REVATIO - PACKAGE LEAFLET - LEAFLETS

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Revatio - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Sildenafil

Revatio 20 mg film-coated tablets

Revatio package inserts are available for pack sizes:

Revatio 20 mg film-coated tablets
Revatio 0.8 mg / ml solution for injection
Revatio 10 mg / ml powder for oral suspension

Why is Revatio used? What is it for?

Revatio contains the active substance sildenafil which belongs to a class of medicines called phosphodiesterase type 5 (PDE5) inhibitors.

Revatio reduces the blood pressure in the blood vessels of the lungs by dilating the blood vessels in the lungs. Revatio is used to treat adults and children and adolescents aged 1 to 17 with high pressure in the blood vessels of the lungs (pulmonary arterial hypertension).

Contraindications When Revatio should not be used

Do not take Revatio:

if you are allergic to sildenafil or any of the other ingredients of this medicine
if you are taking medicines that contain nitrates or if you are taking substances that release nitric oxide, such as amyl nitrate ("poppers"). These medicines are often used to relieve attacks of chest pain (or "angina pectoris"). Revatio can cause a considerable increase in the effects of these medicines. Tell your doctor if you are taking any of these medicines. If you are unsure, consult your doctor or pharmacist
if you are taking riociguat. This medicine is used to treat "pulmonary arterial hypertension (ie high blood pressure in the lungs) and chronic thromboembolic pulmonary hypertension (ie high blood pressure in the lungs secondary to blood clots). PDE5 inhibitors have been shown to like Revatio, they increase the blood pressure lowering effect of this medicine. If you are taking riociguat or are unsure, please tell your doctor.
if you have recently had a stroke, heart attack or if you have had severe liver disease or very low blood pressure (<90/50 mmHg).
if you are taking a medicine to treat fungal infections, such as ketoconazole or itraconazole or medicines containing ritonavir (for HIV).
if you have ever had vision loss caused by a problem with the blood flow to the nerve in the eye called non-arteritic anterior ischemic optic neuropathy (NAION).

Precautions for use What you need to know before taking Revatio

Talk to your doctor before taking Revatio if:

the disease is due to obstruction or narrowing of a pulmonary vein rather than an "artery.
have a severe heart problem.
you have heart ventricle problems.
have high blood pressure in the blood vessels of the lungs.
have low blood pressure while at rest.
you lose large amounts of body fluids (dehydration), which can occur when you sweat a lot or when you don't drink enough fluids. This can happen if you are sick with a fever, vomiting or diarrhea.
have a rare inherited eye disease (retinitis pigmentosa).
have a "red blood cell abnormality (sickle cell anemia), a blood cell tumor (leukemia), a bone marrow tumor (multiple myeloma) or any disease or deformity of the penis.
you currently have a stomach ulcer, a bleeding disorder (such as haemophilia) or a nosebleed problem.
you take medicines for erectile dysfunction.

When used for the treatment of erectile dysfunction (ED), with PDE5 inhibitors, including sildenafil, the following visual side effects have been reported, with frequency not known: partial, sudden, temporary or permanent decrease or loss of vision in one or both eyes.

If you experience sudden decrease or loss of vision, stop taking Revatio and contact your doctor immediately.

Prolonged and sometimes painful erections have been reported in men after taking sildenfil. If you have an erection that lasts continuously for more than 4 hours, stop taking Revatio and contact your doctor immediately.

Special precautions for patients with kidney or liver problems

If you have kidney or liver problems, you should tell your doctor as your dose may need to be adjusted.

Children

Revatio should not be given to children under 1 year of age.

Interactions Which drugs or foods may change the effect of Revatio

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Medicines that contain nitrates or substances that release nitric oxide, such as amyl nitrate ("poppers"). These medicines are often used to relieve attacks of angina pectoris or 'chest pain' (see section 2. What you need to know before you take Revatio).
Tell your doctor or pharmacist if you are already taking riociguat.
Treatments for pulmonary arterial hypertension (eg bosentan, iloprost) ask your doctor or pharmacist for advice before taking Revatio.
Medicines containing St John's wort (herbal medicine), rifampicin (used to treat bacterial infections), carbamazepine, phenytoin and phenobarbital (also used for epilepsy).
Medicines that inhibit blood clotting (e.g. warfarin), even if no side effects have been shown.
Medicines containing erythromycin, clarithromycin, telithromycin (these are antibiotics used to treat some bacterial infections), saquinavir (for HIV) or nefazodone (for depression), as a dose adjustment may be required.
Alpha-blocker therapy (eg doxazosin) for the treatment of high blood pressure or prostate problems, as the combination of the two medicines could cause symptoms that lead to lowering of blood pressure (eg dizziness, light-headedness) .

Warnings It is important to know that:

Revatio with food and drink

You should not drink grapefruit juice while being treated with Revatio.

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to become pregnant, ask your doctor or pharmacist for advice before taking this medicine.

Revatio should not be taken during pregnancy unless absolutely necessary. Revatio should not be given to women of childbearing potential unless they are using adequate contraceptive methods.

Stop breast-feeding when you start treatment with Revatio. Revatio should not be given to women who are breastfeeding because it is not known whether the medicine passes into breast milk.

Driving and using machines

Revatio can cause dizziness and can affect vision. Before driving and operating machines you will need to be aware of how you react to this medicine.

Revatio contains lactose

If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicine.

Dose, Method and Time of Administration How to use Revatio: Posology

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

For adults, the recommended dose is 20 mg three times a day (taken 6-8 hours apart) with or without food.

Use in children and adolescents

For children and adolescents 1 to 17 years of age, the recommended dose is 10 mg three times a day for children and adolescents ≤ 20 kg or 20 mg three times a day for children and adolescents> 20 kg, to be taken with or without food. Higher doses should not be used in children. This medicine should only be used in case of administration of 20 mg three times a day. Other pharmaceutical forms may be more appropriate for administration to patients weighing ≤ 20 kg and other younger patients who are unable to swallow tablets.

If you forget to take Revatio

If you forget to take Revatio, take the missed dose as soon as you remember and then continue taking the medicine at the usual time. Do not take a double dose to make up for a forgotten dose.

If you stop taking Revatio

Suddenly stopping treatment with Revatio may worsen your symptoms. Do not stop taking Revatio unless your doctor tells you to. Your doctor may tell you to reduce your dose over a few days before stopping treatment completely. .

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Revatio

You should not take more medicine than your doctor has prescribed for you.

If you take more medicine than prescribed, contact your doctor immediately. Taking more Revatio than you should may increase your risk of known side effects.

Side Effects What are the side effects of Revatio

Like all medicines, Revatio can have side effects, although not everybody gets them.

If you experience any of the following side effects, you should stop taking Revatio and contact your doctor immediately:

if you experience sudden decrease or loss of vision (frequency not known)
if you get an erection which lasts continuously for more than 4 hours. Prolonged and sometimes painful erections have been reported with sildenafil with unknown frequency.

Adults

Very commonly reported side effects (may affect more than 1 in 10 people) were headache, flushing of the face, indigestion, diarrhea and pain in the arms or legs.

