Instruction maxigra
Instruction maxigra
Instruction maxigra
Instruction maxigra
for medical use of the drug MAXIGRA (MAXIGRA)

Composition:

active ingredient: sildenafil;

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

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

the shell: hypromellose, macrogol 6000, titanium dioxide (E 171), talc, Indigo Carmine (E 132).

Dosage form. Film-coated tablets.

Main physicochemical properties: round, biconvex tablets coated with a blue film.

Pharmacotherapeutic group. Agent used for erectile dysfunction. Sildenafil. ATC code G04B E03.

Pharmacological properties.

Фармакодинаміка.

Pharmacodynamics. Sildenafil is a drug for oral administration intended for the treatment of erectile dysfunction. The drug restores reduced erectile function by increasing blood flow to the penis while sexual stimulation.

The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. The released nitric oxide activates the guanylate cyclase enzyme, which stimulates the increase of cyclic guanosine monophosphate (cGMP) level, which, in turn, causes relaxation of smooth muscle of the cavernous bodies, allowing inflow of blood.

Sildenafil is a powerful and selective inhibitor of cGMP-specific phosphodiesterase 5 (PDE5) in cavernous bodies, where PDE5 is responsible for the degradation of cGMP. The effects of sildenafil on erection are peripheral. Sildenafil does not have a direct relaxing effect on isolated human corpus cavernosum, but powerfully enhances the relaxing effect of NO on this tissue. When a metabolic pathway NO/cGMP is activated while sexual stimulation, the inhibition with sildenafil PDE5 leads to increased levels of cGMP in the cavernous bodies. Thus, in order for sildenafil to cause the necessary pharmacological effect, sexual stimulation is necessary.

in vitro studies have shown the selectivity of sildenafil effect on PDE5, which is actively involved in the erection process. The effect of sildenafil on РDE5 is more powerful than on other known phosphodiesterases. This effect is 10 times more powerful than the effect on PDE6, involved in the processes of phototransformation in retina. When using maximum recommended doses for sildenafil, the PDE5 selectivity is to 80 times higher than the РDЕ1 selectivity, 700 times higher than PDE3, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10 and PDE11 selectivity. In particular, the PDE5 selectivity of sildenafil is 4000 times higher than PDE3-cGMP specific isoform of phosphodiesterase selectivity, which is involved in the regulation of cardiac contractility.

To assess the time during which the use of sildenafil leads to erection in response to sexual stimulation 2 special clinical studies were conducted. In clinical studies involving patients who used sildenafil pc the time median before erection of patients, who have achieved erections with rigidity of 60 % (sufficient to perform sexual Activity), was 25 min (range 12-37 minutes) during RigiScan. In a separate study using RigiScan, sildenafil was still able to induce an erection in 4-5 hours after using.

Sildenafil causes a slight and short-term decrease of blood pressure, which in most cases has no clinical implications. The average maximum decrease in systolic blood pressure in the supine position after oral administration of sildenafil at a dose of 100 mg was 8.4 mm Hg. The corresponding change in diastolic blood pressure in the supine position was 5.5 mm Hg. This decrease in blood pressure is well coordinated with the vasodilatory action of sildenafil, possibly due to increased levels of cGMP in the vascular smooth muscle. Single oral administration of sildenafil at doses up to 100 mg by healthy volunteers did not cause any clinically significant changes in the electrocardiogram.

In the study of hemodynamic effects of single oral administration of sildenafil at a dose of 100 mg in 14 patients with severe coronary heart disease (with stenosis of less than one coronary artery more than 70%), mean systolic and diastolic blood pressure at rest decreased by 7% and 6%, respectively, relative to the baseline. Mean pulmonary systolic pressure decreased by 9%. Sildenafil did not lead to a change in cardiac output and did not reduce blood flow through the stenotic coronary arteries.

No clinically significant differences were demonstrated for the time prior to the occurrence of limiting angina when using sildenafil compared with placebo in double-blind placebo-controlled clinical studies using a physical exercise test involving 144 patients with erectile dysfunction and chronic stable angina, who constantly used antianginal drugs (except nitrates).

