Sigra

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SIGRA

Composition:

Active substance: sildenafil;

One film-coated tablet contains: 70 mg of sildenafil citrate equivalent to 50 mg of sildenafil, or 140 mg of sildenafil citrate equivalent to 100 mg of sildenafil;

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, sodium croscarmellose, magnesium stearate, Opadry Blue (hypromellose, titanium dioxide (E 171), lactose monohydrate, triacetin (E 1518), indigo carmine (E 132)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

50 mg tablets: blue, rhombus-shaped, biconvex film-coated tablets, embossed with "BAFNA" on one side and smooth on the other;

100 mg tablets: blue, triangular-shaped film-coated tablets, with a break line on one side and smooth on the other.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Sigra is an oral medication intended for the treatment of erectile dysfunction. It restores impaired erectile function during sexual stimulation by enhancing blood flow to the penis.

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

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for cGMP breakdown. The effects of sildenafil on erection are peripheral. Sildenafil does not directly relax isolated human corpus cavernosum tissue, but it strongly potentiates the relaxing effect of NO on this tissue. During sexual stimulation, when the NO/cGMP metabolic pathway is activated, sildenafil’s inhibition of PDE5 results in 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 sildenafil’s selectivity for PDE5, which actively participates in the erectile process. Sildenafil’s action on PDE5 is more potent than on other known phosphodiesterases and exceeds its effect on PDE6—involved in retinal phototransduction—by 10-fold. At maximum recommended doses, sildenafil’s selectivity for PDE5 is 80 times greater than for PDE1, 700 times higher than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. Specifically, sildenafil’s selectivity for PDE5 exceeds its selectivity for PDE3—a cGMP-specific phosphodiesterase isoform involved in cardiac contractility regulation—by 4000-fold.

Pharmacokinetics.

Absorption and bioavailability

Sildenafil is rapidly absorbed, reaching maximum plasma concentrations 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), maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) increase proportionally with dose.

When sildenafil is taken with food, the extent of absorption is reduced, with a mean delay in time to reach maximum plasma concentration (Tmax) of 60 minutes and a mean reduction in Cmax by 29%.

Distribution

The mean steady-state volume of distribution (Vd) is 105 L, indicating extensive tissue distribution. 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 protein binding of sildenafil and its major N-desmethyl metabolite is about 96%, the mean maximum free (unbound) plasma concentration of sildenafil is 18 ng/mL (38 nmol). The degree of protein binding is independent of total sildenafil concentrations.

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

Metabolism

Sildenafil is metabolized primarily by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite results from N-demethylation of sildenafil. The metabolite’s selectivity for PDE5 is comparable to that of sildenafil, and its activity against PDE5 is approximately 50% of the parent compound. Plasma concentrations of the metabolite are about 40% of those of sildenafil in plasma. 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, and the elimination half-life is 3–5 hours. After both oral and intravenous administration, sildenafil is excreted primarily as metabolites in feces (approximately 80% of the oral dose) and to a lesser extent in urine (approximately 13% of the oral dose).

Pharmacokinetics in special patient populations

Elderly patients

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

Renal impairment

In volunteers with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil after a single 50 mg dose remained unchanged. Mean AUC and Cmax of the N-desmethyl metabolite increased by up to 126% and 73%, respectively, compared to age-matched healthy volunteers. 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 patients with mild to moderate hepatic cirrhosis (Child-Pugh classes A and B), sildenafil clearance was reduced, leading to increases in AUC by 84% and Cmax by 47% compared to patients of similar age with normal liver function. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

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

For effective action of Siger, sexual stimulation is required.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicine.
• 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, as this 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., due to 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 the following conditions: 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.

Effects 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 sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although increased frequency of adverse events 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 concentration (500 mg once daily) and sildenafil (single 100 mg dose) resulted in a 300% increase in Cmax (4-fold) and a 1000% increase in plasma AUC of sildenafil (11-fold). 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 AUC. No effect of sildenafil on saquinavir pharmacokinetics was observed (see section "Dosage and administration"). More potent CYP3A4 inhibitors such as ketoconazole and itraconazole are expected to have a more pronounced effect.

Administration of sildenafil (100 mg single dose) with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days) resulted in an 182% increase in sildenafil AUC. In healthy male volunteers, azithromycin (500 mg daily for 3 days) had no effect on 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 co-administered 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 sildenafil plasma levels.

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

Although specific interaction studies with all medicinal products have not been conducted, population pharmacokinetic analysis data indicate that sildenafil pharmacokinetics were not altered when co-administered with medicinal products belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitor group (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, beta-blockers, or CYP450 metabolism inducers (such as rifampicin, barbiturates).