Commonly reported side effects (may affect up to 1 in 10 people) include: subcutaneous infections, flu symptoms, sinusitis, decreased number of red blood cells (anemia), fluid retention, sleep disturbances, anxiety, headache, tremor , pinprick sensation, burning sensation, reduced sense of touch, bleeding in the back of the eye, effects on vision, blurred vision and sensitivity to light, effects on color perception, eye irritation, inflammation / redness of the eyes, dizziness, bronchitis, nosebleed, increased nasal discharge, cough, stuffy nose, stomach inflammation, gastroenteritis, heartburn, haemorrhoids, abdominal distension, dry mouth, hair loss, redness of the skin, night sweats , muscle aches, back pain and increased body temperature.

Uncommonly reported side effects (may affect up to 1 in 100 people) include: decreased visual acuity, double vision, abnormal sensation in the eye, penile bleeding, blood in semen and / or urine, and excessive development of the male breast.

Rash, a "sudden decrease or loss of hearing" and decrease in blood pressure, with frequency not known (frequency cannot be estimated from the available data), have also been reported.

Children and adolescents

The following serious adverse events have been reported commonly (may affect up to 1 in 10 people): pneumonia, heart failure, right heart failure, heart-related shock, high blood pressure in the lungs, chest pain, fainting, respiratory infection, bronchitis , viral stomach and intestinal infection, urinary tract infection and dental caries.

The following serious adverse events were considered treatment related and were reported uncommonly (may affect up to 1 in 100 people): allergic reactions (such as skin rash, swelling of the face, lips and tongue, wheezing, difficulty breathing or swallowing), convulsions, irregular heartbeat, hearing impairment, shortness of breath, inflammation of the digestive system, wheezing due to breathing problems.

Very commonly reported side effects (may affect more than 1 in 10 people) were: headache, vomiting, throat infection, fever, diarrhea, flu and nosebleeds.

Commonly reported side effects (may affect up to 1 in 10 people) were: nausea, increased erections, pneumonia and runny nose.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the package, after EXP. The expiry date refers to the last day of the month.

Do not store above 30 ° C. Store in the original package to protect from moisture.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Other Information

What Revatio contains

The active ingredient is sildenafil. Each tablet contains 20 mg of sildenafil (as citrate).
The excipients are:

Internal part: microcrystalline cellulose, calcium hydrogen phosphate (anhydrous), croscarmellose sodium, magnesium stearate. Coating: hypromellose, titanium dioxide (E171), lactose monohydrate, glycerol triacetate.

What Revatio looks like and contents of the pack

Revatio tablets are white, film-coated and have a round shape. The tablets are marked "PFIZER" on one side and "RVT 20" on the other. The tablets are available in blister packs of 90 tablets and blister packs of 300 tablets. Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Revatio can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

REVATIO 20 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20 mg of sildenafil (in the form of citrate).

Excipient (s) with known effect

Each tablet also contains 0.7 mg of lactose.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablets.

White, round and biconvex film-coated tablets debossed "PFIZER" on one side and "RVT 20" on the other.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Adults

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

Pediatric population

Treatment of pediatric patients aged 1-17 years with pulmonary arterial hypertension. Efficacy in terms of improving exercise capacity or pulmonary haemodynamics has been demonstrated in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease (see section 5.1).

04.2 Posology and method of administration

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

Dosage

Adults

The recommended dose is 20 mg three times a day (TID). For patients who forget to take Revatio, doctors should advise to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to make up for a forgotten dose.

Pediatric population (1 to 17 years)

For pediatric patients aged 1-17 years, the recommended dose in patients ≤ 20 kg is 10 mg three times a day and for patients> 20 kg it is 20 mg three times a day. In pediatric patients with pulmonary arterial hypertension (Pulmonary Arterial Hypertension, PAH) doses higher than those recommended should not be used (see also sections 4.4 and 5.1). The 20 mg tablets should not be used in cases where 10 mg is to be administered three times a day (TID) to younger patients. Other pharmaceutical forms are available for administration to patients weighing ≤ 20 kg and other younger patients who are unable to swallow tablets.

Patients being treated with other medicines

In general, any dose adjustments should only be made after a "careful benefit-risk assessment. A dose reduction to 20 mg twice daily should be considered when administering sildenafil to patients already being treated with drug inhibitors. CYP3A4, 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 use of sildenafil with multiple inhibitors. potent CYP3A4, see section 4.3. Dosage adjustments may be required when sildenafil is co-administered with CYP3A4 inducers (see section 4.5).

Special populations

Elderly (≥ 65 years old)

Dosage adjustments are not required in elderly patients. Clinical efficacy as measured by distance walked in 6 minutes may be lower in elderly patients.

Renal impairment

In patients with impaired renal function, including those with severe impairment (creatinine clearance

Hepatic impairment

No starting dose adjustments are required in patients with hepatic impairment (Child-Pugh Class A and B). A dose reduction to 20 mg twice daily should only be considered after careful risk-benefit assessment if therapy is not well tolerated.

Revatio is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) (see section 4.3).

Pediatric population

The safety and efficacy of Revatio in children aged less than 1 year have not been established. There are no data available.

Discontinuation of treatment

Limited data suggest that abrupt discontinuation of Revatio is not associated with sudden worsening of pulmonary arterial hypertension. However, in the event of sudden clinical worsening on withdrawal of the medicinal product, a gradual dose reduction is recommended. Intensive monitoring is recommended during the treatment withdrawal period.

Method of administration

Revatio is for use now only | e. The tablets should be taken approximately 6 to 8 hours apart, on a full or empty stomach.

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with nitric oxide donors (such as amyl nitrate) or with nitrates in any form is contraindicated due to the hypotensive effects of nitrates (see section 5.1).

Co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulants, such as riociguat, is contraindicated as it may lead to symptomatic hypotension (see section 4.5).

Combination with more potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) (see section 4.5).

Patients who have lost sight in one eye due to non-arteritic anterior ischemic optic neuropathy (Non-arteritic Anterior Ischaemic Optic Neuropathy, NAION), regardless of whether this event was related to previous use of a PDE5 inhibitor (see section 4.4).

The safety of sildenafil has not been studied in the following patient subgroups and its use is therefore contraindicated:

Severe hepatic impairment,

Recent history of stroke or myocardial infarction,

Severe hypotension (blood pressure

04.4 Special warnings and appropriate precautions for use

The efficacy of Revatio has not been established in patients with severe pulmonary arterial hypertension (functional class IV). If the clinical situation worsens, therapies that are recommended in the severe phase of the disease (eg epoprostenol) should be considered (see The benefit / risk balance of sildenafil has not been established in patients with WHO functional class I pulmonary arterial hypertension.

Studies have been conducted with sildenafil in forms of pulmonary arterial hypertension (Pulmonary Arterial Hypertension, PAH) related to primary (idiopathic) disease, and in forms of PAH associated with connective tissue disease or congenital heart disease (see section 5.1). The use of sildenafil in other forms of PAH is not recommended.

In the long-term extension pediatric study, an increase in deaths was observed in patients administered higher than recommended doses. Therefore, higher than recommended doses should not be used in pediatric patients with PAH (see also sections 4.2 and 5.1).

