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.
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.
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.
Pulmonary arterial hypertension:
Note: Consult a pulmonary arterial hypertension specialist for all management decisions; choice of therapy is dependent on etiology, risk stratification, and cardiopulmonary comorbidities (Ref).
<40 kg: Oral: Initial and maintenance: 62.5 mg twice daily.
≥40 kg: Oral: 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 (Ref).
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 (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary. Bosentan is unlikely to be removed by dialysis (due to high molecular weight and extensive plasma protein binding).
Hepatic impairment at treatment initiation:
Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate to severe impairment (Child-Pugh class B and C) and/or baseline transaminase >3 times ULN: Avoid use; systemic exposure is significantly increased in patients with moderate impairment (has not been studied in severe impairment).
Hepatotoxicity during treatment: Modification based on transaminase elevation:
Transaminase elevations accompanied by clinical symptoms of hepatotoxicity (unusual fatigue, nausea, vomiting, abdominal pain, fever, or jaundice) or a serum bilirubin ≥2 times ULN: Discontinue treatment.
AST/ALT >3 times but ≤5 times ULN: >40 kg: Confirm with additional test; if confirmed, reduce dose to 62.5 mg twice daily or interrupt treatment and monitor at least every 2 weeks. If transaminase levels return to pretreatment values, may continue or reintroduce treatment (at the starting dose), as appropriate. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.
AST/ALT >5 times but ≤8 times ULN: >40 kg: Confirm with additional test; if confirmed, stop treatment. Monitor transaminase levels at least every 2 weeks. If transaminase levels return to pretreatment values, may reintroduce treatment (at the starting dose) as appropriate. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.
AST/ALT >8 times ULN: Stop treatment and do not reintroduce.
Refer to adult dosing.
(For additional information see "Bosentan: Pediatric drug information")
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 (Ref).
Children ≥12 years and Adolescents (Ref): 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.
No dosage adjustment required. Bosentan is unlikely to be removed by dialysis (due to high molecular weight and extensive plasma protein binding).
Baseline: Children ≥3 years and Adolescents:
Mild impairment: No dosage adjustment necessary.
Moderate to severe impairment and/or baseline transaminase >3 times ULN: Avoid use; systemic exposure is significantly increased in patients with moderate impairment (has not been studied in severe impairment).
Hepatotoxicity during therapy: Adjustment based on transaminase elevation:
Transaminase elevations accompanied by clinical symptoms of hepatotoxicity (unusual fatigue, nausea, vomiting, abdominal pain, fever, or jaundice) or a serum bilirubin ≥2 times ULN: Children ≥3 years and Adolescents: Discontinue treatment; there is no experience with reintroduction.
AST/ALT >3 times but ≤5 times ULN:
Children 3 to ≤12 years and Adolescents ≤40 kg: Confirm with additional test; if confirmed, interrupt treatment with no prior dose reduction. If transaminase levels return to pretreatment values, may reintroduce treatment at the dose used prior to treatment interruption. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.
Adolescents >40 kg: Confirm with additional test; if confirmed, reduce dose to 62.5 mg twice daily or interrupt treatment and monitor at least every 2 weeks. If transaminase levels return to pretreatment values, may continue or reintroduce treatment at 62.5 mg twice daily, as appropriate. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.
AST/ALT >5 times but ≤8 times ULN:
Children 3 to ≤12 years and Adolescents ≤40 kg: Confirm with additional test; if confirmed, stop treatment. Monitor transaminase levels at least every 2 weeks. If transaminase levels return to pretreatment values, consider reintroduction at the dose used prior to treatment interruption. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.
Adolescents >40 kg: Confirm with additional test; if confirmed, stop treatment. Monitor transaminase levels at least every 2 weeks. If transaminase levels return to pretreatment values, may reintroduce treatment at 62.5 mg twice daily, as appropriate. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.
AST/ALT >8 times ULN: Children ≥3 years and Adolescents: Stop treatment and do not reintroduce.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>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
Hypersensitivity to bosentan or any component of the formulation; concurrent use of cyclosporine or glyburide; patients who are or may become pregnant.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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).
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.
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Tracleer: 62.5 mg, 125 mg [contains corn starch]
Generic: 62.5 mg, 125 mg
Tablet Soluble, Oral:
Tracleer: 32 mg [scored; contains aspartame]
May be product dependent
Tablet,Dispersible (Tracleer Oral)
32 mg (per each): $268.28
Tablets (Bosentan Oral)
62.5 mg (per each): $209.14 - $221.00
125 mg (per each): $209.14 - $221.00
Tablets (Tracleer Oral)
62.5 mg (per each): $268.28
125 mg (per each): $268.28
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Tracleer: 62.5 mg, 125 mg [contains corn starch]
Generic: 62.5 mg, 125 mg
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.
Note: Bosentan has been classified as a hazardous substance by NIOSH due to its associated risk of birth defects; double gloving, a protective gown, and preparation in a controlled device is recommended when splitting, crushing, or handling broken tablets; if not prepared in a controlled device, respiratory and eye/face protection as well as ventilated engineering controls are recommended. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration or handling of bodily fluids/waste (Ref).
