three times daily) and sildenafil (single 100 mg dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in AUC. No effect of sildenafil on the pharmacokinetics of saquinavir was observed (see section "Dosage and administration"). More potent CYP3A4 inhibitors such as ketoconazole and itraconazole are expected to have a more pronounced effect.

Administration of sildenafil (single 100 mg dose) with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days) resulted in an 182% increase in sildenafil AUC. In healthy male volunteers, azithromycin (500 mg daily for 3 days) did not affect AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its major circulating metabolite. Cimetidine (a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor) at a dose of 800 mg, when administered concomitantly with 50 mg sildenafil in healthy volunteers, increased plasma concentrations of sildenafil by 56%.

Grapefruit juice is a weak inhibitor of intestinal CYP3A4 and may cause a moderate increase in plasma levels of sildenafil.

Single-dose administration of antacids (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil.

Although specific interaction studies with all medicinal products have not been conducted, population pharmacokinetic analysis data indicate that the pharmacokinetics of sildenafil were not altered when co-administered with medicinal products belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, β-adrenoreceptor antagonists, or CYP450 metabolism inducers (such as rifampicin, barbiturates). In a study involving healthy male volunteers, concomitant administration of the endothelin antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19) at steady state (125 mg twice daily) and sildenafil at steady state (80 mg three times daily) resulted in a 62.6% and 55.4% reduction in AUC and Cmax of sildenafil, respectively. Therefore, concomitant use of potent CYP3A4 inducers such as rifampicin may lead to a more pronounced decrease in plasma concentrations of sildenafil.

Nicorandil is a hybrid of a potassium channel opener and a nitrate. The nitrate component implies a potential for serious interaction with sildenafil.

Effects of sildenafil on other medicinal products

In vitro studies

Sildenafil is a weak inhibitor of cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC50 > 150 µmol). Since peak plasma concentrations of sildenafil are approximately 1 µmol, the influence of TEGREM on the clearance of substrates of these isoenzymes is unlikely.

There are no data on the interaction between sildenafil and non-specific phosphodiesterase inhibitors such as theophylline and dipyridamole.

In vivo studies

Since it is known that sildenafil affects the NO/cGMP metabolism pathway, it has been established that sildenafil potentiates the hypotensive effect of nitrates; therefore, concomitant use with NO donors or nitrates in any form is contraindicated (see section "Contraindications").

Riociguat

Preclinical studies demonstrated additive systemic blood pressure-lowering effects when PDE5 inhibitors were used concomitantly with riociguat. Clinical studies have shown that riociguat enhances the hypotensive effect of PDE5 inhibitors. In patients participating in the study, no positive clinical effect was observed with concomitant use of PDE5 inhibitors and riociguat. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated (see section "Contraindications").

Concomitant use of sildenafil and α-adrenoreceptor blockers may lead to symptomatic hypotension in some susceptible patients. Such reactions most commonly occurred within 4 hours after sildenafil administration (see sections "Special precautions for use" and "Dosage and administration"). In three specific drug interaction studies, the α-adrenoreceptor blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were administered concomitantly to patients with benign prostatic hyperplasia whose condition had been stabilized on doxazosin. In these populations, mean additional reductions in supine blood pressure were 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, and mean reductions in standing blood pressure were 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. When sildenafil was administered concomitantly with doxazosin to patients whose condition had been stabilized on doxazosin, symptomatic orthostatic hypotension was occasionally observed. These reports described episodes of dizziness and presyncope, but no syncope.

No significant interactions were observed when sildenafil (50 mg) was administered concomitantly with tolbutamide (250 mg) or warfarin (40 mg), both metabolized by CYP2C9.

Sildenafil (50 mg) did not prolong bleeding time induced by acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers at a mean peak blood ethanol level of 80 mg/dL.

In patients taking sildenafil, no differences in adverse effect profile were observed compared to placebo when concomitantly administered with antihypertensive drug classes such as diuretics, β-adrenoreceptor blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and α-adrenoreceptor blockers. In a specific interaction study, concomitant administration of sildenafil (100 mg) and amlodipine to patients with arterial hypertension resulted in an additional 8 mm Hg reduction in supine systolic blood pressure and a 7 mm Hg reduction in diastolic blood pressure. These additional reductions in blood pressure were comparable in magnitude to those observed with sildenafil alone in healthy volunteers (see section "Pharmacological properties").

Sildenafil 100 mg did not affect the pharmacokinetic parameters of the HIV protease inhibitors saquinavir and ritonavir, which are CYP3A4 substrates.

In healthy male volunteers, administration of sildenafil at steady state (80 mg three times daily) increased AUC and Cmax of bosentan (125 mg twice daily) by 49.8% and 42%, respectively.

Adding a single dose of sildenafil to sacubitril/valsartan at steady state in patients with arterial hypertension was associated with a significantly greater reduction in blood pressure compared to sacubitril/valsartan monotherapy. Therefore, caution should be exercised when prescribing sildenafil to patients receiving sacubitril/valsartan.

Special precautions for use.

Before initiating therapy, a medical history should be obtained and a physical examination performed to diagnose erectile dysfunction and determine its possible causes.

