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Bosentan

Pronunciation

(boe SEN tan)

Dosage Forms

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

Tablet, Oral:

Tracleer: 62.5 mg, 125 mg

Brand Names: U.S.

  • Tracleer

Pharmacologic Category

  • Endothelin Receptor Antagonist
  • Vasodilator

Pharmacology

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

Distribution

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

Metabolism

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

Excretion

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

Time to Peak

Plasma: 3 to 5 hours

Half-Life Elimination

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

Protein Binding

Plasma: >98% primarily to albumin

Special Populations: Renal Function Impairment

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

Special Populations: Hepatic Function Impairment

Exposure to bosentan would be significantly increased; avoid use in those with moderate or severe liver impairment or elevated aminotransferases more than 3 times the ULN.

Use: Labeled Indications

Pulmonary arterial hypertension: Treatment of pulmonary artery hypertension (PAH) (WHO Group I) in patients with WHO/NYHA Class II, III, or IV symptoms to improve exercise capacity and decrease the rate of clinical deterioration. Note: According to treatment guidelines from the Fifth World Symposium on Pulmonary Hypertension (WSPH), only a small number of PAH patients with WHO-FC IV symptoms (ie, severely ill patients) were included in clinical trials, therefore, most experts consider bosentan second-line therapy in these patients (WSPH [Gailè 2013]).

Contraindications

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

Canadian labeling: Additional contraindications (not in U.S. labeling): Moderate-to-severe hepatic impairment and/or baseline ALT or AST >3 times the upper limit of normal (ULN), particularly when total bilirubin >2 times ULN

Dosing: Adult

Pulmonary artery hypertension: Oral:

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

≥40 kg: Initial: 62.5 mg twice daily for 4 weeks; increase to maintenance dose of 125 mg twice daily. Doses >125 mg twice daily do not appear to confer additional clinical benefit but may increase risk of liver toxicity.

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

Missed doses: If a dose is missed, administer as soon as remembered; if it is almost time for the next dose, take at the usual scheduled time. Do not administer a double dose to make up for a missed dose.

Coadministration with ritonavir (US labeling): Oral: (Note: The Canadian labeling recommends the following dose adjustments with coadministration of any protease inhibitor):

Dosage adjustment for concurrent use with ritonavir:

Coadministration of bosentan in patients currently receiving ritonavir for at least 10 days: Begin with bosentan 62.5 mg once daily or every other day based on tolerability

Coadministration of ritonavir in patients currently receiving bosentan: Discontinue bosentan 36 hours prior to the initiation of ritonavir. After at least 10 days of the protease inhibitor regimen, resume bosentan 62.5 mg once daily or every other day based on tolerability.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Pulmonary artery hypertension: Oral:

US labeling: Children >12 years and Adolescents: Refer to adult dosing.

Canadian labeling: Children ≥3 years and Adolescents (based on limited data):

10 to 20 kg: Initial: 31.25 mg once daily for 4 weeks; increase to maintenance dose of 31.25 mg twice daily

>20 to 40 kg: Initial: 31.25 mg twice daily for 4 weeks; increase to maintenance dose of 62.5 mg twice daily

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

Dosing: Renal Impairment

No dosage adjustment necessary. Bosentan is unlikely to be removed by dialysis (due to high molecular weight and extensive plasma protein binding).

Dosing: Hepatic Impairment

Hepatic impairment at treatment initiation:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate to severe impairment (Child-Pugh class B and C) and/or baseline transaminase >3 times ULN: Use should be avoided; systemic exposure is significantly increased in patients with moderate impairment (not studied in patients with severe impairment).

Hepatotoxicity during treatment: Modification based on transaminase elevation:

Transaminase elevations accompanied by clinical symptoms of hepatic injury (unusual fatigue, nausea, vomiting, abdominal pain, fever, or jaundice) or a serum bilirubin ≥2 times ULN: Discontinue treatment.

AST/ALT >3 times but ≤5 times ULN: Confirm with additional test; if confirmed, reduce dose to 62.5 mg twice daily or interrupt treatment and monitor at least every 2 weeks. If transaminase levels return to pretreatment values, may continue or reintroduce treatment (at the starting dose), as appropriate. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.

AST/ALT >5 times but ≤8 times ULN: Confirm with additional test; if confirmed, stop treatment. Monitor transaminase levels at least every 2 weeks. If transaminase levels return to pretreatment values, may reintroduce treatment (at the starting dose) as appropriate. Following reinitiation, recheck within 3 days and at least every 2 weeks thereafter.

AST/ALT >8 times ULN: Stop treatment and do not reintroduce.

Extemporaneously Prepared

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]). When cutting tablets, NIOSH recommends double gloving and a protective gown; if not prepared in a controlled device, respiratory protection as well as ventilated engineering controls are recommended. When compounding an oral liquid or suspension, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH 2014).

