Revatio online in Australia

Use

Therapeutic indications

Adults

Treatment of pulmonary arterial hypertension in adult patients in functional class II and III according to the WHO classification, to improve exercise capacity. Efficacy has been demonstrated in idiopathic pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.

Pediatric population

Treatment of pulmonary arterial hypertension in children and adolescents from 1 year to 17 years.

Efficacy in terms of improving exercise capacity or pulmonary hemodynamics has been demonstrated in idiopathic pulmonary hypertension and in pulmonary hypertension associated with congenital heart disease (see section Pharmacodynamic properties).

Dosage and method of administration

Treatment should only be initiated and controlled by a physician experienced in the treatment of pulmonary arterial hypertension. In case of deterioration of the clinical state despite treatment with Revatio, therapeutic alternatives should be considered.

Dose

Adults

The recommended dose is 20 mg three times a day. Physicians should advise patients that if they miss treatment, they should take the missed dose as soon as possible and then continue with the prescribed dose. Patients should not take a double dose to make up for a missed one.

Pediatric population (1 year to 17 years)

In children and adolescents aged 1 year to 17 years, the recommended dose is: body weight ≤ 20 kg: 10 mg three times a day

body weight plus 20 kg: 20 mg three times a day.

The doses used in pediatrics in the treatment of PAH should not exceed those previously recommended (see also the Warnings and precautions for use and pharmacodynamic properties sections). . 20 mg tablets should not be used in younger patients for whom the recommended dose is 10 mg 3 times daily. There are other dosage forms available for administration in patients with a body weight ≤ 20 kg or younger patients who cannot swallow tablets.

Concomitant treatments

In general, any dose adjustment will only be considered after evaluating the benefit / risk ratio of the drug combination. A dose reduction to 20 mg twice daily should be considered when sildenafil is administered in combination with treatment with CYP3A4 inhibitors such as erythromycin or saquinavir. A dose reduction to 20 mg once daily is recommended when co-administered with more potent CYP3A4 inhibitors such as clarithromycin, telithromycin, and nefazodone. For the use of sildenafil with the most potent CYP3A4 inhibitors, see section Contraindications. The dose of sildenafil may need to be adjusted if co-administered with CYP3A4 inducers (see section Interactions with other medicinal products and other forms of interaction).

Special populations

Elderly (≥ 65 years old)

No dose adjustment is required in the elderly. The clinical efficacy on the distance traveled in 6 minutes may be less in the elderly.

Renal insufficiency

No initial dose adjustment is required in case of renal impairment, including in severe renal impairment (creatinine clearance minus 30 ml / min). A downward dose adjustment to 20 mg twice daily should be considered after careful risk / benefit evaluation only if treatment is not well tolerated.

Patients with liver failure.

No initial dose adjustment is necessary in patients with hepatic impairment (Child-Pugh classes A and B). A downward dose adjustment to 20 mg twice daily should be considered after careful risk / benefit evaluation only if treatment is not well tolerated.

Revatio is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) (see section Contraindications).

Pediatric population

In children younger than 1 year, the efficacy and safety of Revatio have not been established. No data available.

Treatment interruption

Limited data suggests that abrupt discontinuation of Revatio is not associated with a rebound effect with worsening pulmonary hypertension. However, to avoid the possible occurrence of sudden clinical deterioration at the time of discontinuation, the dose should be gradually decreased. Further monitoring is recommended during downtime.

Administration form

Oral use only.

The tablets should be taken approximately every 6 to 8 hours with or without food.

Prescription and delivery conditions

List I.

Medication subject to hospital prescription.

Prescription reserved for specialists and services in cardiology, internal medicine, pulmonology.

Duration and special precautions for conservation

Conversation duration:

5 years.

Special precautions for storage:

Do not store above 30 ° C in the original container to protect it from moisture.

Preclinical safety data

Non-clinical data from conventional studies of safety pharmacology, repeated-dose toxicology, genotoxicity and carcinogenicity, toxicity in reproductive function, and embryo-fetal development have revealed no particular risk to humans.

In neonates of rats treated before and after calving with 60 mg / kg sildenafil, a decrease in litter size, weight of the newborn was observed on day 1, and survival at 4 days. exposures on the order of 50 times the expected human exposure for a 20 mg dose three times daily. Effects in non-clinical studies have been observed at exposures well above the maximum exposure when administered to humans to give them predictive value for use in clinical practice.