Oral: May be administered without regard to meals.
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.
Hazardous agent (NIOSH 2024 [table 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Tracleer: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021290s039,209279s005lbl.pdf
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.
Digital ulcers in systemic sclerosis; Raynaud phenomenon in systemic sclerosis
Tracleer may be confused with TriCor
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs (contraindicated in pregnancy) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Community/Ambulatory Care Settings).
Substrate of CYP2C9 (Minor), CYP3A4 (Minor), OATP1B1/1B3; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP3A4 (Moderate);
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Abemaciclib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Abemaciclib. Risk X: Avoid
Abiraterone Acetate: CYP3A4 Inducers (Moderate) may decrease serum concentration of Abiraterone Acetate. Risk C: Monitor
Acalabrutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Acalabrutinib. Risk C: Monitor
Adagrasib: May increase serum concentration of Bosentan. Risk X: Avoid
ALfentanil: CYP3A4 Inducers (Moderate) may decrease 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. Risk D: Consider Therapy Modification
Alpelisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Alpelisib. Risk C: Monitor
ALPRAZolam: CYP3A4 Inducers (Moderate) may decrease serum concentration of ALPRAZolam. Risk C: Monitor
AmLODIPine: CYP3A4 Inducers (Moderate) may decrease serum concentration of AmLODIPine. Risk C: Monitor
Antihepaciviral Combination Products: CYP3A4 Inducers (Moderate) may decrease serum concentration of Antihepaciviral Combination Products. Risk X: Avoid
Apremilast: CYP3A4 Inducers (Moderate) may decrease serum concentration of Apremilast. Risk C: Monitor
Aprepitant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Aprepitant. Risk C: Monitor
ARIPiprazole Lauroxil: CYP3A4 Inducers (Moderate) may decrease serum concentration of ARIPiprazole Lauroxil. Risk C: Monitor
ARIPiprazole: CYP3A4 Inducers (Moderate) may decrease serum concentration of ARIPiprazole. Risk C: Monitor
Artemether and Lumefantrine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Artemether and Lumefantrine. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Artemether and Lumefantrine. Specifically, concentrations of dihydroartemisinin (DHA), the active metabolite of artemether may be decreased. Risk C: Monitor
Asciminib: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Atazanavir: Bosentan may decrease serum concentration of Atazanavir. Atazanavir may increase 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. Risk D: Consider Therapy Modification
Atogepant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with CYP3A4 inducers. When used for treatment of chronic migraine, use of atogepant with CYP3A4 inducers should be avoided. Risk D: Consider Therapy Modification
Atorvastatin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Atorvastatin. Risk C: Monitor
Atrasentan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Atrasentan. Risk X: Avoid
Avacopan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Avacopan. Risk X: Avoid
Avanafil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Avanafil. Risk X: Avoid
Avapritinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Avapritinib. Risk X: Avoid
Axitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Axitinib. Management: Concurrent use of axitinib with a moderate CYP3A4 inducer should be avoided when possible. If any such combination is necessary, monitor for reduced axitinib efficacy. Risk D: Consider Therapy Modification
Bedaquiline: CYP3A4 Inducers (Moderate) may decrease serum concentration of Bedaquiline. CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Bedaquiline. Risk X: Avoid
Belumosudil: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Avoid coadministration of belumosudil with these substrates of OATP1B1/1B3 for which minimal concentration increases can cause serious adverse effects. If coadministration is required, dose reductions of the OATP1B1/1B3 substrate may be required. Risk D: Consider Therapy Modification
Benzhydrocodone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Benzhydrocodone. Specifically, the serum concentrations of hydrocodone may be reduced. Risk C: Monitor
Bortezomib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Bortezomib. Risk C: Monitor
Bosutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Bosutinib. Risk C: Monitor
Brexpiprazole: CYP3A4 Inducers (Moderate) may decrease serum concentration of Brexpiprazole. Risk C: Monitor
Brigatinib: CYP3A4 Inducers (Moderate) may decrease 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. Risk D: Consider Therapy Modification
Bulevirtide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Coadministration of bulevirtide with OATP1B1/1B3 (also known as SLCO1B1/1B3) substrates should be avoided when possible. If used together, close clinical monitoring is recommended. Risk D: Consider Therapy Modification
Buprenorphine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Buprenorphine. Risk C: Monitor
BusPIRone: CYP3A4 Inducers (Moderate) may decrease serum concentration of BusPIRone. Risk C: Monitor
Cabozantinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Cabozantinib. Management: For cabozantinib tablets (Cabometyx), avoid combined use if possible. If combined, increase cabozantinib by 20 mg from previous dose, max 80 mg daily. For cabozantinib capsules (Cometriq), monitor for reduced cabozantinib efficacy if combined. Risk D: Consider Therapy Modification
Calcifediol: CYP3A4 Inducers (Moderate) may decrease serum concentration of Calcifediol. Risk C: Monitor
Calcitriol (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Calcitriol (Systemic). Risk C: Monitor
Cannabis: CYP3A4 Inducers (Moderate) may decrease serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased. Risk C: Monitor
