Ambrisentan

Name: Ambrisentan

Ambrisentan Interactions

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Tell your doctor about all your current medicines and any you start or stop using, especially:

  • cyclosporine.

This list is not complete. Other drugs may interact with ambrisentan, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Ambrisentan Brand Names

Ambrisentan may be found in some form under the following brand names:

  • Letairis

Ambrisentan FDA Warning

WARNING: CONTRAINDICATED IN PREGNANCY

Do not administer this medication to a pregnant woman because it may cause fetal harm. Ambrisentan is very likely to produce serious birth defects if used by pregnant women, as this effect has been seen consistently when it is administered to animals.

Pregnancy must therefore be excluded before the initiation of treatment with ambrisentan and prevented during treatment and for one month after stopping treatment by the use of two acceptable methods of contraception unless the patient has had a tubal sterilization or chooses to use a Copper T 380A IUD or LNg 20 IUS, in which case no additional contraception is needed. Obtain monthly pregnancy tests.

Because of the risk of birth defects, ambrisentan is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). As a component of the program, prescribers, patients, and pharmacies must enroll in the program.

Interactions for Ambrisentan

Metabolized by UGT enzymes 1A9S, 2B7S, and 1A3S and by CYP3A4 and CYP2C19 isoenzymes in vitro.1 3 14 32

Appears to be a substrate of P-glycoprotein and organic anion transport protein (OATP).1 3

Does not inhibit P-glycoprotein.1 3

Does not inhibit or induce CYP enzymes at clinically relevant concentrations.1 31

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP2C19: Pharmacokinetic interaction possible but not likely to be clinically important.1 3

Inhibitors or inducers of CYP3A4: Pharmacokinetic interaction possible but clinically important interaction demonstrated to date only with cyclosporine (a CYP3A4 inhibitor).1 34

Drugs Affecting the Organic Anion Transport Protein (OATP)

Potential pharmacokinetic interaction with drugs that inhibit OATP.1 34

Drugs Affecting the P-glycoprotein Transport System

Pharmacokinetic interactions possible with inhibitors or inducers of P-glycoprotein.1 34 36

Drugs Affecting Uridine Diphosphate Glucuronosyltransferase Enzymes

Pharmacokinetic interactions possible with drugs that induce UGT but not likely to be clinically important.1

Specific Drugs

Drug

Interaction

Comments

Cyclosporine

Increased AUC and peak plasma ambrisentan concentrations by 2- and 1.5-fold, respectively; no change in cyclosporine exposure1 34

Limit ambrisentan dosage to 5 mg once daily1 34

No adjustment of cyclosporine dosage required1

Digoxin

Modest increase in digoxin exposure1 35

Not considered clinically important; no dosage adjustments necessary1 35

Hormonal contraceptives

Ethinyl estradiol/norethindrone: No clinically important change in systemic exposure to oral contraceptive1 37

No dosage adjustments necessary1

Ketoconazole

Modest increase in ambrisentan exposure and half-life1 32

Not considered clinically important; no dosage adjustments necessary1 32

Mycophenolate mofetil

Pharmacokinetics of either drug not altered1

No dosage adjustments necessary1

Omeprazole

Peak plasma concentrations and systemic exposure of ambrisentan not substantially altered1

No dosage adjustments necessary1

PDE type 5 inhibitors (sildenafil, tadalafil)

Clinically important pharmacokinetic interaction not observed1 24 31 33

No dosage adjustments necessary1 24 31 33

Rifampin

Increased ambrisentan exposure by twofold, but effect was transient and not considered clinically important1 36

No dosage adjustments necessary1 36

Ritonavir

Peak plasma concentrations and systemic exposure of ambrisentan not altered1

No dosage adjustments necessary1

Tacrolimus

Peak plasma concentrations and systemic exposure of ambrisentan not altered1

No dosage adjustments necessary1

Warfarin

Clinically important interaction not observed1 2 4 9 14 24 30

No dosage adjustments necessary1 24 30

Proper Use of ambrisentan

Take ambrisentan exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Also, do not stop taking ambrisentan without checking with your doctor first.

It is very important that you understand the rules of the Letairis® REMS program. Read the patient Medication Guide. Ask your doctor or pharmacist if you have any questions. You might be asked to sign a form to show that you understand the information.

Swallow the tablet whole. Do not crush, break, or chew it. You may take ambrisentan with or without food.

Dosing

The dose of ambrisentan will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of ambrisentan. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage form (tablets):
    • For pulmonary arterial hypertension:
      • Adults—At first, 5 milligrams (mg) once a day. Your doctor may increase your dose to 10 mg once a day, if needed.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of ambrisentan, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

What do I need to tell my doctor BEFORE I take Ambrisentan?

