Juxtapid - Drug Monograph

Introduction

Juxtapid (lomitapide) is an oral microsomal triglyceride transfer protein (MTP) inhibitor indicated as an adjunct to a low-fat diet and other lipid-lowering treatments for homozygous familial hypercholesterolemia (HoFH). This orphan drug represents a significant advancement in managing this rare genetic disorder characterized by extremely elevated LDL cholesterol levels and premature cardiovascular disease.

Mechanism of Action

Lomitapide inhibits microsomal triglyceride transfer protein (MTP), which is essential for the assembly and secretion of apolipoprotein B-containing lipoproteins in the liver and intestine. By binding to and inhibiting MTP, Juxtapid reduces the synthesis and secretion of chylomicrons and very low-density lipoproteins (VLDL), ultimately leading to decreased plasma levels of LDL cholesterol, total cholesterol, and apolipoprotein B.

Indications

Juxtapid is approved for use in adults with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments, including LDL apheresis, and a low-fat diet to reduce:

• LDL-C
• Total cholesterol
• Apolipoprotein B
• Non-HDL-C

Dosage and Administration

• Hepatic impairment: Contraindicated in moderate or severe impairment
• Renal impairment: No dosage adjustment necessary
• Elderly: Use with caution
• Pediatric: Safety and effectiveness not established

Pharmacokinetics

Contraindications

• Pregnancy
• Moderate or severe hepatic impairment
• Concomitant use with strong CYP3A4 inhibitors
• Active liver disease or unexplained persistent elevations of serum transaminases

Warnings and Precautions

• Hepatic toxicity: Monitor ALT, AST, and alkaline phosphatase before starting and regularly during treatment
• Gastrointestinal effects: May cause diarrhea, nausea, vomiting, and dyspepsia
• Fat-soluble vitamin deficiency: May reduce absorption of fat-soluble vitamins; supplementation recommended
• Embryofetal toxicity: Can cause fetal harm; requires effective contraception

Drug Interactions

• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): Contraindicated
• Moderate CYP3A4 inhibitors (e.g., fluconazole, diltiazem): Reduce Juxtapid dose
• Warfarin: Monitor INR closely
• P-glycoprotein substrates: Use with caution

Adverse Effects

• Diarrhea (93%)
• Nausea (65%)
• Abdominal pain (40%)
• Dyspepsia (34%)
• Vomiting (32%)

• Hepatotoxicity (elevated transaminases)
• Hepatic steatosis
• Vitamin deficiency
• Pancreatitis (rare)

Monitoring Parameters

• Liver function tests (ALT, AST, alkaline phosphatase) at baseline, regularly during treatment, and as clinically indicated
• LDL-C, total cholesterol, non-HDL-C, apo B levels
• Fat-soluble vitamin levels (A, D, E, K)
• Complete blood count
• Pregnancy testing in women of childbearing potential
• Adherence to low-fat diet (<20% of daily calories from fat)

Patient Education

• Take medication on an empty stomach with water only
• Adhere strictly to low-fat diet (<20% fat calories)
• Report any symptoms of liver problems (nausea, vomiting, abdominal pain, fatigue, jaundice)
• Use effective contraception during treatment
• Take prescribed vitamin supplements
• Report any unusual bleeding or bruising
• Inform all healthcare providers about Juxtapid use
• Do not breastfeed while taking this medication

References

1. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013;381(9860):40-46. 2. Juxtapid [package insert]. Cambridge, MA: Aegerion Pharmaceuticals, Inc.; 2021. 3. FDA. Juxtapid (lomitapide) capsules prescribing information. Accessed [2023]. 4. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341-350. 5. Gagné C, Gaudet D, Bruckert E; for the Lomitapide Study Group. Efficacy and safety of lomitapide in patients with homozygous familial hypercholesterolaemia: a randomized, double-blind, placebo-controlled clinical trial. Atherosclerosis. 2012;223(2):318-325.