Volibris 5mg &10mg Tablets

VOLIBRIS is indicated for the treatment of pulmonary arterial hypertension (PAH):

• to improve exercise capacity, decrease the symptoms of PAH and delay clinical worsening.
• in combination with tadalafil to reduce the risk of clinical failure (a composite of death, PAH hospitalisation, disease progression, and unsatisfactory clinical response), and to increase satisfactory clinical response and exercise ability.

Treatment should only be initiated by a medical practitioner experienced in the treatment of PAH.

Posology

Recommended adult dosage:

VOLIBRIS as a single agent:

VOLIBRIS treatment should be initiated at a dose of 5 mg once daily. Consider increasing the dose to 10 mg once daily if 5 mg is tolerated.

VOLIBRIS used with tadalafil:

When used in combination with tadalafil, the VOLIBRIS dose should be titrated to 10 mg once daily.

Use with ciclosporin A:

When co-administered with ciclosporin A, the dose of VOLIBRIS should be limited to 5 mg once daily (see section 4.5).

Recommended paediatric and adolescent dosage:

Safety and efficacy of VOLIBRIS have not been established in patients under 18 years of age and therefore, the use of VOLIBRIS in these patients is not recommended.

Dosage instructions in special populations:

Elderly: No dose adjustment is required in patients aged 65 years and over (see section 5.2).

Renal impairment: Renal metabolism and excretion of ambrisentan is minimal, so dose adjustment is unlikely to be required in patients with renal impairment.

Hepatic impairment: VOLIBRIS has not been studied in subjects with severe hepatic impairment or with clinically significant elevated hepatic transaminases. However, hepatic impairment might be expected to increase exposure (C max and AUC) to ambrisentan, since its main routes of metabolism are glucuronidation and, to a lesser extent, oxidation, with subsequent elimination in the bile. Therefore, VOLIBRIS is not recommended in this patient population (section 4.4 and 5.2).

Method of administration: VOLIBRIS is for oral use and can be administered with or without food.

VOLIBRIS is contraindicated in:

• patients with hypersensitivity to ambrisentan, or to any other ingredients.
• pregnancy and lactation (see section 4.6).
• severe hepatic impairment (see section 4.4).
• idiopathic pulmonary fibrosis (IPF) with or without pulmonary hypertension.

Hepatic impairment: Hepatic enzyme elevations have been observed with VOLIBRIS (see section 5.2). Therefore, hepatic function should be evaluated prior to initiation of VOLIBRIS. If aminotransferases (alanine aminotransferase, ALT or aspartate aminotransferase, AST) are greater than 3 times upper limit of normal, initiation of VOLIBRIS is not recommended (see section 4.3). In addition, monthly monitoring of aminotransferases is recommended. If patients develop clinically significant aminotransferase elevations or if aminotransferase elevations are accompanied by signs or symptoms of hepatic injury (e.g. jaundice), VOLIBRIS therapy should be discontinued. In patients without clinical symptoms of hepatic injury or of jaundice, re-initiation of VOLIBRIS may be considered following resolution of hepatic enzyme abnormalities. Hepatic injury and auto-immune hepatitis are known to occur in PAH patients and auto-antibodies are frequently found in IPAH. Cases consistent with auto-immune hepatitis, including possible exacerbation of underlying auto-immune hepatitis, and hepatic injury have been reported with VOLIBRIS therapy. Therefore, patients should be monitored for signs of hepatic injury and caution exercised when VOLIBRIS is used alone or concomitantly with other medicinal products known to be associated with hepatic injury as the additive effects of VOLIBRIS with these medicines are not known. Management of auto-immune hepatitis in PAH patients should be optimised prior to initiation of VOLIBRIS and during VOLIBRIS therapy. If patients develop signs or symptoms of hepatitis or suffer exacerbation of existing auto-immune hepatitis VOLIBRIS should be discontinued.

Haematological changes: Reductions in haemoglobin concentrations and haematocrit have been observed with VOLIBRIS and there have been cases where this has resulted in anaemia, sometimes requiring transfusion. In clinical trials, decreases in haemoglobin and haematocrit were observed within the first few weeks of therapy and generally stabilised thereafter. The mean decrease in haemoglobin from baseline to the end of treatment for patients receiving VOLIBRIS in 12-week placebo-controlled studies was 0,8 g/dl. Mean decreases from baseline (ranging from 0,9 to 1,2 g/dl) in haemoglobin concentrations persisted for up to 4 years of treatment with VOLIBRIS in the long-term open-label extension of the pivotal Phase 3 clinical studies. It is recommended that haemoglobin is measured prior to initiation of VOLIBRIS, again at one month and periodically thereafter. Initiation of VOLIBRIS therapy is not recommended for patients with clinically significant anaemia. If a clinically significant decrease in haemoglobin is observed during therapy and other causes have been excluded, discontinuation of VOLIBRIS should be considered.

