Orphacol

1 

  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of new 
safety information. Healthcare professionals are asked to report any suspected adverse reactions. See 
section 4.8 for how to report adverse reactions. 
 
 
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 monohydrate (145.79 mg per capsule). 
 
For the 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  



3 

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. 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 suitable analytical techniques) 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 (see 
section 4.4). 
 
Familial hypertriglyceridemia 



4 

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 the active substance or to any of the excipients listed in section 6.1. 
 
Concomitant use of phenobarbital with cholic acid (see section 4.5). 
 
4.4 Special warnings and precautions for use 
 
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. 
 
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 



5 

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 (less than 20 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 
 
Cholic acid has no or negligible influence on the ability to drive and use machines. 
 
 
4.8 Undesirable effects 
 
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). 
 



6 

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. 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. 
 
Other special populations 
Please refer to section 4.2 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 national reporting system listed in Appendix V. 
 
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 and derivatives, 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 diseases 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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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 treatment 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 and 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 mice 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.  



8 

 
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 (bovine origin), 
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/PVDC-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 



9 

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 
Date of latest renewal: 24 April 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

http://www.ema.europa.eu/


10 

This medicinal product is subject to additional monitoring. This will allow quick identification of new 
safety information. Healthcare professionals are asked to report any suspected adverse reactions. See 
section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orphacol 250 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 250 mg of cholic acid. 
 
Excipient(s) with known effect: Lactose monohydrate (66.98 mg per capsule). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule(capsule). 
 
Oblong, opaque, green 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  



11 

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, 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 suitable analytical techniques) 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 (see 
section 4.4). 
 
Familial hypertriglyceridemia 



12 

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 the active substance or to any of the excipients listed in section 6.1. 
 
Concomitant use of phenobarbital with cholic acid (see section 4.5). 
 
4.4 Special warnings and precautions for use 
 
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. 
 
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 



13 

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 (less than 20 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 
 
Cholic acid has no or neglible influence on the ability to drive and use machines. 
 
 
4.8 Undesirable effects 
 
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). 
 



14 

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. 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. 
 
Other special populations 
Please refer to section 4.2 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 national reporting system listed in Appendix V. 
 
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 and derivatives, 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 diseases 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. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


15 

 
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 treatment 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. 
 
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 and 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 mice 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. 
 



16 

 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule content: 
Lactose monohydrate,  
Colloidal anhydrous silica, 
Magnesium stearate. 
 
Capsule shell: 
Gelatin (bovine origin), 
Titanium dioxide (E171), 
Carmine blue (E132), 
Yellow Iron Oxide (E172). 
 
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/PVDC-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 
 
 



17 

8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/870/004  
EU/1/13/870/005  
EU/1/13/870/006  
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 12 September 2013 
Date of latest renewal: 24 April 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

http://www.ema.europa.eu/


18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE  

 
C. OTHER CONDITIONS OR RESTRICTIONS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 
SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
E. SPECIFIC OBLIGATIONS TO COMPLETE POST-

AUTHORISATION MEASURES FOR THE MARKETING 
AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES 



19 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Laboratoires CTRS 
63, rue de l'Est 
92100 Boulogne-Billancourt 
France 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.  
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 

USE OF THE MEDICINAL PRODUCT   
 
• Risk Management Plan (RMP) 

 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed 
RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the 
RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 
• Additional risk minimisation measures 
 
The MAH, in agreement with the competent authorities in the Member States, shall implement, prior to 
the launch, an educational programme for physicians aiming to provide educational material on correct 
diagnosis and therapeutic managements of 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 and 
to inform on expected and potential risks associated with the treatment.  
 
The physician educational programme should contain the following key elements: 
 
• Prescription of a supratherapeutic dose (MedDRA term: drug toxicity) 



20 

• Risk of gallstones 
 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR 
THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES 
 
This being an approval under exceptional circumstances and pursuant to Article 14(8) of Regulation (EC) 
No 726/2004, the MAH shall conduct, within the stated timeframe, the following measures: 
 

Description 
 

Due Date 

CTRS commits to monitor the safety and efficacy in patients treated with Orphacol from a 
patient surveillance database for which the protocol has been endorsed by the CHMP and 
is documented in the Orphacol RMP.  
The objectives of this surveillance programme is to monitor accumulating data on efficacy 
and safety in 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 with Orphacol in infants, children, adolescents and adults. 
Reports on recruitment progress of the patient surveillance database will be analysed and 
reported to the CHMP at the time of PSURs (for safety) and of the Annual Re-
assessments (for efficacy and safety). Progress and results from the database will form the 
basis of the annual reassessments of the benefit/risk profile of Orphacol. 

