Linerixibat

There are no data on the use of linerixibat in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Use of linerixibat during pregnancy is expected to result in minimal fetal exposure because systemic absorption following oral administration is low. Linerixibat may inhibit the absorption of fat-soluble vitamins. In animal reproduction studies, in which linerixibat was administered orally to pregnant rabbits and rats during the period of organogenesis, no malformations or effects on embryo-fetal survival were reported at exposures 470 and 1,100 times the recommended human dose, respectively.

The background risk of birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Linerixibat has low absorption following oral administration, and exposure of the infant to linerixibat through breast milk is not expected at the recommended dosage. There are no data on the presence of linerixibat in human milk, effects on the breastfed infant, or effects on milk production. Linerixibat may reduce absorption of fat-soluble vitamins. Monitor maternal FSV levels and increase FSV intake if FSV deficiency is observed during lactation.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for linerixibat and any potential adverse effects on the breastfed child from linerixibat or from the underlying maternal condition.

Carcinogenesis

Linerixibat was not tumorigenic in a 2-year oral carcinogenicity study in rats with oral administration of up to 1,000 mg/kg/day (approximately 3,900 times the recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice, no drug-related tumors were observed following administration of linerixibat up to 160 mg/kg/day.

Mutagenesis

Linerixibat was negative in in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (rat bone marrow micronucleus) assays.

Impairment of Fertility

No effects on fertility or early embryonic development were observed in male and female rats treated orally with linerixibat up to 1,000 mg/kg/day.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of linerixibat is based on Study 1, a randomized, double-blind, placebo-controlled, 24-week study of linerixibat 40 mg administered orally twice daily.

Drug discontinuation due to adverse reactions was seen more frequently in linerixibat-treated patients (14%) than in placebo-treated patients (5%). Diarrhea, abdominal pain, ALT increase, and AST increase were the most common causes of treatment discontinuation.

Common Adverse Reactions

Table 1 displays the most common adverse reactions that occurred in at least 5% of linerixibat-treated patients in Study 1.

Table 1. Adverse Reactions Occurring in ≥5% of Adult Patients with PBC Treated with Linerixibat in Study 1 (24 weeks), Safety Dataset^a:

^a Adverse reactions were only included in table above if they occurred more frequently in patients treated with linerixibat compared to placebo-treated patients.
^b Diarrhea includes diarrhea and frequent bowel movements.
^c Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort.
^d Hemorrhage includes contusion, ecchymosis, epistaxis, gastric hemorrhage, hematochezia, hemorrhagic disorder, intermenstrual bleeding, melena, petechiae, skin hemorrhage, vaginal hemorrhage, hematocrit decreased, and diarrhea hemorrhagic.

Less Common Adverse Reactions

Additional adverse reactions that occurred more frequently in the linerixibat group compared to placebo group, in less than <5% of patients, included hyperbilirubinemia, hypertriglyceridemia, urinary tract infections, and dry mouth.

Specific Adverse Reactions

Liver Test Elevations

In Study 1, liver test elevations (ALT, AST, TB, or ALP) were observed more commonly in linerixibat-treated patients 17 (14%) compared to placebo-treated patients 7 (6%). Six (5%) of linerixibat-treated patients discontinued treatment due to liver test elevations during the study, compared to 2 (2%) of placebo-treated patients. Elevations in ALT to more than 3 times baseline levels occurred in 8 (7%) of linerixibat-treated patients compared to 4 (3%) of placebo-treated patients. Elevations in TB to more than 2 times baseline levels occurred in 9 (8%) of linerixibat-treated patients compared to 3 (3%) of placebo-treated patients.

Diarrhea

In Study 1, diarrhea was observed in 74 (62%) of patients in the linerixibat-treated group compared to 21 (18%) in the placebo-treated group. Most diarrhea events occurred within the first 20 days of initiating treatment. Of those who experienced diarrhea, 56/74 (76%) of linerixibat-treated patients and 10/21 (48%) of placebo-treated patients, did so within the first 20 days. Of the patients who experienced diarrhea, most were mild (46/74, 62%) or moderate (25/74, 34%) with 4% (3/74) of cases being severe in the linerixibat-treated group compared to 62% (13/21) mild, 38% (8/21) moderate, and 0% severe cases in the placebo-treated group. Discontinuation of treatment due to diarrhea occurred in 4% of patients in the linerixibat-treated group compared to <1% in the placebo group.

Fat-Soluble Vitamin Deficiency

In Study 1, FSV deficiency was reported in 2 (2%) of linerixibat-treated patients compared to 1 (<1%) of placebo-treated patients during the 24 weeks of treatment.