Tracleer

Endothelin Receptor Antagonists for PAH

NOTE: To ensure careful patient monitoring, bosentan can only be prescribed through the Bosentan REMS Program and dispensed by a specialty pharmacy distributor. Bosentan will not be available in commercial pharmacies. Information about the Bosentan REMS Program is available at www.BosentanREMSProgram.com.
Hazardous Drugs Classification
NIOSH 2016 List: Group 3
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.

cirrhosis / Delayed / 0-1.0
hepatic failure / Delayed / 0-1.0
hepatotoxicity / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
teratogenesis / Delayed / Incidence not known

elevated hepatic enzymes / Delayed / 2.0-14.0
fluid retention / Delayed / 11.0-11.0
edema / Delayed / 11.0-11.0
peripheral edema / Delayed / 11.0-11.0
chest pain (unspecified) / Early / 5.0-5.0
hypotension / Rapid / 4.0-4.0
palpitations / Early / 4.0-4.0
anemia / Delayed / 3.0-3.0
hyperbilirubinemia / Delayed / 0.3-0.3
jaundice / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
blurred vision / Early / Incidence not known

infection / Delayed / 22.0-22.0
headache / Early / 15.0-15.0
syncope / Early / 5.0-5.0
flushing / Rapid / 4.0-4.0
arthralgia / Delayed / 4.0-4.0
sinusitis / Delayed / 4.0-4.0
weight gain / Delayed / Incidence not known
pharyngitis / Delayed / Incidence not known
rash / Early / Incidence not known
oligospermia / Delayed / Incidence not known
diaphoresis / Early / Incidence not known
dizziness / Early / Incidence not known
vomiting / Early / Incidence not known
nausea / Early / Incidence not known
nasal congestion / Early / Incidence not known

Bosentan is known to cause a substantial risk for hepatotoxicity. Monitor liver function tests (LFTs) at baseline and then monthly during bosentan therapy. Avoid initiating bosentan in patients with known moderate or severe hepatic disease or impairment (Child-Pugh Class B and C) and in those patients with a baseline elevation of hepatic enzymes more than 3 times the upper limit of normal (ULN), since evaluation of potential drug-induced hepatic injury may be more difficult in such patients. Significant increases in systemic exposure to bosentan and its active metabolite have been observed in patients with moderate hepatic impairment. No initial dose adjustment is needed in patients with mild hepatic impairment. Adherence to LFT monitoring schedules is necessary to aid in the detection of potential drug-induced hepatic injury in any treated patient. Elevations in serum aminotransferases that occur during bosentan therapy require close attention. If elevated LFTs occur during bosentan therapy, more frequent monitoring and either dosage reduction or treatment interruption is necessary. Bosentan therapy should be discontinued if hepatic enzyme elevations are accompanied by increased serum bilirubin (i.e., at least 2 times the ULN) and/or clinical signs of hepatic disease or hepatitis (e.g., nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue). There is no experience with the reintroduction of bosentan in these circumstances. In the setting of close monitoring in the postmarketing period, 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 also have been rare reports of hepatic failure. The contribution of bosentan in these cases could not be excluded. In at least 1 case, the initial presentation (after more than 20 months of treatment) included pronounced elevations in LFTs and hyperbilirubinemia accompanied by nonspecific symptoms, all of which resolved slowly over time after discontinuation of bosentan. In patients who have previously experienced liver function abnormalities while taking bosentan, ambrisentan may be considered. In an open-label study, 36 patients who had previously discontinued endothelin receptor antagonists, including bosentan, due to elevated aminotransferase more than 3 times the ULN were treated with ambrisentan. Patients received ambrisentan 2.5 mg PO once daily for 4 weeks, followed by 5 mg PO once daily for 20 weeks, and then 2.5 mg, 5 mg, or 10 mg PO once daily thereafter. After a median of 13 months of followup, 50% of patients were receiving ambrisentan 10 mg PO once daily. One patient receiving 5 mg PO once daily experienced a mild elevation in LFTs that required a temporary dose reduction to 2.5 mg PO once daily; the patient subsequently tolerated 10 mg PO once daily. During this study, no patients discontinued ambrisentan secondary to LFT elevations.

Bosentan is contraindicated for use in pregnancy. While there are no adequate and well-controlled studies in pregnant women, animal studies demonstrate that bosentan is a teratogen and likely to cause major birth defects when administered during human pregnancy. In rats, bosentan use at doses 2 times the maximum recommended human dose (MRHD) resulted in serious dose-dependent teratogenic effects including malformations of the head, mouth, face, and large blood vessels. Bosentan increased stillbirths and mortality at oral doses 2 and 10 times the MRHD.

Discuss the reproductive risk of bosentan and contraception requirements, including the need for pregnancy testing prior to treatment initiation, monthly during treatment, and for 1 month after discontinuation with the female patient of childbearing potential. Advise female patients of childbearing potential to contact their physician immediately if there is any delay in the onset of menses or any other reason to suspect pregnancy. If the pregnancy test is positive, the physician and patient must discuss the risks to the woman, pregnancy, and the fetus. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives, may not be reliable, as bosentan is a significant inducer of the hepatic CYP3A4 isoenzyme. Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Bosentan carries a potential for infertility in males; decreased sperm counts have been observed in male patients receiving bosentan. It is unclear whether effects on fertility are reversible. Preclinical animal data also suggest that bosentan, like other endothelin receptor antagonists, may have an adverse effect on spermatogenesis.

Tracleer

Rx

Specific, competitive endothelin-receptor antagonist
Indicated for pulmonary arterial hypertension adult and pediatric patients 3 years of age and older
Due to a potential for hepatotoxicity and fetal harm, prescribers, pharmacies, and patients must enroll in the Bosentan REMS Program

†Indicates off-label use

Aminotransferases more than 3 times the upper limit of normal (ULN) at baseline:
Avoid use.
 
Aminotransferase elevation more than 3 to 5 times ULN during treatment:
Adults and Adolescents weighing more than 40 kg: Repeat test to confirm. If confirmed, reduce the dose to 62.5 mg twice daily or interrupt treatment and monitor LFTs at least every 2 weeks. When levels return to baseline, treatment may continue or be reintroduced at 62.5mg twice daily; reassess LFTs within 3 days.
All other pediatric patients: Repeat test to confirm. If confirmed, interrupt treatment with no prior dose reductions. When levels return to baseline, reintroduce bosentan at the dose used prior to treatment interruption; reassess LFTs within 3 days.
 
Aminotransferase elevation more than 5 to 8 times ULN during treatment:
Adults and Adolescents weighing more than 40 kg: Repeat test to confirm. If confirmed, discontinue treatment and monitor LFTs at least every 2 weeks. When levels return to baseline, consider reintroduction of bosentan 62.5 mg twice daily; reassess LFTs within 3 days.
All other pediatric patients: Repeat test to confirm. If confirmed, discontinue treatment and monitor LFTs at least every 2 weeks. When levels return to baseline, consider reintroduction of bosentan at the dose used prior to treatment interruption; reassess LFTs within 3 days.
 
Aminotransferase elevation more than 8 times ULN and/or accompanied by clinical symptoms of hepatotoxicity or bilirubin elevation at least 2 times ULN during treatment:
Discontinue treatment permanently.

No dosage adjustments are needed.
 
Intermittent hemodialysis:
It is not known whether bosentan is removed by hemodialysis.

