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Bosentan

Medically reviewed by Drugs.com. Last updated on Aug 11, 2020.

Pronunciation

(boe SEN tan)

Dosage Forms

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

Tablet, Oral:

Tracleer: 62.5 mg, 125 mg

Generic: 62.5 mg, 125 mg

Tablet Soluble, Oral:

Tracleer: 32 mg [scored; contains aspartame]

Brand Names: U.S.

  • Tracleer

Pharmacologic Category

  • Endothelin Receptor Antagonist
  • Vasodilator

Pharmacology

Endothelin receptor antagonist that blocks endothelin receptors on endothelium and vascular smooth muscle (stimulation of these receptors is associated with vasoconstriction). Bosentan blocks both ETA and ETB receptors, with a slightly higher affinity for the A subtype.

Distribution

Vd: ~18 L (does not distribute into RBCs)

Metabolism

Hepatic via CYP2C9 and 3A4 to three metabolites (one active, contributing ~10% to 20% pharmacologic activity); steady-state plasma concentrations are 50% to 65% of those attained after single dose (most likely due to autoinduction of liver enzymes); steady-state is attained within 3 to 5 days

Excretion

Feces (as metabolites); urine (<3% as unchanged drug)

Time to Peak

Plasma: 3 to 5 hours

Half-Life Elimination

~5 hours; prolonged with heart failure, possibly with PAH

Protein Binding

Plasma: >98%, primarily to albumin

Special Populations: Renal Function Impairment

In patients with severe renal impairment (CrCl 15 to 30 mL/minute), concentrations of the 3 metabolites may increase 2-fold, although it is not clinically significant.

Special Populations: Hepatic Function Impairment

Exposure to bosentan may be significantly increased in hepatic impairment.

Special Populations: Children

Exposure to bosentan reaches a plateau at lower doses in pediatric patients than in adults, and doses >2 mg/kg twice daily do not increase the exposure to bosentan in pediatric patients.

Use: Labeled Indications

Pulmonary arterial hypertension: Treatment of pulmonary artery hypertension (PAH) (WHO Group I) in adults with WHO-FC II, III, or IV symptoms to improve exercise ability and to decrease clinical deterioration; treatment of PAH (WHO Group 1) in pediatric patients ≥3 years with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), resulting in an improvement in exercise ability.

Off Label Uses

Digital ulcers in systemic sclerosis

Based on small controlled trials, bosentan may be effective for patients with digital ulcers caused by systemic sclerosis. Bosentan has been found to decrease the number of new ulcers but has not been found to improve healing of existing ulcers [Korn 2004], [Matucci-Cerinic 2011].

Based on the European League Against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis, bosentan should be considered to reduce the number of new digital ulcers caused by systemic sclerosis, especially in patients with multiple ulcers despite use of first-line agents [EULAR [Kowal-Bielecka 2017]].

Raynaud phenomenon in systemic sclerosis

Data from controlled and noncontrolled trials evaluating bosentan in the management of secondary Raynaud phenomenon demonstrate conflicting results in clinical and microvascular assessments [Giordano 2010], [Hettema 2007], [Moore 2007], [Nguyen 2010].

Based on the EULAR recommendations for the treatment of systemic sclerosis, bosentan has no confirmed efficacy in the treatment of Raynaud phenomenon in systemic sclerosis patients but is effective in the reduction of digital ulcers, particularly multiple ulcers, and should be considered after other therapies have failed [EULAR [Kowal-Bielecka 2017]].

Contraindications

Hypersensitivity to bosentan or any component of the formulation; concurrent use of cyclosporine or glyburide; women who are or may become pregnant.

Canadian labeling: Additional contraindications (not in US labeling): Moderate to severe hepatic impairment (eg, ALT or AST >3 times ULN, particularly when total bilirubin >2 times ULN).

Dosing: Adult

Pulmonary artery hypertension: Oral:

Note: A clinician with expertise in pulmonary arterial hypertension should be consulted for all management decisions (ACCP [Klinger 2019]).