Note: Tablets are not scored; a commercial pill cutter should be used to prepare a 31.25 mg dose from the 62.5 mg tablet; the half-cut 62.5 mg tablets are stable for up to 4 weeks when stored at room temperature in the high-density polyethylene plastic bottle provided by the manufacturer.

Crushing of the tablets is not recommended; bosentan tablets will disintegrate rapidly (within 5 minutes) in 5 to 25 mL of water to create a suspension. An appropriate aliquot of the suspension can be used to deliver the prescribed dose. Any remaining suspension should be discarded. Bosentan should not be mixed or dissolved in liquids with a low (acidic) pH (eg, fruit juices) due to poor solubility; the drug is most soluble in solutions with a pH >8.5.

Administration

May be administered with or without food, once in the morning and once in the evening.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]). NIOSH recommends single gloving for administration of intact tablets. If administering cut tablets, NIOSH recommends double gloves, a protective gown, and respiratory protection (if a powder is generated). If cutting tablets, NIOSH recommends double gloving and a protective gown; if not prepared in a controlled device, respiratory protection as well as ventilated engineering controls are recommended (NIOSH 2014).

Dietary Considerations

Avoid grapefruit and grapefruit juice.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

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

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

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

Atazanavir: Bosentan may decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Bosentan. Management: Concurrent use of atazanavir (without ritonavir) and bosentan is not recommended. Bosentan dose adjustments are required when used together with atazanavir/ritonavir. Consider therapy modification

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

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

Boceprevir: Bosentan may decrease the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of Bosentan. Monitor therapy

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

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

Cobicistat: May increase the serum concentration of Bosentan. Management: See full drug interaction monograph for details. Consider therapy modification

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

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

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

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

CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

CYP2C9 Inhibitors (Strong): May increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

CYP3A4 Substrates: Bosentan may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Darunavir: Bosentan may decrease the serum concentration of Darunavir. Darunavir may increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking darunavir/ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting darunavir/ritonavir; wait at least 10 days before restarting bosentan. Consider therapy modification

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

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

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

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

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

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

Fosamprenavir: Bosentan may decrease the serum concentration of Fosamprenavir. Fosamprenavir may increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking fosamprenavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting fosamprenavir; wait at least 10 days before restarting bosentan. Consider therapy modification

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

GlyBURIDE: May enhance the hepatotoxic effect of Bosentan. GlyBURIDE may increase the metabolism of Bosentan. Bosentan may increase the metabolism of GlyBURIDE. Avoid combination

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

GuanFACINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating concomitant therapy with moderate CYP3A4 inducers. Increase guanfacine dose gradually over 1-2 weeks if moderate CYP3A4 inducer therapy is just beginning. Consider therapy modification

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

Ibrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrutinib. Management: Although moderate CYP3A inducers are not specifically contraindicated with ibrutinib, prescribing information indicates that they may decrease AUC up to 3-fold. If possible, alternatives with less CYP3A induction should be considered. Consider therapy modification

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

Indinavir: May increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of Indinavir. Management: Initiate bosentan at, or adjust bosentan to, 62.5 mg once daily or every other day (based on tolerability) in indinavir-treated patients (see ritonavir for dosing if that agent is used). Additionally, monitor for possible reduced response to indinavir. Consider therapy modification

Lopinavir: May increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of Lopinavir. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking lopinavir/ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting lopinavir/ritonavir; wait at least 10 days before restarting bosentan. Consider therapy modification

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

Nelfinavir: May increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of Nelfinavir. Management: Initiate bosentan at, or adjust bosentan dose to, 62.5 mg once daily or every other day (based on tolerability) in patients who receive nelfinavir. Additionally, monitor for possible reduced clinical response to nelfinavir. Consider therapy modification

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

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

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

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

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

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

RifAMPin: May decrease the serum concentration of Bosentan. Following the initial several weeks of concurrent rifampin, this effect is most likely. RifAMPin may increase the serum concentration of Bosentan. This effect is most likely to be observed within the initial few weeks of concurrent therapy (and may be greatest immediately following initiation of the combination). Management: Weekly monitoring of liver function tests during the first 4 weeks of concurrent therapy is recommended, with a return to normal recommended monitoring thereafter as appropriate. Monitor therapy

Ritonavir: May increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg daily or every other day in adult patients who have been on ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting ritonavir; wait until at least 10 days on ritonavir before restarting. Consider therapy modification

Rolapitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rolapitant. Management: Monitor for reduced rolapitant response. Recommended dexamethasone regimens should be used with rolapitant. Higher dexamethasone doses or more prolonged use may increase the potential for a significant interaction. Monitor therapy

Saquinavir: Bosentan may decrease the serum concentration of Saquinavir. Saquinavir may increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking saquinavir/ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting saquinavir/ritonavir; wait at least 10 days before restarting bosentan. Consider therapy modification