Capivasertib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Capivasertib. Risk X: Avoid
Capmatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Capmatinib. Risk X: Avoid
CarBAMazepine: CYP3A4 Inducers (Moderate) may decrease serum concentration of CarBAMazepine. Risk C: Monitor
Cariprazine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Cariprazine. Risk X: Avoid
Ceftobiprole Medocaril: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid
Ceritinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ceritinib. Risk C: Monitor
Clarithromycin: Bosentan may increase active metabolite exposure of Clarithromycin. Specifically, bosentan may increase concentrations of 14-hydroxyclarithromycin. Bosentan may decrease serum concentration of Clarithromycin. Clarithromycin may increase 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. Risk D: Consider Therapy Modification
Clindamycin (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Clindamycin (Systemic). Risk C: Monitor
CloZAPine: CYP3A4 Inducers (Moderate) may decrease serum concentration of CloZAPine. Risk C: Monitor
Cobicistat: May increase serum concentration of Bosentan. Bosentan may decrease serum concentration of Cobicistat. 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. Risk D: Consider Therapy Modification
Cobimetinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Cobimetinib. Risk X: Avoid
Codeine: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Codeine. Risk C: Monitor
Copanlisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Copanlisib. Risk C: Monitor
Crinecerfont: CYP3A4 Inducers (Moderate) may decrease serum concentration of Crinecerfont. Management: Double the evening dose of crinecerfont and continue the morning dose unchanged during coadministration with moderate CYP3A4 inducers. See full interaction monograph for details. Risk D: Consider Therapy Modification
Crizotinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Crizotinib. Risk C: Monitor
CycloSPORINE (Systemic): May increase serum concentration of Bosentan. Bosentan may decrease serum concentration of CycloSPORINE (Systemic). Risk X: Avoid
CYP3A4 Inhibitors (Strong): May increase serum concentration of Bosentan. Risk C: Monitor
Daclatasvir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Risk D: Consider Therapy Modification
Dapsone (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Dapsone (Systemic). Risk C: Monitor
Daridorexant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Daridorexant. Risk X: Avoid
Darolutamide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Dasabuvir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Dasabuvir. Risk X: Avoid
Dasatinib: CYP3A4 Inducers (Moderate) may increase serum concentration of Dasatinib. Risk C: Monitor
Deflazacort: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Deflazacort. Risk X: Avoid
DexAMETHasone (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of DexAMETHasone (Systemic). Risk C: Monitor
DiazePAM: CYP3A4 Inducers (Moderate) may decrease serum concentration of DiazePAM. Risk C: Monitor
Dienogest: CYP3A4 Inducers (Moderate) may decrease serum concentration of Dienogest. Risk C: Monitor
DilTIAZem: CYP3A4 Inducers (Moderate) may decrease serum concentration of DilTIAZem. Risk C: Monitor
Disopyramide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Disopyramide. Risk C: Monitor
Doravirine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Doravirine. Risk C: Monitor
DOXOrubicin (Conventional): CYP3A4 Inducers (Moderate) may decrease serum concentration of DOXOrubicin (Conventional). Risk X: Avoid
DroNABinol: CYP3A4 Inducers (Moderate) may decrease serum concentration of DroNABinol. Risk C: Monitor
Dronedarone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Dronedarone. Risk C: Monitor
Duvelisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Duvelisib. Management: Avoid if possible. If used, on day 12 of combination increase duvelisib from 25 mg twice daily to 40 mg twice daily or from 15 mg twice daily to 25 mg twice daily. Resume prior duvelisib dose 14 days after stopping moderate CYP3A4 inducer. Risk D: Consider Therapy Modification
Dydrogesterone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Dydrogesterone. Risk C: Monitor
Efavirenz: CYP3A4 Inducers (Moderate) may decrease serum concentration of Efavirenz. Risk C: Monitor
Elacestrant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Elacestrant. Risk X: Avoid
Elbasvir and Grazoprevir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid
Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Risk C: Monitor
Eliglustat: CYP3A4 Inducers (Moderate) may decrease serum concentration of Eliglustat. Risk C: Monitor
Eltrombopag: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Encorafenib: May increase serum concentration of Bosentan. Bosentan may decrease serum concentration of Encorafenib. Risk C: Monitor
Ensartinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ensartinib. Risk X: Avoid
Entrectinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Entrectinib. Risk X: Avoid
Enzalutamide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Enzalutamide. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Enzalutamide. Risk C: Monitor
Erdafitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Erdafitinib. Management: If a moderate CYP3A4 inducer must be used at the start of erdafitinib, administer erdafitinib at a dose of 9 mg daily. If a moderate CYP3A4 inducer is discontinued, continue erdafitinib at the same dose unless there is evidence of drug toxicity. Risk D: Consider Therapy Modification
Erlotinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Erlotinib. Management: Avoid the combination of erlotinib and strong CYP3A4 inducers whenever possible. If this combination must be used, increase erlotinib dose by 50 mg increments every 2 weeks as tolerated, to a maximum of 450 mg/day. Risk D: Consider Therapy Modification
Estrogen Derivatives: CYP3A4 Inducers (Moderate) may decrease serum concentration of Estrogen Derivatives. Risk C: Monitor
