Chemical formula: C₁₉H₂₀Br₂N₆O₄S Molecular mass: 588.273 g/mol PubChem compound: 16004692
Macitentan interacts in the following cases:
Patients with renal impairment may run a higher risk of experiencing hypotension and anaemia during treatment with macitentan. Therefore, monitoring of blood pressure and haemoglobin should be considered. There is no clinical experience with the use of macitentan in PAH patients with severe renal impairment. Caution is recommended in this population. There is no experience with the use of macitentan in patients undergoing dialysis, therefore macitentan is not recommended in this population.
In the presence of ketoconazole 400 mg once daily, a strong CYP3A4 inhibitor, exposure to macitentan increased approximately 2-fold. The predicted increase was approximately 3-fold in the presence of ketoconazole 200 mg twice daily using physiologically based pharmacokinetic (PBPK) modelling. The uncertainties of such modelling should be considered. Exposure to the active metabolite of macitentan was reduced by 26%. Caution should be exercised when macitentan is administered concomitantly with strong CYP3A4 inhibitors.
Concomitant treatment with rifampicin 600 mg daily, a potent inducer of CYP3A4, reduced the steady-state exposure to macitentan by 79% but did not affect the exposure to the active metabolite. Reduced efficacy of macitentan in the presence of a potent inducer of CYP3A4 such as rifampicin should be considered. The combination of macitentan with strong CYP3A4 inducers should be avoided.
Elevations of liver aminotransferases (AST, ALT) have been associated with PAH and with endothelin receptor antagonists (ERAs). Macitentan is not to be initiated in patients with severe hepatic impairment or elevated aminotransferases (>3 × ULN) and is not recommended in patients with moderate hepatic impairment. Liver enzyme tests should be obtained prior to initiation of macitentan.
Patients should be monitored for signs of hepatic injury and monthly monitoring of ALT and AST is recommended. If sustained, unexplained, clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × ULN, or by clinical symptoms of liver injury (e.g., jaundice), macitentan treatment should be discontinued.
Reinitiation of macitentan may be considered following the return of hepatic enzyme levels to within the normal range in patients who have not experienced clinical symptoms of liver injury. The advice of a hepatologist is recommended.
The development of testicular tubular atrophy in male animals was observed after treatment with macitentan. The relevance of this finding to humans is unknown, but a deterioration of spermatogenesis cannot be excluded.
At steady-state, the exposure to sildenafil 20 mg three times a day was increased by 15% during concomitant administration of macitentan 10 mg once daily. Sildenafil, a CYP3A4 substrate, did not affect the pharmacokinetics of macitentan, while there was a 15% reduction in the exposure to the active metabolite of macitentan. These changes are not considered clinically relevant. In a placebo-controlled trial in patients with PAH, the efficacy and safety of macitentan in combination with sildenafil were demonstrated.
The use of macitentan is not recommended in patients undergoing dialysis.
Decrease in haemoglobin concentrations has been associated with endothelin receptor antagonists (ERAs) including macitentan. In placebo-controlled studies, macitentan-related decreases in haemoglobin concentration were not progressive, stabilised after the first 4–12 weeks of treatment and remained stable during chronic treatment. Cases of anaemia requiring blood cell transfusion have been reported with macitentan and other ERAs. Initiation of macitentan is not recommended in patients with severe anaemia. It is recommended that haemoglobin concentrations be measured prior to initiation of treatment and tests repeated during treatment as clinically indicated.
Cases of pulmonary oedema have been reported with vasodilators (mainly prostacyclins) when used in patients with pulmonary veno-occlusive disease. Consequently, if signs of pulmonary oedema occur when macitentan is administered in patients with PAH, the possibility of pulmonary veno-occlusive disease should be considered.
There are no data from the use of macitentan in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is still unknown. Macitentan is contraindicated during pregnancy and in women of childbearing potential who are not using reliable contraception.
It is unknown whether macitentan is excreted in human milk. In rats, macitentan and its metabolites are excreted into milk during lactation. A risk to the breastfeeding child cannot be excluded. Macitentan is contraindicated during breastfeeding.
Macitentan treatment should only be initiated in women of childbearing potential when the absence of pregnancy has been verified, appropriate advice on contraception provided, and reliable contraception is practised. Women should not become pregnant for 1 month after discontinuation of macitentan. Monthly pregnancy tests during treatment with macitentan are recommended to allow the early detection of pregnancy.
The development of testicular tubular atrophy in male animals was observed after treatment with macitentan. The relevance of this finding to humans is unknown, but a deterioration of spermatogenesis cannot be excluded.
Macitentan has minor influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g., headache, hypotension) that may influence the ability to drive and use machines.
The most commonly reported adverse reactions are nasopharyngitis (14%), headache (13.6%) and anaemia (13.2%). The majority of adverse reactions are mild to moderate in intensity.
The safety of macitentan has been evaluated in a long-term placebo-controlled trial of 742 patients with symptomatic PAH. The mean treatment duration was 103.9 weeks in the macitentan 10 mg group, and 85.3 weeks in the placebo group. Adverse reactions associated with macitentan obtained from this clinical study are given below.
Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Very common: Nasopharyngitis, Bronchitis
Common: Pharyngitis, Influenza, Urinary tract infection
Very common: Anaemia, haemoglobin decrease5
Common: Leukopenia6, Thrombocytopenia7
Common: Aminotransferase elevations4
Uncommon: Hypersensitivity reactions (e.g., angioedema, pruritus, rash)1
Very common: Headache
Common: Hypotension2
Common: Nasal congestion1
Very common: Oedema, fluid retention3
1 Data derived from pooled placebo-controlled studies.
2 Hypotension has been associated with the use of ERAs including macitentan. In a long-term doubleblind study in patients with PAH, hypotension was reported for 7.0% and 4.4% of patients on macitentan 10 mg and placebo, respectively. This corresponded to 3.5 events/100 patient-years on macitentan 10 mg compared to 2.7 events/100 patient-years on placebo.
3 Oedema/fluid retention has been associated with the use of ERAs including macitentan. In a longterm double-blind study in patients with PAH, the incidence of oedema AEs in the macitentan 10 mg and placebo treatment groups was 21.9% and 20.5%, respectively. In a double-blind study in patients with idiopathic pulmonary fibrosis, the incidence of peripheral oedema AEs in the macitentan and placebo treatment groups was 11.8% and 6.8%, respectively. In two double-blind clinical studies in patients with digital ulcers associated with systemic sclerosis, the incidences of peripheral oedema AEs ranged from 13.4% to 16.1% in the macitentan 10 mg groups and from 6.2% to 4.5% in the placebo groups.
The incidence of aminotransferase elevations (ALT/AST) >3 × ULN was 3.4% on macitentan 10 mg and 4.5% on placebo in a double-blind study in patients with PAH. Elevations >5 × ULN occurred in 2.5% of patients on macitentan 10 mg versus 2% of patients on placebo.
In a double-blind study in patients with PAH, macitentan 10 mg was associated with a mean decrease in haemoglobin versus placebo of 1 g/dL. A decrease from baseline in haemoglobin concentration to below 10 g/dL was reported in 8.7% of patients treated with macitentan 10 mg and 3.4% of placebo-treated patients.
In a double-blind study in patients with PAH, macitentan 10 mg was associated with a decrease in mean leucocyte count from baseline of 0.7 × 109/L versus no change in placebo-treated patients.
In a double-blind study in patients with PAH, macitentan 10 mg was associated with a decrease in mean platelet count of 17 × 109/L, versus a mean decrease of 11 × 109/L in placebo-treated patients.
The safety of macitentan in children and adolescents below 18 years has not yet been established.
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