Cholic acid

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 3βHydroxy-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.

No data are available for patients with renal impairment. The dose of cholic acid should be adjusted individually.

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.

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.

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.

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.

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.

Cholic acid and its metabolites are excreted in human milk, but at therapeutic doses of cholic acid, no effects on the breastfed newborns/infants are anticipated. Cholic acid can be used during breast-feeding.

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.

Fertility

No data on the effects of cholic acid on fertility are available. At therapeutic doses, no effect on fertility is anticipated.

Cholic acid has no or negligible influence on the ability to drive and use machines.

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.

List of adverse reactions

The following 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

Description of selected adverse reactions

The development of pruritus and/or diarrhoea has been observed during treatment with Cholic acid. 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.

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.