n.
Interaction with CYP1A2 substrates with narrow therapeutic index
Obeticholic acid may increase the exposure to concomitant medicinal products that are CYP1A2 substrates. Therapeutic monitoring of CYP1A2 substrates with narrow therapeutic index (e.g. theophylline and tizanidine) is recommended.
Medicinal products that affect obeticholic acid
Bile acid binding resins
Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce efficacy of obeticholic acid. When concomitant bile acid binding resins are administered, obeticholic acid should be taken at least 4-6 hours before or 4-6 hours after taking a bile acid binding resin, or at as great an interval as possible.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no data on the use of obeticholic acid in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of obeticholic acid during pregnancy.
Breast-feeding
It is unknown whether obeticholic acid is excreted in human milk. Based on animal studies and intended pharmacology, obeticholic acid is not expected to interfere with breast-feeding or the growth or development of a breast-fed child. A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from obeticholic acid therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman (see section 5.3).
Fertility
No fertility data is available in humans. Animal studies do not indicate any direct or indirect effects on fertility or reproduction (see section 5.3).
4.7 Effects on ability to drive and use machines
Obeticholic acid has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions were pruritus (63%) and fatigue (22%). Adverse reactions leading to discontinuation were 1% in the OCALIVA titration arm and 11% in the OCALIVA 10 mg arm. The most common adverse reaction leading to discontinuation was pruritus. The majority of pruritus occurred within the first month of treatment and tended to resolve over time with continued dosing.
Tabulated list of adverse reactions
The adverse reactions reported with OCALIVA in the phase III clinical study are listed in the table below by MedDRA system organ class and by frequency. Frequencies are defined as: 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).
Table 2. Frequency of adverse reactions in PBC patients*
System Organ Class
Very common
Common
Endocrine disorders
Thyroid function abnormality
Nervous system disorders
Dizziness
Cardiac disorders
Palpitations
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
Gastrointestinal disorders
Abdominal pain and discomfort
Constipation
Skin and subcutaneous tissue disorders
Pruritus
Eczema, Rash
Musculoskeletal and connective tissue disorders
Arthralgia
General disorders and administration site conditions
Fatigue
Oedema peripheral, Pyrexia
* Adverse reactions are defined as events occurring at a rate of greater than or equal to 5% of |
