Orphacol 50毫克硬胶囊（通用名为“胆酸”）是一种治疗胆汁酸合成先天缺陷的胆酸药剂 通用名称：胆酸硬胶囊 商品名称：Orphacol 类    型：新配方 药理作用：替换一些缺少胆汁酸。降低生产异常胆汁酸和正常活动，因此减少的症状. 适应症：遗传性代谢缺陷 包装规格： 50mgx30粒/盒 50mgx60粒/盒 250mgx30粒/盒 Orphacol 50 milligram capsules 1. Name of the medicinal product Orphacol 50 mg hard capsules 2. Qualitative and quantitative composition Each hard capsule contains 50 mg of cholic acid. Excipient(s) with known effect: Lactose (145.79 mg per capsule). For a full list of excipients, see section 6.1. 3. Pharmaceutical form Hard capsule (capsule). Oblong, opaque, blue and white capsule. 4. Clinical particulars 4.1 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. 4.2 Posology and method of administration Treatment must be initiated and monitored by an experienced gastroenterologist/hepatologist or a paediatric gastroenterologist/hepatologist in the case of paediatric patients. In case of persistent lack of therapeutic response to cholic acid monotherapy, other treatment options should be considered (see section 4.4). 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 gas chromatography-mass spectrometry (GC-MS) or equivalent technology coupled to mass spectrometry. 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, l2α-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. 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 GGT is not elevated and if serum bile acid levels are falling or in the normal range. After the initiation period, serum and/or 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 (see section 4.6). Special populations Elderly population (≥65 years old) There is no experience in elderly patients. The dose of cholic acid should be adjusted individually. Renal impairment No data are available for patients with renal impairment. The dose of cholic acid should be adjusted individually. Hepatic impairment Limited data are available for patients with minor to severe hepatic impairment related to 3β-Hydroxy-Δ5-C27-steroid oxidoreductase deficiency or Δ4-3-Oxosteroid-5β-reductase deficiency. Patients are expected to present with some degree of hepatic impairment at diagnosis, which improves under cholic acid therapy. The dose of cholic acid should be adjusted individually. No experience exists in patients with hepatic impairment from causes other than 3β-Hydroxy-Δ5-C27-steroid oxidoreductase deficiency or Δ4-3-Oxosteroid-5β-reductase deficiency and no dose recommendation can be given. Patients with hepatic impairment should be monitored closely. Familial hypertriglyceridemia Patients with newly diagnosed or a family history of familial hypertriglyceridemia are expected to poorly absorb cholic acid in the intestine. The cholic acid dose for patients with familial hypertriglyceridemia will have to be established and adjusted as described, but an elevated dose, notably higher than the 500 mg daily limit for adult patients, may be required and safe. Paediatric population Cholic acid therapy has been used for infants from one month of age, and for children and adolescents. The dose recommendations reflect the use in this population. The daily dose in infants from 1 month to 2 years of age, children and adolescents ranges from 5 to 15 mg/kg and must be adjusted individually for each patient. Method of administration Orphacol capsules must be taken with food at approximately the same time each day, in the morning and/or evening. Administration with food may increase cholic acid bioavailability and improve tolerability. Regular and fixed times of administration support the patient's or caregiver's compliance. Capsules must be swallowed whole with water, without chewing. For infants and children who cannot swallow capsules, the capsules may be opened and the content added to infant formula or juice. For additional information, see section 6.6. 4.3 Contraindications Hypersensitivity to cholic acid or to any of the excipients. Concomitant use of phenobarbital with cholic acid (see section 4.5). 4.4 Special warnings and precautions for use Treatment with cholic acid 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, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction Phenobarbital antagonises the effect of cholic acid. Use of phenobarbital in patients with 3β-Hydroxy-Δ5-C27-steroid oxidoreductase deficiency or Δ4-3-Oxosteroid-5β-reductase deficiency treated with cholic acid is contraindicated (see section 4.3). Alternative treatments should be used. Ciclosporin alters the pharmacokinetics of cholic acid by inhibition of the hepatic uptake and hepatobiliary secretion of bile acids, as well as its pharmacodynamics by inhibition of cholesterol 7α-hydroxylase. Co-administration should be avoided. If administration of ciclosporin is considered necessary, serum and urine bile acid levels should be closely monitored and the cholic acid dose adjusted accordingly. Bile acid sequestrants (cholestyramine, colestipol, colesevelam) and certain antacids (e.g. aluminium hydroxide) bind bile acids and lead to their elimination. Administration of these medicinal products is expected to reduce the effect of cholic acid. The dose of bile acid sequestrants or antacids must be separated from the dose of cholic acid by an interval of 5 hours, regardless of which medicinal product is administered first. The effect of food on the bioavailability of cholic acid has not been studied. There is a theoretical possibility that administration with food may increase cholic acid bioavailability and improve tolerability. 4.6 Fertility, pregnancy and lactation Women of childbearing potential There is no need for contraceptive measures in women of childbearing potential treated with cholic acid or their partners. Women of childbearing potential should conduct a pregnancy test as soon as a pregnancy is suspected. Pregnancy There is a limited amount of data (4 pregnancy outcomes) from the use of cholic acid in pregnant women. The exposed pregnancies showed no adverse reactions to cholic acid and resulted in normal, healthy children. