Joker

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Joker (Joker)

Composition:

Active substance: sildenafil;

1 ml of oral suspension contains 35.1 mg of sildenafil citrate (equivalent to 25.0 mg of sildenafil);

1 actuation delivers 0.5 ml of suspension containing 12.5 mg of sildenafil;

Excipients: sodium benzoate (E 211), anhydrous citric acid, sucralose, acesulfame potassium (E 950), hypromellose, xanthan gum, "Mint" flavoring (501500 TPO5041), additional flavoring (SC2411602), purified water.

1 "Mint" flavoring (501500 TPO504) contains corn maltodextrin, flavor components (menthofuran 0.6%, pulegone 0.2%, estragole 0.09%), and modified corn starch E 1450 (7.9%).

2 Additional flavoring (SC241160) contains natural flavoring substances, E-955 sucralose (94.5%), potato maltodextrin, and monoammonium glycyrrhizinate (0.4%).

Pharmaceutical form. Oral suspension.

Main physicochemical properties: white to almost white suspension, free from foreign particles, with a minty odor.

Pharmacotherapeutic group.

Agents used in erectile dysfunction. Sildenafil.

ATC code G04BE03.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Sildenafil is an oral medication intended for the treatment of erectile dysfunction. Under normal conditions—that is, during sexual stimulation—the drug restores impaired erectile function by enhancing blood flow to the penis.

The physiological mechanism responsible for erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Released NO then activates the enzyme guanylate cyclase, which stimulates an increase in levels of cyclic guanosine monophosphate (cGMP). This, in turn, causes relaxation of the smooth muscle in 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 the breakdown of cGMP. The effects of sildenafil on erection are peripheral in nature. Sildenafil does not exert a direct relaxing effect on 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. Thus, for sildenafil to produce the desired pharmacological effect, sexual stimulation is required.

Pharmacodynamic effects

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 times more potent than its effect on PDE6, which is involved in phototransduction processes in the retina. At maximum recommended doses, selectivity is 80 times greater compared to PDE1 and more than 700 times greater compared to PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. In particular, sildenafil’s selectivity for PDE5 exceeds its selectivity for PDE3—the cAMP-specific phosphodiesterase isoform involved in the regulation of cardiac contractility—by 4000-fold.

Pharmacokinetics

Absorption

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

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

Distribution

The mean steady-state volume of distribution (Vd) for sildenafil is 105 liters, indicating extensive distribution into body tissues. After a single 100 mg oral dose, the mean peak total plasma concentration of sildenafil is approximately 440 ng/mL (CV 40%). Since sildenafil (and its major metabolite, N-desmethyl, in systemic circulation) is 96% bound to plasma proteins, this results in a mean peak free sildenafil plasma concentration of 18 ng/mL (38 nM). Protein binding is independent of total drug concentration.

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

Metabolism

Sildenafil is primarily metabolized by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite is formed via N-demethylation of sildenafil. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and exhibits approximately 50% of the in vitro potency of the parent compound for PDE5. Plasma concentrations of this metabolite are approximately 40% of those observed for sildenafil. The N-desmethyl metabolite is further metabolized, with a terminal half-life of 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, excretion of sildenafil metabolites occurs primarily 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, leading to approximately 90% higher plasma concentrations of sildenafil and its active N-demethylated metabolite compared to younger healthy volunteers (aged 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-desmethylated metabolite increased by up to 126% and 73%, respectively, compared to values in age-matched volunteers with normal renal function. However, due to high 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-desmethylated metabolite increased significantly—by 200% and 79%, 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 have not been studied.

Clinical characteristics.

Indications.

Recommended for use in adult 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 medicinal product.
• Concomitant use with NO donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the NO/cGMP metabolic pathway (see section "Pharmacodynamics") 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 where sexual activity is not recommended (e.g., patients with 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 (NAION), regardless of whether this condition was associated with prior use of PDE5 inhibitors or not (see section "Special precautions for use").
• 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 diseases 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 is primarily mediated by CYP3A4 (major pathway) and CYP2C9 (minor pathway) isoenzymes 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 increased incidence of adverse events was not observed in these patients when sildenafil was used concomitantly with CYP3A4 inhibitors, consideration should be given to initiating treatment with a sildenafil dose of 25 mg (2 actuations of the dispenser).

