endothelin receptor antagonists
Treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression.
Acts as an endothelin receptor antagonist. Endothelin mediates vasocontriction, fibrosis, proliferation, hypertrophy and inflammation. Antagonizing endothelin effects delays vascular hypertrophy and organ damage.
Delayed sequelae of progression of PAH (death, need for initiation of parenteral prostanoids, increased frequency of hospitalization, diminished exercise tolerance or need for other interventions)
Absorption: Absorption follows oral administration, bioavailability Unknown.
Protein Binding: Macitentan–>99%; active metabolite–>99%
Metabolism and Excretion: Extensively metabolized, primarily by the CYP3A4 enzyme system with conversion to a pharmacologically active metabolite that contributes 40% of activity. 50% excreted in urine as metabolites, 24% in feces.
Half-life: Macitentan–16 hr; active metabolite–48 hr
TIME/ACTION PROFILE (improvement in primary endpoints†)
|PO||within 6 mos||12–18 mos||unknown|
- Strong inhibitors or inducers of the CYP3A4 enzyme system (can significantly alter drug effectiveness/risk of toxicity)
- OB: Causes fetal harm, should not be used during pregnancy
- Lactation: Discontinue drug or breastfeeding
Use Cautiously in:
- Pulmonary veno-occlusive disease (↑ risk of pulmonary edema);
- Rep: Females with childbearing potential (pregnancy must be excluded prior to treatment and for 1 mo following treatment, effective contraception must be utilized);
- Pedi: Safety and effectiveness not established.
Adverse Reactions/Side Effects
Derm: pruritis, rash
Resp: pulmonary edema
GU: ↓ sperm count
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
PO: (Adults)10 mg once daily.
Tablets: 10 mg
- Monitor hemodynamic parameters and exercise tolerance prior to and periodically during therapy.
- Assess for signs and symptoms of pulmonary edema (shortness of breath). If confirmed, discontinue therapy.
- Monitor for signs and symptoms of hypersensitivity reactions (angioedema, pruritus, rash). May need to discontinue macitentan.
Lab Test Considerations: Obtain a negative pregnancy test prior to beginning, monthly during therapy, and 1 mo following treatment.
- Monitor hepatic function periodically during therapy. May cause ↑ AST, ALT, and bilirubin. If clinically relevant ↑ of AST or ALT occur, or if ↑ are accompanied by ↑ bilirubin >2 x upper limit of normal, or by clinical symptoms of hepatotoxicity, discontinue therapy. May re initiate therapy when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.
- Monitor CBC before starting and periodically during therapy. May cause ↓ hemoglobin. Avoid therapy in patients with severe anemia.
- Activity intolerance (Indications)
- Only available through a restricted program, Opsumit Risk Evaluation and Mitigation Strategy (REMS). Prescribers and pharmacies must be enrolled and certified. All female patients must enroll and comply with pregnancy testing and contraception requirements. Male patients do not need to enroll.
- PO: Administer once daily at the same time each day. Swallow tablets whole, do not break, crush, or chew.
- Instruct patient to take macitentan as directed. Take missed doses as soon as remembered unless almost time for next dose; do not double doses.
- Advise patients to notify health care professional if symptoms of hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, itching) occur.
- Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
- Rep: Caution female patients that macitentan may harm fetus. Instruct females to use effective contraception (intrauterine device IUD, contraceptive implants, tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods) during and for at least a mo following discontinuation of therapy. If a partner's vasectomy is method of contraception, a hormone or barrier method must be used along with this method. Counsel patient on emergency contraception. May decrease sperm count in male patients. Advise female patient to notify health care professional immediately if pregnancy is suspected and avoid breastfeeding.
Increased exercise tolerance.
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