Kolbam - summary of medicine characteristics

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concomitant use with phenobarbital (see section 4.5).

4.4 Special warnings and precautions for use

Treatment with cholic acid should be stopped if in case of abnormal hepatocellular function, as measured by prothrombin time, hepatocellular function 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 hypertriglyce­ridaemia

Patients with newly diagnosed, or a family history of, familial hypertriglyce­ridaemia may have poor absorption of cholic acid from the intestine. The cholic acid dose for patients with familial triglyceridaemia will have to be established and adjusted as necessary (see section 4.2).

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies with cholic acid and concomitantly administered medicinal products or food have been carried out.

Phenobarbital has been shown to increase the pool size and turnover of cholic acid and therefore has an antagonistic effect to the desired action of cholic acid in patients. Therefore use of phenobarbital in patients treated with cholic acid is contraindicated (see section 4.3).

Drug interactions with cholic acid mainly relate to medicinal products capable of interrupting the enterohepatic circulation of bile acids, such as the sequestering agents cholestyramine, colestipol, or colesevelam. Aluminium-based antacids have been shown to adsorb bile acids in vitro and may be expected to reduce the levels of cholic acid in the same manner as the bile acid sequestering agents. Should the use of a preparation containing one of these substances be necessary, it must be taken at least 5 hours before or after cholic acid.

Ciclosporin alters the pharmacokinetics of cholic acid by inhibition of the hepatic uptake and hepatobiliary secretion of bile acids, as well as via its pharmacodynamics by inhibiting cholesterol 7a-hydroxylase. Co-administration should be avoided. If administration of ciclosporin is considered necessary, serum and urinary bile acid levels should be closely monitored and the cholic acid dose adjusted accordingly.

Oestrogens, oral contraceptives and clofibrate (and perhaps other lipid-lowering substances) increase hepatic cholesterol secretion and encourage cholesterol gallstone formation and hence may counteract the effectiveness of cholic acid. Any medicinal products implicated in drug-induced cholestasis through inhibition of transporters could reduce the effectiveness of cholic acid treatment on coadministration. In these cases, serum/bile levels of cholic acid should be closely monitored and the dose adjusted accordingly.

The effect of food on the bioavailability of cholic acid has not been studied. There is a theoretical possibility that administration of food may increase cholic acid bioavailability and improve tolerability. It is recommended that cholic acid is taken with food (see section 4.2).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited safety data from the use of cholic acid in pregnant women. Pregnancies with normal outcomes have been reported in women taking cholic acid.

The limited data from animal studies do not indicate direct reproductive toxicity (see section 5.3). The use of cholic acid may be considered during pregnancy if the doctor considers that the benefits to the patient outweigh the possible risk.

Breastfeeding

There is insufficient information on the excretion of cholic acid and its metabolites in human milk.

Available data in animals have shown excretion of cholic acid in milk (see section 5.3). At therapeutic doses, no effects on the breastfed newborn infant are anticipated since the systemic exposure of the breastfeeding mother to cholic acid is negligible (see section 5.2). Cholic acid can be used during breastfeeding if the doctor considers that the benefits to the patient outweigh the possible risk.

Fertility

There are no data on the effects of cholic acid on fertility. 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

Summary of the safety profile

Adverse reactions in patients (both adults and children) receiving cholic acid are generally mild to moderate in severity; the main reactions observed are given in the table below. The events were transitory and generally did not interfere with the therapy.

Tabulated list of adverse reactions

Based on clinical trial data, adverse reactions in patients (both adults and children) receiving cholic acid are generally mild to moderate in severity and are provided in the following table.

Adverse reactions are ranked according to system organ class, using the following convention: very common (> 1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

The adverse reactions reported in the literature with an unknown frequency are also reported in the following table.

MedDRA System Organ Class	Preferred Term	Frequency
Nervous system disorders	Mild peripheral neuropathy	Common
Gastrointestinal disorders	Diarrhoea Mild nausea Mild reflux Moderate diarrhoea Reflux esophagitis	Common Common Common Common Common
Hepatobiliary disorders	Jaundice Increased serum transaminases Gallstones	Common Not known Not known
Skin and subcutaneous tissue disorders	Skin lesion Pruritus	Common Not known
General disorders and administration site conditions	Malaise	Common

Description of selected adverse reactions

Adverse reactions reported in the literature are pruritus and increased serum transaminases in one or two children treated with high doses of cholic acid; however, these adverse reactions disappeared with a reduced dosage. Diarrhoea is also known to occur in cases of excessive dosing with cholic acid. Gallstones have been reported after long-term therapy.

