LIVMARLI Oral solution Ref.[50565] Active ingredients: Maralixibat

Maralixibat acts by inhibiting the ileal bile acid transporter (IBAT) and disrupting enterohepatic circulation of bile acids. Therefore, conditions, medicinal products or surgical procedures that impair either gastrointestinal motility or enterohepatic circulation of bile acids have the potential to impact the efficacy of maralixibat.

Diarrhoea has been reported as a very common adverse reaction when taking maralixibat (section 4.8). Diarrhoea may lead to dehydration. Patients should be monitored regularly to ensure adequate hydration during episodes of diarrhoea.

Patients with chronic diarrhoea requiring intravenous fluid or nutritional intervention were not studied in clinical trials.

In clinical trials, ALT elevations were observed in some patients receiving maralixibat treatment. These elevations were observed in the absence of bilirubin increases and are of unknown clinical significance. Liver function tests should be monitored in patients prior to start and during treatment with maralixibat.

Assessment of fat-soluble vitamin (FSV) levels (Vitamins A, D, E) and international normalised ratio (INR) are recommended for all patients prior to initiating Livmarli, with monitoring per standard clinical practice. If FSV deficiency is diagnosed, supplemental therapy should be prescribed.

Excipients with known effect

This medicinal product contains 364.5 mg propylene glycol (E1520) in each mL of oral solution. This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

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, being an inhibitor of bile acid absorption, has not been fully evaluated with regard to the interaction potential with the bile acid Ursodeoxycholic acid (UDCA).

Maralixibat is minimally absorbed, is not significantly metabolised, and is not a substrate of active substance transporters; therefore, other concomitant medicinal products are not known to effect the disposition of maralixibat.

Maralixibat is not known to inhibit or induce other cytochrome P450 in patients; therefore, maralixibat is not predicted to affect the disposition of concomitant medicinal products through those mechanisms.

Pregnancy

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 (see section 5.3). 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 Livmarli during pregnancy.

Breast-feeding

No effects on the breastfed newborn/infant are anticipated since the systemic exposure of the breast-feeding woman to maralixibat is negligible. Livmarli 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 (see section 5.3).

Livmarli 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). Table 2 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).

Table 2. 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 Livmarli 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 Livmarli is interrupted, Livmarli can be restarted as tolerated when diarrhoea or abdominal pain improve (section 4.2).

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 Appendix V.

Not applicable.