Cardiovascular risk factors

Since sexual activity carries a certain cardiovascular risk, prior to initiating any treatment for erectile dysfunction, the physician should assess the patient's cardiovascular status. Sildenafil has vasodilatory effects, resulting in mild and transient reduction in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, the physician must carefully consider whether such an effect could adversely affect patients with underlying cardiovascular conditions, especially when combined with sexual activity. Patients particularly sensitive to vasodilators include those with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with the rare multisystem atrophy syndrome, one of the manifestations of which is severe autonomic regulation of blood pressure.

The medicinal product TEGRUM potentiates the hypotensive effect of nitrates (see section "Contraindications").

During the post-marketing period, serious cardiovascular adverse reactions have been reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, arterial hypertension, and arterial hypotension, which temporally coincided with sildenafil use. Most of these patients had pre-existing cardiovascular risk factors. The majority of such adverse reactions occurred during or immediately after sexual intercourse, while only a few occurred shortly after sildenafil administration without sexual activity. Therefore, it is not possible to determine whether the development of such adverse reactions is directly related to risk factors or whether other factors contributed to their occurrence.

Priapism

Medicinal products for the treatment of erectile dysfunction, including sildenafil, should be prescribed with caution in patients with anatomical penile deformity (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients with conditions predisposing to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia).

After the drug was introduced to the market, cases of prolonged erection and priapism have been reported. If erection lasts longer than 4 hours, patients should seek immediate medical help. Without prompt treatment, priapism may lead to penile tissue damage and permanent loss of potency.

Concomitant use with other PDE5 inhibitors or other erectile dysfunction treatments

The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or with pulmonary arterial hypertension treatments containing sildenafil (e.g., the medicine REVCATIO), or with other erectile dysfunction treatments have not been studied. Therefore, the use of such combinations is not recommended.

Effect on vision

Spontaneous reports of visual disturbances have been associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Spontaneous reports and data from observational studies have indicated cases of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition, associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be advised that in case of sudden visual impairment, use of the medicinal product TEGRUM should be discontinued and immediate medical advice sought (see section "Contraindications").

Concomitant use with ritonavir

Concomitant use of sildenafil and ritonavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with α-adrenoreceptor blockers

Sildenafil should be used with caution in patients taking α-adrenoreceptor blockers, as this combination may lead to symptomatic hypotension in some susceptible individuals. Symptomatic hypotension usually occurs within 4 hours after sildenafil administration. To minimize the potential for postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized with α-adrenoreceptor blockers before initiating sildenafil therapy. Consideration should also be given to starting with a dose of 25 mg (see section "Posology and method of administration"). In addition, patients should be informed about the appropriate actions to take if symptoms of orthostatic hypotension occur.

Effect on bleeding

Studies on human platelets have demonstrated that sildenafil in vitro potentiates the anti-aggregatory effects of sodium nitroprusside. There is no information available on the safety of sildenafil use in patients with bleeding disorders or acute peptic ulcer. Therefore, sildenafil may be used in these patient groups only after careful benefit-risk assessment.

After administration of a 100 mg dose to healthy volunteers, no effect on sperm morphology or motility was observed (see section "Pharmacodynamics").

Hearing loss

Physicians should advise patients to discontinue PDE5 inhibitors, including the medicinal product TEGRUM, and seek immediate medical help in case of sudden decrease or loss of hearing. These events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE5 inhibitors, including the medicinal product TEGRUM. It is not possible to determine whether these events are directly related to PDE5 inhibitor use or to other factors.

Concomitant use with antihypertensive agents

The medicinal product TEGRUM exerts systemic vasodilatory effects and may further reduce blood pressure in patients taking antihypertensive medications. In a specific drug interaction study, concomitant oral administration of amlodipine (5 mg or 10 mg) and sildenafil (100 mg) resulted in an average additional reduction of systolic blood pressure by 8 mm Hg and diastolic blood pressure by 7 mm Hg.

Sexually transmitted diseases

The use of the medicinal product TEGRUM does not protect against sexually transmitted diseases. Patients should be instructed about necessary preventive measures to protect against sexually transmitted infections, including human immunodeficiency virus.

Use during pregnancy or breastfeeding

The medicinal product TEGRUM is not intended for use in women.

Ability to affect reaction speed when driving or operating machinery

The medicinal product may have a minor influence on the ability to drive or operate machinery. Since dizziness and visual disturbances have been reported during clinical trials with sildenafil, patients should determine their individual response to TEGRUM before driving or operating machinery.

Method of Administration and Dosage.

The medication is administered orally.

For effective action of the medicinal product TEGRUM, sexual stimulation is required.

Adults

The recommended dose of the medicinal product TEGRUM is 50 mg, taken as needed approximately one hour before sexual activity. Depending on the efficacy and tolerability of the drug, the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended dosing frequency is once daily. When TEGRUM is taken with food, the onset of action may be delayed compared to administration on an empty stomach.

Elderly Patients

Dose adjustment is not required for elderly patients (aged 65 years and older).

Patients with Renal Impairment

For patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the recommended dose is the same as stated above in the section "Adults".