Abacavir; Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with bosentan; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Bosentan is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Abemaciclib: (Major) Avoid coadministration of bosentan with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Consider alternative treatments. Abemaciclib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 53%, 41%, and 29% respectively.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with bosentan can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If bosentan is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Bosentan is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with bosentan can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bosentan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bosentan is a moderate CYP3A4 inducer.
Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with bosentan can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bosentan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with bosentan is necessary; consider increasing the dose of oxycodone as needed. If bosentan is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Adagrasib: (Major) Avoid concomitant use of adagrasib and bosentan as the systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions. Bosentan is a CYP2C9 and CYP3A substrate; adagrasib is a moderate CYP2C9 and strong CYP3A inhibitor.
Alfentanil: (Moderate) Drugs that induce cytochrome P450 3A4, including bosentan, may decrease the effectiveness of alfentanil, a substrate for the cytochrome 3A4 isoenzyme. Induction of alfentanil metabolism may take several days.
Amiodarone: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes, including amiodarone.
Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with bosentan is necessary. Amlodipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Atorvastatin: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with bosentan is necessary. Amlodipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Benazepril: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with bosentan is necessary. Amlodipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Celecoxib: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with bosentan is necessary. Amlodipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Olmesartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with bosentan is necessary. Amlodipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with bosentan is necessary. Amlodipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with bosentan is necessary. Amlodipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of bosentan and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Coadministration may also increase the plasma concentrations of bosentan. The potential for increased bosentan effects should be monitored.
Aprepitant, Fosaprepitant: (Moderate) Use caution if bosentan and aprepitant, fosaprepitant are used concurrently, and monitor for a possible decrease in the efficacy of aprepitant; an increase in bosentan-related adverse effects may also occur for several days after administration of a multi-day aprepitant regimen. Bosentan is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of bosentan. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Additionally, bosentan is a moderate CYP3A4 inducer and aprepitant, fosaprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for low-to-moderate inducers. Finally, aprepitant, fosaprepitant is a CYP2C9 inducer and bosentan is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
Asciminib: (Moderate) Monitor for an increase in bosentan-related adverse reactions if concomitant use of asciminib is necessary. Concomitant use may increase bosentan exposure. Administration of bosentan with both asciminib 200 mg twice daily and a strong or moderate CYP3A inhibitor is not recommended. Bosentan is a CYP2C9 and CYP3A substrate; asciminib is a moderate CYP2C9 inhibitor at a dose of 200 mg twice daily, and a weak CYP2C9 inhibitor at doses less than 200 mg twice daily.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with bosentan can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bosentan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bosentan is a moderate CYP3A4 inducer.
Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with bosentan is necessary; consider increasing the dose of oxycodone as needed. If bosentan is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Atazanavir: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Atazanavir; Cobicistat: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied. (Major) The plasma concentrations of bosentan may increase when administered with regimens containing cobicistat and atazanavir or darunavir. In addition, coadministration may result in decreased concentrations of cobicistat, atazanavir, and darunavir. In patients receiving the antiretrovirals for at least 10 days, start bosentan at 62.5 mg daily or every other day (depending on tolerability). When the antiretrovirals are initiated in a patients currently receiving bosentan, discontinue bosentan at least 36 hours prior to starting the antiretroviral regimen. After at least 10 days, restart bosentan at 62.5 mg daily or every other day based on tolerability. If switching from a ritonavir boosted antiretroviral regimen to a cobicistat boosted regimen, maintain current bosentan dose.
Atogepant: (Major) Avoid use of atogepant and bosentan when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with bosentan. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and bosentan is a moderate CYP3A inducer.
Avacopan: (Major) Avoid concomitant use of avacopan and bosentan due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and bosentan is a moderate CYP3A inducer.
Avanafil: (Minor) Avanafil is primarily metabolized by CYP3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as bosentan, will decrease plasma levels of avanafil, however, no interaction studies have been performed. Concomitant use is not recommended.
Avapritinib: (Major) Avoid coadministration of avapritinib with bosentan due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Avatrombopag: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with bosentan. In patients starting bosentan while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as bosentan decrease avatrombopag exposure, which may reduce efficacy.
Axitinib: (Major) Avoid coadministration of axitinib with bosentan if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and bosentan is a moderate CYP3A4 inducer.
Bedaquiline: (Major) Avoid concurrent use of bosentan with bedaquiline. Bosentan is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with bosentan may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If concomitant use is necessary, consider increasing the benzhydrocodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Discontinuation of bosentan may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If bosentan is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Bosentan is an inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
Berotralstat: (Moderate) Use caution if coadministration of berotralstat with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions; however, a bosentan dose adjustment is not necessary. Administration of bosentan with both berotralstat and a strong or moderate CYP2C9 inhibitor is not recommended. Bosentan is a CYP3A4 and CYP2C9 substrate; berotralstat is a moderate CYP3A4 inhibitor.
Brigatinib: (Major) Avoid coadministration of brigatinib with bosentan due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with bosentan, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of bosentan, resume the brigatinib dose that was tolerated prior to initiation of bosentan. Brigatinib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and bosentan are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; bosentan is a moderate inducer of CYP3A4.
Buprenorphine: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes, including buprenorphine.
Buprenorphine; Naloxone: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes, including buprenorphine.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with bosentan can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bosentan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bosentan is a moderate CYP3A4 inducer.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with bosentan can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bosentan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bosentan is a moderate CYP3A4 inducer.
Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering bosentan with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bosentan is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Cannabidiol: (Moderate) Consider a dose reduction of bosentan as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Increased bosentan exposure is possible. Bosentan is a CYP2C9 substrate. In vitro data predicts inhibition of CYP2C9 by cannabidiol potentially resulting in clinically significant interactions.
Capmatinib: (Major) Avoid coadministration of capmatinib and bosentan due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
Carbamazepine: (Moderate) Coadministration of bosentan and carbamazepine may result in decreased plasma concentrations of both drugs; monitor for loss of therapeutic effect. Bosentan is an inducer of cytochrome P450 3A4, the major isoform responsible for carbamazepine's metabolism. If a patient is stable on carbamazepine therapy and bosentan is initiated, monitor plasma carbamazepine concentrations and clinical efficacy; a carbamazepine dosage adjustment may be necessary. Additionally, carbamazepine may theoretically decrease serum concentrations of bosentan. Carbamazepine is an inducer of both CYP2C9 and CYP3A4, the isoenzymes known to be involved in the metabolism of bosentan.
Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as bosentan, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear. In addition, orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
Ceritinib: (Moderate) Use caution if coadministration of ceritinib with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions; however, a bosentan dose adjustment is not necessary. Administration of bosentan with both ceritinib and a strong or moderate CYP2C9 inhibitor is not recommended. Ceritinib is a strong CYP3A4 inhibitor and a weak CYP2C9 inhibitor. Bosentan is a CYP3A4 and CYP2C9 substrate.
Chloramphenicol: (Moderate) Chloramphenicol is a potent inhibitor of CYP3A4. Chloramphenicol may increase the risk of toxicity from CYP3A4 substrates such as bosentan. Excessive bosentan dosage can result in hypotension or elevated hepatic enzymes.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with bosentan can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bosentan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bosentan is a moderate CYP3A4 inducer.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with bosentan can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If bosentan is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Bosentan is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with bosentan can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bosentan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Ciprofloxacin: (Moderate) Coadministration of bosentan, a CYP3A4 substrate, with ciprofloxacin, a CYP3A4 inhibitor, may increase the plasma concentrations of bosentan. No dosage adjustment of bosentan is needed, however, the potential for increased bosentan effects, such as hepatic injury or decreased blood pressure, should be monitored.
Clarithromycin: (Major) Coadministration of bosentan and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Coadministration may also increase the plasma concentrations of bosentan. The potential for increased bosentan effects should be monitored.
