Novagra 50

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NOVAGRA 50 (NOVAGRA 50) NOVAGRA 100 (NOVAGRA 100)

Composition:

Active substance: sildenafil;

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

Excipients: calcium hydrogen phosphate, microcrystalline cellulose, sodium croscarmellose, povidone, colloidal anhydrous silicon dioxide, magnesium stearate, Instacoat IC-S-091 (pink).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: 50 mg tablets: round pink biconvex film-coated tablets with a score line on one side and smooth on the other side;

100 mg tablets: round pink biconvex film-coated tablets, smooth on both sides.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Sildenafil is an orally administered agent 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 penile erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Released NO activates the enzyme guanylate cyclase, which stimulates an increase in cyclic guanosine monophosphate (cGMP) levels. This, in turn, induces relaxation of the smooth muscle of the corpus cavernosum, promoting blood inflow.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for cGMP degradation. The effects of sildenafil on erection are peripheral. Sildenafil does not exert direct relaxant effects on isolated human corpus cavernosum tissue, but it strongly potentiates the relaxant effect of NO on this tissue. When the NO/cGMP metabolic pathway is activated by sexual stimulation, sildenafil’s inhibition of PDE5 leads to increased cGMP levels in the corpus cavernosum. Thus, for sildenafil to produce the required pharmacological effect, sexual stimulation is necessary.

Effects on pharmacodynamics. In vitro studies have demonstrated sildenafil’s selectivity for PDE5, the enzyme actively involved in the erectile process. The inhibitory effect of sildenafil on PDE5 is stronger than on other known phosphodiesterases. This effect is 10-fold more potent against PDE5 than against PDE6, an enzyme involved in retinal phototransduction. At maximum recommended doses, sildenafil’s selectivity for PDE5 is 80 times greater than for PDE1, 700 times greater than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. Specifically, sildenafil’s selectivity for PDE5 is 4000 times greater than for PDE3—a cGMP-specific phosphodiesterase isoform involved in the regulation of 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), the area under the plasma concentration-time curve (AUC) and Cmax of sildenafil increase proportionally with dose.

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

Distribution. The mean steady-state volume of distribution (Vd) is 105 L, indicating extensive distribution into body tissues. After a single 100 mg oral dose of sildenafil, the mean peak 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 peak concentration of free sildenafil in plasma reaches approximately 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.

Metabolism. Sildenafil is metabolized primarily by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite is formed via N-demethylation of sildenafil. The metabolite’s selectivity for PDE5 is comparable to that of sildenafil, and its activity against PDE5 is approximately 50% of the parent compound. Plasma concentrations of this metabolite are approximately 40% of sildenafil plasma concentrations. The N-desmethyl metabolite undergoes further metabolism, with an elimination half-life of approximately 4 hours.

Elimination. The total clearance of sildenafil is 41 L/h, resulting in an elimination half-life of 3–5 hours. Following both oral and intravenous administration, sildenafil is excreted primarily as metabolites in feces (approximately 80% of the orally administered dose) and to a lesser extent in urine (approximately 13% of the orally administered dose).

Pharmacokinetics in Special Patient Populations

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

Renal impairment. In volunteers with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil remained unchanged after a single 50 mg oral dose. Mean AUC and Cmax of the N-desmethyl metabolite increased by 126% and 73%, respectively, compared to age-matched volunteers with normal renal function. However, due to high inter-individual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance <30 mL/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax by 100% and 88%, respectively, compared to age-matched controls with normal renal function. Additionally, AUC and Cmax of the N-desmethyl metabolite increased significantly by 79% and 200%, respectively.

Hepatic impairment. In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh classes A and B), sildenafil clearance was reduced, leading to 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.

Novagra 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 Novagra 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 nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the nitric oxide/cGMP pathway and potentiate the hypotensive effect of nitrates.
• Concomitant use of PDE5 inhibitors (including sildenafil) with guanylate cyclase stimulators such as riociguat is contraindicated, as it may lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction").
• Conditions in which sexual activity is inadvisable (e.g., severe cardiovascular disorders such as unstable angina or severe heart failure).
• Loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy, regardless of whether this condition is related to prior use of PDE5 inhibitors.
• Presence of conditions such as severe hepatic impairment, arterial hypotension (blood pressure below 90/50 mm Hg), recent stroke or myocardial infarction, and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a small number of such patients have genetic disorders of retinal phosphodiesterases), as the safety of sildenafil has not been studied in these patient subgroups.