In patients with severe renal impairment (creatinine clearance < 30 mL/min), sildenafil clearance is reduced; therefore, a starting dose of 25 mg should be considered. Depending on efficacy and tolerability, the dose may be gradually increased to 50 mg and then to 100 mg, if necessary.

Patients with Hepatic Impairment

In patients with hepatic impairment (e.g., cirrhosis), sildenafil clearance is reduced; therefore, a starting dose of 25 mg should be considered. Depending on efficacy and tolerability, the dose may be gradually increased to 50 mg and then to 100 mg, if necessary.

Patients Taking Other Medicinal Products

If patients are concurrently taking CYP3A4 inhibitors (see section "Interaction with Other Medicinal Products and Other Types of Interactions"), a starting dose of 25 mg should be considered (except for ritonavir, which is not recommended to be used concomitantly with sildenafil; see section "Special Precautions").

To minimize the risk of postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized with α-adrenoreceptor blockers before initiating sildenafil therapy. A starting dose of 25 mg should also be considered (see sections "Interaction with Other Medicinal Products and Other Types of Interactions" and "Special Precautions").

Children

The medicinal product TEGRUM is not indicated for use in individuals under 18 years of age.

Overdose.

During clinical trials involving healthy volunteers, adverse reactions observed with single doses of sildenafil up to 800 mg were similar to those observed with lower doses but occurred more frequently and were more severe. Administration of sildenafil at a dose of 200 mg did not increase efficacy but led to an increased incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

In case of overdose, standard supportive measures should be applied as needed. Hemodialysis is unlikely to accelerate sildenafil clearance due to the high degree of protein binding and the absence of urinary excretion of sildenafil.

Adverse Reactions

The safety profile of sildenafil is based on data obtained from 9,570 patients during 74 double-blind, placebo-controlled clinical trials. The most commonly reported adverse reactions were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, hot flushes, visual disturbances, cyanopsia, and blurred vision. Information on adverse reactions from post-marketing surveillance was collected over a period of more than 10 years.

All clinically significant adverse reactions observed during clinical trials more frequently than with placebo are listed below according to the MedDRA standardized medical terminology system organ classes, with the following frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), and rare (≥ 1/10,000, < 1/1,000). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections and infestations: uncommon – rhinitis.

Immune system disorders: uncommon – hypersensitivity reactions.

Nervous system disorders: very common – headache; common – dizziness; uncommon – somnolence, hypoesthesia; rare – stroke, transient ischemic attack, seizures, seizure recurrence, syncope.

Eye disorders: common – color vision disturbances, visual disturbances, blurred vision; uncommon – lacrimation disorders, eye pain, photophobia, photopsia, ocular hyperemia, visual brightness, conjunctivitis; rare – non-arteritic anterior ischemic optic neuropathy, retinal vessel occlusion, retinal hemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters, iris disorders, mydriasis, halos around light sources in the visual field, eye swelling, eye edema, eye disorders, conjunctival hyperemia, eye irritation, abnormal sensations in the eyes, eyelid edema, scleral discoloration.

Ear and labyrinth disorders: uncommon – vertigo, tinnitus; rare – deafness.

Cardiac disorders: uncommon – tachycardia, palpitations; rare – sudden cardiac death, myocardial infarction, ventricular arrhythmia, atrial fibrillation, unstable angina.

Vascular disorders: common – facial flushing, hot flushes; uncommon – hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders: common – nasal congestion; uncommon – epistaxis, nasal sinus congestion; rare – throat tightness, nasal mucosal edema, nasal dryness.

Gastrointestinal disorders: common – nausea, dyspepsia; uncommon – gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth; rare – oral hypoesthesia.

Skin and subcutaneous tissue disorders: uncommon – rash; rare – Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: uncommon – myalgia, limb pain.

Renal and urinary disorders: uncommon – hematuria.

Reproductive system and breast disorders: rare – penile hemorrhage, priapism, hematospermia, prolonged erection.

General disorders and administration site conditions: uncommon – chest pain, increased fatigue, feeling of warmth; rare – irritation.

Investigations: uncommon – increased heart rate.

The following events were observed in < 2% of patients during controlled clinical trials; causal relationship has not been established. Reports included events that had a probable relationship to the use of the drug. Events not listed were mild and reports were too imprecise to be meaningful.

General disorders: facial swelling, photosensitivity reactions, shock, asthenia, pain, sudden fall, abdominal pain, sudden injury.

Cardiovascular disorders: angina pectoris, AV block, migraine, postural hypotension, myocardial ischemia, cerebral vessel thrombosis, cardiac arrest, ECG abnormalities, cardiomyopathy.

Gastrointestinal disorders: glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal liver function tests, rectal bleeding, gingivitis.

Blood and lymphatic system disorders: anemia, leukopenia.

Metabolism and nutrition disorders: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.

Musculoskeletal and connective tissue disorders: arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

Nervous system disorders: ataxia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes.

Respiratory, thoracic and mediastinal disorders: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.

Skin and subcutaneous tissue disorders: urticaria, herpes, pruritus, increased sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

Specific sensations: sudden decrease or loss of hearing, ear pain, eye hemorrhage, cataract, dry eyes.