Retinitis pigmentosa

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

Vasodilating action

When prescribing sildenafil, physicians should carefully consider whether the mild to moderate vasodilatory effects of sildenafil may have adverse consequences in patients with certain underlying conditions, e.g. hypotensive patients, fluid-depleted patients, with severe flow obstruction. left ventricular or autonomic dysfunction (see section 4.4).

Cardiovascular risk factors

In the post-marketing period of sildenafil in male subjects with erectile dysfunction, serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmias, cerebrovascular haemorrhage, transient ischemic attack, hypertension and hypotension in temporal association have been reported. "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 soon after sildenafil" in the absence of of sexual activity. It is not possible to determine whether these events are directly related to these or other factors.

Priapism

Sildenafil should be used with caution in patients with anatomical deformations of the penis (e.g. angulation, cavernous fibrosis or Peyronie's disease) or in patients with conditions that may predispose to priapism (e.g. sickle cell anemia, multiple myeloma or leukemia).

Prolonged erections and priapism have been reported in post-marketing experience with sildenafil. If an erection persists for more than 4 hours, the patient should seek medical attention immediately. If priapism is not treated immediately, penile tissue damage may occur. and permanent loss of erectile function (see section 4.8).

Vaso-occlusive crises in patients with sickle cell anemia

Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell anemia. In one clinical study, cases of vaso-occlusive seizures requiring hospitalization were reported more commonly by patients taking Revatio than those receiving placebo, leading to premature discontinuation of this study.

Events related to visual function

Cases of visual disturbances have been reported spontaneously in association with the use of sildenafil and other PDE5 inhibitors. Cases of non-arteritic anterior ischemic optic neuropathy, a rare condition, have been reported both spontaneously and in an observational study in association with "use of sildenafil and other PDE5 inhibitors (see section 4.8). In the presence of any sudden visual disturbance, Revatio should be stopped immediately and alternative therapy considered (see section 4.3).

Alpha blockers

Caution is warranted when sildenafil is administered to patients treated with an alpha blocker as co-administration may cause symptomatic hypotension in susceptible individuals (see section 4.5). To minimize the development of postural hypotension, patients should be haemodynamically stabilized with alpha-blocker treatment prior to initiating sildenafil treatment. Doctors should advise patients what to do if they have symptoms of postural hypotension.

Bleeding disorders

Studies on human platelets indicate that sildenafil potentiates the antiplatelet effect of sodium nitroprusside in vitro. No information is available regarding the safety of sildenafil administration in patients with bleeding disorders or with active peptic ulcer.

Therefore, sildenafil should only be administered to these patients after a "careful risk-benefit assessment."

Vitamin K antagonists

In patients with pulmonary arterial hypertension, an increased risk of bleeding may occur when sildenafil treatment is initiated in patients who are already taking a Vitamin K antagonist, particularly in patients with pulmonary arterial hypertension secondary to connective tissue disease.

Veno-occlusive disease

No data are available on sildenafil in patients with pulmonary hypertension associated with pulmonary veno-occlusive disease. However, cases of life-threatening pulmonary edema have been reported with vasodilators (mainly prostacyclin) used in these patients. Therefore, should signs of pulmonary edema occur when sildenafil is administered to patients with pulmonary hypertension, the possibility of associated veno-occlusive disease should be considered.

Galactose intolerance

Lactose monohydrate is present in the film coating of the tablets. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use of sildenafil with bosentan

The efficacy of sildenafil in patients already receiving bosentan therapy has not been demonstrated with certainty (see sections 4.5 and 5.1).

Concomitant use with other PDE5 inhibitors

The safety and efficacy of sildenafil when administered together with other PDE5 inhibitors, including Viagra, have not been studied in patients with pulmonary arterial hypertension.

Concomitant use of such medicinal products is therefore not recommended (see section 4.5).

04.5 Interactions with other medicinal products and other forms of interaction

Effects of other medicinal products on sildenafil

Education in vitro

Sildenafil is metabolised primarily by cytochrome P450 (CYP) isoenzymes 3A4 (major route) and 2C9 (secondary route). Therefore, inhibitors of these isoenzymes may reduce the clearance of sildenafil and inducers of these isoenzymes may increase the clearance of sildenafil. For dosing recommendations, see sections 4.2 and 4.3.

Education in vivo

Co-administration of oral sildenafil and intravenous epoprostenol was evaluated (see sections 4.8 and 5.1).

The efficacy and safety of sildenafil co-administered with other treatments for pulmonary arterial hypertension (eg, ambrisentan, iloprost) has not been studied in controlled clinical trials. Therefore, caution is recommended in case of co- administration.

The safety and efficacy of sildenafil when co-administered with other PDE-5 inhibitors have not been studied in patients with pulmonary arterial hypertension (see section 4.4).

Population pharmacokinetic analysis performed in pulmonary arterial hypertension clinical studies indicates a reduction in sildenafil clearance and / or an increase in oral bioavailability when administered together with CYP3A4 substrates and following the combination of CYP3A4 substrates with beta- blockers. These were the only factors with a statistically significant impact on the pharmacokinetics of sildenafil in patients with pulmonary arterial hypertension. Exposure to sildenafil in patients treated with CYP3A4 substrates and CYP3A4 substrates plus beta-blockers was 43% and 66% higher, respectively, than in patients not receiving these drug classes. to sildenafil was 5 times greater with the 80 mg three times daily dose than the exposure achieved with the 20 mg three times daily dose. This concentration range corresponds to the "increase in sildenafil exposure" observed in clinical studies. interactions specifically conducted with CYP3A4 inhibitors (with the exclusion of the most potent of the CYP3A4 inhibitors, eg ketoconazole, itraconazole, ritonavir).

It appears that inducers of CYP3A4 have a significant impact on the pharmacokinetics of sildenafil in patients with pulmonary arterial hypertension and this was confirmed in the interaction study. in vivo conducted with bosentan, a CYP3A4 inducer.

Co-administration of bosentan (moderate inducer of CYP3A4, CYP2C9 and possibly also CYP2C19) 125 mg twice daily and sildenafil 80 mg three times daily (at steady-state), performed for 6 days in healthy volunteers resulted in a 63% reduction in the AUC of sildenafil. A population pharmacokinetic analysis of sildenafil data in adult PAH patients in clinical trials including a 12-week study to evaluate the "Efficacy and safety of oral sildenafil 20 mg three times daily added to a stable dose of bosentan (62.5 mg - 125 mg twice daily) indicated a reduction in sildenafil exposure when co-administered. bosentan, similar to that observed in healthy volunteers (see sections 4.4 and 5.1).

The efficacy of sildenafil should be closely monitored in patients concomitantly using strong CYP3A4 inducers, such as carbamazepine, phenytoin, phenobarbital, St. John's wort and rifampicin.

Co-administration of ritonavir, an HIV protease inhibitor and highly specific cytochrome P450 inhibitor, at steady state (500 mg twice / day) and sildenafil (100 mg single dose), resulted in an increase of 300 % (4-fold) sildenafil Cmax and a 1,000% (11-fold) increase in plasma sildenafil AUC. At 24 hours, sildenafil plasma levels were still approximately 200 ng / mL, compared with approximately 5 ng / mL detected when sildenafil was administered alone. This finding is consistent with the marked effects that ritonavir exerts on a wide range of cytochrome P450 substrates. Based on these pharmacokinetic results, co-administration of sildenafil and ritonavir is contraindicated in patients with pulmonary arterial hypertension (see section 4.3).

