4.1. Therapeutic indications

Adults

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

Paediatric population

Treatment of paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary haemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease (see section 5.1).

4.2. Posology and method of administration

Treatment should only be initiated and monitored by a physician experienced in the treatment of pulmonary arterial hypertension. In case of clinical deterioration in spite of sildenafil treatment, alternative therapies should be considered.

Posology

Adults

The recommended dose is 20 mg three times a day (TID). Physicians should advise patients who forget to take sildenafil to take a dose as soon as possible and then continue with the normal dose.

Patients should not take a double dose to compensate for the missed dose.

Paediatric population (1 year to 17 years)

For paediatric patients aged 1 year to 17 years old, the recommended dose in patients ≤ 20 kg is 10 mg three times a day and for patients > 20 kg is 20 mg three times a day.

Higher than recommended doses should not be used in paediatric patients with PAH (see also sections 4.4 and 5.1). The 20 mg tablet should not be used in cases where 10 mg TID should be administered in younger patients. Other pharmaceutical forms are available for administration to patients ≤ 20 kg and other younger patients who are not able to swallow tablets.

Patients using other medicinal products

In general, any dose adjustment should be administered only after a careful benefit-risk assessment. A downward dose adjustment to 20 mg twice daily should be considered when sildenafil is co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir. A downward dose adjustment to 20 mg once daily is recommended in case of co-administration with more potent CYP3A4 inhibitors clarithromycin, telithromycin and nefazodone. For the use of sildenafil with the most potent CYP3A4 inhibitors, see section 4.3. Dose adjustments for sildenafil may be required when co-administered with CYP3A4 inducers (see section 4.5).

Special populations

Elderly (≥ 65 years)

Dose adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute walk distance could be less in elderly patients.

Renal impairment

Initial dose adjustments are not required in patients with renal impairment, including severe renal impairment (creatinine clearance < 30 ml/min). A downward dose adjustment to 20 mg twice daily should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.

Hepatic impairment

Initial dose adjustments are not required in patients with hepatic impairment (Child-Pugh class A and B). A downward dose adjustment to 20 mg twice daily should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.

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

Paediatric population (children less than 1 year and neonates)

Outside its authorised indications, sildenafil should not be used in neonates with persistent pulmonary hypertension of the newborn as risks outweigh the benefits (see section 5.1). The safety and efficacy of sildenafil in other conditions in children below 1 year of age has not been established. No data are available.

Discontinuation of treatment

Limited data suggest that the abrupt discontinuation of sildenafil is not associated with rebound worsening of pulmonary arterial hypertension. However to avoid the possible occurrence of sudden clinical deterioration during withdrawal, a gradual dose reduction should be considered. Intensified monitoring is recommended during the discontinuation period.

Method of administration

Sildenafil is for oral use only. Tablets should be taken approximately 6 to 8 hours apart with or without food.

4.3. 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 nitrite) or nitrates in any form due to the hypotensive effects of nitrates (see section 5.1).

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

Combination with the most potent of the CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir) (see section 4.5).

Patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure (see section 4.4).

The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated:

Severe hepatic impairment,

Recent history of stroke or myocardial infarction,

Severe hypotension (blood pressure < 90/50 mmHg) at initiation.

4.4. Special warnings and precautions for use

The efficacy of sildenafil has not been established in patients with severe pulmonary arterial hypertension (functional class IV). If the clinical situation deteriorates, therapies that are recommended at the severe stage of the disease (eg, epoprostenol) should be considered (see section 4.2). The benefit-risk balance of sildenafil has not been established in patients assessed to be at WHO functional class I pulmonary arterial hypertension.

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

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

Retinitis pigmentosa

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

Vasodilatory action

When prescribing sildenafil, physicians should carefully consider whether patients with certain underlying conditions could be adversely affected by sildenafil's mild to moderate vasodilatory effects, for example patients with hypotension, patients with fluid depletion, severe left ventricular outflow obstruction or autonomic dysfunction (see section 4.4).

Cardiovascular risk factors

In post-marketing experience with sildenafil for male erectile dysfunction, serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported in temporal association with the use of sildenafil. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse and a few were reported to occur shortly after the use of sildenafil without sexual activity. It is not possible to determine whether these events are related directly to these factors or to other factors.