Etoposide Phosphate: CYP3A4 Inducers (Moderate) may decrease serum concentration of Etoposide Phosphate. Risk C: Monitor
Etoposide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Etoposide. Risk C: Monitor
Etravirine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Etravirine. Risk C: Monitor
Everolimus: CYP3A4 Inducers (Moderate) may decrease serum concentration of Everolimus. Risk C: Monitor
Exemestane: CYP3A4 Inducers (Moderate) may decrease serum concentration of Exemestane. Risk C: Monitor
Fedratinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Fedratinib. Risk X: Avoid
Felodipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Felodipine. Risk C: Monitor
FentaNYL: CYP3A4 Inducers (Moderate) may decrease serum concentration of FentaNYL. Risk C: Monitor
Fexinidazole: CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Fexinidazole. Risk X: Avoid
Finerenone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Finerenone. Risk X: Avoid
Flibanserin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Flibanserin. Risk X: Avoid
Fluconazole: May increase serum concentration of Bosentan. Risk X: Avoid
Fosaprepitant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite aprepitant. Risk C: Monitor
Fosnetupitant: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Fosnetupitant. Risk C: Monitor
Fostamatinib: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Fostamatinib. Risk C: Monitor
Fruquintinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Fruquintinib. Management: Avoid this combination when possible. If combined, continue the same fruquintinib dose, but monitor for reduced fruquintinib efficacy. Risk D: Consider Therapy Modification
Ganaxolone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ganaxolone. Management: Avoid concomitant use of ganaxolone and moderate CYP3A4 inducers whenever possible. If combined, consider increasing the dose of ganaxolone, but do not exceed the maximum recommended daily dose. Risk D: Consider Therapy Modification
Gefitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Gefitinib. Risk C: Monitor
Gemfibrozil: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Gemigliptin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Gemigliptin. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Gemigliptin. Risk C: Monitor
Gepirone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Gepirone. Risk C: Monitor
Gepotidacin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Gepotidacin. Risk C: Monitor
Glasdegib: CYP3A4 Inducers (Moderate) may decrease 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. Risk D: Consider Therapy Modification
Glecaprevir and Pibrentasvir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Glecaprevir and Pibrentasvir. Risk C: Monitor
GlyBURIDE: May increase hepatotoxic effects of Bosentan. GlyBURIDE may decrease serum concentration of Bosentan. Bosentan may decrease serum concentration of GlyBURIDE. Risk X: Avoid
GuanFACINE: CYP3A4 Inducers (Moderate) may decrease 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. Risk D: Consider Therapy Modification
Hormonal Contraceptives: CYP3A4 Inducers (Moderate) may decrease serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a moderate CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider Therapy Modification
HYDROcodone: CYP3A4 Inducers (Moderate) may decrease serum concentration of HYDROcodone. Risk C: Monitor
Hydrocortisone (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Hydrocortisone (Systemic). Risk C: Monitor
Ibrexafungerp: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ibrexafungerp. Risk X: Avoid
Ibrutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ibrutinib. Risk C: Monitor
Idelalisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Idelalisib. Risk C: Monitor
Ifosfamide: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Ifosfamide. CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Ifosfamide. Risk C: Monitor
Imatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Imatinib. Risk C: Monitor
Irinotecan Products: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Irinotecan Products. Specifically, concentrations of SN-38 may be reduced. Risk C: Monitor
Isavuconazonium Sulfate: CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Moderate) may decrease isavuconazole serum concentrations. Risk C: Monitor
Isradipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Isradipine. Risk C: Monitor
Istradefylline: CYP3A4 Inducers (Moderate) may decrease serum concentration of Istradefylline. Risk C: Monitor
Itraconazole: CYP3A4 Inducers (Moderate) may decrease serum concentration of Itraconazole. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Itraconazole. Risk C: Monitor
Ivabradine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ivabradine. Risk X: Avoid
Ivacaftor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ivacaftor. Risk C: Monitor
Ixabepilone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ixabepilone. Risk C: Monitor
Ixazomib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ixazomib. Risk C: Monitor
Ketamine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ketamine. Risk C: Monitor
Ketoconazole (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Ketoconazole (Systemic). Risk C: Monitor
Lapatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lapatinib. Risk C: Monitor
Larotrectinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Larotrectinib. Management: Double the larotrectinib dose if used together with a moderate CYP3A4 inducer. Following discontinuation of the moderate CYP3A4 inducer, resume the previous dose of larotrectinib after a period of 3 to 5 times the inducer's half-life. Risk D: Consider Therapy Modification
Lazertinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lazertinib. Risk X: Avoid
Lefamulin (Intravenous): CYP3A4 Inducers (Moderate) may decrease serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with moderate CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider Therapy Modification
Lefamulin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with moderate CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider Therapy Modification
