INSTRUCTION for medical use of the medicinal product POTENTIALE (POTENTIALE)

Composition:

Active substance: sildenafil citrate;

1 tablet contains sildenafil citrate equivalent to sildenafil – 50 mg or 100 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, hypromellose, magnesium stearate, colloidal anhydrous silicon dioxide, titanium dioxide (E 171), talc, propylene glycol, polyethylene glycol 6000 (macrogol 6000), indigo carmine (E 132).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, film-coated tablets, blue-colored (for 50 mg dosage) or blue-colored (for 100 mg dosage), with convex upper and lower surfaces. When examined under a magnifying glass, the cross-section reveals a core surrounded by a single continuous layer.

Pharmacotherapeutic group. Agents used in erectile dysfunction. Sildenafil. ATC code G04BE03.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Sildenafil is an orally administered drug 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 underlying erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Released NO activates the enzyme guanylate cyclase, which stimulates an increase in levels of cyclic guanosine monophosphate (cGMP). This, in turn, causes relaxation of the smooth musculature of the corpus cavernosum, 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 a direct relaxant effect on isolated human corpus cavernosum tissue, but it strongly potentiates the relaxing effect of NO on this tissue. When the NO/cGMP metabolic pathway is activated during sexual stimulation, sildenafil’s inhibition of PDE5 leads to increased cGMP levels in the corpus cavernosum. Thus, for sildenafil to produce its desired pharmacological effect, sexual stimulation is required.

Effect on pharmacodynamics. In vitro studies have demonstrated 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 phototransduction processes in the retina. 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. In particular, sildenafil’s selectivity for PDE5 is 4000 times greater than for PDE3 – the cGMP-specific isoenzyme of phosphodiesterase involved in regulation of 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% (ranging from 25% to 63%). Within the recommended dose range (25 to 100 mg), AUC and Cmax values 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 maximum 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 maximum free plasma concentration of sildenafil reaches approximately 18 ng/mL (38 nmol). The extent of 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 after 90 minutes.

Biotransformation. Sildenafil is metabolized primarily by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite is formed via 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-demethylated 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. Following both oral and intravenous administration, excretion of sildenafil occurs primarily in the form of metabolites via feces (approximately 80% of the orally administered dose), with a lesser amount excreted in urine (approximately 13% of the orally administered 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 values in age-matched volunteers without renal impairment. However, due to high individual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance below 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 without renal impairment. Additionally, AUC and Cmax of the N-desmethyl metabolite were significantly increased 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, leading to increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers without hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

The drug is recommended for use in men with erectile dysfunction, defined as the inability to achieve or maintain an erection of the penis sufficient for successful sexual intercourse.

For the drug to be effective, sexual stimulation is required.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the drug.
Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the nitric oxide/cyclic guanosine monophosphate (cGMP) metabolic pathway and potentiates 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).
Loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy, 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 occurs primarily via the 3A4 isoform (main pathway) and the 2C9 iso游戏副本

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 some degree of cardiovascular risk, physicians should evaluate the cardiovascular status of patients prior to initiating any treatment for erectile dysfunction. Sildenafil exerts vasodilatory effects, resulting in mild and transient reduction in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, physicians must carefully consider whether such an effect could adversely affect patients with underlying medical conditions, particularly when combined with sexual activity. Patients who may be 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 manifestation of which is severe autonomic regulation of blood pressure.

Sildenafil potentiates the hypotensive effect of nitrates (see section "Contraindications").

In the post-marketing period, serious cardiovascular adverse events have been reported, including myocardial infarction, unstable angina, SCD (sudden cardiac death), ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, arterial hypertension, and arterial hypotension, which temporally coincided with sildenafil use. In most, but not all patients, cardiovascular risk factors were present. Many of these adverse events occurred during or immediately after sexual intercourse, and only a few occurred shortly after sildenafil use 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. Medications for the treatment of erectile dysfunction, including sildenafil, should be administered with caution to patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease) or to patients with conditions that may predispose to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia).