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% reduction in AUC and a 55.4% reduction in Cmax of sildenafil, respectively. Therefore, concomitant use of potent CYP3A4 inducers such as rifampicin may lead to a more pronounced decrease in plasma sildenafil concentrations.

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

Effects of sildenafil on other medicinal products

In vitro studies

Sildenafil is a weak inhibitor of cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC50 >150 µmol). Since peak plasma concentrations of sildenafil are approximately 1 µmol, the effect of Siger 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 it is known that sildenafil affects the NO/cGMP metabolic pathway, it has been established that sildenafil potentiates the hypotensive effect of nitrates; therefore, its concomitant use with nitric oxide 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. No positive clinical effect was observed in patients participating in the study when PDE5 inhibitors were used concomitantly with riociguat. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated (see section "Contraindications").

Concomitant use of sildenafil and alpha-adrenoreceptor blockers may lead to symptomatic hypotension in some susceptible patients. This reaction most commonly occurs within 4 hours after sildenafil administration (see sections "Special precautions for use" and "Dosage and administration"). When sildenafil (25 mg, 50 mg, and 100 mg) was co-administered with the alpha-adrenoreceptor blocker doxazosin (4 mg and 8 mg) in patients with benign prostatic hyperplasia whose condition had been stabilized with doxazosin, 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. In some cases, symptomatic orthostatic hypotension has been reported when sildenafil was used concomitantly with doxazosin in patients whose condition had been stabilized with doxazosin. These reports described episodes of dizziness and presyncope, but not syncope.

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

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

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers at average maximum blood ethanol levels 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, beta-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and alpha-adrenoreceptor blockers. When sildenafil (100 mg) was co-administered with 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 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.

Administration of sildenafil at steady state (80 mg three times daily) resulted in a 49.8% increase in AUC and a 42% increase in Cmax of bosentan (125 mg twice daily).

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, physicians should assess the cardiovascular status of patients before starting any treatment for erectile dysfunction. Sildenafil has a vasodilatory effect, resulting in mild and transient reduction in blood pressure. Before prescribing sildenafil, physicians must carefully consider whether this effect could adversely affect patients with underlying cardiovascular 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) and patients with the rare multisystem atrophy syndrome, one of the manifestations of which is severe autonomic regulation of arterial blood pressure.

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

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 sildenafil. In most, but not all, patients, risk factors for cardiovascular disease were present. Many of these adverse reactions occurred during or immediately after sexual intercourse, and only a few occurred shortly after sildenafil intake without sexual activity. Therefore, it is not possible to determine whether the occurrence of such adverse reactions is directly related to risk factors or whether their development is caused by other factors.

Priapism. Medicinal products for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease) or in patients with conditions that may predispose to priapism (such as sickle-cell anaemia, multiple myeloma, or leukaemia).

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

Concomitant use with other PDE5 inhibitors or other erectile dysfunction treatments. The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other medicinal products 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 cases in observational studies have also reported non-arteritic anterior ischemic 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 loss occurs, the drug should be discontinued immediately and 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 alpha-blockers. Sildenafil should be used with caution in patients taking alpha-blockers, as this combination may lead to symptomatic hypotension in susceptible individuals. Symptomatic hypotension usually occurs within 4 hours after sildenafil administration. To minimize the potential for symptomatic hypotension in patients taking alpha-blockers, their condition should be stabilized with alpha-blockers before initiating sildenafil therapy. In addition, consideration should be given to starting with a dose of 25 mg (see section "Method of administration and dosage"). Patients should also be informed about actions to take if symptoms of orthostatic hypotension occur.

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

The film coating of Sigrа tablets contains lactose; therefore, the drug should not be administered to men with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

After administration of a 100 mg dose, no effect on sperm morphology or motility was observed.

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

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

Sexually transmitted diseases. The use of Sigrа does not protect against sexually transmitted diseases. Consideration should be given to advising patients on necessary preventive measures to protect against sexually transmitted diseases, including human immunodeficiency virus.

Use during pregnancy or breastfeeding.

The drug is not intended for use in women.

Ability to affect reaction rate when driving or operating machinery.

No studies have been conducted on the effect of the drug on the ability to drive vehicles or operate machinery.

Since dizziness and visual disturbances have been reported with sildenafil use, patients should be warned against driving or operating machinery until their individual response to the drug has been determined.

Method of Administration and Dosage

The drug is taken orally.

For effective action of the drug Sigrа, sexual stimulation is required.

Adults.

The recommended dose is 50 mg, taken as needed approximately one hour before sexual activity. Depending on efficacy and tolerability, the dose may be increased to 100 mg or decreased to 25 mg*, using sildenafil in another dosage form. The maximum recommended dose is 100 mg. The maximum recommended frequency of administration is once daily. When Sigrа 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 of 30–80 mL/min), the recommended dose is the same as that stated above under "Adults."

Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min), consideration should be given to starting with a dose of 25 mg*. Depending on efficacy and tolerability, the dose may be increased 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), consideration should be given to starting with a dose of 25 mg*. Depending on efficacy and tolerability, the dose may be increased 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 types of interactions"), consideration should be given to starting with a dose of 25 mg* (except for ritonavir, the concomitant use of which with sildenafil is not recommended).

The recommended initial dose for patients taking CYP3A4 inhibitors, except ritonavir (the use of which together with sildenafil is not recommended), is 25 mg*.

To minimize the risk of postural hypotension in patients taking alpha-blockers, their condition should be stabilized with alpha-blockers prior to initiating sildenafil therapy. Also, consideration should be given to starting with an initial dose of 25 mg* (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").

*Administer in the appropriate dosage.

Children.

The drug is not intended for use in children (under 18 years of age).

Overdose.

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

In case of overdose, standard supportive measures should be applied as needed. Acceleration of sildenafil clearance by hemodialysis is unlikely due to the high degree of drug binding to plasma proteins and the absence of sildenafil elimination in urine.

Adverse reactions.

The most commonly reported adverse reactions were headache, flushing, dyspepsia, visual disturbances, nasal congestion, back pain, dizziness, nausea, hot flushes, vision disorders, cyanopsia, and blurred vision.

Within each frequency group, adverse reactions are listed in order of decreasing severity.

System–organ–class	Adverse reactions
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*, loss of consciousness, syncope.
Eye disorders	Common: color vision disorders**, visual disturbances, blurred vision.
	Uncommon: tear film disorders***, eye pain, photophobia, photopsia, eye hyperemia, visual brightness, conjunctivitis, conjunctival disorders, other eye disorders.
	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, appearance of bright circles around light sources (halos) in the visual field, eye swelling, eye swelling, eye disorders, conjunctival hyperemia, eye irritation, abnormal sensations in eyes, eyelid edema, scleral discoloration.
Ear and labyrinth disorders	Uncommon: dizziness, tinnitus.
	Rare: deafness.
Vascular disorders	Common: facial flushing, hot flushes.
	Uncommon: arterial hypertension, arterial hypotension.
Cardiac disorders	Uncommon: palpitations, tachycardia.
	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	Uncommon: chest pain, increased fatigue, feeling of warmth.
	Rare: irritation.
Investigations	Uncommon: increased heart rate.

* - Reported only during post-marketing surveillance.

** - Visual perception disturbances: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.

*** - Lacrimation disorders: dry eyes, abnormal lacrimation, and increased lacrimation.

The following events were observed in < 2% of patients; causal relationship has not been established. Reports included events that were considered likely related to the use of the drug. Events not listed were mild and reports were too imprecise to be of significance.

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 vascular thrombosis, sudden 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 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 and subcutaneous tissue: 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.

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

Post-marketing experience. Since adverse reactions are reported voluntarily from a population of uncertain size during the post-marketing period, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events were reported due to their seriousness, frequency of reporting, lack of clear alternative explanation, or a combination of these factors.

Cardiovascular and cerebrovascular events. Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebral hemorrhage, subarachnoid hemorrhage, intracerebral hemorrhage, and pulmonary hemorrhage, which occurred in temporal association with sildenafil use. 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 shortly after sildenafil use without sexual activity. Other events occurred within hours or days after drug use 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: 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.

Nervous system: Anxiety, transient global amnesia.

Special senses.

Hearing. Cases of sudden decrease or loss of hearing, occurring in temporal association with drug 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, to pre-existing risk factors for hearing loss, to a combination of these factors, or to other factors.

Vision: Temporary vision loss, eye redness, eye burning, increased intraocular pressure, retinal edema, retinal vascular disorders or hemorrhage, vitreous body detachment.

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

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

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

Pack No. 1: 1 tablet in a blister, 1 blister in a cardboard pack.

Pack No. 4: 4 tablets in a blister, 1 blister in a cardboard pack.

Prescription status. Prescription only.

Manufacturer. Bafna Pharmaceuticals Ltd., India.

Manufacturer's address.

147, Madhavaram Red Hills Road, Grantlyon Village, Vadakarai, Chennai, Tamil Nadu IN 600052, India.

Marketing Authorization Holder. JIVDHARA PHARMA PRIVATE LIMITED.

Address of the Marketing Authorization Holder.

504, Block-B, Shiv Angan Complex, Sallaiya, Bhopal, Madhya Pradesh, 462026, India.