Sildenafil Viatris 20 mg FC tablets

Treatment of pulmonary arterial hypertension (PAH). SILDENAFIL VIATRIS has been shown to improve exercise ability and to reduce mean pulmonary arterial pressure.

Posology
Use in adults:
The recommended dose is 20 mg three times a day. Tablets should be taken approximately 6 to 8 hours apart with or without food. Efficacy of SILDENAFIL VIATRIS at a dose of 20 mg three times a day has not been established in a sufficient number of patients beyond 12 weeks of treatment.

Special populations
Use in the elderly: Dosage adjustments are not required in elderly patients.
Use in patients with impaired renal function: Dose adjustments are not required in patients with renal impairment (see section 4.3).
Use in patients with impaired hepatic function: Dose adjustments are not required in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). Patients with severe hepatic impairment (Child-Pugh class C) have not been studied (see section 4.3).
Paediatric population: Safety and effectiveness of SILDENAFIL VIATRIS have not yet been demonstrated in children.
Use in patients using other medicines: Co-administration of erythromycin or saquinavir and more potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) with SILDENAFIL VIATRIS is contraindicated (see sections 4.3 and 4.5). Dose adjustments of SILDENAFIL VIATRIS may be required when co-administered with bosentan or other CYP3A4 inducers (see section 4.5).

Method of administration
SILDENAFIL VIATRIS tablets are for oral use.

• 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 4.4 and 4.5).
• Combination with the most potent of the CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, saquinavir) (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 (Child-Pugh class C).
  • Recent history of stroke or myocardial infarction.
  • Severe hypotension (blood pressure < 90/50 mmHg) at initiation.
  • Severe impairment of renal function (creatinine clearance < 30 mL/min).
• Hypersensitivity to sildenafil or to any of the excipients (see 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 sections 4.4 and 4.5).

There is no controlled clinical data on the safety or efficacy of SILDENAFIL VIATRIS in the following groups; if prescribed, this should be done with caution.

• Patients who have suffered a myocardial infarction, stroke or life-threatening dysrhythmia within the last 6 months (see section 4.3).
• Patients with resting hypertension (BP > 170/110 mmHg).
• Patients with cardiac failure or coronary artery disease causing unstable angina.
• Patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).
• Patients with severe hepatic impairment (see section 4.3).

Vasodilatory action
SILDENAFIL VIATRIS has systemic vasodilatory properties that resulted in mild and transient decreases in supine blood pressure in healthy volunteers. Medical doctors should carefully consider whether their patients with certain underlying conditions could be affected adversely by such vasodilatory effects, for example, patients with a low blood pressure, patients with fluid depletion, severe left ventricular outflow obstruction (e.g. aortic stenosis, hypertrophic obstructive cardiomyopathy) or autonomic dysfunction (see section 4.3).

Cardiovascular risks
In post-marketing experience with sildenafil (the active ingredient of SILDENAFIL VIATRIS) for male erectile dysfunction, serious cardiovascular events, including myocardial infarction, unstable angina pectoris, sudden cardiac death, ventricular dysrhythmia, 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 pre-existing cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after the use of sildenafil and sexual activity. It is not possible to determine whether these events are related directly to these factors or to other factors.

Priapism and anatomical penis deformation
SILDENAFIL VIATRIS should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronieu2019s 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 VIATRIS in post-marketing experience. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. Priapism is a urological emergency. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result (see section 4.8).

Alpha-blockers
Concomitant administration of SILDENAFIL VIATRIS to patients taking alpha-blocker therapy 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 VIATRIS treatment. Medical doctors should advise patients what to do in the event of postural hypotensive symptoms.

Bleeding disorders
SILDENAFIL VIATRIS has no effect on bleeding time, including during co-administration with aspirin. In vitro studies with human platelets indicate that SILDENAFIL VIATRIS potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide donor). There is no safety information on the administration of SILDENAFIL VIATRIS to patients with bleeding disorders or active peptic ulceration. Therefore, SILDENAFIL VIATRIS should be administered with caution to these patients.

Vitamin K antagonists
The incidence of epistaxis was higher in patients with pulmonary arterial hypertension secondary to connective tissue disease (SILDENAFIL VIATRIS 12,9 %, placebo 0 %) than in primary pulmonary hypertension patients (SILDENAFIL VIATRIS 3,0 %, placebo 2,4 %) and was higher in SILDENAFIL VIATRIS-treated patients treated with concomitant oral vitamin K antagonist (8,8 % versus 1,7 % not treated with concomitant Vitamin K antagonist).

Veno-occlusive disease
Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease. Since there are no clinical data on administration of SILDENAFIL VIATRIS to patients with pulmonary veno-occlusive disease, administration of SILDENAFIL VIATRIS to such patients is not recommended.

Ocular risks
There were indications in a large epidemiological study of an increased risk of retinal detachment during regular use of PDE5 inhibitors. Non-arteritic anterior ischaemic optic neuropathy (NAION), a cause of decreased vision or loss of vision, has been reported post-marketing with the use of PDE5 inhibitors, including SILDENAFIL VIATRIS (see section 4.8). Most of these patients had risk factors such as low cup to disc ratio ('crowded disk'), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidaemia and smoking. In the event of any sudden visual defect or if sudden vision loss occurs in one or both eyes, SILDENAFIL VIATRIS should be stopped immediately, and alternative treatment should be considered. It is not possible to determine whether NAION is related directly to the use of PDE5 inhibitors or other factors. Medical doctors should discuss with patients the increased risk of NAION in individuals who have already experienced NAION. The patients should be advised to seek immediate medical attention in case of sudden vision loss.