  • If you have an allergy to ambrisentan or any other part of ambrisentan.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have idiopathic pulmonary fibrosis (IPF).
  • If you have liver disease.
  • If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take ambrisentan with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

How do I store and/or throw out Ambrisentan?

  • Store in the original container at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.

Pronunciation

(am bri SEN tan)

Pharmacology

Blocks endothelin receptor subtypes ETA and ETB on vascular endothelium and smooth muscle. Stimulation of ETA receptors, located primarily in pulmonary vascular smooth muscle cells is associated with vasoconstriction and cellular proliferation. Stimulation of ETB receptors, located in both pulmonary vascular endothelial cells and smooth muscle cells is associated with vasodilation, antiproliferative effects, and endothelin clearance. Although ambrisentan blocks both ETA and ETB receptors, the affinity is greater for the ETA receptor (>4,000-fold higher affinity).

Metabolism

Hepatic via CYP3A4, CYP2C19, and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S; in vitro studies also suggest it is a substrate of organic anion transporting polypeptides (OATP) 1B1 and 1B3 and P-glycoprotein (P-gp)

Excretion

Primarily nonrenal

Time to Peak

~2 hours

Half-Life Elimination

~9 hours

Protein Binding

99%

Dosing Hepatic Impairment

Preexisting impairment:

US labeling:

Mild impairment: There are no dosage adjustments provided in the manufacturer’s labeling; exposure may be increased.

Moderate or severe impairment: Use not recommended.

Canadian labeling:

Mild or moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and monitor closely.

Severe impairment: Use is contraindicated.

ALT or AST >3 times ULN at baseline: Use is contraindicated.

Impairment developing during therapy:

US labeling:

ALT or AST >5 times ULN: Discontinue therapy.

ALT or AST increased with signs/symptoms of hepatic injury or with bilirubin >2 times ULN: Discontinue therapy.

Canadian labeling:

ALT or AST >3 times ULN: Discontinue therapy.

ALT or AST increased with signs/symptoms of hepatic injury or with bilirubin >2 times ULN: Discontinue therapy.

May consider reinitiation after ALT or AST levels normalize and if there are no signs/symptoms of hepatic injury or jaundice.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Store in original packaging.

Pregnancy Risk Factor X Pregnancy Considerations

[US Boxed Warning]: May cause birth defects; use in pregnancy is contraindicated. Exclude pregnancy prior to initiation of therapy and obtain pregnancy tests monthly during treatment and for 1 month after therapy is complete. Reliable contraception must be used during therapy and for 1 month after stopping treatment. Based on animal studies, ambrisentan is likely to produce major birth defects if used by pregnant women. Two reliable methods of contraception (eg, hormone method with a barrier method or 2 barrier methods) must be used throughout treatment and for 1 month after stopping treatment. Patients who have undergone a tubal ligation or the insertion of a contraceptive implant or intrauterine device (Copper T 380A or LNg 20) do not require additional contraceptive measures. A missed menses or suspected pregnancy should be reported to a healthcare provider and prompt immediate pregnancy testing. Sperm counts may be reduced in men during treatment (as observed with bosentan). Women with pulmonary arterial hypertension are encouraged to avoid pregnancy (McLaughlin 2009; Taichman 2014).

Patient Handout

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Liver Dose Adjustments

-Mild impairment: Dose adjustment may be required; however, no specific guidelines have been suggested. Caution is recommended.
-Moderate or severe impairment: Use not recommended.

If hepatic impairment develops after starting on the drug, the cause should be fully investigated and the drug should be discontinued if:
-ALT or AST elevations are greater than 5 times the upper limit of normal (ULN)
-ALT or AST elevations are accompanied by bilirubin elevations of greater than 2 times the ULN
-ALT or AST elevations are accompanied by signs or symptoms of liver dysfunction and other causes have been excluded

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for AMBRISENTAN. It includes medication guide, elements to assure safe use, and implementation system. For additional information: http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNING:
Embryo-Fetal Toxicity:
-Do not administer to pregnant females because it may cause fetal harm.
-Drug is very likely to produce serious birth defects as this effect has been consistently seen in animal studies.
Recommendations:
-Exclude pregnancy before treatment initiation.
-Acceptable methods of contraception should be used during treatment and for 1 month following discontinuation of treatment.
-A negative pregnancy test must be obtained prior to each prescription and 1 month following discontinuation of treatment.
-Because of the risk of embryo-fetal toxicity, females can only receive drug through a restricted program called the Letairis REMS program.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

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