Lomitapide (Monograph)

Brand name: Juxtapid
Drug class:

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Antilipemic agent; microsomal triglyceride transfer protein (MTTP) inhibitor.

Uses for Lomitapide

Dyslipidemias

Adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce LDL-cholesterol, total cholesterol, apolipoprotein B (apo B), and non-HDL-cholesterol concentrations in the management of homozygous familial hypercholesterolemia (designated an orphan drug by US FDA for use in this condition).

Safety and efficacy not established in patients with hypercholesterolemia who do not have homozygous familial hypercholesterolemia.

Effects on cardiovascular morbidity and mortality not established.

Lomitapide Dosage and Administration

General

• Begin low-fat diet (i.e., <20% of total calories from fat) prior to initiation of lomitapide therapy and continue this diet during treatment to reduce risk of adverse GI effects.

• Obtain liver function tests (i.e., ALT, AST, alkaline phosphatase, and total bilirubin concentrations) prior to initiation of therapy and at recommended intervals during therapy. (See Hepatotoxicity under Cautions.)

• Supplement with 400 units of vitamin E and at least 200 mg of linoleic acid, 210 mg of alpha-linolenic acid, 110 mg eicosapentaenoic acid (EPA), and 80 mg of docosahexaenoic acid (DHA). (See Fat-soluble Vitamin and Fatty Acid Deficiency under Cautions.)

• Exclude pregnancy before initiating therapy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Restricted Distribution Program

• Lomitapide can only be prescribed and dispensed by healthcare providers and pharmacies certified through the Juxtapid REMS program.

• Additional information available at 855-898-2743 or [Web].

Administration

Oral Administration

Administer orally once daily without food, ≥2 hours after evening meal.

Swallow capsules whole with a glass of water; do not open, crush, dissolve, or chew.

If a dose is missed, take next dose at regularly scheduled time. If therapy is interrupted for >1 week, contact healthcare provider prior to reinitiation of therapy.

Dosage

Available as lomitapide mesylate; dosage expressed in terms of lomitapide.

Adults

Dyslipidemias

Homozygous Familial Hypercholesterolemia

Oral

Initially, 5 mg once daily. Continue initial dosage for ≥2 weeks.

After receiving initial dosage for ≥2 weeks, may increase dosage gradually (i.e., at intervals of ≥4 weeks) in stepwise manner (i.e., to 10, 20, 40, and then 60 mg daily) based on safety and tolerability.

Maintenance dosage should be individualized, taking into account patient's goals and response to therapy. (See Prescribing Limits under Dosage and Administration.)

Dosage Modification

Hepatotoxicity

If hepatotoxicity occurs, reduce lomitapide dosage, or interrupt or permanently discontinue therapy and investigate probable cause. (See Table 1.)

Concomitant Use with CYP3A4 Inhibitors

Concomitant use with moderate or potent CYP3A4 inhibitors is contraindicated. (See Interactions.)

Do not exceed lomitapide dosage of 30 mg daily when used concomitantly with weak CYP3A4 inhibitors.

Prescribing Limits

Adults

Homozygous Familial Hypercholesterolemia

Oral

Maximum 60 mg daily.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Do not exceed 40 mg daily. (See Hepatic Impairment under Cautions.)

Moderate or severe hepatic impairment (Child-Pugh class B or C): Use is contraindicated.

Renal Impairment

End-stage renal disease requiring dialysis: Do not exceed 40 mg daily. (See Renal Impairment under Cautions.)

Renal impairment or end-stage renal disease not requiring dialysis: Not studied.

Geriatric Patients

Select dosage with caution because of possible age-related decreases in hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Cautions for Lomitapide

Contraindications

• Moderate or severe hepatic impairment (Child-Pugh class B or C).

• Active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations.

• Pregnancy.

• Concomitant use with moderate or potent CYP3A4 inhibitors.

Warnings/Precautions

Warnings

Hepatotoxicity

Increases in serum aminotransferase (ALT and/or AST) concentrations reported; persistent and severe (≥10 times the ULN) elevations also reported. No concomitant or subsequent clinically meaningful elevations in bilirubin, INR, or alkaline phosphatase concentrations. Serum aminotransferase concentrations typically declined within 1–4 weeks following reduction in lomitapide dosage or interruption of therapy.

Hepatic steatosis, with or without concomitant increases in serum aminotransferase concentrations, reported. May be reversible following discontinuance of therapy; however, not known whether histologic sequelae remain, particularly after long-term therapy. Hepatic steatosis is a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. Long-term consequences of hepatic steatosis associated with lomitapide therapy unknown. However, there is concern that lomitapide-induced hepatic steatosis could result in steatohepatitis, which can progress to cirrhosis over several years.