Steady-state co-administration (1200 mg three times daily) of saquinavir, an HIV protease inhibitor and inhibitor of CYP3A4 and sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax. and a 210% increase in sildenafil AUC Sildenafil did not alter the pharmacokinetics of saquinavir For dosing recommendations, see section 4.2.

When a single 100 mg dose of sildenafil was co-administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days) there was a 182% increase in systemic exposure to sildenafil (AUC). For dosing recommendations, see section 4.2. In healthy male volunteers, there was no effect of azithromycin (500 mg / day for 3 days) on the AUC, Cmax, Tmax, elimination constant or half-life of sildenafil or its major circulating metabolite. No adjustment of the circulating metabolite is required. Dosage. Co-administration of cimetidine (800 mg), a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, and sildenafil (50 mg) in healthy volunteers, resulted in a 56% increase in plasma concentrations of sildenafil. a dosage adjustment.

The more potent of the CYP3A4 inhibitors such as ketoconazole and itraconazole are expected to have effects similar to ritonavir (see section 4.3). CYP3A4 inhibitors such as clarithromycin, telithromycin and nefazodone are expected to have an intermediate effect between that of ritonavir and that of CYP3A4 inhibitors such as saquinavir or erythromycin, while a 7-fold increase in drug exposure is assumed. 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 and CYP3A4 substrates may cause a further increase in sildenafil exposure compared to when CYP3A4 substrates were administered alone. .

Grapefruit juice is a weak inhibitor of CYP3A4 of intestinal wall metabolism and therefore may result in modest increases in plasma levels of sildenafil. No dosage adjustment is necessary, but concomitant use of sildenafil and grapefruit juice is not recommended.

Single dose administration of antacid (magnesium hydroxide / aluminum hydroxide) did not change the bioavailability of sildenafil.

Co-administration of oral contraceptives (ethinyl estradiol 30 micrograms and levonorgestrel 150 micrograms) did not alter the pharmacokinetics of sildenafil.

Nicorandil is a hybrid that works as a nitrate and as a medicine that activates potassium channels. As a nitrate it can cause serious interactions when given together with sildenafil (see section 4.3).

Effects of sildenafil on other medicinal products

Education in vitro

Sildenafil is a weak inhibitor of the cytochrome P450 isoenzymes: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50> 150 μM).

There are no data on interactions between sildenafil and non-specific phosphodiesterase inhibitors, such as theophylline or dipyridamole.

Education in vivo

No significant interactions were observed when sildenafil (50 mg) was co-administered with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9.

Sildenafil had no significant effect on atorvastatin exposure (11% increase in AUC) suggesting that sildenafil has no clinically relevant effect on CYP3A4. No interactions were observed between sildenafil (100 mg single dose) and acenocoumarol.

Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with maximum blood alcohol levels averaging 80 mg / dl.

In a study in healthy volunteers, sildenafil at steady state (80 mg three times daily) resulted in a 50% increase in the AUC of bosentan (125 mg twice daily). a study in adult PAH patients on background therapy with bosentan (62.5 mg - 125 mg twice daily) indicated an increase (20% (95% CI: 9.8 - 30.8) in AUC of bosentan when co-administered with sildenafil at steady state (20 mg three times daily), which is less than that observed in healthy volunteers when co-administered with sildenafil 80 mg three times daily (see sections 4.4 and 5.1).

In a specific interaction study, where sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients, the additional reduction in supine systolic blood pressure was 8 mmHg. The corresponding additional reduction in diastolic blood pressure in the supine position was 7 mmHg These additional blood pressure reductions were comparable to those seen when sildenafil was administered alone to healthy volunteers.

In three specific interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg or 100 mg) were administered concurrently in patients with benign prostatic hypertrophy (BPH) stabilized with therapy In these study populations, additional mean reductions in supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg and 8/4 mmHg, respectively, and mean additional reductions in standing blood pressure, respectively, were observed. 6/6 mmHg, 11/4 mmHg and 4/5 mmHg When sildenafil and doxazosin were administered together in patients stabilized on doxazosin therapy, there have been rare reports of patients experiencing symptomatic postural hypotension.

These cases included dizziness and light-headedness, but not syncope. Co-administration of sildenafil with alpha-blockers to treated patients may cause symptomatic hypotension in susceptible individuals (see section 4.4).

Sildenafil (100 mg single dose) did not alter the steady state pharmacokinetics of the HIV protease inhibitor, saquinavir, which is a substrate / inhibitor of CYP3A4.

Consistent with the established effects on the nitric oxide / cGMP pathway (see section 5.1), sildenafil has been observed to potentiate the hypotensive effects of nitrates and therefore co-administration with nitric oxide donors or nitrates in any form is contraindicated (see section 4.3).

Riociguat: Preclinical studies have shown an additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. Clinical studies have shown that riociguat increases the hypotensive effect of PDE5 inhibitors. There was no evidence of a favorable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated (see section 4.3).

Sildenafil did not have a clinically significant impact on the plasma levels of oral contraceptives (ethinyl estradiol 30 mcg and levonorgestrel 150 mcg).

Pediatric population

Interaction studies have only been performed in adults.

04.6 Pregnancy and breastfeeding

Women of childbearing age and contraception in men and women

Due to the lack of data on the effects of Revatio in pregnant women, Revatio is not recommended for women of childbearing potential unless they are also using adequate contraceptive measures.

Pregnancy

No data are available on the use of sildenafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy and embryonal / fetal development. Animal studies have shown toxicity on postnatal development (see section 5.3).

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

Feeding time

It is not known whether sildenafil passes into breast milk. Revatio should not be given to women who are breastfeeding.

Fertility

Non-clinical data revealed no special hazard for humans based on conventional fertility studies (see section 5.3).

04.7 Effects on ability to drive and use machines

Revatio moderately affects the ability to drive or use machines.

As dizziness and disturbed vision were reported in clinical trials with sildenafil, patients should be aware of how they react to Revatio before driving or operating machinery.

04.8 Undesirable effects

Summary of the safety profile

In the pivotal placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of 207 patients were randomized to and treated with Revatio at doses of 20 mg, 40 mg or 80 mg TID and 70 patients were randomized to placebo. Duration of treatment was was 12 weeks. In patients treated with sildenafil at doses of 20 mg, 40 mg and 80 mg TID, the overall frequency of treatment discontinuation was 2.9%, 3.0% and 8.5% respectively compared to 2.9% with placebo. Of the 277 subjects treated in the pivotal study, 259 were enrolled in a long-term extension study. Doses up to 80 mg three times a day were administered (4 times the recommended 20 mg dose). three times a day) and after 3 years 87% of 183 patients undergoing study treatment were taking Revatio 80 mg TID.