Concomitant administration of the HIV protease inhibitor ritonavir, a very potent inhibitor of P450, at steady-state concentration (500 mg twice 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 when sildenafil was administered alone, indicating a significant effect of ritonavir on a broad range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Given these pharmacokinetic data, concomitant use of sildenafil and ritonavir is not recommended (see section "Special precautions for use"); in any case, the maximum dose of sildenafil should not exceed 25 mg (2 actuations of the dispenser) within 48 hours.

Concomitant administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a dose providing steady-state concentration (1200 mg three times daily), and sildenafil (single 100 mg dose) resulted in a 140% increase in 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"). It is expected that more potent CYP3A4 inhibitors, such as ketoconazole and itraconazole, will have a more pronounced effect.

Administration of sildenafil (single 100 mg 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 daily for 3 days) did not affect AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil and its major circulating metabolite. Cimetidine (a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor) at a dose of 800 mg co-administered with sildenafil 50 mg 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-dose administration of antacids (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil.

Although specific interaction studies with all medicinal products have not been conducted, population pharmacokinetic analysis data showed that the pharmacokinetics of sildenafil were not altered when co-administered with medicinal products belonging to the class 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-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 concentration of sildenafil.

Nicorandil is a hybrid of a potassium channel activator and a nitrate. The nitrate component implies the possibility of serious interaction with sildenafil.

Effect of sildenafil on other medicinal products

In vitro studies

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC50 > 150 μM). Since peak plasma concentrations of sildenafil are approximately 1 μmol, the effect of the drug on the clearance of substrates of these isoenzymes is unlikely. There are no data on the interaction of sildenafil with non-specific phosphodiesterase inhibitors such as theophylline and dipyridamole.

In vivo studies

Since it is known that sildenafil affects the metabolism of NO/cGMP (see section "Pharmacodynamics"), 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 have demonstrated an additive systemic effect on blood pressure reduction 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-adrenoreceptor blockers may lead to symptomatic hypotension in some susceptible patients. Such reactions most commonly occurred within 4 hours after sildenafil administration (see sections "Dosage and administration" and "Special precautions for use"). 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 co-administered 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. Concomitant use of sildenafil and doxazosin in patients whose condition was stabilized on doxazosin was occasionally associated with symptomatic hypotension. Reports described episodes of dizziness and pre-syncope, but not syncope.

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

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

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

In patients receiving sildenafil, no differences in adverse effect profile were observed compared to placebo when concomitantly using 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, concomitant administration of sildenafil (100 mg) and amlodipine in patients with arterial hypertension resulted in an additional 8 mmHg reduction in supine systolic blood pressure and a 7 mmHg reduction in diastolic blood pressure.

These additional reductions in blood pressure were comparable in magnitude to those observed with sildenafil alone in healthy volunteers (see section "Pharmacological properties").

Sildenafil at a dose of 100 mg did not affect the pharmacokinetic parameters of 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 alone. Therefore, caution should be exercised when initiating sildenafil in patients receiving sacubitril/valsartan therapy.

Special precautions for use.

To diagnose erectile dysfunction, determine possible causes of the disease, and prescribe appropriate treatment, a thorough evaluation of the patient's medical history and a comprehensive medical examination are required.

For oral use only. Do not administer by any other route.

Cardiovascular risk factors.

Since sexual activity carries a certain cardiovascular risk, before initiating any treatment for erectile dysfunction, physicians must assess the patient's cardiovascular status.

Sildenafil exerts a vasodilatory effect, manifested as mild and transient reduction in arterial blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, physicians should carefully consider whether this effect may adversely affect patients with underlying cardiovascular conditions, particularly when combined with sexual activity. Patients who may be more sensitive to vasodilators include those with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with the rare multisystem atrophy syndrome, one of the features of which is severe autonomic nervous system dysfunction in blood pressure regulation.