Clozapine: (Moderate) Concomitant use of clozapine and bosentan can increase the risk and severity of hypotension by potentiating the effect of bosentan; monitor for hypotension. In addition, bosentan is an inducer of CYP3A4 and clozapine is partially metabolized by this isoenzyme. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP3A4 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
Cobicistat: (Major) The plasma concentrations of bosentan may increase when administered with regimens containing cobicistat and atazanavir or darunavir. In addition, coadministration may result in decreased concentrations of cobicistat, atazanavir, and darunavir. In patients receiving the antiretrovirals for at least 10 days, start bosentan at 62.5 mg daily or every other day (depending on tolerability). When the antiretrovirals are initiated in a patients currently receiving bosentan, discontinue bosentan at least 36 hours prior to starting the antiretroviral regimen. After at least 10 days, restart bosentan at 62.5 mg daily or every other day based on tolerability. If switching from a ritonavir boosted antiretroviral regimen to a cobicistat boosted regimen, maintain current bosentan dose.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with bosentan due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and bosentan is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Codeine: (Moderate) Concomitant use of codeine with bosentan can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bosentan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bosentan is a moderate CYP3A4 inducer.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with bosentan can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bosentan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bosentan is a moderate CYP3A4 inducer.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with bosentan can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bosentan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bosentan is a moderate CYP3A4 inducer.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with bosentan can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bosentan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bosentan is a moderate CYP3A4 inducer.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with bosentan can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If bosentan is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Bosentan is a moderate CYP3A4 inducer.
Conivaptan: (Moderate) Use caution if coadministration of conivaptan with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions; however, a bosentan dose adjustment is not necessary. Administration of bosentan with both conivaptan and a strong or moderate CYP2C9 inhibitor is not recommended. Bosentan is a CYP3A and CYP2C9 substrate; conivaptan is a moderate CYP3A inhibitor.
Conjugated Estrogens; Medroxyprogesterone: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Crizotinib: (Moderate) Use caution if coadministration of crizotinib with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions; however, a bosentan dose adjustment is not necessary. Administration of bosentan with both crizotinib and a strong or moderate CYP2C9 inhibitor is not recommended. Bosentan is a CYP3A and CYP2C9 substrate; crizotinib is a moderate CYP3A inhibitor.
Cyclosporine: (Contraindicated) The concomitant administration of bosentan and cyclosporine A is contraindicated. During the first day of coadministration with cyclosporine, trough concentrations of bosentan are increased by about 30-fold. Steady-state, bosentan plasma concentrations are 3- to 4-fold higher with concurrent cyclosporine administration. In addition, coadministration of bosentan at higher than approved doses (500-1000 mg PO twice daily) decreases the plasma concentrations of cyclosporine A (CYP3A4 substrate) by approximately 50%. In the cyclosporine interaction study, clinical toxicity has been observed, including: severe headache, nausea, vomiting, mild decreases in blood pressure, and small increases in heart rate; no serious adverse effects were reported.
Daclatasvir: (Major) Increase the dose of daclatasvir to 90 mg PO once daily if coadministered with bosentan due to decreased daclatasvir exposure resulting in potential loss of virologic control. Daclatasvir is a CYP3A substrate; bosentan is a moderate CYP3A inducer. Coadministration of a moderate CYP3A inducer reduced the daclatasvir AUC by 63%.
Danazol: (Moderate) Danazol is a CYP3A4 inhibitor, and may reduce the hepatic metabolism of CYP3A4 substrates including bosentan. Excessive bosentan dosage can result in hypotension or elevated hepatic enzymes.
Dapsone: (Moderate) Closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia if coadministration with bosentan is necessary. Dapsone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis).
Daridorexant: (Major) Avoid concomitant use of daridorexant and bosentan. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Darifenacin: (Minor) Bosentan may induce the CYP3A4 metabolism of darifenacin and thereby reduce its oral bioavailability. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
Darunavir: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Darunavir; Cobicistat: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied. (Major) The plasma concentrations of bosentan may increase when administered with regimens containing cobicistat and atazanavir or darunavir. In addition, coadministration may result in decreased concentrations of cobicistat, atazanavir, and darunavir. In patients receiving the antiretrovirals for at least 10 days, start bosentan at 62.5 mg daily or every other day (depending on tolerability). When the antiretrovirals are initiated in a patients currently receiving bosentan, discontinue bosentan at least 36 hours prior to starting the antiretroviral regimen. After at least 10 days, restart bosentan at 62.5 mg daily or every other day based on tolerability. If switching from a ritonavir boosted antiretroviral regimen to a cobicistat boosted regimen, maintain current bosentan dose.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied. (Major) The plasma concentrations of bosentan may increase when administered with regimens containing cobicistat and atazanavir or darunavir. In addition, coadministration may result in decreased concentrations of cobicistat, atazanavir, and darunavir. In patients receiving the antiretrovirals for at least 10 days, start bosentan at 62.5 mg daily or every other day (depending on tolerability). When the antiretrovirals are initiated in a patients currently receiving bosentan, discontinue bosentan at least 36 hours prior to starting the antiretroviral regimen. After at least 10 days, restart bosentan at 62.5 mg daily or every other day based on tolerability. If switching from a ritonavir boosted antiretroviral regimen to a cobicistat boosted regimen, maintain current bosentan dose.
Deflazacort: (Major) Avoid concomitant use of deflazacort and bosentan. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; bosentan is a moderate inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
Delavirdine: (Major) Bosentan is a significant inducer of CYP3A4 hepatic enzymes. Theoretically, bosentan may increase the clearance of delavirdine (CYP3A4 substrate); however, this interaction has not been studied. In addition, delavirdine may inhibit two pathways for bosentan metabolism (CYP3A4 and CYP2C9). It is important to review all the medications taken concurrently with bosentan. According to the manufacturer, coadministration of bosentan with a potent CYP2C9 inhibitor plus a CYP3A4 inhibitor is not recommended; large increases in bosentan plasma concentrations are expected with such combinations.
Desogestrel; Ethinyl Estradiol: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Diazepam: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes, including diazepam.
Dienogest; Estradiol valerate: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Diltiazem: (Major) Avoid coadministration of diltiazem and bosentan if possible due to decreased plasma concentrations of diltiazem; additionally, increased plasma concentrations of bosentan may occur. If coadministration unavoidable, monitor blood pressure and heart rate and adjust the diltiazem and bosentan dose based on clinical response. Diltiazem is a CYP3A4 substrate and inhibitor; bosentan is a CYP3A4 substrate and moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased diltiazem exposure by 69% and decreased exposure to desacetyldiltiazem by 75%.
Disulfiram: (Moderate) Disulfiram inhibits CYP2C9 and may theoretically lead to elevated plasma concentrations of bosentan when coadministered. Monitor for potential adverse effects of bosentan during coadministration; excessive bosentan dosage may result in hypotension or elevated hepatic enzymes.
Dolutegravir: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with bosentan; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Bosentan is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Dolutegravir; Lamivudine: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with bosentan; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Bosentan is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering bosentan with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bosentan is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with bosentan; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Bosentan is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Doravirine: (Moderate) Concurrent administration of doravirine and bosentan may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Concurrent administration of doravirine and bosentan may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer.
Doxorubicin Liposomal: (Major) Bosentan is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of bosentan and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
Doxorubicin: (Major) Bosentan is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of bosentan and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with bosentan is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; bosentan is a moderate inducer of CYP2C9 and 3A4. Concomitant use may result in decreased plasma concentrations of dronabinol.
Dronedarone: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A. Bosentan induces and is a substrate for CYP3A4. Coadministration of CYP3A4 inducers, such as bosentan, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy; plasma concentrations of bosentan may also be increased.
Drospirenone: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Drospirenone; Estetrol: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Drospirenone; Estradiol: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be neces sary.
Drospirenone; Ethinyl Estradiol: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Duvelisib: (Major) Avoid concomitant use of duvelisib with bosentan. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib; the systemic exposure of bosentan may also increase resulting in an increase in treatment-related adverse reactions. If concomitant use is necessary, increase the dose of duvelisib on day 12 of coadministration from 25 mg PO twice daily to 40 mg PO twice daily; or from 15 mg PO twice daily to 25 mg PO twice daily; a bosentan dose adjustment is not necessary. Administration of bosentan with both duvelisib and a strong or moderate CYP2C9 inhibitor is not recommended. When bosentan has been discontinued for at least 14 days, resume duvelisib at the dose taken prior to initiating treatment with bosentan. Duvelisib is a CYP3A substrate and a moderate CYP3A4 inhibitor. Bosentan is a moderate CYP3A inducer and a CYP3A4 and CYP2C9 substrate. Coadministration of duvelisib with another moderate CYP3A inducer for 12 days decreased duvelisib exposure by 35%.
