Kolbam

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 15 mg/kg/day. Where the dose calculated is not a multiple of 50, the nearest dose below the maximum of 15 mg/kg/day should be selected, provided that is sufficient to suppress urinary bile acids.

If not, the next higher dose should be selected. Patients should be monitored initially every 3 months during the first year then 6 monthly during the subsequent three years and annually thereafter. In case of persistent lack of therapeutic response to cholic acid monotherapy, other treatment options should be considered, see section

Summary of the safety profile Adverse reactions in patients (both adults and children) receiving cholic acid are generally mild to moderate in severity; the main reactions observed are given in the table below. The events were transitory and generally did not interfere with the therapy.

Tabulated list of adverse reactions Based on clinical trial data, adverse reactions in patients (both adults and children) receiving cholic acid are generally mild to moderate in severity and are provided in the following table. Adverse reactions are ranked according to system organ class, using the following convention: very common (≥ 1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

The adverse reactions reported in the literature with an unknown frequency are also reported in the following table. MedDRA System Organ Class Preferred Term Frequency Nervous system disorders Mild peripheral neuropathy Common Gastrointestinal disorders Diarrhoea Common Mild nausea Mild reflux Moderate diarrhoea Common Common Common Reflux esophagitis Common Hepatobiliary disorders Jaundice Increased serum transaminases Gallstones Common Not known Not known Skin and subcutaneous tissue disorders Skin lesion Pruritus Common Not known General disorders and administration site conditions Malaise Common Medicinal product no longer authorised6 Description of selected adverse reactions Adverse reactions reported in the literature are pruritus and increased serum transaminases in one or two children treated with high doses of cholic acid; however, these adverse reactions disappeared with a reduced dosage.

Diarrhoea is also known to occur in cases of excessive dosing with cholic acid. Gallstones have been reported after long-term therapy. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

4. During the initiation of therapy and dose adjustment, serum and urine bile acid levels should be monitored intensively by using suitable analytical techniques. The concentrations of the abnormal bile Medicinal product no longer authorised3 acid metabolites synthesised subsequently 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 Kolbam.

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 suitable analytical techniques) and liver parameters should be determined annually, at a minimum, and the dose adjusted accordingly. 6). 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.

4). 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 are 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.

1. 5).