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

Since the introduction of sildenafil into widespread clinical practice, serious cardiovascular events have been reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic 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. The majority of such events occurred during or immediately after sexual intercourse, and only a few occurred shortly after sildenafil administration without sexual activity. Therefore, it is not possible to determine whether the development of such adverse reactions is directly related to risk factors or whether their occurrence is due to other factors.

Priapism.

Medicinal products for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with anatomical deformity of the penis (such as curvature, cavernosal fibrosis, or Peyronie's disease) or in patients with conditions predisposing to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). Since the market introduction of sildenafil, cases of prolonged erection and priapism have been reported. If erection lasts longer than 4 hours, patients should seek immediate medical assistance. Without prompt treatment, priapism may lead to penile tissue damage and permanent loss of potency.

Concomitant use with other PDE5 inhibitors or other erectile dysfunction medications.

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

Effect on vision.

Visual disturbances and cases of non-arteritic anterior ischemic optic neuropathy have been observed in association with sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Spontaneous reports and data from observational studies have indicated rare cases of non-arteritic anterior ischemic optic neuropathy 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 medicinal product 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 who are concurrently using α-adrenoblockers, as in some cases this may lead to symptomatic hypotension in susceptible individuals (see section "Interaction with other medicinal products and other forms of interaction"). Symptomatic hypotension usually occurs within 4 hours after sildenafil administration. To minimize the potential for postural hypotension in patients receiving α-adrenoreceptor blockers, their condition should be stabilized on α-blocker therapy before initiating sildenafil. Consideration should also be given to starting with an initial dose of 25 mg (2 actuations of the dispenser) (see section "Method of administration and dosage"). Additionally, patients should be informed about appropriate actions to take if symptoms of orthostatic hypotension occur.

Effect on bleeding.

In vitro studies on human platelets indicate that sildenafil enhances the anti-aggregatory effect of sodium nitroprusside. There is no safety data available regarding the use of sildenafil in patients with a predisposition to bleeding or with active peptic ulcer; therefore, sildenafil should be prescribed to these patients only after careful benefit-risk assessment.

Hearing loss.

Physicians should advise patients to discontinue PDE5 inhibitors, including sildenafil, and seek immediate medical attention in case of sudden decrease or loss of hearing. These events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE5 inhibitors, including 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 arterial blood pressure in patients taking antihypertensive medications. In a specific drug interaction study, concomitant administration of amlodipine (5 mg or 10 mg) and oral sildenafil 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 sildenafil does not protect against sexually transmitted diseases. Consideration should be given to informing patients about necessary preventive measures to protect against sexually transmitted diseases, including human immunodeficiency virus.

Fertility.

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

Use during pregnancy or breastfeeding.

The medicinal product 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. During clinical trials, dizziness and visual disturbances were reported with sildenafil use; therefore, patients should determine their individual response to the medicinal product before driving or operating machinery.

Method of Administration and Dosage.

Adults

The recommended dose is 2 ml (4 actuations of the dispenser), equivalent to 50 mg of sildenafil, taken as needed approximately one hour before sexual activity. Based on efficacy and tolerability, the dose may be reduced to 1 ml (2 actuations of the dispenser), equivalent to 25 mg of sildenafil. Additionally, the physician will recommend the dose most appropriate for each individual patient.

The maximum recommended dose is 2 ml (4 actuations of the dispenser), equivalent to 50 mg of sildenafil. The maximum recommended frequency of intake is once daily. The drug's effect may manifest later when taken with food compared to administration on an empty stomach (see section "Pharmacokinetics").

Number of actuations of the dispenser	Amount of suspension released, ml	Amount of sildenafil, mg
2	1	25
4	2	50

Each actuation of the dispenser releases 0.5 mL of suspension containing 12.5 mg of sildenafil.

Special patient groups

Elderly patients.

No dosage adjustment is required for elderly patients (aged 65 years and older).

Patients with renal impairment.

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

Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance <30 mL/min), a starting dose of 25 mg (2 actuations of the dispenser) should be considered. Depending on efficacy and tolerability, the dose may be gradually increased if necessary to 50 mg and then to 100 mg.