Priapism

Sildenafil should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).

Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result (see section 4.8).

Vaso-occlusive crises in patients with sickle cell anaemia

Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell anaemia. In a clinical study events of vaso-occlusive crises requiring hospitalisation were reported more commonly by patients receiving sildenafil than those receiving placebo leading to the premature termination of this study.

Visual events

Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil and other PDE5 inhibitors. Cases of non-arteritic anterior ischaemic optic neuropathy, a rare condition, have been reported spontaneously and in an observational study in connection with the intake of sildenafil and other PDE5 inhibitors (see section 4.8). In the event of any sudden visual defect, the treatment should be stopped immediately and alternative treatment should be considered (see section 4.3).

Alpha-blockers

Caution is advised when sildenafil is administered to patients taking an alpha-blocker as the co-administration may lead to symptomatic hypotension in susceptible individuals (see section 4.5). In order to minimise the potential for developing postural hypotension, patients should be haemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Physicians should advise patients what to do in the event of postural hypotensive symptoms.

Bleeding disorders

Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside in vitro. There is no safety information on the administration of sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore sildenafil should be administered to these patients only after careful benefit-risk assessment.

Vitamin K antagonists

In pulmonary arterial hypertension patients, there may be a potential for increased risk of bleeding when sildenafil is initiated in patients already using a Vitamin K antagonist, particularly in patients with pulmonary arterial hypertension secondary to connective tissue disease.

Veno-occlusive disease

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

Excipient intolerance

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

This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially 'sodium-free'.

Use of sildenafil with bosentan

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

Concomitant use with other PDE5 inhibitors

The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor products, including Viagra, has not been studied in PAH patients and such concomitant use is not recommended (see section 4.5).

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on sildenafil

In vitro studies

Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. For dose recommendations, see sections 4.2 and 4.3.

In vivo studies

Co-administration of oral sildenafil and intravenous epoprostenol has been 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 PDE5 inhibitors has not been studied in pulmonary arterial hypertension patients (see section 4.4).

Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the only factors with a statistically significant impact on sildenafil pharmacokinetics in patients with pulmonary arterial hypertension. The exposure to sildenafil in patients on CYP3A4 substrates and CYP3A4 substrates plus beta-blockers was 43 % and 66 % higher, respectively, compared to patients not receiving these classes of medicines. Sildenafil exposure was 5-fold higher at a dose of 80 mg three times a day compared to the exposure at a dose of 20 mg three times a day. This concentration range covers the increase in sildenafil exposure observed in specifically designed drug interaction studies with CYP3A4 inhibitors (except with the most potent of the CYP3A4 inhibitors eg, ketoconazole, itraconazole, ritonavir).

CYP3A4 inducers seemed to have a substantial impact on the pharmacokinetics of sildenafil in pulmonary arterial hypertension patients, which was confirmed in the in-vivo interaction study with CYP3A4 inducer bosentan.

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

Efficacy of sildenafil should be closely monitored in patients using concomitant potent CYP3A4 inducers, such as carbamazepine, phenytoin, phenobarbital, St John's wort and rifampicine.

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

Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg three times a day) with sildenafil (100 mg single dose) resulted in a 140 % increase in sildenafil Cmax and a 210 % increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. For dose recommendations, see section 4.2.

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

The most potent of the CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have effects similar to ritonavir (see section 4.3). CYP3A4 inhibitors like clarithromycin, telithromycin and nefazodone are expected to have an effect in between that of ritonavir and CYP3A4 inhibitors like saquinavir or erythromycin, a seven-fold increase in exposure is assumed. Therefore dose adjustments are recommended when using CYP3A4 inhibitors (see section 4.2).

The population pharmacokinetic analysis in pulmonary arterial hypertension patients suggested that co-administration of beta-blockers in combination with CYP3A4 substrates might result in an additional increase in sildenafil exposure compared with administration of CYP3A4 substrates alone.

Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest increases in plasma levels of sildenafil. No dose adjustment is required but the concomitant use of sildenafil and grapefruit juice is not recommended.

Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of sildenafil.

Co-administration of oral contraceptives (ethinyloestradiol 30 µg and levonorgestrel 150 µg) did not affect the pharmacokinetics of sildenafil.

Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has the potential to have serious interaction with sildenafil (see section 4.3).