Renal and urinary disorders: cystitis, nocturia, increased frequency of urination, gynecomastia, urinary incontinence, ejaculation disorders, genital swelling, anorgasmia.

Post-marketing experience

After the drug was marketed, the following adverse reactions have been identified. Because these are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events were reported due to their seriousness, frequency of reporting, lack of clear alternative explanation, or a combination of these factors.

Cardiovascular and cerebrovascular events: Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebral hemorrhage, subarachnoid hemorrhage, intracerebral hemorrhage, and pulmonary hemorrhage, which were temporally associated with sildenafil use. Most, but not all, patients had underlying cardiovascular risk factors. Many of these events occurred during or immediately after sexual activity, and several occurred immediately after sildenafil use without sexual activity. Other events occurred within hours or days after sildenafil use and sexual activity. It is not possible to determine whether these events are related to drug use, sexual activity, underlying risk factors, a combination of these factors, or other factors.

Blood and lymphatic system disorders: vaso-occlusive crisis. In a small, prematurely terminated study of the medicinal product REVATIO (sildenafil) in patients with pulmonary arterial hypertension secondary to sickle cell anemia, vaso-occlusive crises requiring hospitalization were reported more frequently with sildenafil than with placebo. The clinical relevance of this information for patients using sildenafil for the treatment of erectile dysfunction is unknown.

Nervous system disorders: anxiety, transient global amnesia.

Specific sensations

Ear and labyrinth disorders: After marketing, cases of sudden decrease or loss of hearing, temporally associated with sildenafil use, have been reported. In some cases, medical conditions and other factors that could have contributed to the development of hearing-related adverse reactions were reported. In many cases, information on subsequent medical follow-up is lacking. It is not possible to determine whether these events are directly related to sildenafil use, underlying risk factors for hearing loss, a combination of these factors, or other factors.

Eye disorders: transient vision loss, eye redness, eye burning, increased intraocular pressure, retinal edema, retinal vascular disorders or hemorrhage, vitreous detachment.

Rarely, after marketing, cases of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of vision loss including permanent vision loss, temporally associated with PDE5 inhibitors, including sildenafil, have been reported. In many, but not all, patients, anatomical or vascular risk factors for NAION were present, including (but not limited to): small cup-to-disc ratio (crowded optic disc), age over 50 years, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are directly related to the use of PDE5 inhibitors, underlying anatomical or vascular risk factors, a combination of all these factors, or other factors.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

1 or 4 tablets in a blister, 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC NPF "MIKROKHM" (responsible for batch release, excluding batch control/testing).

Manufacturer's address and location of operations.

5 Budyndustrіi St., Kyiv, 01013, Ukraine

Marketing Authorization Holder.

LLC NPF "MIKROKHM".

Address of Marketing Authorization Holder.

5 Budyndustrіi St., Kyiv, 01013, Ukraine.

INSTRUCTIONS

for medical use of the medicinal product

TEGRUM

(TEGRUM)

Composition:

Active substance: sildenafil;

One tablet contains 70.225 mg of sildenafil citrate, equivalent to 50 mg of sildenafil;

One tablet contains 140.450 mg of sildenafil citrate, equivalent to 100 mg of sildenafil;

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: white or off-white, biconvex tablets with smooth surface, film-coated.

Pharmacotherapeutic group.

Medicinal products used in urology. Agents used in erectile dysfunction. Sildenafil. ATC code G04B E03.

Pharmacological Properties

Pharmacodynamics

Sildenafil is an oral medication indicated for the treatment of erectile dysfunction. During sexual stimulation, the drug restores impaired erectile function by enhancing blood flow to the penis.

The physiological mechanism responsible for penile erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Released NO activates the enzyme guanylate cyclase, which increases levels of cyclic guanosine monophosphate (cGMP), leading to relaxation of smooth muscle in the corpus cavernosum and promoting blood inflow.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for cGMP degradation. The effects of sildenafil on erection are peripheral in nature. Sildenafil does not directly relax isolated human corpus cavernosum tissue, but it strongly potentiates the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated during sexual stimulation, sildenafil's inhibition of PDE5 increases cGMP levels in the corpus cavernosum. Therefore, sexual stimulation is required for sildenafil to produce its desired pharmacological effect.

In vitro studies have shown that sildenafil is selective for PDE5, which actively participates in the erectile process. The effect of sildenafil on PDE5 is significantly stronger than on other known phosphodiesterases. This effect is 10 times more potent than its effect on PDE6, which is involved in retinal phototransduction. At maximum recommended doses, sildenafil's selectivity for PDE5 is 80 times greater than for PDE1, 700 times greater than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. Specifically, sildenafil's selectivity for PDE5 is 4000 times greater than for PDE3—a cAMP-specific phosphodiesterase isoform involved in regulating cardiac contractility.

Pharmacokinetics

Absorption

When sildenafil is taken with food, the rate of absorption is reduced, with a mean delay in Tmax to 60 minutes and a mean reduction in Cmax by 29%.