Fluid retention: Peripheral oedema has been observed with VOLIBRIS. Peripheral oedema may also be a clinical consequence of PAH. Most cases of peripheral oedema in clinical studies with VOLIBRIS were mild to moderate in severity. Post-marketing reports of fluid retention occurring within weeks after starting VOLIBRIS have been received and, in some cases, have required intervention with a diuretic or hospitalisation for fluid management or decompensated heart failure. If patients have pre-existing fluid overload, this should be managed as clinically appropriate prior to starting VOLIBRIS. If clinically significant fluid retention develops during therapy with VOLIBRIS, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as VOLIBRIS or underlying heart failure, and the possible need for specific treatment or discontinuation of VOLIBRIS therapy.

Pulmonary veno-occlusive disease: If patients develop acute pulmonary oedema during initiation of therapy with vasodilating medicines such as VOLIBRIS, the possibility of pulmonary veno-occlusive disease should be considered.

Excipients: VOLIBRIS contains lactose monohydrate. Patients with rare hereditary conditions of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance, should not take VOLIBRIS (see section 2). VOLIBRIS contains the azo colourant Allura red AC Aluminium Lake (E129), which can cause allergic reactions. VOLIBRIS contains lecithin derived from soya. If a patient is hypersensitive to soya, VOLIBRIS must not be used.

Ambrisentan is primarily metabolised by glucuronidation and to a lesser extent by oxidative metabolism, principally by CYP3A and to a lesser extent by CYP2C19. Ambrisentan did not inhibit or induce phase I or II drug metabolising enzymes at clinically relevant concentrations in non-clinical studies, suggesting a low potential for ambrisentan to alter the profile of medicines metabolised by these pathways. The potential for ambrisentan to induce CYP3A4 activity was explored in healthy volunteers, with results suggesting a lack of inductive effect of ambrisentan on the CYP3A4 isoenzyme.

• Ciclosporin: Steady-state co-administration of VOLIBRIS and ciclosporin A (an inhibitor of P-glycoprotein [P-gp] and organic anion transporting polypeptide [OATP]) resulted in a 2-fold increase in ambrisentan exposure in healthy volunteers. Therefore the dose of VOLIBRIS should be limited to 5 mg once daily when co-administered with ciclosporin A (see section 4.2). No clinically relevant effect of ambrisentan on ciclosporin A exposure was observed.
• Ketoconazole: Steady state administration of ketoconazole (a strong inhibitor of CYP3A4) did not result in a clinically significant increase in exposure to VOLIBRIS.
• Rifampicin: Co-administration of rifampin (an inhibitor of OATP, a strong inducer of CYP3A and 2C19, and inducer of P-gp and uridine-diphospho-glucuronosyltransferases [UGTs]) was associated with a transient (approximately 2-fold) increase in ambrisentan exposure following initial doses in healthy volunteers. However, by day 7, steady state administration of rifampin had no clinically relevant effect on ambrisentan exposure. No dose adjustment of VOLIBRIS is required when co-administered with rifampin.
• Omeprazole: In PAH clinical studies, co-administration of VOLIBRIS and omeprazole (an inhibitor of CYP2C19) did not significantly affect the pharmacokinetics of ambrisentan.
• Sildenafil: Co-administration of VOLIBRIS with a phosphodiesterase inhibitor, either sildenafil or tadalafil (both substrates of CYP3A4) in healthy volunteers, did not significantly affect the pharmacokinetics of the phosphodiesterase inhibitor or ambrisentan.
• Oral contraceptives: In a clinical study in healthy subjects, steady state dosing with VOLIBRIS 10 mg did not significantly affect the single-dose pharmacokinetics of the ethinyl estradiol and norethindrone components of a combined oral contraceptive. Based on this pharmacokinetic study, ambrisentan would not be expected to significantly affect exposure to oestrogen- or progestogen-based contraceptives.
• Warfarin: Ambrisentan had no effects on the steady state pharmacokinetics and anti-coagulant activity of warfarin in a healthy volunteer study. Warfarin also had no clinically significant effects on the pharmacokinetics of ambrisentan. In addition, in clinical studies of PAH patients, VOLIBRIS had no overall effect on the weekly warfarin-type anticoagulant dose, prothrombin time (PT) and international normalised ratio (INR).
• Digoxin: Steady-state administration of VOLIBRIS in healthy volunteers had no clinically relevant effects on the single-dose pharmacokinetics of digoxin, a substrate for P-gp.

Pregnancy: VOLIBRIS is contraindicated in pregnancy (see section 4.3). Animal studies in rats and rabbits have shown that ambrisentan is teratogenic, which is a class effect of ERAs (endothelin receptor antagonists).

