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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(boe SEN tan)
Generic Available (U.S.)
No
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm089801.pdf, must be dispensed with this medication.
REMS Components
Elements to Assure Safe Use; Implementation System; Medication Guide
Prescribing and Access Restrictions
As a requirement of the REMS program, access to this medication is restricted. Bosentan (Tracleer®) is only available through Tracleer® Access Program (T.A.P.). Only prescribers and pharmacies registered with T.A.P. may prescribe and dispense bosentan. Further information may be obtained from the manufacturer, Actelion Pharmaceuticals (1-866-228-3546).
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Use: Labeled Indications
Treatment of pulmonary artery hypertension (PAH) (WHO Group I) in patients with NYHA Class II, III, or IV symptoms to improve exercise capacity and decrease the rate of clinical deterioration
Pregnancy Risk Factor
X
Pregnancy Considerations
[U.S. Boxed Warning]: Use in pregnancy is contraindicated; may cause birth defects. Exclude pregnancy prior to initiation of therapy, monthly during therapy and one month after stopping bosentan. Two reliable methods of contraception must be used during therapy and for one month after stopping treatment except in patients with tubal ligation or an implanted IUD (Copper T 380A or LNg 20). No other contraceptive measures are required for these patients. Women of childbearing potential should avoid exposure to dust generated from broken or split tablets, especially if repeated exposure is expected (tablet splitting is currently outside of product labeling). Sperm counts may be reduced in men during treatment. No changes in sperm function or hormone levels have been noted.
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to bosentan or any component of the formulation; concurrent use of cyclosporine or glyburide; pregnancy
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
Warnings/Precautions
Boxed Warnings:
• Hepatic effects: See “Concerns related to adverse effects” below.
• Pregnancy: See “Special populations” below.
• REMS program: See “Other warnings/precautions” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
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). Further evaluation may be necessary to determine cause and appropriate treatment or discontinuation of therapy. Use with caution in patients with severe chronic heart failure; associated with increased incidence of hospitalization possibly due to fluid retention.
• Hematologic changes: A reduction in hematocrit/hemoglobin may be observed within the first few weeks of therapy with subsequent stabilization of levels. Hemoglobin reductions >15% have been observed in some patients. Measure hemoglobin prior to initiating therapy, at 1 and 3 months, and every 3 months thereafter. Significant decreases in hemoglobin in the absence of other causes may warrant the discontinuation of therapy.
• Hepatic effects: [U.S. Boxed Warning]: Has been associated with a high incidence (~11%) of significant transaminase elevations, and rare cases of unexplained hepatic cirrhosis have occurred, including after long-term therapy. 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. Avoid use in moderate-to-severe hepatic impairment or patients with elevated serum transaminases (>3 times upper limit of normal [ULN]) at baseline. Monitor hepatic function closely (at least monthly) for the duration of treatment. Treatment should be stopped in patients who develop elevated transaminases (ALT or AST) in combination with symptoms of hepatic injury (unusual fatigue, jaundice, nausea, vomiting, abdominal pain, and/or fever) or elevated serum bilirubin ≥2 times ULN. Safety of reintroduction is unknown.
• Spermatogenesis: Sperm count may be reduced in men during treatment. No changes in sperm function or hormone levels have been noted. Fertility issues may require discussion with patient.
Disease-related concerns:
• Pulmonary veno-occlusive disease (PVOD): Discontinue in any patient with pulmonary edema suggestive of PVOD.
Concurrent drug therapy issues:
• High potential for interactions: Bosentan may interact with many medications, resulting in potentially serious and/or life-threatening adverse events (see Drug Interactions).
Special populations:
• Pregnancy: [U.S. Boxed Warning]: Use in pregnancy is contraindicated; may cause birth defects. Exclude pregnancy prior to initiation of therapy, monthly during therapy and 1 month after stopping bosentan. Two reliable methods of contraception must be used during therapy and for one month after stopping treatment except in patients with tubal ligation or an implanted IUD (Copper T 380A or LNg 20). No other contraceptive measures are required for these patients. A missed menses should be reported to healthcare provider and prompt immediate pregnancy testing. Women of childbearing potential should avoid exposure to dust generated from broken or split tablets, especially if repeated exposure is expected (tablet splitting is currently outside of product labeling).