Distribution

The mean steady-state volume of distribution (Vd) is 105 liters, indicating extensive distribution of the drug into body tissues. After a single 100 mg oral dose, the mean peak total plasma concentration of sildenafil is approximately 440 ng/mL (coefficient of variation 40%). Since binding of sildenafil and its major N-desmethyl metabolite to plasma proteins is about 96%, the mean peak free plasma concentration of sildenafil reaches approximately 18 ng/mL (38 nmol). The degree of plasma protein binding is independent of total sildenafil concentrations.

In healthy volunteers who received a single 100 mg dose of sildenafil, less than 0.0002% (mean 188 ng) of the administered dose was found in semen 90 minutes after dosing.

Metabolism

Sildenafil is metabolized primarily by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite results from N-demethylation of sildenafil. The metabolite's selectivity for PDE5 is comparable to that of sildenafil, and its activity against PDE5 is approximately 50% of the parent compound. Plasma concentrations of this metabolite are about 40% of those of sildenafil. The N-desmethyl metabolite undergoes further metabolism, and its elimination half-life is approximately 4 hours.

Elimination

Pharmacokinetics in Special Patient Populations

Elderly Patients

In healthy elderly volunteers (aged 65 years and older), reduced clearance of sildenafil was observed, leading to approximately 90% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite compared to younger healthy volunteers (18–45 years). Due to age-related differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%.

Renal Impairment

Hepatic Impairment

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh classes A and B), sildenafil clearance was reduced, leading to increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with normal liver function. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

TEGRUM is recommended for use in men with erectile dysfunction, defined as the inability to achieve or maintain a penile erection sufficient for successful sexual performance.

For effective action of TEGREM, sexual stimulation is required.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the NO/cGMP metabolic pathway and potentiate the hypotensive effect of nitrates;
Concomitant use of PDE5 inhibitors (including sildenafil) with guanylate cyclase stimulators such as riociguat is contraindicated, as it may lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction");
Conditions in which sexual activity is not recommended (e.g., severe cardiovascular disorders such as unstable angina or severe heart failure);
Unilateral sudden vision loss due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this condition is associated with prior use of PDE5 inhibitors;
Presence of conditions such as severe hepatic impairment, arterial hypotension (blood pressure below 90/50 mm Hg), recent stroke or myocardial infarction, and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a small number of such patients have genetic disorders of retinal phosphodiesterases), as the safety of sildenafil has not been studied in these patient subgroups.

Interaction with other medicinal products and other forms of interaction.

Effects of other medicinal products on sildenafil

In vitro studies

Sildenafil metabolism is primarily mediated by cytochrome P450 isoenzyme 3A4 (major pathway) and to a lesser extent by isoenzyme 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance, while inducers may increase its clearance.

In vivo studies

Population pharmacokinetic analysis of clinical trial data demonstrated reduced sildenafil clearance when co-administered with CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, cimetidine). Although no increase in adverse events was observed with concomitant use of sildenafil and CYP3A4 inhibitors, consideration should be given to initiating sildenafil at a dose of 25 mg.

Concomitant administration of the HIV protease inhibitor ritonavir, a very potent inhibitor of P450, at steady-state concentration (500 mg once daily) and sildenafil (single 100 mg dose) resulted in a 300% increase (4-fold) in sildenafil Cmax and a 1000% increase (11-fold) in plasma AUC. After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL when sildenafil was administered alone, indicating a significant effect of ritonavir on a broad range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Based on these pharmacokinetic data, concomitant use of sildenafil and ritonavir is not recommended (see section "Special precautions for use"); in any case, the maximum dose of sildenafil should not exceed 25 mg within 48 hours.

Concomitant administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a dose providing steady-state concentration (1200 mg three times daily) and sildenafil (single 100 mg dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in AUC. No effect of sildenafil on saquinavir pharmacokinetics was observed (see section "Dosage and administration"). More potent CYP3A4 inhibitors such as ketoconazole and itraconazole are expected to have a more pronounced effect.

Grapefruit juice is a weak inhibitor of intestinal CYP3A4 and may cause a moderate increase in plasma levels of sildenafil.

Single administration of antacids (magnesium hydroxide/aluminum hydroxide) did not affect sildenafil bioavailability.

Although specific interaction studies with all medicinal products have not been conducted, population pharmacokinetic analysis data indicate that sildenafil pharmacokinetics were not altered when co-administered with medicinal products belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, β-adrenergic antagonists, or CYP450 metabolism inducers (e.g., rifampicin, barbiturates). In a study involving healthy male volunteers, concomitant administration of the endothelin antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19) at steady state (125 mg twice daily) and sildenafil at steady state (80 mg three times daily) resulted in a 62.6% and 55.4% reduction in AUC and Cmax of sildenafil, respectively. Therefore, concomitant use of potent CYP3A4 inducers such as rifampicin may lead to a more pronounced decrease in plasma sildenafil concentrations.

Nicorandil is a hybrid of a potassium channel opener and a nitrate. The nitrate component may lead to a serious interaction with sildenafil.

Effects of sildenafil on other medicinal products

In vitro studies

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC50 > 150 µmol). Since peak plasma concentrations of sildenafil are approximately 1 µmol, the effect of TEGREM on the clearance of substrates of these isoenzymes is unlikely.