In a placebo-controlled study conducted with Revatio as an add-on to intravenous epoprostenol in pulmonary arterial hypertension, a total of 134 patients were treated with Revatio (pre-set titration starting from 20 mg and moving to 40 mg and then to 80 mg, three times daily, based on tolerability) and epoprostenol and 131 patients were treated with placebo and epoprostenol. The treatment duration was 16 weeks. The overall frequency of treatment discontinuation in sildenafil / epoprostenol treated patients due to adverse events was 5.2% compared to 10.7% in placebo / epoprostenol treated patients. Previously unreported adverse reactions, which occurred more frequently in the sildenafil / epoprostenol treatment group, were ocular hyperaemia, blurred vision, nasal congestion, night sweats, back pain and dry mouth. Known adverse reactions such as headache, facial flushing, pain in extremities and edema were observed more frequently in sildenafil / epoprostenol treated patients than in placebo / epoprostenol treated patients. Of the subjects who completed the initial study, 242 were enrolled in a long-term extension study. Doses up to 80 mg TID were administered and after 3 years 68% of 133 patients undergoing study treatment were taking Revatio 80 mg TID.

In the two placebo-controlled studies, adverse events were generally mild to moderate in severity. The most commonly reported adverse reactions in association with the use of Revatio (percentage greater than or equal to 10%) compared to placebo were headache, flushing, dyspepsia, diarrhea and pain in extremities.

Table of adverse reactions

Adverse reactions that occurred with> 1% in patients treated with Revatio and that were more frequent (difference> 1%) with Revatio in the pivotal pivotal study or the pooled data for Revatio, covering both Placebo-controlled studies in pulmonary arterial hypertension, at doses of 20, 40 or 80 mg TID, are listed in the table below grouped by class and frequency (very common (≥ 1/10), common (≥ 1/100 to

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

Post-marketing experience reports are listed in italics.

MedDRA System Organ Class (V.14.0) Adverse reaction Infections and infestations common cellulite, flu, bronchitis, sinusitis, rhinitis, gastroenteritis Disorders of the blood and lymphatic system common anemia Metabolism and nutrition disorders common fluid retention Psychiatric disorders common insomnia, anxiety Nervous system disorders Very common headache common migraine, tremors, paraesthesia, burning sensation, hypoesthesia Eye disorders common retinal haemorrhage, visual impairment, vision blurred, photophobia, chromatopsia, cyanopsia, eye irritation, ocular hyperaemia Uncommon reduced visual acuity, diplopia, abnormal sensation in the eyes Not known Non-arteritic Anterior Ischaemic Optic Neuropathy (NAION) *, retinal vascular occlusion *, visual field defect * Ear and labyrinth disorders common dizziness Not known sudden hearing loss Vascular pathologies Very common flushing of the face Not known hypotension Respiratory, thoracic and mediastinal disorders common epistaxis, cough, nasal congestion Gastrointestinal disorders Very common diarrhea, dyspepsia common gastritis, gastroesophageal reflux disease, haemorrhoids, abdominal distension, dry mouth Skin and subcutaneous tissue disorders common alopecia, erythema, night sweats Not known rash Musculoskeletal and connective tissue disorders Very common pain in extremities common myalgia, back pain hematuria Renal and urinary disorders Uncommon hematuria Diseases of the reproductive system and breast Uncommon penile haemorrhage, haematospermia, gynaecomastia Not known priapism, increased erection General disorders and administration site conditions common pyrexia

* These adverse events / reactions have been reported in patients receiving sildenafil for male erectile dysfunction (DEM).

Pediatric population

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

The adverse reaction profile observed in this pediatric study was generally consistent with that of adults (see table above). The most common adverse reactions occurring (with a frequency ≥ 1%) in patients treated with Revatio (combined doses) and with a frequency> 1% in patients treated with placebo were pyrexia, upper respiratory tract infections (11.5% each ), vomiting (10.9%), increased erection (including spontaneous penile erections in males) (9.0%), nausea, bronchitis (4.6% each), pharyngitis (4.0% ), rhinorrhea (3.4%) and pneumonia, rhinitis (2.9% each).

Of the 234 pediatric subjects treated in the short-term placebo-controlled study, 220 entered the long-term extension study. Subjects who received active sildenafil therapy continued with the same treatment regimen, while those in the placebo group in the short-term study were re-randomized to sildenafil treatment. The most common adverse reactions reported throughout the duration of the short- and long-term studies were generally similar to those observed in the short-term study. Adverse reactions reported in> 10% of the 229 sildenafil treated subjects (combined dose group, including 9 patients who had not continued in the long-term study) were: upper respiratory tract infection (31%), headache (26 %), vomiting (22%), bronchitis (20%), pharyngitis (18%), pyrexia (17%), diarrhea (15%), flu and epistaxis (12% each). Most of these adverse reactions were considered to be mild to moderate in severity.

Serious adverse events were reported in 94 (41%) of 229 subjects receiving sildenafil. Of the 94 subjects reporting a serious adverse event, 14/55 subjects (25.5%) were in the low dose group, 35/74 subjects (47.3%) in the medium dose group and 45/100 subjects (45 %) to the high dose group. The most common serious adverse events reported with a frequency ≥1% in patients receiving sildenafil (combined doses) were: pneumonia (7.4%), heart failure, pulmonary hypertension (5.2% each), infection upper respiratory tract (3.1%), right ventricular failure, gastroenteritis (2.6% each), syncope, bronchitis, bronchopneumonia, pulmonary arterial hypertension (2.2% each), chest pain, dental caries (1.7 % each), cardiogenic shock, viral gastroenteritis, urinary tract infection (1.3% each).

The following serious adverse events were considered treatment related: enterocolitis, seizures, hypersensitivity, stridor, hypoxia, sensorineural hearing loss, and ventricular arrhythmia.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

04.9 Overdose

In volunteer studies with single doses up to 800 mg, adverse reactions were similar to those seen with lower doses, but the incidence rate and severity of events were increased. With single doses of 200 mg the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion and visual disturbances) increased.

In the event of an overdose, necessary standard supportive measures should be taken.

Hemodialysis does not accelerate renal clearance because sildenafil is highly bound to plasma proteins and is not eliminated in the urine.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC code: G04B E03

Mechanism of action

Sildenafil is a potent selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), the enzyme responsible for the breakdown of cGMP. In addition to the presence of this enzyme in the carvenous body of the penis, PDE5 is also present in the smooth muscle of the vessels Therefore, sildenafil increases cGMP in pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension this may lead to vasodilation of the pulmonary vascular bed and, to a lesser extent, vasodilation of the systemic circulation.

Pharmacodynamic effects

Studies in vitro demonstrated that sildenafil has a selectivity for PDE5. Its effect is higher for PDE5 than for other phosphodiesterases. It has a 10 times higher selectivity than that for PDE6, which is involved in phototransduction of the retina. It has a selectivity 80 times higher than that for PDE1 and over 700 times for PDE2, 3, 4, 7, 8, 9, 10 and 11. Specifically, the selectivity of sildenafil for PDE5 is 4,000 times higher than that for PDE3, the specific cAMP phosphodiesterase isoenzyme involved in the control of cardiac contractility.