- PSUR 
- Annual Re-
assessment 

 



21 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

 



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



23 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orphacol 50 mg hard capsules 
Cholic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 50 mg cholic acid. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 hard capsules 
60 hard capsules 
120 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Do not chew. 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



24 

9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Laboratoires CTRS 
63, rue de l’Est 
92100 Boulogne-Billancourt 
France 
E-mail: ctrs@ctrs.fr 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/870/001 [30 hard capsules] 
EU/1/13/870/002 [60 hard capsules] 
EU/1/13/870/003 [120 hard capsules] 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number}  



25 

SN: {number}  
NN: {number}  
 



26 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orphacol 250 mg hard capsules 
Cholic acid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 250 mg cholic acid. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 hard capsules 
60 hard capsules 
120 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Do not chew. 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



27 

9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Laboratoires CTRS 
63, rue de l’Est 
92100 Boulogne-Billancourt 
France 
E-mail: ctrs@ctrs.fr 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/870/004 [30 hard capsules] 
EU/1/13/870/005 [60 hard capsules] 
EU/1/13/870/006 [120 hard capsules] 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  



28 

NN: {number}  



29 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orphacol 50 mg capsules 
Cholic acid 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Laboratoires CTRS 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



30 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orphacol 250 mg capsules 
Cholic acid 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Laboratoires CTRS 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



32 

PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

Orphacol 50 mg hard capsules 
Orphacol 250 mg hard capsules 

Cholic acid 
 

This medicine is subject to additional monitoring. This will allow quick identification of new safety 
information. You can help by reporting any side effects you may get. See the end of section 4 for how to 
report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains  
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet: 
1. What Orphacol is and what it is used for 
2. What you need to know before you take Orphacol 
3. How to take Orphacol 
4. Possible side effects 
5. How to store Orphacol 
6. Contents of the pack and other information 
 
 
1. What Orphacol is and what it is used for 
 
Orphacol contains cholic acid, a bile acid which is normally produced by the liver. Certain medical 
conditions are caused by defects in bile acid production and Orphacol is used to treat infants from one 
month to 2 years of age, children, adolescents and adults with these medical conditions. The cholic acid 
contained in Orphacol replaces the bile acids that are missing due to the defect in bile acid production. 
 
 
2. What you need to know before you take Orphacol 
 
Do not take Orphacol 
- if you are allergic to cholic acid or any of the other ingredients of this medicine (listed in section 6). 
- if you are taking phenobarbital, a medicine to treat epilepsy. 
 
Warnings and precautions 
During your treatment, your doctor will carry out various blood and urine tests at different time to see how 
your body is handling this medicine and to help work out the dose that you need. More frequent tests will 
be needed if you are growing fast, if you are ill (if you have e.g. liver problems), or if you are pregnant. 
 
Other medicines and Orphacol 
Tell your doctor or pharmacist if you are taking, have recently taken any or might take other medicines. 
 
Some medicines used to lower cholesterol levels, so-called bile acid sequestrants (cholestyramine, 
colestipol, colesevelam), and medicines to treat heartburn that contain aluminium may lessen the effect of 



33 

Orphacol. If you take these medicines, take Orphacol at least 5 hours before or at least 5 hours after taking 
these other medicines.  
Ciclosporin (a medicine used to suppress the immune system) may also change the effect of Orphacol. 
Please tell your doctor if you are taking ciclosporin. 
 
Pregnancy and breast-feeding 
Please consult your doctor if you plan to become pregnant. Take a pregnancy test as soon as you suspect 
you may be pregnant. It is very important to continue taking Orphacol during pregnancy. 
 
If you become pregnant during treatment with Orphacol, your doctor will decide which treatment and dose 
is best in your situation. As a precaution, you and your unborn child should be closely monitored during 
pregnancy. 
 
