VI.2 Elements for a public summary VI.2.1 Overview of disease epidemiology VI.2.2 Summary of treatment benefits

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1 VI.2 Elements for a public summary VI.2.1 Overview of disease epidemiology Pulmonary arterial hypertension (a high blood pressure in the blood vessels in the lungs) is a rare disease. Historically, the incidence rates for pulmonary arterial hypertension (PAH) were estimated to be 1-2 cases per million adults, the National Institute of Health Registry in During the last three years, there has been an increase in the amount of epidemiological data on PAH and its underlying conditions. The latest incidence and occurrence rates for PAH in adults are estimated to be and cases per million, respectively, according to registry-based French and Scottish data. Furthermore, it is now recognised that PAH may manifest in both genders and all ages. The occurrence of PAH is more frequent in females (approximately 2:1 ratio). 2, 3 VI.2.2 Summary of treatment benefits This is a generic medicine (a medicine that is developed to be the same as a reference medicine that has already been authorized). Thus, extensive medical literature is available for sildenafil in the proposed therapeutic indications. VI.2.3 Unknowns relating to treatment benefits The safety of sildenafil has not been studied in patients with any known rare inherited eye disease such as retinitis pigmentosa. There are no data from the use of sildenafil in pregnant women. The effect of the long term use of sildenafil on the risk of death is unknown. Also, the safety of sildenafil in patients with impaired kidney function and underlying heart and blood vessel disease is not fully known.

2 VI.2.4 Summary of safety concerns Important identified risks: Risk What is known Preventability Drug interactions with organic nitrate, bosentan (and other CYP3A4 inducers) Concomitant use of nitrates and sildenafil can cause profound and prolonged drops in blood pressure. For this reason, it is not recommended to use sildenafil in patients who take medicines containing nitrates or nitric oxide such as amyl nitrate (medicines usually given for relief of angina pectoris or chest pain). Sildenafil and bosentan are often co-administered for pulmonary arterial hypertension (high blood pressure in the lungs) treatment. The blood level of sildenafil can be decreased by half if co-administered with bosentan, though the clinical significance of this remains uncertain. The effective use of sildenafil in Yes. Before starting sildenafil treatment, the patient should inform their treating doctor or pharmacist if they are taking, have recently taken, or might take medicines containing nitrates, bosentan or carbamazepine, phenytoin, phenobarbital, St John s Wort (herbal medicinal product) and rifampicin. The effective use of sildenafil should be closely monitored in patients using concomitant potent CYP3A4 inducers, such as St. John s Wort (herbal medicinal product), rifampicin, carbamazepine, phenytoin and phenobarbital, and if required the sildenafil dose should be adjusted.

3 Sickle cell crisis (vasoocclusive crisis) in patients with sickle cell disease Increased risk of death in children and adolescents (increased relative mortality in the paediatric population) patients already on bosentan therapy has not been demonstrated. Cytochrome P450 3A4 (CYP3A4), is an important enzyme in the body, mainly found in the liver and in the intestine. It helps with the breaking down of medicines, so that they can be removed from the body. Sildenafil is mainly broken down by CYP450 enzyme. Therefore, sildenafil clearance may be increased when used simultaneously with potent CYP3A4 inducers, such as St. John s Wort (herbal medicinal product), rifampicin (used to treat bacterial infections), carbamazepine, phenytoin, and phenobarbital (used, among others, to treat epilepsy). A vaso-occlusive crisis is a common painful complication due to an abnormality of red blood cells. Events of vaso-occlusive crises requiring hospitalization were reported more commonly in patients taking sildenafil. For children and adolescent patients aged 1 year to 17 years old, the recommended sildenafil dose in patients less than equal to 20 kg is 10 mg three times a day and for patients more than 20 kg is Yes. Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell anaemia (a decrease in the amount of red blood cells or 51haemoglobin in the blood). Before taking sildenafil, the patient should inform their treating doctor if they are having an abnormality of red blood cells. Yes. Sildenafil should not be used at doses higher than the recommended doses in paediatric patients with pulmonary arterial

