Data from FDA - Curated by EPG Health - Last updated 04 September 2018

Indication(s)

1 INDICATIONS AND USAGE OPSUMIT is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). OPSUMIT also reduced 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) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). OPSUMIT also reduced 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 were treated with OPSUMIT monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids. 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)].

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Advisory information

contraindications
4 CONTRAINDICATIONS Pregnancy (4.1) 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, apprise the patient of the potential hazard to a fetus [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
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 (5.3)] Fluid Retention [see Warnings and Precautions (5.4)] Decrease in Hemoglobin [see Warnings and Precautions (5.5)] 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 1-866-228-3546 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)]. 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 postapproval 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) 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 (5.3)]. 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 (5.4)]. Cardiac disorders: symptomatic hypotension

Usage information

Dosing 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 Initiate treatment with OPSUMIT in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy test during treatment [see Use in Specific Populations (8.6)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Nursing mothers: discontinue OPSUMIT or breastfeeding (8.3). 8.1 Pregnancy Pregnancy Category X. Risk Summary OPSUMIT may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Macitentan was teratogenic in rabbits and rats at all doses tested. A no-effect dose was not established in either species. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus [see Contraindications (4.1)]. Animal Data In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities. Administration of macitentan to female rats from late pregnancy through lactation caused reduced pup survival and impairment of the male fertility of the offspring at all dose levels tested. 8.3 Nursing Mothers It is not known whether OPSUMIT is present in human milk. Macitentan and its metabolites were present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions from macitentan in nursing infants, nursing mothers should discontinue nursing or discontinue OPSUMIT. 8.4 Pediatric Use The safety and efficacy of OPSUMIT in children have not been established. 8.5 Geriatric Use Of the total number of subjects in the clinical study of OPSUMIT for PAH, 14% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 8.6 Females and Males of Reproductive Potential Females Pregnancy Testing: Female patients of reproductive potential must have a negative pregnancy test prior to starting treatment with OPSUMIT and monthly pregnancy tests during treatment with OPSUMIT. Advise patients to contact their health care provider if they become pregnant or suspect they may be pregnant. Perform a pregnancy test if pregnancy is suspected for any reason. For positive pregnancy tests, counsel patients on the potential risk to the fetus [see Boxed Warning and Dosage and Administration (2.2)]. Contraception: Female patients of reproductive potential must use acceptable methods of contraception during treatment with OPSUMIT and for 1 month after treatment with OPSUMIT. Patients may choose one highly effective form of contraception (intrauterine devices (IUD), contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see Boxed Warning]. Males Testicular effects: Like other endothelin receptor antagonists, OPSUMIT may have an adverse effect on spermatogenesis [see Warnings and Precautions (5.7) and Nonclinical Toxicology (13.1)].
Pregnancy and lactation
8.3 Nursing Mothers It is not known whether OPSUMIT is present in human milk. Macitentan and its metabolites were present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions from macitentan in nursing infants, nursing mothers should discontinue nursing or discontinue OPSUMIT.

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). 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)].

More information

Category Value
Authorisation number NDA204410
Agency product number Z9K9Y9WMVL
Orphan designation No
Product NDC 66215-501
Date Last Revised 21-05-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling Store at 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature].
Marketing authorisation holder Actelion Pharmaceuticals US, Inc.
Warnings WARNING: EMBRYO-FETAL TOXICITY Do not administer OPSUMIT to a pregnant female because it may cause fetal harm [see Contraindications (4.1), Warnings and Precautions (5.1), Use in Specific Populations (8.1)]. Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception [see Use in Specific Populations (8.6)]. For all female patients, OPSUMIT is available only through a restricted program called the OPSUMIT Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions (5.2)]. WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning Do not administer OPSUMIT to a pregnant female because it may cause fetal harm (4.1, 5.1, 8.1). Females of reproductive potential: exclude pregnancy before start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after treatment by using acceptable methods of contraception (2.2, 8.6). For all female patients, OPSUMIT is available only through a restricted program called the OPSUMIT Risk Evaluation and Mitigation Strategy (REMS) (5.2).