Efavirenz: (Minor) Bosentan is metabolized by CYP2C9 and CYP3A4 isoenzymes. Although not studied, efavirenz may induce these isoenzymes and thereby alter the plasma concentrations of bosentan. It is prudent to monitor bosentan therapy for loss of efficacy during coadministration.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) Bosentan is metabolized by CYP2C9 and CYP3A4 isoenzymes. Although not studied, efavirenz may induce these isoenzymes and thereby alter the plasma concentrations of bosentan. It is prudent to monitor bosentan therapy for loss of efficacy during coadministration.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Minor) Bosentan is metabolized by CYP2C9 and CYP3A4 isoenzymes. Although not studied, efavirenz may induce these isoenzymes and thereby alter the plasma concentrations of bosentan. It is prudent to monitor bosentan therapy for loss of efficacy during coadministration.
Elacestrant: (Major) Avoid concurrent use of elacestrant and bosentan due to the risk of decreased elacestrant exposure which may reduce its efficacy. Elacestrant is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced elacestrant overall exposure by 55% to 73%.
Elagolix; Estradiol; Norethindrone acetate: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Elbasvir; Grazoprevir: (Major) Concurrent administration of elbasvir with bosentan should be avoided if possible. Bosentan is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) Concurrent administration of grazoprevir with bosentan should be avoided if possible. Bosentan is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response.
Eltrombopag: (Moderate) Use caution and monitor for adverse reactions if eltrombopag and bosentan are coadministered. Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as bosentan, may exhibit an increase in systemic exposure if coadministered with eltrombopag.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministation of bosentan with elvitegravir may result in elevated bosentan plasma concentrations and reduced elvitegravir concentrations. In patients receiving the antiretroviral for at least 10 days, start bosentan at 62.5 mg daily or every other day (depending on tolerability). When the antiretroviral is initiated in a patients currently receiving bosentan, discontinue bosentan at least 36 hours prior to starting the antiretroviral. After at least 10 days, restart bosentan at 62.5 mg daily or every other day based on tolerability. (Major) The plasma concentrations of bosentan may increase when administered with regimens containing cobicistat and atazanavir or darunavir. In addition, coadministration may result in decreased concentrations of cobicistat, atazanavir, and darunavir. In patients receiving the antiretrovirals for at least 10 days, start bosentan at 62.5 mg daily or every other day (depending on tolerability). When the antiretrovirals are initiated in a patients currently receiving bosentan, discontinue bosentan at least 36 hours prior to starting the antiretroviral regimen. After at least 10 days, restart bosentan at 62.5 mg daily or every other day based on tolerability. If switching from a ritonavir boosted antiretroviral regimen to a cobicistat boosted regimen, maintain current bosentan dose.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministation of bosentan with elvitegravir may result in elevated bosentan plasma concentrations and reduced elvitegravir concentrations. In patients receiving the antiretroviral for at least 10 days, start bosentan at 62.5 mg daily or every other day (depending on tolerability). When the antiretroviral is initiated in a patients currently receiving bosentan, discontinue bosentan at least 36 hours prior to starting the antiretroviral. After at least 10 days, restart bosentan at 62.5 mg daily or every other day based on tolerability. (Major) The plasma concentrations of bosentan may increase when administered with regimens containing cobicistat and atazanavir or darunavir. In addition, coadministration may result in decreased concentrations of cobicistat, atazanavir, and darunavir. In patients receiving the antiretrovirals for at least 10 days, start bosentan at 62.5 mg daily or every other day (depending on tolerability). When the antiretrovirals are initiated in a patients currently receiving bosentan, discontinue bosentan at least 36 hours prior to starting the antiretroviral regimen. After at least 10 days, restart bosentan at 62.5 mg daily or every other day based on tolerability. If switching from a ritonavir boosted antiretroviral regimen to a cobicistat boosted regimen, maintain current bosentan dose.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering bosentan with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bosentan is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Close clinical monitoring is advised when administering bosentan with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bosentan is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Encorafenib: (Major) Avoid coadministration of encorafenib and bosentan due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Entrectinib: (Major) Avoid coadministration of entrectinib with bosentan due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Erdafitinib: (Major) If coadministration of erdafitinib and bosentan is necessary at the initiation of erdafitinib therapy, administer the dose of erdafitinib as recommended (8 mg once daily with potential to increase the dose to 9 mg on days 14 to 21 based on phosphate levels and tolerability). If bosentan must be added to erdafitinib therapy after the initial dose increase period (days 14 to 21), increase the dose of erdafitinib up to 9 mg. If bosentan is discontinued, continue erdafitinib at the same dose in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 and CYP2C9 substrate. Bosentan is a moderate CYP3A4 and CYP2C9 inducer.
Erlotinib: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with bosentan; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and bosentan is a moderate CYP3A4 inducer.
Erythromycin: (Moderate) Co-administration of bosentan with erythromycin, a CYP3A4 inhibitor, may increase the plasma concentrations of bosentan. The potential for increased bosentan effects should be monitored. The severity of this interaction is increased when erythromycin is combined with a potent CYP 2C9 inhibitor, like sulfisoxazole.
Estradiol; Levonorgestrel: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Estradiol; Norethindrone: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Estradiol; Norgestimate: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Estradiol; Progesterone: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Estrogens affected by CYP3A inducers: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use two acceptable contraception methods during treatment and for one month after discontinuation of bosentan therapy. The patient may choose one highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or two barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on bosentan, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and bosentan is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Ethinyl Estradiol; Norelgestromin: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Ethinyl Estradiol; Norgestrel: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Ethotoin: (Moderate) Bosentan is a significant inducer of CYP2C9 hepatic enzymes. Theoretically, bosentan can increase ethotoin clearance via hepatic induction. Monitor ethotoin levels.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Etonogestrel: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Etonogestrel; Ethinyl Estradiol: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with bosentan is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
Ezetimibe; Simvastatin: (Moderate) Co-administration of bosentan decreases the plasma concentrations of simvastatin, a CYP3A4 substrate, and its active metabolite, by approximately 50%. The possibility of reduced anti-lipemic efficacy should be considered. Patients receiving simvastatin should have cholesterol levels monitored after adding bosentan therapy to evaluate the need for anti-lipemic dosage adjustment.
Fedratinib: (Major) Avoid coadministration of fedratinib with bosentan as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. The systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions. Fedratinib is a CYP3A4 substrate and moderate CYP3A4 inhibitor; bosentan is a CYP3A4 substrate and moderate CYP3A4 inducer. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as bosentan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of bosentan during coadministration with fenofibric acid.
Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with bosentan is necessary. If bosentan is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a moderate CYP3A4 inducer like bosentan with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Finasteride; Tadalafil: (Moderate) Bosentan reduces tadalafil systemic exposure by 42% and Cmax by 27% with multiple-dose coadministration. Tadalafil has no significant effect on the exposure of bosentan. Bosentan is a substrate and moderate inducer of CYP3A; tadalafil is a CYP3A substrate.
Finerenone: (Major) Avoid concurrent use of finerenone and bosentan due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased overall exposure to finerenone by 80%.
Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and CYP3A4 inducers, such as bosentan, is not recommended.
Fluconazole: (Major) Coadministration of fluconazole with bosentan is not recommended due to the potential for large increases in bosentan exposure. Fluconazole is a CYP3A4 and CYP2C9 inhibitor; bosentan is metabolized by both CYP3A4 and CYP2C9.
Fluorouracil, 5-FU: (Moderate) Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan. Fluorouracil, 5-FU is an inhibitor of CYP2C9 isoenzymes. The inhibition of CYP2C9 appears to be greater after higher total doses of fluorouracil are administered. Fluorouracil, 5-FU may significantly inhibit CYP2C9-mediated metabolism of bosentan. Monitor for potential adverse effects of bosentan during coadministration; excessive dosage may result in hypotension or elevated hepatic enzymes.
Fluoxetine: (Moderate) Bosentan is metabolized by CYP2C9 and CYP3A4. Fluoxetine may inhibit both of these isoenzymes and thereby increase the plasma concentrations of bosentan. It is prudent to monitor for potential adverse effects of bosentan during coadministration with fluoxetine; excessive dosage may result in hypotension or elevated hepatic enzymes.
Fluvoxamine: (Moderate) Bosentan is metabolized by CYP2C9 and CYP3A4. Fluvoxamine is a moderate inhibitor of both CYP2C9 and CYP3A4 pathways. Concomitant therapy with fluvoxamine may increase the plasma concentrations of bosentan. Monitor for potential adverse effects of bosentan during coadministration; excessive dosage may result in hypotension or elevated hepatic enzymes.
Fosamprenavir: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Fosphenytoin: (Moderate) Bosentan is a significant inducer of CYP2C9 and CYP3A4 hepatic isoenzymes. Theoretically, bosentan can increase the hepatic clearance of phenytoin, a CYP2C9 substrate, after its conversion from fosphenytoin. However, this interaction has not been studied.
Ganaxolone: (Major) Avoid concurrent use of ganaxolone and bosentan due to the risk of decreased ganaxolone efficacy. If concomitant use is unavoidable, consider increasing ganaxolone dose without exceeding the maximum daily dose. Ganaxolone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Gemfibrozil: (Moderate) Use bosentan and gemfibrozil together with caution. Bosentan is a substrate of the OATP1B1 transporter. Gemfibrozil inhibits OATP1B1. Coadministration may result in an increase in bosentan exposure. A dose reduction of bosentan may be required if used concomitantly with gemfibrozil.
