Name: Orphacol 50 mg hard capsules.

Nature and contents of container: PVC-aluminium blister of 10 capsules. Pack sizes: 30, 60, 120. Not all pack sizes may be marketed.

Therapeutic indications : Orphacol is indicated for the treatment of inborn errors in primary bile acid synthesis due to 3β-Hydroxy-Δ5 -C27-steroid oxidoreductase deficiency or Δ4 -3-Oxosteroid-5β-reductase deficiency in infants, children and adolescents aged 1 month to 18 years and adults.

Pharmacotherapeutic group: Bile and liver therapy, bile acid preparations, ATC code: A05AA03 Cholic acid is the predominant primary bile acid in man. In patients with inborn deficiency of 3β-Hydroxy-Δ5 -C27-steroid oxidoreductase and Δ4 -3-Oxosteroid-5β-reductase, the biosynthesis of primary bile acids is reduced or absent. Both inborn dieseases are extremely rare, with a prevalence in Europe of about 3 to 5 patients with 3β-Hydroxy-Δ5 -C27-steroid oxidoreductase deficiency per 10 million inhabitants, and an estimated ten-fold lower prevalence for Δ4 -3-Oxosteroid-5β-reductase deficiency. In the absence of treatment, unphysiologic cholestatic and hepatotoxic bile acid metabolites are predominant in the liver, serum and urine. The rational basis for treatment consists of restoration of the bile aciddependent component of bile flow enabling restoration of biliary secretion and biliary elimination of toxic metabolites; inhibition of the production of the toxic bile acid metabolites by negative feedback on cholesterol 7α-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis; and improvement of the patient’s nutritional status by correcting intestinal malabsorption of fats and fat-soluble vitamins. Clinical experience has been reported in the literature from small cohorts of patients and single case reports; absolute patient numbers are small due to the rarity of the conditions. This rarity also made the conduct of controlled clinical studies impossible. Overall, cholic acid treatment results for about 60 patients with 3β-Hydroxy-Δ5 -C27-steroid oxidoreductase deficiency are reported in the literature. Detailed long-term data on treatment with cholic acid monotherapy are available for 14 patients observed for up to 12.9 years. Cholic acid reatment results for seven patients with Δ4 -3-Oxosteroid-5β-reductase deficiency 7 for up to 14 years are reported in the literature. Detailed medium- to long-term data are available for 5 of these patients, of whom 1 has been treated with cholic acid monotherapy. Oral cholic acid therapy has been shown to: postpone or obviate the need for liver transplantation; restore normal laboratory parameters; improve histological lesions of the liver, and significantly improve all of the patient’s symptoms. Mass spectrometry analysis of urine during cholic acid therapy shows the presence of cholic acid and a marked reduction, or even complete elimination of the toxic bile acid metabolites. This reflects restoration of an effective feedback control of bile acid synthesis and a metabolic equilibrium. In addition, blood cholic acid concentration was normal and fat-soluble vitamins were restored to their normal range. Paediatric population The clinical experience reported in the literature is from a patient population with inborn deficiency of 3β-Hydroxy-Δ5 -C27-steroid oxidoreductase or Δ4 -3-Oxosteroid-5β-reductase that includes principally infants from the age of one month, children and adolescents. However, absolute numbers of cases are small. This medicinal product has been authorised under “Exceptional Circumstances”. This means that due to the rarity of the disease and for ethical reasons it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.

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