ORPHACOL

Treatment must be initiated and monitored by an experienced gastroenterologist/hepatologist or a paediatric gastroenterologist/hepatologist in the case of paediatric patients. 4). Patients should be monitored as follows: 3-monthly during the first year, 6-monthly during the subsequent three years and annually thereafter (see below).

Posology The dose must be adjusted for each patient in a specialised unit according to blood and/or urine chromatographic bile acid profiles. 3β-Hydroxy-Δ5-C27-steroid oxidoreductase deficiency The daily dose ranges from 5 to 15 mg/kg in infants, children, adolescents and adults.

In all age groups, the minimum dose is 50 mg and the dose is adjusted in 50 mg steps. In adults, the daily dose should not exceed 500 mg. Δ4-3-Oxosteroid-5β-reductase deficiency The daily dose ranges from 5 to 15 mg/kg in infants, children, adolescents and adults.

In all age groups, the minimum dose is 50 mg and the dose is adjusted in 50 mg steps. In adults, the daily dose should not exceed 500 mg. The daily dose may be divided if it consists of more than one capsule in order to mimic the continuous production of cholic acid in the body and to reduce the number of capsules that need to be taken per administration.

During the initiation of therapy and dose adjustment, serum and/or urine bile acid levels should be monitored intensively (at least every three months during the first year of treatment, every six months during the second year) using suitable analytical techniques.

The concentrations of the abnormal bile acid metabolites synthesised in 3β-Hydroxy-Δ5-C27-steroid oxidoreductase deficiency (3β, 7α-dihydroxy- and 3β, 7α, 12α-trihydroxy-5-cholenoic acids) or in Δ4-3-Oxosteroid-5β-reductase deficiency (3- oxo-7α-hydroxy- and 3-oxo-7α, 12α-dihydroxy-4-cholenoic acids) should be determined.

At each investigation, the need for dose adjustment should be considered. 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 Orphacol.

The dose should be adjusted accordingly, as described above. Liver parameters should also be monitored, preferentially more frequently than serum and/or urine bile acid levels. Concurrent elevation of serum gamma glutamyltransferase (GGT), alanine aminotransferase (ALT) and/or serum bile acids above normal levels may indicate overdose.

Summary of the safety profile Due to the rarity of the diseases, the information about the most serious and/or most frequently occurring adverse reactions is limited. Diarrhoea, increased transaminases and pruritus have been associated with overdosage and disappeared after dose reduction.

Development of gallstones associated with long-term treatment have been reported in very limited number of patients. Tabulated list of adverse reactions The following table lists adverse reactions reported in the literature under treatment with cholic acid.

The frequency of these reactions is not known (cannot be estimated from the available data). MedDRA System Organ Class Adverse reaction Gastrointestinal disorders Diarrhoea Hepatobiliary disorders Transaminases increased Gallstones Skin and subcutaneous tissue disorders Pruritus Description of selected adverse reactions The development of pruritus and/or diarrhoea has been observed during treatment with Orphacol.

These reactions abated after dose reduction and are suggestive of overdose. 9). Gallstones have been reported after long-term therapy. Paediatric population The presented safety information is derived principally from paediatric patients.

The available literature is not sufficient to detect a difference in the safety of cholic acid within paediatric age groups or between paediatric patients and adults. 2 for use of Orphacol in special populations. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Cases of severe hepatotoxicity, including cases with fatal outcome, have been reported, with the use of cholic acid. Treatment with cholic acid in patients with pre- existing hepatic impairment should be given under close monitoring and, for all patients, should be stopped if abnormal hepatocellular function, as measured by prothrombin time, does not improve within 3 months of the initiation of cholic acid treatment.

A concomitant decrease of urine total bile acids should be observed. Treatment should be stopped earlier if there are clear indicators of severe hepatic failure. Familial hypertriglyceridemia Patients with newly diagnosed or a family history of familial hypertriglyceridaemia may have poor absorption of cholic acid from the intestine.

The dose of cholic acid in such patients should be established and adjusted as described, but an elevated dose, notably higher than the 500 mg daily limit for adult patients, may be required. Excipients Orphacol capsules contain lactose.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

1. 5).