Glasdegib: (Major) Avoid coadministration of glasdegib and bosentan due to the potential for decreased glasdegib exposure and risk of decreased efficacy. If concurrent use cannot be avoided, increase the glasdegib dosage (i.e., from 100 mg PO daily to 200 mg PO daily; or from 50 mg PO daily to 100 mg PO daily). Resume the previous dose of glasdegib after bosentan has been discontinued for 7 days. Glasdegib is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer was predicted to decrease the glasdegib AUC value by 55%.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and bosentan as coadministration may increase serum concentrations of bosentan and increase the risk of adverse effects. Bosentan is a substrate of organic anion transporting polypeptide (OATP) 1B1/3; glecaprevir is an inhibitor of OATP1B1/3. (Moderate) Caution is advised with the coadministration of pibrentasvir and bosentan as coadministration may increase serum concentrations of bosentan and increase the risk of adverse effects. Bosentan is a substrate of organic anion transporting polypeptide (OATP) 1B1/3; pibrentasvir is an inhibitor of OATP1B1/3.
Glimepiride: (Moderate) Bosentan is an inducer of CYP2C9 and is expected to reduce plasma concentrations of oral antidiabetic agents that are predominantly metabolized by CYP2C9 enzymes, such as glimepiride. Blood glucose monitoring is prudent following addition of bosentan therapy to such antidiabetic drugs.
Glipizide: (Moderate) Bosentan is an inducer of CYP2C9 and is expected to reduce plasma concentrations of oral antidiabetic agents that are predominantly metabolized by CYP2C9 enzymes, such as glipizide; blood glucose monitoring is prudent following addition of bosentan therapy to such antidiabetic drugs.
Glipizide; Metformin: (Moderate) Bosentan is an inducer of CYP2C9 and is expected to reduce plasma concentrations of oral antidiabetic agents that are predominantly metabolized by CYP2C9 enzymes, such as glipizide; blood glucose monitoring is prudent following addition of bosentan therapy to such antidiabetic drugs.
Glyburide: (Contraindicated) Coadministration of bosentan and glyburide is contraindicated, and alternative antidiabetic agents should be considered. An increased risk of elevated liver enzymes has been observed in patients receiving concomitant therapy with bosentan and glyburide. Coadministration of bosentan decreases the plasma concentrations of glyburide by approximately 40%. The plasma concentrations of bosentan are also decreased by approximately 30%.
Glyburide; Metformin: (Contraindicated) Coadministration of bosentan and glyburide is contraindicated, and alternative antidiabetic agents should be considered. An increased risk of elevated liver enzymes has been observed in patients receiving concomitant therapy with bosentan and glyburide. Coadministration of bosentan decreases the plasma concentrations of glyburide by approximately 40%. The plasma concentrations of bosentan are also decreased by approximately 30%.
Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with bosentan can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bosentan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Guanfacine: (Major) Bosentan may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if bosentan is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If bosentan is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with a centrally-acting adrenergic agonist such as guanfacine. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and bosentan is a moderate CYP3A4 inducer.
Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with bosentan can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bosentan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Hydrocodone: (Moderate) Concomitant use of hydrocodone with bosentan can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bosentan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with bosentan can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bosentan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with bosentan can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bosentan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with bosentan. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and bosentan is a moderate CYP3A inducer.
Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with bosentan is necessary; consider increasing the dose of oxycodone as needed. If bosentan is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Idelalisib: (Major) Coadministration of idelalisib with bosentan may increase bosentan exposure; monitor patients for signs and symptoms of bosentan-related adverse reactions (e.g., hepatotoxicity and anemia). Idelalisib is a strong CYP3A4 inhibitor and bosentan is a CYP3A substrate. The bosentan plasma concentration increased by 100% when bosentan was administered with another strong CYP3A inhibitor in a drug interaction study.
Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with bosentan is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; bosentan is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
Indinavir: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Infigratinib: (Major) Avoid concurrent use of infigratinib and bosentan. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Isavuconazonium: (Major) Concomitant use of isavuconazonium with bosentan may result in increased serum concentrations of bosentan and decreased concentrations of isavuconazonium. Bosentan is a substrate and inducer of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concomitant administration of a single dose of rifampin (a known inducer of CYP2C9 and CYP3A4) and bosentan in normal volunteers has resulted in increased mean bosentan serum concentrations (trough) by 6-fold; however, coadministration of rifampin with bosentan decreases bosentan serum concentrations at steady-state by about 60%. The effect of bosentan on rifampin serum concentrations has not been assessed. When concomitant use is justified after weighing the risks and benefits, the manufacturer recommends monitoring LFTs weekly for the first 4 weeks, and then to follow routine recommendations for monitoring LFTs during bosentan therapy.
Isoniazid, INH; Rifampin: (Major) Concomitant administration of a single dose of rifampin (a known inducer of CYP2C9 and CYP3A4) and bosentan in normal volunteers has resulted in increased mean bosentan serum concentrations (trough) by 6-fold; however, coadministration of rifampin with bosentan decreases bosentan serum concentrations at steady-state by about 60%. The effect of bosentan on rifampin serum concentrations has not been assessed. When concomitant use is justified after weighing the risks and benefits, the manufacturer recommends monitoring LFTs weekly for the first 4 weeks, and then to follow routine recommendations for monitoring LFTs during bosentan therapy.
Isradipine: (Moderate) Closely monitor blood pressure if coadministration of isradipine with bosentan is necessary; decreased plasma concentrations of isradipine may occur. Isradipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Itraconazole: (Moderate) Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan. Coadministration of bosentan with ketoconazole, a potent CYP3A4 inhibitor, has been shown to increase the plasma concentrations of bosentan by approximately 2-fold. No dosage adjustment of bosentan is needed; however, the potential for increased bosentan effects should be monitored. Although data are lacking, itraconazole could also increase bosentan plasma concentrations via CYP3A4 inhibition.
Ketoconazole: (Moderate) Use caution if coadministration of ketoconazole with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in bosentan-related adverse reactions; however, a bosentan dose adjustment is not necessary. Administration of bosentan with both ketoconazole and a strong or moderate CYP2C9 inhibitor is not recommended. Bosentan is a CYP3A4 and CYP2C9 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the plasma concentrations of bosentan by approximately 2-fold.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Coadministration of bosentan and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Coadministration may also increase the plasma concentrations of bosentan. The potential for increased bosentan effects should be monitored.
Larotrectinib: (Major) Avoid concurrent use of larotrectinib and bosentan due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If bosentan is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of bosentan. Larotrectinib is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Lefamulin: (Major) Avoid coadministration of lefamulin with bosentan unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer.
Lemborexant: (Major) Avoid coadministration of lemborexant and bosentan as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer.
Lenacapavir: (Major) Avoid concurrent use of lenacapavir and bosentan due to the risk of decreased lenacapavir exposure which may result in loss of therapeutic effect and development of resistance. The exposure of bosentan may also be increased. Lenacapavir is a CYP3A substrate and moderate CYP3A inhibitor and bosentan is a CYP3A substrate and moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced lenacapavir overall exposure by 56%.
Leniolisib: (Major) Avoid concomitant use of leniolisib and bosentan. Concomitant use may decrease leniolisib exposure which may reduce its efficacy. Leniolisib is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced leniolisib overall exposure by 58%.
Lesinurad: (Moderate) Bosentan may decrease the systemic exposure and therapeutic effect of lesinurad; monitor for potential reduction in efficacy. Bosentan is a CYP2C9 inducer, and lesinurad is a CYP2C9 substrate.
Lesinurad; Allopurinol: (Moderate) Bosentan may decrease the systemic exposure and therapeutic effect of lesinurad; monitor for potential reduction in efficacy. Bosentan is a CYP2C9 inducer, and lesinurad is a CYP2C9 substrate.
Letermovir: (Major) Concurrent administration of letermovir and bosentan is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Also, the risk for bosentan-related adverse reactions may increase during cocurrent administration with letermovir. Do not administer bosentan to patients receiving letermovir with cyclosporine as bosentan is contraindicated for use with cyclosporine; bosentan plasma concentrations were markedly increased by cyclosporine. Additionally, treatment with bosentan and letermovir with a CYP2C9 inhibitor is not recommended. Letermovir is a moderate inhibitor of CYP3A4. Bosentan is a CYP3A substrate and letermovir is a moderate CYP3A4 inhibitor. Because bosentan is also metabolized by CYP2C9, a large increase in bosentan plasma concentrations may occur if the patient is receiving concomitant treatment with a CYP2C9 inhibitor in addition to letermovir.
Leuprolide; Norethindrone: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Levamlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with bosentan is necessary. Amlodipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Levoketoconazole: (Moderate) Use caution if coadministration of ketoconazole with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in bosentan-related adverse reactions; however, a bosentan dose adjustment is not necessary. Administration of bosentan with both ketoconazole and a strong or moderate CYP2C9 inhibitor is not recommended. Bosentan is a CYP3A4 and CYP2C9 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the plasma concentrations of bosentan by approximately 2-fold.
Levonorgestrel: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Levonorgestrel; Ethinyl Estradiol: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Hormon al contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and bosentan is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. The exposure of bosentan may also be increased, increasing the risk for bosentan-related adverse reactions. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; bosentan is a CYP3A4 substrate and moderate CYP3A4 inducer.
