DESCRIPTION

Tracleer is the proprietary name for bosentan, an endothelin receptor antagonist that belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2´]-bipyrimidin-4-yl]- benzenesulfonamide monohydrate and has the following structural formula:

Bosentan has a molecular weight of 569.64 and a molecular formula of C₂₇H₂₉N₅O₆S·H₂O. Bosentan is a white to yellowish powder. It is poorly soluble in water (1.0 mg/100 mL) and in aqueous solutions at low pH (0.1 mg/100 mL at pH 1.1 and 4.0; 0.2 mg/100 mL at pH 5.0). Solubility increases at higher pH values (43 mg/100 mL at pH 7.5). In the solid state, bosentan is very stable, is not hygroscopic and is not light sensitive.

Tracleer is available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: corn starch, pregelatinized starch, sodium starch glycolate, povidone, glyceryl behenate, magnesium stearate, hydroxypropylmethylcellulose, triacetin, talc, titanium dioxide, iron oxide yellow, iron oxide red, and ethylcellulose. Each Tracleer 62.5 mg tablet contains 64.54 mg of bosentan monohydrate, equivalent to 62.5 mg of anhydrous bosentan. Each Tracleer 125 mg tablet contains 129.08 mg of bosentan monohydrate, equivalent to 125 mg of anhydrous bosentan.

Tracleer is also available as a 32 mg tablet for oral suspension and contains the following excipients: cellulose microcrystalline, calcium hydrogen phosphate anhydrous, croscarmellose sodium, silica colloidal anhydrous, tartaric acid, tutti frutti flavor, aspartame (E951), acesulfame potassium, and magnesium stearate. Each dispersible tablet contains 1.87 mg of phenylalanine. Each dispersible tablet contains 33.045 mg of bosentan monohydrate, equivalent to 32 mg anhydrous bosentan.

INDICATIONS

Tracleer is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):

• in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO 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 heart disease with left-to-right shunts (18%) [see Clinical Studies].
• in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expectedto result in an improvement in exercise ability.

DOSAGE AND ADMINISTRATION

Required Monitoring

Healthcare professionals who prescribe Tracleer must enroll in the Tracleer REMS Program and must comply with the required monitoring to minimize the risks associated with Tracleer [see WARNINGS AND PRECAUTIONS].

Obtain a pregnancy test in females of reproductive potential prior to Tracleer treatment, monthly during treatment and one month after stopping Tracleer. Initiate treatment with Tracleer in females of reproductive potential only after a negative pregnancy test [see BOX WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Measure liver aminotransferase levels prior to initiation of treatment and then monthly [see WARNINGS AND PRECAUTIONS].

HOW SUPPLIED

Dosage Forms And Strengths

62.5 mg tablets: round, biconvex, orange-white tablets, debossed with identification marking “62,5”

125 mg tablets: oval, biconvex, orange-white tablets, debossed with identification marking “125”

32 mg tablets for oral suspension: clover-shaped, quadrisected, pale yellow to off-white tablets, debossed with identification marking “32” on the side opposite the quadrisection lines

Storage And Handling

62.5 mg film-coated, round, biconvex, orange-white tablets, debossed with identification marking “62,5”, packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap or in foil blister-strips for hospital unit-dosing.

NDC 66215-101-06: Bottle containing 60 tablets.
NDC 66215-101-03: Carton of 30 tablets in 10 blister strips of 3 tablets.

125 mg film-coated, oval, biconvex, orange-white tablets, debossed with identification marking “125”, packaged in a white high-density polyethylene bottle and a white polypropylene childresistant cap or in foil blister-strips for hospital unit-dosing.

NDC 66215-102-06: Bottle containing 60 tablets.
NDC 66215-102-03: Carton of 30 tablets in 10 blister strips of 3 tablets.

32 mg tablets for oral suspension, pale yellow to off-white, clover-shaped, quadrisected on one side and debossed with “32” on the other side, packaged in child resistant Aluminum/Aluminum peel-push blisters.

NDC 66215-103-56: Carton of 56 tablets for oral suspension in 4 blister-strips of 14 tablets.
NDC 66215-103-14: Blister strip of 14 tablets for oral suspension.

Store at 20°C – 25°C (68°F – 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature]. These storage temperatures apply to both filmcoated and dispersible tablets. Divided dispersible tablets should be stored under the same conditions and used within 7 days. Tablet pieces may be returned to the opened blister and stored there out of reach of children for up to 7 days.

SIDE EFFECTS

The following important adverse reactions are described elsewhere in the labeling:

• Hepatotoxicity [see BOX WARNING, WARNINGS AND PRECAUTIONS]
• Embryo-fetal Toxicity [see BOX WARNING, WARNINGS AND PRECAUTIONS]
• Fluid Retention [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety data on Tracleer were obtained from 13 clinical studies (9 placebo-controlled and 4 openlabel) in 870 adult patients with PAH and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg twice daily) were administered for a variety of durations. The exposure to Tracleer in these trials ranged from 1 day to 4.1 years (n=94 for 1 year; n=61 for 1.5 years; and n=39 for more than 2 years). Exposure of PAH patients (n=328) to Tracleer ranged from 1 day to 1.7 years (n=174 more than 6 months and n=28 more than 12 months).

Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in adult patients with PAH were more frequent on Tracleer (6%; 15/258 patients) than on placebo (3%; 5/172 patients). In this database the only cause of discontinuations > 1% and occurring more often on Tracleer was abnormal liver function.

PRECAUTIONS

Hepatotoxicity

ALT or AST > 3 x ULN were observed in 11% of Tracleer-treated patients (n = 658) compared to 2% of placebo-treated patients (n = 280). Three-fold increases were seen in 12% of 95 pulmonary arterial hypertension (PAH) patients on 125 mg twice daily and 14% of 70 PAH patients on 250 mg twice daily. Eight-fold increases were seen in 2% of PAH patients on 125 mg twice daily and 7% of PAH patients on 250 mg twice daily. Bilirubin increases to ≥ 3 x ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with Tracleer. In a pooled analysis of four pediatric studies conducted in PAH (n =100), elevations in liver aminotransferases ≥ 3 × ULN were observed in 2% of patients. The combination of hepatocellular injury (increases in aminotransferases of > 3 x ULN) and increases in total bilirubin (≥ 2 x ULN) is a marker for potential serious hepatotoxicity.

Elevations of AST or ALT associated with Tracleer are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic, and usually have been reversible after treatment interruption or cessation. Aminotransferase elevations also may reverse spontaneously while continuing treatment with Tracleer.

Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly [see DOSAGE AND ADMINISTRATION]. Discontinue Tracleer if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN.

Avoid initiation of Tracleer in patients with elevated aminotransferases (> 3 x ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult [see BOX WARNING, DOSAGE AND ADMINISTRATION, Use In Specific Populations].

In WHO Functional Class II patients, consider whether the benefits of Tracleer are sufficient to offset the risk of hepatotoxicity, which may preclude future use as their disease progresses.

Embryo-Fetal Toxicity

Based on data from animal reproduction studies, Tracleer may cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test prior to Tracleer treatment, monthly during treatment and for one month after stopping treatment. Advise females of reproductive potential to use two reliable forms of contraception during treatment with Tracleer and for at least one month after the last dose [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].

Tracleer is only available for females through a restricted program under REMS [see Prescribing And Distribution Program For Tracleer].