<40 kg: Initial and maintenance: 62.5 mg twice daily.

≥40 kg: Initial: 62.5 mg twice daily; after 4 weeks, may increase to a maximum dose of 125 mg twice daily.

Note: When discontinuing treatment, consider a reduction in dosage to 62.5 mg twice daily for 3 to 7 days to avoid clinical deterioration, then stop treatment.

Digital ulcers in systemic sclerosis (off-label use): Oral: 62.5 mg twice daily for 4 weeks followed by an increase to a maintenance dose of 125 mg twice daily (Korn 2004; Matucci-Cerinic 2011).

Raynaud phenomenon in systemic sclerosis (off-label use): Oral: 62.5 mg twice daily for 4 weeks followed by an increase to a maintenance dose of 125 mg twice daily (Giordano 2010; Hettema 2007).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Pulmonary arterial hypertension: Note: Doses >125 mg twice daily do not provide additional benefit sufficient to offset the increased risk of hepatic injury.

Infants and Children <12 years: Oral: Initial: 1 mg/kg/dose twice daily; increase to a target dose of 2 mg/kg/dose twice daily; maximum dose: 125 mg/dose (AHA/ATS [Abman 2015]; Berger 2017).

Children ≥12 years and Adolescents (AHA/ATS [Abman 2015]): Oral:

>20 to 40 kg: Initial: 31.25 mg twice daily; increase to a target dose of 62.5 mg twice daily.

>40 kg: Initial: 62.5 mg twice daily; increase to a target dose of 125 mg twice daily.

Alternate dosing: Manufacturer's labeling:

Children ≥3 years:

4 to 8 kg: Oral: 16 mg twice daily.

>8 to 16 kg: Oral: 32 mg twice daily.

>16 to 24 kg: Oral: 48 mg twice daily.

>24 to 40 kg: Oral: 64 mg twice daily.

Adolescents:

≤40 kg: Oral: 62.5 mg twice daily.

>40 kg: Oral: Initial: 62.5 mg twice daily for 4 weeks; increase to target dose of 125 mg twice daily.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Extemporaneously Prepared

Note: Tablets for oral suspension (32 mg dispersible tablets) are commercially available.

6.25 mg/mL Oral Suspension

Note: The following personal protective equipment should be used when preparing bosentan oral suspension: Double gloving, protective gown and a respiratory mask if preparation does not occur in a fume hood.

A 6.25 mg/mL oral suspension may be made from nondispersable tablets and a 1:1 mixture of FlavorPlus and FlavorSweet. Crush three 62.5 mg tablets in a ceramic mortar. Add a small amount of glycerin and reduce to a fine powder. Add ~10 mL of the vehicle and triturate; add an additional 10 mL of vehicle and transfer to a calibrated amber bottle. Rinse the mortar and pestle with 10 mL vehicle and add to bottle to bring the final volume to 30 mL. Stable for 30 days when stored in a amber bottle at room temperature or under refrigeration.

Malik A, Gorman G, Coward L, Arnold JJ. Stability of an extemporaneously compounded oral suspension of bosentan. Hosp Pharm. 2016;51(5):389-95. doi: 10.1310/hpj5105-389.27303093

Administration

Administer with or without food.

Tablets for oral suspension (dispersible tablets): Disperse in a minimal amount of water immediately before administration. The 32 mg dispersible tablet may be divided into halves; do not break into quarters.

Storage

Store film-coated and dispersible tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store divided dispersible tablet pieces in the opened blister for up to 7 days.