Easy and temporary violation of the ability to distinguish colors (blue/green) was detected when conducting a 100-hue test of Farnsworth-Munsell in 1 hour after the administration of sildenafil at a dose of 100 mg. These effects disappeared completely in 2 hours after the drug administration. The possible mechanism of this change in color recognition is chained to the inhibition of PDE6 involved in the phototransformation cascade of reactions in the retina. Sildenafil does not affect visual acuity or contrast sensitivity. In small placebo-controlled clinical studies involving patients with documented macular dystrophy (n=9), the use of sildenafil (once at a dose of 100 mg) did not cause significant changes in the results of the studies of vision (visual acuity, Amsler grid, modeling of traffic light color recognition, Humphrey perimeter and photostress).

Single oral administration of sildenafil at a dose of 100 mg by healthy volunteers did not affect sperm motility or morphology.

Additional data of clinical studies.

Sildenafil was used by more than 8,000 patients aged 19 to 87 years in clinical studies. The following groups of patients were represented: elderly patients (19.9 %), patients with hypertension (30.9 %), patients with diabetes mellitus (20.3 %), with coronary heart disease (5.8 %), with hyperlipidemia (19.8 %), with spinal cord injuries (0.6 %),with depression (5.2 %), with transurethral resection of the prostate gland (3.7 %), with radical prostatectomy (3.3 %). Groups of patients were not sufficiently represented or included in clinical studies: patients after surgery on pelvic organs, patients after radiation therapy, patients with severe renal or hepatic insufficiency and patients with some cardiovascular diseases.

The number of patients reporting about improved erectile function was 62 % (25 mg), 74% (50 mg), and 82% (100 mg), in fixed-dose studies compared to 25% in the placebo group. The number of cases of sildenafil withdrawal was low in controlled clinical studies, and similar to that in the placebo group

For all these studies, the number of patients who reported about improvement after the use of sildenafil was as follows: patients with psychogenic erectile dysfunction (84%), patients with mixed erectile dysfunction (77%), patients with organic erectile dysfunction (68%), elderly patients (67%), patients with diabetes mellitus (59%), patients with coronary heart disease (69%), patients with hypertension (68%), patients with transurethral resection of prostate glands (61%), patients with radical prostatectomy (43%)), patients with spinal cord injuries (83 %), patients with depression (75%). The safety and efficacy of sildenafil have been confirmed by long-term studies.

Pharmacokinetics.

Absorption. Sildenafil is rapidly absorbed. The maximum plasma concentrations of the drug are reached within 30-120 minutes (with a median of 60 minutes) after its oral administration on an empty stomach. The average absolute bioavailability after oral administration is 41 % (with a range of values from 25 to 63 %). In the recommended range of doses (25 to 100 mg), the AUC and C max of sildenafil after oral administration are increased proportionally to the dose.

Using of sildenafil during meals the level of absorption is reduced, with an average lengthening of the T max of 60 minutes and an average reduction of C max by 29 %.

Distribution. The steady-state volume of distribution (Vd) is 105 liters, which indicates the distribution of the drug in the body tissues. After a single oral administration of sildenafil at a dose of 100 mg, the average maximum total plasma concentration of sildenafil is approximately 440 ng / ml (coefficient of variation is 40 %). Since the binding of sildenafil and its main N- demethylated metabolite to plasma proteins reaches 96 %, the average maximum plasma concentration of free sildenafil reaches 18 ng/ml (38 nmol). The degree of binding to plasma proteins does not depend on the total concentrations of sildenafil.

Healthy volunteers who used sildenafil once in a dose of 100 mg within 90 minutes had less than 0.0002 % (average 188 ng) of the administered dose in the ejaculate.

