STRONGDEX

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT STRONDEX (STRONDEX)

Composition:

Active substance: sildenafil;

One dose contains 17.56 mg of sildenafil citrate, equivalent to 12.5 mg of sildenafil;

Excipients: propylene glycol, ethanol 96%, macrogol-400, levomenthol, diluted hydrochloric acid, lemon oil, sucralose.

Pharmaceutical form. Metered oral spray.

Main physicochemical properties: clear liquid with a yellowish or greenish-yellow tint, with a characteristic odor.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

Sildenafil is an oral medication intended for the treatment of erectile dysfunction. During sexual stimulation, the drug restores impaired erectile function by enhancing venous blood inflow to the corpora cavernosa.

The physiological mechanism responsible for erection involves the release of nitric oxide (NO) in the corpora cavernosa during sexual stimulation. Released NO activates the enzyme guanylate cyclase, which stimulates an increase in the level of cyclic guanosine monophosphate (cGMP), leading to relaxation of the smooth musculature of the corpora cavernosa and promoting blood inflow.

Sildenafil is a potent, selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) in the corpora cavernosa, where PDE5 is responsible for cGMP degradation. The effects of sildenafil on erection are peripheral in nature. Sildenafil does not exert a direct relaxing effect on isolated human corpora cavernosa, 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 results in increased cGMP levels in the corpora cavernosa. Therefore, for sildenafil to produce the desired pharmacological effect, sexual stimulation is required.

In vitro studies have demonstrated that sildenafil is selective for PDE5, which actively participates in the process of erection. The effect of sildenafil on PDE5 is more potent than on other known phosphodiesterases. This effect is 10 times 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. Specifically, sildenafil's selectivity for PDE5 is 4000 times greater than for PDE3—an isoform of cAMP-specific phosphodiesterase involved in the regulation of cardiac contractility.

Pharmacokinetics

Absorption

The rate of sildenafil absorption in spray form is somewhat higher compared to solid oral dosage forms, as the active substance, which has low aqueous solubility, is administered already in dissolved form. Maximum plasma concentration is reached on average within 60 minutes after administration on an empty stomach. The mean absolute bioavailability of sildenafil after oral administration is 41% (with a range of 25–63%). When sildenafil is taken with food, the extent of absorption is reduced, with an average delay in Tmax by 60 minutes and an average reduction in maximum concentration (Cmax) by 29%.

Distribution

The mean steady-state volume of distribution (Vd) is 105 liters, indicating extensive tissue distribution. After a single 50 mg dose of STRONDEX spray, the mean peak total plasma concentration of sildenafil is approximately 200 ng/mL (with a coefficient of variation of 40%). The extent of binding of sildenafil and its major N-desmethyl metabolite to plasma proteins is about 96%, and is independent of the total concentration of sildenafil.

Metabolism

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. The plasma concentration of this metabolite is about 40% of the plasma concentration of sildenafil. The N-desmethyl metabolite undergoes further metabolism, and its elimination half-life is approximately 4 hours.

Elimination

The 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 metabolites occurs predominantly in feces (approximately 80% of the orally administered dose) and to a lesser extent 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 (unbound) 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 values of the area under the plasma concentration-time curve (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 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 with normal liver function. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

STRONDEX 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 STRONDEX, 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, since sildenafil is known to affect the nitric oxide (NO)/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 inadvisable (e.g., severe cardiovascular disorders such as unstable angina or severe heart failure);
• Unilateral vision loss 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 mmHg), 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 forms of interaction.

Effect of other medicinal products on sildenafil

In vitro studies

Metabolism of sildenafil occurs primarily via the 3A4 isoform (major pathway) and the 2C9 isoform (minor pathway) of cytochrome P450 (CYP). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance, while inducers of these isoenzymes may increase sildenafil clearance.

In vivo studies

Population pharmacokinetic analysis of clinical trial data demonstrated reduced clearance of sildenafil when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although an increase in the frequency of adverse reactions was not observed when sildenafil was used concomitantly with CYP3A4 inhibitors, consideration should be given to initiating sildenafil therapy at a dose of 25 mg.

