Dosing and uses of Opsumit (macitentan)
Adult dosage forms and strengths
tablet
- 10mg
Pulmonary Arterial Hypertension
Indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to delay disease progression
10 mg PO qDay
Dosage modifications
Renal impairment
- Severe (CrCl 15-29 mL/min): No dosage modification needed
- Exposure to macitentan and its active metabolite were increased by 30% and 60% respectively (this increase is not considered clinically relevant)
Hepatic impairment
- Mild, moderate, or severe (Child-Pugh Class A, B, and C): No dosage modification needed
- Exposure to macitentan was decreased by 21%, 34%, and 6% and exposure to the active metabolite was decreased by 20%, 25%, and 25% in subjects with mild, moderate or severe hepatic impairment respectively (this decrease is not considered clinically relevant)
Administration
May take with or without food
Pediatric dosage forms and strengths
Safety and efficacy not established
Opsumit (macitentan) adverse (side) effects
>10%
Nasopharyngitis (20%)
Headache (14%)
Anemia (13%)
Bronchitis (12%)
1-10%
Urinary tract infection (9%)
Influenza (6%)
Postmarketing Reports
Hypersensitivity reactions (angioedema, pruritus and rash)
Nasal congestion
Edema/fluid retention
Symptomatic hypotension
Warnings
Black box warnings
Pregnancy contraindication
- Likely to produce serious birth defects if used by pregnant women; this effect has been seen consistently when administered to animals
- Negative pregnancy test result required before initiating and prevention of pregnancy required monthly during treatment and for 1 month after treatment by the use of at least 2 reliable methods of contraception (unless tubal sterilization or Copper T 380A IUD or LNg 20 IUD inserted, in which case no other contraception required)
- If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method
Restricted distribution program
- Because of risks of birth defects, available only through restricted distribution program called the Opsumit REMS program
- May be dispensed only to patients enrolled in and meet all conditions of the REMS program
Contraindications
Pregnancy
Cautions
Other endothelin receptor antagonists (ERAs) have been associated with elevated liver aminotransferases, hepatotoxicity, and liver failure; obtain liver enzymes tests before initiating and repeat as clinically warranted; discontinue if aminotransferase elevations are accompanied by clinical symptoms of hepatoxicity
ERAs associated with decreased hemoglobin and hematocrit concentrations; initiation not recommended if severe anemia present
If pulmonary edema occurs, consider the possibility of associated pulmonary veno-occlusive disease, and if confirmed, discontinue drug
Avoid coadministration with strong CYP3A4 inhibitors
ERAs associated with adverse effects on spermatogenesis; counsel men about potential effects on fertility
Pregnancy and lactation
Pregnancy category: X; consistently shown to have teratogenic effects when administered to animals
In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities; administration 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
Lactation: Unknown if distributed in human breast milk; due to presence of macitentan and metabolites in milk of lactating rats and potential for serious adverse effects in nursing infants, do not recommend use while nursing
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Opsumit (macitentan)
Mechanism of action
Endothelin receptor antagonist (ET); prevents binding of ET-1 to both ET-A and ET-B receptors with high affinity to ET receptors in pulmonary arterial smooth muscle cells; active metabolite 20% as potent as parent compound
Absorption
Peak plasma time: 8 hr
Absolute bioavailability: Unknown
Distribution
Protein bound: >99%; mainly to albumin and to a lesser extent alpha-1-glycoprotein
Vd: 50 L; 40 L (active metabolite)
Metabolism
Metabolized by liver: Mainly by CYP3A4, minor amount by CYP2C19; primarily metabolized by oxidative depropylation of the sulfamide to active metabolite
Active metabolite: At steady state, systemic exposure of active metabolite is 3-times the exposure of macitentan; active metabolite thought to contribute approximately 40% of total pharmacologic activity
Elimination
Half-life: 16 hr; 48 hr (active metabolite)
Excretion: 50% urine; 24% feces