Patients with hepatic impairment.

Since sildenafil clearance is reduced in patients with hepatic impairment (e.g., cirrhosis), a starting dose of 25 mg (2 actuations of the dispenser) should be considered. Depending on efficacy and tolerability, the dose may be gradually increased if necessary to 50 mg and then to 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"), a starting dose of 1 mL (2 actuations of the dispenser), equivalent to 25 mg of sildenafil, should be considered (except for ritonavir, which is not recommended to be used concomitantly with sildenafil; see section "Special warnings and precautions for use").

To minimize the potential for postural hypotension in patients taking α-adrenoreceptor blockers, patients should be stabilized on α-adrenoreceptor blockers prior to initiating sildenafil treatment. A starting dose of 1 mL (2 actuations of the dispenser), equivalent to 25 mg of sildenafil, should also be considered (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").

Method of administration.

For oral use only. Under no circumstances should the solution be administered by any other route.

It is recommended to take on an empty stomach, as absorption may be delayed when taken with food.

Before first use, the dispenser must be primed by pressing the actuator three times to fill the dispenser. Failure to prime the dispenser may result in delivery of a lower dose upon first use.

Under no circumstances should the medicinal product be administered intranasally or subcutaneously.

1. Shake the bottle vigorously before each use to resuspend the sediment of the medicinal product. (See Fig. 1).

1. Turn the dispenser to the open position (see Fig. 2).

1. For first use only: press the dispenser actuator three times to prime it; do not use the first dose of the product expelled from the dispenser after the third press (due to the design of the dispenser, no product is dispensed during the first two actuations).
2. Tilt the head slightly backward. Place the dispenser into the mouth. Press the dispenser as many times as needed according to the dose prescribed by your doctor, and administer the suspension onto the tongue, immediately swallowing it with saliva. Avoid direct contact between the tip of the dispenser and the inside of the mouth or tongue (see Fig. 3).

1. Turn the dispenser to the closed position (see Fig. 4).

Children.

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

Overdose.

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

In case of overdose, standard supportive measures should be adopted as required. Enhanced clearance of sildenafil by hemodialysis is unlikely due to the high plasma protein binding of the drug and the absence of urinary elimination of sildenafil.

Adverse reactions.

Safety profile summary.

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 during clinical trials in patients receiving sildenafil were headache, facial flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, hot flushes, visual disturbances, cyanopsia, and blurred vision.

Information on adverse reactions from post-marketing experience with sildenafil has been collected over more than 10 years. Since not all adverse reactions are reported to the marketing authorization holder and included in the safety database, the frequency of these reactions cannot be precisely determined.

Tabulated list of adverse reactions.

The following clinically relevant adverse reactions, observed during clinical trials at a frequency greater than with placebo, are listed by system organ class and frequency:

• Very common (≥1/10);
• Common (≥1/100, <1/10);
• Uncommon (≥1/1000, <1/100);
• Rare (≥1/10000, <1/1000);
• Very rare (<1/10000);
• Frequency not known (cannot be estimated from available data), reported from post-marketing experience.

Within each frequency category, adverse effects are presented in order of decreasing severity.

Clinically significant adverse reactions observed in controlled clinical trials at a frequency greater than placebo, and clinically significant adverse reactions observed during the post-marketing period.

Infections and infestations

Uncommon: Rhinitis.

Immune system disorders

Uncommon: Hypersensitivity.

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 disorders**, visual disturbances, blurred vision.

Uncommon: Lacrimation disorders***, eye pain, photophobia, photopsia, eye hyperemia, visual brightness, conjunctivitis, dry eye, eye swelling, eyelid swelling, eye irritation, abnormal eye sensations, conjunctival hyperemia, eye edema, iris disorders, mydriasis, halos around lights in visual field, eye discharge, scleral discoloration.

Rare: Non-arteritic anterior ischemic optic neuropathy*, retinal vessel occlusion*, retinal hemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, reduced visual acuity, myopia, asthenopia, floaters, iris abnormalities, pupillary dilation, halos around light sources (halo) in visual field, eye swelling, eyelid edema, eye disorders, conjunctival hyperemia, eye irritation, abnormal eye sensations, eyelid edema, scleral discoloration.