Concomitant administration of the HIV protease inhibitor ritonavir, a very potent inhibitor of P450, at steady-state concentrations (500 mg once daily), and sildenafil (single 100 mg dose) resulted in a 300% increase (4-fold) in Cmax and a 1000% increase (11-fold) in plasma AUC of sildenafil. After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL typical after sildenafil alone, due to the significant effect of ritonavir on a broad spectrum 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"); the maximum sildenafil dose should under no circumstances exceed 25 mg within 48 hours.

Concomitant administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a dose providing steady-state concentrations (1200 mg three times daily), and sildenafil (single 100 mg dose) resulted in a 140% increase in Cmax and a 210% increase in AUC of sildenafil. 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 AUC of sildenafil. In healthy male volunteers, azithromycin (500 mg once daily for 3 days) did not affect AUC, Cmax, time to maximum concentration (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 CYP3A4 in the intestinal wall and may cause a moderate increase in plasma levels of sildenafil.

Single 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 calcium channel activator and nitrate. The nitrate component implies a potential for serious interaction with sildenafil.

Effect 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 the maximum plasma concentration of sildenafil is approximately 1 µmol, the influence of STRO NDEX 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, 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" and "Dosage and administration"). In three 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 was stabilized on doxazosin. In these populations, mean additional reductions in supine blood pressure were 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, and mean reductions in standing blood pressure were 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively. Symptomatic orthostatic hypotension was occasionally reported with concomitant use of sildenafil and doxazosin in patients whose condition was stabilized on doxazosin. These reports described episodes of dizziness and pre-syncope, but no 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 at a mean maximum blood ethanol level of 80 mg/dL.

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

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

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 potential 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, manifested by mild and transient reduction in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, the physician must carefully consider whether this effect could adversely affect patients with underlying cardiovascular conditions, particularly when combined 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 manifestation of which is severe autonomic nervous system dysregulation of blood pressure.

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

During 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, but not all, of these patients had pre-existing cardiovascular risk factors. Many 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 occurrence of such adverse reactions is directly related to risk factors or is caused by other factors.

Priapism

Medicinal products for the treatment of erectile dysfunction, including sildenafil, should be prescribed with caution to patients with anatomical deformation of the penis (angulation, cavernosal fibrosis, or Peyronie's disease) or to 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 an erection lasts more 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 medications

The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or with other medications for pulmonary arterial hypertension containing sildenafil, 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 findings from a surveillance study have indicated cases of non-arteritic anterior ischaemic optic neuropathy, a rare condition, associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be advised that if sudden visual impairment occurs, use of the medicinal product STRENDEX 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 patients. Symptomatic hypotension usually occurs within 4 hours after sildenafil administration. To minimize the potential development of postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized with α-adrenoreceptor blockers before initiating sildenafil therapy. Additionally, consideration should be given to starting treatment with a 25 mg dose (see section "Method of administration and dosage"). Patients should also be informed about 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 effect of sodium nitroprusside. There is no information available on the safety of sildenafil use in patients with coagulation disorders or acute peptic ulcer. Therefore, sildenafil use in these patient groups should only be considered after careful assessment of benefit-risk ratio.

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 use of PDE5 inhibitors, including the medicinal product STRENDEX, and seek immediate medical help if sudden decrease or loss of hearing occurs. These events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of 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

The medicinal product STRENDEX 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 in systolic blood pressure of 8 mm Hg and diastolic blood pressure of 7 mm Hg.

Sexually transmitted diseases

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

Use during pregnancy or breastfeeding.

The medicinal product STRENDEX 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 STRENDEX before driving a vehicle or operating machinery.

Method of Administration and Dosage

The medicinal product STRENDEX is sprayed into the oral cavity without inhaling the spray. To enhance the effect of the spray, it is recommended to hold it in the mouth for some time. One dose of the drug contains 12.5 mg of sildenafil. Dosage is determined based on the patient's condition and sensitivity to sildenafil within the range of 12.5–75 mg. The recommended single dose is 25–37.5 mg (2 or 3 consecutive actuations). The medicinal product should be administered 20–30 minutes prior to sexual activity. Depending on the efficacy and tolerability of the drug, the dose may be increased up to 75 mg. The maximum recommended dose is 75 mg.