Effects of sildenafil on other medicinal products

In vitro studies

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

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

In vivo studies

No significant interactions were shown 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 (AUC increased 11 %), suggesting that sildenafil does not have a 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 acetyl salicylic acid (150 mg).

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

In a study of healthy volunteers sildenafil at steady state (80 mg three times a day) resulted in a 50 % increase in bosentan AUC (125 mg twice daily). A population pharmacokinetic analysis of data from a study of adult PAH patients on background bosentan therapy (62.5 mg - 125 mg twice a day) indicated an increase (20% (95% CI: 9.8 - 30.8)) of bosentan AUC with co-administration of steady-state sildenafil (20 mg three times a day) of a smaller magnitude than seen in healthy volunteers when co-administered with 80 mg sildenafil three times a day (see sections 4.4 and 5.1).

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

In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, and mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively were observed. When sildenafil and doxazosin were administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in susceptible individuals (see section 4.4).

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

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

Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable 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 had no clinically significant impact on the plasma levels of oral contraceptives (ethinyloestradiol 30 µg and levonorgestrel 150 µg).

Addition of a single dose of sildenafil to sacubitril/valsartan at steady state in patients with hypertension was associated with a significantly greater blood pressure reduction compared to administration of sacubitril/valsartan alone. Therefore, caution should be exercised when sildenafil is initiated in patients treated with sacubitril/valsartan.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential and contraception in males and females

Due to lack of data on effects of sildenafil in pregnant women, sildenafil is not recommended for women of childbearing potential unless also using appropriate contraceptive measures.

Pregnancy

There are no data from the use of sildenafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy and embryonal/foetal development. Studies in animals have shown toxicity with respect to postnatal development (see section 5.3).

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

Breast-feeding

There are no adequate and well controlled studies in lactating women. Data from one lactating woman indicate that sildenafil and its active metabolite N-desmethylsildenafil are excreted into breast milk at very low levels. No clinical data are available regarding adverse events in breast-fed infants, but amounts ingested would not be expected to cause any adverse effects. Prescribers should carefully assess the mother's clinical need for sildenafil and any potential adverse effects on the breast-fed child.

Fertility

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

4.7. Effects on ability to drive and use machines

Sildenafil has moderate influence on the ability to drive and use machines.

As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be aware of how they might be affected by sildenafil, before driving or using machines.

4.8. Undesirable effects

Summary of the safety profile

In the pivotal placebo-controlled study of sildenafil in pulmonary arterial hypertension, a total of 207 patients were randomized to and treated with 20 mg, 40 mg, or 80 mg TID doses of sildenafil and 70 patients were randomized to placebo. The duration of treatment was 12 weeks. The overall frequency of discontinuation in sildenafil treated patients at doses of 20 mg, 40 mg and 80 mg TID 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 entered a long-term extension study. Doses up to 80 mg three times a day (4 times the recommended dose of 20 mg three times a day) were administered and after 3 years 87 % of 183 patients on study treatment were receiving sildenafil 80 mg TID.

In a placebo-controlled study of sildenafil as an adjunct to intravenous epoprostenol in pulmonary arterial hypertension, a total of 134 patients were treated with sildenafil (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day, as tolerated) and epoprostenol, and 131 patients were treated with placebo and epoprostenol. The duration of treatment was 16 weeks. The overall frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events was 5.2 % compared to 10.7 % in the placebo/epoprostenol treated patients. Newly reported adverse reactions, which occurred more frequently in the sildenafil/ epoprostenol group, were ocular hyperaemia, vision blurred, nasal congestion, night sweats, back pain and dry mouth. The known adverse reactions headache, flushing, pain in extremity and oedema were noted in a higher frequency in sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients. Of the subjects who completed the initial study, 242 entered a long-term extension study. Doses up to 80 mg TID were administered and after 3 years 68 % of 133 patients on study treatment were receiving sildenafil 80 mg TID.

In the twoplacebo-controlled studies adverse events were generally mild to moderate in severity. The most commonly reported adverse reactions that occurred (greater or equal to 10 %) on sildenafil compared to placebo were headache, flushing, dyspepsia, diarrhoea and pain in extremity.

In a study to assess the effects of different dose levels of sildenafil the safety data for sildenafil 20 mg TID (recommended dose) and for sildenafil 80 mg TID (4 times the recommended dose), were consistent with the established safety profile of sildenafil in previous adult PAH studies.