Since the drug was introduced to the market, cases of prolonged erection and priapism have been reported. If an erection lasts longer than 4 hours, patients should seek immediate medical assistance. In the absence of prompt treatment, priapism may lead to penile tissue damage and permanent loss of potency.

Concomitant use with other PDE5 inhibitors or other erectile dysfunction medications. The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other medications for the treatment of pulmonary arterial hypertension containing sildenafil (e.g., Revatio), or with other erectile dysfunction medications 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 findings from observational studies have also 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 if they experience sudden vision loss, they should discontinue the medication and seek immediate medical attention (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 typically occurs within 4 hours after sildenafil administration. To minimize the potential for postural hypotension, patients on α-adrenoreceptor blockers should have their condition stabilized on these agents before initiating sildenafil therapy. Additionally, consideration should be given to starting with a dose of 25 mg (see section "Dosage and administration"). Patients should also be informed about appropriate actions to take if symptoms of postural hypotension occur.

Effect on bleeding. Platelet studies in humans have demonstrated that in vitro, 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 active peptic ulceration. Therefore, the use of sildenafil in these patient groups should only be considered after careful assessment of benefit-risk balance.

Administration of a 100 mg dose to healthy volunteers showed no effect on sperm morphology or motility (see section "Pharmacodynamics").

Hearing loss. Physicians should advise patients to discontinue PDE5 inhibitors, including Potentiale, 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 PDE5 inhibitors, including sildenafil. 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. Sildenafil 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 this medication 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 medication is not intended for use in women.

Ability to affect reaction speed when driving vehicles or operating machinery.

Studies on the effect of the medication on the ability to drive vehicles or operate machinery have not been conducted.

Since dizziness and visual disturbances have been reported during clinical trials with sildenafil, patients should determine their individual response to the medication before driving a vehicle or operating machinery.

Method of Administration and Dosage

The medication should be administered orally.

Adults. The recommended dose is 50 mg, taken as needed approximately 1 hour before sexual activity. Depending on efficacy and tolerability, the dose may be increased to 100 mg or reduced to 25 mg*. The maximum recommended dose is 100 mg. The maximum recommended dosing frequency is once daily. When the medication is taken with food, its onset of action may be delayed compared to administration on an empty stomach.

Elderly patients. Dose adjustment in elderly patients (≥ 65 years of age) is not required.

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 that indicated above for adults.

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

Patients with hepatic impairment. Since sildenafil clearance is reduced in patients with hepatic impairment (e.g., cirrhosis), the recommended starting dose is 25 mg*. Depending on efficacy and tolerability, the dose may be increased to 50 mg and 100 mg.

Patients taking other medicinal products. If patients are concurrently taking CYP3A4 inhibitors (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"), consideration should be given to initiating treatment with a 25 mg dose* (except for ritonavir, which is not recommended to be co-administered with sildenafil—see section "Special Warnings and Precautions for Use").

To minimize the potential risk of postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized on α-adrenoreceptor blockers prior to initiating sildenafil therapy. Additionally, consideration should be given to initiating treatment with a 25 mg dose* (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

* When prescribing sildenafil at a dose of 25 mg, use the medication in the appropriate dosage strength or pharmaceutical form.

Children.

The medication is not indicated for use in individuals under 18 years of age.

Overdose.

In clinical studies involving healthy volunteers, adverse reactions observed with single doses of sildenafil up to 800 mg were similar to those seen at 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 implemented as required. Enhanced clearance of sildenafil by hemodialysis is unlikely due to the high degree of plasma protein binding and the absence of urinary excretion of sildenafil.

Side effects.

Infections and infestations: rhinitis.

Immune system disorders: hypersensitivity.

Nervous system disorders: headache, dizziness, somnolence, hypoesthesia, stroke, transient ischemic attack, seizures*, seizure recurrence*, syncope, ataxia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes.

