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SUMMARY
- Poor aqueous solubility and chemical instability in liquid state presented barriers to designing an oral solution formulation of macitentan.1
- OPSUMIT is currently available in the United States (US) as a 10 mg film-coated tablet for oral administration.2,3
- The US Food and Drug Administration (FDA) acknowledged that OPSUMIT 10 mg tablets are immediate-release film-coated tablets without any special delivery system that might be jeopardized by splitting, crushing, or chewing.4
CLINICAL DATA
Development of Macitentan Oral Liquid Formulation
The technical feasibility and stability of an oral solution of macitentan had been investigated by Actelion, but low solubility of macitentan in various aqueous media at physiological pH (≤1 mcg/mL) made it challenging to achieve an oral solution.1,5 Macitentan is insoluble in water and aqueous media with pH in the range of 1.2 to 9.6 Macitentan is sensitive to hydrolysis of the sulfamide group, which leads to poor stability in liquid state.5 Photostability testing found degradation of macitentan was observed in solution in all solvents tested.7 None of the systems investigated were found to be suitable for developing a macitentan oral solution due to issues with solubility and/or stability, leading to the conclusion that the development of an oral solution formulation was not feasible due to the physicochemical characteristics of the compound.1 Additional potential solvent systems on a laboratory scale were investigated, but these more complex aqueous formulations were deemed unsatisfactory.5
OPSUMIT Tablet Formulation
OPSUMIT is currently available in the US as a 10 mg film-coated tablet for oral administration.2,3 The tablet coating is an immediate release film (Opadry AMB® Aqueous Moisture Barrier, Colorcon, West Point, US) designed to provide a barrier to moisture.8 This film-coated tablet formulation of macitentan 10 mg was developed for a phase 3 study and subsequently marketed as OPSUMIT in the US.6,9 The FDA acknowledged that OPSUMIT 10 mg tablets are immediate-release film-coated tablets without any special delivery system that might be jeopardized by splitting, crushing, or chewing.4
Literature Search
A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, DERWENT® (and/or other resources, including internal/external databases) was conducted on 17 September 2025.
| 1 | Therapeutic Goods Administration (TGA). Australian Public Assessment Report for macitentan. Australian Government Therapeutic Goods Administration (TGA); 2014. https://www.tga.gov.au/sites/default/files/auspar-macitentan-140428.pdf |
| 2 | OPSUMIT (macitentan) [Prescribing Information]. Titusville, NJ: Actelion Pharmaceuticals US, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/OPSUMIT-pi.pdf |
| 3 | US Food and Drug Administration (FDA). New Drug Application (NDA) Number 204410: OPSUMIT (macitentan). US Food and Drug Administration (FDA); https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=204410 Accessed September 17, 2025. |
| 4 | US Food and Drug Administration. Opsumit (macitentan) NDA 204410. Other Review(s). US Food and Drug Administration; 2013. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000OtherR.pdf Accessed September 17, 2025. |
| 5 | Therapeutic Goods Administration (TGA). Australian Public Assessment Report Attachment 2: Extract from the Clinical Evaluation Report (AusPAR-CER) for macitentan. Australian Government Therapeutic Goods Administration (TGA); 2013. |
| 6 | US Food and Drug Administration (FDA). Opsumit FDA Drug Approval Package - Clinical Pharmacology and Biopharmaceutics Review. US Food and Drug Administration (FDA); 2013. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000ClinPharmR.pdf Accessed September 17, 2025. |
| 7 | European Medicines Agency (EMA). European Public Assessment Report: OPSUMIT. European Medicines Agency (EMA); 2013. Accessed September 17, 2025. |
| 8 | Kummer O, Haschke M, Hammann F, et al. Comparison of the dissolution and pharmacokinetic profiles of two galenical formulations of the endothelin receptor antagonist macitentan. Eur J Pharm Sci. 2009;38(4):384-388. |
| 9 | Sidharta PN, Treiber A, Dingemanse J. Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan. Clin Pharmacokinet. 2015;54(5):457-471. |
