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, including bile salt transport to biliary canaliculi, have the potential to reduce the efficacy of maralixibat.

For this reason patients with PFIC2 who have a complete absence or lack of function of Bile Salt Export Pump (BSEP) protein (i.e., patients with BSEP3 subtype of PFIC2) are not expected to respond to 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.

ALT and AST elevation was observed in some patients receiving maralixibat (section 4.8). 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.

PFIC patients with impaired ability to metabolise and/or eliminate propylene glycol (e.g., those with hepatic and/or renal impairment, patients <5 years of age) are at increased risk of developing propylene glycol toxicity when receiving high doses of Livmarli. Reduced dose of Livmarli is recommended in such patients (see section 4.2 and section 4.4 “Propylene glycol and potential risk of toxicity”); PFIC patients with severe hepatic and/or renal impairment should not be treated with Livmarli (see section 4.3).

Excipients with known effect

Propylene glycol and potential risk of toxicity

This medicinal product contains 364.5 mg propylene glycol (E1520) in each mL of oral solution.

ALGS: administration of 380 mcg/kg QD dose of Livmarli will result in exposure up to 17 mg/kg/day propylene glycol.

PFIC: Administration of 285 mcg/kg BID dose of Livmarli will result in exposure up to 26 mg/kg/day propylene glycol and 570 mcg/kg BID dose of Livmarli will result in exposure up to 50 mg/kg/day propylene glycol.

Total amounts of propylene glycol from all medicines and food supplements, including Livmarli oral solution, should be taken into account when assessing the potential risk of toxicity from propylene glycol, especially in patients with limited ability to metabolise or excrete propylene glycol (e.g., patients below 5 years of age, or those with reduced renal, or hepatic function) (see sections 4.2 and 4.3). Co-administration with any substrate for alcohol dehydrogenase such as ethanol may increase risk of toxicity from propylene glycol.

Adverse events related to potential propylene glycol toxicity include: e.g., hyperosmolality (with or without lactic acidosis), renal dysfunction (acute tubular necrosis), acute renal failure; cardiotoxicity (arrhythmia, hypotension); central nervous system depression (depression, coma, seizures), respiratory depression, dyspnoea; liver dysfunction; haemolytic reaction (intravascular haemolysis) and haemoglobinuria; or multisystem organ dysfunction. Patients should be monitored for signs and symptoms of possible propylene glycol toxicity.

Sodium

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 gastrointestinal 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. Due to the propylene glycol content, as a precautionary measure, it is preferable to avoid the use of Livmarli during breastfeeding.

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

Over 280 patients with cholestatic liver diseases aged 1 month to 24 years have been treated with maralixibat in blinded and open-label clinical studies, including 94 patients with ALGS treated for up to 5 years, and 134 patients with PFIC treated for up to 7 years.

The safety profile of maralixibat is consistent across all indications and age groups.The most frequently occurring adverse reactions in ALGS patients older than 12 months of age were diarrhoea (36.0%) followed by abdominal pain (29.1%). Similarly, diarrhoea (27.7%) and abdominal pain (6.4%) were the most common adverse reactions in PFIC patients older than 12 months of age. The most frequently occurring adverse reaction in ALGS patients younger than 12 months of age was diarrhoea (20.0%). Similarly, diarrhoea (23.5%) was the most common adverse reaction in PFIC patients younger than 12 months of age.

Tabulated list of adverse reactions

For ALGS, the safety profile of maralixibat is based on a pooled analysis of data from a review of 5 clinical studies in patients (n=86) aged between 1 and 17 (median of 5 years); median duration of exposure was 2.5 years (range: 1 day to 5.5 years).

For PFIC, the safety profile is primarily based upon analysis of the double-blind placebo-controlled data in the pivotal PFIC trial and the open label extension study (n=93, with 88 patients treated with the recommended dose of maralixibat). Patients treated with maralixibat were aged between 1 and 17 years old (median of 4 years); median duration of exposure was 83.5 weeks (range: 1.7 to 177.1 weeks). Additional evidence on long-term safety was collected on lower dose of maralixibat (≥266 mcg/kg/day) in a phase 2 clinical study (LUM001-501) and an open-label long-term follow-up study (MRX-800; total duration of exposure up-to 7 years).

In the age group younger than 1 year of age 17 patients with ALGS and 10 patients with PFIC have been treated with recommended doses of maralixibat (see section 5.1).

Table 3 presents the adverse reactions reported from these analyses.

Adverse reactions in patients treated with maralixibat 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 3. Adverse reactions reported in patients with ALGS and PFIC:

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 ALGS patient. No adverse reactions of diarrhoea or abdominal pain were serious. The time to onset for diarrhoea and abdominal pain in the majority of cases was within the first month of treatment. For both ALGS and PFIC, the median duration for diarrhoea and abdominal pain episodes was less than 1 week. No dose response relationship was observed for diarrhoea or abdominal pain. Treatment was interrupted or dose was reduced due to adverse gastrointestinal reactions in 4 (4.7%) of ALGS patients and 3 (6.4%) of PFIC patients, and led to improvement or resolution of the adverse reactions. One PFIC patient (2.1%) with mild diarrhoea discontinued treatment; otherwise, no patients discontinued Livmarli due to gastrointestinal 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).

Elevations in ALT and AST, partly accompanied with increase in bilirubin were mostly transitory and mild or moderate in intensity.

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.