Orphacol can be used during breast-feeding. Tell your doctor if you plan to breast-feed or are breast-
feeding before you take Orphacol. 
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines 
Orphacol is not expected to have an effect on the ability to drive and use machines. 
 
Orphacol contains lactose 
Orphacol contains a certain sugar (lactose monohydrate). If you have been told by your doctor that you 
have an intolerance to some sugars, contact your doctor before taking Orphacol. 
 
 
3. How to take Orphacol 
 
Always take Orphacol exactly as your doctor has told you. Check with your doctor if you are not sure. 
 
The usual starting dose is 5 to 15 mg per kilogram body weight every day in infants, children, adolescents 
and adults. 
 
Before treatment your doctor will make an assessment from your laboratory tests to determine the correct 
dose for you. The dose will then be further adjusted by your doctor depending on your body’s response.  
 
Orphacol capsules are taken by mouth with a meal at approximately the same time each day, in the 
morning and/or evening. Taking Orphacol at regular times with a meal will help you remember to take 
this medicine, and may help your body to better take it up. Capsules must be swallowed whole with water. 
Do not chew. 
 
If your doctor has prescribed a dose which requires you to take more than one capsule per day, you and 
your doctor can decide how this will be taken during the day. You may for example take one capsule in 
the morning and one in the evening. This way, you will have to take fewer capsules at once.  
 
Use in children 
For babies and children who cannot swallow capsules, the capsule can be opened and its contents added to 
baby formula or apple/orange or apple/apricot juice adapted for small children. 
 
If you take more Orphacol than you should 
If you have taken more Orphacol than you should, contact your doctor as soon as possible. He will assess 
your laboratory test results and advise you when you should resume your treatment with your normal 
dose. 



34 

 
If you forget to take Orphacol 
Take your next dose when you would normally take it. Do not take a double dose to make up for a 
forgotten dose. 
 
If you stop taking Orphacol 
There is a risk of permanently damaging your liver if you stop taking Orphacol. You should never stop 
taking Orphacol unless your doctor advises you to do so. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Several patients have experienced itching and/or diarrhoea, however, it is not known how likely this is to 
occur (frequency cannot be estimated from the available data). If itching and/or diarrhoea last for more 
than three days, tell your doctor. 
 
For several patients an increase of liver enzymes (serum transaminases) have been reported during the 
treatment with Orphacol (frequency cannot be estimated from the available data). Your doctor will decide 
what to do if this happens to you. 
 
Gallstones have been reported after long-term therapy with Orphacol. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By 
reporting side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store Orphacol 
 
Keep out of the reach and sight of children. 
 
Do not use Orphacol after the expiry date which is stated on the carton and blister after EXP. The expiry 
date refers to the last day of that month. 
 
Store below 30°C. 
 
Medicines should not be disposed of via wasterwater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Orphacol contains  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


35 

- The active substance is cholic acid.  
Orphacol 50 mg: Each hard capsule contains 50 mg of cholic acid. 
Orphacol 250 mg: Each hard capsule contains 250 mg of cholic acid. 

- The other ingredients are: 
Content of capsules: Lactose monohydrate (see section 2 under ‘Orphacol contains lactose’ for 
more information), colloidal anhydrous silica, magnesium stearate 
Capsule shell:  
Orphacol 50 mg: gelatin, titanium dioxide (E171), carmine blue (E132); 
Orphacol 250 mg: gelatin, titanium dioxide (E171), carmine blue (E132), yellow iron oxide (E172). 

 
What Orphacol looks like and contents of the pack 
Orphacol is available as hard capsules (capsules) of oblong shape. Capsules of 50 mg cholic acid are blue 
and white and capsules of 250 mg cholic acid are green and white. They are contained in blisters of 
10 capsules each. 
Pack sizes are available in 30, 60 and 120 capsules. 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder 
Laboratoires CTRS 
63, rue de l’Est 
92100 Boulogne-Billancourt 
France 
 
Manufacturer 
Laboratoires CTRS 
63, rue de l'Est 
92100 Boulogne-Billancourt 
France 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Laboratoires CTRS 
Tél/Tel: +32 (0)2 40 11 442 
ctrs@ctrs.fr   
 