The maximum recommended frequency of administration is once daily.

Elderly Patients

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

Patients with Renal Impairment

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

Due to reduced sildenafil clearance in patients with severe renal impairment (creatinine clearance < 30 mL/min), the recommended dose of STRENDEX is 12.5–25 mg. Depending on efficacy and tolerability, the dose may be gradually increased up to 75 mg.

Patients with Hepatic Impairment

Since sildenafil clearance is reduced in patients with hepatic impairment, the recommended dose of STRENDEX is 12.5–25 mg. Depending on efficacy and tolerability, the dose may be gradually increased up to 75 mg.

Patients Taking Other Medicinal Products

If patients are concurrently using CYP3A4 inhibitors (except ritonavir, the concomitant use of which with sildenafil is not recommended; see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"), consideration should be given to initiating treatment with a dose of 25 mg.

To minimize the risk of orthostatic hypotension, the condition of patients taking α-adrenoreceptor blockers should be stabilized before initiating sildenafil therapy. The recommended initial dose of STRENDEX for such patients is 12.5–25 mg.

Instructions for Use

Before the first use, the spray should be primed by several rapid actuations into the air until a uniform mist is produced. The product is now ready for use.

If more than 24 hours have passed since the last use, the first spray should be released into the air to prevent administering an incomplete dose.

The bottle should be held vertically with the spray nozzle pointing upwards.

Bring the bottle close to the mouth and administer the solution with a short, sharp press on the spray pump as follows:

• take a deep breath;
• hold the breath;
• press sharply on the spray pump to administer the solution into the mouth;
• close the mouth and breathe through the nose only for the next 30 seconds.

The solution should not be inhaled. To ensure proper delivery, press the spray pump fully without interruption. The spray function should be checked periodically, especially after prolonged periods of non-use.

Children

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

Overdose

During clinical trials involving healthy 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 applied as necessary. 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 group, adverse reactions are listed in decreasing order of 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 – colour vision disturbances**, visual disturbances, blurred vision; uncommon – lacrimation disorders***, eye pain, photophobia, photopsia, eye hyperemia, visual brightness, conjunctivitis, dry eye, eye irritation, abnormal eye sensations, eyelid edema, eye swelling, eye disorders, conjunctival hyperemia, eye irritation, iris disorders, mydriasis, halos around lights in visual field; 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 in visual field, eye edema, eyelid swelling, eye disorders, conjunctival hyperemia, eye irritation, abnormal eye sensations, 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.

* Reported only in post-marketing studies.
** Colour vision disturbances: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.
*** Lacrimation disorders: dry eyes, lacrimation disorders, increased lacrimation.

The following events were observed in < 2% of patients in controlled clinical trials; causal relationship has not been established. Reports included events with a probable relationship to drug use. Events not listed were mild and reports were too imprecise 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, increased cough.

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 urinary frequency, galactorrhea, urinary incontinence, ejaculation disorders, genital swelling, anorgasmia.

Post-marketing experience

The following adverse reactions have been identified after marketing authorization. As these are voluntarily reported 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 severity, frequency, lack of clear alternative explanation, or a combination of these factors.

Cardiovascular, cerebrovascular, and vascular events: Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebral hemorrhage, subarachnoid and intracerebral hemorrhage, and pulmonary hemorrhage, occurring in temporal association with sildenafil use. Most patients had underlying cardiovascular risk factors. Most events occurred during or immediately after sexual activity; a few 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 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 erectile dysfunction is unknown.

Nervous system disorders: anxiety, transient global amnesia.

Special senses

Ear and labyrinth disorders: After marketing authorization, 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 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.

Rare cases of non-arteritic anterior ischemic optic neuropathy (NAION), leading to vision loss including permanent vision loss, temporally associated with PDE5 inhibitors, including sildenafil, have been reported post-marketing. Many patients had underlying 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, underlying anatomical or vascular risk factors, a combination of these, or other factors.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 ml (64 doses) or 5 ml (32 doses) in polymer or light-resistant glass bottles in a cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

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

Manufacturer's address and location of operations.

5 Budyndustrії St., Kyiv, 01013, Ukraine.

Marketing Authorization Holder.

