Adegra

INSTRUCTIONS for MEDICAL USE of the MEDICINAL PRODUCT ADEGRA (ADEGRA)

Composition:

Active substance: sildenafil;

1 film-coated tablet contains sildenafil citrate equivalent to sildenafil 50 mg or 100 mg;

Excipients: dibasic calcium phosphate, monohydrate lactose, microcrystalline cellulose, magnesium stearate, sodium croscarmellose, hypromellose, talc, titanium dioxide (E 171), macrogol-6000; for 50 mg tablets: erythrosine (E 124); for 100 mg tablets: indigo carmine (E 133).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

for 50 mg tablets: film-coated tablets, pink in colour, diamond-shaped, with "50" embossed on one side;

for 100 mg tablets: film-coated tablets, blue in colour, diamond-shaped, with "100" embossed on one side.

Pharmacotherapeutic group. Agents used in erectile dysfunction. Sildenafil. ATC code G04B E03.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Sildenafil is an oral medication intended 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. Released NO activates the enzyme guanylate cyclase, which stimulates an increase in the level of cyclic guanosine monophosphate (cGMP), leading to relaxation of the smooth muscle of 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 the breakdown of cGMP. The effect of sildenafil on erection is peripheral. Sildenafil does not exert a direct relaxant effect on isolated human corpus cavernosum tissue, but it strongly potentiates the relaxing effect of NO on this tissue. During activation of the NO/cGMP metabolic pathway, which occurs under 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 more potent than its effect on other known phosphodiesterases. This effect is 10 times more potent than its effect on PDE6, which is involved in phototransduction processes in the retina. At maximum recommended doses, sildenafil's selectivity for PDE5 is 80 times greater than for PDE1, 700 times greater than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. In particular, sildenafil's selectivity for PDE5 is 4000 times greater than for PDE3 – the cAMP-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 extent of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%.

Distribution. The mean steady-state volume of distribution (Vd) is 105 liters, indicating distribution of the drug 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 free plasma concentration of sildenafil reaches approximately 18 ng/mL (38 nmol). The degree of protein binding is independent of total sildenafil concentrations.

In healthy volunteers who received 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 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite is formed via N-demethylation of sildenafil. The metabolite's selectivity for PDE5 is comparable to that of sildenafil, and its activity against PDE5 is approximately 50% of the parent compound. Plasma concentration of this metabolite is about 40% of the plasma concentration of sildenafil. The N-desmethyl metabolite undergoes further metabolism, and its elimination half-life is approximately 4 hours.

Elimination. Total clearance of sildenafil is 41 L/hour, resulting in an elimination half-life of 3–5 hours. Following both oral and intravenous administration, excretion of sildenafil occurs 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 (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-desmethyl metabolite increased by up to 126% and 73%, respectively, compared to age-matched volunteers without renal impairment. However, due to high individual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance <30 mL/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax by 100% and 88%, respectively, compared to age-matched volunteers without renal impairment. Additionally, AUC and Cmax of the N-desmethyl metabolite were significantly increased by 200% and 79%, respectively.

Hepatic impairment. In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh classes A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers without hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

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

For Adgera 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 affects the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway and potentiates the hypotensive effect of nitrates.
• Concomitant use of PDE5 inhibitors (including sildenafil) with guanylate cyclase stimulators such as riociguat is contraindicated, as it may lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction").
• Conditions in which sexual activity is inadvisable (e.g., severe cardiovascular disorders such as unstable angina or severe heart failure).
• Unilateral vision loss due to non-arteritic anterior ischemic optic neuropathy, regardless of whether this condition was previously associated with PDE5 inhibitor use.
• Conditions such as severe hepatic impairment, arterial hypotension (blood pressure below 90/50 mm Hg), recent stroke or myocardial infarction, and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a small number of such patients have genetic disorders of retinal phosphodiesterases), since the safety of sildenafil has not been studied in these patient subgroups.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on sildenafil.