Leflunomide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Lemborexant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lemborexant. Risk X: Avoid
Lenacapavir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lenacapavir. Risk X: Avoid
Leniolisib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Leniolisib. Risk X: Avoid
Leniolisib: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid
Lercanidipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lercanidipine. Risk C: Monitor
Letermovir: Bosentan may decrease serum concentration of Letermovir. Risk X: Avoid
Levamlodipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Levamlodipine. Risk C: Monitor
Levoketoconazole: CYP3A4 Inducers (Moderate) may decrease serum concentration of Levoketoconazole. Risk C: Monitor
Levomethadone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Levomethadone. Risk C: Monitor
LinaGLIPtin: CYP3A4 Inducers (Moderate) may decrease serum concentration of LinaGLIPtin. Risk C: Monitor
Lonafarnib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lonafarnib. Risk X: Avoid
Lorlatinib: CYP3A4 Inducers (Moderate) may increase hepatotoxic effects of Lorlatinib. CYP3A4 Inducers (Moderate) may decrease serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with moderate CYP3A4 inducers. If such a combination must be used, increase lorlatinib to 125 mg daily. Monitor for reduced lorlatinib efficacy and consider closer monitoring of AST, ALT, and bilirubin. Risk D: Consider Therapy Modification
Lovastatin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lovastatin. Risk C: Monitor
Lumacaftor and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lumacaftor and Ivacaftor. Risk C: Monitor
Lumateperone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lumateperone. Risk X: Avoid
Lurasidone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Lurasidone. Management: After chronic treatment (7 days or more) with a moderate CYP3A4 inducer, lurasidone dose increases may be needed. Monitor closely for decreased lurasidone effects and increase the lurasidone dose as needed. Risk D: Consider Therapy Modification
Macimorelin: Coadministration of Bosentan and Macimorelin may alter diagnostic results. Risk C: Monitor
Macitentan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Macitentan. Risk C: Monitor
Maraviroc: CYP3A4 Inducers (Moderate) may decrease serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice/day, but only if not receiving a strong CYP3A4 inhibitor. Not recommended for pediatric patients not also receiving a strong CYP3A4 inhibitor. Contraindicated in patients with CrCl less than 30 mL/min. Risk D: Consider Therapy Modification
Maribavir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Maribavir. Risk C: Monitor
Mavacamten: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mavacamten. Risk X: Avoid
Mavorixafor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mavorixafor. Risk C: Monitor
Mefloquine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mefloquine. Risk C: Monitor
Meperidine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Meperidine. CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Meperidine. Specifically, concentrations of normeperidine, the CNS stimulating metabolite, may be increased. Risk C: Monitor
Methadone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Methadone. Risk C: Monitor
MethylPREDNISolone: CYP3A4 Inducers (Moderate) may decrease serum concentration of MethylPREDNISolone. Risk C: Monitor
Mianserin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mianserin. Risk C: Monitor
Midazolam: CYP3A4 Inducers (Moderate) may decrease serum concentration of Midazolam. Risk C: Monitor
Midostaurin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Midostaurin. Risk C: Monitor
MiFEPRIStone: May increase serum concentration of Bosentan. Risk X: Avoid
Mirodenafil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mirodenafil. Risk C: Monitor
Mitapivat: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mitapivat. Management: Consider alternatives to this combination when possible. If combined, monitor hemoglobin and titrate mitapivat beyond 50 mg twice daily, if needed, but do not exceed doses of 100 mg twice daily. Risk D: Consider Therapy Modification
Mobocertinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Mobocertinib. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Mobocertinib. Risk X: Avoid
Montelukast: CYP3A4 Inducers (Moderate) may decrease serum concentration of Montelukast. Risk C: Monitor
Naldemedine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Naldemedine. Risk C: Monitor
Naloxegol: CYP3A4 Inducers (Moderate) may decrease serum concentration of Naloxegol. Risk C: Monitor
Neratinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Neratinib. Risk X: Avoid
Netupitant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Netupitant. Risk C: Monitor
Nevirapine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nevirapine. Risk C: Monitor
NIFEdipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of NIFEdipine. Risk C: Monitor
Nilotinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nilotinib. Risk C: Monitor
Nilvadipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nilvadipine. Risk C: Monitor
NiMODipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of NiMODipine. Risk C: Monitor
Nirmatrelvir and Ritonavir: May increase serum concentration of Bosentan. Management: Consider alternative COVID-19 treatments in patients taking bosentan. If nirmatrelvir and ritonavir must be used, discontinue bosentan at least 36 hours before initiation of nirmatrelvir and ritonavir. Monitor for increased bosentan toxicities. Risk D: Consider Therapy Modification
Nirogacestat: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nirogacestat. Risk X: Avoid
Nisoldipine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Nisoldipine. Risk X: Avoid
Olaparib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Olaparib. Risk X: Avoid
