Chemical formula: C₃₇H₄₈N₄O₈S₂ Molecular mass: 740.93 g/mol
Odevixibat interacts in the following cases:
In in vitro studies, odevixibat was shown to be an inhibitor of CYP3A4/5. In adult healthy subjects, concomitant use of odevixibat decreased the area under the curve (AUC) of oral midazolam (a CYP3A4 substrate) by 30% and 1-OH-midazolam exposure by less than 20%, which is not considered clinically relevant.
Odevixibat is a substrate for the efflux transporter P-glycoprotein (P-gp). In adult healthy subjects, co-administration of the strong P-gp inhibitor itraconazole increased the plasma exposure of a single dose of odevixibat 7 200 mcg by approximately 50-60%. This increase is not considered clinically relevant.
There are no available clinical data for the use of odevixibat in patients with moderate or severe renal impairment or end-stage renal disease (ESRD) requiring haemodialysis. However, due to the minimal plasma concentrations and negligible renal excretion, no dose adjustment is required for these patients.
Odevixibat has not been sufficiently studied in patients with severe hepatic impairment (Child-Pugh C). Due to minimal absorption, no dose adjustment is required. Close monitoring, however, is advised for patients with end-stage liver disease or progression to decompensation.
In an interaction study with a lipophilic combination oral contraceptive containing ethinyl estradiol (EE) (0.03 mg) and levonorgestrel (LVN) (0.15 mg) conducted in adult healthy females, concomitant use of odevixibat had no impact on the AUC of LVN and decreased the AUC of EE by 17%, which is not considered clinically relevant. Interaction studies with other lipophilic medicinal products have not been performed, therefore, an effect on the absorption of other fat-soluble medicinal products cannot be excluded.
There are no or limited data from the use of odevixibat in pregnant women. Animal studies have shown reproductive toxicity. Odevixibat is not recommended during pregnancy and in women of childbearing potential not using contraception.
It is unknown whether odevixibat or its metabolites are excreted in human milk. There is insufficient information on the excretion of odevixibat in animal milk.
A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from odevixibat therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.
Women of childbearing potential should use an effective method of contraception when treated with odevixibat.
No fertility data are available in humans. Animal studies do not indicate any direct or indirect effects on fertility or reproduction.
Odevixibat has no or negligible influence on the ability to drive and use machines.
The most commonly reported adverse reaction was diarrhoea reported in (7%) of patients.
The table lists adverse reactions identified in clinical trials in patients with PFIC aged between 4 months to 25 years of age (median 3 years 7 months).
Adverse reactions are ranked according to system organ class, using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000) and not known (cannot be estimated from the available data).
Table 1. Frequency of adverse reactions in PFIC patients:
| MedDRA system organ class | Frequency | Adverse drug reaction |
|---|---|---|
| Gastrointestinal disorders | Common | diarrhoea, abdominal paina, diarrhoea haemorrhagic, faeces soft |
| Hepatobiliary disorders | Very common | ALT increased |
| Common | hepatomegaly AST increased |
a Includes abdominal pain upper
ALT = alanine aminotransferase
AST = aspartate aminotransferase
Gastrointestinal adverse reactions occurred at a frequency of 11% in patients treated with odevixibat. Adverse reactions of diarrhoea, abdominal pain and faeces soft were of short duration with most events ≤5 days in duration; median time to first onset was 16 days. All reports were mild to moderate in severity and non-serious. Two patients experienced an adverse reaction of clinically significant diarrhoea defined as diarrhoea that persisted for 21 or more days without any other aetiology, was severe in intensity, required hospitalisation or was considered an important medical event, or presented with concurrent dehydration requiring treatment with oral or intravenous rehydration and/or other treatment intervention. Treatment interruption was reported for diarrhoea in 4% of patients and discontinuation of odevixibat due to diarrhoea was reported in 1%.
The most commonly reported adverse reaction in ALGS patients treated with odevixibat in clinical trials was diarrhoea (11.5%).
Table 2 lists adverse reactions identified in patients with ALGS.
Adverse reactions are ranked according to system organ class and frequency grouping. Frequencies are defined 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).
Table 2. Frequency of adverse reactions reported in patients with ALGS:
| MedDRA system organ class | Very common | Common |
|---|---|---|
| Gastrointestinal disorders | Diarrhoea* | abdominal pain*a, vomiting* |
| Hepatobiliary disorders | hepatic enzyme increasedb |
a Includes abdominal pain upper
b Includes hepatic enzyme increased, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased.
* See section ‘Description of selected adverse reactions’.
Adverse reactions of diarrhoea occurred at a frequency of 11.5% in ALGS patients treated with odevixibat. Median time to onset of diarrhoea was 14.5 days and median duration was 4 days.
Clinically significant diarrhoea that persisted for 3 or more days without any other aetiology was reported in 5.8% of patients. No treatment interruptions or discontinuations were reported for diarrhoea.
Adverse reactions of abdominal pain and vomiting were reported in 7.7% and 3.8% of patients, respectively; none were concurrent with adverse reactions of diarrhoea. Median time to onset of abdominal pain was 1.5 days and median duration was 6 days. For vomiting, median time to onset was 2.5 days and median duration was 13.5 days. With the exception of one treatment interruption for abdominal pain, there were no other treatment interruptions or discontinuations due to abdominal pain or vomiting.
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