Other warnings/precautions:
• REMS program: [U.S. Boxed Warning]: Because of the risks of hepatic impairment and the high likelihood of teratogenic effects, bosentan is only available through the T.A.P. restricted distribution program. Patients, prescribers, and pharmacies must be registered with and meet conditions of T.A.P. Call 1-866-228-3546 for more information.
Adverse Reactions
>10%:
Cardiovascular: Edema (11%)
Central nervous system: Headache (15%)
Endocrine & metabolic: Spermatogenesis inhibition (25%)
Hematologic: Hemoglobin decreased (≥1 g/dL in up to 57%; <11 g/dL: 3% to 6%; typically in first 6 weeks of therapy)
Hepatic: Transaminases increased (≥3 times ULN; up to 12%; dose-related)
Respiratory: Respiratory tract infection (22%)
1% to 10%:
Cardiovascular: Chest pain (5%), syncope (5%), flushing (4%), hypotension (4%), palpitation (4%)
Dermatologic: Pruritus (2%)
Hematologic: Anemia (3%)
Hepatic: Abnormal hepatic function (4%)
Neuromuscular & skeletal: Arthralgia (4%)
Respiratory: Sinusitis (4%)
<1%, postmarketing, and/or case reports: Anaphylaxis, angioneurotic edema, heart failure (exacerbation), cirrhosis (prolonged therapy), hyperbilirubinemia, hypersensitivity, jaundice, leukocytoclastic vasculitis, leukopenia, liver failure (rare), neutropenia, peripheral edema, rash, thrombocytopenia, weight gain
Metabolism/Transport Effects
Substrate of CYP2C9 (major), CYP3A4 (major), SLCO1B1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP2C9 (strong), CYP3A4 (strong)
Drug Interactions
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Bosentan. Risk C: Monitor therapy
ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double aripiprazole dose when initiating concomitant therapy with a CYP3A4 inducer (e.g., carbamazepine). Monitor response and adjust aripiprazole dose as clinically indicated. If CYP3A4 inducer is discontinued, reduce aripiprazole dose to 10-15 mg/day. Risk D: Consider therapy modification
Boceprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Boceprevir. Management: Avoid strong CYP3A4 inducers with boceprevir when possible, and closely monitor response to boceprevir if such a combination cannot be avoided. Carbamazepine, phenytoin, phenobarbital, rifampin, and St. John's wort are considered contraindicated. Risk D: Consider therapy modification
Bortezomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bortezomib. Risk X: Avoid combination
Brentuximab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor therapy
Clarithromycin: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Clarithromycin. Clarithromycin may increase the serum concentration of CYP3A4 Inducers (Strong). CYP3A4 Inducers (Strong) may decrease the serum concentration of Clarithromycin. Risk D: Consider therapy modification
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: 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. Risk D: 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. Risk D: Consider therapy modification
Crizotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Crizotinib. Risk X: Avoid combination
CycloSPORINE: Bosentan may decrease the serum concentration of CycloSPORINE. CycloSPORINE may increase the serum concentration of Bosentan. Risk X: Avoid combination
CycloSPORINE (Systemic): Bosentan may decrease the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Bosentan. Risk X: Avoid combination
CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy
CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Risk D: Consider therapy modification
CYP2C9 Substrates: CYP2C9 Inducers (Strong) may increase the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
CYP3A4 Substrates: CYP3A4 Inducers (Strong) may increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Dasatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasatinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing dasatinib dose and monitor clinical response and toxicity closely. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Diclofenac: CYP2C9 Inducers (Strong) may decrease the serum concentration of Diclofenac. Risk C: Monitor therapy
Dronedarone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronedarone. Risk X: Avoid combination
Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Management: According to eltrombopag prescribing information, consideration of a preventative dose reduction may be warranted. Risk D: Consider therapy modification
Everolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers, but if strong CYP3A4 inducers cannot be avoided, consider gradually (in 5 mg increments) increasing the everolimus dose from 10 mg/day to 20 mg/day (adult doses). Risk X: Avoid combination
Exemestane: CYP3A4 Inducers (Strong) may decrease the serum concentration of Exemestane. Management: Exemestane prescribing information recommends using an increased dose (50 mg/day) in patients receiving concurrent strong CYP3A4 inducers. Monitor patients closely for evidence of toxicity and/or inadequate clinical response. Risk D: Consider therapy modification
Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse drug reactions, consider increasing gefitinib dose to 500 mg daily in patients receiving strong CYP3A4 inducers. Carefully monitor clinical response and development of adverse reactions. Risk D: Consider therapy modification
GlyBURIDE: May enhance the hepatotoxic effect of Bosentan. Bosentan may increase the metabolism of GlyBURIDE. GlyBURIDE may increase the metabolism of Bosentan. Risk X: Avoid combination
GuanFACINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Consider increasing the guanfacine dose (within the labeled dosage range) when such a combination is used. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
HMG-CoA Reductase Inhibitors: Bosentan may increase the metabolism of HMG-CoA Reductase Inhibitors. Exceptions: Fluvastatin; Pravastatin; Rosuvastatin. Risk C: Monitor therapy
Imatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Imatinib. Management: Avoid concurrent use of imatinib with strong CYP3A4 inducers when possible. If such a combination must be used, increase imatinib dose by at least 50% and monitor the patient's clinical response closely. Risk D: Consider therapy modification
Indinavir: Bosentan may decrease the serum concentration of Indinavir. Indinavir may increase the serum concentration of Bosentan. 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. Risk D: Consider therapy modification
Ixabepilone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixabepilone. Management: Avoid this combination whenever possible. If this combination must be used, a gradual increase in ixabepilone dose from 40 mg/m2 to 60 mg/m2 (given as a 4-hour infusion), as tolerated, should be considered. Risk D: Consider therapy modification
Lapatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Risk X: Avoid combination
Linagliptin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong CYP3A4 inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Risk D: Consider therapy modification
Lurasidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurasidone. Risk X: Avoid combination
Maraviroc: CYP3A4 Inducers (Strong) may decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice daily when used with strong CYP3A4 inducers. This does not apply to patients also receiving strong CYP3A4 inhibitors. Do not use maraviroc with strong CYP3A4 inducers in patients with Clcr less than 30 mL/min. Risk D: Consider therapy modification
Nelfinavir: Bosentan may decrease the serum concentration of Nelfinavir. Nelfinavir may increase the serum concentration of Bosentan. 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. Risk D: Consider therapy modification
NIFEdipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NIFEdipine. Management: Consider alternatives to nifedipine for patients who are using strong CYP3A4 inducers. At least one specific brand of nifedipine (Adalat CC) lists this combination as contraindicated. Risk D: Consider therapy modification
Nilotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib. Risk X: Avoid combination
Nisoldipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nisoldipine. Risk X: Avoid combination
Pazopanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pazopanib. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2C9 Substrates. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: Bosentan may decrease the serum concentration of Phosphodiesterase 5 Inhibitors. Phosphodiesterase 5 Inhibitors may increase the serum concentration of Bosentan. Risk C: Monitor therapy
Praziquantel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Praziquantel. Management: Avoid concomitant use of praziquantel with strong CYP3A4 inducers. Discontinue rifampin 4 weeks prior to initiation of praziquantel therapy. Rifampin may be resumed the day following praziquantel completion. Risk X: Avoid combination
Ranolazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Rivaroxaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rivaroxaban. Risk X: Avoid combination
Roflumilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast. Management: Roflumilast U.S. prescribing information recommends against combining strong CYP3A4 inducers with roflumilast. The Canadian product monograph makes no such recommendation but notes that such agents may reduce roflumilast therapeutic effects. Risk X: Avoid combination
RomiDEPsin: CYP3A4 Inducers (Strong) may decrease the serum concentration of RomiDEPsin. Risk X: Avoid combination
Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Risk C: Monitor therapy
SORAfenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib. Risk X: Avoid combination
SUNItinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing sunitinib dose and monitor clinical response and toxicity closely. Risk D: Consider therapy modification
Telaprevir: Bosentan may decrease the serum concentration of Telaprevir. Telaprevir may increase the serum concentration of Bosentan. Risk C: Monitor therapy
Ticagrelor: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ticagrelor. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Tolvaptan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tolvaptan. Management: If concurrent use is necessary, increased doses of tolvaptan (with close monitoring for toxicity and clinical response) may be needed. Risk X: Avoid combination
Toremifene: CYP3A4 Inducers (Strong) may decrease the serum concentration of Toremifene. Risk X: Avoid combination
Ulipristal: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ulipristal. Risk C: Monitor therapy
Vandetanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vandetanib. Risk X: Avoid combination
Vemurafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Bosentan may increase the metabolism of Vitamin K Antagonists. Risk C: Monitor therapy
Zuclopenthixol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zuclopenthixol. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: Bioavailability of bosentan is not affected by food. Bosentan serum concentrations may be increased by grapefruit juice.
Herb/Nutraceutical: Avoid St John's wort (may decrease serum concentrations of bosentan).
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).
Mechanism of Action
Blocks endothelin receptors on vascular endothelium and smooth muscle. Stimulation of these receptors is associated with vasoconstriction. Although bosentan blocks both ETA and ETB receptors, the affinity is higher for the A subtype.
Pharmacodynamics/Kinetics
Distribution: Vd: ~18 L
Protein binding, plasma: >98% primarily to albumin
Metabolism: Hepatic via CYP2C9 and 3A4 to three primary metabolites (one contributing ~10% to 20% pharmacologic activity); autoinduction may occur with chronic dosing
Bioavailability: ~50%
Half-life elimination: 5 hours; prolonged with heart failure, possibly in PAH
Time to peak, plasma: 3-5 hours
Excretion: Feces (as metabolites); urine (<3% as unchanged drug)
Dosage
Oral:
Adolescents >12 years and Adults: Pulmonary artery hypertension:
<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 3-7 days (to avoid clinical deterioration).
Canadian labeling (not in U.S. labeling): Children 3-18 years:
10-20 kg: Initial: 31.25 mg once daily for 4 weeks; increase to maintenance dose of 31.25 mg twice daily
>20-40 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
Coadministration with protease inhibitor regimen:
Dosage adjustment for concurrent use with atazanavir/ritonavir, darunavir/ritonavir, fosamprenavir, lopinavir/ritonavir, ritonavir, saquinavir/ritonavir, tipranavir/ritonavir:
Coadministration of bosentan in patients currently receiving one of these protease inhibitor regimens for at least 10 days: Begin with bosentan 62.5 mg once daily or every other day based on tolerability
Coadministration of one of these protease inhibitor regimens in patients currently receiving bosentan: Discontinue bosentan 36 hours prior to the initiation of an above regimen. After at least 10 days of the protease inhibitor regimen, resume bosentan 62.5 mg once daily or every other day based on tolerability.
Dosage adjustment for concurrent use with indinavir or nelfinavir:
Coadministration of bosentan in patients currently receiving indinavir or nelfinavir: Begin with bosentan 62.5 mg once daily or every other day based on tolerability
Coadministration of indinavir or nelfinavir in patients currently receiving bosentan: Adjust bosentan to 62.5 mg once daily or every other day based on tolerability
Dosage adjustment in renal impairment: No dosage adjustment required.
