Maxigra

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MAXIGRA (MAXIGRA)

Composition:

Active substance: sildenafil;

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

Excipients: mannitol (E 421), crospovidone (type A), povidone K-30, maize starch, sodium lauryl sulfate, magnesium stearate, colloidal anhydrous silicon dioxide;

coating: hypromellose, macrogol 6000, titanium dioxide (E 171), talc, indigo carmine (E 132).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: round, biconvex film-coated tablets of blue color.

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 leading to 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), resulting in relaxation of the smooth musculature 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 cGMP degradation. The effects of sildenafil on erection are peripheral in nature. Sildenafil does not exert a direct relaxant effect 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 during sexual stimulation, sildenafil-induced 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 the selectivity of sildenafil's action on PDE5, which actively participates in the erectile process. The effect of sildenafil on PDE5 is more potent than on other known phosphodiesterases. This effect is 10-fold more potent than its effect on PDE6, which is involved in phototransduction in the retina. At maximum recommended doses, the selectivity of sildenafil for PDE5 exceeds its selectivity for PDE1 by 80-fold, for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11 by 700-fold, and particularly, its selectivity for PDE5 exceeds that for PDE3 by 4000-fold—PDE3 being the cGMP-specific phosphodiesterase isoform involved in regulating cardiac contractility.

Pharmacokinetics.

Absorption. Sildenafil is rapidly absorbed. Maximum plasma concentration (Cmax) is reached within 30–120 minutes (median 60 minutes) after oral administration on an empty stomach. The mean absolute bioavailability after oral administration is 41% (ranging from 25 to 63%). Within the recommended dose range (25 to 100 mg), AUC (area under the plasma concentration-time curve) 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 by 29%.

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

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

Biotransformation. Sildenafil metabolism is primarily mediated by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The principal 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 about 40% of sildenafil plasma concentrations. 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, resulting in an elimination half-life of 3–5 hours. Following both oral and intravenous administration, excretion of sildenafil metabolites occurs primarily in feces (approximately 80% of the orally administered dose) and to a lesser extent in urine (approximately 13% of the orally administered dose).

Pharmacokinetics in special patient populations.

Elderly patients. In healthy elderly volunteers (aged 65 years and older), reduced clearance of sildenafil was observed, leading to approximately 90% higher plasma concentrations of sildenafil and its active N-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. However, mean AUC and Cmax of the N-desmethyl metabolite were increased by 126% and 73%, respectively, compared to age-matched volunteers with normal renal function. Nevertheless, 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 200% and 79%, 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 (84%) and Cmax (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.

Treatment of erectile dysfunction, defined as the inability to achieve or maintain a penile erection sufficient for successful sexual intercourse.

For effective action, Maxigra requires sexual stimulation.

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/cyclic guanosine monophosphate (cGMP) pathway and potentiates the hypotensive effect of nitrates.
• Concomitant use of phosphodiesterase-5 (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 types of interactions").
• Conditions in which sexual activity is inadvisable (e.g., severe cardiovascular disorders such as unstable angina or severe heart failure).
• Sudden loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy, regardless of whether this condition is associated with prior use of PDE5 inhibitors or not.
• 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 patients with these conditions.

Interaction with other medicinal products and other types of interactions.

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 (e.g., ketoconazole, erythromycin, cimetidine). Although an increase in the frequency of adverse events was not observed during concomitant use of sildenafil and CYP3A4 inhibitors, the recommended initial dose of sildenafil is 25 mg.

Concomitant administration of the HIV protease inhibitor ritonavir, a very potent P450 inhibitor, at steady-state concentration (500 mg once daily) and sildenafil (single dose 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, 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 providing steady-state concentration (1200 mg three times daily) and sildenafil (single dose 100 mg) resulted in a 140% increase in sildenafil Cmax and a 210% increase in AUC. No effect of sildenafil on the pharmacokinetics of saquinavir was observed. 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 specific 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) did not affect AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its major circulating metabolite. Cimetidine (a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor) at a dose of 800 mg, when co-administered with sildenafil 50 mg in healthy volunteers, increased plasma concentrations of sildenafil by 56%.

Grapefruit juice is a weak inhibitor of intestinal CYP3A4 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 the pharmacokinetics of sildenafil were not altered when co-administered with medicinal products belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, calcium channel antagonists, beta-adrenergic receptor antagonists, or CYP450 metabolism inducers (such as rifampicin, barbiturates).

