ORPHACOL Hard capsule Ref.[7571] Active ingredients: Cholic acid

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 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 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.

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.

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.

3 years.

Store below 30°C.

PVC/PVDC-aluminium blister of 10 capsules.

Pack sizes: 30, 60, 120.

Not all pack sizes may be marketed.

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.