Interaction with other medicinal products and other forms of interaction.

Effects of other medicinal products on sildenafil.

In vitro studies. Sildenafil metabolism is primarily mediated by cytochrome P450 isoenzyme 3A4 (major pathway) and to a lesser extent by isoenzyme 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 an increased incidence 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 use of the HIV protease inhibitor ritonavir, a very potent inhibitor of P450, with sildenafil (single 100 mg dose) resulted in a 300% increase in sildenafil Cmax (4-fold) and a 1000% increase in plasma AUC (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 wide 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; in any case, the maximum sildenafil dose should not exceed 25 mg within 48 hours.

Concomitant use of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor administered at a dose providing steady-state concentrations (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. Sildenafil did not affect the pharmacokinetics of saquinavir. More potent CYP3A4 inhibitors such as ketoconazole and itraconazole are expected to have a more pronounced effect.

When sildenafil (single 100 mg dose) was administered concomitantly with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days), a 182% increase in sildenafil AUC was observed. 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 administered concomitantly with 50 mg sildenafil in healthy volunteers, increased plasma concentrations of sildenafil by 56%.

In a study involving healthy male volunteers, concomitant administration of bosentan—an endothelin antagonist (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 sildenafil concentrations.

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.

Grapefruit juice is a weak inhibitor of CYP3A4 in the intestinal wall and may cause a moderate increase in plasma sildenafil levels.

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

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 inhibitor group (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, calcium channel blockers, beta-adrenergic blockers, or CYP450 metabolism inducers (such as rifampicin, barbiturates).

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

Effect of sildenafil on other medicinal products.

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

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

In vivo studies. Since sildenafil is known to affect NO/cGMP metabolism, it has been established that this drug 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 an additive systemic blood pressure-lowering effect when PDE5 inhibitors were used concomitantly with riociguat. Clinical studies showed 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-adrenergic blockers may lead to symptomatic arterial hypotension in some susceptible patients. Such reactions most commonly occurred within 4 hours after sildenafil administration (see section "Dosage and administration" and "Special precautions"). In three specific drug interaction studies, the alpha-adrenergic 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 on doxazosin. In these populations, 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. When sildenafil was used concomitantly with doxazosin in patients whose condition had been stabilized on doxazosin, symptomatic orthostatic hypotension (episodes of dizziness and pre-syncope, but no syncope) was occasionally reported.

No significant interactions were observed when sildenafil (50 mg) was administered concomitantly 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 mean maximum blood ethanol levels of 80 mg/dL.

In patients taking sildenafil, no differences in adverse effect profile were observed compared to placebo when concomitantly using antihypertensive drug classes such as diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive agents (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and alpha-adrenergic blockers. In a specific interaction study, concomitant administration of sildenafil and amlodipine in patients with arterial hypertension resulted in an additional 8 mm Hg reduction in supine systolic blood pressure and a 7 mm Hg reduction in diastolic blood pressure. These additional reductions in blood pressure were comparable in magnitude to those observed with sildenafil alone in healthy volunteers (see section "Pharmacological properties").

Sildenafil 100 mg did not affect the pharmacokinetic parameters of the 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.

Adding a single dose of sildenafil to steady-state sacubitril/valsartan 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.

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, prior to initiating any treatment for erectile dysfunction, physicians must assess the patient's cardiovascular status. Sildenafil has a vasodilatory effect, which manifests as mild and transient reduction in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, physicians should carefully consider whether this effect could adversely affect patients with underlying cardiovascular conditions, particularly in combination with sexual activity. Patients who are particularly sensitive to vasodilators include those with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with the rare multisystem atrophy syndrome, one of the manifestations of which is severe autonomic nervous system dysfunction in blood pressure regulation.