Nicorandil is a hybrid of a calcium channel activator and a nitrate. The nitrate component may lead to a serious interaction with sildenafil.

In a study involving healthy male volunteers, concomitant administration of the endothelin antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19) at steady state (125 mg twice daily) and sildenafil at steady state (80 mg three times daily) resulted in a 62.6% and 55.4% reduction in AUC and Cmax of sildenafil, respectively. Therefore, concomitant use of potent CYP3A4 inducers such as rifampicin may lead to a more pronounced decrease in plasma concentration of sildenafil.

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 Maxigra 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 this drug 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. 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").

Adding a single dose of sildenafil to steady-state sacubitril/valsartan in patients with arterial hypertension was associated with significantly greater blood pressure reduction compared to sacubitril/valsartan alone. Therefore, caution should be exercised when initiating sildenafil in patients receiving sacubitril/valsartan.

Concomitant use of sildenafil and alpha-adrenergic receptor 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 alpha-adrenergic receptor blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were administered simultaneously 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. Symptomatic orthostatic hypotension was occasionally reported when sildenafil was used concomitantly with 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 caused by acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers at mean peak 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, antihypertensives (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers, and alpha-adrenergic receptor blockers. In a specific interaction study with concomitant administration of sildenafil (100 mg) and amlodipine in patients with arterial hypertension, an additional reduction in supine systolic blood pressure of 8 mm Hg was observed. The corresponding reduction in diastolic blood pressure was 7 mm Hg. These additional 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 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 cardiac risk, physicians should assess the cardiovascular status of patients before starting any treatment for erectile dysfunction. Sildenafil has a vasodilatory effect, manifested by mild and transient reduction in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, physicians must carefully consider whether this effect could have an adverse impact on patients with underlying cardiovascular conditions, particularly when combined with sexual activity. Patients who are more sensitive to vasodilators include those with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with the rare multisystem atrophy syndrome, one of the manifestations of which is severe autonomic regulation of blood pressure.

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

In 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 Maxigra. Most, but not all, of these patients had underlying cardiovascular risk factors. Many of these adverse events occurred during or immediately after sexual intercourse, and only a few occurred shortly after taking Maxigra 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. Medications for the treatment of erectile dysfunction, including sildenafil, should be prescribed with caution in patients with anatomical penile deformity (e.g., angulation, cavernosal fibrosis, or Peyronie's disease) or in patients with conditions that may predispose to priapism (sickle cell anaemia, multiple myeloma, or leukaemia).

Post-marketing reports have included cases of prolonged erection and priapism. 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 medications. The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other medications for the treatment of pulmonary arterial hypertension containing sildenafil (e.g., Revatio), or with other erectile dysfunction treatments, have not been studied; therefore, 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 findings 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 to discontinue use of Maxigra and seek immediate medical attention in case of sudden vision loss (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 sildenafil administration. To minimize the risk of orthostatic hypotension, sildenafil therapy should only be initiated in hemodynamically stable patients who are taking alpha-blockers. The recommended starting dose for such patients is 25 mg of sildenafil (see section "Method of administration and dosage"). Additionally, patients should be informed about appropriate actions to take if symptoms of orthostatic hypotension occur.

Effect on bleeding. Studies on human platelets have demonstrated that sildenafil potentiates the anti-aggregatory effects of sodium nitroprusside in vitro. 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 patient groups should only be considered after careful assessment of the benefit-risk ratio.

No effect on sperm morphology or motility was observed in healthy volunteers after a 100 mg dose (see section "Pharmacodynamics").

Hearing loss. Physicians should advise patients to discontinue use of PDE5 inhibitors, including Maxigra, and seek immediate medical attention in case of sudden decrease or loss of hearing. These events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE5 inhibitors, including Maxigra. 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. Maxigra 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 pressure by 8 mm Hg and diastolic pressure by 7 mm Hg.

Sexually transmitted diseases. Maxigra does not protect against sexually transmitted diseases. Patients should be instructed on the necessity of protective measures to prevent transmission of sexually transmitted infections, including human immunodeficiency virus.

Use during pregnancy or breastfeeding.

Maxigra 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 or operate machinery.

