Synera

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CINEGRA (SINEGRA)

Composition:

Active substance: sildenafil;

1 tablet contains sildenafil citrate equivalent to sildenafil 25 mg;

1 tablet contains sildenafil citrate equivalent to sildenafil 50 mg;

1 tablet contains sildenafil citrate equivalent to sildenafil 100 mg;

Excipients: calcium hydrogen phosphate anhydrous, microcrystalline cellulose, sodium croscarmellose, colloidal silicon dioxide anhydrous, magnesium stearate, Opadry II Blue 85F20578 coating: polyvinyl alcohol, macrogol 4000, titanium dioxide (E 171), talc, indigo carmine aluminium lake (E 132), yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg tablets: blue, film-coated, round-square shaped tablets;

50 mg tablets: blue, film-coated, round-square shaped tablets with a break line on both sides;

100 mg tablets: blue, film-coated, round-square shaped tablets with a double break line on one side.

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

Pharmacological Properties

Pharmacodynamics

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

The physiological mechanism responsible for erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide activates the enzyme guanylate cyclase, which stimulates an increase in levels of cyclic guanosine monophosphate (cGMP), resulting in relaxation of smooth muscle in the corpus cavernosum and 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 effect of sildenafil on erection is peripheral. Sildenafil does not exert a direct relaxant effect on isolated human corpus cavernosum, but it strongly potentiates the relaxing effect of NO on this tissue. When the NO/cGMP pathway is activated during sexual stimulation, sildenafil's inhibition of PDE5 leads to increased cGMP levels in the corpus cavernosum. Thus, for sildenafil to produce the desired pharmacological effect, sexual stimulation is required.

Effect on pharmacodynamics. In vitro studies have demonstrated that sildenafil is selective for PDE5, which actively participates in the process of erection. The effect of sildenafil on PDE5 is much stronger than on other known phosphodiesterases. This effect is 10 times more potent than its effect on PDE6, which is involved in phototransduction in the retina. At maximum recommended doses, sildenafil's selectivity for PDE5 is 80 times greater than for PDE1, and 700 times higher than for PDE2, 3, 4, 7, 8, 9, 10, and 11. In particular, sildenafil's selectivity for PDE5 is 4000 times greater than for PDE3—an isoform of cAMP-specific phosphodiesterase involved in regulating cardiac contractility.

Pharmacokinetics

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

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

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

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

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

Elimination. Total clearance of sildenafil is 41 L/h, with a terminal half-life of 3–5 hours. After oral or intravenous administration, sildenafil is excreted as metabolites, 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-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-demethylated metabolite increased by up to 126% and 73%, respectively, compared to 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, 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-demethylated 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 increased 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.

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

For effective action of Sinigra, 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/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 or not.
• 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 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.

Effects of other medicinal products on sildenafil.

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

In vivo studies. Population pharmacokinetic analysis of clinical trial data demonstrated reduced clearance of sildenafil when co-administered with CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, cimetidine). Although an increased incidence of adverse events was not observed when sildenafil was co-administered with CYP3A4 inhibitors, consideration should be given to initiating treatment with a 25 mg dose of sildenafil.

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 sildenafil Cmax and a 1000% increase (11-fold) in plasma AUC. After 24 hours, plasma levels of sildenafil were still approximately 200 ng/mL compared to approximately 5 ng/mL when sildenafil was administered alone, indicating a significant effect of ritonavir on a broad range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Due to these pharmacokinetic data, concomitant use of sildenafil and ritonavir is not recommended (see section "Special precautions for use"); in any case, the maximum dose of sildenafil should not exceed 25 mg within 48 hours.

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

Administration of sildenafil (single 100 mg dose) with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days) resulted in an 182% increase in systemic exposure to sildenafil (AUC). In healthy male volunteers, azithromycin (500 mg daily for 3 days) did not affect AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its major circulating metabolite. Cimetidine (a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor) at a dose of 800 mg, when co-administered with 50 mg sildenafil in healthy volunteers, increased plasma concentration 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 co-administered with medicinal products belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme 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 concentration of sildenafil.

