Tracleer Bosentan Tablets

Step Forward with Tracleer

For patients with pulmonary arterial hypertension (PAH, WHO Group I) WHO Class II, III, IV
Diagnose PAH* EarlyInvestigate and ScreenConfirm HemodynamicsDetermine Functional ClassDon't Watch and Wait

Confirm pulmonary arterial hypertension*
with right heart catheterization

 Hemodynamic changes correlate with disease progression.1,2
 RHC confirms a PAH* diagnosis and can help determine disease severity.1
 Hemodynamics are important prognostic indicators in PAH.*1

Clinical definition of pulmonary arterial hypertension*


In previous guidelines, PVR>3 Wood units was included in the definition of PAH*.1


Hemodynamic measurements, calculations, and normal values
  Normal hemodynamic values at rest
Measurement   Average (mm Hg) Range (mm Hg)
RAP4
 a wave
v wave
6
5
2-7
2-7
mRAP4
 Elevated mRAP may be indicative of
right ventricular failure3
3
1-5
RVP4
 peak systolic
end diastolic
25
4
15-30
1-7
PAP4
 peak systolic
end diastolic
25
9
15-30
4-12
mPAP1,3
 Reduce variability by consistently
measuring pressures over 2 to 3
respiratory cycles at end-exhalation1
14
8-20
CO4,5
 Fick calculation†
 
4-8 L/min
CI6
 Obtained by Fick calculation or
thermodilution
 
2.5-4.2 L/min/m2
PCWP4
 Confirm that PCWP is not a damped
PA pressure by using a precise a and v
waveform timed against ECG or
LV pressure7
9
4-12
LAP4
 a wave
v wave
10
12
4-16
6-21
LVP4
 peak systolic
end diastolic
130
8
90-140
5-12

  Normal hemodynamic values at rest  
Vascular
resistance
Average4
(dyn•sec/cm5)
Range4
(dyn•sec/cm5)
 
SVR
1100
700-1600
 SVR = 80 (Aom – RAm) Qs[3]
TPR
200
100-300
 Should be used primarily in patients
in whom measurement of LA or PCWP
is not possible8
PVR
70
20-130
 PVR = 80 (mPAP–PCWP)/CO[9]

†Fick calculation3: CO (L/min) =  O2 consumption (mL/min)
Arteriovenous O2 difference (vol %) x 1.36 x Hgb x 10

Note: All measurement should be conducted at end-exhalation.1 Individual hospital guidelines can vary for hemodynamic measurements and calculations needed to diagnose PAH* with right heart catheterization. This chart is for reference only and is not intended to provide medical advice or to replace individual hospital guidelines.

Aom mean aortic pressure; CI cardiac index; CO cardiac output; Hgb hemoglobin; LAP left atrial pressure; LVP left ventricular pressure; mPAP mean pulmonary arterial pressure; mRAP mean right atrial pressure; PAP pulmonary arterial pressure; PASP pulmonary arterial systolic pressure; PCWP pulmonary capillary wedge pressure; PVR pulmonary vascular resistance; Qs systemic blood flow; RAm mean right atrial pressure; RAP right atrial pressure; RHC right heart catheterization; RVP right ventricular pressure; RVEF right ventricular ejection fraction; SVR systemic vascular resistance; TPR total pulmonary resistance.

*INDICATION
Tracleer is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital systemic-to-pulmonary shunts (18%).

Considerations for use
Patients with WHO class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the risk of liver injury in WHO class II patients, which may preclude future use as their disease progresses.

IMPORTANT SAFETY INFORMATION
Because of the risks of liver injury and birth defects, Tracleer may be prescribed and dispensed only through the Tracleer Access Program (T.A.P.), a restricted distribution program, by calling 1-866-228-3546. Only prescribers and pharmacies registered with T.A.P. may prescribe and distribute Tracleer. Tracleer may be dispensed only to patients who are enrolled in and meet all conditions of T.A.P.