Tabulated list of adverse reactions

Adverse reactions which occurred in > 1 % of sildenafil-treated patients and were more frequent (> 1 % difference) on sildenafil in the pivotal study or in the sildenafil combined data set of both the placebo-controlled studies in pulmonary arterial hypertension, at doses of 20, 40 or 80 mg TID are listed in the table below by class and frequency grouping (very common (≥ 1/10), common (≥1/100 to < 1/10), uncommon (≥ 1/1000 to ≤ 1/100) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Reports from post-marketing experience are included in italics.

Table 1: Adverse reactions from sildenafil placebo-controlled studies in PAH and post-marketing experience in adults

MedDRA system organ class (V.14.0)

Adverse reaction

Infections and infestations

Common

cellulitis, influenza, bronchitis, sinusitis, rhinitis, gastroenteritis

Blood and lymphatic system disorders

Common

anaemia

Metabolism and nutrition disorders

Common

fluid retention

Psychiatric disorders

Common

insomnia, anxiety

Nervous system disorders

Very common

headache

Common

migraine, tremor, paraesthesia, burning sensation, hypoaesthesia

Eye disorders

Common

retinal haemorrhage, visual impairment, vision blurred, photophobia, chromatopsia, cyanopsia, eye irritation, ocular hyperaemia

Uncommon

visual acuity reduced, diplopia, abnormal sensation in eye

Not known

Non-arteritic anterior ischaemic optic neuropathy (NAION)*, Retinal vascular occlusion*, Visual field defect*

Ear and labyrinth disorders

Common

vertigo

Not known

sudden hearing loss

Vascular disorders

Very common

flushing

Not Known

hypotension

Respiratory, thoracic and mediastinal disorders

Common

epistaxis, cough, nasal congestion

Gastrointestinal disorders

Very common

diarrhoea, dyspepsia

Common

gastritis, gastrooesophageal 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 extremity

Common

myalgia, back pain

Renal and urinary disorders

Uncommon

haematuria

Reproductive system and breast disorders

Uncommon

penile haemorrhage, haematospermia, gynaecomastia

Not known

priapism, erection increased

General disorders and administration site conditions

Common

pyrexia

*These adverse events/reactions have been reported in patients taking sildenafil for the treatment of male erectile dysfunction (MED).

Paediatric population

In the placebo-controlled study of sildenafil in patients 1 to 17 years of age with pulmonary arterial hypertension, a total of 174 patients were treated three times a day with either low (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 dose (20 mg in patients ≥ 8-20 kg; 40 mg in patients ≥ 20-45 kg; 80 mg in patients > 45 kg) regimens of sildenafil and 60 were treated with placebo.

The adverse reactions profile seen in this paediatric study was generally consistent with that in adults (see table above). The most common adverse reactions that occurred (with a frequency ≥ 1 %) in sildenafil patients (combined doses) and with a frequency > 1 % over placebo patients were pyrexia, upper respiratory tract infection (each 11.5%), vomiting (10.9%), erection increased (including spontaneous penile erections in male subjects) (9.0%), nausea, bronchitis (each 4.6%), pharyngitis (4.0%), rhinorrhoea (3.4%), and pneumonia, rhinitis (each 2.9%).

Of the 234 paediatric subjects treated in the short-term, placebo-controlled study, 220 subjects entered the long-term extension study. Subjects on active sildenafil therapy continued on the same treatment regimen, while those in the placebo group in the short-term study were randomly reassigned to sildenafil treatment.

The most common adverse reactions reported across the duration of the short-term and long-term studies were generally similar to those observed in the short-term study. Adverse reactions reported in >10% of 229 subjects treated with sildenafil (combined dose group, including 9 patients that did not continue into the long-term study) were upper respiratory infection (31%), headache (26%), vomiting (22%), bronchitis (20%), pharyngitis (18%), pyrexia (17%), diarrhoea (15%), and influenza, epistaxis (12% each). Most of these adverse reactions were considered mild to moderate in severity.

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

The following serious adverse events were considered to be treatment related, enterocolitis, convulsion, hypersensitivity, stridor, hypoxia, neurosensory deafness and ventricular arrhythmia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In single dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased. At single doses of 200 mg the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, and altered vision) was increased.

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