Dosage adjustment in hepatic impairment: Avoid use in patients with pretreatment moderate-to-severe hepatic insufficiency and/or transaminase increases >3 times ULN
Modification based on transaminase elevation:
If any elevation, regardless of degree, is accompanied by clinical symptoms of hepatic injury (unusual fatigue, nausea, vomiting, abdominal pain, fever, or jaundice) or a serum bilirubin ≥2 times ULN, treatment should be stopped.
AST/ALT >3 times but ≤5 times ULN: Confirm with additional test; if confirmed, reduce dose or interrupt treatment. Monitor transaminase levels at least every 2 weeks. May continue or reintroduce treatment, as appropriate, following return to pretreatment values. When reintroducing treatment, begin with starting dose and 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. May reintroduce treatment, as appropriate, at starting dose, following return to pretreatment values. Recheck within 3 days and at least every 2 weeks thereafter following reinitiation.
AST/ALT >8 times ULN: Stop treatment and do not reintroduce.
Administration: Oral
May be administered with or without food, once in the morning and once in the evening. Women of childbearing potential should avoid excessive handling of broken tablets.
Monitoring Parameters
Serum transaminase (AST and ALT) and bilirubin should be determined prior to the initiation of therapy and at monthly intervals thereafter. Monitor for clinical signs and symptoms of liver injury (eg, abdominal pain, fatigue, fever, jaundice, nausea, vomiting).
A woman of childbearing potential must have a negative pregnancy test prior to the initiation of therapy and monthly thereafter (prior to shipment of monthly refill). Hemoglobin and hematocrit should be measured at baseline, at 1 month and 3 months of treatment, and every 3 months thereafter (generally stabilizes after 4-12 weeks of treatment).
Dietary Considerations
May be taken with or without food. Avoid grapefruit and grapefruit juice.
Patient Education
Take with or without food. You may experience headache or GI upset. Report persistent headache or GI problems, swelling of extremities, unusual weight gain, runny nose or persistent signs of a cold, increased shortness of breath, chest pain or palpitations, unusual fatigue or weakness, yellowing of skin or eyes, abdominal pain, fever, or change in color of stool or urine.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Endothelin antagonists have caused bleeding gums; there have been no specific reports for bosentan
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Psychiatric Treatment
Carbamazepine, other anticonvulsants, and St John's wort may decrease the effects of bosentan. Conversely, nefazodone may increase the effects of bosentan.
Nursing: Physical Assessment/Monitoring
Assess for fluid retention.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral:
Tracleer®: 62.5 mg, 125 mg
Extemporaneously Prepared
Hazardous agent: Use appropriate precautions for handling and disposal.
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. Since bosentan is classified as a teratogen (Pregnancy Risk Factor X), individuals should avoid exposure to bosentan powder (dust) by taking appropriate measures (eg, using gloves and mask); women of childbearing potential should avoid exposure to dust generated from broken or split tablets.
Crushing of the tablets is not recommended; bosentan tablets will disintegrate rapidly (within 5 minutes) in 5-25 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.
References
Badesch DB, Abman SH, Simonneau G, et al, “Medical Therapy for Pulmonary Arterial Hypertension: Updated ACCP Evidence-Based Clinical Practice Guidelines,” Chest, 2007, 131(6):1917-28.
Barst RJ, Ivy D, Dingemanse J, et al, “Pharmacokinetics, Safety, and Efficacy of Bosentan in Pediatric Patients With Pulmonary Arterial Hypertension,” Clin Pharmacol Ther, 2003, 73(4):372-82.
McLaughlin VV, Archer SL, Badesch DB, et al, “ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: Developed in Collaboration with the American College of Chest Physicians, American Thoracic Society, Inc, and the Pulmonary Hypertension Association,” J Am Coll Cardiol, 2009, 53(11):1573-619.
Rosenzweig EB, Ivy DD, Widlitz A, et al, “Effects of Long-Term Bosentan in Children With Pulmonary Arterial Hypertension,” J Am Coll Cardiol, 2005, 46(4):697-704.
International Brand Names
Lexi-Comp.com
Last full review/revision January 2012
Content last modified January 2012
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