There are no data on the interaction between sildenafil and non-specific phosphodiesterase inhibitors such as theophylline and dipyridamole.

In vivo studies

Since sildenafil is known to affect the NO/cGMP metabolic pathway, it has been established that sildenafil potentiates the hypotensive effect of nitrates; therefore, concomitant use of sildenafil with NO donors or nitrates in any form is contraindicated (see section "Contraindications").

Riociguat

Preclinical studies have demonstrated additive systemic blood pressure-lowering effects when PDE5 inhibitors are used concomitantly with riociguat. Clinical studies have shown that riociguat enhances the hypotensive effect of PDE5 inhibitors. In patients participating in the study, no positive clinical effect was observed with concomitant use of PDE5 inhibitors and riociguat. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated (see section "Contraindications").

Concomitant use of sildenafil and α-adrenergic blockers may lead to symptomatic hypotension in some susceptible patients. This reaction most commonly occurred within 4 hours after sildenafil administration (see sections "Special precautions for use" and "Dosage and administration"). In three drug interaction studies, the α-adrenergic blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were administered concomitantly to patients with benign prostatic hyperplasia whose condition had been stabilized on doxazosin. In these populations, mean additional reductions in supine blood pressure were 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, and mean reductions in standing blood pressure were 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. Symptomatic orthostatic hypotension occasionally occurred when sildenafil was used concomitantly with doxazosin in patients whose condition had been stabilized on doxazosin. These reports included episodes of dizziness and presyncope, but not syncope.

No significant interactions were observed with concomitant administration of sildenafil (50 mg) and tolbutamide (250 mg) or warfarin (40 mg), both metabolized by CYP2C9.

Sildenafil (50 mg) did not prolong bleeding time induced by acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with a mean maximum blood ethanol concentration of 80 mg/dL.

No differences in adverse effect profile were observed in patients taking sildenafil compared to placebo when concomitantly administered with antihypertensive drug classes such as diuretics, β-blockers, ACE inhibitors, angiotensin II antagonists, vasodilators and centrally acting antihypertensives, adrenergic neuron blockers, calcium channel blockers, and α-adrenergic blockers. In a specific interaction study, concomitant administration of sildenafil (100 mg) and amlodipine to patients with arterial hypertension resulted in an additional 8 mm Hg reduction in supine systolic blood pressure and a 7 mm Hg reduction in diastolic blood pressure. These additional reductions in blood pressure were comparable in magnitude to those observed with sildenafil alone in healthy volunteers (see section "Pharmacological properties").

Sildenafil 100 mg did not affect the pharmacokinetic parameters of the HIV protease inhibitors saquinavir and ritonavir, which are CYP3A4 substrates.

In healthy male volunteers, administration of sildenafil at steady state (80 mg three times daily) increased AUC and Cmax of bosentan (125 mg twice daily) by 49.8% and 42%, respectively.

Special precautions for use.

Prior to initiating therapy, a medical history should be obtained and a physical examination performed to diagnose erectile dysfunction and determine its possible causes.

Cardiovascular risk factors

Since sexual activity carries a certain degree of cardiovascular risk, before initiating any treatment for erectile dysfunction, the physician should assess the patient's cardiovascular status. Sildenafil has vasodilatory effects, which manifest as mild and transient reduction in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, the physician must carefully consider whether such an effect could adversely affect patients with underlying cardiovascular conditions, particularly in combination with sexual activity. Patients who are more sensitive to vasodilators include those with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with the rare multisystem atrophy syndrome, one of the manifestations of which is severe autonomic regulation of arterial blood pressure.

The medicinal product TEGRUM potentiates the hypotensive effect of nitrates (see section "Contraindications").

In the post-marketing period, serious adverse cardiovascular events have been reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, arterial hypertension, and arterial hypotension, which temporally coincided with sildenafil use. Most of these patients had pre-existing cardiovascular risk factors. The majority of these adverse reactions occurred during or immediately after sexual intercourse, and only a few occurred shortly after sildenafil administration without sexual activity. Therefore, it is not possible to determine whether the development of such adverse reactions is directly related to risk factors or whether their occurrence is due to other factors.

Priapism

Medicinal products for the treatment of erectile dysfunction, including sildenafil, should be prescribed with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients with conditions predisposing to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia).

Since the product launch, cases of prolonged erection and priapism have been reported. If an erection lasts longer than 4 hours, patients should seek immediate medical assistance. Without prompt treatment, priapism may lead to penile tissue damage and permanent loss of potency.

Concomitant use with other PDE5 inhibitors or other erectile dysfunction treatments

The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or with pulmonary arterial hypertension treatments containing sildenafil (e.g., the product REVATIO), or with other erectile dysfunction treatments, have not been studied. Therefore, such combinations are not recommended.

Effect on vision

Spontaneous reports of visual disturbances have been associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Spontaneous reports and data from observational studies have indicated cases of non-arteritic anterior ischaemic optic neuropathy (NAION), a rare condition, associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be advised that if they experience sudden visual loss, they should discontinue use of the medicinal product TEGRUM and seek immediate medical advice (see section "Contraindications").

