Ambrisentan Cipla 5mg & 10mg FC Tablets

AMBRISENTAN CIPLA is indicated for the treatment of:

• Pulmonary arterial hypertension (PAH), to improve exercise capacity, decrease the symptoms of PAH, and delay clinical worsening.

Treatment with AMBRISENTAN CIPLA should only be initiated by a medical doctor experienced in the treatment of PAH.

Posology

Recommended adult dosage

AMBRISENTAN CIPLA 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.

Use in combination with ciclosporin A

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

Special populations

Elderly patients

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 patient with renal impairment. There is limited experience with ambrisentan in individuals with severe renal impairment (creatinine clearance <30 mL/min), therapy should be initiated cautiously in this group and particular care taken if the dose is increased to 10 mg.

Hepatic impairment

AMBRISENTAN CIPLA has not been studied in individual with severe hepatic impairment or with clinically significant elevated hepatic transaminases. However hepatic impairment would 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, AMBRISENTAN CIPLA is not recommended in this patient population (see section 4.4 and 5.2).

Paediatric population

There are no data available on the use of AMBRISENTAN CIPLA in patients under 18 years of age and therefore, the use AMBRISENTAN CIPLA in these patients is not recommended.

Method of administration

AMBRISENTAN CIPLA is for oral use and can be administered with or without food.

AMBRISENTAN CIPLA is contraindicated in:

• patients with hypersensitivity to ambrisentan or any other ingredients of AMBRISENTAN CIPLA (section 6.1).
• pregnancy and lactation (see section 4.6)
• women of child-bearing potential who are not using reliable contraception
• patients with severe hepatic impairment (see section 4.4)
• patients with baseline value of hepatic aminotransferases [aspartate aminotransferases (AST) and /or alanine aminotransferases (ALT)] > values more than 3 times the upper limit of normal
• patients with idiopathic pulmonary fibrosis (IPF) with or without pulmonary hypertension.

Hepatic impairment

Hepatic enzyme elevations have been observed with AMBRISENTAN CIPLA. (see section 5.1). Therefore, hepatic function should be evaluated prior to initiation of AMBRISENTAN CIPLA. If aminotransferases (alanine aminotransferase, ALT or aspartate aminotransferase, AST) are greater than 3 times upper limit of normal, Initiation of AMBRISENTAN CIPLA 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), AMBRISENTAN CIPLA therapy should be discontinued. In patients without clinical symptoms of hepatic injury or of jaundice, re-initiation of AMBRISENTAN CIPLA 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 AMBRISENTAN CIPLA therapy. Therefore, patients should be monitored for signs of hepatic injury and caution exercised when AMBRISENTAN CIPLA is used alone or concomitantly with other medicines known to be associated with hepatic injury as the additive effects of AMBRISENTAN CIPLA with these medicines are not known. Management of auto-immune hepatitis in PAH patients should be optimised prior to initiation of AMBRISENTAN CIPLA and during AMBRISENTAN CIPLA therapy. If patients develop signs or symptoms of hepatitis or suffer exacerbation of existing auto-immune hepatitis AMBRISENTAN CIPLA should be discontinued.

Haematological changes

Reductions in haemoglobin concentrations and haematocrit have been observed with AMBRISENTAN CIPLA and there have been cases where this has resulted In anaemia, sometimes requiring transfusion. It is recommended that haemoglobin and/or haematocrit levels are measured prior to initiation of AMBRISENTAN CIPLA again at one month and periodically thereafter. Initiation of AMBRISENTAN CIPLA therapy is not recommended for patients with clinically significant anaemia. If a clinically significant decrease in haemoglobin or haematocrit is observed during therapy and other causes have been excluded, dose reduction or discontinuation of treatment should be considered.

Fluid retention

Peripheral oedema has been observed with AMBRISENTAN CIPLA. Peripheral oedema may also be a clinical consequence of PAH. If clinically significant fluid retention develops during therapy with AMBRISENTAN CIPLA, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as AMBRISENTAN CIPLA or underlying heart failure, and the possible need for specific treatment or discontinuation of AMBRISENTAN CIPLA therapy.

Women of child-bearing age

AMBRISENTAN CIPLA treatment must not be initiated in women of child-bearing age unless the result of a pre-treatment pregnancy test is negative and reliable contraception is practiced. If there is any doubt on what contraceptive advice should be given to the individual patient, consultation with a gynaecologist should be considered. Monthly pregnancy tests during treatment with ambrisentan are recommended (see section 4.3 and 4.6).

Pulmonary veno-occlussive disease

Cases of pulmonary oedema have been reported with vasodilating medicines, when used in patients with pulmonary veno-occlusive disease. If patients develop acute pulmonary oedema during initiation of therapy with vasodilating medicines such as AMBRISENTAN CIPLA, the possibility of pulmonary veno-occluslve disease should be considered.

Lactose intolerance

AMBRISENTAN CIPLA contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

AMBRISENTAN CIPLA is primarily metabolised by glucuronidation and to a lesser extent by oxidative metabolism, principally by CYP3A and CYP2C19. AMBRISENTAN CIPLA does not Inhibit or induce phase I or II drug metabolising enzymes at clinically relevant concentrations in non-clinical studies. A suggesting a low potential for AMBRISENTAN CIPLA to alter the profile of medicines metabolised by these pathways.

Ciclosporin A

Steady-state co-administration of AMBRISENTAN CIPLA and ciclosporin A, increases plasma concentrations of ambrisentan by about 2-fold and more than doubles the AUC; therefore, doses of AMBRISENTAN CIPLA should be limited to 5 mg once daily when co-administered with ciclosporin A (see section 4.2).

