Tracleer

bosentan

Tracleer

Pharmacologic class: Endothelin-receptor antagonist, vasodilator

Therapeutic class: Antihypertensive

Pregnancy risk category X

FDA Box Warning

• Drug causes at least 3 × ULN (upper limit of normal) of alanine aminotransferase and aspartate aminotransferase levels in about 11% of patients (along with elevated bilirubin in a few cases). These changes indicate potentially serious hepatic injury. Obtain serum transaminase levels before therapy begins and then monthly.

• Transaminase elevations warrant close attention. Avoid giving drug to patients with baseline transaminase levels more than 3 × ULN, because monitoring for hepatic injury may be more difficult. Stop therapy if transaminase elevations are accompanied by indications of hepatic injury or if bilirubin level is 2 × ULN or higher.

• Rare postmarketing cases of unexplained hepatic cirrhosis occurred after prolonged therapy in patients with multiple comorbidities and drug therapies.

• Drug is contraindicated in pregnancy because it's likely to cause major birth defects. Exclude pregnancy before therapy starts, and instruct patient to use reliable contraceptive method. Caution patient not to use hormonal contraceptives alone, because drug may render these ineffective; instruct her to use additional forms of contraception. Obtain monthly pregnancy tests.

• Because of potential hepatic injury and to reduce risk of fetal exposure, drug may be prescribed only through Tracleer Access Program.

Action

Binds to and blocks receptor sites for endothelin A and B in endothelium and vascular smooth muscle. This action reduces elevated endothelin levels in patients with pulmonary arterial hypertension, and inhibits vasoconstriction resulting from endothelin-1 (ET-1).

Availability

Tablets: 62.5 mg, 125 mg

Indications and dosages

Patients with pulmonary arterial hypertension (World Health Organization Group 1) to improve exercise ability and to decrease clinical worsening

Adults: Initially, 62.5 mg P.O. b.i.d. for 4 weeks; increase to maintenance dosage of 125 mg P.O. b.i.d. In patients older than age 12 who weigh less than 40 kg (88 lb), initial and maintenance dosages are 62.5 mg b.i.d.

Dosage adjustment

• Aminotransferase elevations more than 3 × upper limit of normal
• Concurrent use of lopinavir/ritonavir

Contraindications

• Hypersensitivity to drug
• Patients receiving concurrent cyclosporine or glyburide
• Pregnancy

Precautions

Use cautiously in:
• moderate to severe hepatic impairment (avoid use)
• mild hepatic impairment
• mitral stenosis, pulmonary veno-occlusive disease
• fluid retention, decreased sperm count, decreased hemoglobin level and hematocrit
• concurrent use of a CYP2C9 inhibitor and a strong or moderate CYP3A inhibitor (not recommended)
• concurrent use of tacrolimus
• elderly patients
• breastfeeding patients
• children younger than age 12 (safety and efficacy not established).

Administration

• Give tablets in morning and evening, with or without food.
• Consider gradual dosage reduction when discontinuing drug.

Adverse reactions

CNS: headache, fatigue

CV: edema, hypotension, palpitations

EENT: nasopharyngitis

GI: dyspepsia

Hepatic: hepatic dysfunction, hepatic injury, hepatotoxicity

Skin: pruritus, flushing

Interactions

Drug-drug.Cyclosporine: decreased cyclosporine blood level, increased bosentan blood level

CYP2C9 inhibitors (such as amiodarone, fluconazole), moderate CYP3A inhibitors (such as amprenavir, diltiazem, erythromycin, fluconazole), strong CYP3A inhibitors (such as itraconazole, ketoconazole): largely increased bosentan plasma concentration

Drugs metabolized by CYP2C9 and CYP3A: decreased plasma concentrations of these drugs

Glyburide: decreased blood levels of both drugs, increased risk of hepatic damage

Hormonal contraceptives: decreased bosentan efficacy

Lopinavir/ritonavir combination: increased bosentan trough concentration

Simvastatin and other statins: decreased effects of these drugs

Drug-diagnostic tests.Hematocrit, hemoglobin: decreased values

Transaminases: increased values

Patient monitoring

• Assess serum transaminase levels within first 3 days of therapy and then monthly.
• Evaluate hemoglobin level 1 month after therapy and then every 3 months.

If signs of pulmonary edema occur, consider the possibility of underlying pulmonary venoocclusive disease and discontinue treatment if necessary.
• Assess female patient for pregnancy every month during therapy.