4 Nose bleeds (epistaxis)/bleeding events 20 mg (1 tablet) three times a day. Higher than recommended doses should not be used in children and adolescents patients with pulmonary arterial hypertension (high blood pressure in the lungs). The 20 mg tablet should not be used in cases where 10 mg three times a day should be administered in younger patients. Other pharmaceutical forms are available for administration to patients less than or equal to 20 kg and other younger patients who are not able to swallow tablets. In the long term pediatric study, an increase in deaths was observed in patients who were administered higher than the recommended dose of sildenafil. There is no information on the safety of the administration of sildenafil in patients with bleeding disorders or active peptic ulceration (stomach ulcer). There may be a potential for increased risk of bleeding when sildenafil is initiated in patients with high blood pressure in the blood vessels in the lungs who are already using a Vitamin K antagonist (medicines that reduce blood clotting by reducing the action of vitamin K). Nose bleed is the most common (may affect up to 1 in 10 people) side effect reported with sildenafil use. hypertension (high blood pressure in the blood vessels in the lungs). Yes. Before taking sildenafil, the patient should inform their treating doctor if they currently have a stomach ulcer, a bleeding disorder (such as haemophilia), or problems with nose bleeds. Sildenafil should only be administered to these patients after a careful benefit-risk assessment. Important potential risks: Risk What is known

5 Decreased blood pressure (hypotension) An eye problem, usually due to loss of blood flow to the optic nerve (non-arteritic anterior ischaemic optic neuropathy) Hearing loss Hypotension has been reported at an unknown frequency (frequency cannot be estimated from the available data) with sildenafil use. Sildenafil should not be used in patients with very low blood pressure (< 90/50 mmhg). When prescribing sildenafil, physicians should carefully consider patients with hypotension as they could be adversely affected by sildenafil s mild to moderate vasodilatory effects (widening of blood vessels). Caution is advised when sildenafil is administered to patients taking an alpha-blocker therapy (e.g. doxazosin) for the treatment of high blood pressure or prostate problems, as the combination of the two medicines may cause symptoms resulting in the lowering of blood pressure (e.g. dizziness, light headedness). NAION refers to a loss of blood flow to the optic nerve (a nerve that connects the eye to the brain). NAION is a side effect reported with sildenafil use at an unknown frequency. Patients should not take sildenafil if they have ever had loss of vision because of NAION. Patients are advised to contact a doctor immediately if they experience any sudden decrease or loss of vision while taking sildenafil. A sudden decrease or loss of hearing has been reported with sildenafil use at an unknown frequency. An acute bleeding into the lungs due to unapproved use of sildenafil in paediatric population (pulmonary haemorrhage in off-label paediatric patients) Drug interactions with epoprostenol, iloprost, guanylate cyclase stimulators, and PDE5 inhibitors As safe and effective use of sildenafil is not known in children below 1 year of age, sildenafil should not be given to children below 1 year of age. Co-administration of oral sildenafil and intravenous epoprostenol in patients with pulmonary arterial hypertension (high blood vessels in the lungs) resulted in the occurrence of new adverse events of blurred vision, nasal congestion, night sweats, back pain, dry mouth, and hyperaemia (an excess of blood in the vessels supplying an organ or other part of the body), along with known adverse reactions of headache, flushing, pain in extremity and oedema (abnormal fluid accumulation in tissues or body cavities). The safe and effective use of sildenafil co-administered with other treatments for pulmonary arterial hypertension (eg, iloprost) has not been studied. Therefore, care is advised in cases of co-administration. The co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators such as riociguat (used for treatment of high blood pressure in the lungs), is contraindicated as it may potentially lead to symptomatic hypotension. Patients should inform their treating doctor or pharmacist if they are taking, have recently taken, or might take epoprostenol, iloprost, riociguat or other PDE5 inhibitors.