No undesirable effects, which may be of clinical significance, have been observed in animals with clinically relevant exposure levels that have not been observed in clinical studies.

Incompatibilities

Aimlessly.

Employment precautions

Contraindications

Hypersensitivity to the active substance or to any of the excipients included in the Composition section.

Combination with so-called "nitric oxide donors" (such as amyl nitrite) or with nitrates in any form, due to the hypotensive effects of nitrates (see section Pharmacodynamic properties).

Co-administration of PDE5 inhibitors, such as sildenafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated due to the risk of symptomatic hypotension (see section Interactions with other medicinal products and other forms of interaction)

Combination with the most powerful CYP3A4 inhibitors (for example: ketoconazole, itraconazole, ritonavir) (see section Interactions with other medicinal products and other forms of interaction).

Patients with loss of vision in one eye due to anterior non-arteritic ischemic optic neuropathy (NAIAN), regardless of whether or not this event was associated with previous exposure to a PDE5 inhibitor (see Warnings and precautions for use).

The safety of sildenafil has not been studied in the following patient subgroups and, therefore, its use is contraindicated in patients with severe hepatic impairment, recent history of stroke, or myocardial infarction. , severe hypotension (blood pressure minus 90/50 mmHg) at baseline.

Pregnancy and lactation

Women of childbearing age and contraception in men and women.

Due to lack of data in pregnant women, Revatio is not recommended in women of childbearing age unless appropriate contraceptive measures are used.

Pregnancy

There are no data on the use of sildenafil in pregnant women. Animal studies show no direct or indirect harmful effects on gestation and fetal development of the embryo-9. Animal studies have shown toxicity in postnatal development (see section Preclinical safety data).

Due to lack of data, Revatio should not be used in pregnant women unless absolutely necessary.

Breastfeeding

The passage to breast milk is unknown. Revatio should not be administered to lactating women.

Fertility

Conventional preclinical fertility studies have revealed no particular risk to humans (see section Preclinical Safety Data).

Warnings and precautions for use

The efficacy of Revatio has not been established in patients with severe pulmonary hypertension (functional class IV). If the clinical condition worsens, recommended treatments should be considered in the severe stage of the disease (for example, epoprostenol) (see section 4.2).

The benefit / risk balance for sildenafil has not been established in patients in functional class I (WHO classification of pulmonary arterial hypertension).

Studies have been conducted with sildenafil in primary (idiopathic) pulmonary hypertension, pulmonary hypertension associated with connective tissue disease, or congenital heart disease (see Pharmacodynamic properties section). Sildenafil is not recommended for use in other forms of PAH.

During the long-term follow-up phase of a pediatric study, an increase in deaths was observed in patients receiving higher doses than those recommended in the Dosage and Method of Administration section above. Consequently, the doses used in pediatrics in the treatment of pulmonary arterial hypertension should not exceed the recommended doses (see also the Dosage and Method of Administration and Pharmacodynamic Properties sections)

Retinitis pigmentosa

The safety of sildenafil has not been studied in patients with known inherited degenerative disorders of the retina, such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases) and therefore the use of sildenafil is not recommended.

Vasodilator effect

When prescribing sildenafil, the possibility of a deleterious effect related to the mild to moderate vasodilatory properties of sildenafil should be carefully considered in patients with certain underlying conditions such as hypotension, fluid depletion, major obstruction to left ventricular ejection, or nervous system dysfunction. autonomous (see section 4.4).

Cardiovascular risk factors.

During the experience gained since the commercialization of sildenafil in erectile dysfunction in humans, serious cardiovascular events such as myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebral hemorrhage Transient, vascular ischemic attacks, hypertension and hypotension have been reported, in relation to the use of sildenafil. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many events have been reported to occur during or shortly after intercourse, and some were reported to occur after using sildenafil without sexual activity. It is not possible to determine if these events are directly related to these or other factors.

Priapism

Sildenafil should be used with caution in patients with an anatomic malformation of the penis (such as angulation, sclerosis of the corpora cavernosa, or Peyronie's disease) or in patients with conditions that may predispose them to priapism (such as sickle cell anemia), multiple myeloma, or leukemia.

