LETAIRIS

Endothelin Receptor Antagonists for PAH

NOTE: Due to the risk of birth defects, all prescribers, patients, and pharmacies must enroll in a risk evaluation and mitigation strategy (REMS) program.
Hazardous Drugs Classification
NIOSH 2016 List: Group 3
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.

Administer with or without food. Do not split, crush, or chew the tablets.

angioedema / Rapid / Incidence not known
teratogenesis / Delayed / Incidence not known

peripheral edema / Delayed / 17.0-38.0
anemia / Delayed / 7.0-7.0
fluid retention / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
testicular atrophy / Delayed / Incidence not known
hypotension / Rapid / Incidence not known

headache / Early / 34.0-34.0
nasal congestion / Early / 6.0-16.0
cough / Delayed / 13.0-13.0
flushing / Rapid / 4.0-4.0
sinusitis / Delayed / 3.0-3.0
dyspepsia / Early / 3.0-3.0
rash / Early / Incidence not known
malaise / Early / Incidence not known
vomiting / Early / Incidence not known
fever / Early / Incidence not known
nausea / Early / Incidence not known
fatigue / Early / Incidence not known
anorexia / Delayed / Incidence not known
oligospermia / Delayed / Incidence not known
asthenia / Delayed / Incidence not known
dizziness / Early / Incidence not known

Ambrisentan is contraindicated during pregnancy. Data on ambrisentan use during pregnancy is limited; however, it may cause fetal harm if administered to a pregnant woman. When administered to animals, ambrisentan caused teratogenic effects including abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. To prevent ambrisentan exposure during pregnancy, a REMS program has been developed. This program requires prescribers, pharmacists, and patients to comply with certain conditions before prescribing, dispensing, or receiving ambrisentan. If pregnancy does occur during treatment, the prescriber and patient should discuss the potential hazard to a fetus and desirability of continuing the pregnancy. Prescribers should report all cases of pregnancy to the FDA MedWatch program at 800-FDA-1088 and the REMS program.[33320]

Discuss the reproductive risk of ambrisentan and contraception requirements, including the need for pregnancy testing before and during therapy with the female patient of childbearing potential. For females of childbearing potential, exclude pregnancy prior to initiation of therapy. Follow-up pregnancy tests should occur monthly and for 1 month after stopping treatment. Advise female patients of childbearing potential to contact their physician immediately if they become pregnant or suspect they may be pregnant. If a pregnancy test is positive, counsel the patient on the potential risk to the fetus and discuss options. To prevent pregnancy, females of reproductive potential must use acceptable contraception methods during treatment and for 1 month after discontinuation of ambrisentan therapy. The patient may choose a single highly effective contraceptive form, including an intrauterine device (IUD), contraceptive implant, or tubal sterilization, or a combination of a hormonal contraceptive with a barrier method or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Counsel patients on pregnancy planning and prevention, including emergency contraception. Ambrisentan carries a potential for infertility in males; decreased sperm counts have been observed in male patients receiving endothelin receptor antagonists. Preclinical data also suggest that ambrisentan, like other endothelin receptor antagonists, may have an adverse effect on spermatogenesis.

LETAIRIS

Rx

Oral, selective endothelin-A receptor antagonist
Used for pulmonary arterial hypertension (PAH)
Prescribers, pharmacies, and female patients must enroll in the Ambrisentan REMS program due to the potential for fetal harm

5 mg PO once daily for 4 weeks, with or without tadalafil, then increase dose to 10 mg PO once daily as needed and tolerated.

5 to 10 mg PO once daily.

Ambrisentan is not recommended in patients with moderate or severe hepatic impairment. Information is not available for patients with mild hepatic impairment; however, exposure to ambrisentan may be increased in these patients. Discontinue ambrisentan if aminotransferase elevations are greater than 5 times ULN or if elevations are accompanied by bilirubin greater than 2 times ULN or by signs or symptoms of liver dysfunction and other causes are excluded.

CrCl 20 mL/min or greater: No dosage adjustment necessary.
CrCl less than 20 mL/min: Pharmacokinetic studies have not been conducted; data on dosage adjustment are not available.

Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Acetaminophen; Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Acetaminophen; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Alfuzosin: (Moderate) The manufacturer warns that the combination of alfuzosin with antihypertensives, such as ambrisentan, has the potential to cause hypotension in some patients.
Amiloride: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Amphetamine: (Minor) Sympathomimetics such as amphetamine or dextroamphetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy of ambrisentan.
Amphetamine; Dextroamphetamine Salts: (Minor) Sympathomimetics such as amphetamine or dextroamphetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy of ambrisentan.
Amphetamine; Dextroamphetamine: (Minor) Sympathomimetics such as amphetamine or dextroamphetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy of ambrisentan.
Articaine; Epinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Benzphetamine: (Minor) Sympathomimetics such as benzphetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy of ambrisentan.
Brompheniramine; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Brompheniramine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Bupivacaine; Epinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Chlorpheniramine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Codeine; Phenylephrine; Promethazine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
Cyclosporine: (Major) When coadministering ambrisentan with cyclosporine, the ambrisentan dose should not be titrated to the recommended maximum daily dose. Limit the adult dose of ambrisentan to 5 mg once daily when coadministered with cyclosporine. Cyclosporine is a strong inhibitor of P-glycoprotein, OATP, and CYP3A4. In vitro data indicate ambrisentan is a substrate of P-glycoprotein, OATP, and CYP3A4. Cyclosporine twice daily (targeting a trough concentration of 150 - 200 ng/mL) and ambrisentan (5 mg once daily) were coadministered in a 14-day repeated dose study in healthy volunteers. The AUC and Cmax of ambrisentan increased approximately 2-fold and 1.5-fold, respectively.
Dextroamphetamine: (Minor) Sympathomimetics such as amphetamine or dextroamphetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy of ambrisentan.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Diazoxide: (Major) Additive hypotensive effects can occur with the concomitant administration of diazoxide and ambrisentan. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving other antihypertensive agents.
Diethylpropion: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Diphenhydramine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Dobutamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Dopamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Dutasteride; Tamsulosin: (Minor) Because symptoms of orthostasis (e.g., postural hypotension, dizziness, vertigo) are reported more frequently in tamsulosin-treated vs. placebo patients, there is a potential risk of enhanced hypotensive effects when co-administered with antihypertensive agents.
Ephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Ephedrine; Guaifenesin: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Epinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Eplerenone: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Epoprostenol: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Etomidate: (Minor) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with ambrisentan may increase the risk of developing hypotension.
General anesthetics: (Minor) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with ambrisentan may increase the risk of developing hypotension.
Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Iloprost: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties such as ambrisentan. Careful monitoring of blood pressure is suggested during concurrent therapy.
Isoflurane: (Minor) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with ambrisentan may increase the risk of developing hypotension.
Isoproterenol: (Moderate) Isoproterenol is not a potent vasopressor; however, it does increase cardiac output. The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents.
Ketamine: (Minor) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with ambrisentan may increase the risk of developing hypotension.
Lidocaine; Epinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Lisdexamfetamine: (Minor) Sympathomimetics such as lisdexamfetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy of ambrisentan.
Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Mepivacaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
Methamphetamine: (Minor) Sympathomimetics such as methamphetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with methamphetamine.
Methylphenidate Derivatives: (Moderate) Methylphenidate derivatives can reduce the hypotensive effect of antihypertensive agents. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidates and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate derivatives.
Midodrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Minoxidil: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Monoamine oxidase inhibitors: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties such as ambrisentan. Careful monitoring of blood pressure is suggested during concurrent therapy.
Nitroprusside: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Norepinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by ambrisentan. If these drugs are used together, closely monitor for changes in blood pressure.
Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
Phendimetrazine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Phenelzine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties such as ambrisentan. Careful monitoring of blood pressure is suggested during concurrent therapy.
Phenoxybenzamine: (Moderate) Phenoxybenzamine is an antagonist at alpha-receptors. The hypotensive effects of phenoxybenzamine can be additive with those of other antihypertensive agents.
Phentermine: (Major) Sympathomimetics, such as phentermine, can antagonize the effects of vasodilators such as ambrisentan when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Phentermine; Topiramate: (Major) Sympathomimetics, such as phentermine, can antagonize the effects of vasodilators such as ambrisentan when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Phentolamine: (Moderate) Although the duration of action of phentolamine is short, its onset is very rapid. The hypotensive effects of phentolamine can be additive with that of other antihypertensive agents.
Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Potassium-sparing diuretics: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Prazosin: (Moderate) Prazosin is well-known to produce a 'first-dose' phenomenon. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving other antihypertensive agents. Lower dosages of each agent should be used.
Prilocaine; Epinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Promethazine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Propofol: (Minor) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with ambrisentan may increase the risk of developing hypotension.
Rasagiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
Sevoflurane: (Minor) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with ambrisentan may increase the risk of developing hypotension.
Sildenafil: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents.
Sotalol: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Sparsentan: (Contraindicated) Concomitant use of sparsentan and endothelin receptor antagonists (ERAs) is contraindicated due to the additive risk for serious adverse effects such as hypotension, syncope, hyperkalemia, and renal dysfunction.
Spironolactone: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Tamsulosin: (Minor) Because symptoms of orthostasis (e.g., postural hypotension, dizziness, vertigo) are reported more frequently in tamsulosin-treated vs. placebo patients, there is a potential risk of enhanced hypotensive effects when co-administered with antihypertensive agents.
Tizanidine: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Tranylcypromine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties such as ambrisentan. Careful monitoring of blood pressure is suggested during concurrent therapy.
Triamterene: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.