Drug Interactions

Abemaciclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Abemaciclib. Avoid combination

Abiraterone Acetate: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Abiraterone Acetate. Monitor therapy

Acalabrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Acalabrutinib. Monitor therapy

Alfentanil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Alfentanil. Management: If concomitant use of alfentanil and moderate CYP3A4 inducers is necessary, consider dosage increase of alfentanil until stable drug effects are achieved. Monitor patients for signs of opioid withdrawal. Consider therapy modification

Antihepaciviral Combination Products: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Antihepaciviral Combination Products. Avoid combination

Apremilast: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Apremilast. Monitor therapy

Aprepitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Aprepitant. Monitor therapy

ARIPiprazole: CYP3A4 Inducers (Moderate) may decrease the serum concentration of ARIPiprazole. Monitor therapy

ARIPiprazole Lauroxil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of ARIPiprazole Lauroxil. Monitor therapy

Asunaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir. Avoid combination

Atazanavir: Bosentan may decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Bosentan. Management: Concurrent use of unboosted atazanavir (without ritonavir or cobicistat) and bosentan is not recommended. Bosentan dose adjustments and increased monitoring are recommended when used together with boosted atazanavir. See interaction monograph for details. Consider therapy modification

Avanafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Avanafil. Avoid combination

Avapritinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Avapritinib. Avoid combination

Axitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib. Avoid combination

Bedaquiline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline. Avoid combination

Benzhydrocodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Benzhydrocodone. Specifically, the serum concentrations of hydrocodone may be reduced. Monitor therapy

Bortezomib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bortezomib. Monitor therapy

Bosutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib. Avoid combination

Brexpiprazole: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Brexpiprazole. Monitor therapy

Brigatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inducers when possible. If combined, increase the daily dose of brigatinib in 30 mg increments after 7 days of treatment with the current brigatinib dose, up to maximum of twice the dose. Consider therapy modification

Cabozantinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cabozantinib. Monitor therapy

Capmatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Capmatinib. Avoid combination

Clarithromycin: Bosentan may increase serum concentrations of the active metabolite(s) of Clarithromycin. Specifically, bosentan may increase concentrations of 14-hydroxyclarithromycin. Bosentan may decrease the serum concentration of Clarithromycin. Clarithromycin may increase the serum concentration of Bosentan. Management: Consider alternative antimicrobial if possible. The clinical activity of clarithromycin may be altered, and increased bosentan toxicity may be expected. Consider therapy modification

CloZAPine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of CloZAPine. Monitor therapy

Cobicistat: May increase the serum concentration of Bosentan. Management: Dose adjustment of bosentan and increased monitoring for bosentan toxicities is necessary when these agents are combined. See full drug interaction monograph for details. Consider therapy modification

Cobimetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib. Avoid combination

Codeine: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Codeine. Monitor therapy

Copanlisib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Copanlisib. Monitor therapy

Crizotinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Crizotinib. Monitor therapy

CycloSPORINE (Systemic): May increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of CycloSPORINE (Systemic). Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Bosentan. Monitor therapy

CYP3A4 Substrates (High risk with Inducers): CYP3A4 Inducers (Moderate) may decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Exceptions: Apixaban; Bromperidol; Rivaroxaban. Monitor therapy

Daclatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Consider therapy modification

Dapsone (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dapsone (Systemic). Monitor therapy

Dasabuvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dasabuvir. Avoid combination

Deflazacort: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Deflazacort. Avoid combination

Doravirine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Doravirine. Monitor therapy

Elbasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elbasvir. Avoid combination

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Monitor therapy

Eltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Monitor therapy

Encorafenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Encorafenib. Avoid combination

Entrectinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Entrectinib. Avoid combination

Erdafitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Erdafitinib. Management: Dose modifications of erdafitinib may be required. See full monograph for details. Consider therapy modification

Estriol (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Systemic). Monitor therapy

Estriol (Topical): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Topical). Monitor therapy

Estrogen Derivatives (Contraceptive): Bosentan may decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use an alternative (i.e., non-hormonal) means of contraception for all women of childbearing potential who are using bosentan, and do not rely on hormonal contraceptives alone. Consider therapy modification

Etoposide: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Etoposide. Monitor therapy

Etoposide Phosphate: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Etoposide Phosphate. Monitor therapy

Etravirine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Etravirine. Monitor therapy

