stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.tazemetostatMonitor Closely (1)tazemetostat will decrease the level or effect of macitentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.tecovirimatMonitor Closely (1)tecovirimat will decrease the level or effect of macitentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.tipranavirSerious - Use Alternative (1)tipranavir will increase the level or effect of macitentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministering macitentan with strong CYP3A4 inhibitors tucatinibSerious - Use Alternative (1)tucatinib will increase the level or effect of macitentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.voriconazoleSerious - Use Alternative (1)voriconazole will increase the level or effect of macitentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministering macitentan with strong CYP3A4 inhibitors voxelotorSerious - Use Alternative (1)voxelotor will increase the level or effect of macitentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid. >10% Nasopharyngitis (20%) Headache (14%) Anemia (13%) Bronchitis (12%) 1-10% Urinary tract infection (9%) Hemoglobin <10 g/dL (8.7%) Influenza (6%) Elevated aminotransferases >3 x ULN (3.4%) Elevated aminotransferases >8 x ULN (2.1%) Postmarketing Reports 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; in most cases alternative causes could be identified (heart failure, hepatic congestion, autoimmune hepatitis); ERAs have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure General disorders and administration site conditions: Edema/fluid retention; cases of edema and fluid retention occurred within weeks of starting macitentan, some requiring intervention with a diuretic, fluid management, or hospitalization for decompensated heart failure Cardiac disorders: Symptomatic hypotension Vascular disorders: Flushing Black Box Warnings Pregnancy contraindication Do not administer to pregnant women because it may cause fetal harm Females of reproductive potential: Exclude pregnancy before starting treatment, monthly during treatment, and 1 month after stopping treatment Prevent pregnancy during treatment and for 1 month after stopping treatment by using acceptable methods of contraception (see Pregnancy) 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 All females, regardless of reproductive potential, must enroll in the OPSUMIT REMS Program before initiating; male patients are not enrolled in the REMS Females of reproductive potential must comply with the pregnancy testing and contraception requirements Prescribers must be certified with the program by enrolling and completing training Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive macitentan Contraindications History of hypersensitivity reaction to drug or excipients Pregnancy; consistently shown to have teratogenic effects in animal studies Cautions If pulmonary edema occurs, consider the possibility of associated pulmonary veno-occlusive disease, and if confirmed, discontinue drug Decreases in hemoglobin concentration and hematocrit reported; decreases in hemoglobin seldom require transfusion; initiation of therapy is not recommended in patients with severe anemia; measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated Hepatotoxicity 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 Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching) If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 x ULN, or by clinical symptoms of hepatotoxicity, discontinue therapy Consider re-initiation of therapy when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity Fluid retention Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment Postmarketing cases of edema and fluid retention occurring within weeks of starting therapy, some requiring intervention with a diuretic or hospitalization for decompensated heart failure, reported Monitor for signs of fluid retention after initiating therapy; if clinically significant fluid retention develops, evaluate patient to determine the cause, such as the therapy being administered or underlying heart failure, and the possible need to discontinue therapy Drug interaction overview Macitentan is a CYP3A4 substrate Strong CYP3A4 inducers significantly reduce macitentan systemic exposure; avoid coadministration Avoid coadministration with strong CYP3A4 inhibitors, as macitentan systemic exposure is ~doubled; use other PAH treat option when CYP3A4 inhibitors are needed as part of HIV treatment 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) modelling; avoid concomitant use of drug with moderate dual inhibitors of CYP3A4 and CYP2C9 (such as fluconazole and amiodarone) Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with macitentan should also be avoided Pregnancy Based on data from animal reproduction studies, therapy 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 mother and fetus associated with pulmonary arterial hypertension in pregnancy; there are limited data on use in pregnant women; the drug was teratogenic in rabbits and rats at all doses tested; if drug is used during pregnancy, or if patient becomes pregnant while taking this drug, advise the patient of risk to a fetus In patients with pulmonary arterial hypertension, pregnancy is associated with increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction and premature labor Pregnancy testing Verify pregnancy status of females of reproductive potential prior to initiating therapy, monthly during treatment and one month after stopping treatment; the patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected; if pregnancy test is positive, the physician and patient must discuss risks to her, the pregnancy, and fetus Contraception Female patients of reproductive potential must use acceptable methods of contraception during treatment and for 1 month after stopping Patients may choose 1 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 2 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 Infertility Based on findings in animals, drug may impair fertility in males of reproductive potential; not known whether effects on fertility would be reversible Therapy may have an adverse effect on spermatogenesis; counsel men about potential effects on fertility Lactation There are no data on presence of macitentan in human milk, effects on breastfed infant, or on milk production; because of potential for serious adverse reactions in breastfed infants advise women not to breastfeed during treatmentPregnancy 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. Mechanism of Action Endothelin receptor antagonist (ERA); prevents binding of endothelin (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 form 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 Oral Administration May take with or without food BRAND FORM. UNIT PRICE PILL IMAGE Opsumit oral- 10 mg tabletOpsumit oral- 10 mg tabletCopyright © 2010 First DataBank, Inc.Print Patient Educationmacitentan oral MACITENTAN - ORAL (MA-si-TEN-tan) COMMON BRAND NAME(S): Opsumit WARNING: Macitentan must not be used during pregnancy. It may harm an unborn baby. It is important to prevent pregnancy while taking this medication and for 1 month after treatment. Female patients must use reliable birth control during treatment and for 1 month after the end of treatment. Ask your doctor which forms of birth control to use while taking this medication. Female patients must take a pregnancy test before starting treatment, monthly during treatment, and 1 month after stopping treatment. If you become pregnant or think you may be pregnant, tell your doctor right away.For female patients to receive this medication in the United States, they must understand, agree to, and carefully follow the requirements of the Macitentan REMS Program. If you are a female patient that lives in Canada or any other country, consult your doctor and pharmacist for your country's regulations. USES: Macitentan is used to treat high blood pressure in the lungs (pulmonary arterial hypertension). This condition is thought to be caused by increased levels of a certain natural substance (endothelin-1). This medication blocks the effects of endothelin-1, which helps decrease the blood pressure in the lungs, and reduces the risk of worsening of symptoms and hospital stays due to the disease. HOW TO USE: Read the Medication Guide and, if available, the Patient Information Leaflet provided by your pharmacist before you start taking macitentan and each time you get a refill. If you have any questions, ask your doctor or pharmacist.Take this medication by mouth with or without food as directed by your doctor, usually once daily. Swallow the tablet whole. Do not split, crush, or chew the tablet.Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day.Do not increase your dose or use this drug more often or for longer than prescribed. Your condition will not improve any faster, and your risk of side effects will increase.Since this drug can be absorbed through the skin and lungs and may harm an unborn baby, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from the tablets.Tell your doctor if your condition does not improve or if it worsens. SIDE EFFECTS: Runny nose, sore throat, cough, headache, chills, or body aches may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Tell your doctor right away if you have any serious side effects, including: signs of low red blood cell count (such as unusual tiredness, rapid breathing, pale skin, shortness of breath, fast heartbeat), unusual weight gain, new or worsening swelling of the hands/ankles/feet.Macitentan may rarely cause serious liver disease. Tell your doctor right away if you have any symptoms of liver disease, including: nausea/vomiting that doesn't stop, loss of appetite, dark urine, stomach/abdominal pain, yellowing eyes/skin.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of