Macitentan
FDA Drug Information • Also known as: Opsumit
- Brand Names
- Opsumit
- Drug Class
- Endothelin Receptor Antagonist [EPC]
- Route
- ORAL
- Dosage Form
- TABLET, FILM COATED
- Product Type
- HUMAN PRESCRIPTION DRUG
⚠ Boxed Warning (Black Box)
WARNING: EMBRYO-FETAL TOXICITY OPSUMIT is contraindicated for use during pregnancy because it may cause fetal harm based on animal data [see Contraindications (4.1) , Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ]. Therefore, for females of reproductive potential, exclude pregnancy before the start of treatment with OPSUMIT. Advise use of effective contraception before the initiation of treatment, during treatment, and for one month after stopping treatment with OPSUMIT [see Dosage and Administration (2.2) , Use in Specific Populations (8.3) ]. When pregnancy is detected, discontinue OPSUMIT as soon as possible [see Warnings and Precautions (5.1) ]. WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Based on animal data, OPSUMIT may cause fetal harm if used during pregnancy ( 4.1 , 5.1 , 8.1 ). Females of reproductive potential: exclude pregnancy before start of treatment. Prevent pregnancy prior to initiation of treatment, during treatment and for one month after treatment by using effective methods of contraception ( 2.2 , 8.3 ). When pregnancy is detected, discontinue OPSUMIT as soon as possible ( 5.1 ).
Description
11 DESCRIPTION OPSUMIT ® (macitentan) is an endothelin receptor antagonist. The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide. It has a molecular formula of C 19 H 20 Br 2 N 6 O 4 S and a molecular weight of 588.27. Macitentan is achiral and has the following structural formula: Macitentan is a crystalline powder that is insoluble in water. In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive. OPSUMIT is available as a 10 mg film-coated tablet for once daily oral administration. The tablets include the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A. The tablets are film-coated with a coating material containing polyvinyl alcohol, soya lecithin, talc, titanium dioxide, and xanthan gum. Chemical Structure
What Is Macitentan Used For?
1 INDICATIONS AND USAGE OPSUMIT is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adults to reduce the risks of disease progression and hospitalization for PAH ( 1.1 ). 1.1 Pulmonary Arterial Hypertension OPSUMIT is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adults to reduce the risks of disease progression and hospitalization for PAH. Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II–III symptoms treated for an average of 2 years. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%) [see Clinical Studies (14.1) ] .
Dosage and Administration
2 DOSAGE AND ADMINISTRATION 10 mg once daily . Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended ( 2.1 ). 2.1 Recommended Dosage The recommended dosage of OPSUMIT is 10 mg once daily for oral administration. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended. 2.2 Pregnancy Testing in Females of Reproductive Potential Exclude pregnancy before initiating treatment with OPSUMIT in females of reproductive potential [see Boxed Warning , Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.3) ] .
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: Embryo-fetal Toxicity [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Fluid Retention [see Warnings and Precautions (5.3) ] Decrease in Hemoglobin [see Warnings and Precautions (5.4) ] Most common adverse reactions (more frequent than placebo by ≥3%) are anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, and urinary tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Actelion at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Safety data for OPSUMIT were obtained primarily from one placebo-controlled clinical study in 742 patients with PAH (SERAPHIN study) [see Clinical Studies (14.1) ]. The exposure to OPSUMIT in this trial was up to 3.6 years with a median exposure of about 2 years (N=542 for 1 year; N=429 for 2 years; and N=98 for more than 3 years). The overall incidence of treatment discontinuations because of adverse events was similar across OPSUMIT 10 mg and placebo treatment groups (approximately 11%). Table 2 presents adverse reactions more frequent on OPSUMIT than on placebo by ≥3%. Table 2: Adverse Reactions Adverse Reaction OPSUMIT 10 mg (N=242) (%) Placebo (N=249) (%) Anemia 13 3 Nasopharyngitis/pharyngitis 20 13 Bronchitis 12 6 Headache 14 9 Influenza 6 2 Urinary tract infection 9 6 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of OPSUMIT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: hypersensitivity reactions (angioedema, pruritus and rash) Vascular disorders : flushing Respiratory, thoracic and mediastinal disorders: nasal congestion Gastrointestinal disorders: Elevations of liver aminotransferases (ALT, AST) and liver injury have been reported with OPSUMIT use; in most cases alternative causes could be identified (heart failure, hepatic congestion, autoimmune hepatitis). Endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure [see Warnings and Precautions (5.2) ] . General disorders and administration site conditions: edema/fluid retention. Cases of edema and fluid retention occurred within weeks of starting OPSUMIT, some requiring intervention with a diuretic, fluid management or hospitalization for decompensated heart failure [see Warnings and Precautions (5.3) ]. Cardiac disorders: symptomatic hypotension
