metabolism. Minor/Significance Unknown.lasmiditanSerious - Use Alternative (1)lasmiditan increases effects of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.leniolisibSerious - Use Alternative (1)leniolisib will increase the level or effect of ambrisentan by Other (see comment). Avoid or Use Alternate Drug. Leniolisib, an OATP1B1 and OATP1B3 inhibitor, may increase systemic exposure of these substrates letermovirMonitor Closely (1)letermovir increases levels of ambrisentan by Other (see comment). Use Caution/Monitor. Comment: Letermovir, an OATP1B1/3 inhibitor may increase plasma concentrations of coadministered OATP1B1/3 substrates.levoketoconazoleMinor (2)levoketoconazole will increase the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown. levoketoconazole will increase the level or effect of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.lonafarnibSerious - Use Alternative (1)lonafarnib will increase the level or effect of ambrisentan by affecting hepatic enzyme CYP2C19 metabolism. Avoid or Use Alternate Drug. Lonafarnib may increase the AUC and peak concentration of CYP2C19 substrates. If coadministration unavoidable, monitor for adverse reactions and reduce the CYP2C19 substrate dose in accordance with its approved product labeling.lumacaftor/ivacaftorMonitor Closely (1)lumacaftor/ivacaftor, ambrisentan. affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C19 substrates. .mitotaneMonitor Closely (1)mitotane decreases levels of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.modafinilMinor (1)modafinil will increase the level or effect of ambrisentan by affecting hepatic enzyme CYP2C19 metabolism. Minor/Significance Unknown.nefazodoneMinor (1)nefazodone will increase the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.nelfinavirMinor (1)nelfinavir will increase the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.nevirapineMinor (1)nevirapine will decrease the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.nicardipineMinor (1)nicardipine will increase the level or effect of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.omeprazoleMinor (1)omeprazole will increase the level or effect of ambrisentan by affecting hepatic enzyme CYP2C19 metabolism. Minor/Significance Unknown.pentobarbitalMinor (1)pentobarbital will decrease the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.phenobarbitalMinor (1)phenobarbital will decrease the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.phenytoinMinor (1)phenytoin will decrease the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.ponatinibMonitor Closely (1)ponatinib increases levels of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.posaconazoleMinor (1)posaconazole will increase the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.primidoneMinor (1)primidone will decrease the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.quinidineMinor (1)quinidine will increase the level or effect of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.ranolazineMinor (1)ranolazine will increase the level or effect of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.ribociclibMinor (1)ribociclib will increase the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.rifabutinMinor (1)rifabutin will decrease the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.rifampinMonitor Closely (2)rifampin will decrease the level or effect of ambrisentan by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. rifampin will decrease the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration was associated with a transient 2-fold increase in ambrisentan AUC; however, by day 7, rifampin had no clinically important effect on ambrisentan. Use with caution.rifapentineMinor (1)rifapentine will decrease the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.rucaparibMonitor Closely (1)rucaparib will increase the level or effect of ambrisentan by affecting hepatic enzyme CYP2C19 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP2C19 substrates, if clinically indicated.sarecyclineMonitor Closely (1)sarecycline will increase the level or effect of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor for toxicities of P-gp substrates that may require dosage reduction when coadministered with P-gp inhibitors.shepherd's purseMinor (1)shepherd's purse, ambrisentan. Other (see comment). Minor/Significance Unknown. Comment: Theoretically, shepherd's purse may interfere with BP control.simvastatinMinor (1)simvastatin will increase the level or effect of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.sofosbuvir/velpatasvirMonitor Closely (1)sofosbuvir/velpatasvir increases levels of ambrisentan by Other (see comment). Use Caution/Monitor. Comment: Velpatasvir inhibits OATP1B1, OATP1B3, and OATP2B1 transporters. .sotorasibSerious - Use Alternative (1)sotorasib will decrease the level or effect of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If use is unavoidable, refer to the prescribing information of the P-gp substrate for dosage modifications.sparsentanContraindicated (1)sparsentan, ambrisentan. Either increases toxicity of the other by pharmacodynamic synergism. Contraindicated. Coadministration of endothelin antagonists with sparsentan is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (eg, acute renal failure).St John's WortMinor (1)St John's Wort will decrease the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.stiripentolMonitor Closely (2)stiripentol will increase the level or effect of ambrisentan by affecting hepatic enzyme CYP2C19 metabolism. Modify Therapy/Monitor Closely. Consider reducing the dose of CYP2C19 substrates, if adverse reactions are experienced when administered concomitantly with stiripentol. stiripentol will increase the level or effect of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Consider reducing the dose of P-glycoprotein (P-gp) substrates, if adverse reactions are experienced when administered concomitantly with stiripentol.tecovirimatMonitor Closely (1)tecovirimat will increase the level or effect of ambrisentan by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. Tecovirimat is a weak inhibitor of CYP2C8 and CYP2C19. Monitor for adverse effects if coadministered with sensitive substrates of these enzymes.tepotinibSerious - Use Alternative (1)tepotinib will increase the level or effect of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If concomitant use unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.tolvaptanMinor (1)tolvaptan will increase the level or effect