Silkay 125 Dosage/Direction for Use

General: Bosentan treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks and then increased to the maintenance dose of 125 mg twice daily. Doses above 125 mg twice daily 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. In the case of clinical deterioration (e.g. decrease in 6-minute walk test distance by at least 10% compared with pre-treatment measurement) despite Bosentan treatment for at least 8 weeks (target dose for at least 4 weeks), alternative therapies should be considered. However, some patients who show no response after 8 weeks of treatment with Bosentan may respond favorably after an additional 4 to 8 weeks of treatment. In the case of late clinical deterioration despite treatment with Bosentan (i.e. after several months of treatment), the treatment should be re-assessed. Some patients not responding well to 125 mg twice daily of Bosentan may slightly improve their exercise capacity when the dose is increased to 250 mg twice daily. A careful benefit/risk assessment should be made, taking into consideration that the liver toxicity is dose dependent.
Required monitoring: Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated.
Dosage adjustment and monitoring in patients developing aminotransferase abnormalities: The table 1 as follows summarizes the dosage adjustment and monitoring recommendations for patients who develop aminotransferase elevations > 3 x ULN during therapy with Bosentan. 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 x ULN, treatment with Bosentan should be stopped. There is no experience with the re-introduction of Bosentan in these circumstances. (See Table 1.)

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Use in women of childbearing potential: Initiate treatment in females of child-bearing potential only after a negative pregnancy and only in females who are using two reliable methods of contraception. Females who have had a tubal sterilization or a Copper T 380A IUD of LNg 20 IUS inserted do not require other forms of contraception. Effective contraception must be practiced throughout treatment and for one month after stopping Bosentan. Females should seek contraceptive advice as needed from a gynecologist or similar expert. Urine or serum pregnancy tests should be obtained monthly in females of childbearing potential taking Bosentan.
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 Bosentan did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.
Dosage adjustment in hepatically impaired patients: Because there is in vitro and in vivo evidence that the main route of excretion of Bosentan is biliary, liver impairment could be expected to increase exposure (C_max and AUC) of Bosentan.
Mild liver impairment was shown not to impact the pharmacokinetics of Bosentan. The influence of moderate or severe liver impairment on the pharmacokinetics of Bosentan has not been evaluated. There are no specific data to guide dosing in hepatically impaired patients. (See Precautions); caution should be exercised in patients with mildly impaired liver function. Bosentan 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 twice daily. There is limited information about the safety and efficacy of Bosentan in children between ages of 12 and 18 years.
Discontinuation of treatment: There is limited experience with abrupt discontinuation of Bosentan. No evidence for acute rebound has been observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction (62.5 mg twice daily for 3 to 7 days) should be considered.