Since dizziness and visual disturbances have been reported in clinical trials with sildenafil, patients should determine their individual response to Maxigra before driving or operating machinery.

Dosage and Administration

The drug is administered orally.

For Maxigra to be effective, sexual stimulation is required.

Adults.

The recommended dose of Maxigra is 50 mg, taken approximately one hour before sexual activity as needed. 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 frequency of administration is once daily. When Maxigra is taken with food, the onset of action may be delayed compared to administration on an empty stomach.

Elderly patients.

Dose adjustment in elderly patients (≥ 65 years of age) is not required.

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."

In patients with severe renal impairment (creatinine clearance < 30 mL/min), clearance of sildenafil is reduced; therefore, the recommended dose is 25 mg. Depending on efficacy and tolerability, the dose may be increased to 50 mg or 100 mg.

Patients with hepatic impairment.

In patients with hepatic impairment (e.g., cirrhosis), clearance of sildenafil is reduced; therefore, 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 medicinal products (e.g., ketoconazole, erythromycin, cimetidine, ritonavir).

The recommended starting dose for patients taking CYP3A4 inhibitors, except for ritonavir (the concomitant use of which with sildenafil is not recommended), is 25 mg* (see sections "Interaction with Other Medicinal Products and Other Forms of Interactions" and "Special Warnings and Precautions for Use").

To minimize the risk of orthostatic hypotension, patients taking alpha-blockers should have their condition stabilized prior to initiating sildenafil therapy. The recommended starting dose of sildenafil is 25 mg* (see sections "Interaction with Other Medicinal Products and Other Forms of Interactions" and "Special Warnings and Precautions for Use").

* Administer in the appropriate dosage strength or pharmaceutical form.

Children.

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

Overdose.

In clinical studies involving healthy volunteers, adverse reactions following single doses of sildenafil up to 800 mg were similar to those observed at lower doses but occurred more frequently and were more severe. Administration of sildenafil at a dose of 200 mg did not result in increased efficacy but was associated with 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 required. Hemodialysis is unlikely to accelerate sildenafil clearance due to the high degree of plasma protein binding and lack of urinary elimination of sildenafil.

Adverse Reactions

All clinically significant adverse reactions observed in clinical trials more frequently than with placebo are listed below according to the "System–Organ–Class" classification 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). In addition, the frequency of clinically significant adverse reactions reported during post-marketing experience is defined as unknown.

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, hypoesthesia.

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

Eye disorders.

Common: colour vision disturbance**, visual disorders, blurred vision.

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

Rare: non-arteritic anterior ischaemic optic neuropathy*, retinal vascular occlusion*, retinal haemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters in vitreous body, iris disorders, mydriasis, halos around light sources in 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: vertigo, 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: arterial hypertension, arterial 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 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: 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 surveillance.

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

*** Lacrimation disorders: dry eyes, lacrimation disorder, 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 considered likely related 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 vascular 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, cough exacerbation.

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

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

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

Post-marketing experience. The following adverse reactions have been identified after marketing authorization. As these reactions are reported voluntarily from an unknown population size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events were included 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, 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 several hours or days after sildenafil 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 underlying 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 sildenafil use 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 Maxigra for the treatment of erectile dysfunction is unknown.

Nervous system. Anxiety, transient global amnesia.

Specific senses.

Hearing. Cases of sudden decrease or loss of hearing, occurring in temporal association with sildenafil use, have been reported after marketing authorization. In some cases, medical conditions and other factors that could have contributed to hearing-related adverse reactions were reported. In many cases, information on subsequent medical follow-up is lacking. It is not possible to determine whether these events are directly related to Maxigra use, 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 after marketing authorization in temporal association with PDE5 inhibitors, including sildenafil. 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, arterial hypertension, coronary artery disease, hyperlipidaemia, 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 suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with national regulatory requirements.

Shelf life. 4 years.

Storage conditions.

No special storage conditions required.

Keep out of the reach of children.

Packaging.

1 or 4 tablets in a blister; 1 blister per cardboard package.

Prescription status.

Prescription only.

Manufacturer/Marketing Authorisation Holder.

Pharmaceutical Works “POLPHARMA” S.A.

Address of manufacturer and location of its operations.

19, Pelplinska Str., 83-200 Starogard Gdanski, Poland.