Macitentan

Caution should be exercised when macitentan is administered concomitantly with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir).

In the presence of ketoconazole 400 mg once daily, 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 moderate dual inhibitors of CYP3A4 and CYP2C9 (e.g., fluconazole and amiodarone).

Caution should also be exercised when macitentan is administered concomitantly with both a moderate CYP3A4 inhibitor (e.g., ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitor (e.g., miconazole, piperine).

In the presence of fluconazole 400 mg daily, a moderate dual inhibitor of CYP3A4 and CYP2C9, exposure to macitentan may increase approximately 3.8-fold based on PBPK modelling. However, there was no clinically relevant change in exposure to the active metabolite of macitentan. The uncertainties of such modelling should be considered.

In the presence of strong CYP3A4 inducers reduced efficacy of macitentan could occur. The combination of macitentan with strong CYP3A4 inducers (e.g., rifampicin, St. John’s wort, carbamazepine, and phenytoin) should be avoided.

There is no clinical experience with the use of macitentan in PAH patients with severe renal impairment. The use of macitentan is not recommended in patients undergoing dialysis.

Macitentan is not recommended in patients with moderate hepatic impairment.

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.

n the presence of fluconazole 400 mg daily, a moderate dual inhibitor of CYP3A4 and CYP2C9, exposure to macitentan may increase approximately 3.8-fold based on PBPK modelling. However, there was no clinically relevant change in exposure to the active metabolite of macitentan. The uncertainties of such modelling should be considered.

Caution should be exercised when macitentan is administered concomitantly with moderate dual inhibitors of CYP3A4 and CYP2C9 (e.g., fluconazole and amiodarone).

Caution should also be exercised when macitentan is administered concomitantly with both a moderate CYP3A4 inhibitor (e.g., ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitor (e.g., miconazole, piperine).

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.

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.

Initiation of macitentan is not recommended in patients with severe anaemia.

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.

Use in women of childbearing potential/Contraception in males and females

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.

Male fertility

The development of testicular tubular atrophy in male animals was observed after treatment with macitentan. Decreases in sperm count have been observed in patients taking ERAs. Macitentan, like other ERAs, may have an adverse effect on spermatogenesis in men.

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.

Summary of the safety profile.

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.

Tabulated list of adverse reactions

The safety of macitentan has been evaluated in a long-term placebo-controlled trial of 742 patients with symptomatic PAH (SERAPHIN study). 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 tabulated below. Post-marketing adverse reactions are also included.

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).

¹ Data derived from pooled placebo-controlled studies.

Description of selected adverse reactions

² Hypotension has been associated with the use of ERAs including macitentan. In a long-term double--blind 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.

Laboratory abnormalities

⁴ Liver aminotransferases

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.

⁵ Haemoglobin

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.

⁶ White blood cells

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.

⁷ Platelets

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.

Long-term safety

Of the 742 patients who participated in the pivotal SERAPHIN double-blind study, 550 patients entered a long-term open-label (OL) extension study. (The OL cohort included 182 patients who continued on macitentan 10 mg and 368 patients who received placebo or macitentan 3 mg and crossed over to macitentan 10 mg.)

Long-term follow-up of these 550 patients for a median exposure of 3.3 years and a maximum exposure of 10.9 years showed a safety profile that was consistent as described above during the SERAPHIN double-blind phase.

Paediatric population

The safety of macitentan in children and adolescents below 18 years has not yet been established.