Concomitant use with ritonavir

Concomitant use of sildenafil and ritonavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with α-adrenoreceptor blockers

Sildenafil should be used with caution in patients taking α-adrenoreceptor blockers, as this combination may lead to symptomatic hypotension in some susceptible patients. Symptomatic hypotension usually occurs within 4 hours after sildenafil administration. To minimize the potential for postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized with α-adrenoreceptor blockers before initiating sildenafil therapy. In addition, consideration should be given to starting with an initial dose of 25 mg (see section "Method of administration and dosage"). Patients should also be informed about the appropriate actions to take if symptoms of orthostatic hypotension occur.

Effect on bleeding

In vitro studies on human platelets have demonstrated that sildenafil potentiates the anti-aggregatory effects of sodium nitroprusside. There is no information available on the safety of sildenafil use in patients with bleeding disorders or acute peptic ulcer. Therefore, sildenafil should be used in these patient groups only after careful assessment of the benefit-risk ratio.

Administration of a 100 mg dose to healthy volunteers did not show any effect on sperm morphology or motility (see section "Pharmacodynamics").

Hearing loss

Physicians should advise patients to discontinue use of PDE5 inhibitors, including the medicinal product TEGRUM, and seek immediate medical help if they experience sudden decrease or loss of hearing. These events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE5 inhibitors, including TEGRUM. It is not possible to determine whether these events are directly related to the use of PDE5 inhibitors or to other factors.

Concomitant use with antihypertensive agents

The medicinal product TEGRUM exerts systemic vasodilatory effects and may further reduce blood pressure in patients taking antihypertensive medicinal products. In a specific drug interaction study, concomitant oral administration of amlodipine (5 mg or 10 mg) and sildenafil (100 mg) resulted in an average additional reduction in systolic pressure of 8 mm Hg and diastolic pressure of 7 mm Hg.

Sexually transmitted diseases

The use of the medicinal product TEGRUM does not protect against sexually transmitted diseases. Patients should be instructed on the necessary preventive measures to protect against sexually transmitted diseases, including human immunodeficiency virus (HIV).

Use during pregnancy or breastfeeding

The medicinal product TEGRUM is not intended for use in women.

Ability to affect reaction speed when driving or operating machinery

Method of administration and dosage.

The drug is taken orally.

For effective action of the medicinal product TEGRUM, sexual stimulation is required.

Adults

The recommended dose of the medicinal product TEGRUM is 50 mg, taken as needed approximately one hour before sexual activity. Depending on the efficacy and tolerability of the drug, the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of administration is once daily. When TEGRUM is taken with food, the onset of action may be delayed compared to administration on an empty stomach.

Elderly patients

Dose adjustment is not required for elderly patients (aged 65 years and older).

Patients with renal impairment

For patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the recommended dose is the same as stated above in the section "Adults".

Patients with hepatic impairment

Patients taking other medicinal products

If patients are concurrently using CYP3A4 inhibitors (see section "Interaction with other medicinal products and other types of interactions"), a starting dose of 25 mg should be considered (except for ritonavir, which is not recommended to be used concomitantly with sildenafil; see section "Special precautions for use").

To minimize the risk of postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized with α-adrenoreceptor blockers before initiating sildenafil therapy. A starting dose of 25 mg should also be considered (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").

Children

The medicinal product TEGRUM is not indicated for use in individuals under 18 years of age.

Overdose.

During clinical studies in volunteers, administration of single doses of sildenafil up to 800 mg resulted in adverse reactions similar to those observed with lower doses, but they occurred more frequently and were more severe. Administration of sildenafil at a dose of 200 mg did not increase efficacy but led to an increased incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

In case of overdose, standard supportive measures should be implemented as needed. Hemodialysis is unlikely to accelerate sildenafil clearance due to the high degree of plasma protein binding and the absence of urinary excretion of sildenafil.

Adverse Reactions

The safety profile of sildenafil is based on data from 9,570 patients in 74 double-blind, placebo-controlled clinical trials. The most commonly reported adverse reactions were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, hot flushes, visual disturbances, cyanopsia, and blurred vision. Information on adverse reactions from post-marketing surveillance has been collected over a period of more than 10 years.

All clinically significant adverse reactions observed during clinical trials more frequently than with placebo are listed below according to the MedDRA standardized medical terminology system organ classes, with the following frequency categories: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), and rare (≥ 1/10,000, < 1/1,000). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Infections and infestations: uncommon – rhinitis.

Immune system disorders: uncommon – hypersensitivity reactions.

Nervous system disorders: very common – headache; common – dizziness; uncommon – somnolence, hypoesthesia; rare – stroke, transient ischemic attack, seizures, seizure recurrence, syncope.

Eye disorders: common – color vision disturbance, visual disturbances, blurred vision; uncommon – lacrimation disorders, eye pain, photophobia, photopsia, ocular hyperemia, visual brightness, conjunctivitis, eye irritation, abnormal sensations in the eye, eyelid edema, scleral discoloration; rare – non-arteritic anterior ischemic optic neuropathy, retinal vessel occlusion, retinal hemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters, iris disorders, mydriasis, halos around lights (halo vision), eye swelling, eye swelling, eye disorders, conjunctival hyperemia, eye irritation, abnormal eye sensations, eyelid edema, scleral discoloration.