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

During the post-marketing period, serious cardiovascular adverse reactions have been reported, including myocardial infarction, unstable angina, sudden cardiac arrest, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, arterial hypertension, and arterial hypotension, which temporally coincided with the use of Novagra. Most (but not all) of these patients had underlying cardiovascular risk factors. Many of these adverse reactions occurred during or immediately after sexual intercourse, and only a few occurred shortly after taking Novagra 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 influenced by other factors.

Priapism.

Medications for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with anatomical penile deformities (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients with conditions predisposing to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia).

After the drug was introduced to the market, cases of prolonged erection and priapism have been reported. If an erection lasts longer than 4 hours, patients should seek immediate medical assistance. Without prompt treatment, priapism may lead to penile tissue damage and permanent loss of erectile function.

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 with 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, such combinations are not recommended.

Effect on vision.

Spontaneous reports of visual disturbances have been associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Spontaneous reports and data from observational studies have indicated cases of 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 impairment occurs, they should discontinue using Novagra and seek immediate medical advice (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 some susceptible individuals. Symptomatic hypotension usually occurs within 4 hours after taking sildenafil. To minimize the risk of orthostatic hypotension, sildenafil therapy should only be initiated in hemodynamically stable patients who are already on alpha-blocker therapy, and their condition should be stabilized on alpha-blockers before starting sildenafil. Consideration should also be given to starting with a dose of 25 mg (see section "Dosage and administration"). In addition, patients should be informed about appropriate actions to take if symptoms of orthostatic hypotension occur.

Effect on haemostasis.

Studies on human platelets have demonstrated that in vitro, sildenafil potentiates the anti-aggregatory effects of sodium nitroprusside. There is no information available on the safety of sildenafil use in patients with bleeding disorders or active peptic ulcer. Therefore, the use of sildenafil in such patients should only be considered after careful assessment of the benefit-risk ratio.

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

Hearing loss. Physicians should advise patients to discontinue use of PDE5 inhibitors, including Novagra, and seek immediate medical help if sudden decrease or loss of hearing occurs. These events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE5 inhibitors, including Novagra. 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. Novagra exerts systemic vasodilatory effects and may further reduce blood pressure in patients taking antihypertensive medications. In a specific drug interaction study, concomitant oral administration of amlodipine (5 mg or 10 mg) and sildenafil (100 mg) resulted in an average additional reduction of systolic blood pressure by 8 mm Hg and diastolic blood pressure by 7 mm Hg.

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

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially sodium-free. This information may be provided to patients on a low-sodium diet.

Use during pregnancy or breastfeeding.

Novagra is not intended for use in women.

Ability to affect reaction rate when driving or operating machinery.

Novagra may have a minor influence on the ability to drive or operate machinery. Since dizziness and visual disturbances have been reported in clinical trials with sildenafil, patients should assess their individual response to Novagra before driving or operating machinery.

Method of Administration and Dosage

The medication should be taken orally.

Adults.

The recommended dose of Novagra 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. The maximum recommended dose is 100 mg.

The maximum recommended dose should not be taken more than once per day. The onset of action of Novagra may be delayed when taken with food compared to administration on an empty stomach.

Elderly Patients.

No dose adjustment is required for elderly patients.

Patients with Renal Impairment.

Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance less than 30 mL/min), the recommended starting dose is 25 mg. Depending on efficacy and tolerability, the dose may be increased to 50 mg or 100 mg.

Patients with Hepatic Impairment.

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

Patients Taking Other Medications.

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

To minimize the potential risk of postural hypotension in patients taking alpha-blockers, such patients should first be stabilized on alpha-blocker therapy before initiating sildenafil. Additionally, consideration should be given to starting with a dose of 25 mg (see sections "Special Warnings" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children.

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

Overdose.

During clinical trials involving healthy volunteers, single doses of sildenafil up to 800 mg resulted in adverse reactions similar to those observed at 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 a higher incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

In case of overdose, standard supportive measures should be implemented as needed. Hemodialysis is unlikely to accelerate sildenafil clearance due to the high degree of plasma protein binding and the absence of urinary excretion of sildenafil.