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

4.9 Overdose

Episodes of symptomatic overdose (or excessive dosing regimen) have been reported, including accidental overdose. Clinical features were limited to pruritus and diarrhoea. Laboratory tests showed elevation of serum gamma glutamyltransferase (Gamma GT) 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 event of overdose the patient should be monitored and treated symptomatically.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Bile and liver therapy, bile acid preparations; ATC code: A05AA03

Mechanism of action                         ­'Q

After administration of cholic acid a down-regulation of bile acid synthesis occurs and there is a strong decrease or almost complete disappearance of abnormal bile acids. Concurrent with the disappearance of atypical bile acid metabolites, there is a consistent reduction and normalization in serum liver enzymes. Treatment with oral cholic acid stimulates bile flow and secretion, inhibits production and accumulation of hepatotoxic and cholestatic bile acid precursors and facilitates fat absorption without toxic side effects at therapeutic doses.

Pharmacodynamic effects                    '­“ZV

Inborn errors of primary bile acid synthesis involve congenital defects in the primary enzymes responsible for catalysing key reactions in the synthesis of cholic and chenodeoxycholic acids. There are several enzyme defects described in the literature. Some of the primary defects include but are not limited to:

Sterol 27-hydroxylase deficiency (presenting as CTX)

AMACR deficiency

CYP7A1 deficiency

Treatment with exogenous cholic acid is intended to replace physiological bile acid in cases of inborn errors of bile acid synthesis. Cholic acid is one of the primary bile acids in man on which essential physiological functions depend. The purpose of substituting missing cholic acid is to restore the main functions of this bile acid consisting of lipid transport in the form of mixed micelles, the activation of co-lipase and fat digestion and absorption, the absorption of fat-soluble vitamins, and the induction of bile flow, thus preventing cholestasis.

The pharmacodynamic action of cholic acid is feedback inhibition of the synthesis of toxic partial bile acid biosynthetic products that result from blockages in the normal bile acid synthetic pathway. Cholic acid down-regulates bile acid biosynthesis via activation of farnesoid X receptor, which represses transcription of the CYP7A1 gene encoding cholesterol 7a-hydroxylase, the rate-limiting enzyme of bile acid synthesis. In each of the primary bile acid deficiencies due to enzyme defects in the biosynthetic pathway, absence of primary bile acids leads to cholestasis and unregulated accumulation of toxic bile acid precursors. The rationale for cholic acid therapy is improvement of bile flow and fat absorption and restoration of a physiologic feedback inhibition on bile acid synthesis, lowering the production of toxic bile acid precursors.

Clinical efficacy and safety

Study CAC-91–10–10, (Investigation in the pathogenesis of liver disease in patients with inborn errors of bile acid metabolism) was conducted from 1992–2009 to evaluate the therapeutic efficacy and safety of cholic acid to treat patients with identified inborn errors of bile acid metabolism. The study was an open-label, single arm, non-randomized design. A total of 85 patients took part in the clinical study. Of these 85 patients, 52 presented with disorders in primary bile acid synthesis including the following 3 single enzymes:

Sterol 27-hydroxylase deficiency (presenting as CTX; n=5)

AMACR deficiency (n=1)

CYP7A1 deficiency (n=1)

A total of 79 patients received cholic acid treatment, 49 of these suffered from a primary enzyme defect.

Study CAC-002–01, (an open-label, single-centre, non-randomized continuation study of cholic acid capsules in subjects with inborn errors of bile acid synthesis), was the continuation of study CAC-91–10–10 and started on 1 Jan 2010. The study was completed on 31 July 2016. It followed an open-label, single arm, non-randomized design and included eligible subjects who had previously received cholic acid through CAC-91–10–10 and CAC-001–01, and newly diagnosed subjects. Therapeutic efficacy and safety of cholic acid treatment in patients with inborn errors of bile acid metabolism were evaluated. A total of 53 patients took part in the clinical study and received at least one dose of cholic acid; 22 (42%) were treatment naive, i.e., received their first dose of cholic acid during study CAC-002–01. Of the 53 patients treated, 41 (77%) presented with disorders in primary bile acid synthesis including sterol 27-hydroxylase deficiency (presenting as CTX; n=8), and AMACR deficiency (n=1).