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

Effects of sildenafil on other medicinal products.

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

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

In vivo studies. Since sildenafil is known to affect nitric oxide/cyclic guanosine monophosphate (cGMP) metabolism, it has been established that sildenafil potentiates the hypotensive effect of nitrates; therefore, concomitant use of sildenafil with nitric oxide donors or nitrates in any form is contraindicated (see section "Contraindications").

Riociguat. Preclinical studies have demonstrated an additive systemic blood pressure-lowering effect 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. This reaction most commonly occurred within 4 hours after sildenafil 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 had been stabilized with doxazosin. In these patients, mean additional reductions in supine blood pressure were 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, and mean reductions in standing blood pressure were 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. Cases of symptomatic orthostatic hypotension have been reported with concomitant use of sildenafil and doxazosin in patients whose condition had been stabilized with doxazosin. These 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 a mean maximum blood ethanol concentration of 80 mg/dL.

In patients taking sildenafil, no differences in adverse effect profile were observed compared to placebo when co-administered with antihypertensive drug classes such as diuretics, β-adrenergic receptor blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and α-adrenergic receptor blockers. In a specific interaction study with concomitant administration of sildenafil (100 mg) and amlodipine in patients with arterial hypertension, an additional reduction in supine systolic blood pressure of 8 mm Hg was observed. The corresponding reduction in diastolic blood pressure was 7 mm Hg. 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 CYP3A4 substrates.

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

Concomitant use of sildenafil with medicinal products containing sacubitril/valsartan has been associated with enhanced hypotension in patients compared to sacubitril/valsartan alone. Therefore, sildenafil should be initiated with caution in patients receiving sacubitril/valsartan.

Special precautions for use.

A medical history and physical examination should be conducted to diagnose erectile dysfunction and identify potential underlying causes prior to initiating pharmacological treatment.

Cardiovascular risk factors. Since sexual activity carries a certain cardiovascular risk, physicians should assess the cardiovascular status of patients before initiating any treatment for erectile dysfunction. Sildenafil has vasodilatory effects, which manifest as mild and transient reduction in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, physicians must carefully consider whether such an effect could adversely affect patients with underlying 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 of the manifestations of which is severe autonomic regulation of blood pressure.

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

In the post-marketing period, serious cardiovascular adverse reactions have been reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, arterial hypertension, and arterial hypotension, which temporally coincided with the use of Viagra. 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 taking Viagra 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. Medications for the treatment of erectile dysfunction, including sildenafil, should be prescribed with caution in patients with anatomical deformities of the penis (such as angulation, cavernous fibrosis, or Peyronie's disease) or in patients with conditions that may predispose 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 were 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 treatments. The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other medications for the treatment of pulmonary arterial hypertension containing sildenafil (e.g., Revatio), or with other erectile dysfunction treatments, have not been studied. Therefore, the use of such combinations is not recommended.

Effect on vision. Spontaneous reports of visual disturbances have been associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Spontaneous reports and data from observational studies have indicated cases of non-arteritic anterior ischaemic optic neuropathy (NAION), a rare condition, associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be advised that if they experience sudden vision loss, they should discontinue use of Viagra 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 prescribed 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 taking sildenafil. To minimize the potential for postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized with α-blockers before initiating sildenafil therapy. Additionally, consideration should be given to starting with an initial dose of 25 mg (see section "Dosage and administration"). 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 in vitro, sildenafil potentiates the anti-aggregatory effects of sodium nitroprusside. There is no information on the safety of sildenafil use in patients with bleeding disorders or active peptic ulcer. Therefore, sildenafil use in these patient groups should only be considered after careful assessment of benefit-risk ratio.

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

Hearing loss. Physicians should advise patients to discontinue use of PDE5 inhibitors, including Viagra, 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 Viagra. 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. Viagra has 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 Viagra (100 mg) resulted in an average additional reduction of systolic blood pressure by 8 mm Hg and diastolic blood pressure by 7 mm Hg.

