Posology : מינונים

4.2       Posology and method of administration

Treatment must be initiated and monitored by physicians, including paediatricians, experienced in the management of the specific deficiencies.

Posology

The recommended dosage for cholic acid in the treatment of inborn errors of primary bile acid synthesis is 10-15 mg/kg per day, either as a single daily dose or in divided doses, for both adult and paediatric patients. The dose should be subsequently titrated to the desired effect but should not exceed a maximum of 15mg/kg/day.

Where the dose calculated is not a multiple of 50, the nearest dose below the maximum of 15mg/kg/day should be selected, provided that is sufficient to suppress urinary bile acids. If not, the next higher dose should be selected.
The recommended dosage in patients with concomitant familial hypertriglyceridemia is 11 to 17 mg/kg once daily or in two divided doses and is adjusted based on clinical response.
• Monitor AST, ALT, GGT, alkaline phosphatase, bilirubin and INR every month for the first 3 months, every 3 months for the next 9 months, every 6 months during the next three years and annually thereafter. Administer the lowest dose that effectively maintains liver function
• Discontinue CHOLBAM if liver function does not improve within 3 months of starting treatment, if complete biliary obstruction develops, or if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis; continue to monitor liver function and consider restarting a lower dose when parameters return to baseline.

During the initiation of therapy and dose adjustment, serum and urine bile acid levels should be monitored intensively using gas chromatography-mass spectrometry (GC-MS) or equivalent technology coupled to mass spectrometry. The concentrations of the abnormal bile acid metabolites synthesised subesquently should be determined. The lowest dose of cholic acid that effectively reduces the bile acid metabolites to as close to zero as possible should be chosen.

Patients that have previously been treated with other bile acids or other cholic acid preparations should be closely monitored in the same manner during the initiation of treatment with Cholic acid FGK. The dose should be adjusted accordingly, as described above.

Liver parameters should also be monitored. Concurrent elevation of serum gamma glutamyltransferase (Gamma GT), alanine aminotransferase (ALT) and/or serum bile acids above normal levels may indicate overdose. Transient elevations of transaminases at the initiation of cholic acid treatment have been observed and do not indicate the need for a dose reduction if Gamma GT is not elevated and if serum bile acid levels are falling or in the normal range.

After the initiation period, serum and urine bile acids (using mass spectrometry technology) and liver parameters should be determined annually, at a minimum, and the dose adjusted accordingly.
Additional or more frequent investigations should be undertaken to monitor therapy during periods of fast growth, concomitant disease and pregnancy

Special populations

Patients with familial hypertriglyceridaemia
Patients with newly diagnosed or a family history of familial hypertriglyceridaemia are expected to poorly absorb cholic acid from the intestine. The cholic acid dose for patients with familial hypertriglyceridaemia will have to be established and adjusted as necessary, an elevated dose may be required in order to suppress urinary bile acids.

Paediatric population
The safety and efficacy of cholic acid in neonates less than one month of age has not been established.
No data are available.

Elderly patients (older than 65 years)
The safety and efficacy of cholic acid in elderly patients has not been established. No data available.
Renal impairment
No data are available for patients with renal impairment. However, these patients should be carefully monitored and the dose of cholic acid titrated individually.

Hepatic impairment
The majority of patients with inborn errors of bile acid metabolism presented with some degree of hepatic impairment at the time of diagnosis; in most patients, the hepatic impairment improved or resolved with treatment. The dose of cholic acid should be adjusted individually.

No data regarding cholic acid treatment are available in patients with inborn errors of bile acid metabolism with hepatic impairment unrelated to their primary disease. In the absence of clinical experience in such patients population, no recommendations on dosage adjustment can be made.
Patients with hepatic impairment unrelated to their primary disease who are treated with cholic acid are monitored closely.

Method of administration
It is recommended that cholic acid is taken with food at approximately the same time each day, in the morning and/or evening. The capsules should be swallowed whole with water.
Use in the pediatric population.
For infants and children who cannot swallow capsules, the capsule may be opened gently and the contents mixed with food. For young infants the contents may be mixed with infant formula, expressed breast milk or fruit puree and for infants and children under 6 years, mixed with soft food such as mashed potatoes or apple puree. The mixture should be administered immediately after preparation.
Mixing of the capsule contents is designed to mask any unpleasant taste which results from the capsules being opened but no data on the compatibility or palatability are available. The capsule contents will remain as fine granules in the milk or food.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.