In vitro studies. Sildenafil is metabolized primarily by 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 an increased incidence of adverse events was not observed with concomitant use of sildenafil and CYP3A4 inhibitors, consideration should be given to initiating sildenafil therapy with a 25 mg dose.

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 dose of 100 mg) 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, consistent with the 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 (see section "Special precautions for use"); in any case, the maximum sildenafil dose should not exceed 25 mg within 48 hours.

Concomitant administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a dose providing steady-state concentration (1200 mg three times daily) and sildenafil (single 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 (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 (AUC) of sildenafil. 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, 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 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 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, β-adrenergic blockers, 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 sildenafil concentrations.

Nicorandil is a hybrid of a potassium 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 isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC50 > 150 µmol). Since peak plasma concentrations of sildenafil are approximately 1 µmol, the effect of Adgera 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 NO/cGMP metabolism, it has been established that sildenafil potentiates the hypotensive effect of nitrates; therefore, 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. 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 blockers may lead to symptomatic hypotension in some susceptible patients. This reaction most commonly occurred within 4 hours after sildenafil administration (see sections "Special precautions for use" and "Dosage and administration"). In three specific drug interaction studies, the α-adrenergic blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were co-administered to patients with benign prostatic hyperplasia whose condition had been stabilized on doxazosin. In these populations, mean additional reductions in supine blood pressure were 7/7 mm Hg, 9/5 mm Hg, 8/4 mm Hg, and mean reductions in standing blood pressure were 6/6 mm Hg, 11/4 mm Hg, 4/5 mm Hg, respectively. Symptomatic orthostatic hypotension was occasionally reported with concomitant use of sildenafil and doxazosin in patients whose condition had been stabilized on doxazosin. These reports described dizziness and pre-syncope, but no syncope.

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

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

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

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

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 initiating any treatment for erectile dysfunction. Sildenafil has vasodilatory effects, manifested 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 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) and patients with the rare multisystem atrophy syndrome, one of the manifestations of which is severe autonomic regulation of blood pressure.

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

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

Post-marketing 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 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 treatments for pulmonary arterial hypertension containing sildenafil, 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 received in association with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Spontaneous reports and cases in a surveillance study have described non-arteritic anterior ischaemic optic neuropathy, a rare condition, associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be advised that in case of sudden visual impairment, Adagra should be discontinued and immediate medical advice sought (see section "Contraindications").

Concomitant use with ritonavir. Concomitant use of sildenafil and ritonavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with α-adrenoreceptor blockers. Sildenafil should be used with caution in patients taking α-adrenoreceptor blockers, as this combination may lead to symptomatic hypotension in some susceptible patients. Symptomatic hypotension usually occurs within 4 hours after taking sildenafil. To minimize the potential for postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized with α-adrenoreceptor blockers before initiating sildenafil therapy. Consideration should also be given to starting with a dose of 25 mg (see section "Method of administration and dosage"). In addition, patients should be informed about the actions to take if symptoms of orthostatic hypotension occur.

Effect on bleeding. Studies on human platelets have demonstrated in vitro 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 active peptic ulcer. Therefore, sildenafil use in such patients should only be considered after careful assessment of the benefit-risk ratio.

Lactose. The film coating of the tablets contains lactose. Adagra should not be used in men with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

The presence of the excipient erythrosine (E 124) may cause allergic reactions.

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 PDE5 inhibitors, including Adagra, 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 the use of PDE5 inhibitors, including Adagra. 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. Adagra 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 Adagra (100 mg) resulted in an average additional reduction of systolic pressure by 8 mm Hg and diastolic pressure by 7 mm Hg.

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

Use during pregnancy or breastfeeding.

Adagra is not intended for use in women.

Ability to affect reaction speed 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 during clinical trials with sildenafil, patients should determine their individual response to Adagra before driving a vehicle or operating machinery.

Method of Administration and Dosage

The medication is administered orally.