Eye disorders: color vision disturbances**, visual disturbances, blurred vision, tear film disorders***, eye pain, photophobia, photopsia, eye hyperemia, visual brightness, conjunctivitis, non-arteritic anterior ischemic optic neuropathy*, retinal vascular occlusion*, retinal hemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters, iris disorders, mydriasis, appearance of bright circles around light sources (halos) 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: dizziness, tinnitus, deafness.

Cardiac disorders: tachycardia, palpitations, SCD (sudden cardiac death)*, myocardial infarction, ventricular arrhythmia*, atrial fibrillation, unstable angina, flushing, hot flushes, hypertension, hypotension, angina, AV block, migraine, postural hypotension, myocardial ischemia, cerebral vessel thrombosis, sudden cardiac arrest, abnormal ECG findings, cardiomyopathy.

Respiratory, thoracic and mediastinal disorders: nasal congestion, epistaxis, nasal sinus congestion, throat tightness, nasal mucosal edema, nasal dryness, bronchial asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.

Gastrointestinal disorders: nausea, dyspepsia, gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth, oral hypoesthesia, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal liver function test results, rectal bleeding, gingivitis.

Skin and subcutaneous tissue disorders: rash, Stevens-Johnson syndrome*, toxic epidermal necrolysis*, urticaria, herpes, pruritus, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

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

Renal and urinary disorders: hematuria, cystitis, nocturia, increased frequency of urination, urinary incontinence.

Reproductive system and breast disorders: penile bleeding, priapism*, hemospermia, prolonged erection, breast enlargement, ejaculation disorders, genital swelling, anorgasmia.

Blood and lymphatic system disorders: anemia, leukopenia.

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

General disorders and administration site conditions: chest pain, increased fatigue, feeling of warmth, irritation, facial swelling, photosensitivity reactions, shock, asthenia, pain, sudden fall, abdominal pain, accidental injuries.

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

Investigations: increased heart rate.

* Reported only during post-marketing surveillance.

** Color vision disturbances: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.

*** Tear film disorders: dry eyes, tear film disorders, and increased lacrimation.

Post-marketing experience.

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 the use of the drug. Most, but not all, patients had pre-existing cardiovascular risk factors. Many of these events occurred during or immediately after sexual activity, and several occurred immediately after taking the drug without sexual activity. Other events occurred within hours or days after drug intake and sexual activity. It is not possible to determine whether these events are directly related to the use of the drug, to sexual activity, to pre-existing risk factors, to a combination of these factors, or to 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 taking Potentiale for the treatment of erectile dysfunction is unknown.

Nervous system disorders: anxiety, transient global amnesia.

Specific sensations.

Ears. Cases of sudden decrease or loss of hearing, occurring in temporal association with sildenafil use, have been reported. In some cases, medical conditions and other factors that could have contributed to hearing-related adverse reactions were noted. 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, to pre-existing risk factors for hearing loss, to a combination of these factors, or to other factors.

Eyes. Transient vision loss, eye redness, eye burning, increased intraocular pressure, retinal edema, retinal vascular disorders or hemorrhage, vitreous detachment.

Cases of non-arteritic anterior ischemic optic neuropathy (NAION), leading to visual impairment including permanent vision loss, have been reported in temporal association with the use of PDE5 inhibitors, including Potentiale. Many, but not all, patients had pre-existing anatomical or vascular risk factors for NAION, 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 PDE5 inhibitor use, to pre-existing anatomical or vascular risk factors, to a combination of these factors, or to other factors.

Reporting suspected adverse reactions. Reporting of suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals should report any suspected adverse reactions in accordance with applicable legislation.

Shelf life. 3 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

2 tablets in a blister; 1 or 2 blisters in a cardboard box;

1 tablet in a blister; 1, 2, or 4 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

JSC "Tekhnolog".

Manufacturer's address and place of business.

8 Stara Prorina Street, Uman, Cherkasy region, Ukraine, 20300.