Ear and labyrinth disorders

Uncommon: Dizziness, tinnitus.

Rare: Hearing loss.

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, dry nose.

Gastrointestinal disorders

Common: Nausea, dyspepsia.

Uncommon: Gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth.

Rare: Oral hypoesthesia.

Skin and subcutaneous tissue disorders

Uncommon: Rash.

Rare: Stevens-Johnson syndrome*, toxic epidermal necrolysis*.

Musculoskeletal and connective tissue disorders

Uncommon: Myalgia, limb pain.

Renal and urinary disorders

Uncommon: Hematuria.

Reproductive system and breast disorders

Rare: Penile bleeding, priapism*, hematospermia, prolonged erection.

General disorders and administration site conditions

Uncommon: Chest pain, increased fatigue, feeling of warmth.

Rare: Irritation.

Investigations

Uncommon: Increased heart rate.

* Reported only during post-marketing experience.

** Colour vision disorders: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.

*** Lacrimation disorders: dry eyes, lacrimation disorders, increased lacrimation.

The following adverse reactions were observed in <2% of patients during controlled clinical trials; their causal relationship to sildenafil use is uncertain. Adverse reactions with a probable relationship to the drug have been reported. However, mild adverse reactions and those reported too imprecisely to be meaningful were not included.

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

Cardiovascular system: Angina pectoris, AV block, migraine, postural hypotension, myocardial ischemia, cerebral vessel thrombosis, sudden cardiac arrest, abnormal ECG findings, cardiomyopathy.

Gastrointestinal tract: 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 system: Arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

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

Respiratory system: Asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.

Skin: Urticaria, herpes, pruritus, increased sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

Specific sensory disorders: Sudden decrease or loss of hearing, ear pain, eye hemorrhage, cataract, dry eyes.

Genitourinary system: Cystitis, nocturia, increased urinary frequency, breast enlargement, urinary incontinence, ejaculation disorders, genital swelling, anorgasmia.

Post-marketing experience. The following adverse reactions have been identified after marketing authorization of this medicinal product. Since these are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions have been included due to factors such as severity, frequency of reporting, lack of clear alternative cause, or a combination of these factors.

Cardiovascular and cerebrovascular 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, but not all, patients had underlying cardiovascular risk factors. Many of these events occurred during or immediately after sexual activity, and several occurred shortly after sildenafil use without sexual activity. Other events occurred within hours or days after sildenafil use and sexual activity. It is not possible to determine whether these events are related to the drug, sexual activity, underlying risk factors, a combination of these, or other factors.

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

Nervous system disorders: Anxiety, transient global amnesia.

Specific sensory disorders.

Hearing. Cases of sudden decrease or loss of hearing, occurring in temporal association with sildenafil use, have been reported post-marketing. In some cases, medical conditions and other factors that could have contributed to hearing-related adverse reactions were reported. In many cases, information on follow-up medical evaluation is lacking. It is not possible to determine whether these events are directly related to drug use, underlying risk factors for hearing loss, a combination of these factors, or other factors.

Vision. Transient vision loss, eye redness, eye burning, increased intraocular pressure, retinal edema, retinal vascular disorders or hemorrhage, vitreous detachment. Rarely, post-marketing reports have described cases of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent vision loss, occurring in temporal association with PDE5 inhibitors, including sildenafil. Many patients had underlying anatomical or vascular risk factors for NAION, including 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.

Shelf life – 3 years.

Shelf life after first opening of the bottle – 12 months.

Storage conditions.

Keep out of reach of children.

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

Packaging.

30 ml in a bottle with a dosing pump; 1 bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer(s).

FARMALIDER, S.A.

and

EDEFARM, S.L.

Manufacturer's address and location of operations.

C/Aragoneses, 2, Alcobendas, 28108 Madrid, Spain.

and

Polígono Industrial Enchilagardel Rul, 117, Villamarchante, 46191 Valencia, Spain.