Sildenafil causes mild and transient decreases in systemic blood pressure which, in most cases, do not translate into clinical effects. After chronic administration of 80 mg three times daily in patients with systemic hypertension the mean change in systolic and diastolic pressure from baseline was a reduction of 9.4 mmHg and 9.1 mmHg, respectively. After chronic administration of 80 mg three times a day in patients with pulmonary arterial hypertension minor effects of blood pressure reduction (a reduction in both systolic and diastolic blood pressure by 2 mmHg) were observed. At the recommended dose of 20 mg three times a day, no reductions in systolic blood pressure were seen or diastolic.

Administration of single oral doses of sildenafil up to 100 mg to healthy volunteers produced no clinically relevant effects on ECG. Following chronic administration of 80 mg three times daily in patients with pulmonary arterial hypertension, no clinically relevant effects were reported. to the ECG.

In a study on the haemodynamic effects of a single oral dose of 100 mg sildenafil in 14 patients with severe coronary artery disease (Coronary Artery Disease, CAD) (stenosis of at least one "coronary artery> 70%), mean resting systolic and diastolic blood pressure values decreased by 7% and 6% respectively from baseline. Mean systolic pulmonary pressure decreased by 9% Sildenafil did not alter cardiac output and did not impair blood circulation through stenotic coronary arteries.

In some subjects, with the aid of the Farnsworth-Munsell 100 HUE test, one hour after the administration of a 100 mg dose, slight and transient alterations in color perception (blue / green) were detected, without evident effects. 2 hours after administration. It is assumed that the mechanism underlying this alteration in color perception is related to the inhibition of PDE6, which is involved in the phototransduction cascade in the retina. Sildenafil does not affect visual acuity or color sense. In a placebo-controlled study in a small number of patients (n = 9) with documented early age-related macular degeneration, the use of sildenafil (single 100 mg dose) showed no clinically significant alterations to the sight tests performed (visual acuity, Amsler reticle, ability to perceive colors with simulation of traffic lights, Humphrey perimetry and photostress).

Clinical efficacy and safety

Efficacy in adult patients with pulmonary arterial hypertension (PAH)

A randomized, double-blind, placebo-controlled study was conducted in 278 patients with primary pulmonary arterial hypertension, pulmonary arterial hypertension associated with connective tissue disease, and pulmonary arterial hypertension following surgical repair of congenital heart lesions. randomized to one of four treatment groups: placebo, sildenafil 20 mg, sildenafil 40 mg, or sildenafil 80 mg, three times daily. Of the 278 randomized patients, 277 received at least one dose of study drug. The study population consisted of 68 (25%) men and 209 (75%) women with a mean age of 49 years (range: 18-81 years) and with a 6-minute distance measurement at baseline between 100 and 450 meters (inclusive) (average = 344 meters). Primary pulmonary hypertension was diagnosed in 175 patients (63%), pulmonary arterial hypertension with connective tissue disease was diagnosed in 84 patients (30%), and pulmonary arterial hypertension following surgery was diagnosed in 18 patients (7%) reparative of congenital heart malformations. Most of the patients were in WHO Functional Class II (107/277; 39%) or III (160/277; 58%) with a mean walking distance in 6 minutes at baseline of 378 and 326 meters, respectively; fewer patients were Class I (1/277; 0.4%) or IV (9/277; 3%). Patients with left ventricular ejection fraction left ventricle

Sildenafil (or placebo) was added to patients' background therapy which could have included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, or oxygen. The use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted as adjunct therapy and the addition of arginine was also not permitted. Patients who did not respond to previous treatment with bosentan were excluded from the study.

The primary efficacy endpoint was the change from baseline in 6-minute walk distance (6MWD) after 12 weeks. A statistically significant increase in 6MWD was observed in all 3. sildenafil treated groups compared to placebo. The placebo-corrected increases in 6MWD were 45 meters (p

When analyzed by WHO functional class, a statistically significant increase in 6MWD was observed in the 20 mg dose group. For class II and III, placebo-corrected increases of 49 meters (p = 0.0007) and 45 meters (p = 0.0031) were observed, respectively.

The improvement in 6MWD was evident after 4 weeks of treatment and this effect was maintained at weeks 8 and 12. Results were generally consistent in the subgroups based on etiology (primary pulmonary arterial hypertension and associated with Connective Tissue Disease ), WHO functional class, gender, race, geographical area, mean pulmonary arterial pressure (mean Pulmonary Arterial Pressure - mPAP) and pulmonary vascular resistance index (Pulmonary Vascular Resistance Index - PVRI).

Patients with all doses of sildenafil achieved statistically significant reductions in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) compared to patients treated with placebo. The effects of placebo-corrected treatment on mPAP were - 2.7 mmHg (p = 0.04), - 3.0 mmHg (p = 0.01), and - 5.1 mmHg (p

A greater proportion of patients receiving each of the sildenafil doses (i.e. 28%, 36%, and 42% of subjects taking sildenafil at doses of 20 mg, 40 mg and 80 mg TID, respectively) showed improvement to at least one WHO functional class at 12 weeks, compared to placebo (7%). The respective odds ratios were 2.92 (p = 0.0087), 4.32 (p = 0.0004) and 5.75 (p

Long-term survival data in the naive population

Patients enrolled in the pivotal study were eligible to participate in an open-label long-term extension study. After 3 years, 87% of patients were taking a dose of 80 mg TID. A total of 207 patients were treated with Revatio in the main study and their long-term survival was evaluated for a minimum of 3 years. In this population, Kaplan-Meier survival estimates at 1, 2 and 3 years were 96%, 91% and 82%, respectively. In patients with WHO functional class II at baseline, survival at 1, 2 and 3 years was 99%, 91% and 84%, respectively, and for patients with WHO functional class III at baseline it was 94%, 90% and 81%, respectively.

Efficacy in adult patients with pulmonary arterial hypertension (when Revatio is used in combination with epoprostenol)

A randomized, double-blind, placebo-controlled study was performed in 267 patients with intravenous epoprostenol stabilized pulmonary arterial hypertension. Patients with pulmonary arterial hypertension included those with primary pulmonary arterial hypertension (212/267; 79%) and with pulmonary arterial hypertension associated with connective tissue disease (55/267; 21%). Most patients were WHO Functional Class II (68/267; 26%) or III (175/267; 66%); a number of patients were functional class I (3/267; 1%) or IV (16/267; 6%) at baseline; for a small number of patients (5/267; 2%), the WHO Functional Class was not Note.

Patients were randomized to placebo or sildenafil treatment (with predetermined titration starting from 20 mg and increasing to 40 mg up to 80 mg, three times daily, based on tolerability) when used in combination with epoprostenol intravenously. intravenous.