In all studies, a dose of 10–15 mg/kg/day was administered.

Efficacy was demonstrated in two ways:

• (a) treatment with cholic acid leads to an improvement in liver function as demonstrated by improved liver function test values,

• (b) Fast Atom Bombardment-Mass Spectrometry (FAB-MS) data demonstrated efficacy by showing that cholic acid treatment led to a suppression of the abnormal urine bile acids that initially led to the diagnosis.

Of all the patients treated in Study CAC-91–10–10, 49 patients presented with a single enzyme defect. In this set of patients, about one quarter were below or at most 6 months of age at diagnosis, and about one third were between 7 and 36 months. On average, patients in this subgroup were 3 years at treatment start, minimum and maximum ages were 0 and 14 years, respectively.

In Study CAC-002–01, the mean age of patients at baseline was 9.0 years, with ages ranging from 0.1 to 35.6 years. Affected patients often present with significant comorbidities, including CNS impairment, which would not be treated by addressing the bile defect effects.

Of 49 patients with a single enzyme defect treated in Study CAC-91–10–10 and included in the safety analysis, 42 had at least one pre- and one post-treatment assessment for urine bile acids and liver function tests; height and weight and were included in the primary efficacy analysis.

Of the 52 patients described above that were included in Study CAC-91–10–10 during the 17-year study period, 6 died, 3 had no evidence of treatment, 4 terminated the study, 10 were lost to follow-up, and for 1, data retrieval was unsuccessful.

Of the 41 patients described above that were treated in Study CAC-002–01, 13 patients discontinued: 8 due to AEs, 1 for lack/loss of efficacy, 1 was lost to follow-up, and 3 withdrew consent.

In Study CAC-91–10–10, the efficacy analysis showed that treatment with cholic acid significantly improved (i.e., decreased) urinary bile acid excretion in patients with single enzyme defects. General improvements in the degree of atypical urine bile acids were also seen in individual defect groups. In patients with CTX (N=3), urinary bile acids at baseline were normal for 1 patient and elevated for 2 patients, elevated for all patients in the worst post-treatment analysis, and normal in the best postbaseline assessment for all 3 patients. Serum transaminases were below the ULN for 1 patient and elevated (>2 times the ULN) for 2 patients at baseline, were elevated for 2 patients in the worst postbaseline analysis but were below the ULN for all 3 patients in the best post-treatment analysis.

The efficacy analysis also demonstrated that treatment with cholic acid significantly improved ALT and AST values for patients stratified by single enzyme defects. Regarding primary diagnoses, shifts towards improvements in ALT and AST values were shown in individual defect groups.

In Study CAC-002–01 for patients overall with single-enzyme defects, urinary bile acids and serum transaminases did not change significantly from baseline to worst post-baseline value. Statistically significant changes were seen in the baseline to the best post-baseline analysis of urinary bile acids, with substantial decreases in marked, significant, and slight abnormalities as well as increases in normal spectra. Statistically significant improvements were also observed in the baseline to best postbaseline analyses of serum transaminases. Height and weight showed similar improvements. Mean total bilirubin values remained stable in the baseline to worst post-baseline value analysis and decreased in the baseline to best post-baseline analysis.

Among the subgroup of patients with CTX (n=8), 3 transi cholic acid treatment at study start. The remaining 5 patie were normal for all patients (100%) at baseline and worst pos patients (88%) at the best post-baseline assessment; 1 patient bile acids at best post-baseline assessment. Serum transaminases were below the ULN for most patients (71–100%) at baseline and for most patients (86%) at the worst post-baseline assessment and for all patients (100%) at the best post-baseline assessment.

Paediatric population                    '-ZV

The clinical experience reported is from a patient population with disorders in primary bile acid synthesis that includes principally infants from the age of one month, children and adolescents.

Other information

This medicinal product has been authorised under ‘exceptional circumstances,’ which 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

Distribution and pharmacological effects of bile acids such as cholic acid are mainly limited to the enterohepatic circulation, which includes the intestine, portal vein, liver and biliary tract.

