bosentan (Rx)

Brand and Other Names:Tracleer
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 62.5 mg
  • 125 mg

tablet, for oral suspension

  • 32 mg
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Pulmonary Arterial Hypertension (PAH)

Indicated to improve exercise ability and decrease worsening of PAH; effectiveness shown in NYHA II-IV, idiopathic or heritable PAH, connective tissue diseases that result in PAH, and PAH associated with congenital heart disease with left-to-right shunts

<40 kg: Maintain dose at 62.5 mg PO q12hr

>40 kg: 62.5 mg PO q12hr for 4 weeks and then increased to maintenance dosage 125 mg PO q12hr

Discontinuation of treatment: Consider a reduction in dosage to 62.5 mg PO q12hr for 3-7 days

See Administration

Dosage Modifications

Elevated ALT/AST levels

  • Discontinue if elevated ALT/AST levels are accompanied with clinical symptoms of hepatotoxicity (eg, nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy, fatigue) or bilirubin ≥2X ULN; reintroduction studies have not been established
  • Confirm test, if confirmed, reduce/hold dose as described below
  • >12 years and >40 kg: Reduce dose to 62.5 mg PO q12hr or interrupt treatment and monitor liver tests at least q2weeks; if levels return to pretreatment values, continue or reintroduce treatment at 62.5mg PO q12hr; reassess levels within 3 days
  • >5 and <8X ULN
    • Interrupt treatment and monitor AST/ALT at least q2weeks
    • >12 years and >40 kg: If levels return to pretreatment values, consider reintroducing dose to 62.5 mg PO q12hr; reassess levels within 3 days
  • >8X ULN
    • Stop treatment; reintroduction should not be considered

Liver impairment

  • Mild: No dose adjustment required
  • Moderate or severe: Avoid use
  • AST/ALT >3X ULN: Avoid use

Coadministration with ritonavir

  • Have been receiving ritonavir for at least 10 days: Initiate bosentan at the recommended starting dose qDay or every other day based on tolerability
  • Have been receiving bosentan: Discontinue bosentan <36 hr prior to initiating ritonavir; resume bosentan at recommended initial dose qDay or every other day after at least 10 days of ritonavir treatment

Idiopathic Pulmonary Fibrosis (Orphan)

Orphan indication sponsor

  • Actelion Pharmaceuticals Ltd; Gewerbestrasse 16, CH-4123; Switzerland

Systemic Sclerosis (Orphan)

Reduction of the number (treatment) of new digital ulcers in patients with systemic sclerosis

Orphan indication sponsor

  • Actelion Pharmaceuticals Ltd; Gewerbestrasse 16, CH-4123; Switzerland

Dosage Strengths & Forms

tablet, film-coated

  • 62.5mg
  • 125 mg

tablet, for oral suspension

  • 32 mg

Pulmonary Arterial Hypertension (PAH)

Indicated in children and adolescents aged ≥3 years with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR)

See Administration

<3 years: Safety and efficacy not established

3 to ≥12 years

  • ≥4-8 kg: Maintain dose at 16 mg PO q12hr
  • >8-16 kg: Maintain dose at 32 mg PO q12hr
  • >16-24 kg: Maintain dose at 48 mg PO q12hr
  • >24-40 kg: Maintain dose at 64 mg PO q12hr

>12 years

  • <40 kg: Maintain dose at 62.5mg PO q12hr
  • >40 kg: 62.5mg PO q12hr initially for 4 weeks, then increase to maintenance dose 125 mg PO q12hr

Dosage Modifications

Discontinue if elevated ALT/AST levels are accompanied with clinical symptoms of hepatotoxicity (eg, nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy, fatigue) or bilirubin ≥2X ULN; reintroduction should not be considered