Metabolism. The metabolism of sildenafil is carried out mainly with the participation of microsomal liver isoenzymes CYP3A4 (main rout) and CYP2C9 (secondary rout). The main circulating metabolite is formed by N-demethylation of sildenafil. The selectivity of the metabolite relative to PDЕ5 is comparable with sildenafil selectivity and activity of the metabolite relative to PDE5 is approximately 50 % activity of the initial substance. Plasma concentrations of this metabolite are approximately 40 % of the concentration of sildenafil in plasma. The N-demethylated metabolite is further metabolized and its half-life is approximately 4 hours.

Elimination. The total clearance of sildenafil is 41 l/h, which causes its half-life of 3-5 hours. Both after oral and after intravenous administration, the excretion of sildenafil in the form of metabolites is carried out mainly with feces (about 80% of the administered oral dose) and less with urine (about 13% of the administered dose).

Elderly patients Healthy elderly volunteers (over 65 years) had a decrease in the clearance of sildenafil, which led to an increase in plasma concentrations of sildenafil and its active N-demethylated metabolite by about 90% compared with the corresponding concentrations healthy younger volunteers had (18-45 years). Due to age differences in plasma protein binding the corresponding increase in the plasma concentration of free sildenafil was approximately 40 %.

Kidney failure. Volunteers with impaired kidney function of mild and moderate level (creatinine clearance from 30 to 80 ml / min) after a single oral administration at a dose of 50 mg had unchanged pharmacokinetics of sildenafil. Average AUC and C max of N-demethylated metabolite increased by 126% and 73%, respectively, compared with such indicators volunteers of the same age without kidney dysfunction had. However, due to high individual variability, these differences were not statistically significant. Volunteers with severe kidney impairment (creatinine clearance is below 30 ml / min) had decreased clearance of sildenafil, which led to average increases in AUC and C maxmax by 100% and 88%, respectively, compared with volunteers of the same age without kidney impairment. In addition, the values of AUC and C max N-demethylated metabolite significantly increased by 79% and 200%, respectively.

Hepatic decompensation. Volunteers with mild and moderate liver cirrhosis (class A and B according to Child-Pugh classification) had decreased sildenafil clearance, which led to the increase of AUC (84%) and C maxmax (47%) compared with volunteers of the same age without hepatic impairment. The pharmacokinetics of sildenafil of patients with severe hepatic impairment has not been studied.

 

Clinical characteristics.

Indication.

Treatment of erectile dysfunction, which are defined as the inability to get and keep the erection of the penis necessary for successful sexual Activity.

For the effective result of the drug Maxigra sexual stimulation is necessary.

 

Contraindication.

  • Hypersensitivity to the active substance or any of the excipients of the drug.
  • Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form, since sildenafil is known to affect the pathways of nitric oxide/cyclic guanosine monophosphate (cGMP) metabolism and potentiates the hypotensive effect of nitrates.
  • Conditions when sexual activity is not recommended (e.g. severe cardiovascular disorders such as unstable angina and severe heart failure).
  • Loss of vision in one eye due to non-arterial anteriorischemic optic neuropathy, regardless of whether this pathology is related to the previous use of PDE5 inhibitors or not.
  • Severe hepatic impairment, hypotension (blood pressure below 90/50 mm Hg. St.), recent stroke or myocardial infarction, and known hereditary degenerative retinal diseases such as pigment retinitis (a small number of such patients have genetic disorders of retinal phosphodiesterases), because the safety of using sildenafil by such patients has not been studied.
 

Drug interaction and other types of interactions.

Effects of other drugs on sildenafil.

In vitro studies. in vitro.

Metabolism of sildenafil occurs mainly with the participation of the 3A4 isoform (main rout) and 2C9 isoform (secondary rout) of cytochrome P450 (CYP). Therefore, inhibitors of these isoenzymes are able to reduce the clearance of sildenafil.

In vitro studies. in vivo.

Population pharmacokinetic data from patients in clinical trials also indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine). Although the co-administration of sildenafil and CYP3A4 inhibitors, no increased frequency of adverse reactions was observed. The recommended initial dose of sildenafil is 25 mg.