The primary efficacy endpoint was the change from baseline to week 16 in the 6-minute walking distance test. There was a statistically significant clinical benefit of sildenafil over placebo in a 6-minute walking distance. A Placebo-corrected mean increase over a distance of 26 meters was observed in favor of sildenafil (95% CI: 10.8, 41.2) (p = 0.0009). For patients with a baseline walking distance ≥ 325 meters, the treatment effect was 38.4 meters in favor of sildenafil; for patients with a distance walked at baseline

Patients treated with sildenafil achieved a statistically significant reduction in mean pulmonary blood pressure (mPAP) compared to patients treated with placebo. A placebo-corrected mean treatment effect of -3.9 mmHg was observed in favor of sildenafil (95% CI: -5.7; -2.1) (p = 0.00003). A secondary endpoint is time to clinical worsening, defined as the time from randomization to the onset of the first event of clinical worsening (death, lung transplant, initiation of bosentan therapy, or clinical deterioration requiring modification of epoprostenol therapy). Treatment with sildenafil significantly prolonged the time to clinical worsening of pulmonary arterial hypertension compared with placebo (p = 0.0074). Clinical worsening events occurred in 23 patients in the placebo group (17.6%). compared with 8 patients in the sildenafil treatment group (6.0%).

Long-term survival data in the background study with epoprostenol

Patients enrolled in the epoprostenol add-on therapy study were eligible for enrollment in an open-label long-term extension study. At 3 years, 68% of patients were taking a dose of 80 mg TID. In total, 134 patients are were treated with Revatio in the initial study and their long-term survival was assessed for a minimum of 3 years. In this population, the 1, 2, and 3-year Kaplan-Meier survival estimates were 92%, respectively, 81 % and 74%.

Efficacy and safety in adult patients with PAH (use in combination with bosentan)

A randomized, double-blind, placebo-controlled study was conducted in 103 clinically stable subjects with PAH (WHO functional class II and III) who had been on bosentan for at least three months. Patients with PAH included subjects with PAH. primary and PAH associated with connective tissue disease. Patients were randomized to either placebo or sildenafil (20 mg three times daily) in combination with bosentan (62.5-125 mg twice daily).

The primary efficacy endpoint was a change in 6MWD from baseline at week 12. Results indicate that there is no significant difference in the mean change from baseline in 6MWD found between sildenafil (20 mg three times daily) and placebo (13 , 62 m (95% CI: -3.89 to 31.12) and 14.08 m (95% CI: -1.78 to 29.95), respectively).

Differences in 6MWD were observed between patients with primary PAH and patients with PAH associated with connective tissue disease. For subjects with primary PAH (67 subjects), the mean changes from baseline were 26.39 m (95% CI: 10.70 to 42.08) and 11.84 m (95% CI: -8.83 to 32.52), for the sildenafil and placebo groups, respectively. However, for subjects with PAH associated with connective tissue disease (36 subjects), the mean changes from baseline were -18.32 m (95% CI: -65.66 to 29.02) and 17.50 m (95% CI: -9.41 to 44.41), for the sildenafil and placebo groups, respectively.

Overall, adverse events were generally similar between the two treatment groups (sildenafil plus bosentan vs. bosentan alone) and consistent with the known safety profile of sildenafil taken as monotherapy (see sections 4.4 and 4.5).

Pediatric population

A total of 234 subjects aged 1 to 17 years were treated in a randomized, double-blind, multicenter, placebo-controlled, parallel-group, variable-dose study. Subjects (38% male and 62% female) had a body weight ≥ 8 kg, and had primary pulmonary hypertension (PPH) [33%], or pulmonary arterial hypertension (PAH) secondary to congenital heart disease [systemic-pulmonary shunt 37 %, surgical repair 30%]. In this trial, 63 of 234 patients (27%) were aged and 171 of 234 patients (73%) were 7 years of age or older (low dose sildenafil = 40; medium dose = 38; and high dose = 49; placebo = 44 ). Most subjects belonged to WHO functional class I (75/234; 32%) or class II (120/234; 51%) at baseline; fewer patients belonged to class III (35/234; 15%) or class IV (1/234; 0.4%); for some patients (3/234; 1.3%), the WHO functional class was not known.

The patients had never received specific therapy for PAH, and the use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not allowed in the study, and neither was supplementation with arginine, nitrates, alpha blockers and potent inhibitors. of CYP450 3A4. The primary objective of the study was to evaluate the efficacy of 16 weeks of chronic oral sildenafil treatment in pediatric patients to improve exercise ability, according to the test.

Cardiopulmonary Exercise (Cardiopulmonary Exercise Test, CPET) in patients who developed enough to allow testing (n = 115). Secondary endpoints included hemodynamic monitoring, symptom assessment, WHO functional class, background treatment changes, and quality of life measurements.

The subjects were distributed into one of three sildenafil treatment groups: they were given three times daily regimens of Revatio at low (10 mg), medium (10-40 mg) or high (20-80 mg) doses, or placebo. . The actual doses administered in one group depended on body weight (see section 4.8). The percentage of patients treated with supportive medicines at baseline (anticoagulants, digoxin, calcium channel blockers, diuretics and / or oxygen) was similar in the sildenafil combination treatment group (47.7%) and in the placebo treatment group ( 41.7%).

The primary endpoint was the placebo-corrected percent change in peak VO2 from baseline to week 16, based on CPET in the combined dose groups (Table 2). A total of 106 of 234 subjects (45 %), which included children ≥ 7 years of age who developed enough to allow testing. Children oxygen consumed (VO2) was comparable in all sildenafil treatment groups (17.37 to 18.03 ml / kg / min), and slightly higher for the placebo treatment group (20.02 ml / kg / min). The results of the main analysis (combined dose groups versus placebo) were not statistically significant (p = 0.056) (see Table 2). The estimated difference between the mean dose of sildenafil and placebo was 11.33% (95 % CI: 1.72 to 20.94) (see Table 2).

Table 2: Placebo-corrected percent change in peak VO2 from baseline by active treatment groups

Treatment group Estimated difference 95% Confidence Interval Low dose (n = 24) 3,81 -6,11; 13,73 Average dose (n = 26) 11,33 1,72; 20,94 High dose (n = 27) 7,98 -1,64; 17,60 Combined dose groups (n = 77) 7.71 (p = 0.056) -0,19; 15,60

n = 29 for the placebo group

Estimates based on ANCOVA with adjustments for VO2 covariates, peak baseline, etiology and body weight groups

Dose-related improvements were observed with pulmonary vascular resistance index (Pulmonary Vascular Resistance Index, PVRI) and mean pulmonary arterial pressure (mean Pulmonary Arterial Pressure, mPAP). The medium and high dose sildenafil groups both showed reductions in PVRI compared to placebo, of 18% (95% CI: 2% to 32%) and 27% (95% CI: 14% to 39%) , respectively; while the low dose group showed no significant difference compared to placebo (2% difference). The medium and high dose sildenafil groups showed changes in mPAP from baseline compared to placebo of -3.5 mmHg (95% CI: -8.9, 1.9) and -7.3 mmHg (95% IC: -12.4; -2.1), respectively; while the low dose group showed a small difference compared to placebo (difference of 1.6 mmHg). With the cardiac index, improvements were observed in all three sildenafil groups compared to placebo, 10%, 4% and 15% for the low, medium and high dose groups, respectively.

Significant improvements in functional class were demonstrated only in subjects with high sildenafil dose compared to placebo. The odds ratios for the low, medium, and high dose sildenafil groups relative to placebo were 0.6 (95% CI: 0.18, 2.01), 2.25 (95% CI: 0.75, 6). , 69) and 4.52 (95% CI: 1.56; 13.10), respectively.