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). It is extremely important that pregnant women continue their therapy during pregnancy. As a precautionary measure, pregnant women and their unborn children should be closely monitored. Breastfeeding Cholic acid and its metabolites are excreted in human milk, but at therapeutic doses of Orphacol, no effects on the breastfed newborns/infants are anticipated. Orphacol can be used during breast-feeding. Fertility No data on the effects of cholic acid on fertility are available. At therapeutic doses, no effect on fertility is anticipated. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. Cholic acid has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects 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). Gastrointestinal disorders Diarrhoea Hepatobiliary disorders Transaminases increased Gallstones Skin and subcutaneous tissue disorders Pruritus 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. Patients presenting with pruritus and/or persistent diarrhoea should be investigated for a potential overdose by a serum and/or urine bile acid assay (see section 4.9). 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. 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: Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard 4.9 Overdose Episodes of symptomatic overdose have been reported, including accidental overdose. Clinical features were limited to pruritus and diarrhoea. Laboratory tests showed elevation of serum gamma glutamyltransferase (GGT) transaminases and serum bile acid concentrations. Reduction of the dose led to resolution of the clinical signs and correction of abnormal laboratory parameters. In the case of an accidental overdose, treatment should be continued at the recommended dose after normalisation of clinical signs and/or biological abnormalities. 5. Pharmacological properties 5.1 Pharmacodynamic properties 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 acid-dependent 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 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. 5.2 Pharmacokinetic properties Cholic acid, a primary bile acid, is partially absorbed in the ileum. The remaining part is transformed by reduction of the 7α-hydroxy group to deoxycholic acid (3α, 12α-dihydroxy) by intestinal bacteria. Deoxycholic acid is a secondary bile acid. More than 90 % of the primary and secondary bile acids are reabsorbed in the ileum by a specific active transporter and are recycled to the liver by the portal vein; the remainder is excreted in the faeces. A small fraction of bile acids is excreted in urine. No pharmacokinetic study data for Orphacol are available. 5.3 Preclinical safety data The available non-clinical data in the literature reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. The studies have however not been conducted to the same level of detail as for a pharmaceutical agent, as cholic acid is a physiological substance in animals and humans. The intravenous LD50 of cholic acid in mice is 350 mg/kg body weight. Parenteral administration may cause haemolysis and cardiac arrest. Administered orally, bile acids and salts generally have only a minor toxic potential. The oral LD50 in mouse is 1520 mg/kg. In repeated-dose studies, frequently reported effects of cholic acid have included decreased body weight, diarrhoea and liver damage with elevated transaminases. Increased liver weight and gallstones have been reported in repeated dose studies in which cholic acid was co-administered with cholesterol. Cholic acid showed non significant mutagenic activity in a battery of genotoxicity tests performed in vitro. Animal studies showed that cholic acid did not induce any teratogenic effect or foetal toxicity. 6. Pharmaceutical particulars 6.1 List of excipients Capsule content: Lactose monohydrate, Colloidal anhydrous silica, Magnesium stearate. Capsule shell: Gelatin, Titanium dioxide (E171), Carmine blue (E132). 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage Store below 30°C. 6.5 Nature and contents of container PVC-aluminium blister of 10 capsules. Pack sizes: 30, 60, 120. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Use in the paediatric population See also section 4.2. For infants and children who cannot swallow capsules, the capsules may be opened and the content added to infant formula, or infant-adapted apple/orange or apple/apricot juice. Other food such as fruit compote or yoghurt may be suitable for administration, but no data on the compatibility or palatability are available. Any unused product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Laboratoires CTRS 63, rue de l'Est 92100 Boulogne-Billancourt France 8. Marketing authorisation number(s) EU/1/13/870/001 EU/1/13/870/002 EU/1/13/870/003 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 12 September 2013 10. Date of revision of the text 03/2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu Product details for Orphacol Name Orphacol Agency product number EMEA/H/C/001250 Active substance cholic acid International non-proprietary name (INN) or common name cholic acid Therapeutic area Digestive System DiseasesMetabolism, Inborn Errors Anatomical therapeutic chemical (ATC) code A05AA03 Additional monitoring This medicine is under additional monitoring. This means that it is being monitored even more intensively than other medicines. For more information, see medicines under additional monitoring. Treatment of rare diseases This medicine has an "orphan designation" which means that it is used to treat life-threatening or chronically debilitating conditions that affect no more than five in 10,000 people in the European Union, or are medicines which, for economic reasons, would be unlikely to be developed without incentives. Exceptional Circumstances There were "exceptional circumstances" concerning the approval of this medicine. This happens when the applicant can show that they are unable to provide comprehensive data on the efficacy and safety of the medicine for which authorisation is being sought, due to the rarity of the condition it is intended for, limited scientific knowledge in the area concerned, or ethical considerations involved in the collection of such data. Publication details Publication details for Orphacol Marketing-authorisation holder Laboratoires CTRS Revision 1 Date of issue of marketing authorisation valid throughout the European Union 12/09/2013