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

Nitrates
SILDENAFIL VIATRIS increases the anti-hypertensive effect of nitrates (see sections 4.3 and 4.5). Patients who suffer acute cardiovascular events must not be treated with nitrates if they have or may have taken sildenafil (as contained in SILDENAFIL VIATRIS), as severe life-threatening hypotension can occur (see section 4.3).

Interaction with guanylate cyclase stimulators
Like PDE5 inhibitors, guanylate cyclase stimulators (such as riociguat) cause changes in intracellular cGMP. Both PDE5 inhibitors and guanylate cyclase stimulators have a vasodilation effect. If the cGMP level rises when the two mechanisms of action combine, an additive effect on systemic blood pressure can be expected, with an increased risk of symptomatic hypotension (see section 4.5). SILDENAFIL VIATRIS must not be used together with guanylate cyclase stimulators (see section 4.3).

Lactose warning
SILDENAFIL VIATRIS contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take SILDENAFIL VIATRIS.

Use of SILDENAFIL VIATRIS with bosentan
The efficacy of SILDENAFIL VIATRIS in patients already on bosentan therapy has not been conclusively demonstrated (see section 4.5). Concomitant use with other PDE5 inhibitors
The safety and efficacy of SILDENAFIL VIATRIS when co-administered with other PDE5 inhibitors has not been studied in PAH patients and such concomitant use is not recommended (see sections 4.3 and 4.5).

Effects of other medicines 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
The efficacy and safety of sildenafil co-administered with other treatments for pulmonary arterial hypertension (e.g. 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 VIATRIS when co-administered with other PDE5 inhibitors has not been studied in pulmonary arterial hypertension patients (see section 4.3 and 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 medicine interaction studies with CYP3A4 inhibitors (except with the most potent of the CYP3A4 inhibitors e.g. 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 and a 55,4% decrease in sildenafil C max. The combination of both medicines did not lead to clinically significant changes of blood pressure. 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 u2013 125 mg twice a day) indicated a decrease in sildenafil exposure with bosentan co-administration, similar to that observed in healthy volunteers (see section 4.2 and 4.4). Efficacy of SILDENAFIL VIATRIS should be closely monitored in patients using concomitant potent CYP3A4 inducers, such as carbamazepine, phenytoin, phenobarbital, St John's wort and rifampicin. 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 C max 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 VIATRIS 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 C max 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, C max, T max, 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 VIATRIS 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 u03bcg and levonorgestrel 150 u03bcg) 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).

Pregnancy
There are no data from the use of SILDENAFIL VIATRIS in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy and embryonal/foetal development. However, tests on animals have shown toxicity in terms of post-natal development. Due to lack of data, SILDENAFIL VIATRIS should not be used in pregnant women.

Breast-feeding
There are no adequate and well controlled studies in breastfeeding women. Limited data indicates that sildenafil, as contained in SILDENAFIL VIATRIS and its active metabolites pass into breast milk to a minimal extent. SILDENAFIL VIATRIS should not be administered to breastfeeding mothers.

SILDENAFIL VIATRIS 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 VIATRIS, before driving, using machines or performing hazardous tasks.

a. Summary of the safety profile
The most frequently reported adverse reactions that occurred on SILDENAFIL VIATRIS compared to placebo were headache, flushing, dyspepsia, diarrhoea and pain in extremity.

b. Tabulated summary of adverse reactions
MedDRA system organ class
Frequency
Adverse reactions
Infections and infestations
Frequent
Cellulitis, influenza, sinusitis not otherwise specified (NOS).
Blood and lymphatic system disorders
Frequent
Anaemia NOS.
Metabolism and nutrition disorders
Frequent
Fluid retention.
Psychiatric disorders
Frequent
Insomnia, anxiety.
Nervous system disorders
Frequent
Headache, migraine NOS, tremor, paraesthesia, burning sensation NOS, hypoaesthesia.
Eye disorders
Frequent
Reduced visual acuity, retinal haemorrhage, visual disturbance NOS, photophobia, diplopia, chromatopsia, cyanopsia, abnormal sensation in eye, eye irritation, blurred vision.
Not known
Visual field defects, non-arteritic anterior ischaemic optic neuropathy (NAION), a cause of decreased vision or loss of vision (see section 4.4), retinal vessel occlusion.
Ear and labyrinth disorders
Frequent
Vertigo.
Not known
Unilateral or bilateral loss of hearing (sensorinearal deafness) with or without associated vestibular symptoms (tinnitus and/or dizziness).
Vascular disorders
Frequent
Flushing.
Not known
Hypotension, various haemorrhages (eye, cerebral, pulmonary haemorrhage).
Respiratory, thoracic and mediastinal disorders
Frequent
Bronchitis NOS, epistaxis, rhinitis NOS, cough, swelling of the nasal mucosa.
Gastrointestinal disorders
Frequent
Diarrhoea, dyspepsia, gastritis NOS, gastroenteritis NOS, gastroesophageal reflux disease, haemorrhoids, abdominal distension, dry mouth.
Skin and subcutaneous tissue disorders
Frequent
Alopecia, erythema.
Not known
Rash.
Musculoskeletal and connective tissue disorders
Frequent
Pain in extremity, back pain, myalgia.
Reproductive system and breast disorders
Frequent
Gynaecomastia.
Not known
Prolonged erection, priapism.
General disorders and administration site conditions
Frequent
Pyrexia, night sweats.
Investigations
Frequent
Weight increase.

Signs and symptoms
u2022 In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8).
u2022 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.
u2022 At single doses of 200 mg the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, and altered vision) was increased.

Treatment
u2022 In cases of overdose, standard supportive and symptomatic 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.