Lactation: It is not known whether ambrisentan is excreted in human milk. Mothers on VOLIBRIS should not breastfeed their infants (see section 4.3).

Fertility: The development of testicular tubular atrophy in male animals has been linked to the chronic administration of VOLIBRIS. The effect on male human fertility is not known.

There have been no studies to investigate the effect of VOLIBRIS on driving performance or the ability to operate machinery. A detrimental effect on such activities is not anticipated from the known safety profile.

VOLIBRIS is very likely to produce serious birth defects if used by pregnant women, as this effect has been seen consistently when it is administered to animals (see section 4.3). Pregnancy must therefore be excluded before the initiation of treatment with VOLIBRIS and prevented thereafter by reliable methods of contraception. Pregnancy tests during treatment with VOLIBRIS are recommended as clinically indicated. Women of childbearing potential should be advised to contact their physician immediately if they become pregnant or suspect they may be pregnant.

Experience from pivotal clinical studies: The safety of VOLIBRIS was evaluated during clinical trials in more than 480 patients with PAH. Adverse drug reactions (ADRs) from clinical trial data are listed below by system organ class and frequency. Frequencies are placebo corrected and defined as common (u2265 1/100, < 1/10) and uncommon (u2265 1/1 000, < 1/100). Adverse reaction frequency categories assigned based on clinical trial experience may not reflect the frequency of adverse events occurring during normal clinical practice.

Blood and lymphatic system disorders: Common: anaemia (decreases in haemoglobin and/or haematocrit)

Immune system disorders: Uncommon: hypersensitivity (e.g. angioedema, rash)

Nervous system disorders: Common: headache

Cardiac disorders: Common: palpitations

Vascular disorders: Common: flushing

Respiratory, thoracic and mediastinal disorders: Common: nasal congestion (the incidence was dose-related), sinusitis, nasopharyngitis

Gastrointestinal disorders: Common: abdominal pain, constipation

General disorders and administration site disorders: Common: fluid retention, peripheral oedema.

Experience from long-term clinical studies: The long-term safety (>3 months) of VOLIBRIS was evaluated in more than 500 patients with PAH. Adverse reactions from non-placebo controlled clinical trial data are listed below. Frequencies are defined as very common (u22651/10) and common (u22651/100, <1/10).

Blood and lymphatic system disorders: Very common: anaemia (decreases in haemoglobin and/or haematocrit)

Immune system disorders: Common: hypersensitivity (including medicine hypersensitivity)

Nervous system disorders: Very common: dizziness, headache

Cardiac disorders: Very common: palpitations

Vascular disorders: Very common: flushing (including hot flush)

Respiratory, thoracic and mediastinal disorders: Very common: nasal congestion, sinusitis, nasopharyngitis, dyspnoea (including dyspnoea exertional)

Gastrointestinal disorders: Very common: abdominal pain (including upper and lower), nausea

Common: vomiting, constipation

Skin and subcutaneous tissue disorders: Common: rash (rash erythematous, rash generalised, rash macular, rash popular, rash pruritic)

General disorders and administration site conditions: Very common: fatigue, fluid retention (including fluid overload), peripheral oedema

Common: asthenia.

Eye disorders: Common: visual impairment (including vision blurred).

Experience from a clinical study with VOLIBRIS used in combination with tadalafil: The safety of VOLIBRIS used in combination with tadalafil was evaluated in 302 patients with PAH in a double-blind, active-controlled clinical trial (>3 months; median exposure 534 days). The adverse reactions observed were generally consistent with the safety profile of VOLIBRIS used alone. The following adverse reactions were seen more frequently in the combination of VOLIBRIS with tadalafil than with either medicine alone: Gastrointestinal disorders: Very common: vomiting. In addition, the following adverse reaction was observed: Ear and labyrinth disorders: Common: tinnitus.

Post-marketing experience: In addition to adverse reactions identified from clinical studies, the following adverse reactions were identified during post-approval use of VOLIBRIS. Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Blood and lymphatic system disorders: anaemia requiring transfusion

Cardiac disorders: heart failure (associated with fluid retention)

Vascular disorders: hypotension

Hepatobiliary disorders: hepatic transaminases increased, hepatic injury, auto-immune hepatitis (see section 4.4). Cases of auto-immune hepatitis, including cases of exacerbation of auto-immune hepatitis, and hepatic injury of unclear aetiology have been reported during VOLIBRIS therapy.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of VOLIBRIS is important. It allows continued monitoring of the benefit/risk balance of VOLIBRIS. Health care providers are asked to report any suspected adverse reactions to: SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Symptoms and signs: In healthy volunteers, single doses of 50 and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea, and nasal congestion. Due to its mechanism of action, an overdose of VOLIBRIS also could potentially result in hypotension.

Treatment: In the case of pronounced hypotension, active cardiovascular support may be required. No specific antidote is available.