Adverse Reactions

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

Information on adverse reactions from post-marketing surveillance was collected over a period of more than 9 years. Since not all adverse reactions were reported and not all were included in the safety database, the frequency of such reactions cannot be reliably determined.

All clinically significant adverse reactions observed in clinical trials more frequently than with placebo are listed in the table below according to the "System–Organ–Class" classification and frequency: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), and rare (≥ 1/10,000 and < 1/1,000).

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

Infections and infestations

Uncommon: Rhinitis.

Immune system disorders

Uncommon: Hypersensitivity.

Nervous system disorders

Very common: Headache.

Common: Dizziness.

Uncommon: Somnolence, hypoaesthesia.

Rare: Stroke, transient ischaemic attack, seizures*, seizure recurrence*, syncope.

Eye disorders

Common: Colour vision disorders**, visual disturbances, blurred vision.

Uncommon: Lacrimation disorders***, eye pain, photophobia, photopsia, eye hyperaemia, brightness of vision, conjunctivitis.

Rare: Non-arteritic anterior ischaemic optic neuropathy*, retinal vessel occlusion*, retinal haemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters, iris disorders, mydriasis, halos around light sources in the visual field, eye oedema, eye swelling, eye disorders, conjunctival hyperaemia, eye irritation, abnormal sensations in eyes, eyelid oedema, scleral discolouration.

Ear and labyrinth disorders

Uncommon: Dizziness, tinnitus.

Rare: Deafness.

Cardiac disorders

Uncommon: Tachycardia, palpitations.

Rare: Sudden cardiac death*, myocardial infarction, ventricular arrhythmia*, atrial fibrillation, unstable angina.

Vascular disorders

Common: Facial flushing, hot flushes.

Uncommon: Hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders

Common: Nasal congestion.

Uncommon: Epistaxis, nasal sinus congestion.

Rare: Throat tightness, nasal mucosal oedema, nasal dryness.

Gastrointestinal disorders

Common: Nausea, dyspepsia.

Uncommon: Gastro-oesophageal reflux disease, vomiting, upper abdominal pain, dry mouth.

Rare: Oral hypoaesthesia.

Skin and subcutaneous tissue disorders

Uncommon: Rash.

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

Musculoskeletal and connective tissue disorders

Uncommon: Myalgia, limb pain.

Renal and urinary disorders

Uncommon: Haematuria.

Reproductive system and breast disorders

Rare: Penile haemorrhage, priapism*, haemospermia, prolonged erection.

General disorders and administration site conditions

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

Rare: Irritation.

Investigations

Uncommon: Increased heart rate.

* Reported only during post-marketing studies.

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

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

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

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

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

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

Blood and lymphatic system: Anaemia, leucopenia.

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

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

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

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

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

Specific sensations: Sudden decrease or loss of hearing, ear pain, eye haemorrhage, cataract, dry eyes.

Urogenital 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 during post-marketing use. Because these reactions 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 events were reported due to their severity, 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 haemorrhage, subarachnoid haemorrhage, intracerebral haemorrhage, and pulmonary haemorrhage, occurring in temporal association with the use of Novagra. 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 taking Novagra without sexual activity. Others occurred within hours or days after taking Novagra and engaging in sexual activity. It is not possible to determine whether these events are related to the use of the drug, to sexual activity, to pre-existing risk factors, to a combination of these, 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 anaemia, vaso-occlusive crises requiring hospitalization were reported more frequently with sildenafil than with placebo. The clinical significance of this information for patients taking Novagra for the treatment of erectile dysfunction is unknown.

Nervous system: Anxiety, transient global amnesia.

Specific sensations.

Hearing. Post-marketing cases of sudden decrease or loss of hearing temporally associated with the use of Novagra 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 unavailable. It is not possible to determine whether these events are directly related to the use of Novagra, 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 oedema, retinal vascular disorders or haemorrhage, vitreous detachment.

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

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

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging. 1, 2, or 4 tablets in a blister; 1 blister per cardboard box. 4 tablets in a blister; 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Marxans Pharma Ltd.

Manufacturer's address and place of business.
Plot No. L-82, L-83, Verna Industrial Estate, Verna Goa, IN-403 722, India.