Sexually transmitted diseases. The use of Viagra does not protect against sexually transmitted diseases. Consideration should be given to informing patients about necessary preventive measures to protect against sexually transmitted infections, including human immunodeficiency virus.

Use during pregnancy or breastfeeding.

Viagra is not intended for use in women.

Ability to drive and use machines.

Viagra may have a minor influence on the ability to drive or use machinery. Since dizziness and visual disturbances have been reported during clinical studies with sildenafil, patients should determine their individual response to Viagra before driving a vehicle or operating machinery.

Method of Administration and Dosage

The medication should be administered orally.

Adults. The recommended dose of the drug Sinegra is 50 mg, taken as needed approximately one hour before sexual activity. Depending on the efficacy and tolerability of the drug, the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended dose should not be taken more than once daily. When Sinegra is taken with food, the onset of action may be delayed compared to administration on an empty stomach.

Elderly patients. Dose adjustment is not required for elderly patients (≥ 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 is the same as stated above in the section "Adults."

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

Patients with hepatic insufficiency. In patients with hepatic impairment (e.g., cirrhosis), sildenafil clearance is reduced; therefore, a starting dose of 25 mg should be considered. Depending on efficacy and tolerability, the dose may be gradually increased, 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 25 mg should be considered (except for ritonavir, which should not be co-administered with sildenafil—see section "Special warnings and precautions for use").

To minimize the potential for postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized with α-adrenoreceptor blockers prior to initiating sildenafil therapy. Additionally, a starting dose of 25 mg should be considered (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Children.

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

Overdose.

In clinical studies 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 occurring more frequently and with greater severity. Administration of sildenafil at a dose of 200 mg did not increase efficacy but led to an increased incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

In case of overdose, standard supportive measures should be implemented as required. 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 most commonly reported adverse reactions were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, visual disturbances, cyanopsia, and blurred vision.

Adverse reactions observed during clinical studies are listed below by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000).

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

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

Cardiovascular disorders: common – flushing; uncommon – tachycardia, palpitations, arterial hypertension/hypotension; rare – sudden cardiac death*, myocardial infarction, ventricular arrhythmia*, atrial fibrillation, unstable angina.

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

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

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

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

Renal and urinary disorders: uncommon – hematuria.

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

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

Investigations: uncommon – increased heart rate.

* Reported only in post-marketing studies.

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

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

The following events were observed during clinical studies; causal relationship has not been established. Reports included events that were likely related to the use of the medicinal product. Events not listed were mild and reported too imprecisely to be meaningful.

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

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

Gastrointestinal system: 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 system: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.

Skin disorders: urticaria, herpes, pruritus, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

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

Urogenital system: cystitis, nocturia, increased frequency of urination, breast enlargement, urinary incontinence, ejaculation disorders, genital swelling, anorgasmia.

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

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

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

Nervous system: anxiety, transient global amnesia.

Specific senses.

Hearing. Post-marketing reports have included cases of sudden decrease or loss of hearing temporally associated with the use of Viagra. In some cases, medical conditions and other factors that may have contributed to the hearing adverse events were reported. In many cases, follow-up medical information is lacking. It is not possible to determine whether these events are directly related to the use of Viagra, to pre-existing risk factors for hearing loss, to a combination of these factors, or to other factors.

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

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions in accordance with national regulatory requirements.

Shelf life.

25 mg tablets: 3 years.

50 mg and 100 mg tablets: 4 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of the reach of children.

Packaging.

1 tablet in a blister, 1 blister in a cardboard package.

4 tablets in a blister, 1 blister in a cardboard package.

Prescription category.

Prescription only.

Manufacturer.

Nobel Ilac Sanai ve Ticaret A.S.

Manufacturer's address and place of business.

Sankaklar District, Eskikarakoca Avenue, No: 299, 81100 Duzce, Turkey.