Since its commercialization, prolonged erections and priapism have been reported in patients receiving sildenafil. If an erection lasts more than 4 hours, the patient should immediately consult a doctor. If priapism is not treated immediately, it can cause damage to the penile tissue and permanent impotence (see section 4.8).

Vaso-occlusive crisis in patients with sickle cell anemia

Sildenafil should not be used in patients with high blood pressure secondary to sickle cell anemia. In a clinical study, vaso-occlusive crisis events requiring hospitalization were reported more frequently in patients receiving Revatio than in those receiving placebo, leading to the premature discontinuation of this study.

Visual side effects

Visual abnormalities have been reported after the use of sildenafil and other PDE5 inhibitors. Spontaneous cases of anterior non-arteritic ischemic optic neuropathy, a rare condition, have been reported as part of an observational study after the use of sildenafil and other PDE5 inhibitors (see section 4.8). In the event of any sudden visual abnormality, treatment should be discontinued immediately and a therapeutic alternative should be considered (see section 4.3).

Concomitant treatment with an alpha-blocking drug

Caution should be exercised when administering sildenafil to patients receiving alpha-blockers, as concomitant administration may cause symptomatic hypotension in those who are predisposed (see section Interactions with other medicinal products and other forms of interactions). To minimize the risk of orthostatic hypotension, patients should be stabilized hemodynamically with their alpha-blocker therapy before starting sildenafil treatment. Patients should be informed of the action to take in case of symptoms of orthostatic hypotension.

Hemorrhagic disorders.

Studies in human blood platelets show that sildenafil enhances the antiplatelet effect of sodium nitroprusside in vitro. There are no data on the safety of sildenafil in patients with bleeding disorders or active peptic ulcer. Therefore, sildenafil should only be administered to these patients after careful evaluation of the risk-benefit balance.

Concomitant treatment with an antivitamin K

In patients with pulmonary hypertension, the risk of bleeding may increase when sildenafil is started in patients already using an antivitamin K (AVK) medication, especially in patients with pulmonary hypertension secondary to connective tissue disease.

Venoocclusive disease

There are no data available for sildenafil in patients with pulmonary hypertension associated with veno-occlusive pulmonary disease. However, life-threatening pulmonary edema has been reported with vasodilators (mainly prostacyclin) when the latter are used in this type of patient. Therefore, if signs of pulmonary edema appear when sildenafil is administered to patients with pulmonary hypertension, the possibility of associated veno-occlusive disease should be considered.

Galactose intolerance

The film coating of the tablet contains lactose monohydrate. Patients with hereditary galactose intolerance, Lapp lactase deficiency, or glucose or galactose malabsorption should not take this medicine.

Sildenafil combination with bosentan

The efficacy of sildenafil in patients already treated with bosentan has not been conclusively demonstrated (see sections Interactions with other medicinal products and other forms of interactions and pharmacodynamic properties).

Concomitant use with other PDE5 inhibitors

The safety and efficacy of combining sildenafil with other medications that contain a PDE5 inhibitor, including Viagra, have not been studied in pulmonary arterial hypertension (PAH). Therefore, the use of such combinations is not recommended (see section Interactions with other medicinal products and other forms of interaction).

Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on sildenafil

In vitro studies

Sildenafil is metabolized mainly by isoenzymes 3A4 (main route) and 2C9 (secondary route) of cytochrome P450 (CYP). Therefore, inhibitors of these isoenzymes can decrease sildenafil clearance, whereas inducers of these isoenzymes can increase sildenafil clearance. For recommendations on dose adjustments, see Dosage and Method of Administration and Contraindications sections.

In vivo studies

Concomitant administration of oral sildenafil and intravenous epoprostenol has been studied (see section 4.8 and Pharmacodynamic properties).

The efficacy and safety of sildenafil in combination with other treatments for pulmonary arterial hypertension (eg ambrisentan, iloprost) have not been studied in controlled clinical trials. Therefore, caution is recommended when combining treatments.

The safety and efficacy of sildenafil in co-administration with other PDE5 inhibitors in patients with pulmonary arterial hypertension have not been studied (see section 4.4).

