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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

OPSUMIT® (macitentan)

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OPSUMIT - Drug-Drug and Pharmacokinetic Interaction Studies

Last Updated: 08/16/2024

SUMMARY

Strong cytochrome P450 3A4 (CYP3A4) inducers (eg, rifampin) reduce exposure to macitentan: avoid co-administration with OPSUMIT.¹
Strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir) increase exposure to macitentan: avoid co-administration with OPSUMIT.²
Caution should be exercised when OPSUMIT is administered concomitantly with moderate dual inhibitors of CYP3A4 and CYP2C9 (eg, fluconazole, amiodarone).³
Caution should also be exercised when OPSUMIT is administered concomitantly with both a moderate CYP3A4 inhibitor (eg, ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and a moderate CYP2C9 inhibitor (eg, miconazole, piperine).³

BACKGROUND

Drug-Drug Interactions and Pharmacokinetics (PK)/Pharmacodynamics (PD)

Macitentan has four primary metabolic pathways. Oxidative depropylation of the sulfamide yields a pharmacologically active metabolite. This reaction catalyzed by cytochrome P450 (CYP) 3A4 with minor contributions of CYP2C8, CYP2C9 and CYP2C19.⁴ Macitentan is not a substrate of P-glycoprotein. Hepatic uptake is mostly driven by passive diffusion and is not dependent on organic anion transporting polypeptide transport.²

Macitentan and its active metabolites are not associated with clinically relevant inhibitory or inducing effects on cytochrome P450 enzymes.⁵ Clinical interaction studies performed in healthy adults indicated no effect of macitentan on drugs metabolized by CYP2C9 (R-warfarin⁶) or CYP3A4 (S-warfarin,⁶ sildenafil,⁷ hormonal contraceptive⁸).

CLINICAL DATA

Phase 1 Studies

Please refer to table: Phase 1 Macitentan Studies Related to Drug-drug Interactions, PK/PD, and Special Populations.

Phase 1 Macitentan Studies Related to Drug-drug Interactions, PK/PD, and Special Populations¹^,²^,⁶^-¹⁶

Study ID	Objectives	Key Results
Bruderer et al and Sidharta et al¹^,¹⁰ Sidharta et al¹¹	Safety, tolerability, PK and PD	Macitentan: t½ ≈ 16 hours¹ Active metabolite (ACT-373898): t½ ≈ 16 hours¹ Active metabolite (ACT-132577): t_½ = 65.6 hours⁹ t_½ ≈ 48 hours¹¹
Bruderer et al⁹	Food interactions	Can be administered irrespective of food intake
Sidharta et al⁶	DDI: warfarin	No clinically relevant interactions
Sidharta et al⁷	DDI: sildenafil	No clinically relevant interactions
Atsmon et al²	DDI: ketoconazole	Approximately doubled macitentan 10 mg exposure
Bruderer et al¹²	Gender and race	No clinically relevant effects
Sidharta et al¹³	Tolerability and safety in hepatic impairment	No clinically significant increase in exposure
Bruderer et al¹	DDI: rifampin	Significantly reduced macitentan exposure
Bruderer et al¹	DDI: cyclosporine	No clinically relevant interactions
Lindegger et al¹⁴	QTc interval	Does not prolong the QT/QTc interval
Hurst et al⁸	DDI: OCs	No effect on the PK of OCs
Huppertz et al¹⁵	DDI: rivaroxaban	No effect on the pharmacokinetics of rivaroxaban
Huppertz et al¹⁵	DDI: St. John’s Wort	Macitentan 10 mg: Exposure reduced to about one half Active metabolite: Exposure unchanged
Csonka et al¹⁶	DDI: rosuvastatin	No effect on the PK of rosuvastatin 10 mg
	DDI: riociguat	No effect on the PK of riociguat 1 mg
		Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan 10 mg and its active metabolite
Abbreviations: DDI, drug-drug interaction; OC, oral contraceptive; PD, pharmacodynamics; PK, pharmacokinetics; t_½, half-life.

In Vivo Studies

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 physiologically based PK modeling. However, there was no clinically relevant change in exposure to the active metabolite of macitentan. Caution should be exercised when OPSUMIT is administered concomitantly with moderate dual inhibitors of CYP3A4 and CYP2C9 (eg, fluconazole and amiodarone).³

Caution should also be exercised when OPSUMIT is administered concomitantly with both a moderate CYP3A4 inhibitor (eg, ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and a moderate CYP2C9 inhibitor (eg, miconazole, piperine).³

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 02 August 2024.

References

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1	Bruderer S, Aanismaa P, Homery MC, et al. Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J. 2012;14(1):68-78.
2	Atsmon J, Dingemanse J, Shaikevich D, et al. Investigation of the effects of ketoconazole on the pharmacokinetics of macitentan, a novel dual endothelin receptor antagonist, in healthy subjects. Clin Pharmacokinet. 2013;52(8):685-692.
3	Data on File. Macitentan. CCDS. Janssen Research & Development, LLC. EDMS-ERI-205905239.; 2020.
4	Sidharta PN, Treiber A, Dingemanse J. Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan. Clin Pharmacokinet. 2015;54(5):457-471.
5	Correale M, Ferraretti A, Monaco I, et al. Endothelin-receptor antagonists in the management of pulmonary arterial hypertension: where do we stand? Vasc Heal Risk Manag. 2018;14:253-264.
6	Sidharta PN, Dietrich H, Dingemanse J. Investigation of the effect of macitentan on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. Clin Drug Invest. 2014;34(8):545-552.
7	Sidharta P, Giersbergen P van, Wolzt M, et al. Investigation of mutual pharmacokinetic interactions between macitentan, a novel endothelin receptor antagonist, and sildenafil in healthy subjects. Br J Clin Pharmacol. 2014;78(5):1035-1042.
8	Hurst N, Pellek M, Dingemanse J, et al. Lack of pharmacokinetic interactions between macitentan and a combined oral contraceptive in healthy female subjects. J Clin Pharmacol. 2016;56(6):669-674.
9	Bruderer S, Hopfgartner G, Seiberling M, et al. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica. 2012;42(9):901-910.
10	Sidharta PN, Giersbergen PL van, Halabi A, et al. Macitentan: entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol. 2011;67(10):977-984.
11	Sidharta PN, Giersbergen PL van, Dingemanse J. Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects. J Clin Pharmacol. 2013;53(11):1131-1138.
12	Bruderer S, Marjason J, Sidharta P, et al. Pharmacokinetics of macitentan in caucasian and Japanese subjects: the influence of ethnicity and sex. Pharmacology. 2013;91(5-6):331-338.
13	Sidharta P, Lindegger N, Ulc I, et al. Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment. J Clin Pharmacol. 2014;54(3):291-300.
14	Lindegger N, Sidharta PN, Reseski K, et al. Macitentan, a dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension, does not affect cardiac repolarization in healthy subjects. Pulm Pharmacol Ther. 2014;29(1):41-48.
15	Huppertz A, Werntz L, Meid AD, et al. Rivaroxaban and macitentan can be co-administered without dose adjustment but the combination of rivaroxaban and St. John’s Wort should be avoided. British journal of clinical pharmacology. 2018;84(12):2903-2913.
16	Csonka D, Bruderer S, Schultz A, et al. Effect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects. Clin Drug Invest. 2019;39(12):1223-1232.