Lopinavir; Ritonavir: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Lorlatinib: (Major) Avoid concomitant use of lorlatinib and bosentan due to decreased plasma concentrations of lorlatinib, which may reduce its efficacy. If concomitant use is necessary, increase the dose of lorlatinib to 125 mg PO once daily. Lorlatinib is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Administration with another moderate CYP3A inducer decreased lorlatinib exposure by 23%.
Lovastatin: (Moderate) Co-administration of bosentan may decrease the plasma concentrations of lovastatin, a CYP3A4 substrate. The possibility of reduced anti-lipemic efficacy should be considered. Patients receiving CYP3A4 metabolized statins should have cholesterol levels monitored after adding bosentan therapy to evaluate the need for anti-lipemic dosage adjustment.
Lumateperone: (Major) Avoid coadministration of lumateperone and bosentan as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer.
Lurasidone: (Moderate) Concurrent use of lurasidone and CYP3A4 inducers, such as bosentan, may lead to a decrease in efficacy of lurasidone. If lurasidone is used with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone dose after chronic treatment (7 days or more). In addition, due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of antihypertensive agents. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Macimorelin: (Major) Discontinue bosentan and allow a sufficient washout period to pass before administering macimorelin. Use of these drugs together can decrease macimorelin plasma concentrations, and may result in a false positive test for growth hormone deficiency. Drug interaction studies involving macimorelin have not been conducted; however, macimorelin is primarily metabolized by CYP3A4 and bosentan is a CYP3A4 inducer.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with bosentan due to risk for reduced mavacamten efficacy. Concomitant use decreases mavacamten exposure. Mavacamten is a CYP3A substrate and bosentan is a moderate CYP3A inducer.
Medroxyprogesterone: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Bosentan is an inducer of CYP3A4 and may increase the metabolism of mefloquine if coadministered. Concomitant administration can reduce the clinical efficacy of mefloquine, increasing the risk of Plasmodium falciparum resistance during treatment of malaria.
Methadone: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes including methadone.
Mifepristone: (Major) The use of mifepristone with bosentan is not recommended. Use of a strong CYP3A4 inhibitor like mifepristone will likely lead to large increases in bosentan plasma concentrations. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration. Bosentan may also induce mifepristone metabolism via CYP3A4. Avoid the use of mifepristone and potent CYP3A inducers due to the potential for reduced mifepristone exposure and reduced efficacy.
Mitapivat: (Major) Avoid coadministration of mitapivat with bosentan, if possible, due to decreased mitapivat efficacy. Coadministration decreases mitapivat concentrations. If concomitant use is necessary, up-titration of mitapivat may be required. Monitor hemoglobin and titrate the mitapivat dose based on response; do not exceed 100 mg PO twice daily. Mitapivat is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased mitapivat overall exposure by 55% to 60%.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and bosentan. Coadministration may decrease mobocertinib exposure resulting in decreased efficacy. Mobocertinib is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Use of a moderate CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 58%.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with bosentan is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for reduced sirolimus efficacy if sirolimus is coadministered with bosentan. Concomitant use may decrease sirolimus exposure. Sirolimus is a CYP3A substrate and bosentan is a moderate CYP3A inducer.
Nefazodone: (Moderate) Nefazodone is a CYP3A4 inhibitor, and may increase the risk of toxicity from bosentan which is partially metabolized by CYP3A4 isoenzymes. Excessive bosentan dosage can result in hypotension or elevated hepatic enzymes.
Nelfinavir: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Neratinib: (Major) Avoid concomitant use of bosentan with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
Niacin; Simvastatin: (Moderate) Co-administration of bosentan decreases the plasma concentrations of simvastatin, a CYP3A4 substrate, and its active metabolite, by approximately 50%. The possibility of reduced anti-lipemic efficacy should be considered. Patients receiving simvastatin should have cholesterol levels monitored after adding bosentan therapy to evaluate the need for anti-lipemic dosage adjustment.
Nifedipine: (Moderate) Closely monitor blood pressure if coadministration of nifedipine with bosentan is necessary; decreased plasma concentrations of nifedipine may occur. Nifedipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Nimodipine: (Moderate) Closely monitor blood pressure if coadministration of nimodipine with bosentan is necessary; decreased plasma concentrations of nimodipine may occur. Nimodipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and bosentan and consider an alternative COVID-19 therapy. If ritonavir-boosted nirmatrelvir must be used, discontinue use of bosentan at least 36 hours before starting ritonavir-boosted nirmatrelvir. Coadministration may increase bosentan exposure resulting in increased toxicity and/or decrease nirmatrelvir exposure and reduce its efficacy. Bosentan is a CYP3A substrate and moderate CYP3A inducer; nirmatrelvir is a CYP3A substrate and CYP3A inhibitor. (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with bosentan due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and bosentan is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Norethindrone: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Norethindrone; Ethinyl Estradiol: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Norgestimate; Ethinyl Estradiol: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Norgestrel: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Olanzapine; Fluoxetine: (Moderate) Bosentan is metabolized by CYP2C9 and CYP3A4. Fluoxetine may inhibit both of these isoenzymes and thereby increase the plasma concentrations of bosentan. It is prudent to monitor for potential adverse effects of bosentan during coadministration with fluoxetine; excessive dosage may result in hypotension or elevated hepatic enzymes.
Olaparib: (Major) Avoid coadministration of olaparib with bosentan due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and bosentan is a moderate CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with a moderate CYP3A inducer is predicted to decrease the olaparib Cmax by 31% and the AUC by 60%.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with bosentan is necessary. Amlodipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Olutasidenib: (Major) Avoid concurrent use of olutasidenib and bosentan due to the risk of decreased olutasidenib exposure which may reduce its efficacy. Olutasidenib is a CYP3A substrate and bosentan is a moderate CYP3A inducer.
Omaveloxolone: (Major) Avoid concurrent use of omaveloxolone and bosentan. Concurrent use may decrease omaveloxolone exposure which may reduce its efficacy. Omaveloxolone is a CYP3A substrate and bosentan is a moderate CYP3A inducer.
Oritavancin: (Moderate) Coadministration of oritavancin and bosentan may result in increases or decreases in bosentan exposure and may increase side effects or decrease efficacy of bosentan. Bosentan is metabolized by CYP3A4 and CYP2C9. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C9. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with bosentan is necessary; consider increasing the dose of oxycodone as needed. If bosentan is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Paclitaxel: (Minor) Co-administration of bosentan with other drugs which are metabolized by hepatic enzymes has not been studied. Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes including paclitaxel.
Pacritinib: (Major) Avoid concurrent use of pacritinib with bosentan due to the risk of decreased pacritinib exposure which may impair efficacy. Pacritinib is a CYP3A substrate and bosentan is a moderate CYP3A inducer.
Palovarotene: (Major) Avoid concomitant use of palovarotene and bosentan. Concurrent use may decrease palovarotene exposure which may reduce its efficacy. Palovarotene is a CYP3A substrate and bosentan is a moderate CYP3A inducer.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and bosentan due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by more than 50%.
Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with bosentan due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of bosentan occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Bosentan is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
Perindopril; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with bosentan is necessary. Amlodipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Phenytoin: (Moderate) Bosentan is a significant inducer of CYP2C9 hepatic enzymes. Theoretically, bosentan can increase phenytoin clearance via hepatic induction. Monitor phenytoin levels.
Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as bosentan. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
Pioglitazone; Glimepiride: (Moderate) Bosentan is an inducer of CYP2C9 and is expected to reduce plasma concentrations of oral antidiabetic agents that are predominantly metabolized by CYP2C9 enzymes, such as glimepiride. Blood glucose monitoring is prudent following addition of bosentan therapy to such antidiabetic drugs.
Pirtobrutinib: (Major) Avoid concurrent use of pirtobrutinib and bosentan due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. If concomitant use is necessary, an empiric pirtobrutinib dosage increase is required. If the current dosage is 200 mg once daily, increase the dose to 300 mg; if the current dosage is 50 mg or 100 mg once daily, increase the dose by 50 mg. Pirtobrutinib is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Concomitant use reduced pirtobrutinib overall exposure by 27%.
Posaconazole: (Moderate) Posaconazole and bosentan should be coadministered with caution due to an increased potential for bosentan-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of bosentan. These drugs used in combination may result in elevated bosentan plasma concentrations, causing an increased risk for bosentan-related adverse events.
Pralsetinib: (Major) Avoid concurrent use of bosentan and pralsetinib due to the risk of decreased pralsetinib exposure which may reduce its efficacy. If concomitant use is necessary, increase the current dose of pralsetinib (400 mg to 600 mg; 300 mg to 500 mg; 200 mg to 300 mg) starting on day 7 of coadministration. Pralsetinib is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased the pralsetinib overall exposure by 45%.
Praziquantel: (Major) In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Therefore, use of praziquantel with bosentan, a CYP3A4 inducer, should be done with caution as concomitant use may produce therapeutically ineffective concentrations of praziquantel.
Pretomanid: (Major) Avoid coadministration of pretomanid with bosentan as concurrent use may decrease pretomanid exposure which may lead to decreased efficacy. Pretomanid is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased pretomanid exposure by 35%.
Progesterone: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Progestins: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Protease inhibitors: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Quizartinib: (Major) Avoid concomitant use of bosentan with quizartinib due to the risk of decreased quizartinib exposure which may reduce its efficacy. Quizartinib is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased the quizartinib overall exposure by 90%.