Co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with Viagra (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC. In 24 hours, the plasma levels of sildenafil were still approximately 200 ng/ml, compared with the level of approximately 5 ng/ml, which typical for the use of sildenafil separately, corresponding to a significant effect of ritonavir on a wide range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Given these pharmacokinetic data, the co-administration of sildenafil and ritonavir is not recommended; in any case, the maximum dose of sildenafil under any circumstances should not exceed 25 mg within 48 hours.

Co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with Viagra (100 mg single dose) resulted in a 140% increase in sildenafil C maxmax and a 210% increase in sildenafil AUC. Sildenafil does not affect the pharmacokinetics of saquinavir. A stronger CYP3A4 inhibitor such as ketoconazole or itraconazole could be expected to have greater effect.

When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 182% increase in sildenafil AUC. Healthy male volunteers had no effect of azithromycin (500 mg daily for 3 days) on AUC, С max, Tmax, elimination rate constant and subsequent half-life of sildenafil or its major circulating metabolite. Cimetidine (cytochrome P450 inhibitor and nonspecific CYP3A4 inhibitor) at a dose of 800 mg, when co-administered with sildenafil at a dose of 50 mg to healthy volunteers led to an increase in plasma concentrations of sildenafil by 56 %.

Grapefruit juice is a poor inhibitor of CYP3A4 in the intestinal wall and can potent a moderate increase in plasma levels of sildenafil.

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

Although specific interaction studies with all drugs has not been conducted, according to the population pharmacokinetic analysis, the pharmacokinetics of sildenafil were not varied during its co-administration with drugs belonging to the group of CYP2C9 inhibitors (tolbutamide, warfarin, phenytoin) and to the group of CYP2D6 inhibitors (such as selective serotonin reuptake inhibitor, tricyclic antidepressants), of the thiazide and thiazide-like diuretics group, of the loop and potassium-sparing diuretics,of the angiotensin converting enzyme inhibitors, of the calcium and beta-adrenergic receptors antagonists, or inducers of CYP450 metabolism (such as rifampicin, barbiturates).

Nicorandil is a hybrid of calcium channel activator and nitrate. Nitrate component determines the possibility of its serious interaction with sildenafil.

Effects of sildenafil on other drugs.

In vitro studies.in vitro.

Sildenafil is a poor inhibitor of cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IR 50 150 µmol). Given sildenafil peak plasma concentrations of approximately 1 µmol, it is unlikely that Maxigra will potent the clearance of substrates of these isoenzymes.

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

In vivo studies.in vivo.

Since sildenafil is known to affect the metabolism of nitric oxide/cyclic guanosine monophosphate (cGMP), it has been found that this drug potentiates the hypotensive effect of nitrates, so its co-administration with nitric oxide donors or with nitrates in any form is contraindicated.

The co-administration of sildenafil and alpha-adrenoceptor blockers can lead to the development of symptomatic hypotension in some predisposed patients. This reaction often occurred within 4 hours after administration of sildenafil. In the course of 3 studies of specific drug interactions the blocker of alpha-adrenoreceptor doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) were co-administrated in patients with benign prostatic hyperplasia, which stabilization has been obtained using doxazosin. In these populations there was an average additional decrease in blood pressure in the supine position by 7/7 mm Hg, 9/5 mm Hg and 8/4 mm Hg and the average decrease in blood pressure in the standing position by 6/6 mm Hg, 11/4 mm Hg, 4/5 mm Hg respectively. While the co-administration of sildenafil and doxazosin in patients, which stabilization have been obtained using doxazosin, it was reported sometimes about the development of symptomatic orthostatic hypotension. These reports referred to cases of dizziness and fainting, but without syncope.

No significant interactions were shown with co-administration of sildenafil (50 mg), tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by CYP2C9.

Sildenafil (50 mg) did not extend the bleeding caused by acetylsalicylic acid (150 mg).

Sildenafil (50 mg) didn’t potentiate the hypotensive effect of alcohol in healthy volunteers with an average maximum levels of 80mg/dl of ethanol in blood.

