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Ambrisentan

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U.S. BRAND NAMES — Letairis®

PHARMACOLOGIC CATEGORY
Endothelin Antagonist
Vasodilator

DOSING: ADULTS — Pulmonary arterial hypertension: Oral: Initial: 5 mg once daily; if tolerated, may increase to maximum 10 mg once daily

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT — No dosage adjustment is required in mild-to-moderate renal impairment. No data available for use in severe renal impairment.

DOSING: HEPATIC IMPAIRMENT — Avoid use in patients with moderate-to-severe hepatic insufficiency. Dose reductions may be required in patients with mild hepatic insufficiency.

DOSING: ADJUSTMENT FOR TOXICITY — Modifications based on transaminase elevation:

If any elevation, regardless of degree, is accompanied by clinical symptoms of hepatic injury (unusual fatigue, nausea, vomiting, abdominal pain, fever, or jaundice) or a serum bilirubin >2 times ULN, treatment should be stopped and not reintroduced.

AST/ALT >3 but ≤ 5 times ULN: Confirm with additional test; if confirmed, reduce dose or interrupt treatment. Monitor transaminase levels at least every 2 weeks until levels are <3 times ULN. Reinitiate treatment as appropriate with return to pretreatment values and with more frequent checks of transaminase levels. AST/ALT >5 but ≤ 8 times ULN: Confirm with additional test; if confirmed, stop treatment. Monitor transaminase levels until they are <3 times ULN. May reintroduce treatment, as appropriate, at starting dose, following return to pretreatment values. More frequent checks of transaminase levels are required after resuming therapy. AST/ALT >8 times ULN: Stop treatment and do not reintroduce.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet:
Letairis®: 5 mg, 10 mg

DOSAGE FORMS: CONCISE
Tablet:
Letairis®: 5 mg, 10 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Swallow tablet whole. Do not split, crush, or chew tablets. May be administered with or without food.

USE — Treatment of pulmonary artery hypertension (PAH) World Health Organization (WHO) Group I in patients with WHO Class II or III symptoms to improve exercise capacity and decrease the rate of clinical deterioration

ADVERSE REACTIONS SIGNIFICANT
>10%:
Cardiovascular: Peripheral edema (17%)
Central nervous system: Headache (15%)

1% to 10%:
Cardiovascular: Palpitation (5%), flushing (4%)
Gastrointestinal: Constipation (4%), abdominal pain (3%)
Hematologic: Hemoglobin decreased (7% to 10%)
Hepatic: Liver enzymes increased (1% to 3%)
Respiratory: Nasal congestion (6%), dyspnea (4%), nasopharyngitis (3%), sinusitis (3%)

Postmarketing and/or case reports: Fluid retention

CONTRAINDICATIONS — Pregnancy

Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to ambrisentan or any component of the formulation

WARNINGS / PRECAUTIONS
Boxed warnings: Hepatic impairment: See “Disease-related concerns” below Letairis Education and Access Program (LEAP): See “Other Warnings/precautions” below Pregnancy: See “Special populations” below

Concerns related to adverse effects: Fluid retention/peripheral edema: Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur; a higher incidence is seen in elderly patients. There have also been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization). Further evaluation may be necessary to determine cause and appropriate treatment or discontinuation of therapy. Hematologic changes: A reduction in hematocrit/hemoglobin may be observed within the first few weeks of therapy with subsequent stabilization of levels. Hemoglobin reductions >15% have been observed in some patients. Measure hemoglobin prior to initiating therapy, at 1 month, and periodically thereafter. Significant decreases in hemoglobin in the absence of other causes may warrant the discontinuation of therapy. Spermatogenesis: Sperm count may be reduced in men during treatment (as observed with bosentan). No changes in sperm function or hormone levels have been noted. Fertility issues may require discussion with patient.

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Disease-related concerns: Hepatic impairment: [U.S. Boxed Warning]: Avoid use in moderate-to-severe hepatic impairment. Has been associated with significant transaminase (ALT or AST) elevations (>3 times upper limit of normal [ULN]) in up to 3% of treated patients. Transaminase elevations are dose dependent. Avoid use in patients with elevated serum transaminases (>3 times ULN) at baseline. An increase in bilirubin may be observed as well. Monitor hepatic function closely (at least monthly) for the duration of treatment. Reduce dose or interrupt therapy if transaminases >3 times ULN and ≤ 5 times ULN and discontinue therapy with levels >5 times ULN and ≤ 8 times ULN. Treatment should be stopped in patients who develop elevated transaminases >8 times ULN, elevated transaminases accompanied by symptoms of hepatic injury (unusual fatigue, jaundice, nausea, vomiting, abdominal pain, and/or fever) or elevated serum bilirubin >2 times ULN. Safety of reintroduction is unknown. Use caution in mild hepatic impairment. Dose reduction may be necessary. Pulmonary veno-occlusive disease (PVOD): Discontinue in any patient with pulmonary edema suggestive of PVOD.