Ranolazine: (Moderate) Coadministration of ranolazine with CYP3A enzyme inducers such as bosentan may result in a decreased metabolism of ranolazine. Monitor antianginal response to ranolazine closely during initiation of bosentan.
Relugolix; Estradiol; Norethindrone acetate: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Rifampin: (Major) Concomitant administration of a single dose of rifampin (a known inducer of CYP2C9 and CYP3A4) and bosentan in normal volunteers has resulted in increased mean bosentan serum concentrations (trough) by 6-fold; however, coadministration of rifampin with bosentan decreases bosentan serum concentrations at steady-state by about 60%. The effect of bosentan on rifampin serum concentrations has not been assessed. When concomitant use is justified after weighing the risks and benefits, the manufacturer recommends monitoring LFTs weekly for the first 4 weeks, and then to follow routine recommendations for monitoring LFTs during bosentan therapy.
Rilpivirine: (Moderate) Close clinical monitoring is advised when administering bosentan with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bosentan is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Rimegepant: (Major) Avoid coadministration of rimegepant with bosentan; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Ripretinib: (Major) Avoid coadministration of ripretinib with bosentan. If concomitant use is unavoidable, increase the frequency of ripretinib dosing from 150 mg once daily to 150 mg twice daily; monitor for clinical response and tolerability. Resume once daily dosing of ripretinib 14 days after discontinuation of bosentan. Coadministration is predicted to decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A and bosentan is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Ritlecitinib: (Moderate) Use caution if coadministration of ritlecitinib with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions; however, a bosentan dose adjustment is not necessary. Administration of bosentan with both ritlecitinib and a strong or moderate CYP2C9 inhibitor is not recommended. Bosentan is a CYP3A and CYP2C9 substrate; ritlecitinib is a moderate CYP3A inhibitor.
Ritonavir: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Saquinavir: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Segesterone Acetate; Ethinyl Estradiol: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and bosentan due to the risk of decreased selpercatinib exposure which may reduce its efficacy. Selpercatinib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with bosentan is predicted to decrease selpercatinib exposure by 40% to 70%.
Selumetinib: (Major) Avoid coadministration of selumetinib and bosentan due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
Simvastatin: (Moderate) Co-administration of bosentan decreases the plasma concentrations of simvastatin, a CYP3A4 substrate, and its active metabolite, by approximately 50%. The possibility of reduced anti-lipemic efficacy should be considered. Patients receiving simvastatin should have cholesterol levels monitored after adding bosentan therapy to evaluate the need for anti-lipemic dosage adjustment.
Siponimod: (Moderate) Concomitant use of siponimod and bosentan is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Use of siponimod with bosentan is not recommended in any patient if they are also receiving a strong CYP3A4 inducer. Siponimod is a CYP2C9 and CYP3A4 substrate; bosentan is a moderate CYP2C9 and CYP3A4 inducer. Across CYP2C9 genotypes, coadministration of a moderate CYP3A4 inducer reduced siponimod exposure by up to 52%, according to in silico evaluation. Coadministration with a moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57% in CY2C9*1/*1 subjects.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of bosentan. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and bosentan is a moderate CYP3A inducer.
Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with bosentan. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; bosentan is an inducer of CYP3A4. Additionally, velpatasvir is an inhibitor of the organic anion transporting polypeptides OATP1B1 and OATP1B3. Coadministration with substrates of these transporters, such as bosentan, may increase their exposure.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with bosentan. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; bosentan is an inducer of CYP3A4. Additionally, velpatasvir is an inhibitor of the organic anion transporting polypeptides OATP1B1 and OATP1B3. Coadministration with substrates of these transporters, such as bosentan, may increase their exposure. (Major) Avoid coadministration of voxilaprevir (a CYP3A4 substrate) with moderate to strong inducers of CYP3A4, such as bosentan. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy. In addition, voxilaprevir, an Organic Anion Transporting Polypeptides 1B1 (OATP1B1) inhibitor, may alter concentrations of bosentan, an OATP1B1 substrate.
Solifenacin: (Minor) Bosentan is a significant inducer of CYP2C9 and CYP3A4 hepatic isoenzymes. Theoretically, bosentan can increase the hepatic clearance of solifenacin, a CYP3A4 substrate. However, this interaction has not been studied.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and bosentan; sonidegib levels may be decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Sparsentan: (Contraindicated) Concomitant use of sparsentan and endothelin receptor antagonists (ERAs) is contraindicated due to the additive risk for serious adverse effects such as hypotension, syncope, hyperkalemia, and renal dysfunction.
St. John's Wort, Hypericum perforatum: (Major) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4. Coadministration of St. John's wort could decrease the efficacy of some medications metabolized by this enzyme, such as bosentan. Clinicians should observe patients closely if St. John's wort is used.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if bosentan must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with bosentan is necessary; consider increasing the dose of sufentanil injection as needed. If bosentan is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Sulfamethoxazole potently inhibits CYP2C9 and may theoretically lead to elevated plasma concentrations of bosentan when coadministered. Monitor for potential adverse effects of bosentan during coadministration. Excessive bosentan dosage may result in hypotension or elevated hepatic enzymes.
Tacrolimus: (Moderate) Drugs such as bosentan, which can induce cytochrome P-450 3A4, can decrease whole blood concentrations of tacrolimus. Monitoring of tacrolimus whole blood concentrations is recommended if any of the hepatic enzyme inducing agents are used concurrently with tacrolimus.
Tadalafil: (Moderate) Bosentan reduces tadalafil systemic exposure by 42% and Cmax by 27% with multiple-dose coadministration. Tadalafil has no significant effect on the exposure of bosentan. Bosentan is a substrate and moderate inducer of CYP3A; tadalafil is a CYP3A substrate.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with bosentan as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
Telmisartan; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with bosentan is necessary. Amlodipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Tipranavir: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Tolazamide: (Moderate) Bosentan may induce CYP2C9 metabolism of tolazamide based on theoretical cytochrome P-450 interactions.
Tolbutamide: (Moderate) Bosentan is expected to reduce plasma concentrations of tolbutamide via induction of CYP2C9 enzymes. Blood glucose monitoring is prudent following addition of bosentan therapy.
Trandolapril; Verapamil: (Moderate) Closely monitor blood pressure and for increased bosentan toxicity if coadministration of verapamil with bosentan is necessary; decreased verapamil and/or increased bosentan plasma concentrations may occur. Verapamil is a CYP3A4 substrate and inhibitor; bosentan is a CYP3A4 substrate and moderate CYP3A4 inducer.
Tucatinib: (Moderate) Use caution if coadministration of tucatinib with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions; however, a bosentan dose adjustment is not necessary. Administration of bosentan with both tucatinib and a strong or moderate CYP2C9 inhibitor is not recommended. Bosentan is a CYP3A4 and CYP2C9 substrate; tucatinib is a strong CYP3A4 inhibitor.
Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with bosentan as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer.
Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and bosentan is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
Venetoclax: (Major) Avoid the concomitant use of venetoclax and bosentan; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
Verapamil: (Moderate) Closely monitor blood pressure and for increased bosentan toxicity if coadministration of verapamil with bosentan is necessary; decreased verapamil and/or increased bosentan plasma concentrations may occur. Verapamil is a CYP3A4 substrate and inhibitor; bosentan is a CYP3A4 substrate and moderate CYP3A4 inducer.
Voclosporin: (Major) Avoid coadministration of voclosporin with bosentan. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Voclosporin is a sensitive CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease voclosporin exposure by 70%.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of vonoprazan and bosentan due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of vonoprazan and bosentan due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) Coadministration of bosentan and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Coadministration may also increase the plasma concentrations of bosentan. The potential for increased bosentan effects should be monitored.
Voriconazole: (Major) Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan. It is important to review all the medications taken concurrently with bosentan. According to the manufacturer, coadministration of bosentan with a potent CYP2C9 inhibitor plus a CYP3A4 inhibitor is not recommended; large increases in bosentan plasma concentrations are expected with such combinations. Voriconazole potently inhibits CYP2C9 and 3A4 isoenzymes. It is prudent to avoid voriconazole use during bosentan therapy when feasible.
Voxelotor: (Major) Avoid coadministration of voxelotor and bosentan as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. The systemic exposure of bosentan may also be increased resulting in an increase in treatment-related adverse reactions. If coadministration is unavoidable, increase voxelotor dosage to 2,000 mg PO once daily in patients 12 years and older. In patients 4 to 11 years old, weight-based dosage adjustments are recommended; consult product labeling for specific recommendations. Voxelotor is a substrate of CYP3A and moderate CYP3A inhibitor; bosentan is a CYP3A substrate and moderate CYP3A inducer. Coadministration of voxelotor with a moderate CYP3A inducer is predicted to decrease voxelotor exposure by up to 24%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with bosentan is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Bosentan is a moderate CYP2C9/CYP3A4 inducer and the enantiomers of warfarin are substrates of CYP2C9/CYP3A4. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zafirlukast: (Moderate) Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes by zafirlukast may increase the plasma concentration of bosentan. Monitor for potential adverse effects of bosentan during coadministration with zafirlukast. Excessive bosentan dosage may result in hypotension or elevated hepatic enzymes.
Zanubrutinib: (Major) Avoid concurrent use of zanubrutinib and bosentan due to the risk of decreased zanubrutinib exposure which may reduce its efficacy. If concomitant use is necessary, increase the zanubrutinib dose to 320 mg twice daily and monitor response. Resume the previous dose of zanubrutinib if bosentan is discontinued. Zanubrutinib is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer decreased zanubrutinib exposure by 44%.