Adults. The recommended dose of Adhegra 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* tablets. The maximum recommended dose is 100 mg. The maximum recommended frequency of dosing is once daily. When Adhegra 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, consideration should be given to starting with a dose of 25 mg*. Depending on efficacy and tolerability, the dose may be gradually increased from 50 mg up to 100 mg as needed.

Patients with hepatic impairment. In patients with hepatic impairment (e.g., cirrhosis), sildenafil clearance is reduced; therefore, consideration should be given to starting with a dose of 25 mg*. Depending on efficacy and tolerability, the dose may be gradually increased to 50 mg and then to 100 mg as needed.

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

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

*If a 25 mg dose of sildenafil is required, use a medicinal product that allows for such dosing.

Children

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

Overdose

During clinical trials in volunteers, administration of 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 the event of overdose, standard supportive measures should be implemented as necessary. Enhanced clearance of sildenafil by hemodialysis is unlikely due to the high degree of plasma protein binding and the absence of urinary elimination of sildenafil.

Adverse Reactions

The safety profile of Adigra is based on data obtained from 9,570 patients in 74 double-blind, placebo-controlled clinical trials. The most commonly reported adverse reactions were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, hot flushes, visual disturbances, cyanopsia, and blurred vision. Information on adverse reactions from post-marketing surveillance was collected over a period of more than 10 years. Since not all adverse reactions were reported to the marketing authorization holder and not all were included in the safety database, the frequency of such reactions cannot be reliably determined.

All clinically relevant adverse reactions observed during clinical trials more frequently than with placebo are listed below according to 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). 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, hypaesthesia.

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

Eye disorders.

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

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

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

Ear and labyrinth disorders.

Uncommon: Dizziness, tinnitus.

Rare: Hearing loss.

Cardiac disorders.

Uncommon: Tachycardia, palpitations.

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

Vascular disorders.

Common: Facial flushing, hot flushes.

Uncommon: Hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders.

Common: Nasal congestion.

Uncommon: Epistaxis, nasal sinus congestion.

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

Gastrointestinal disorders.

Common: Nausea, dyspepsia.

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

Rare: Oral hypaesthesia.

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, fatigue, hot flush.

Rare: Irritation.

Investigations.

Uncommon: Increased heart rate.

* Reported only in post-marketing experience.

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

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

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

General: Facial swelling, 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, 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 disorders: 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.

Genitourinary system: Cystitis, nocturia, increased urinary frequency, gynaecomastia, urinary incontinence, ejaculation disorder, genital swelling, anorgasmia.

Post-marketing experience. The following adverse reactions have been identified after marketing authorization. As these are voluntarily reported from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events are 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 haemorrhage, subarachnoid haemorrhage, intracerebral haemorrhage, and pulmonary haemorrhage, which occurred in temporal association with Adigra use. Most, but not all, patients had underlying cardiovascular risk factors. Many of these events occurred during or immediately after sexual activity, and several occurred shortly after taking Adigra without sexual activity. Others occurred within hours or days after taking Adigra and engaging in sexual activity. It is not possible to determine whether these events are related to the drug, sexual activity, underlying risk factors, a combination of these, or other factors.

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

Nervous system: Anxiety, transient global amnesia.

Specific sensations.

Hearing. Post-marketing reports include cases of sudden decrease or loss of hearing temporally associated with Adigra use. In some cases, medical conditions and other factors that may have contributed to hearing-related 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 Adigra use, underlying risk factors for hearing loss, a combination of these, or other factors.

Vision: Temporary vision loss, eye redness, eye burning, increased intraocular pressure, retinal oedema, retinal vascular disorders or haemorrhage, vitreous detachment.

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

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

Shelf life. 3 years.

Storage conditions.

Store in the original packaging, out of the reach of children, at temperatures not exceeding 25°C.

Packaging.

4 film-coated tablets in a blister; 1 blister per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Gracure Pharmaceuticals Ltd

Manufacturer's address and place of business.

E-1105, Industrial Area, Sector III, Bhivadi, Alwar District, Rajasthan, 301019.