Concurrent drug therapy issues: High potential for interactions: Use caution in patients taking strong inhibitors or inducers of CYP3A4 or CYP2C19, inhibitors of P-glycoprotein (eg, cyclosporine), or agents which affect glucuronidation metabolism via uridine 5′-diphosphate glucuronosyltransferase (UGT) enzymes.

Special populations: Pregnancy: [U.S. Boxed Warning]: Use in pregnancy is contraindicated; may cause birth defects. Exclude pregnancy prior to initiating therapy and monthly thereafter during therapy. Two reliable methods of contraception must be used during therapy and for one month after stopping treatment except in patients with tubal ligation or an implanted IUD (Copper T 380A or LNg 20). No other contraceptive measures are required for these patients. A missed menses should be reported to healthcare provider and prompt immediate pregnancy testing.

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Other warnings/precautions: Letairis Education and Access Program (LEAP): [U.S. Boxed Warning]: Because of the risks of hepatic impairment and the high likelihood of teratogenic effects, ambrisentan is only available through the LEAP restricted distribution program. Patients, prescribers, and pharmacies must be registered with and meet conditions of LEAP. Call 1-866-664-5327 for more information.

RESTRICTIONS — Ambrisentan (Letairis®) is only available through the limited distribution program (Letairis Education and Access Program [LEAP]). Only prescribers and pharmacies registered with LEAP may prescribe and dispense ambrisentan. Further information may be obtained from the manufacturer, Gilead Sciences, Inc (1-866-664-5327).

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP3A4 (major), 2C19 (major), P-glycoprotein

DRUG INTERACTIONS
CycloSPORINE: May increase the serum concentration of Ambrisentan. Risk C: Monitor therapy

CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy

CYP2C19 Inhibitors (Moderate): May decrease the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy

CYP2C19 Inhibitors (Strong): May decrease the metabolism of CYP2C19 Substrates. Risk D: Consider therapy modification

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of
CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS
Food: Grapefruit/grapefruit juice may increase levels/effects of ambrisentan.

Herb/Nutraceutical: Avoid St John’s wort (concurrent use may decrease levels/effects of ambrisentan).

PREGNANCY RISK FACTOR — X (show table)

PREGNANCY IMPLICATIONS — [U.S. Boxed Warning]: Use in pregnancy is contraindicated. Based on animal studies, ambrisentan is likely to produce major birth defects if used by pregnant women. Pregnancy must be excluded prior to initiation of therapy and follow-up pregnancy tests should be obtained monthly. Two reliable methods of contraception must be used throughout treatment and for one month after stopping treatment unless the patient has undergone a tubal ligation or the insertion of an intrauterine device (Copper T 380A or LNg 20). No other contraceptive measures are required for these patients.

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LACTATION — Excretion in breast milk unknown/not recommended

DIETARY CONSIDERATIONS — May be taken with or without food. Avoid grapefruit and grapefruit juice.

MONITORING PARAMETERS — Serum transaminase (AST and ALT) and bilirubin should be determined prior to the initiation of therapy (baseline) and at monthly intervals thereafter. Monitor for clinical signs and symptoms of liver injury (eg, abdominal pain, fatigue, fever, jaundice, nausea, vomiting). Reduce dose or interrupt therapy if transaminases >3 times ULN and ≤ 5 times ULN and discontinue therapy with levels >5 times ULN and ≤ 8 times ULN. Monitor levels every 2 weeks until they are <3>8 times ULN, elevated transaminases with accompanying symptoms of hepatic injury, or bilirubin >2 times ULN. Monitor for significant peripheral edema and evaluate etiology if it occurs.

A woman of childbearing potential must have a negative pregnancy test prior to the initiation of therapy and monthly thereafter. Hemoglobin and hematocrit should be measured at baseline, at 1 month, and periodically thereafter (generally stabilizes after the first few weeks of treatment).

CANADIAN BRAND NAMES — Volibris®

INTERNATIONAL BRAND NAMES — Volibris (CZ, EE, GB, IE, SE)

MECHANISM OF ACTION — Blocks endothelin receptor subtypes ETA and ETB on vascular endothelium and smooth muscle. Stimulation of these receptors in smooth muscle cells is associated with vasoconstriction. Simulation of ETB receptors in endothelial cells is associated with vasodilation and antiproliferative effects. Although ambrisentan blocks both ETA and ETB receptors, the affinity is greater for the A subtype. Improvement in symptoms of pulmonary artery hypertension and a decrease in the rate of clinical deterioration have been demonstrated in clinical trials.

PHARMACODYNAMICS / KINETICS
Absorption: Rapid

Protein binding: 99%

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 transport protein (OATP) and P-glycoprotein (P-gp)

Half-life elimination: ~9 hours

Time to peak, plasma: ~2 hours

Excretion: Primarily nonrenal

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