Ear and labyrinth disorders: uncommon – dizziness, tinnitus; rare – deafness.

Cardiac disorders: uncommon – tachycardia, palpitations; rare – sudden cardiac death, myocardial infarction, ventricular arrhythmia, atrial fibrillation, unstable angina.

Vascular disorders: common – facial flushing, hot flushes; uncommon – hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders: common – nasal congestion; uncommon – epistaxis, nasal sinus congestion; rare – throat tightness, nasal mucosal edema, nasal dryness.

Gastrointestinal disorders: common – nausea, dyspepsia; uncommon – gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth; rare – oral hypoesthesia.

Skin and subcutaneous tissue disorders: uncommon – rash; rare – Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: uncommon – myalgia, limb pain.

Renal and urinary disorders: uncommon – hematuria.

Reproductive system and breast disorders: rare – penile bleeding, priapism, hematospermia, prolonged erection.

General disorders and administration site conditions: uncommon – chest pain, increased fatigue, feeling of warmth; rare – irritation.

Investigations: uncommon – increased heart rate.

The following events were observed in < 2% of patients in controlled clinical trials; a causal relationship has not been established. Reports included events considered likely related to the use of the drug. Events not listed were mild and reported too imprecisely to be meaningful.

General disorders: facial edema, photosensitivity reactions, shock, asthenia, pain, sudden fall, abdominal pain, sudden injury.

Cardiovascular disorders: angina pectoris, AV block, migraine, postural hypotension, myocardial ischemia, cerebral vessel thrombosis, sudden cardiac arrest, ECG abnormalities, cardiomyopathy.

Gastrointestinal disorders: glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal liver function tests, rectal bleeding, gingivitis.

Blood and lymphatic system disorders: anemia, leukopenia.

Metabolism and nutrition disorders: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.

Musculoskeletal and connective tissue disorders: arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

Nervous system disorders: ataxia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes.

Respiratory, thoracic and mediastinal disorders: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, cough exacerbation.

Skin and subcutaneous tissue disorders: urticaria, herpes, pruritus, increased sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

Special senses: sudden decrease or loss of hearing, ear pain, ocular hemorrhage, cataract, dry eyes.

Renal and urinary disorders: cystitis, nocturia, increased frequency of urination, galactorrhea, urinary incontinence, ejaculation disorders, genital swelling, anorgasmia.

Post-marketing experience

After the drug was marketed, the following adverse reactions have been identified. Because these are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events were included due to their seriousness, frequency of reporting, lack of clear alternative explanation, or a combination of these factors.

Cardiovascular and cerebrovascular events: Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebral hemorrhage, subarachnoid hemorrhage, intracerebral hemorrhage, and pulmonary hemorrhage, which occurred in temporal association with sildenafil use. Most, but not all, patients had underlying cardiovascular risk factors. Many of these events occurred during or immediately after sexual activity, and several occurred shortly after sildenafil use without sexual activity. Other events occurred within hours or days after sildenafil use and sexual activity. It is not possible to determine whether these events are related to the drug, sexual activity, underlying risk factors, a combination of these, or other factors.

Blood and lymphatic system disorders: vaso-occlusive crisis. In a small, prematurely terminated study of REVATIO (sildenafil) in patients with pulmonary arterial hypertension secondary to sickle cell anemia, vaso-occlusive crises requiring hospitalization were reported more frequently with sildenafil than with placebo. The clinical significance of this information for patients using sildenafil for the treatment of erectile dysfunction is unknown.

Nervous system disorders: anxiety, transient global amnesia.

Special senses

Ear and labyrinth disorders: After marketing, cases of sudden decrease or loss of hearing temporally associated with sildenafil use have been reported. In some cases, medical conditions and other factors that may have contributed to hearing-related adverse reactions were reported. In many cases, follow-up medical information is lacking. It is not possible to determine whether these events are directly related to sildenafil use, underlying risk factors for hearing loss, a combination of these, or other factors.

Eye disorders: transient vision loss, eye redness, eye burning, increased intraocular pressure, retinal edema, retinal vascular disorders or hemorrhage, vitreous detachment.

Rarely, after marketing, cases of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent vision loss, have been reported in temporal association with PDE5 inhibitors, including sildenafil. Many, but not all, patients had anatomical or vascular risk factors for NAION, including (but not limited to): low cup-to-disc ratio (crowded optic disc), age over 50 years, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are directly related to PDE5 inhibitor use, underlying anatomical or vascular risk factors, a combination of all these factors, or other factors.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

1 or 4 tablets in a blister pack, 1 blister in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC NVF "MIKROKHEM" (production unit (all stages of manufacturing process))

Manufacturer's address and place of business.

33 Lenin Street, Rubizhne, Luhansk Oblast, 93000, Ukraine

Marketing authorization holder.

LLC NVF "MIKROKHEM".

Address of the marketing authorization holder.

5 Budynstustriyi Street, Kyiv, 01013, Ukraine