Ambrisentan

Ambrisentan comes as a tablet to take by mouth. It is usually taken with or without food once a day. Take ambrisentan at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take ambrisentan exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole; do not split, chew, or crush them.

Your doctor may start you on a low dose of ambrisentan and gradually increase your dose.

Ambrisentan controls the symptoms of PAH but does not cure it. Continue to take ambrisentan even if you feel well. Do not stop taking ambrisentan without talking to your doctor. If you suddenly stop taking ambrisentan, your condition may worsen.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

• headache
• flushing
• dizziness
• nausea
• nasal congestion

Do not let anyone else take your medication.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Before taking ambrisentan, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to ambrisentan or to any of its ingredients
• are pregnant, plan to become pregnant, or become pregnant during treatment
• breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Breastfeeding is not recommended while taking ambrisentan. It is not known if ambrisentan can pass through your milk and harm your baby.

If you take too much ambrisentan, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If ambrisentan is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Vasodilator; a propionic-acid,2 3 12 14 17 endothelin-1 (ET-1) type A receptor-selective antagonist.1 2 4 9 12 14

Contraindications

• Pregnancy.1

• Idiopathic pulmonary fibrosis, with or without pulmonary hypertension (WHO group 3).1 (See Pulmonary Fibrosis under Uses.)

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals.1 6 (See Boxed Warning.)

If ambrisentan used during pregnancy or patient becomes pregnant during therapy, apprise of potential fetal hazard.1 (See Advice to Patients.)

Fluid Retention

Peripheral edema reported, usually mild to moderate in severity; occurred with greater frequency and severity in geriatric patients.1 26 Peripheral edema is a known class effect of endothelin-receptor antagonists and also a consequence of PAH.1 26

Fluid retention, sometimes requiring intervention (e.g., diuretics, fluid management, hospitalization), reported.1

If clinically important fluid retention occurs, further evaluate to determine cause; initiate appropriate treatment or discontinue ambrisentan if necessary.1

Fertility in Males

Reduced sperm counts observed in some men with PAH following treatment with another endothelin receptor antagonist (bosentan); possibility of adverse effects on spermatogenesis with ambrisentan cannot be excluded.1

Hematologic Effects

Decreases in hemoglobin and hematocrit reported within first few weeks of treatment, followed by stabilization; hemoglobin decreases do not appear to be related to hemorrhage or hemolysis.1 3 4 9 26

Monitor hemoglobin concentrations prior to initiation, at 1 month, and periodically during therapy.1 3 13

Not recommended in patients with clinically important anemia.1 Consider discontinuance of therapy if clinically important, otherwise unexplained reductions in hemoglobin occur.1 3

Pulmonary Effects

If acute pulmonary edema occurs, consider possibility of pulmonary veno-occlusive disease; if confirmed, discontinue therapy.1

Hepatic Effects

Serious hepatotoxicity (e.g., cirrhosis, liver failure) reported with some endothelin-receptor antagonists (e.g., bosentan, sitaxsentan [not commercially available in the US]).1 20 22 Hepatotoxicity was previously thought to be a class effect of these drugs;3 6 10 11 14 19 20 22 however, further evaluation of data indicate that risk of liver injury with ambrisentan is low.1 19

Monitor AST/ALT concentrations if clinically indicated.1 Discontinue therapy if AST/ALT >5 times ULN or if elevations are accompanied by bilirubin concentrations >2 times ULN or by manifestations of liver impairment and alternative causes have been excluded.1

Specific Populations

Category X.1 (See Fetal/Neonatal Morbidity and Mortality and also Contraindications, under Cautions.)

Not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Safety and efficacy not established in children and adolescents <18 years of age.1 3

Higher incidence of peripheral edema observed in patients ≥65 years of age relative to younger adults.1

Substantially metabolized and eliminated by the liver and biliary system.1 Avoid use in patients with moderate to severe hepatic impairment.1 No information on use in patients with mild hepatic impairment; possible increased systemic exposure.1

Not studied in patients with severe renal impairment or in those undergoing hemodialysis.1

No clinically important effect of mild or moderate renal impairment on ambrisentan disposition.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Peripheral edema,1 23 24 26 nasal congestion,1 23 24 sinusitis,1 24 flushing,1 24 palpitations,1 24 nasopharyngitis,1 24 abdominal pain,1 24 constipation,1 24 dyspnea,1 headache.1 3 23 24 26