of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.triclabendazoleMonitor Closely (1)triclabendazole will increase the level or effect of ambrisentan by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. If plasma concentrations of the CYP2C19 substrates are elevated during triclabendazole, recheck plasma concentration of the CYP2C19 substrates after discontinuation of triclabendazole. trofinetideSerious - Use Alternative (1)trofinetide will increase the level or effect of ambrisentan by Other (see comment). Avoid or Use Alternate Drug. Trofinetide (an OATP131 and OATP13B inhibitor) may increase plasma levels of OATP131 or OATP13B substrates. Avoid coadministration with sensitive substrates.tucatinibMonitor Closely (1)tucatinib will increase the level or effect of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.verapamilMinor (1)verapamil will increase the level or effect of ambrisentan by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.voclosporinMinor (1)voclosporin will increase the level or effect of ambrisentan by Other (see comment). Minor/Significance Unknown. Information suggests voclosporin (an OATP1B1 inhibitor) may increase in the concentration of OATP1B1 substrates is possible. Monitor for adverse reactions of OATP1B1 substrates when coadministered with voclosporin.voriconazoleMinor (1)voriconazole will increase the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown. >10% Peripheral edema (17%) Headache (15%) 1-10% Nasal congestion (6%) Palpitations (5%) Constipation (4%) Dyspnea (4%) Flushing (4%) Abdominal pain (3%) Nasopharyngitis (3%) Sinusitis (3%) Postmarketing Reports Anemia Dizziness Fatigue Fluid retention Heart failure (associated with fluid retention) Nausea Vomiting Increased liver aminotransferases (ALT, AST) Hypersensitivity (eg, angioedema, rash) Symptomatic hypotension Hepatotoxicity Liver failure Black Box Warnings Embryo-fetal toxicity Do not administer ambrisentan to a pregnant female 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 For all female patients, Letairis is available only through a restricted program called the Letairis Risk Evaluation and Mitigation Strategy (REMS) Contraindications Pregnancy Idiopathic pulmonary fibrosis Cautions Fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant (see Pregnancy and Black Box Warnings) Caution with hepatic impairment; may be associated with rare cases of hepatic cirrhosis with prolonged use; not recommended in patients with moderate-to-severe hepatic impairment Discontinue in patients with elevated aminotransferases >5x ULN, or if elevations are accompanied by bilirubin >2X ULN, or signs/symptoms of liver dysfunction Reports of decreased hemoglobin concentrations from baseline that persisted for up to 4 yr of treatment; these decreases were observed within first few weeks of treatment, and stabilized thereafter; the cause of the decrease in hemoglobin is unknown, but it does not appear to result from hemorrhage or hemolysis; measure hemoglobin prior to initiation of therapy, at one month, and periodically thereafter; initiation of therapy is not recommended for patients with clinically significant anemia; if a clinically significant decrease in hemoglobin is observed and other causes have been excluded, consider discontinuing therapy Coadministration with cyclosporine or CYP3A4 or CYP2C19 inhibitors Peripheral edema is known class effect of endothelin receptor antagonists, and also a clinical consequence of pulmonary arterial hypertension (PAH) and worsening PAH; fluid retention in patients with pulmonary hypertension, occurring within weeks of initiating therapy reported; if clinically significant fluid retention develops, with or without associated weight gain, further evaluate to determine cause, such as ambrisentan or underlying heart failure, possible need for specific treatment or discontinuation of therapy Risk of fluid retention and peripheral edema; more common in combination with tadalafil, than with ambrisentan or tadalafil alone Decreased sperm counts observed in human and animal studies with another endothelin receptor antagonist and in animal fertility studies with ambrisentan; therapy may have an adverse effect on spermatogenesis; counsel patients about potential effects on fertility Development of acute pulmonary edema during therapy initiation may occur; if patient develops acute pulmonary edema during initiation of therapy with vasodilating agents such as ambrisentan, the possibility of pulmonary veno-occlusive disease should be considered, and if confirmed therapy should be discontinued. Restricted Distribution Program Because of risk of birth defects, available only through restricted distribution program called the Ambrisentan REMS, by calling 1-888-417-3172; only prescribers and pharmacies certified with Ambrisentan REMS may prescribe and distribute ambrisentan or the brand Letairis Requirements of the REMS program include the following: Prescribers must be certified with the program by enrolling and completing training All females, regardless of reproductive potential, must enroll in the Ambrisentan REMS program prior to initiating treatment Male patients are not enrolled in the REMS Females of reproductive potential must comply with the pregnancy testing and contraception requirements Pharmacies that dispense ambrisentan must be certified with the program and must dispense to female patients who are authorized to receive ambrisentan Pregnancy Based on data from animal reproduction studies, fetal harm may occur when administered to a pregnant woman and is contraindicated during pregnancy There are limited data on use in pregnant women Advise patient of the potential hazard to a fetus Animal data In animal reproduction studies, ambrisentan was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg/day Contraception Female patients of reproductive potential must use acceptable methods of contraception during treatment and for 1 month after stopping treatment Patients should choose one highly effective form of contraception (intrauterine device [IUD], contraceptive implant, or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods) If a partner’s vasectomy is one 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 Infertility Males: Based on findings and preclinical data, endothelin receptor antagonists have an adverse effect on spermatogenesis; counsel patients about the potential effects on fertility Lactation Unknown whether present in human milk Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal conditionPregnancy 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