Ambrisentan/LETAIRIS Oral Tab: 5mg, 10mg

10 mg/day PO.

10 mg/day PO.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Ambrisentan is a selective endothelin-A receptor antagonist. Endothelin-1 (ET-1), a potent autocrine and paracrine peptide produced primarily by vascular endothelial cells, possesses powerful vasoconstrictor and mitogenic properties. Plasma ET-1 concentrations are elevated in patients with pulmonary arterial hypertension (PAH) and correlate with increased mean right atrial pressure and disease severity. Two receptor subtypes, A and B, have been identified to mediate the effects of ET-1 on vascular smooth muscle cells. Stimulation of the endothelin-A receptor results in vasoconstriction and cell proliferation. Stimulation of the endothelin-B receptor produces vasodilation, antiproliferation, and ET-1 clearance. Ambrisentan antagonizes endothelin-A with high affinity and is highly selective for endothelin-A vs. endothelin-B (> 4000-fold). High selectivity for the endothelin-A receptor is believed to offer advantages in blocking the deleterious vasoconstrictive effects of endothelin-A on pulmonary vasculature, while maintaining the vasodilatory and ET-1 clearance functions of endothelin-B in patients with PAH.

Ambrisentan is administered orally. In healthy subjects, pharmacokinetic parameters are dose proportional. Ambrisentan is highly bound to plasma proteins (99%). It is metabolized by CYP3A, CYP2C19, and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. Additionally, in vitro data indicate that it is a substrate of Organic Anion Transport Protein (OATP) and P-glycoprotein (P-gp). Ambrisentan is eliminated primarily by non-renal pathways; however, relative contributions of metabolism and biliary elimination have not been well characterized. The terminal half-life is 15 hours; the effective half-life is 9 hours.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP2C19, UGT 1A9S, UGT 2B7S, UGT 1A3S, OATP, P-gp

After administration, ambrisentan is rapidly absorbed with maximum plasma concentrations occurring within 2 hours in healthy subjects and patients with pulmonary arterial hypertension (PAH). The absolute bioavailability of ambrisentan is not known; food has no effect on bioavailability. The mean clearance of ambrisentan after oral administration is 38 mL/min in healthy subjects and 19 mL/min in patients with PAH.

Ambrisentan is contraindicated during pregnancy. Data on ambrisentan use during pregnancy is limited; however, it may cause fetal harm if administered to a pregnant woman. When administered to animals, ambrisentan caused teratogenic effects including abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. To prevent ambrisentan exposure during pregnancy, a REMS program has been developed. This program requires prescribers, pharmacists, and patients to comply with certain conditions before prescribing, dispensing, or receiving ambrisentan. If pregnancy does occur during treatment, the prescriber and patient should discuss the potential hazard to a fetus and desirability of continuing the pregnancy. Prescribers should report all cases of pregnancy to the FDA MedWatch program at 800-FDA-1088 and the REMS program.[33320]

Discuss the reproductive risk of ambrisentan and contraception requirements, including the need for pregnancy testing before and during therapy with the female patient of childbearing potential. For females of childbearing potential, exclude pregnancy prior to initiation of therapy. Follow-up pregnancy tests should occur monthly and for 1 month after stopping treatment. Advise female patients of childbearing potential to contact their physician immediately if they become pregnant or suspect they may be pregnant. If a pregnancy test is positive, counsel the patient on the potential risk to the fetus and discuss options. To prevent pregnancy, females of reproductive potential must use acceptable contraception methods during treatment and for 1 month after discontinuation of ambrisentan therapy. The patient may choose a single highly effective contraceptive form, including an intrauterine device (IUD), contraceptive implant, or tubal sterilization, or a combination of a hormonal contraceptive with a barrier method or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Counsel patients on pregnancy planning and prevention, including emergency contraception. Ambrisentan carries a potential for infertility in males; decreased sperm counts have been observed in male patients receiving endothelin receptor antagonists. Preclinical data also suggest that ambrisentan, like other endothelin receptor antagonists, may have an adverse effect on spermatogenesis.