Oliceridine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Oliceridine. Risk C: Monitor
Olmutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Olmutinib. Risk C: Monitor
Olutasidenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Olutasidenib. Risk X: Avoid
Omaveloxolone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Omaveloxolone. Risk X: Avoid
Osimertinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Osimertinib. Risk C: Monitor
OxyCODONE: CYP3A4 Inducers (Moderate) may decrease serum concentration of OxyCODONE. Risk C: Monitor
PACLitaxel (Conventional): CYP3A4 Inducers (Moderate) may decrease serum concentration of PACLitaxel (Conventional). Risk C: Monitor
PACLitaxel (Protein Bound): CYP3A4 Inducers (Moderate) may decrease serum concentration of PACLitaxel (Protein Bound). Risk C: Monitor
Pacritinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pacritinib. Risk C: Monitor
Palbociclib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Palbociclib. Risk C: Monitor
Paliperidone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Paliperidone. Risk C: Monitor
Palovarotene: CYP3A4 Inducers (Moderate) may decrease serum concentration of Palovarotene. Risk X: Avoid
PAZOPanib: CYP3A4 Inducers (Moderate) may decrease serum concentration of PAZOPanib. Risk C: Monitor
Pemigatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pemigatinib. Risk X: Avoid
Perampanel: CYP3A4 Inducers (Moderate) may decrease serum concentration of Perampanel. Management: Increase perampanel starting dose to 4 mg/day if used with moderate CYP3A4 inducers. Increase perampanel dose by 2 mg/day no more than once weekly based on response and tolerability. Dose adjustments may be needed if the inducer is discontinued. Risk D: Consider Therapy Modification
Phosphodiesterase 5 Inhibitors: Bosentan may decrease serum concentration of Phosphodiesterase 5 Inhibitors. Phosphodiesterase 5 Inhibitors may increase serum concentration of Bosentan. Risk C: Monitor
Pimavanserin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pimavanserin. Risk X: Avoid
Piperaquine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Piperaquine. Risk C: Monitor
Pirtobrutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pirtobrutinib. Management: Avoid concomitant use if possible. If combined, if the current pirtobrutinib dose is 200 mg once daily, increase to 300 mg once daily. If current pirtobrutinib dose is 50 mg or 100 mg once daily, increase the dose by 50 mg. Risk D: Consider Therapy Modification
PONATinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of PONATinib. Risk C: Monitor
Pralsetinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pralsetinib. Management: If this combo cannot be avoided, increase pralsetinib dose from 400 mg daily to 600 mg daily; from 300 mg daily to 500 mg daily; and from 200 mg daily to 300 mg daily. Risk D: Consider Therapy Modification
Praziquantel: CYP3A4 Inducers (Moderate) may decrease serum concentration of Praziquantel. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for reduced praziquantel efficacy. If possible, stop the moderate CYP3A4 inducer 2 to 4 weeks before praziquantel initiation. Risk D: Consider Therapy Modification
PrednisoLONE (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of PrednisoLONE (Systemic). Risk C: Monitor
PredniSONE: CYP3A4 Inducers (Moderate) may decrease serum concentration of PredniSONE. Risk C: Monitor
Pretomanid: CYP3A4 Inducers (Moderate) may decrease serum concentration of Pretomanid. Risk X: Avoid
Protease Inhibitors: May increase 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. Risk D: Consider Therapy Modification
QUEtiapine: CYP3A4 Inducers (Moderate) may decrease serum concentration of QUEtiapine. Risk C: Monitor
QuiNIDine: CYP3A4 Inducers (Moderate) may decrease serum concentration of QuiNIDine. Risk C: Monitor
QuiNINE: CYP3A4 Inducers (Moderate) may decrease serum concentration of QuiNINE. Risk C: Monitor
Quizartinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Quizartinib. Risk X: Avoid
Ranolazine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ranolazine. Risk X: Avoid
Regorafenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Regorafenib. CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Regorafenib. Risk C: Monitor
Repaglinide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Repaglinide. Risk C: Monitor
Repotrectinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Repotrectinib. Risk X: Avoid
Revumenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Revumenib. Risk X: Avoid
Ribociclib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ribociclib. Risk C: Monitor
RifAMPin: May decrease serum concentration of Bosentan. Following the initial week of concurrent rifampin, this effect is most likely. RifAMPin may increase 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). Risk C: Monitor
Rilpivirine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Rilpivirine. Risk C: Monitor
Rimegepant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Rimegepant. Risk X: Avoid
Ripretinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ripretinib. Management: Avoid this combination if possible. If concomitant use is required, increase ripretinib to 150 mg twice daily. Decrease ripretinib to 150 mg once daily 14 days after stopping a moderate CYP3A4 inducer. Monitor patients for ripretinib response and toxicity Risk D: Consider Therapy Modification
RisperiDONE: CYP3A4 Inducers (Moderate) may decrease serum concentration of RisperiDONE. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of RisperiDONE. Risk C: Monitor
Ritlecitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ritlecitinib. Risk C: Monitor
Roflumilast (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Roflumilast (Systemic). CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Roflumilast (Systemic). Risk C: Monitor
Rolapitant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Rolapitant. Risk C: Monitor
Samidorphan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Samidorphan. Risk C: Monitor
Selpercatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Selpercatinib. Risk X: Avoid
Selumetinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Selumetinib. Risk X: Avoid
Sertraline: CYP3A4 Inducers (Moderate) may decrease serum concentration of Sertraline. Risk C: Monitor
Sildenafil: Bosentan may decrease serum concentration of Sildenafil. Sildenafil may increase serum concentration of Bosentan. Management: When sildenafil is used for treatment of pulmonary arterial hypertension (PAH), coadministration of sildenafil and bosentan is not recommended. Otherwise, monitor for reduced sildenafil efficacy if combined with bosentan. Risk D: Consider Therapy Modification
Simeprevir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Simeprevir. Risk X: Avoid
Simvastatin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Simvastatin. Risk C: Monitor
Sirolimus (Conventional): CYP3A4 Inducers (Moderate) may decrease serum concentration of Sirolimus (Conventional). Risk C: Monitor
Sirolimus (Protein Bound): CYP3A4 Inducers (Moderate) may decrease serum concentration of Sirolimus (Protein Bound). Risk C: Monitor
Sonidegib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Sonidegib. Risk X: Avoid
SORAfenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of SORAfenib. Risk C: Monitor
Sotorasib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Sotorasib. Risk C: Monitor
Sparsentan: May increase adverse/toxic effects of Endothelin Receptor Antagonists. Risk X: Avoid
SUFentanil: CYP3A4 Inducers (Moderate) may decrease serum concentration of SUFentanil. Risk C: Monitor
SUNItinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of SUNItinib. Risk C: Monitor
Suvorexant: CYP3A4 Inducers (Moderate) may decrease serum concentration of Suvorexant. Risk C: Monitor
Suzetrigine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Suzetrigine. Risk X: Avoid
Tacrolimus (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Tacrolimus (Systemic). Risk C: Monitor
Tadalafil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tadalafil. Risk C: Monitor
Tamoxifen: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tamoxifen. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Tamoxifen. Risk C: Monitor
Tasimelteon: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tasimelteon. Risk C: Monitor
Tazemetostat: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tazemetostat. Risk X: Avoid
Temsirolimus: CYP3A4 Inducers (Moderate) may decrease serum concentration of Temsirolimus. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Temsirolimus. Specifically, sirolimus concentrations may be decreased. Risk C: Monitor
Teniposide: CYP3A4 Inducers (Moderate) may decrease serum concentration of Teniposide. Risk C: Monitor
Teriflunomide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tetrahydrocannabinol and Cannabidiol. Risk C: Monitor
Tetrahydrocannabinol: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tetrahydrocannabinol. Risk C: Monitor
Tezacaftor and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tezacaftor and Ivacaftor. Risk C: Monitor
Thiotepa: CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Thiotepa. CYP3A4 Inducers (Moderate) may decrease serum concentration of Thiotepa. Risk C: Monitor
Ticagrelor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ticagrelor. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Ticagrelor. Risk C: Monitor
Tivozanib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tivozanib. Risk C: Monitor
Tofacitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tofacitinib. Risk C: Monitor
Tolvaptan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tolvaptan. Risk C: Monitor
Toremifene: CYP3A4 Inducers (Moderate) may decrease serum concentration of Toremifene. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Toremifene. Risk C: Monitor
Trabectedin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Trabectedin. Risk C: Monitor
TraMADol: CYP3A4 Inducers (Moderate) may decrease serum concentration of TraMADol. Risk C: Monitor
TraZODone: CYP3A4 Inducers (Moderate) may decrease serum concentration of TraZODone. Risk C: Monitor
Tretinoin (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentration of Tretinoin (Systemic). Risk C: Monitor
Triazolam: CYP3A4 Inducers (Moderate) may decrease serum concentration of Triazolam. Risk C: Monitor
Trofinetide: May increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Management: Avoid concurrent use with OATP1B1/1B3 substrates for which small changes in exposure may be associated with serious toxicities. Monitor for evidence of an altered response to any OATP1B1/1B3 substrate if used together with trofinetide. Risk D: Consider Therapy Modification
Tucatinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Tucatinib. Risk C: Monitor
Ubrogepant: CYP3A4 Inducers (Moderate) may decrease 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. Risk D: Consider Therapy Modification
Ulipristal: CYP3A4 Inducers (Moderate) may decrease serum concentration of Ulipristal. Risk X: Avoid
Upadacitinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Upadacitinib. Risk C: Monitor
Valbenazine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Valbenazine. CYP3A4 Inducers (Moderate) may decrease active metabolite exposure of Valbenazine. Risk C: Monitor
Vandetanib: CYP3A4 Inducers (Moderate) may increase active metabolite exposure of Vandetanib. CYP3A4 Inducers (Moderate) may decrease serum concentration of Vandetanib. Risk C: Monitor
Vanzacaftor, Tezacaftor, and Deutivacaftor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vanzacaftor, Tezacaftor, and Deutivacaftor. Risk X: Avoid
Velpatasvir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Velpatasvir. Risk X: Avoid
Vemurafenib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vemurafenib. Risk C: Monitor
Venetoclax: CYP3A4 Inducers (Moderate) may decrease serum concentration of Venetoclax. Risk X: Avoid
Verapamil: CYP3A4 Inducers (Moderate) may decrease serum concentration of Verapamil. Risk C: Monitor