Population pharmacokinetic analysis of data from clinical trials in pulmonary arterial hypertension has shown a decrease in the clearance of sildenafil and / or an increase in its oral bioavailability when administered concurrently with CYP3A4 substrates alone or in combination with beta-blockers. They were the only factors for which a statistically significant effect on the pharmacokinetics of sildenafil was demonstrated in patients with pulmonary arterial hypertension. Systemic exposure to sildenafil in patients treated with CYP3A4 substrates alone and with CYP3A4 substrates associated with beta-blockers was 43% and 66% higher, respectively, compared to patients who did not receive these classes of drugs. Sildenafil exposure was 5 times higher at an 80 mg dose three times a day compared to exposure at a 20 mg dose three times a day. This difference in concentration corresponds to the increase in sildenafil exposure observed during studies of specific drug interactions with CYP3A4 inhibitors (with the exception of the more potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir).

CYP3A4 inducers appeared to have a significant impact on the pharmacokinetics of sildenafil in patients with pulmonary arterial hypertension; which was confirmed during the in vivo interaction study with bosentan, an inducer of CYP3A4.

Co-administration of bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly CYP2C19) at a dose of 125 mg twice a day and sildenafil at a dose of 80 mg three times a day (as a balance) for 6 days in healthy volunteers gave as A 63% decrease in the area under the plasma concentration curve (AUC) of sildenafil resulted.

A population pharmacokinetic analysis of data on the use of sildenafil in adult PAH patients who participated in clinical trials, including a 12-week study, was performed to assess the efficacy and safety of a 20 mg dose of sildenafil administered three times a day. orally daily in combination with a stable dose of bosentan (62.5 mg to 125 mg twice daily). This analysis indicated that concomitant administration of bosentan resulted in a reduction in sildenafil exposure in the same order as that observed in healthy volunteers (see sections 4.4 and 5.1).

The efficacy of sildenafil should be closely monitored in patients receiving a potent CYP3A4 inducer simultaneously, such as carbamazepine, phenytoin, phenobarbital, St. John's wort, and rifampin.

Co-administration of 100 mg single-dose sildenafil antiprotease and ritonavir, a very potent steady state cytochrome P 450 inhibitor (500 mg twice daily), produced a 300% (4-fold) increase in Cmax. sildenafil and a 1000% (11-fold) increase in AUC for sildenafil. After 24 hours, the plasma concentrations of sildenafil were still approximately 200 ng / ml, whereas they were approximately 5 ng / ml when sildenafil was administered alone. These observations are in agreement with the marked effects of ritonavir observed in a large number of cytochrome P 450 substrates. In view of these pharmacokinetic results, the concomitant administration of sildenafil and ritonavir is contraindicated in patients with pulmonary hypertension (see section Contraindications).

Co-administration of sildenafil (100 mg as a single dose) and saquinavir antiprotease, a CYP3A4 inhibitor, at steady state (1200 mg three times daily), produced a 140% increase in Cmax for sildenafil and a 210% increase in the AUC of sildenafil.

Sildenafil has no effect on the pharmacokinetics of saquinavir. For recommendations on dose adjustments, see section 4.2.

A 182% increase in systemic exposure to sildenafil (AUC) when sildenafil (100 mg as a single dose) is administered with erythromycin (moderate CYP3A4 inhibitor), at steady state (500 mg twice daily for 5 days) has been observed. For recommendations on dose adjustments, see section 4.2. In healthy male volunteers, no effect of azithromycin (500 mg daily for 3 days) was observed on AUC, Cmax, tmax, constant elimination rate, or the half-life of sildenafil or its major circulating metabolite. There is no reason to recommend a dosage adjustment. Co-administration of sildenafil (50 mg) and cimetidine (800 mg), a cytochrome P450 inhibitor, and a non-specific CYP3A4 inhibitor, resulted in a 56% increase in plasma sildenafil concentrations in healthy volunteers. There is no reason to recommend a dosage adjustment.

Effects similar to those of ritonavir are expected with the more potent CYP3A4 inhibitors such as ketoconazole and itraconazole (see section 4.3). With CYP3A4 inhibitors such as clarithromycin, telithromycin, and nefazodone, an intermediate effect is expected between that of ritonavir and that of CYP3A4 inhibitors such as saquinavir or erythromycin, assuming an increased exposure by a factor of 7. Therefore, dose adjustments are recommended when CYP3A4 inhibitors are used (see section 4.2).

Population pharmacokinetic analysis in patients with pulmonary arterial hypertension suggested that co-administration of beta-blockers with CYP3A4 substrates may lead to a further increase in sildenafil exposure compared to administration of CYP3A4 substrates alone.

