DOSAGE AND ADMINISTRATION
GENERAL
TRACLEER® treatment should be initiated at a dose of 62.5 mg b.i.d. for 4 weeks and then increased to the maintenance dose of 125 mg b.i.d. Doses above 125 mg b.i.d. did not appear to confer additional benefit sufficient to offset the increased risk of liver injury.
Tablets should be administered morning and evening with or without food.
DOSAGE ADJUSTMENT AND MONITORING IN PATIENTS DEVELOPING AMINOTRANSFERASE ABNORMALITIES
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ALT/AST levelsTreatment and monitoring recommendations
> 3 and
Confirm by another aminotransferase test; if confirmed, reduce the daily dose or interrupt treatment, and monitor aminotransferase levels at least every 2 weeks. If the aminotransferase levels return to pre-treatment values, continue or re-introduce the treatment as appropriate (see below).
> 5 and
Confirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pre-treatment values, consider re-introduction of the treatment (see below).
> 8 × ULN
Treatment should be stopped and re-introduction of TRACLEER® should not be considered. There is no experience with re-introduction of TRACLEER® in these circumstances.
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If TRACLEER® is re-introduced it should be at the starting dose; aminotransferase levels should be checked within 3 days and thereafter according to the recommendations above.
If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin >/= 2 × ULN, treatment should be stopped. There is no experience with the re-introduction of TRACLEER® in these circumstances.
USE IN WOMEN OF CHILD-BEARING POTENTIAL
TRACLEER® treatment should only be initiated in women of child-bearing potential following a negative pregnancy test and only in those who practice adequate contraception that does not rely solely upon hormonal contraceptives, including oral, injectable or implantable contraceptives (see DRUG INTERACTIONS: Hormonal Contraceptives, Including Oral, Injectable and Implantable Contraceptives). Input from a gynecologist or similar expert on adequate contraception should be sought as needed. Urine or serum pregnancy tests should be obtained monthly in women of childbearing potential taking TRACLEER®.
DOSAGE ADJUSTMENT IN RENALLY IMPAIRED PATIENTS
The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment.
DOSAGE ADJUSTMENT IN GERIATRIC PATIENTS
Clinical studies of TRACLEER® did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Clinical experience has not identified differences in responses between elderly and younger patients. In general, caution should be exercised in dose selection for elderly patients given the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this age group.
DOSAGE ADJUSTMENT IN HEPATICALLY IMPAIRED PATIENTS
The influence of liver impairment on the pharmacokinetics of TRACLEER® has not been evaluated. Because there is in vivo and in vitro evidence that the main route of excretion of TRACLEER® is biliary, liver impairment would be expected to increase exposure (Cmax, AUC) to bosentan. There are no specific data to guide dosing in hepatically impaired patients (See WARNINGS); caution should be exercised in patients with mildly impaired liver function. TRACLEER® should generally be avoided in patients with moderate or severe liver impairment.
DOSAGE ADJUSTMENT IN CHILDREN
Safety and efficacy in pediatric patients have not been established.
DOSAGE ADJUSTMENT IN PATIENTS WITH LOW BODY WEIGHT
In patients with a body weight below 40 kg but who are over 12 years of age the recommended initial and maintenance dose is 62.5 mg b.i.d.
DISCONTINUATION OF TREATMENT
There is limited experience with abrupt discontinuation of TRACLEER®. No evidence for acute rebound has been observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction (62.5 mg b.i.d. for 3 to 7 days) should be considered.
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