Everolimus: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Everolimus. Monitor therapy

Fedratinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Fedratinib. Avoid combination

FentaNYL: CYP3A4 Inducers (Moderate) may decrease the serum concentration of FentaNYL. Monitor therapy

Flibanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin. Avoid combination

Fluconazole: May increase the serum concentration of Bosentan. Avoid combination

Fosaprepitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite aprepitant. Monitor therapy

Gemfibrozil: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. See separate drug interaction monographs for agents listed as exceptions. Monitor therapy

Glasdegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Glasdegib. Management: Avoid use of glasdegib and moderate CYP3A4 inducers whenever possible. If combined, increase glasdegib dose from 100 mg daily to 200 mg daily or from 50 mg daily to 100 mg daily. Resume previous glasdegib dose 7 days after discontinuation of the inducer. Consider therapy modification

Glecaprevir and Pibrentasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

GlyBURIDE: May enhance the hepatotoxic effect of Bosentan. GlyBURIDE may decrease the serum concentration of Bosentan. Bosentan may decrease the serum concentration of GlyBURIDE. Avoid combination

Grazoprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase extended-release guanfacine dose by up to double when initiating guanfacine in patients taking CYP3A4 inducers or if initiating a CYP3A4 inducer in a patient already taking extended-release guanfacine. Monitor for reduced guanfacine efficacy. Consider therapy modification

HYDROcodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrutinib. Monitor therapy

Ifosfamide: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Istradefylline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Istradefylline. Monitor therapy

Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ivacaftor. Monitor therapy

Lapatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lapatinib. Monitor therapy

Larotrectinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Larotrectinib. Monitor therapy

Lefamulin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with moderate CYP3A4 inducers unless the benefits outweigh the risks. Consider therapy modification

Lefamulin (Intravenous): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with moderate CYP3A4 inducers unless the benefits outweigh the risks. Consider therapy modification

Lemborexant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lemborexant. Avoid combination

Lercanidipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lercanidipine. Monitor therapy

Letermovir: Bosentan may decrease the serum concentration of Letermovir. Avoid combination

Lorlatinib: CYP3A4 Inducers (Moderate) may enhance the hepatotoxic effect of Lorlatinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with moderate CYP3A4 inducers. If such a combination must be used, monitor AST, ALT, and bilirubin within 48 hours of starting the combination and at least three times within the first week of combined use. Consider therapy modification

Lumacaftor and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lumacaftor and Ivacaftor. Monitor therapy

Lumateperone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lumateperone. Avoid combination

Lurasidone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lurasidone. Management: Monitor for decreased lurasidone effects if combined with moderate CYP3A4 inducers and consider increasing the lurasidone dose if coadministered with a moderate CYP3A4 inducer for 7 or more days. Consider therapy modification

Lurbinectedin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lurbinectedin. Avoid combination

Macimorelin: Bosentan may diminish the diagnostic effect of Macimorelin. Monitor therapy

Macitentan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Macitentan. Monitor therapy

Meperidine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Meperidine. Monitor therapy

MiFEPRIStone: May increase the serum concentration of Bosentan. Avoid combination

Mirodenafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mirodenafil. Monitor therapy

Naldemedine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Naldemedine. Monitor therapy

Naloxegol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Naloxegol. Monitor therapy

Neratinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Neratinib. Avoid combination

NiMODipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of NiMODipine. Monitor therapy

Nisoldipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib. Avoid combination

Oliceridine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Oliceridine. Monitor therapy

Palbociclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib. Management: The US label does not provide specific recommendations concerning use with moderate CYP3A4 inducers, but the Canadian label recommends avoiding use of moderate CYP3A4 inducers. Consider therapy modification

PAZOPanib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of PAZOPanib. Monitor therapy

Pemigatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pemigatinib. Avoid combination

Perampanel: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Perampanel. Management: Increase the perampanel starting dose to 4 mg/day when perampanel is used concurrently with moderate and strong CYP3A4 inducers. Monitor perampanel response closely, particularly with changes to CYP3A4 inducer therapy. Consider therapy modification

Pexidartinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pexidartinib. Monitor therapy

Phosphodiesterase 5 Inhibitors: Bosentan may decrease the serum concentration of Phosphodiesterase 5 Inhibitors. Phosphodiesterase 5 Inhibitors may increase the serum concentration of Bosentan. Monitor therapy

Pimavanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pimavanserin. Avoid combination

Pitolisant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pitolisant. Monitor therapy

Pralsetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pralsetinib. Monitor therapy

Pretomanid: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pretomanid. Avoid combination

Progestins (Contraceptive): Bosentan may decrease the serum concentration of Progestins (Contraceptive). Management: Use an alternative (i.e., non-hormonal) means of contraception for all women of childbearing potential who are using bosentan, and do not rely on hormonal contraceptives alone. Consider therapy modification

Protease Inhibitors: May increase the serum concentration of Bosentan. Management: Dose adjustment of bosentan and increased monitoring for bosentan toxicities is necessary when these agents are combined. See full drug interaction monograph for details. Consider therapy modification

Ranolazine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine. Avoid combination

RifAMPin: May decrease the serum concentration of Bosentan. Following the initial week of concurrent rifampin, this effect is most likely. RifAMPin may increase the serum concentration of Bosentan. This effect is most likely to be observed within the initial few days of concurrent therapy (and may be greatest immediately following initiation of the combination). Monitor therapy

Rimegepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rimegepant. Avoid combination

Rolapitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rolapitant. Monitor therapy

Selpercatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Selpercatinib. Avoid combination

Selumetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Selumetinib. Avoid combination

Simeprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir. Avoid combination

Simvastatin: Bosentan may decrease the serum concentration of Simvastatin. Monitor therapy

Sirolimus: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sirolimus. Monitor therapy

Sonidegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib. Avoid combination

SUNItinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of SUNItinib. Monitor therapy

Tacrolimus (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tacrolimus (Systemic). Monitor therapy

Tazemetostat: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tazemetostat. Avoid combination

Teriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Monitor therapy

Tezacaftor and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tezacaftor and Ivacaftor. Monitor therapy

Tolvaptan: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Management: Avoid concomitant use of OATP1B1/1B3 substrates in patients receiving the Jynarque brand of tolvaptant. Concentrations and effects of the OATP1B1/1B3 substrate would be expected to increase with combined use. Consider therapy modification

Ubrogepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a moderate CYP3A4 inducer. Consider therapy modification

Ulipristal: Bosentan may decrease the serum concentration of Ulipristal. Avoid combination

Upadacitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Upadacitinib. Monitor therapy

Velpatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Velpatasvir. Avoid combination

Vemurafenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vemurafenib. Monitor therapy

Venetoclax: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Venetoclax. Avoid combination

Vitamin K Antagonists (eg, warfarin): Bosentan may increase the metabolism of Vitamin K Antagonists. Monitor therapy

Voriconazole: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voriconazole. Monitor therapy

Vortioxetine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vortioxetine. Monitor therapy

Voxelotor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and moderate CYP3A4 inducers. If concomitant use is unavoidable, increase the voxelotor dose to 2,500 mg once daily. Consider therapy modification

Zanubrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zanubrutinib. Avoid combination

Zolpidem: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zolpidem. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Edema (≤11%)

Central nervous system: Headache (15%)

Hepatic: Increased serum ALT (≥3 times ULN: ≤12%; 8 times ULN: ≤2%; dose-related), increased serum AST (≥3 times ULN: ≤12%; 8 times ULN: ≤2%; dose-related)

Respiratory: Respiratory tract infection (22%)

1% to 10%:

Cardiovascular: Chest pain (5%), syncope (5%), flushing (4%), hypotension (4%), palpitations (4%)

Endocrine & metabolic: Fluid retention (≤2%)

Hematologic & oncologic: Anemia (3%)

Neuromuscular & skeletal: Arthralgia (4%)

Respiratory: Sinusitis (4%)

<1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, DRESS syndrome, hepatic cirrhosis (prolonged therapy), hepatic failure (rare), hypersensitivity reaction, jaundice, leukopenia, nasal congestion, neutropenia, peripheral edema, severe anemia, skin rash, thrombocytopenia

ALERT: U.S. Boxed Warning

Distribution program:

Because of the risks of hepatotoxicity and birth defects, bosentan is available only through a restricted program called the Bosentan REMS Program. Under the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program.