Grapefruit juice is a weak inhibitor of CYP3A4-induced metabolism in the intestinal wall and can cause a slight increase in plasma concentrations of sildenafil. A priori there is no reason to recommend a dosage adjustment, but concomitant intake of grapefruit juice and sildenafil is not recommended as a precaution.

No effect of antacids (magnesium hydroxide / aluminum hydroxide) in single doses on the bioavailability of sildenafil has been demonstrated.

No change in the pharmacokinetics of sildenafil has been demonstrated during concomitant administration of oral contraceptives (30 µg ethinyl estradiol and 150 µg levonorgestrel).

Nicorandil is a hybrid of potassium channel activator and nitro derivative. Due to the nitro derived component, it can cause significant interaction with sildenafil (see section 4.3).

Sildenafil effects on other medicines.

In vitro studies

Sildenafil is a weak inhibitor of isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 plus 150 µM) of cytochrome P 450.

There are no data available on the interaction between sildenafil and nonspecific phosphodiesterase inhibitors, such as theophylline or dipyridamole.

In vivo studies

No significant interaction was observed when co-administered with sildenafil (50 mg) and tolbutamide (250 mg) or warfarin (40 mg), two substances metabolized by CYP2C9.

No significant effect of sildenafil on atorvastatin exposure (11% increase in AUC) has been demonstrated, suggesting that sildenafil has no clinically significant effect on CYP3A4.

No interaction was observed between sildenafil (100 mg single dose) and acenocoumarol.

The potentiation by sildenafil (50 mg) of the prolongation of bleeding time induced by acetylsalicylic acid (150 mg) has not been demonstrated.

Sildenafil (50 mg) potentiation of the alcohol-induced hypotensive effect has not been demonstrated in healthy volunteers with an average maximum blood alcohol concentration of 80 mg / dl.

In a study in healthy volunteers, sildenafil (80 mg three times a day) resulted in a 50% increase in steady state in the AUC of bosentan 125 mg twice a day).

Population pharmacokinetic analysis was performed on data from a study of adult patients with PAH who received stable dose treatment with bosentan (62.5 mg to 125 mg twice daily).

This analysis showed an increase in the AUC of bosentan (20% (95% CI: 9.8 - 30.8), when combined with a stable dose of sildenafil (20 mg three times a day), lower than that observed in healthy volunteers when combine with 80 mg sildenafil three times daily (see sections 4.4 and 4.4).

In a specific interaction study in which sildenafil (100 mg) was administered with amlodipine in hypertensive subjects, an additional decrease in systolic blood pressure at bedtime was 8 mmHg. The corresponding decrease in diastolic blood pressure when lying down was 7 mmHg. These additional decreases in systemic blood pressure were similar to those observed when sildenafil was administered only to healthy volunteers.

In three specific drug interaction studies, alpha-blockers doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign prostatic hypertrophy stabilized by doxazosin therapy. In these studies, additional mean reductions in supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, and additional mean reductions in position blood pressure were observed. standing 6/6 mmHg, 11/4 mmHg and 4/5 mmHg, respectively. When sildenafil and doxazosin were administered simultaneously in patients stabilized with doxazosin therapy, symptomatic orthostatic hypotension was observed in rare cases. Among these cases dizziness and intoxication were described, but without syncope. Concomitant administration of sildenafil to patients receiving alpha-blocker therapy may cause symptomatic hypotension in people with predisposition (see section 4.4).

No effect of sildenafil (100 mg as a single dose) on the pharmacokinetics of antiprotease saquinavir, a CYP3A4 inhibitory substrate, has been observed at steady state.

According to the knowledge of its mode of action at the level of the nitrogen monoxide / cyclic guanosine monophosphate (cGMP) pathway (see section Pharmacodynamic properties), a potentiation of the hypotensive effect of nitro derivatives by sildenafil has been demonstrated; therefore, its concomitant administration with nitric oxide donors or nitro derivatives in any form is contraindicated (see section Contraindications).

Riociguat:

Preclinical studies have shown an increase in the systemic hypotensive effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to increase the hypotensive effects of PDE5 inhibitors. No benefit of association has been demonstrated in the study population. Concomitant use of riociguat with PDE5 inhibitors, such as sildenafil, is contraindicated (see section 4.3).