LLC "MICROCHEM".

You can report any adverse reaction to the medicinal product at +38 (050) 309-83-54 (24/7).

Marketing Authorization Holder's address.

5 Budyndustrії St., Kyiv, 01013, Ukraine.

INSTRUCTIONS

for medical use of the medicinal product

STRONDEX

(STRONDEX)

Composition:

Active substance: sildenafil;

1 dose contains 17.56 mg of sildenafil citrate, equivalent to 12.5 mg of sildenafil;

Excipients: propylene glycol, ethanol 96%, macrogol-400, levomenthol, diluted hydrochloric acid, lemon oil, sucralose.

Pharmaceutical form. Metered oral spray.

Main physicochemical properties: clear liquid with a yellowish or greenish-yellow hue, with a characteristic odor.

Pharmacotherapeutic group.

Medicinal products used in urology. Agents used in 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 venous blood inflow to the corpus cavernosum.

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). This, in turn, induces relaxation of the smooth muscle in the corpus cavernosum, promoting blood inflow.

Sildenafil is a potent, 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 peripherally mediated. Sildenafil does not directly relax isolated human corpus cavernosum tissue, but it strongly potentiates the relaxing effect of NO on this tissue. During activation of the NO/cGMP metabolic pathway, which occurs during sexual stimulation, sildenafil’s inhibition of PDE5 leads to increased cGMP levels in the corpus cavernosum. Therefore, for sildenafil to produce its desired pharmacological effect, sexual stimulation is required.

In vitro studies have demonstrated that sildenafil is selective for PDE5, which plays an active role in the erectile process. The inhibitory effect of sildenafil on PDE5 is significantly stronger than on other known phosphodiesterases. This effect is 10-fold greater 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—an isoform of cAMP-specific phosphodiesterase involved in regulating cardiac contractility.

Pharmacokinetics

Absorption

The rate of sildenafil absorption in spray form is slightly higher compared to solid oral dosage forms, because the active substance, which has low aqueous solubility, is administered already in dissolved form. Maximum plasma concentration is reached on average within 60 minutes after administration on an empty stomach. The mean absolute bioavailability of sildenafil after oral administration is 41% (range: 25–63%). When sildenafil is taken with food, the extent of absorption is reduced, with a mean delay in Tmax by 60 minutes and a mean reduction in maximum concentration (Cmax) by 29%.

Distribution

The mean volume of distribution at steady state (Vd) is 105 liters, indicating extensive tissue distribution. After a single 50 mg dose of STRONDEX spray, the mean peak total plasma concentration of sildenafil is approximately 200 ng/mL (coefficient of variation is 40%). The extent of binding of sildenafil and its major N-desmethyl metabolite to plasma proteins is about 96%, and is independent of the total concentration of sildenafil in plasma.

Metabolism

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 concentration of this metabolite is about 40% of the plasma concentration of sildenafil. 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 in the form of metabolites via feces (approximately 80% of the orally administered dose), and to a lesser extent 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 (unbound) 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 values for the area under the plasma concentration-time curve (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, leading to 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 by 84% and Cmax by 47% compared to age-matched volunteers with normal liver function. The pharmacokinetics of sildenafil in patients with severe hepatic impairment has not been studied.

Clinical characteristics.

Indications.

STRONDEX 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 STRONDEX, 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, since sildenafil is known to affect the nitric oxide (NO)/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), since the safety of sildenafil has not been studied in these patient subgroups.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on sildenafil

In vitro studies

Metabolism of sildenafil occurs primarily via cytochrome P450 (CYP) 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 sildenafil clearance.

In vivo studies

Population pharmacokinetic analysis of clinical trial data demonstrated reduced clearance of sildenafil when administered concomitantly with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although an increase in the frequency of adverse reactions 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 (500 mg once daily), and sildenafil (single dose 100 mg) resulted in a 300% increase (4-fold) in Cmax and a 1000% increase (11-fold) in plasma AUC of sildenafil. After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL typical after sildenafil alone, explained by the significant effect of ritonavir on a broad 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"); the maximum dose of sildenafil should under no circumstances 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 dose 100 mg) resulted in a 140% increase in Cmax and a 210% increase in AUC of sildenafil. 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 (100 mg single dose) and erythromycin, a moderate CYP3A4 inhibitor, at steady-state (500 mg twice daily for 5 days) resulted in an 182% increase in AUC of sildenafil. In healthy male volunteers, azithromycin (500 mg once daily for 3 days) did not affect AUC, Cmax, time to maximum concentration (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 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 administered concomitantly with medicinal products belonging to the group of CYP2C9 inhibitors (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-adrenergic receptor 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 activator and a nitrate. The nitrate component implies the potential for serious interaction with sildenafil.