Hepatotoxicity:

In clinical studies, bosentan caused at least a 3-fold upper limit of normal (ULN) elevation of liver aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated bilirubin in a small number of cases. Because these changes are a marker for potential serious hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly. In the postmarketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (more than 12 months) therapy with bosentan in patients with multiple comorbidities and drug therapies. There have also been reports of liver failure. The contribution of bosentan in these cases could not be excluded.

In at least 1 case, the initial presentation of hepatotoxicity (after more than 20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by nonspecific symptoms, all of which resolved slowly over time after discontinuation of bosentan. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping bosentan if a rise of aminotransferase accompanied by signs or symptoms of liver dysfunction occurs.

Elevations in aminotransferases require close attention. Generally, avoid using bosentan in patients with elevated aminotransferases (greater than 3 times the ULN) at baseline because monitoring for hepatotoxicity may be more difficult. Stop treatment with bosentan if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (eg, abdominal pain, fever, jaundice, nausea, unusual lethargy or fatigue, vomiting) or increases in bilirubin 2 times the ULN or greater. There is no experience with the reintroduction of bosentan in these circumstances.

Embryo-fetal toxicity:

Bosentan is likely to cause major birth defects if used by pregnant women based on animal data. Therefore, pregnancy must be excluded before the start of treatment with bosentan. Throughout treatment and for 1 month after stopping bosentan, women of childbearing potential must use 2 reliable methods of contraception unless the patient has an intrauterine device (IUD) or tubal sterilization in which case no other contraception is needed. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives, should not be used as the sole means of contraception because these may not be effective in patients receiving bosentan. Obtain monthly pregnancy tests.

Warnings/Precautions

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. There have also been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization) for heart failure. If clinically significant fluid retention develops (with or without weight gain), further evaluation is necessary to determine cause and appropriate treatment or discontinuation of therapy. Use with caution in patients with underlying heart failure due to potential complications from fluid retention. In a scientific statement from the American Heart Association, bosentan has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]).

• Hematologic effects: Dose-related decreases in hematocrit/hemoglobin may be observed, usually within the first few weeks of therapy with subsequent stabilization of levels by 4 to 12 weeks of treatment. Monitor hemoglobin prior to treatment initiation, after 1 and 3 months, and every 3 months thereafter. Significant decreases in hemoglobin require further evaluation to determine the cause and specific management.

• Hepatotoxicity: [US Boxed Warning]: Bosentan is associated with transaminase elevations (ALT or AST ≥3 times ULN), and in a small number of cases may occur with elevations in bilirubin. Monitor transaminases at baseline then monthly thereafter. Adjust dosage if elevations in liver enzymes occur without symptoms of hepatic injury or elevated bilirubin. In the postmarketing surveillance (with close monitoring), there have been rare cases of unexplained hepatic cirrhosis after prolonged therapy (>12 months) in patients with multiple comorbidities and drug therapies. There have also been cases of hepatic failure. Treatment should be stopped in patients who develop elevated transaminases either in combination with symptoms of hepatic injury (unusual fatigue, jaundice, nausea, vomiting, abdominal pain, and/or fever) or elevated bilirubin (≥2 times ULN); safety of reintroduction is unknown. Avoid use in patients with baseline serum transaminases >3 times ULN at baseline (monitoring for hepatotoxicity may be more difficult) or moderate to severe hepatic impairment. The combination of hepatocellular injury (transaminase elevations >3 times ULN) and bilirubin increased ≥2 times ULN are a marker for potential serious hepatotoxicity. Transaminase elevations are dose dependent, generally asymptomatic, occur both early and late in therapy, progress slowly, and are usually reversible after treatment interruption or discontinuation. Transaminase elevations may also spontaneously reverse while continuing bosentan treatment. Consider the benefits of treatment versus the risk of hepatotoxicity when initiating therapy in patients with WHO Class II symptoms.