Drug Interactions
7 DRUG INTERACTIONS Strong CYP3A4 inducers (rifampin) reduce exposure to macitentan: avoid co-administration with OPSUMIT ( 7.1 , 12.3 ). Strong CYP3A4 inhibitors (ketoconazole, ritonavir) increase exposure to macitentan: avoid co-administration with OPSUMIT ( 7.2 , 12.3 ) . Moderate dual CYP3A4 and CYP2C9 inhibitors (fluconazole, amiodarone) or use of combined CYP3A4 and CYP2C9 inhibitors may increase exposure to macitentan: avoid co-administration with OPSUMIT ( 7.3 , 12.3 ). 7.1 Strong CYP3A4 Inducers Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure. Concomitant use of OPSUMIT with strong CYP3A4 inducers should be avoided [see Clinical Pharmacology (12.3) ] . 7.2 Strong CYP3A4 Inhibitors Concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of OPSUMIT with strong CYP3A4 inhibitors [see Clinical Pharmacology (12.3) ] . Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment [see Clinical Pharmacology (12.3) ] . 7.3 Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors Concomitant use of moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole is predicted to increase macitentan exposure approximately 4-fold based on physiologically based pharmacokinetic (PBPK) modeling. Avoid concomitant use of OPSUMIT with moderate dual inhibitors of CYP3A4 and CYP2C9 (such as fluconazole and amiodarone) [see Clinical Pharmacology (12.3) ] . Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with OPSUMIT should also be avoided [see Clinical Pharmacology (12.3) ].
Contraindications
4 CONTRAINDICATIONS Pregnancy ( 4.1 ) Hypersensitivity ( 4.2 ) 4.1 Pregnancy OPSUMIT may cause fetal harm when administered to a pregnant woman. OPSUMIT is contraindicated in females who are pregnant. OPSUMIT was consistently shown to have teratogenic effects when administered to animals. If OPSUMIT is used during pregnancy, advise the patient of the potential risk to a fetus [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . 4.2 Hypersensitivity OPSUMIT is contraindicated in patients with a history of a hypersensitivity reaction to macitentan or any component of the product [see Adverse Reactions (6.2) ] .
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, OPSUMIT may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy. There are risks to the mother and the fetus associated with pulmonary arterial hypertension in pregnancy [see Clinical Considerations ] . Available data from postmarketing reports and published literature over decades of use with ERAs in the same class as OPSUMIT have not identified an increased risk of major birth defects; however, these data are limited. Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal ERA use. Macitentan was teratogenic in rabbits and rats at all doses tested. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the risk to a fetus [see Contraindications (4.1) ] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk In patients with pulmonary arterial hypertension, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction and premature labor. Data Animal Data In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities. Administration of macitentan to...
Overdosage
10 OVERDOSAGE OPSUMIT has been administered as a single dose of up to and including 600 mg to healthy subjects (60 times the approved dosage). Adverse reactions of headache, nausea and vomiting were observed. In the event of an overdose, standard supportive measures should be taken, as required. Dialysis is unlikely to be effective because macitentan is highly protein-bound.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING OPSUMIT ® (macitentan) tablets are 10 mg white, film-coated, bi-convex debossed with "10" on both sides and supplied as follows: 15 count /PVC/ PE/PVDC aluminum foil blisters in carton (NDC 66215-501-15) 30 count white high-density polyethylene bottle in carton (NDC 66215-501-30) Store at 20 ºC to 25 ºC (68 ºF to 77 ºF). Excursions are permitted between 15 °C and 30 °C (59 °F and 86 °F). [See USP Controlled Room Temperature] . Keep out of reach of children.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.