Hepatic dysfunction (elevated aminotransferase concentrations with increases in bilirubin concentrations or INR) or hepatic failure not reported.

Perform liver function tests (i.e., ALT, AST, alkaline phosphatase, and total bilirubin concentrations) prior to initiation of therapy; evaluate and manage abnormal concentrations before initiating therapy. During first year of therapy, perform liver function tests (or, at a minimum, ALT and AST concentrations) prior to each increase in dosage or monthly, whichever occurs first. After first year of therapy, perform liver-related tests at least every 3 months and prior to any increase in dosage. If elevations in aminotransferase concentrations occur, reduce lomitapide dosage; if persistent or clinically relevant elevations are observed, interrupt or permanently discontinue therapy and investigate probable cause. (See Hepatotoxicity under Dosage and Administration.)

Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. Advise patients to limit alcohol consumption to ≤1 alcohol-containing drink per day.

Exercise caution when used concomitantly with other potentially hepatotoxic drugs. Concomitant use with other LDL-lowering agents known to increase hepatic fat not recommended. (See Hepatotoxic Drugs under Interactions.)

Other Warnings and Precautions

Juxtapid Registry

A registry has been established to monitor and evaluate the long-term effects of lomitapide. Information available at 877-902-4099 or at [Web].

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals.

Exclude pregnancy prior to initiation of therapy. Advise women of childbearing potential to use an effective method of contraception during therapy. If oral contraceptives are used, do not exceed lomitapide dosage of 30 mg daily. If incomplete absorption of oral contraceptives occurs (e.g., resulting from lomitapide-induced vomiting and diarrhea), may need to use additional contraceptive methods.

If used during pregnancy or if patient becomes pregnant during therapy, discontinue therapy and apprise of potential fetal hazard. (See Advice to Patients.)

Fat-soluble Vitamin and Fatty Acid Deficiency

May reduce absorption of fat-soluble vitamins and serum fatty acids and increase risk of developing fat-soluble nutrient deficiency. Patients predisposed to malabsorption (e.g., those with chronic bowel or pancreatic diseases) may be at increased risk.

Manufacturer recommends use of supplements containing 400 units of vitamin E and at least 210 mg of alpha-linolenic acid, 200 mg of linoleic acid, 110 mg of EPA, and 80 mg of DHA during therapy.

GI Effects

Adverse GI effects, including diarrhea, nausea, dyspepsia, and vomiting frequently observed. Abdominal pain, abdominal discomfort, abdominal distention, constipation, and flatulence also reported. Absorption of concomitantly used oral medications may be affected in patients who develop diarrhea or vomiting during therapy.

To reduce to risk of adverse GI effects, increase dosage gradually and instruct patients to adhere to a low-fat diet (i.e., <20% of total calories from fat) and to take lomitapide without food (≥2 hours after evening meal).

Concomitant Use with CYP3A4 Inhibitors

Concomitant use with CYP3A4 inhibitors may increase exposure to lomitapide.

Concomitant use with moderate or potent CYP3A4 inhibitors is contraindicated. (See Contraindications under Cautions.) If used concomitantly with a weak CYP3A4 inhibitor, do not exceed lomitapide dosage of 30 mg daily. (See Specific Drugs and Foods under Interactions.)

Concomitant Use with Hydroxymethylglutaryl CoA (HMG-CoA) Reductase Inhibitors (Statins)

Concomitant use with certain statins that are metabolized by CYP3A4 (e.g., simvastatin, lovastatin) may result in increased exposure to the statin and possible increased risk of myopathy, including rhabdomyolysis. (See Specific Drugs and Foods under Interactions.)

Concomitant Use with Warfarin

Increases in lomitapide dosage may lead to supratherapeutic anticoagulation with warfarin, and decreases in lomitapide dosage may lead to subtherapeutic anticoagulation. Monitor INR regularly, especially following any changes to lomitapide dosage, and adjust warfarin dosage as clinically indicated. (See Specific Drugs and Foods under Interactions.)

Patients with Hereditary Disorders

Possible diarrhea and malabsorption in patients with rare hereditary disorders, including galactose intolerance, the Lapp lactase deficiency, and glucose-galactose malabsorption; avoid use in such patients.

Specific Populations

Pregnancy

Category X. (See Contraindications and also Fetal/Neonatal Morbidity and Mortality under Cautions.)