Effect 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 the maximum plasma concentration of sildenafil is approximately 1 µmol, the impact of STRONDEX 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 metabolic 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 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 receptor 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-adrenergic receptor 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 was stabilized on doxazosin. In these populations, mean additional reductions in blood pressure in the supine position were 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, and mean reductions in blood pressure in the standing position were 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. Cases of symptomatic orthostatic hypotension were occasionally reported when sildenafil was used concomitantly with doxazosin in patients whose condition was stabilized on doxazosin. These reports described episodes of dizziness and presyncope, but no 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 at a mean maximum blood ethanol level of 80 mg/dL.

In patients receiving sildenafil, there were no differences in the adverse reaction profile compared to placebo when concomitantly using classes of antihypertensive drugs such as diuretics, β-adrenergic receptor blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive agents (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and α-adrenergic receptor blockers. In a specific interaction study, concomitant administration of sildenafil (100 mg) and amlodipine in 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 in healthy volunteers receiving sildenafil alone (see section "Pharmacological properties").

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

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, before starting any treatment for erectile dysfunction, the physician should assess the patient's cardiovascular status. Sildenafil exerts a vasodilatory effect, manifested by mild and transient reduction in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, the physician must carefully consider whether this effect could adversely affect patients with certain underlying diseases, especially in combination with sexual activity. Patients who are 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 nervous system dysfunction in blood pressure regulation.

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

During 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. In most patients, but not all, cardiovascular risk factors were present. Many 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 occurrence of such adverse reactions is directly related to risk factors or is caused by other factors.

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).

Since the product launch, cases of prolonged erection and priapism have been reported. If an erection lasts more 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, with other pulmonary arterial hypertension treatments containing sildenafil, 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 received in association with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Spontaneous reports and data from a surveillance study 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 "Ad游戏副本

Method of Administration and Dosage

The medicinal product STRONDEX is sprayed into the oral cavity without inhaling the spray. To enhance the effect of the spray, it is recommended to hold it in the mouth for some time. One dose of the preparation contains 12.5 mg of sildenafil. Dosage is determined based on the patient's condition and sensitivity to sildenafil within the range of 12.5–75 mg. The recommended single dose is 25–37.5 mg (2 or 3 consecutive actuations). The medicinal product should be administered 20–30 minutes before sexual activity. Depending on the efficacy and tolerability of the drug, the dose may be gradually increased up to 75 mg. The maximum recommended dose is 75 mg.

The maximum recommended frequency of administration is once daily.

Elderly Patients

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

Patients with Renal Impairment

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

Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min), the recommended dose of STRONDEX is 12.5–25 mg. Depending on efficacy and tolerability, the dose may be gradually increased up to 75 mg.

Patients with Hepatic Impairment

Since sildenafil clearance is reduced in patients with hepatic impairment, the recommended dose of STRONDEX is 12.5–25 mg. Depending on efficacy and tolerability, the dose may be gradually increased up to 75 mg.

Patients Taking Other Medicinal Products

If patients are concurrently using CYP3A4 inhibitors (except ritonavir, which is not recommended to be used concomitantly with sildenafil—see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use"), consideration should be given to initiating treatment with a dose of 25 mg.

To minimize the risk of orthostatic hypotension, the condition of patients taking α-adrenoreceptor blockers should be stabilized before initiating sildenafil treatment. The recommended initial dose of STRONDEX for such patients is 12.5–25 mg.

Instructions for Use

Before first use, the spray should be primed by rapidly actuating it several times into the air until a fine, consistent mist is produced. The product is then ready for use.

If more than 24 hours have passed since the last use, the first spray should be released into the air to prevent administering an incomplete dose.

