JUXTAPID can cause elevations in transaminases and hepatic steatosis, as described below [see Warnings and Precautions (5.2)]. To what extent JUXTAPID-associated hepatic steatosis promotes the elevations in transaminases is unknown. Although cases of hepatic dysfunction (elevated transaminases with increase in bilirubin or INR) or hepatic failure have not been reported, there is concern that JUXTAPID could induce steatohepatitis, which can progress to cirrhosis over several years. The clinical studies supporting the safety and efficacy of JUXTAPID in HoFH would have been unlikely to detect this adverse outcome given their size and duration [see Clinical Studies (14)]. 

Elevation of Transaminases

Elevations in transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) are associated with JUXTAPID. In the clinical trial, 10 (34%) of the 29 patients with HoFH had at least one elevation in ALT or AST ≥3× ULN, and 4 (14%) of the patients had at least one elevation in ALT or AST ≥5× ULN. There were no concomitant or subsequent clinically meaningful elevations in bilirubin, INR, or alkaline phosphatase [see Adverse Reactions (6.1)].

During the 78-week HoFH clinical trial, no patients discontinued prematurely because of elevated transaminases. Among the 19 patients who subsequently enrolled in the HoFH extension study, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24× ULN, AST 13× ULN) that had several possible causes, including a drug-drug interaction between JUXTAPID and the strong CYP3A4 inhibitor clarithromycin [see Drug Interactions (7.1)].

Monitoring of Transaminases

Before initiating JUXTAPID and during treatment, monitor transaminases as recommended in Table 3.

Hepatic Steatosis

JUXTAPID increases hepatic fat, with or without concomitant increases in transaminases. Hepatic steatosis is a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. The long-term consequences of hepatic steatosis associated with JUXTAPID treatment are unknown. During the HoFH clinical trial, the median absolute increase in hepatic fat was 6% after both 26 weeks and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy (MRS) [see Adverse Reactions (6.1)]. Clinical data suggest that hepatic fat accumulation is reversible after stopping treatment with JUXTAPID, but whether histological sequelae remain is unknown, especially after long-term use; protocol liver biopsies were not performed in the HoFH clinical trial.

Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking JUXTAPID should not consume more than one alcoholic drink per day. 

Caution should be exercised when JUXTAPID is used with other medications known to have potential for hepatotoxicity, such as isotretinoin, amiodarone, acetaminophen (>4 g/day for ≥3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant administration of JUXTAPID with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.

JUXTAPID has not been studied concomitantly with other LDL-lowering agents that can also increase hepatic fat. Therefore, the combined use of such agents is not recommended.