6 Missing information: Risk What is known Long-term eye (ocular) safety The safety of sildenafil has not been studied in patients with known rare inherited eye diseases such as retinitis pigmentosa, and therefore its use is not recommended. Safety in pregnancy Safety in patients with impaired kidney function (renal impairment) Safety in patients with heart and blood vessel disease (cardiovascular diseases) Long-term death (mortality) There are no data regarding the use of sildenafil in pregnant women. If a patient is pregnant, thinks they may be pregnant, or are planning to have a baby, the patient should ask their doctor or pharmacist for advice before taking this medicine. Sildenafil should not be used during pregnancy unless strictly necessary. Patients should inform their treating doctor if they are having kidney problems as the sildenafil dose may need to be adjusted. Initial dose adjustments are not required in patients with severe kidney problems. A downward dose adjustment to 20 mg twice daily should be considered after a careful benefitrisk assessment, but only if therapy is not well-tolerated. Sildenafil should not be used in patients who have recently had a stroke or a heart attack. Serious cardiovascular events have been reported with the use of sildenafil. Most, but not all, of these patients had pre-existing cardiovascular risk factors. The efficacy of the long term use of sildenafil in adult patients with high blood pressure in the blood vessels in the lungs was studied. A long term survival status was studied for a minimum of 3 years. However, the effect of sildenafil on the risk of death in adult patients with PAH is unknown. VI.2.5 Summary of additional risk minimization measures by safety concern Summary of Product Characteristics (SPC) of Sildenafil Amneal 20 mg film-coated tablets provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PIL). All these risk minimization measures are given in the SPC and PIL of Sildenafil Amneal 20 mg film- coated tablets. This medicine has no additional risk minimization measures. VI.2.6 Planned Post-Authorisation Development Plan No post-authorisation study is planned for this product.

7 VI.2.7 Summary of changes to the Risk Management Plan over time Version Date Safety Concerns Comment Important Identified Risks: o Hypersensitivity to sildenafil or to any of the excipients o Co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form o Combination with the most potent of the CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) o Patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION) o Use in severe hepatic impairment o Use in recent history of stroke or myocardial infarction o Use in severe hypotension (blood pressure < 90/50 mmhg) at initiation o Use in retinitis pigmentosa o Patients with hypotension, fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction o Cardiovascular risk factors o Patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie s disease), or in patients who have conditions which may predispose them to priapism o Patients with pulmonary hypertension Initial submission

8 secondary to sickle cell anaemia o Visual events Important Potential Risks: o Co-administration with alpha-blocker o Bleeding disorders o Vitamin K antagonists o Veno-occlusive disease o Use of sildenafil with bosentan o Concomitant use with other PDE5 inhibitors Missing Information: o Use during pregnancy o Use during breastfeeding o Use in children below 1 year Important Identified Risks: o Drug interactions with nitrate, bosentan (and other CYP3A4 inducers) o Vasoocclusive crisis in patients with sickle cell disease o Increased relative mortality in the paediatric population o Epistaxis/bleeding events Important Potential Risks: o Hypotension o Non-arteritic anterior ischaemic optic neuropathy (NAION) o Hearing loss o Pulmonary haemorrhage in off-label paediatric patients o Drug interactions with epoprostenol, iloprost, guanylate cyclase stimulators, and PDE5 inhibitors Missing Information: o Long-term ocular safety o Safety in pregnancy Safety concerns have been updated as per Agency s suggestion. o Safety in patients with renal impairment o Safety in patients with cardiovascular diseases o Long-term mortality

9 Important Identified Risks: o Drug interactions with organic nitrate, bosentan (and other CYP3A4 inducers) o Vasoocclusive crisis in patients with sickle cell disease o Increased relative mortality in the paediatric population o Epistaxis/bleeding events Important Potential Risks: o Hypotension o Non-arteritic anterior ischaemic optic neuropathy (NAION) o Hearing loss o Pulmonary haemorrhage in off-label paediatric patients o Drug interactions with epoprostenol, iloprost, guanylate cyclase stimulators, and PDE5 inhibitors Missing Information: o Long-term ocular safety o Safety in pregnancy o Safety in patients with renal impairment o Safety in patients with cardiovascular diseases o Long-term mortality Safety concerns have been updated as per Agency s suggestion.

10 Summary EU-Risk Management Plan NL/H/3654/001/DC - Sildenafil Amneal