In patients who used sildenafil, there were no differences in the profile of adverse reactions compared with placebo, while co-administration of such classes of antihypertensive drugs as diuretics, beta-adrenoceptor blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilate and central action), adrenergic neuron blockers, calcium channel blockers and alpha-adrenoceptor blockers. In a special study of the interaction with the co-administrationnof sildenafil (100 mg) and amlodipine in patients with hypertension, there was an additional decrease in systolic blood pressure in the supine position by 8 mm Hg. The corresponding decrease in diastolic blood pressure was 7 mm Hg. The magnitude of these additional reductions in blood pressure were comparable to those observed when using only sildenafil in healthy volunteers.

Sildenafil at a dose of 100 mg did not affect the pharmacokinetic parameters of HIV protease inhibitors, saquinavir and ritonavir, which are substrates CYP3A4.

 

Special warnings and precautions for use

Prior to therapy should collect medical history of the patient and conduct a physical examination to diagnose erectile dysfunction and determine its possible causes.

Since sexual activity is accompanied by a certain risk on the heart, the physician should assess the patient’s cardiovascular system before any treatment of erectile dysfunction. Sildenafil has a vasodilator effect, which is manifested by a slight and short-term decrease in blood pressure. Before prescribing sildenafil, the physician should carefully decide whether such an effect can potent on patients with certain major diseases, especially in combination with sexual activity. Patients with increased sensitivity to vasodilators include patients with left ventricular excretory tract obstruction (for example, aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with rare multisystemic atrophy syndrome, which means a severe violation of blood pressure regulation by the autonomic nervous system.

Maxigra potentiates the hypotensive effect of nitrates.

In post-marketing period it was reported about serious adverse reactions on the cardiovascular system, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension and hypotension, which coincided with the drug Maxigra administration. Most patients, but not all, had risk factors for cardiovascular disease. Many of these adverse reactions were observed during or immediately after Activity, and only some of them were observed soon after the drug Maxigra administration without sexual activity. Therefore, it is impossible to determine whether the development of such adverse reactions are directly related to risk factors, or they are developing due to other factors.

Agents for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

The safety and efficacy of the co-administration of sildenafil with other methods of treatment of erectile dysfunction have not been studied. Therefore, the administration in such combinations is not recommended.

It was reported about the disorders and cases of non-arterial anteriorischemic optic neuropathy associated with the use of sildenafil and other PDE inhibitors. Patients should be warned that in case of a sudden vision dysfunction, the use of the drug Maxigra should be stopped and immediately consultation of a physician is needed.

The co-administration of sildenafil and ritonavir is not recommended.

In patients who use alpha-adrenoceptor blockers sildenafil should be used with caution, since such a combination can lead to symptomatic hypotension in some predisposed patients. Symptomatic hypotension usually occurs within 4 hours after the administration of sildenafil. In order to minimize the risk of orthostatic hypotension, sildenafil therapy can be started only in hemodynamically stable patients who use alpha-adrenoceptor blockers. The recommended initial dose for such patients is 25 mg of sildenafil. In addition, patients should be informed how to act in case of symptoms of orthostatic hypotension.

Human platelet studies have shown that sildenafil potentiates the antiplatelet effects of sodium nitroprusside in vitro There is no information about the safety of sildenafil in patients with bleeding disorders or acute peptic ulcer. Thus, the use of sildenafil in patients of this group is possible only after a careful assessment of the benefit-risk ratio.

Hearing loss. Physicians should advise patients to stop taking PDE5 inhibitors, including Maxigra, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including Maxigra. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.

Co-administration with anti-hypertensives Maxigra has systemic vasodilatory effect and may further lower blood pressure in patients who used anti-hypertensive drugs. In a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and Viagra, 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mm Hg systolic and 7 mm Hg diastolic were noted.

Sexually transmitted diseases. ЗThe use of the drug Maxigra does not protect against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered.

 

Use in pregnancy and lactation.

Maxigra is not indicated for use in females.