• Hypersensitivity: Hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash and angioedema have been observed.

• Pulmonary veno-occlusive disease: If signs of pulmonary edema occur, consider possibility of pulmonary veno-occlusive disease; may require discontinuation of bosentan.

Special populations:

• Pregnancy: [US Boxed Warning]: Bosentan is likely to cause major birth defects if used by pregnant women based on animal data. Therefore, pregnancy must be excluded before the start of treatment with bosentan. Throughout treatment and for 1 month after stopping bosentan, women of childbearing potential must use 2 reliable methods of contraception unless the patient has an intrauterine device (IUD) or tubal sterilization in which case no other contraception is needed. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives, should not be used as the sole means of contraception because these may not be effective in patients receiving bosentan. Obtain monthly pregnancy tests.

Dosage form specific issues:

• Aspartame: Some products may contain aspartame, which is metabolized to phenylalanine and must be avoided (or used with caution) in patients with phenylketonuria.

Other warnings/precautions:

• REMS program: [US Boxed Warning]: Because of the risks of hepatotoxicity and birth defects, bosentan is only available through the Bosentan REMS Program. Patients, prescribers, and pharmacies must enroll with the program. Call 1-866-359-2612 or visit www.BosentanREMSProgram.com for more information.

Monitoring Parameters

Serum transaminase (AST and ALT) and bilirubin (prior to treatment initiation and monthly thereafter, or more frequently if clinically necessary [every 2 weeks following transaminase elevations and 3 days after reintroducing therapy if withheld due to transaminase elevations]). Hemoglobin and hematocrit (at baseline, at 1 month and 3 months of treatment, and every 3 months thereafter [generally stabilizes after 4 to 12 weeks of treatment]).

Pregnancy test in women of childbearing potential (prior to the initiation of therapy, monthly during treatment, and one month after stopping bosentan).

Monitor for clinical signs/symptoms of liver injury (eg, abdominal pain, fatigue, fever, jaundice, nausea, vomiting) and fluid retention.

Reproductive Considerations

Bosentan is contraindicated in females who may become pregnant.

[US Boxed Warning]: Pregnancy must be excluded before the start of treatment with bosentan. Throughout treatment and for 1 month after stopping bosentan, women of childbearing potential must use two reliable methods of contraception unless the patient has an intrauterine device (IUD) or tubal sterilization in which case no other contraception is needed. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives, should not be used as the sole means of contraception because these may not be effective in patients receiving bosentan. Obtain monthly pregnancy tests. When a hormonal or barrier contraceptive is used, one additional method of contraception is still needed if a male partner has had a vasectomy. A missed menses or suspected pregnancy should be reported to a health care provider and prompt immediate pregnancy testing.

Decreased sperm counts and adverse effects on spermatogenesis have been observed in men during treatment; fertility may be impaired. It is not known if effects on fertility are reversible.

Pregnancy Considerations

Bosentan is contraindicated in females who are pregnant.

[US Boxed Warning]: Bosentan is likely to cause major birth defects if used by pregnant women based on animal data.

Women with pulmonary arterial hypertension (PAH) are encouraged to avoid pregnancy (McLaughlin 2009; Taichman 2014).

Patient Education

What is this drug used for?

• It is used to treat high blood pressure in the lungs.

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

• Common cold symptoms

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Severe loss of strength and energy

• Weight gain

• Trouble breathing

• Swelling

• Severe dizziness

• Passing out

• Abnormal heartbeat

• Joint pain

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.