Vilazodone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vilazodone. Risk C: Monitor
VinCRIStine: CYP3A4 Inducers (Moderate) may decrease serum concentration of VinCRIStine. Risk C: Monitor
Vitamin K Antagonists: Bosentan may decrease serum concentration of Vitamin K Antagonists. Risk C: Monitor
Voclosporin: CYP3A4 Inducers (Moderate) may decrease serum concentration of Voclosporin. Risk X: Avoid
Vonoprazan: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vonoprazan. Risk X: Avoid
Vorapaxar: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vorapaxar. Risk X: Avoid
Voriconazole: CYP3A4 Inducers (Moderate) may decrease serum concentration of Voriconazole. Risk C: Monitor
Vortioxetine: CYP3A4 Inducers (Moderate) may decrease serum concentration of Vortioxetine. Risk C: Monitor
Voxelotor: CYP3A4 Inducers (Moderate) may decrease serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and moderate CYP3A4 inducers. If unavoidable, increase the voxelotor dose to 2,000 mg once daily. For children ages 4 to less than 12 years, weight-based dose adjustments are required. See full monograph for details. Risk D: Consider Therapy Modification
Voxilaprevir: CYP3A4 Inducers (Moderate) may decrease serum concentration of Voxilaprevir. Risk X: Avoid
Zaleplon: CYP3A4 Inducers (Moderate) may decrease serum concentration of Zaleplon. Risk C: Monitor
Zanubrutinib: CYP3A4 Inducers (Moderate) may decrease serum concentration of Zanubrutinib. Management: Avoid this combination if possible. If coadministration of zanubrutinib and a moderate CYP3A4 inducer is required, increase the zanubrutinib dose to 320 mg twice daily. Risk D: Consider Therapy Modification
Zolpidem: CYP3A4 Inducers (Moderate) may decrease serum concentration of Zolpidem. Risk C: Monitor
Zopiclone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Zopiclone. Risk C: Monitor
Zuranolone: CYP3A4 Inducers (Moderate) may decrease serum concentration of Zuranolone. Risk X: Avoid
Bioavailability of bosentan is not affected by food.
Evaluate pregnancy status prior to treatment. Exclude pregnancy prior to initiating treatment in patients who could become pregnant. Pregnancy testing is required prior to the initiation of therapy, monthly during treatment, and one month after stopping bosentan. Counsel patients on pregnancy planning, prevention, and emergency contraception. Use is contraindicated in patients who could become pregnant.
Bosentan reduces the efficacy of hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives). Do not use hormonal contraceptives as the only method of contraception. Patients may use one highly effective form of contraception (intrauterine devices [IUD] or tubal sterilization) or a combination of two methods (a hormonal contraceptive with a barrier method or two barrier methods). When a hormonal or barrier contraceptive is used, one additional method of contraception is still needed if the partner has had a vasectomy. Consult drug interactions database for more detailed information related to the use of bosentan and specific contraceptives. A missed menses or suspected pregnancy should be reported to the health care provider.
Decreased sperm counts and adverse effects on spermatogenesis have been observed during treatment; fertility may be impaired. It is not known if effects on fertility are reversible.
Outcome data related to the use of bosentan during pregnancy are limited (Amann 2023, Molelekwa 2005, Streit 2009, Tokgöz 2017). Based on data from animal reproduction studies, use during pregnancy may cause major birth defects. Use is contraindicated in patients who are pregnant.
Agents other than bosentan are recommended for treating systemic sclerosis during pregnancy (ACR [Sammaritano 2020]; Lazzaroni 2023). Patients with pulmonary arterial hypertension (PAH) are encouraged to avoid becoming pregnant (ESC/ERS [Humbert 2022]).
Bosentan is present in breast milk.
Data related to the presence of bosentan in breast milk are available from one case report. The lactating mother was taking bosentan 125 mg twice daily. Breast milk was sampled over 24 hours on days 637 and 651 postpartum. The infant received breast milk ±3 times/day with complementary foods. The highest concentration of bosentan in breast milk occurred 5 hours and 55 minutes after the maternal dose (86.1 mcg/L). The average bosentan breast milk concentration based on AUC0-12h was 49 mcg/L. Authors of the study calculated the dose of bosentan via breast milk for this infant to be 0.29 mcg/kg/day (sampling day 1) and 0.6 mcg/kg/day (sampling day 2), providing a relative infant dose (RID) of 0.01% and 0.02%, respectively, compared to the weight adjusted maternal dose (maternal weight 83 kg). This child was older and receiving limited volumes of breast milk; therefore, the authors also calculated the estimated infant dose of bosentan via breast milk to be 7.43 mcg/kg/day, providing a RID of 0.24% compared to the weight adjusted maternal dose for an infant receiving 150 mL/kg/day of breast milk. Bosentan metabolites were not evaluated. Adverse events were not observed in the infant (Nauwelaerts 2022). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).
Due to the potential for serious adverse reactions in the breastfed infant (eg, fluid retention, hepatotoxicity), breastfeeding is not recommended by the manufacturer.
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 patients who could become pregnant (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.
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)
Protein binding, plasma: >98%, primarily to albumin
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
Bioavailability: ~50%
Half-life elimination: ~5 hours; prolonged with heart failure, possibly in PAH
Time to peak, plasma: 3 to 5 hours
Excretion: Feces (as metabolites); urine (<3% as unchanged drug)
Altered kidney function: 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.
Hepatic function impairment: Exposure to bosentan may be significantly increased in hepatic impairment.
Pediatric: 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.