During administration, the bottle should be held vertically with the spray nozzle pointing upwards.

Bring the bottle close to the mouth and, with a quick, firm press on the spray nozzle, administer the solution into the mouth as follows:

• take a deep breath;
• hold the breath;
• with a quick, firm press on the spray nozzle, administer the solution into the mouth;
• close the mouth and breathe through the nose only for the next 30 seconds.

The solution should not be inhaled. To ensure optimal delivery, press the spray nozzle fully without interruption. The functionality of the spray device should be checked periodically, especially after prolonged periods of non-use.

Children

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

Overdose

During clinical trials involving volunteers, adverse reactions following single doses of sildenafil up to 800 mg were similar to those observed with lower doses but occurred more frequently and were more severe. A dose of 200 mg of sildenafil 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 necessary. Hemodialysis is unlikely to accelerate sildenafil clearance due to the high degree of plasma protein binding and the absence of urinary elimination of sildenafil.

Adverse Reactions

The safety profile of sildenafil is based on data from 9,570 patients involved 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 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 ischaemic attack, seizures*, seizure recurrence*, syncope.

Eye disorders: common – colour vision disturbances**, visual disturbances, blurred vision; uncommon – lacrimation disorders***, eye pain, photophobia, photopsia, eye hyperaemia, bright vision, conjunctivitis; rare – non-arteritic anterior ischaemic optic neuropathy*, retinal vessel occlusion*, retinal haemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters, iris disorders, mydriasis, halos around lights in the visual field, eye swelling, eye swelling, eye disorders, conjunctival hyperaemia, eye irritation, abnormal sensations in eyes, eyelid oedema, 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 oedema, 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 – haematuria.

Reproductive system and breast disorders: rare – penile haemorrhage, priapism*, haemospermia, prolonged erection.

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

Investigations: uncommon – increased heart rate.

* Reported only in post-marketing studies.
** Colour vision disturbances: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.
*** Lacrimation disorders: dry eyes, lacrimation disorders, increased lacrimation.

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

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

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

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

Blood and lymphatic system disorders: anaemia, leucopenia.

Metabolism and nutrition disorders: thirst, oedema, gout, unstable diabetes, hyperglycaemia, peripheral oedema, hyperuricaemia, hypoglycaemia, hypernatraemia.

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

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

Respiratory, thoracic and mediastinal disorders: asthma, dyspnoea, 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 haemorrhage, cataract, dry eyes.

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

Post-marketing experience

The following adverse reactions have been identified after marketing authorization. As these are reported voluntarily from a population of unknown size, it is often not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events are included due to their seriousness, frequency of reporting, lack of clear alternative association, or a combination of these factors.

Cardiovascular and cerebrovascular events: Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebral haemorrhage, subarachnoid haemorrhage, intracerebral haemorrhage, and pulmonary haemorrhage, which occurred in temporal association with sildenafil use. Most patients had underlying cardiovascular risk factors. Most of these events occurred during or immediately after sexual activity; 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 drug use, 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 anaemia, vaso-occlusive crises requiring hospitalization were reported more frequently with sildenafil than with placebo. The clinical significance of this finding 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 authorization, 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 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 oedema, retinal vascular disorders or haemorrhage, vitreous detachment.

Rare cases of non-arteritic anterior ischaemic optic neuropathy (NAION), a cause of decreased vision including permanent vision loss, have been reported post-marketing in temporal association with PDE5 inhibitors, including sildenafil. Many patients had underlying 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, hyperlipidaemia, 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 these, or other factors.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 ml (64 doses) or 5 ml (32 doses) in polymer or light-protected glass bottles in a cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

LLC NPF "MIKROKHEM" (production unit (all stages of the manufacturing process)).

Manufacturer's address and location of operations.

33 Lenin St., Rubizhne, Luhansk Oblast, 93000, Ukraine

Marketing Authorization Holder.

LLC NPF "MIKROKHEM".

Report any adverse reaction during the use of the medicinal product by calling +38 (050) 309-83-54 (24/7).

Marketing Authorization Holder's address.

5 Budynsturiyi St., Kyiv, 01013, Ukraine