LYNAVOY Film-coated tablet Ref.[116436] Active ingredients: Linerixibat

5.1 Liver Test Elevations

In Study 1, liver test elevations were observed more commonly in LYNAVOY-treated patients compared to placebo-treated patients [see Adverse Reactions (6.1)]. Obtain baseline liver tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin [TB], direct bilirubin [DB], alkaline phosphatase [ALP]) prior to initiating treatment with LYNAVOY and monitor the levels per standard clinical practice for PBC patients during treatment with LYNAVOY. If new liver test elevations occur, monitor ALT, AST, TB, DB, and ALP more frequently. If liver test elevations persist, discontinue LYNAVOY.

5.2 Diarrhea

Diarrhea was reported as the most common adverse reaction in patients treated with LYNAVOY [see Adverse Reactions (6.1)].

If diarrhea occurs, advise patients to monitor for dehydration. Consider interrupting or discontinuing LYNAVOY treatment if diarrhea persists.

5.3 Fat-Soluble Vitamin Deficiency

LYNAVOY may adversely affect absorption of fat-soluble vitamins (FSV). FSV include vitamins A, D, E, and K [see Adverse Reactions (6.1)].

Obtain serum FSV levels (vitamins A, D, and E) and INR prior to initiation of LYNAVOY and monitor the levels periodically during treatment, along with any clinical manifestations of FSV deficiency. Supplement with FSV if FSV deficiency is diagnosed. Consider discontinuing LYNAVOY if FSV deficiency persists or worsens despite adequate FSV supplementation.

Bleeding

Bleeding was observed more frequently in LYNAVOY-treated patients compared to placebo-treated patients [see Adverse Reactions (6.1)]. If bleeding occurs, interrupt LYNAVOY treatment and evaluate for potential FSV deficiency. LYNAVOY can be restarted if FSV deficiency is corrected, levels are maintained, and bleeding has resolved.

Bone Fracture

IBAT inhibitors have been associated with bone fractures. Monitor bone health and ensure adequate FSV levels.

The following clinically significant adverse reactions are described elsewhere in labeling:

• Liver Test Elevations [see Warnings and Precautions (5.1)]
• Diarrhea [see Warnings and Precautions (5.2)]
• Fat-Soluble Vitamin Deficiency [see Warnings and Precautions (5.3)]

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 LYNAVOY is based on Study 1, a randomized, double-blind, placebo-controlled, 24-week study of LYNAVOY 40 mg administered orally twice daily [see Clinical Studies (14)].

Drug discontinuation due to adverse reactions was seen more frequently in LYNAVOY-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 LYNAVOY-treated patients in Study 1.

Table 1. Adverse Reactions Occurring in ≥5% of Adult Patients with PBC Treated with LYNAVOY 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 LYNAVOY 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 LYNAVOY 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 LYNAVOY-treated patients 17 (14%) compared to placebo-treated patients 7 (6%). Six (5%) of LYNAVOY-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 LYNAVOY-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 LYNAVOY-treated patients compared to 3 (3%) of placebo-treated patients.

Diarrhea

In Study 1, diarrhea was observed in 74 (62%) of patients in the LYNAVOY-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 LYNAVOY-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 LYNAVOY-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 LYNAVOY-treated group compared to <1% in the placebo group.

Fat-Soluble Vitamin Deficiency

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

7.1 Effects of Bile Acid Binding Resins on LYNAVOY

Instruct patients to take LYNAVOY at least 4 hours before or 4 hours after taking a bile acid binding resin [see Dosage and Administration (2.2)]. Based on in vitro data, bile acid resins may bind linerixibat in the gut [see Clinical Pharmacology (12.3)]. Concomitant use of bile acid binding resins with LYNAVOY can potentially inhibit the effects of LYNAVOY on the ileal bile acid transporter (IBAT)

Risk Summary

There are no data on the use of LYNAVOY in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Use of LYNAVOY during pregnancy is expected to result in minimal fetal exposure because systemic absorption following oral administration is low [see Clinical Pharmacology (12.3)]. Linerixibat may inhibit the absorption of fat-soluble vitamins [see Warnings and Precautions (5.3), Clinical Considerations]. 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 (see Data).

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.

There is a pregnancy safety study that monitors pregnancy exposures and outcomes in women who have taken LYNAVOY during pregnancy. Pregnant women exposed to LYNAVOY, or their healthcare providers, should report LYNAVOY exposure by contacting GlaxoSmithKline at 1-888-825-5249.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Linerixibat may inhibit the absorption of fat-soluble vitamins (FSV). FSV are essential for normal fetal growth and development. Monitor pregnant patients for FSV deficiency and supplement as needed. Increased supplementation of FSVs may be needed during pregnancy [see Warnings and Precautions (5.3)].

Data

Animal Data

No effects on embryo-fetal development were observed in pregnant rats treated orally with linerixibat up to 1,000 mg/kg/day (approximately 1,100 times the recommended dose based on AUC [area under the plasma concentration-time curve]) or in pregnant rabbits treated orally with linerixibat up to 125 mg/kg/day (approximately 470 times the recommended dose based on AUC) during the period of organogenesis. No effects on postnatal development were observed in a pre- and postnatal development study, in which female rats were treated orally with linerixibat up to 1,000 mg/kg/day during organogenesis through lactation. Maternal systemic exposure to linerixibat at the maximum dose tested was approximately 1,100 times the recommended human dose based on AUC.

Risk Summary

Linerixibat has low absorption following oral administration, and exposure of the infant to linerixibat through breast milk is not expected at the recommended dosage [see Clinical Pharmacology (12.3)]. There are no data on the presence of linerixibat in human milk, effects on the breastfed infant, or effects on milk production. LYNAVOY may reduce absorption of fat-soluble vitamins [see Warning and Precautions (5.3)]. 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 LYNAVOY and any potential adverse effects on the breastfed child from LYNAVOY or from the underlying maternal condition.

The safety and efficacy of LYNAVOY have not been established in pediatric patients.

Of the 119 patients that received LYNAVOY in Study 1, 25 (21%) were aged 65 years and older and 3 (3%) were aged 75 years and older [see Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between patients 65 to less than 75 years of age and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].

Clinical studies of LYNAVOY did not include sufficient numbers of patients aged 75 and older to determine whether they respond differently from younger adult patients.

The recommended dosage in patients with renal impairment is the same as in patients with normal renal function because systemic absorption of linerixibat is minimal and has negligible recovery in urine [see Clinical Pharmacology (12.3)]. The safety and effectiveness of LYNAVOY have not been studied in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²), including those on hemodialysis.

The recommended dosage in patients with mild hepatic impairment (Child-Pugh A) is the same as in patients with normal hepatic function. The efficacy and safety of LYNAVOY have not been evaluated in patients with moderate and severe hepatic impairment (Child-Pugh B and C) with decompensated cirrhosis or those with decompensation events [see Clinical Pharmacology (12.3), Clinical Studies (14)]. Avoid use of LYNAVOY in patients with decompensated cirrhosis or those with prior or active decompensation events (e.g. variceal hemorrhage, ascites, hepatic encephalopathy).