Patient teaching

• Tell patient to take drug with or without food in morning and evening.
• Caution female patient to avoid pregnancy, and discuss reliable contraceptive methods. Instruct her to contact prescriber immediately if she thinks she may be pregnant.
• Because of the potential for adverse effects in the breastfeeding infant, a decision should be made to discontinue breastfeeding or discontinue drug, taking into account the importance of drug to the mother.
• Inform patient that he'll undergo CBC measurement and liver function testing regularly during therapy.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs and tests mentioned above.

bosentan

(boe-sen-tan) ,

Tracleer

(trade name)

Classification

Therapeutic: vasodilators
Pharmacologic: endothelin receptor antagonists
Pregnancy Category: X

Indications

Pulmonary arterial hypertension (WHO Group 1).

Action

Antagonizes the effects of the neurohormone endothelin by binding to its receptor sites in endothelium and vascular smooth muscle.

Therapeutic effects

Improved exercise capacity and decreased clinical deterioration.

Pharmacokinetics

Absorption: 50% absorbed following oral administration in normal patients.
Distribution: 18 L.
Protein Binding: >98%.
Metabolism and Excretion: Highly metabolized; one metabolite contributes to pharmacologic activity. Eliminated via biliary excretion; <3% excreted in urine.
Half-life: 5 hr.

Time/action profile (blood levels)

ROUTEONSETPEAKDURATION
POunknown3–5 hrunknown

Contraindications/Precautions

Contraindicated in: Hypersensitivity; Concurrent use of cyclosporine or glyburide; Concurrent use with a CYP2C9 inhibitor and a strong or moderate CYP3A4 inhibitor; Moderate to severe liver impairment or patients with ↑ liver enzymes (>3x ULN); Obstetric / High risk for fetal harm (malformation, stillbirth) if administered to pregnant women. Pregnancy must be ruled out before start of treatment and reliable contraception used throughout treatment. Hormonal contraceptives (all forms) cannot be the sole form of contraception (see drug-drug interactions). Monthly pregnancy tests for women with childbearing potential is recommended throughout course of therapy. Lactation: Lactation.
Use Cautiously in: Women with childbearing potential.; Pediatric: Safety not established.

Adverse Reactions/Side Effects

Central nervous system

  • headache (most frequent)
  • fatigue

Ear, Eye, Nose, Throat

  • nasopharyngitis (most frequent)

Cardiovascular

  • edema
  • hypotension
  • palpitations

Gastrointestinal

  • hepatotoxicity (life-threatening)
  • dyspepsia

Dermatologic

  • flushing
  • pruritus

Genitourinary

  • ↓ sperm counts

Hematologic

  • anemia (most frequent)

Interactions

Drug-Drug interaction

Bosentan is metabolized by and induces the CYP3A4 and 2C9 enzyme systems.May ↓ effectiveness of hormonal contraceptives (additional method of contraception recommended).Significantly ↓ cyclosporine levels; cyclosporine significantly ↑ bosentan levels (concurrent use contraindicated).↑ risk of hepatotoxicity with glyburide (concurrent use contraindicated).Lopinavir/ritonavir or other ritonavir —containing regimens significantly ↑ levels (initiate bosentan at 62.5 mg once daily or every other day if receiving ritonavir-containing regimen for ≥10 days) (if initiating ritonavir in patient already receiving bosentan, discontinue bosentan for ≥36 hr before initiating ritonavir; can resume bosentan after ≥10 days at 62.5 mg once daily or every other day).Ketoconazole ↑ levels.↓ levels of simvastatin, lovastatin, and atorvastatin.↓ levels of warfarin.May ↓ levels of tacrolimus and sirolimus.

Route/Dosage

Oral (Adults) 62.5 mg twice daily for 4 wk initially, then ↑ to maintenance dose of 125 mg twice daily;.
Oral (Adults <40 kg and >12 yr) 62.5 mg twice daily as initial and maintenance dose.

Availability

Tablets: 62.5 mg, 125 mg

Nursing implications

Nursing assessment

  • Assess for signs and symptoms of primary pulmonary hypertension (dyspnea, exercise intolerance) prior to and periodically during therapy.
  • Lab Test Considerations: Monitor serum AST, ALT, and bilirubin prior to and monthly during treatment. If AST and ALT are ↑ >3 and ≤5 times the upper limit of normal, confirm level with a second test. If confirmed, reduce dose or interrupt therapy and monitor AST and ALT every 2 wk. If AST and ALT return to pretreatment levels, continue therapy or resume therapy the starting dose and recheck AST and ALT within 3 days.If AST and ALT are >5 and ≤8 times the upper limit of normal, confirm level with a second test. If confirmed, stop therapy and monitor AST and ALT every 2 wk. Once AST and ALT return to normal levels, reintroduce therapy at starting dose and recheck AST and ALT levels within 3 days. If AST and ALT levels are >8 times the upper limit of normal if clinical symptoms of liver injury (nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue) occur, or if bilirubin levels are ≥2 times the upper limit of normal, discontinue therapy permanently.
    • Monitor hemoglobin and hematocrit levels 1 and 3 mo after initiation of therapy and every 3 mo thereafter. May cause ↓ in hemoglobin.