Liver injury
Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with Tracleer. In a setting of close monitoring, rare cases of liver failure and unexplained hepatic cirrhosis were observed after prolonged treatment. In general, avoid using Tracleer in patients with elevated aminotransferases
(>3 × ULN). Measure liver aminotransferases prior to initiation of treatment and then monthly. Discontinue Tracleer if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥2 × ULN.

Teratogenicity
Based on animal data, Tracleer is likely to cause major birth defects if used during pregnancy. Exclude pregnancy before and during treatment. To prevent pregnancy, females of childbearing potential must use 2 reliable forms of contraception during treatment and for 1 month after stopping Tracleer unless the patient has a tubal sterilization or Copper T 380A IUD or LNg 20-IUS inserted, in which case no other contraception is needed. Monthly pregnancy tests should be obtained.

CONTRAINDICATIONS
Tracleer is contraindicated with cyclosporine A, glyburide, in females who are or may become pregnant, or in patients who are hypersensitive to bosentan or any component of Tracleer.

WARNINGS AND PRECAUTIONS
In clinical trials, Tracleer caused ALT/AST elevations (>3 × ULN) in 11% of patients accompanied by elevated bilirubin in a few cases. The combination of hepatocellular injury (increases in aminotransferases of >3 × ULN) and increases in total bilirubin (≥3 × ULN) is a marker for potential serious liver injury. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. Avoid using Tracleer in patients with moderate or severe liver impairment or elevated ALT/AST >3 × ULN.
If clinically significant fluid retention develops, with or without associated weight gain, the cause, such as Tracleer or underlying heart failure, must be determined. Patients may require treatment or Tracleer therapy may need to be discontinued.
Preclinical data and an open-label safety study (N=25) showed a decline in sperm count of ≥50% in 25% of Tracleer-treated patients after 3 or 6 months. After 6 months, sperm count remained in normal range, with no changes in sperm morphology or motility, or hormone levels. Endothelin receptor antagonists such as Tracleer may adversely affect spermatogenesis.
Treatment with Tracleer can cause a dose-related decrease in hemoglobin (Hgb) and hematocrit. Hgb should be checked after 1 and 3 months, and then every 3 months. Upon marked decrease in Hgb, determine the cause and need for specific treatment.
If signs of pulmonary edema occur, the possibility of associated pulmonary veno-occlusive disease should be considered. Tracleer should be discontinued.

ADVERSE EVENTS
In Tracleer pivotal trials, the most common adverse events occurring more often in Tracleer-treated patients than in patients taking placebo (≥2%) were respiratory tract infection, edema, hypotension, sinusitis, arthralgia, liver function test abnormal, palpitations, and anemia.

Please see full Prescribing Information, including BOXED WARNING about liver injury and pregnancy.

Review determination of functional class status

  1. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. J Am Coll Cardiol. 2009;53:1573-1619.
  2. Rich S, McLaughlin VV. Pulmonary hypertension. In: Libby P, Bonow RO, Mann DL, Zipes DE, eds. Braunwald's Heart Disease. 2 vols. 8th ed. Philadelphia, PA: Saunders Elsevier; 2008:1883-1914.
  3. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(suppl S):S55-S66.
  4. Davidson CJ, Bonow RO. Cardiac catheterization. In: Libby P, Bonow RO, Mann DL, Zipes DE. Braunwald's Heart Disease. 2 vols. 8th ed. Philadelphia, PA: Saunders Elsevier; 2008:439-463.
  5. Cardiovascular Tests and Procedures: Cardiac Catheterization. Merck Manual Professional website. http://www.merck.com/mmpe/sec07/ch070/ch070b.html. Accessed February 2, 2010.
  6. Kaluski E, Shah M, Korbrin I, et al. Right heart catheterization: indications, technique, safety, measurements, and alternatives. Heart Drug. 2003;3:225-235.
  7. Kern MJ, ed. The Cardiac Catheterization Handbook. 4th ed. Philadelphia, PA: Mosby; 2003:135, 158-159.
  8. Grossman W. Blood flow measurement: cardiac output and vascular resistance. In: Baim DS, ed. Grossman's Cardiac Catheterization, Angiography, and Intervention. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:148-162.
  9. Galiè N, Rubin LJ, Hoeper MM, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371:2093-2100.