Maralixibat

Maralixibat is an OATP2B1 inhibitor based on in vitro studies. A decrease in the oral absorption of OATP2B1 substrates (e.g. fluvastatin or rosuvastatin) due to OATP2B1 inhibition in the GI tract cannot be ruled out. Consider monitoring the effects of OATP2B1 substrates as needed.

Maralixibat is also an inhibitor of CYP3A4 based on in-vitro studies. An increase of plasma levels of CYP3A4 substrates (e.g., midazolam, simvastatin) can therefore not be excluded and caution is advised when administering such compounds concomitantly.

Maralixibat has not been sufficiently studied in patients with liver impairment. Close monitoring is advised for patients with end-stage liver disease or progression to decompensation.

There are no data from the use of maralixibat in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. No effects on the foetus during pregnancy are anticipated, since systemic exposure to maralixibat is negligible. As a precautionary measure, it is preferable to avoid the use of maralixibat during pregnancy.

No effects on the breastfed newborn/infant are anticipated since the systemic exposure of the breast-feeding woman to maralixibat is negligible. Maralixibat can be used during breast-feeding.

Fertility

There are no clinical data on the effect of maralixibat on fertility. Animal studies do not indicate any direct or indirect effects on fertility or reproduction.

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

Summary of the safety profile

The most frequently occurring adverse reaction reported in patients older than 12 months of age (N=86) with ALGS who were treated with maralixibat in clinical trials over 5 years was diarrhoea (36.0%) followed by abdominal pain (29.1%). In patients younger than 12 months of age (N=8), the most common adverse reactions were also diarrhoea and abdominal pain, similar to the older children with ALGS. Across the ALGS program, none of the adverse reactions of diarrhoea or abdominal pain were serious.

Tabulated list of adverse reactions

The safety profile of maralixibat is based on a pooled analysis of data from a review of 5 clinical studies in patients aged between 1 and 17 (median of 5 years) with ALGS (N=86). The median duration of exposure was 2.5 years (range: 1 day to 5.5 years). The table below presents the adverse reactions reported from this pooled analysis.

Adverse reactions in patients treated with maralixibat for ALGS are listed below by MedDRA system organ class and frequency grouping. Frequencies are defined as follows: 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), not known (cannot be estimated from the available data).

Adverse reactions reported in patients with ALGS:

Description of selected adverse reactions

All reported events of diarrhoea were mild to moderate in severity; a severe adverse reaction of abdominal pain was reported in 1 patient. The time to onset for diarrhoea and abdominal pain in the majority of cases was within the first month of treatment. The median duration for diarrhoea and abdominal pain were 2 days and 1 day, respectively. No dose response relationship was observed for the incidence of diarrhoea. Treatment was interrupted or dose was reduced due to adverse gastrointestinal reactions in 4 (4.7%) patients and led to improvement or resolution of the adverse reactions. No patients discontinued maralixibat due to these adverse reactions.

If diarrhoea and/or abdominal pain persist and no other etiologies are found, reducing the dose or interrupting treatment should be considered. Dehydration should be monitored and treated promptly. If dosing with maralixibat is interrupted, maralixibat can be restarted as tolerated when diarrhoea or abdominal pain improve.