SAXagliptin: CYP3A4 Inducers may decrease the serum concentration of SAXagliptin. Monitor therapy

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

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

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

Telaprevir: Bosentan may decrease the serum concentration of Telaprevir. Telaprevir may increase the serum concentration of Bosentan. Monitor therapy

Teriflunomide: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Tipranavir: Bosentan may decrease the serum concentration of Tipranavir. Tipranavir may increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking tipranavir/ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting tipranavir/ritonavir; wait at least 10 days before restarting bosentan. Consider therapy modification

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

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

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

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

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

Adverse Reactions

>10%:

Cardiovascular: Edema (11%)

Central nervous system: Headache (15%)

Genitourinary: Inhibition of spermatogenesis (25%)

Hematologic & oncologic: Decreased hemoglobin (typically in first 6 weeks of therapy; ≥1 g/dL: ≤57%; <11 g/dL: 3% to 6%)

Hepatic: Increased serum transaminases (≥3 times ULN: ≤12%; dose-related)

Respiratory: Respiratory tract infection (22%)

1% to 10%:

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

Dermatologic: Pruritus (2%)

Hematologic & oncologic: Anemia (3%)

Hepatic: Hepatic insufficiency (4%)

Neuromuscular & skeletal: Arthralgia (4%)

Respiratory: Sinusitis (4%)

<1% (Limited to important or life-threatening): Anaphylaxis, angioedema, hepatic cirrhosis (prolonged therapy), hepatic failure (rare), hyperbilirubinemia, hypersensitivity angiitis, hypersensitivity reaction, leukopenia, neutropenia, peripheral edema, skin rash, thrombocytopenia, weight gain, worsening of heart failure

ALERT: U.S. Boxed Warning

Distribution program:

Because of the risks of hepatotoxicity and birth defects, bosentan is available only through a restricted program called the Tracleer REMs Program. The Tracleer REMs Program is a component of the bosentan Risk Evaluation and Mitigation Strategy (REMS). Under the bosentan REMS, prescribers, patients, and pharmacies must enroll in the program.

Hepatotoxicity:

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

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

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

Teratogenicity:

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

Warnings/Precautions

Concerns related to adverse effects:

• Fluid retention/peripheral edema: Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur. There have also been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization). If clinically significant fluid retention develops (with or without weight gain), further evaluation is necessary to determine cause and appropriate treatment or discontinuation of therapy. Use with caution in patients with underlying heart failure due to potential complications from fluid retention.

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

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

• Hypersensitivity: Hypersensitivity reactions, including rash and angioedema have been observed.

• Spermatogenesis: Decreased sperm counts have been observed in men during treatment; bosentan may have an adverse effect on spermatogenesis.

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

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warning]: May cause birth defects (based on animal data); use in pregnancy is contraindicated. Exclude pregnancy prior to initiation of therapy and obtain pregnancy tests monthly during treatment. Reliable contraception must be used during therapy and for 1 month after stopping treatment. Hormonal contraceptives (oral, injectable, transdermal, or implantable) should not be used as the sole means of contraception because they may not be effective in patients receiving bosentan. Patients with an intrauterine device (IUD) or tubal ligation do not need additional contraceptive measures.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Other warnings/precautions:

• REMS program: [US Boxed Warning]: Because of the risks of hepatotoxicity and birth defects, bosentan is only available through the Tracleer REMS Program. The Tracleer REMS Program is a component of the bosentan Risk Evaluation and Mitigation Strategy (REMS). Patients, prescribers, and pharmacies must enroll with the program. Call 1-866-228-3546 or visit http://www.tracleer.com for more information.

Monitoring Parameters

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

Pregnancy test in women of childbearing potential (prior to the initiation of therapy and monthly thereafter, prior to shipment of monthly refill).

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

Pregnancy Risk Factor

X

Pregnancy Considerations

[US Boxed Warning]: May cause birth defects (based on animal data); use in pregnancy is contraindicated. Exclude pregnancy prior to initiation of therapy and obtain pregnancy tests monthly during treatment. Reliable contraception must be used during therapy and for 1 month after stopping treatment. Hormonal contraceptives (oral, injectable, transdermal, or implantable) should not be used as the sole means of contraception because they may not be effective in patients receiving bosentan. Patients with an intrauterine device (IUD) or tubal ligation do not need additional contraceptive measures. When a hormonal or barrier contraceptive is used, one additional method of contraception is still needed if a male partner has had a vasectomy. When initiating treatment for women of reproductive potential, a negative pregnancy test should be documented within the first 5 days of a normal menstrual period and ≥11 days after the last unprotected intercourse. A missed menses or suspected pregnancy should be reported to a healthcare provider and prompt immediate pregnancy testing. Sperm counts may be reduced in men during treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, flushing, rhinitis, or pharyngitis. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), loss of strength and energy, shortness of breath, excessive weight gain, swelling of arms or legs, abnormal heartbeat, or joint pain (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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