Ketoconazole

Steady-state administration of ketoconazole (a strong inhibitor of CYP3A4) did not result in a clinically significant increase in exposure to ambrisentan.

Rifampicin

No dose adjustment of AMBRISENTAN CIPLA is required when co-administered with rifampicin. Patients on AMBRISENTAN CIPLA therapy should be closely monitored when starting treatment with rifampicin.

Other targeted PAH treatments

Co-administration of AMBRISENTAN CIPLA and omeprazole (an Inhibitor of CYP2C19) did not significantly affect the pharmacokinetics of ambrisentan. Therefore, caution is recommended in the case of co-administration with other treatments for PAH (e.g. prostanoids and soluble guanylate cyclase stimulators).

Phosphodiesterase inhibitors

Co-administration of AMBRISENTAN CIPLA with a phosphodiesterase inhibitor, either sildenafil or tadalafil (both substrates of CYP3A4) does not significantly affect the pharmacokinetics of the phosphodiesterase inhibitor or ambrisentan (see section 5.2).

Oral contraceptives

Steady-state dosing with AMBRISENTAN CIPLA 10 mg once daily does not significantly affect the single-dose pharmacokinetics of the ethinyl oestradiol and norethindrone components of a combined oral contraceptive. Based on the pharmacokinetic studies, 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 anticoagulant activity of warfarin in a healthy volunteer study. Warfarin also had no clinically significant effects on the pharmacokinetics of ambrisentan. In addition, in patients, ambrisentan had no overall effect on the weekly warfarin-type anticoagulant dose, prothrombin time (PT) and international normalised ratio (INR).

Digoxin

Steady-state administration of AMBRISENTAN CIPLA in healthy volunteers had no clinically relevant effects on the single-dose pharmacokinetics of digoxin, a substrate for P-gp.

Women of Childbearing Potential

AMBRISENTAN CIPLA treatment must not be initiated in women of child-bearing potential unless the result of a pre-treatment pregnancy test is negative and reliable contraception is practiced. Monthly pregnancy tests during treatment with ambrisentan are recommended.

Pregnancy

AMBRISENTAN CIPLA is contraindicated in pregnancy (see section 4.3). Animal studies have shown that ambrisentan is teratogenic. Women receiving ambrisentan must be advised of the risk of foetal harm and alternative therapy initiated if pregnancy occurs.

Breastfeeding

It is not known whether ambrisentan is excreted in human breast milk. Therefore, breastfeeding is contraindicated in patients taking AMBRISENTAN CIPLA, (see section 4.3).

Fertility

The development of testicular tubular atrophy in male animals has been linked to the chronic administration of AMBRISENTAN CIPLA. The effect on male human fertility is not known, but a deterioration of spermatogenesis cannot be excluded. AMBRISENTAN CIPLA 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 AMBRISENTAN CIPLA and prevented thereafter by reliable methods of contraception. Pregnancy tests during treatment with AMBRISENTAN CIPLA are recommended as clinically indicated. Women of childbearing potential should be advised to contact their doctor immediately if they become pregnant.

AMBRISENTAN CIPLA has minor or moderate influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of ambrisentan (such as hypotension, dizziness, asthenia, fatigue) should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills (see section 4.8). Patients should be aware of how they might be affected by ambrisentan before driving or using machines.

a) Summary of the safety profile

Peripheral oedema, fluid retention and headache (including sinus headache, migraine) were the most common adverse reactions observed with AMBRISENTAN CIPLA. The higher dose of 10 mg was associated with a higher incidence of these adverse reactions, and peripheral oedema tended to be more severe in patients u2265 65 years (see section 4.4).

b) Tabulated summary of adverse reactions

Blood and lymphatic system disorders

Frequent: Anaemia (decreased haemoglobin and/or haematocrit).

Immune system disorders

Less frequent: Hypersensitivity reactions (e.g. angioedema, rash, pruritis).

Nervous system disorders

Frequent: headache (including sinus headache, migraine); dizziness.

Eye disorders

Less frequent: Blurred vision, visual impairment.

Ear and labyrinth disorders

Frequent: Tinnitus

Rare: Sudden hearing loss.

Cardiac disorders

Frequent: Palpitations, heart failure (associated with fluid retention).

Vascular disorders

Less frequent: Hypotension, flushing, syncope.

Respiratory, thoracic, and mediastinal disorders

Frequent: Nasal congestion, sinusitis, nasopharyngitis, rhinitis, upper respiratory congestion, dyspnoea, epistaxis.

Gastrointestinal disorders

Frequent: Abdominal pain, constipation, nausea, vomiting, diarrhoea.

Hepatobiliary disorders

Frequent: Increased hepatic transaminases.

Less Frequent: Hepatic injury, autoimmune hepatitis.

General disorders and administration site conditions

Frequent: Fluid retention, peripheral oedema, chest pain/ discomfort, asthenia, fatigue.

Post-marketing experience

In addition to adverse reactions identified from clinical studies, the following adverse reactions were identified during post-approval use of ambrisentan. 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).

Respiratory, thoracic, and mediastinal disorders: dyspnoea

Cases of worsening dyspnoea of unclear aetiology have been reported shortly after starting ambrisentan therapy.

Gastrointestinal disorders: nausea and vomiting.

Hepatobiliary disorders

Common: hepatic transaminases increased

Unknown: 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 has been reported during ambrisentan therapy.

c) Description of selected adverse reactions

Decreased haemoglobin

In the post-marketing period, cases of anaemia requiring blood cell transfusion have been reported (see section 4.4). The frequency of decreased haemoglobin (anaemia) was higher with 10 mg ambrisentan.

Reporting of suspected adverse reactions

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

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 AMBRISENTAN CIPLA also could potentially result in hypotension, active cardiovascular support may be required. No specific antidote is available.