 

The ability to influence the reaction rate when driving vehicles or other mechanisms.

Studies of the effect of the drug on the ability to drive vehicles and work with other mechanisms have not been conducted.

Since in clinical studies of the use of sildenafil cases of dizziness and disorders of the vision organs was reported, before sitting behind the wheel of a vehicle or working with mechanisms, patients need to find out what their individual reaction to the use of the drug Maksigra is.

 

Dosage and administration.

The drug is administered orally.

For the effective result of the drug Maxigra sexual stimulation is necessary.

Adults.

The recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg.

The maximum recommended dosing frequency is once per day. Using Maxigra during eating the effect of the drug may occur later than when using it on an empty stomach.

Elderly patients.

There is no need for dose adjustment in elderly patients (≥ 65 years).

Patients with renal impairment.

Recommended dosage for patients with mild to moderate renal impairment (creatinine clearance from 30 to 80 ml / min) is similar to the dosage given above in the section “Adults”.

Since patients with severe renal impairment (creatinine clearance below 30 ml/min) have reduced sildenafil clearance, the recommended dose is 25 mg. Depending on the effectiveness and tolerability of the drug dose can be increased to 50 mg and 100 mg.

Patients with hepatic impairment.

Since patients with hepatic impairment (e.g. cirrhosis) have reduced sildenafil clearance, the recommended dose for them is 25 mg. Depending on the effectiveness and tolerability of the drug dose can be increased to 50 mg and 100 mg.

Patients administering other drugs (e.g. ketoconazole, erythromycin, cimetidine, ritonavir).

Detailed information is given in the section “Drugs interaction and other types of interactions”.

Consider an initial dose of 25 mg in patients treated with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or saquinavir) or erythromycin, except of ritonavir, which co-administration with sildenafil is not recommended.

In order to minimize the risk of orthostatic hypotension, the condition of patients who use alpha-adrenoceptor blockers should be stabilized before the use of sildenafil. The recommended initial dose of sildenafil is 25 mg.

Maxigra is not indicated for use in females.

 

Children.

Maxigra is not for use in persons under 18 years.

 

Overdosage.

In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were similar to those seen at lower doses but incidence rates and severities were increased. The use of sildenafil at a dose of 200 mg did not lead to an increase in efficiency, but caused an increase in the number of cases of adverse reactions (headache, blood tides, dizziness, dyspepsia, nasal congestion, visual disturbances).

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

 

Adverse reactions.

All clinically significant adverse reactions, which were observed in clinical studies more often than with placebo, are given below in accordance with the classification “System–organ–class” and frequency: very common (≥ 1/10), common (≥ 100 and 1/10), uncommon (≥ 1000 and 1/100) and rare (≥ 10 000 and 1/1000). In addition, the frequency of clinically significant adverse reactions reported in the post-marketing experiment is unknown.

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

Infectious and invasive diseases.

Uncommon: rhinitis.

Immune system disorders

Uncommon: hypersensitivity.

Nervous system disorders.

Very common: headache.

Common: dizziness.

Uncommon: somnolence, hypoesthesia.

Rare: stroke, transient ischemic attack, convulsions*, court relapses*, syncope.

Vision system disorders.

Common: violation of color perception**, vision disorders, vision obscuration.

Uncommon: disorders of lacrimation***, pain in the eyes, photophobia, photopsia, hyperemia of the eyes, brightness of vision, conjunctivitis.

Rare: non-arterial anterior ischemic optic neuropathy*, retinal vascular occlusion*, retinal hemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floating opacities of the vitreous body, iris disorders, mydriasis, the appearance of luminous circles around the light source (halo) in the field of vision, eye edema, swelling of the eyes, eye disorders, conjunctival hyperemia, eye irritation, abnormal sensations in the eyes, swelling of the eyelids, discoloration of the sclera.

Hearing and vestibular apparatus disorders.

Uncommon: dizziness, ringing in the ears.

Rare: deafness.

Heart disorders.