Orally administered cholic acid is absorbed by passive diffusion along the length of the gastrointestinal tract. Once absorbed, exogenous cholic acid will enter into the body’s bile acid pool and will undergo multiple cycles of enterohepatic circulation. Cholic acid will pass to the liver in the portal blood, in which it is moderately bound to albumin. In the liver, cholic acid is extracted from portal blood by multiple mechanisms, including passive diffusion and transporters. Within the liver, cholic acid is amidated in species-specific proportions, with glycine and/or taurine, into a more hydrophilic, conjugated form. Conjugated cholic acid is secreted into bile and will pass into the small intestine where, in association with other components of bile, it will perform its principal digestive function. Conjugated cholic acid is absorbed in the ileum via transporters, passed back to the liver, and enters another cycle of enterohepatic circulation.

Any conjugated cholic acid not absorbed in the ileum will pass into the lower intestine where it may be subject to bacterial metabolism, principally deconjugation and 7-dehydroxylation. Deconjugated cholic acid and deoxycholic acid, the product of 7-dehydroxylation, are passively absorbed in the lower intestine and carried back to the liver in portal blood, where reconjugation will take place. In this manner the vast majority of the bile acid pool is conserved and will cycle multiple times during feeding. Any cholic acid not absorbed will be excreted in the faeces, either unchanged or following dehydroxylation via bacterial metabolism.

5.3 Preclinical safety data No formal preclinical sudies have been conducted; however, data in the literature reveal no

There are a limited number of studies that have demonstrated that cholic acid administered orally for up to 26 weeks at doses significantly greater than the therapeutic dose, was well tolerated in animals with no mortalities, no effects on bodyweight or food consumption and no evidence of significant macroscopic or microscopic findings in the liver. In repeated dose studies, frequently reported effects of cholic acid have included decreased body weight, diarrhoea and liver damage with elevated transaminases although are considered to be associated ith the pharmacological effects of bile acid metabolism. Increased liver weight and gallstones have been reported in repeated dose studies in which cholic acid was co-administered with cholesterol.

Slightly increased blood pressure was evident in rats after 30 days of cholic acid at approximately 4-fold therapeutic dose with increased vasoconstrictor responses to noradrenaline, together with decreased levels of aldosterone and increased corticosterone, but no adverse clinical signs were observed.

Cholic acid is not mutagenic; however, co-administration of cholic acid with known carcinogens has shown increased tumour formation compared to the known carcinogen alone. This has led to the identification of cholic acid as a tumour promoter, considered to be via the hyperproliferation of colorectal epithelium in the presence of secondary bile acids.

Administration of a single dose of cholic acid intravenously to pregnant ewes in late gestation demonstrated systemic exposure of cholic acid in the foetus with no effect on either the mother or the foetuses other than an increase in early deliveries. The relevance of animal data with regards to cholic acid therapy safety is uncertain due to the known high inter-animal variability of bile acid homeostasis. Biliary bile alcohols and bile acids show remarkable structural diversity across animal species.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Capsule content

Silicified microcrystalline cellulose

Magnesium stearate

50 mg Capsule shell

Gelatin

Titanium dioxide (E171)

Red iron oxide (E172)

Printing ink

Shellac (E904)

Propylene Glycol (E1520)

Strong Ammonia Solution (E527)

Potassium Hydroxide (E525)

Black Iron Oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

cinal product must be used within 3 months.

6.4 Special precautions for storage

Do not store above 30°C.

Store in original package in order to protect

6.5 Nature and contents of containerhite, child-resistant closure consisting of

White 185 ml HDPE bottle induction-sealed with a 38 a HDPE grooved screw cap and induction seal (cardboard, wax and aluminium foil) liner. Pack sizes: 90 capsules.

6.6 Special precautions for disposal

Use in the paediatric population

For infants and children who cannot swallow capsules, the capsule may be opened gently and the contents mixed with food. For young infants the contents may be mixed with infant formula, expressed breast milk or fruit puree and for infants and children under 6 years, mixed with soft food such as mashed potatoes or apple puree. The mixture should be administered immediately after preparation. Mixing of the capsule contents is designed to mask any unpleasant taste which results from the capsules being opened but no data on the compatibility or palatability are available. The capsule contents will remain as fine granules in the milk or food.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Retrophin Europe Limited, Palmerston House, Fenian Street

Dublin 2, Ireland

8. MARKETING AUTHORISATION NUMBER

EU/1/13/895/001

9. DATE OF FIRST AUTHORISATION

20 November 2015

10. DATE OF REVISION OF THE TEXT

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European

Medicines Agency

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.