Elevated ALT/AST levels

  • Confirm test, if confirmed
  • >3 and <5X ULN
    • >12 years and >40 kg: Reduce dose to 62.5 mg PO q12hr or interrupt treatment and monitor liver tests at least q2weeks; if levels return to pretreatment values, continue or reintroduce treatment at 62.5mg PO q12hr; reassess levels within 3 days
    • ≥3-12 years and <40 kg: Interrupt treatment; if levels return to pretreatment values, consider reintroduction of initial dose; reassess levels within 3 days
  • >5 and <8X ULN
    • Interrupt treatment and monitor AST/ALT at least q2weeks
    • >12 years and >40 kg: If levels return to pretreatment values, consider reintroducing dose to 62.5 mg PO q12hr; reassess levels within 3 days
    • ≥3-12 years and <40 kg: If levels return to pretreatment values, consider reintroduction of initial dose; reassess levels within 3 days
  • >8X ULN
    • Stop treatment; reintroduction should not be considered

Coadministration with ritonavir

  • Have been receiving ritonavir for at least 10 days: Initiate bosentan at the recommended starting dose qDay or every other day based on tolerability
  • Have been receiving bosentan: Discontinue bosentan <36hr prior to initiation of ritonavir treatment; resume bosentan at recommended initial dose qDay or every other day after at least 10 days of ritonavir treatment
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Interactions

Interaction Checker

and bosentan

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Hgb decreased; >1 g/dL (57%)

            Respiratory tract infection (22%)

            Headache (16%)

            Edema (11%)

            Nasopharyngitis (11%)

            Flushing (10%)

            Hypotension (10%)

            1-10%

            Chest pain (5%)

            Syncope (5%)

            Hypotension (4%)

            Sinusitis (4%)

            Arthralgia (4%)

            Abnormal AST/ALT (4%)

            Palpitations (4%)

            Anemia (4%)

            Postmarketing Reports

            Unexplained hepatic cirrhosis

            Liver failure

            Hypersensitivity, DRESS, and anaphylaxis

            Thrombocytopenia

            Rash

            Jaundice

            Anemia requiring transfusion

            Neutropenia and leukopenia

            Nasal congestion

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            Warnings

            Black Box Warnings

            Hepatotoxicity

            • 3-fold ULN elevation of ALT and AST in ~11% of patients observed
            • Measure serum aminotransferase levels (and bilirubin if aminotransferase levels elevated) at baseline & then monthly
            • Rare cases of unexplained hepatic cirrhosis reported after prolonged therapy (>12 months)
            • Avoid in patients with elevated aminotransferase levels (>3X ULN) at baseline because monitoring liver injury may be more difficult
            • Elevations of AST/ALT associated with treatment are dose-dependent; elevated levels may reverse spontaneously while continuing treatment
            • Discontinue drug if liver aminotransferase elevations accompanied by clinical symptoms of liver injury (eg, nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue) or increases in bilirubin >2X ULN

            Pregnancy Contraindication

            • Likely to produce serious birth defects if used by pregnant women; this effect has been seen consistently when administered to animals
            • Negative pregnancy test result required before initiating & prevention of pregnancy required thereafter
            • Advise the use of at least 2 reliable methods of contraception (unless tubal sterilization or Copper T 380A IUD or LNg 20 IUD inserted, in which case no other contraception required)
            • Obtain monthly pregnancy tests

            Restricted Distribution Program

            • Because of risks of liver injury and birth defects, available only through restricted distribution program called the Tracleer REMS program; available at www.Tracleerrems.com or 1-866-228-3546
            • Healthcare professionals who prescribe bosentan must review educational materials, enroll in the Tracleer REMS program and comply with its requirements
            • Healthcare professionals must review serum ALT/AST and bilirubin; agree to order/monitor tests monthly; confirm females of reproduction potential are no pregnant, and agree to order/monitor pregnancy tests monthly
            • To receive bosentan, all patients must understand the risks and benefits, complete a patient enrollment form
            • Pharmacies that dispense bosentan must enroll in the program and agree to comply with the Tracleer REMS Program requirements

            Contraindications

            Hypersensitivity

            Pregnancy

            Concomitant cyclosporine or glyburide use

            Cautions

            Hypersensitivity of bosentan; observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash, and angioedema

            Monitor LFTs; avoid use if ALT or AST >3 x ULN or bilirubin >2 x ULN (see Black Box Warnings and Dosage Modifications)

            Pulmonary edema may occur; if signs/symptoms arise, consider possibly associated with pulmonary venoocclusive disease and whether treatment should be discontinued