Uncommon: tachycardia, palpitations.

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

Vessels disorder.

Common: flushing, hot flushes.

Uncommon: hypertension, hypotension.

Respiratory system, chest and mediastinal organs disorders.

Often: nasal congestion.

Uncommon: epistaxis, congestion of the sinuses.

Rare: a feeling of compression in the throat, swelling of the nasal mucosa, dryness in the nose.

Gastrointestinal tract disorders.

Common: nausea, dyspepsia.

Uncommon: gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth.

Rare: hypesthesia of the oral cavity.

Skin and subcutaneous tissue disorders.

Uncommon: rash.

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

Locomotor system and connective tissue disorders.

Uncommon: myalgia, pain in the limbs.

Urinary system disorders.

Uncommon: hematuria.

Reproductive system and mammary glands disorders.

Rare: bleeding from the penis, priapism*, hematospermia, prolonged erection.

Common disorders.

Uncommon: chest pain, fatigue, feeling of heat.

Rare: irritation.

Examination.

Uncommon: increased heart rate.

* Reported only during the study since market approval.

** Violation of color perception: chloropeta, chromatopsia, cyanopsia, eritropenia, xanthopsia.

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

The following phenomena were observed in 2% of patients in controlled clinical studies; causal relationship is not defined. Reports included the phenomena observed probable relationship with the drug.

General. Swelling of the face, photosensitivity reactions, shock, asthenia, pain, sudden fall, abdominal pain, sudden injury.

Cardiovascular system: сangina, AV-blockade, migraine, postural hypotension, myocardial ischemia, cerebral thrombosis, sudden cardiac arrest, violations of the ECG results, cardiomyopathy.

Gastrointestinal tract glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, violation of the results of liver tests, rectal bleeding, gingivitis.

Blood and lymphatic system: anemia, leukopenia.

Metabolic and nutritional disorders: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.

Locomotor system: arthritis, arthrosis, tendon rupture, tenosinovitis, bone pain, myasthenia gravis, synovitis.

Nervous system: ataxia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes.

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

Skin: urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis.

Specific senses: sudden decrease or loss of hearing, pain in the ears, hemorrhage in the eye, cataract, dryness in the eyes.

Urogenital system: cystitis, nicturia, increased frequency of urination, breast enlargement, urinary incontinence, ejaculation disorders, edema of the genitals, anorgasm.

Postmarketing Experience. The following adverse reactions have been identified during post approval use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors.

Cardiovascular and cerebrovascular. Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of sildenafil. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after the use of sildenafil and sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors.

Hemic and Lymphatic: VASO-occlusive crisis. In a small, prematurely terminated study of sildenafil in patients with pulmonary arterial hypertension secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported in patients who received sildenafil than in those randomized to placebo. The clinical relevance of this finding to men treated with Maxigra for erectile disfunction is not known.

Nervous: anxiety, transient global amnesia.

Special senses.

Hearing. Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of sildenafil. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of Maxigra, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors

Vision: temporary loss of vision, red eyes, burning eyes, increased intraocular pressure, retinal edema, retinal vascular disease or bleeding, vitreous detachment.

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these phenomena are directly related to the use of PDE5 inhibitors or to existing anatomical or vascular risk factors, or a combination of these factors, or other factors.

Reporting suspected adverse reactions. Reporting suspected adverse reactions after drug registration is important. This allows continuous monitoring of the relationship between benefits and risks associated with the use of this drug. Physicians should report any suspected adverse reactions as required by law.

 

Shelf life. 4 years.

 

Storage.

Does not require special storage conditions.

Keep away from children.

 

Packaging.

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

  Handling. By prescription.   Manufacturer / applicant. Pharmaceutical factory “POLPHARMA” S. A./ Pharmaceutical Works “POLPHARMA” S.A.   The location of the manufacturer and the address of the place of business. 19 Pelplinska Str. 83-200, Starogard Gdansk, Poland/ 19, Pelplinska Str., 83-200 Starogard Gdanski, Poland.