Potential Nursing Diagnoses

Impaired gas exchange (Indications)

Implementation

  • Do not confuse Tracleer with Tricor.
  • Oral: Administer in the morning and evening without regard to food.
    • Bosentan can only be prescribed through the TRACLEER Access Program (T.A.P.) by calling 1–866–228–3546. It is not available at local pharmacies or wholesalers.

Patient/Family Teaching

  • Instruct patient to take bosentan as directed. Take missed doses as soon as remembered unless almost time for next dose; do not double doses. Do not stop taking bosentan without consulting health care professional; may cause an increase in symptoms. Explain the requirements of the TRACLEER Access Program.
  • Advise patient to notify health care professional immediately if nausea, vomiting, fever, abdominal pain, unusual tiredness, stomach pain, or jaundice occurs or if swelling of ankles or legs or difficulty breathing occurs.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking any Rx, OTC, or herbal products.
  • Advise patient of the requirement of monthly lab tests to monitor for liver dysfunction.
  • Caution premenopausal women about the importance of effective contraception, the interaction of bosentan with hormonal contraceptives, and the need for monthly serum or urine pregnancy tests. Crushed or broken tablets should not be handled by pregnant women. Inform men that bosentan may cause decreased sperm count.

Evaluation/Desired Outcomes

  • Improved exercise capacity and decreased rate of clinical progression in patients with primary pulmonary hypertension.

bosentan

A competitive mixed endothelin-A and endothelin-B receptor antagonist used to manage pulmonary arterial hypertension.
 
Adverse effects
Headache, flushing, hepatotoxicity, leg oedema, anaemia.

Tracleer

A brand name for BOSENTAN.
References in periodicals archive ?
In 2001, the US Food and Drug Administration (FDA) approved Tracleer as the treatment for patients with PAH.
Medication name Medication type Oral health effect(s) Fluticasone Nasal corticosteroid None reported ProAir HFA Beta2 agonist Xerostomia Adcirca Phosphodiesterast-5 None reported inhibitor Torsemide Antihypertensive None reported Warfarin Vitamin K antagonist Oral ulcers, taste distortion Ability Antipsychotic Xerostomia Pravachol Antilipemic agent None reported Spironolactone Antihypertensive, None reported diuretic Allopurinol Anti-gout None Trazadone Antidepressant Severe xerostomia Lamictal Anticonvulsant Xerostomia Colchicine Anti-gout Bosentan (generic Endothelia receptor Brandname Tracleer) antagonist, Tracleer vasodilator reported to cause periodontal bleeding.
Actelion's stock had previously declined due to concerns about the upcoming patent expiry of Tracleer (bosentan), the company's first generation drug for PAH.
Actelion markets Tracleer through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia and Switzerland.
1 billion by 2015 from Tracleer, as well as added sales from two experimental drugs in final-stage tests for the condition, said Olav Zilian, an analyst with Helvea AG.
Tracleer, the first pill for treatment of pulmonary hypertension, has been approved by the U.
Special considerations: Because it is teratogenic and can cause serious liver injury, Tracleer must be obtained directly from the manufacturer, with stringent pregnancy prevention measures.
announced positive results for oral endothelin receptor antagonist Tracleer in a Phase III pulmonary arterial hypertension (PAH) study.
Examples of blockbuster orphan drugs include Novartis' leukaemia drug, Glivec/Gleevec (imatinib), with global sales of US$4,695 million in 2011; and Actelion's Tracleer (bosentan), the current gold standard in pulmonary arterial hypertension with sales of CHF1,522 million (US$1,598 million) in 2011.
Acquisition of pharmaceuticals: Tracleer 125 mg tablets, 300 mg vial Tysabri, Atripla, Truvada tablets, Glivec 100 and 400 mg comp, Tasigna 150 and 200 mg cap, Xolair 75 and 150 mg, 0.
Clinical data and the opinions of interviewed thought leaders indicate that Actelion/Nippon Shinyaku's Opsumit has advantages on this attribute over sales-leading Actelion's Tracleer.
Kobrin led the development of several large programs, which supported a successful initial public offering on the Swiss Stock Exchange Moreover, under Dr Kobrin's leadership Tracleer, the flagship drug of Actelion reached regulatory approval world-wide, which was the bases for Actelion's growth to become the largest European-based global biotechnology company.