Bosentan/Tracleer Oral Tab for Susp: 32mg
Bosentan/Tracleer Oral Tab: 62.5mg, 125mg

Weighing more than 40 kg: 250 mg/day PO.
Weighing 40 kg or less: 125 mg/day PO.

Weighing more than 40 kg: 250 mg/day PO.
Weighing 40 kg or less: 125 mg/day PO.

Weighing more than 40 kg: 250 mg/day PO.
Weighing 40 kg or less: 125 mg/day PO.

3 to 12 years weighing 25 to 40 kg: 128 mg/day PO.
3 to 12 years weighing 17 to 24 kg: 96 mg/day PO.
3 to 12 years weighing 9 to 16 kg: 64 mg/day PO.
3 to 12 years weighing 4 to 8 kg: 32 mg/day PO.
1 to 2 years weighing 10 to 20 kg: Safety and efficacy have not been established; however, doses up to 62.5 mg/day PO have been used off-label.
1 to 2 years weighing less than 10 kg: Safety and efficacy have not been established; however, doses up to 4 mg/kg/day or 31.25 mg/day PO have been used off-label.

Weighing 10 to 20 kg: Safety and efficacy have not been established; however, doses up to 62.5 mg/day PO have been used off-label.
Weighing less than 10 kg: Safety and efficacy have not been established; however, doses up to 4 mg/kg/day or 31.25 mg/day PO have been used off-label.

Safety and efficacy have not been established; limited data have reported doses of 2 mg/kg/day PO.

Bosentan is an endothelin-receptor antagonist. Bosentan is a highly substituted pyrimidine derivative, with no chiral centers; it is chemically and pharmacologically related to the parenteral agent tezosentan. Endothelin-1 (ET-1) is a potent endothelium-derived peptide that has been proposed to contribute to the pathogenesis of heart failure and pulmonary hypertension. ET-1 has vasoconstrictive and mitogenic properties. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Two types of endothelin receptors have been identified on vascular smooth muscle cells: A and B; only type B receptors have been found on endothelial cells. Stimulation of type A endothelin receptors mediates vasoconstriction while type B receptors mediate both vasoconstriction and vasodilation. Bosentan is a specific and competitive antagonist at both type A and B endothelin receptors. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors.
 
Bosentan lowers blood pressure in patients with essential hypertension without a reflexive stimulation of the sympathetic or renin-angiotensin system. In pulmonary hypertension, bosentan lowers systemic vascular resistance, pulmonary vascular resistance and mean pulmonary arterial pressure, with a small increase in cardiac output. The increase in cardiac output is likely due to decreased vascular resistance. In two controlled trials of primary pulmonary hypertension (BREATHE-1 , Study 351 , bosentan significantly improved exercise ability (6-minute treadmill test), dyspnea score during walk tests, and WHO functional class. Bosentan also decreased the rate of clinical worsening in patients with WHO Class III or IV symptoms (rate of clinical worsening was assessed as the sum of death, hospitalizations for pulmonary hypertension, treatment discontinuation due to pulmonary hypertension, and need for epoprostenol therapy).

Bosentan is administered orally. It has a small distribution volume (18 L) and is highly bound (more than 98%) to plasma proteins, mainly to albumin. Bosentan does not penetrate into erythrocytes. It is extensively metabolized to 3 metabolites, one of which is pharmacologically active and may contribute about 10% to 20% of the effects. Total clearance after a single IV dose is approximately 4 L/hour in patients with pulmonary arterial hypertension. Due to autoinduction, multiple dosing gradually leads to plasma concentrations which are 50% to 65% of those seen after a single dose. Steady-state is reached within 3 to 5 days. The terminal elimination half-life is about 5 hours. Following hepatic metabolism, bosentan is eliminated by biliary excretion. Less than 3% of an administered oral dose is recovered in the urine.
 
Affected cytochrome P450 isoenzymes: CYP2C9, CYP2C19, CYP3A4
Bosentan is an inducer and a substrate of CYP2C9 and CYP3A4; it may also induce CYP2C19. According to the manufacturer, coadministration with a potent CYP2C9 inhibitor plus a CYP3A4 inhibitor is not recommended; large increases in bosentan plasma concentrations are expected with such combinations. Bosentan has no relevant inhibitory effect on other CYP isoenzymes tested (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4).

Bosentan is contraindicated for use in pregnancy. While there are no adequate and well-controlled studies in pregnant women, animal studies demonstrate that bosentan is a teratogen and likely to cause major birth defects when administered during human pregnancy. In rats, bosentan use at doses 2 times the maximum recommended human dose (MRHD) resulted in serious dose-dependent teratogenic effects including malformations of the head, mouth, face, and large blood vessels. Bosentan increased stillbirths and mortality at oral doses 2 and 10 times the MRHD.

Discuss the reproductive risk of bosentan and contraception requirements, including the need for pregnancy testing prior to treatment initiation, monthly during treatment, and for 1 month after discontinuation with the female patient of childbearing potential. Advise female patients of childbearing potential to contact their physician immediately if there is any delay in the onset of menses or any other reason to suspect pregnancy. If the pregnancy test is positive, the physician and patient must discuss the risks to the woman, pregnancy, and the fetus. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives, may not be reliable, as bosentan is a significant inducer of the hepatic CYP3A4 isoenzyme. Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Bosentan carries a potential for infertility in males; decreased sperm counts have been observed in male patients receiving bosentan. It is unclear whether effects on fertility are reversible. Preclinical animal data also suggest that bosentan, like other endothelin receptor antagonists, may have an adverse effect on spermatogenesis.