Long-term extension study data

Of the 234 pediatric subjects treated in the short-term placebo-controlled study, 220 entered the long-term extension study. Subjects who were assigned to the placebo group in the short-term study were re-randomized to sildenafil treatment; subjects weighing ≤ 20 kg entered the medium or high dose groups (1: 1), while subjects weighing> 20 kg entered the low, medium, or high dose groups (1: 1: 1). Of the 229 subjects who received sildenafil overall, 55, 74 and 100 subjects were in the low, medium and high dose groups, respectively. During the short- and long-term studies, the overall duration of treatment from double-blind initiation for each individual subject ranged from 3 to 3,129 days. In the sildenafil treatment groups, the median duration of sildenafil treatment was of 1,696 days (excluding the 5 subjects who received double-blind placebo and who were not treated in the long-term extension study).

Kaplan-Meier 3-year survival estimates in patients> 20 kg in weight at baseline were 94%, 93%, and 85% in the low, medium, and high dose groups, respectively; for patients ≤ 20 kg in weight at baseline, survival estimates were 94% and 93% for subjects in the medium and high dose groups, respectively (see sections 4.4 and 4.8).

A total of 42 deaths were reported during the study, both in treatment and reported during survival follow-up. 37 deaths occurred prior to the Data Monitoring Committee's decision to scale the dosage in patients to a lower dose, based on the imbalance in mortality data found with increasing sildenafil doses. Among these 37 deaths, the number (%) of deaths were 5/55 (9.1%), 10/74 (13.5%) and 22/100 (22%) in the low, medium and high dose groups, respectively. 5 deaths The causes of death were related to pulmonary arterial hypertension. Doses higher than those recommended should not be used in pediatric patients with pulmonary arterial hypertension (see sections 4.2 and 4.4).

Peak VO2 was assessed 1 year after the initiation of the placebo-controlled study. Of the sildenafil-treated subjects developing to allow for CPET, 59/114 subjects (52%) showed no worsening of the Peak VO2 since initiation of sildenafil treatment. Similarly, 191 of 229 subjects (83%) who received sildenafil had either maintained or improved their WHO functional class at the 1-year assessment.

The European Medicines Agency has postponed the obligation to submit the results of studies of Revatio in neonates with pulmonary arterial hypertension (PAH) (see section 4.2 for information on pediatric use).

05.2 Pharmacokinetic properties

Absorption

Sildenafil is rapidly absorbed. Maximum plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral administration in the fasted state. The mean absolute bioavailability after oral administration is 41% (range 25-63%). After oral administration three times daily, AUC and C increase proportionally over the dose range of 20-40 mg. After oral administration of 80 mg three times daily an increase in plasma levels of sildenafil greater than a dose proportional increase was observed. In patients with pulmonary arterial hypertension, the oral bioavailability of sildenafil following administration of 80 mg three times daily was on average 43% (90% CI: 27% -60%) higher than at the lower doses.

When sildenafil is taken with meals, the rate of absorption is reduced with a mean delay in T of 60 minutes and a mean reduction in C of 29%. However, the extent of absorption was not significantly affected (AUC reduced by 11%).

Distribution

The mean steady state volume of distribution of sildenafil (Vss), i.e. tissue distribution, is 105 l. Following the use of oral doses of 20 mg three times daily, the mean to maximum total plasma concentration of sildenafil at steady state is approximately 113 ng / ml.

Sildenafil and its major circulating metabolite N-desmethyl are 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.

Biotransformation

Sildenafil is mainly metabolised by hepatic microsomal isoenzymes CYP3A4 (major route) and CYP2C9 (secondary route). The main metabolite is derived from the N-demethylation of sildenafil. This metabolite has a selectivity profile for phosphodiesterase similar to that of sildenafil and a potency in vitro for PDE5 approximately 50% of that of unchanged medicinal product.

The N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 hours.

In patients with pulmonary arterial hypertension, plasma concentrations of the N-desmethyl metabolite are approximately 72% of those of sildenafil following administration of 20 mg three times daily (resulting in a 36% contribution to the pharmacological effects of sildenafil). The resulting effect on efficacy is not known.

Elimination

Total body clearance of sildenafil is 41 l / h and terminal half-life is 3-5 hours. After oral or intravenous administration, sildenafil is eliminated as metabolites, mainly in faeces (approximately 80% of the administered oral dose). and to a lesser extent in the urine (approximately 13% of the administered oral dose).

Pharmacokinetics in particular groups of patients

Senior citizens

A reduction in sildenafil clearance was observed in elderly healthy volunteers (≥ 65 years), with plasma concentrations of sildenafil and the active metabolite N-desmethyl approximately 90% higher than those found in younger healthy volunteers (18-45 years). ). Due to age-related differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentrations was approximately 40%.

Renal impairment

In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 ml / min), no alterations in the pharmacokinetics of sildenafil were observed following administration of a single 50 mg oral dose. In volunteers with severe renal impairment (creatinine clearance

In addition, the AUC and Cmax of the N-desmethyl metabolite were significantly increased by 200% and 79%, respectively, in subjects with severe renal impairment compared to subjects with normal renal function.

Hepatic impairment

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh A and B), a reduction in sildenafil clearance was observed, resulting in an increase in AUC (85%) and Cmax (47%), compared to aged volunteers. comparable that did not have hepatic impairment. In addition, the AUC and Cmax of the N-desmethyl metabolite were significantly increased by 154% and 87% respectively in patients with cirrhosis compared to subjects with normal hepatic function. The pharmacokinetics of sildenafil in patients with severe hepatic impairment are not been studied.

Population pharmacokinetics

In patients with pulmonary arterial hypertension, mean steady state concentrations were 20-50% higher over the studied dose range of 20-80 mg three times daily compared to healthy volunteers. twice the Cmin compared to healthy volunteers. Both of these data suggest lower clearance and / or higher oral bioavailability of sildenafil in patients with pulmonary arterial hypertension compared to healthy volunteers.

Pediatric population

From the analysis of the pharmacokinetic profile of sildenafil in patients involved in pediatric clinical trials, body weight was shown to be a good predictor of drug exposure in children. It was estimated that the plasma half-life values of sildenafil ranged from 4.2 to 4.4 hours in the body weight range of 10 to 70 kg and did not show any differences that might appear clinically relevant. Cmax after a single 20 mg oral dose of sildenafil was estimated at 49, 104 and 165 ng / ml for 70, 20 and 10 kg patients, respectively. C after a single 10 mg oral dose of sildenafil was estimated at 24, 53 and 85 ng / ml for 70, 20 and 10 kg patients, respectively. Tmax was calculated at approximately 1 hour and was almost independent of body weight.

05.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential, reproductive and developmental toxicity.

In pups of mice treated with 60 mg / kg of sildenafil before and after birth, a reduction in pup size, a reduction in pup weight on day 1 and a reduction in survival on day 4 with a " drug exposure approximately fifty times the expected human exposure with the 20 mg three times daily dose. Effects in non-clinical studies were observed at exposures considered sufficiently in excess of the maximum human exposure and this indicates little relevance for clinical use.

There were no adverse reactions, with possible relevance for clinical use, in animals at clinically relevant exposure levels that were not also observed in clinical studies.