There is no clinically significant effect of sildenafil on plasma concentrations of oral contraceptives (30 µg ethinyl estradiol and 150 µg levonorgestrel).

Pediatric population

Interaction studies have only been performed in adults.

Caution

Undesirable effects

Summary of the safety profile

In the pivotal placebo-controlled study that used Revatio to treat pulmonary hypertension, a total of 207 patients were randomized to be treated with 20 mg, 40 mg, or 80 mg, three times daily with Revatio tablets. orally and 70 patients were randomized to the placebo group. The expected duration of treatment was 12 weeks. The overall frequency of discontinuation of treatment in patients receiving sildenafil 20 mg, 40 mg, and 80 mg three times daily was 2.9%, 3%, and 8.5%, respectively, compared to 2.9% in placebo. Of the 277 patients randomized to the pivotal study, 259 were included in a long-term follow-up study. Doses of up to 80 mg were administered three times a day (4 times the recommended dose of 20 mg three times a day) and after 3 years, 87% of the 183 patients who remained on treatment received Revatio 80 mg three times a day. . day.

In a placebo-controlled study using Revatio in combination with intravenous epoprostenol for the treatment of pulmonary arterial hypertension, a total of 134 patients were treated with Revatio (according to a dosing regimen) in increasing doses from 20 mg, then 40 mg , then 80 mg, three times a day, depending on tolerance) and epoprostenol, and 131 patients were treated with placebo and epoprostenol. The expected duration of treatment was 16 weeks. The overall frequency of discontinuation of treatment in patients treated with sildenafil / epoprostenol due to adverse reactions was 5.2% compared to 10.7% in patients treated with placebo / epoprostenol. The most recently reported adverse reactions that occurred most frequently in the sildenafil / epoprostenol group were: ocular hyperemia, blurred vision, nasal congestion, night sweats, back pain, and dry mouth. The frequency of previously known side effects, such as headache, redness of the face, pain in the extremities, and edema, was higher in patients treated with sildenafil / epoprostenol than in patients treated with placebo / epoprostenol. Of the subjects who completed the initial study, 242 were included in the long-term extension study. Doses of up to 80 mg were administered three times a day and after 3 years, 68% of the 133 patients who remained on treatment received Revatio 80 mg three times a day.

In two placebo-controlled studies, side effects were generally mild to moderate. The most frequent side effects (frequency greater than or equal to 10%) with Revatio compared to placebo were headache, redness of the face, dyspepsia, diarrhea and pain in the extremities.

Presentation of adverse reactions.

The following table shows the side effects reported in the pivotal study or in all placebo-controlled studies conducted on pulmonary hypertension at doses of 20, 40, or 80 mg three times daily, which occurred in more than 1% of patients treated with Revatio and observed more frequently than in the placebo group (difference of more than 1%). Adverse reactions are listed by class and frequency (very common (≥1 / 10), common (≥1 / 100 to minus 1/10), uncommon (≥1 / 1000 to minus 1/100) and undetermined (not it can be estimated from the available data Within each frequency group, adverse reactions are presented in descending order of severity.

Notifications notified since their commercialization are indicated in italics.

MedDRA Organ System Class Database (V.14.0)

Infections and infestations

Frequent

Undesirable effects

cellulite, flu syndrome, bronchitis, sinusitis, rhinitis, gastroenteritis.

Blood and lymphatic system disorders.

Frequent

anemia

Metabolism and nutrition disorders.

Frequent

fluid retention

Psychiatric disorders

Frequent

insomnia, anxiety

Nervous system disorders

Very common

Frequent

headache

migraine, tremor, paraesthesia, burning sensation, hypoesthesia

Eye disorders

Frequent

retinal hemorrhage, visual impairment, blurred vision, photophobia, chromatopsia, cyanopsy, eye irritation, ocular hyperemia

Rare

decreased visual acuity, diplopia, eye discomfort

Undetermined

Non-arteritic anterior ischemic optic neuropathy (NAION) *, retinal vascular occlusion *, visual field deterioration *

Ear and labyrinth disorders.

Frequent

dizziness

Undetermined

brutal hearing loss

Vascular disorders

Very common

redness of the face

Undetermined

hypotension

Respiratory, thoracic and mediastinal disorders.

Frequent

epistaxis, cough, nasal congestion

Gastrointestinal disorders.