Absorption

Bioavailability

Rapidly absorbed following oral administration,1 3 9 31 33 34 with peak plasma concentrations occurring within approximately 2 hours.1 9 12 31 33 34 Absolute bioavailability unknown.1 3 14

Food

Food does not affect absorption.1 3

Distribution

Extent

Detected in liver and plasma 2–4 hours after administration.3 14

Plasma Protein Binding

99%.1

Elimination

Metabolism

Undergoes hepatic metabolism, principally by glucuronidation and to a lesser extent by hydroxylation.1 14 31 32

Elimination Route

Predominantly nonrenal pathways; contributions of metabolism and biliary excretion not well characterized.1 3 34 Most of radiolabeled dose recovered in feces as unchanged drug or glucuronide metabolite.1 12 14 Undergoes enterohepatic recycling.34

Half-life

Terminal half-life 15 hours; effective half-life approximately 9 hours.1 3 9 33

Special Populations

Potential for increased exposure to ambrisentan in patients with hepatic impairment.1 (See Hepatic Effects under Cautions.)

Serum ambrisentan concentrations not affected in patients with mild or moderate renal impairment (based on studies in individuals with Clcr 20–150 mL/minute).1

Storage

Oral

25°C (may be exposed to 15–30°C) in original package.1

• Risk of fetal harm; importance of advising women of childbearing potential to avoid pregnancy and to use acceptable methods of contraception during and for 1 month following discontinuance of therapy.1 Acceptable methods of contraception include one highly effective form of contraception (intrauterine device [IUD], progesterone implant, or tubal sterilization) or a combination of methods (either one hormonal and one barrier method or 2 barrier methods where one form is the male condom).1 16 Acceptable hormonal methods of contraception include estrogen-progestin combination oral contraceptives or transdermal contraceptive systems, vaginal ring, and progesterone injections.16 Acceptable barrier methods include male condoms, diaphragms with spermicide, and cervical caps with spermicide.16 If the partner has had a vasectomy, an additional hormonal or barrier method must be used.1 16

• Importance of advising women to inform their clinician immediately if a menstrual period is missed or pregnancy is suspected; clinicians should perform a pregnancy test if pregnancy is suspected for any reason and provide counseling on the use of emergency contraception in the event of unprotected sexual intercourse or known or suspected contraceptive failure.1 16 Apprise patient of potential risk to fetus if pregnancy occurs.1

• Importance of female patients enrolling in the Letairis REMS program and complying with all contraceptive and pregnancy testing requirements.1 Importance of monitoring reproductive status of prepubertal females and immediately reporting changes (e.g., breast development, pubic hair) to clinician.16

• Importance of patients not taking ambrisentan if they have idiopathic pulmonary fibrosis.1 16

• Potential risk of liver toxicity.1 Importance of patients informing clinicians of any unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching.1

• Importance of periodic monitoring of RBC counts during treatment.1 16

• Importance of taking ambrisentan as prescribed and of not interrupting or discontinuing therapy without consulting a clinician.16

• Importance of not taking a double dose to make up for a missed dose but instead taking the next scheduled dose.16

• Importance of advising patients to swallow tablets whole and not to split, chew, or crush tablets.1 16

• Importance of distributing the FDA-approved medication guide to every patient who receives ambrisentan and reviewing the information with the patient.1 18 (See REMS.) Importance of patients carefully reading medication guide before initiating therapy and each time prescription is refilled.1 16

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 16

• Importance of informing clinicians of existing or contemplated concomitant therapy including prescription (e.g., cyclosporine) and OTC drugs, as well as any concomitant illnesses.1 16

• Importance of informing patients of other important precautionary information.1 16 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of ambrisentan is restricted.1 (See Restricted Distribution Program under Dosage and Administration.)

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Flushing.
• Stuffy nose.
• Cough.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Pulmonary arterial hypertension: Oral: Initial: 5 mg once daily, with or without tadalafil; at 4-week intervals, as tolerated and necessary, may increase either the dose of ambrisentan (maximum dose: 10 mg/day) or tadalafil (if used concomitantly).

Dosage adjustment for concomitant therapy: Coadministration with cyclosporine: Ambrisentan dose should not exceed 5 mg/day

Refer to adult dosing.

CycloSPORINE (Systemic): May increase the serum concentration of Ambrisentan. Management: Limit ambrisentan dose to 5 mg/day and monitor for ambrisentan adverse reactions in patients receiving systemic cyclosporine. Consider therapy modification

(UK) Use is contraindicated. (AU, US) A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Yes Comments: The effects in the nursing infant are unknown.