Lietuva 
Immedica Pharma AB 
Tel/Puh: +46 (0)8 533 39 500  
info@immedica.com 

България 
Laboratoires CTRS 
Teл.: + 33 (0)1 707 60 637 
ctrs@ctrs.fr  
 

Luxembourg/Luxemburg 
Laboratoires CTRS 
Tél/Tel: +352 278 62 329 
ctrs@ctrs.fr  
 

Česká republika 
Laboratoires CTRS 
Tel.: + 33 (0)1 70 76 06 37 
ctrs@ctrs.fr  
 

Magyarország 
Medis Hungary Kft 
Tel: +36 (2) 380 1028 
info@medis.hu  
 

mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:info@immedica.com
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:info@medis.hu


36 

Danmark 
Immedica Pharma AB  
Tlf: +46 (0)8 533 39 500  
info@immedica.com 
 

Malta 
Laboratoires CTRS 
Tel: +356 2776 1358 
ctrs@ctrs.fr  
 

Deutschland 
Laboratoires CTRS 
Tel: +49 (0)3022153008 
ctrs@ctrs.fr  
 

Nederland 
Laboratoires CTRS 
Tel: +31 (0)2 070 38 155 
ctrs@ctrs.fr  
 

Eesti 
Immedica Pharma AB  
Tel/Puh: +46 (0)8 533 39 500  
info@immedica.com  
 

Norge 
Immedica Pharma AB 
Tel/Puh: +46 (0)8 533 39 500  
info@immedica.com  

Ελλάδα 
Laboratoires CTRS 
Tel: + 33 (0)1 70 76 06 37 
ctrs@ctrs.fr  

Österreich 
Laboratoires CTRS 
Tel: +43 (0)7 208 16 847 
ctrs@ctrs.fr  
 

España 
Laboratoires CTRS 
Tel: + (34) 914 146 613 
ctrs@ctrs.fr  
 

Polska 
Laboratoires CTRS 
Tel.: + 33 (0)1 70 76 06 37 
ctrs@ctrs.fr  
 

France 
Laboratoires CTRS 
Tél: + 33 (0)1 70 76 06 37 
ctrs@ctrs.fr  
 

Portugal 
Laboratoires CTRS 
Tel: + 33 (0)1 70 76 06 37 
ctrs@ctrs.fr  
 

Hrvatska 
Medis Adria d.o.o. 
Tel: +385 (1) 230 3446 
info@medisadria.hr  
 

România 
Laboratoires CTRS 
Tel: + 33 (0)1 70 76 06 37 
ctrs@ctrs.fr  
 

Ireland 
Laboratoires CTRS 
Tel: +353 (0)1 695 00 63 
ctrs@ctrs.fr  
 

Slovenija 
Medis d.o.o. 
Tel: +386 (1) 589 6900 
info@medis.si  
 

Ísland 
Immedica Pharma AB 
Sími: + 46 (0)8 533 39 500 
info@immedica.com 

Slovenská republika 
Laboratoires CTRS 
Tel: + 33 (0)1 70 76 06 37 
ctrs@ctrs.fr  
 

Italia 
Laboratoires CTRS 
Tel: +39 (0)687 501302 
ctrs@ctrs.fr  
 

Suomi/Finland 
Immedica Pharma AB 
Tel/Puh: +46 (0)8 533 39 500  
info@immedica.com 

mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:info@immedica.com
mailto:info@immedica.com
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
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37 

Κύπρος 
Laboratoires CTRS 
Tel: + 33 (0)1 70 76 06 37 
ctrs@ctrs.fr 
 

Sverige 
Immedica Pharma AB  
Tel: +46 (0)8 533 39 500  
info@immedica.com 

Latvija 
Immedica Pharma AB 
Tel: +46 (0)8 533 39 500  
info@immedica.com 

United Kingdom 
Laboratoires CTRS 
Tel: +44 (0)3 301 002 375 
ctrs@ctrs.fr    

  
This leaflet was last revised in 
 
This medicine has been authorised under “Exceptional Circumstances”. 
This means that because of the rarity of this disease and for ethical reasons it has been impossible to get 
complete information on this medicine. 
The European Medicines Agency will review any new information on the medicine every year and this 
leaflet will be updated as necessary. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. There are also links to other websites about rare diseases and treatments. 

mailto:ctrs@ctrs.fr
mailto:ctrs@ctrs.fr
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http://www.ema.europa.eu/

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