            Embryo-fetal toxicity reported; see Black Box Warnings and Pregnancy

            Decreased sperm counts have been observed; preclinical data also suggest bosentan and other endothelin receptor antagonists, may have an adverse effect on spermatogenesis

            Dose-related decrease in hemoglobin and hematocrit may occur with treatment; it is recommended that hemoglobin concentrations be checked after 1, 3 months, and q3months thereafter; if a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine cause and need for specific treatment

            Fluid retention

            • Peripheral edema is a known clinical consequence of PAH, worsening PAH, and is also a known effect of bosentan and other endothelin receptor antagonists
            • In clinical trials with bosentan, combined adverse events of fluid retention or edema were reported
            • Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure
            • If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine whether treatment-related or possible underlying heart failure, and consider need for treatment or discontinuation of bosentan
            • Monitor hemoglobin levels after 1, 3 months of treatment, then every 3 months thereafter

            Drug interactions overview

            • Bosentan is metabolized by CYP2C9 and CYP3A; inhibition of these enzymes may increase the plasma concentration of bosentan
            • Concomitant administration of a CYP2C9 inhibitor (eg, fluconazole, amiodarone), a strong CYP3A inhibitor (eg, ketoconazole, itraconazole) or a moderate CYP3A inhibitor (eg, amprenavir, erythromycin, fluconazole, diltiazem) will likely lead to large increases in plasma concentrations of bosentan
            • Coadministration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with bosentan is not recommended
            • Bosentan is an inducer of CYP3A and CYP2C9; plasma concentrations of drugs metabolized by these two isozymes will be decreased when coadministered bosentan
            • Reduces efficacy of hormonal contraceptives
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            Pregnancy & Lactation

            Pregnancy

            Based on animal data, bosentan may cause fetal harm, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy; see Contraindications and Black Box Warnings

            In animal reproduction studies, oral administration of bosentan to pregnant rats at 2 times the maximum recommended human dose (MRHD) on a mg/m&sup;2 basis caused teratogenic effects in rats (eg, malformations of the head, mouth, face, and large blood vessels)

            Advise pregnant women of the potential risk to a fetus

            Patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected

            If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus

            Based on findings in animals, bosentan may impair fertility in males of reproductive potential; It is unknown whether effects on fertility would be reversible

            Contraception, see Black Box Warnings

            Lactation

            There are no data on the presence of bosentan in human milk, the effects on the breastfed infant, or the effect on milk production

            Because of the potential for serious adverse reactions, such as fluid retention and hepatotoxicity, in breastfed infants from bosentan, advise women not to breastfeed during treatment with bosentan

            Pregnancy 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 involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Competitive antagonist of endothelin-1; blocks endothelin receptors on vascular endothelium and smooth muscle resulting in inhibition of vasoconstriction

            Absorption

            Bioavailability: 50%

            Peak plasma time: 3-5hr

            Duration: 24 hr

            Distribution

            Protein Bound: >98% (primarily to albumin)

            Vd: 18L

            Metabolism

            Metabolized by hepatic CYP2C9 and CYP3A4

            Metabolites: Ro 48-5033 (active metabolite), Ro 47-8634 (inactive metabolite)

            Enzymes induced: CYP2C9, CYP3A4

            Steady-state reached within 3-5 days

            Elimination

            Half-Life: 5-8 hr

            Total clearance: 4L/hr

            Excretion: Feces (predominantly); urine (minimal)

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            Administration

            Oral Suspension Preparation

            If necessary, the 32 mg dispersible tablet can be divided into halves by breaking along the lines cut into the surface

            Advise patients that bosentan dispersible tablets should not be split into quarters

            Each 32 mg dispersible tablet, or tablet part, can be dispersed in a minimal amount of water to make a liquid medicine immediately before administration

            Administer once tablet is fully dispersed

            Oral Administration

            Take with or without food

            If missed a dose, take tablet as soon as possible; do not take 2 doses at the same time; skip the missed dose if close to next administration

            Storage

            Film coated and dispersible tablets: Store at 20-25ºC (68-77ºF)

            Excursions are permitted between 15-30°C (59-86°F)

            Divided dispersible tablets should be stored under the same conditions and used within 7 days

            Tablet pieces may be returned to the opened blister and stored there out of reach of children for up to 7 days

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
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            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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