Very common

diarrhea, dyspepsia

Frequent

gastritis, gastroesophageal reflux, hemorrhoids, bloating, dry mouth

Skin and subcutaneous disorders.

Frequent

alopecia, erythema, night sweats

Undetermined

eruption

Musculoskeletal and connective tissue disorders.

Very common

limb pain

Frequent

myalgia, back pain

Kidney and urinary tract disorders.

Rare

hematuria

Reproductive system and breast function disorders

Rare

bleeding from the penis

hematospermia, gynecomastia

Undetermined

priapism, prolonged erection

General disorders and abnormalities at the site.

administration

Frequent

fever

* These side effects / reactions have been reported in patients taking sildenafil for the treatment of erectile dysfunction in men.

Pediatric population

In a placebo-controlled study of patients aged 1-17 years with pulmonary hypertension, a total of 174 patients were treated three times daily with low-dose Revatio (10 mg in patients over 20 kg; no patient ≤ 20 kg received low dose), i.e. medium doses (10 mg in patients ≥ 8-20 kg; 20 mg in patients ≥ 20-45 kg; 40 mg in patients over 45 kg) or high doses (20 mg in patients ≥ 8-20 kg; 40 mg in patients ≥ 20-45 kg; 80 mg in patients over 45 kg) and 60 patients received a placebo.

The tolerance profile observed in this pediatric study largely corresponds to that of adults (see table above). The most frequently reported adverse reactions (AE) in patients taking Revatio (frequency of occurrence ≥ 1%, all doses) and whose frequency was greater than 1% compared to placebo were: fever (11.5%), tract infections upper respiratory (11.5%), vomiting (10.9%), increased erection (including spontaneous penile erections in male patients) (9%), nausea (4.6%), bronchitis (4.6%), pharyngitis (4%) , runny nose (3.4%), pneumonia (2.9%), rhinitis (2.9%).

Of the 234 pediatric patients treated in the short-term, placebo-controlled study, 220 children were included in the longer-term extension phase. Children who received sildenafil continued treatment with the same dosing schedule, while children in the placebo group were randomly assigned to the sildenafil groups.

The most frequently reported adverse reactions in the short and long-term studies were generally similar to those observed in the short-term study. Adverse reactions reported in more than 10% of the 229 children treated with sildenafil (all doses combined and including 9 patients who did not continue the long-term study) were: upper respiratory tract infections (31%), headache ( 26%), vomiting (22%), bronchitis (20%), pharyngitis (18%), fever (17%), diarrhea (15%), influenza (12%) and epistaxis (12%). Most of these side effects were mild to moderate.

Serious side effects have been reported in 94 (41%) of the 229 children receiving sildenafil. Among the 94 children who reported a serious adverse reaction, 14/55 (25.5%) children were in the low-dose group, 35/74 (47.3%) in the medium-dose group, and 45/100 (45%) in the group. high dose. The most frequent serious adverse reactions with a frequency ≥ 1% in patients with sildenafil (all doses combined) were: pneumonia (7.4%), heart failure (5.2%), pulmonary hypertension (5.2%), upper respiratory tract infection (3.1%), right ventricular failure (2.6%), gastroenteritis (2.6%), syncope (2.2%), bronchitis (2.2%,), bronchopneumonia (2.2%), pulmonary hypertension (2.2%), chest pain (1.7%), dental caries (1.7%), cardiogenic shock (1.3%), viral gastroenteritis (1.3%), urinary tract infection (1.3%).

The following serious side effects have been considered related to treatment: enterocolitis, seizures, hypersensitivity, stridor, hypoxia, sensorineural deafness, and ventricular arrhythmia.

Notification of suspected adverse reactions.

Notification of suspected adverse reactions after authorization of the medicinal product is important. Allows continuous monitoring of the benefit / risk ratio of the medication. Health professionals are requested to report any suspected adverse reactions through the national reporting system listed in Appendix V.

Overdose

In studies in volunteers receiving single doses of up to 800 mg, the side effects were the same as for lower doses, but their incidence and severity increased. At the 200 mg dose, the incidence of adverse effects (headache, redness of the face, dizziness, dyspepsia, nasal congestion and visual disturbances) increased.

In the event of an overdose, the usual symptomatic treatment measures should be implemented as necessary. Since sildenafil is strongly bound to plasma proteins and is not excreted in the urine, renal dialysis is unlikely to increase sildenafil clearance.