Pregnancy registry at 877-902-4099 or [Web] to monitor pregnancy outcomes in women who have been exposed to lomitapide.

Lactation

Not known whether distributed into human milk; discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults. Other reported clinical experience has not identified differences in responses between geriatric and younger patients. Select dosage with caution. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Increased systemic exposure in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). (See Special Populations under Pharmacokinetics.) Not studied in patients with severe hepatic impairment (Child-Pugh class C).

Do not exceed lomitapide dosage of 40 mg daily in patients with mild hepatic impairment (Child-Pugh class A).

Use contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Renal Impairment

Increased systemic exposure in patients with end-stage renal disease undergoing dialysis; do not exceed lomitapide dosage of 40 mg daily. (See Special Populations under Pharmacokinetics.)

Not studied in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease not requiring dialysis.

Common Adverse Effects

Diarrhea, nausea, dyspepsia, vomiting, abdominal pain, weight loss, chest pain, abdominal discomfort, abdominal distention, constipation, flatulence, influenza, nasopharyngitis, increased ALT, fatigue, gastroenteritis, back pain, pharyngolaryngeal pain, gastroesophageal reflux disease, defecation urgency, rectal tenesmus, fever, headache, dizziness, nasal congestion, angina pectoris, palpitations.

Drug Interactions

Metabolized principally by CYP3A4; also may be metabolized to a small extent by CYP isoenzymes 1A2, 2B6, 2C8, and 2C19.

Inhibits CYP3A4 but does not inhibit CYP isoenzymes 1A2, 2B6, 2C9, 2C19, 2D6, or 2E1.

Does not induce CYP isoenzymes 1A2, 3A4, or 2B6.

Inhibitor, but not a substrate, of P-glycoprotein (P-gp).

Does not inhibit breast cancer resistance protein (BCRP).

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Moderate or potent CYP3A4 inhibitors: Possible increased exposure to lomitapide. Concomitant use contraindicated. If concomitant use cannot be avoided, interrupt lomitapide therapy during therapy with the CYP3A4 inhibitor. (See Specific Drugs and Foods under Interactions.)

Weak CYP3A4 inhibitors: Possible increased exposure to lomitapide. If used concomitantly, do not exceed lomitapide dosage of 30 mg daily. (See Specific Drugs and Foods under Interactions.)

Drugs Affected by P-glycoprotein Transport

Substrates of P-gp: Possible increased absorption of P-gp substrate. If used concomitantly, consider dosage reduction of P-gp substrate. (See Specific Drugs and Foods under Interactions.)

Hepatotoxic Drugs

Possible increased risk of hepatotoxicity. Use concomitantly with caution; more frequent monitoring of liver-related tests may be warranted. (See Specific Drugs and Foods under Interactions.)

Concomitant use with other LDL-lowering agents known to increase hepatic fat not studied; therefore, such concomitant use not recommended.

Specific Drugs and Foods

Lomitapide Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is approximately 7%.

Peak plasma concentrations attained in about 6 hours following oral administration.

Pharmacokinetics are approximately dose proportional over single-dose range of 10–100 mg.

Special Populations

In patients with mild hepatic impairment (Child-Pugh class A), peak plasma concentration and AUC are increased by 4 and 47%, respectively, compared with individuals with normal hepatic function. (See Hepatic Impairment under Dosage and Administration.)

In patients with moderate hepatic impairment (Child-Pugh class B), peak plasma concentration and AUC are increased by 361 and 164%, respectively, compared with individuals with normal hepatic function. (See Contraindications under Cautions.)

In patients with end-stage renal disease undergoing dialysis, peak plasma concentration and AUC are 50 and 40% higher, respectively, compared with individuals with normal renal function. (See Renal Impairment under Dosage and Administration.)

Distribution

Extent

Not known whether lomitapide distributes into human milk. (See Lactation under Cautions.)

Plasma Protein Binding

99.8%.

Elimination

Metabolism

Metabolized in the liver, principally by CYP3A4; also may be metabolized to a small extent by CYP isoenzymes 1A2, 2B6, 2C8, and 2C19.

Elimination Route

Excreted in urine (53–60%) as metabolites and in feces (33–35%) mainly as unchanged drug.

Half-life

Approximately 40 hours.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C). Minimize exposure to temperatures up to 40°C. Keep container tightly closed and protect from moisture.

Actions

• Binds directly to and inhibits MTTP in enterocytes and hepatocytes.

• Inhibition of MTTP in enterocytes prevents incorporation of dietary lipids (e.g., triglycerides, cholesteryl esters, phospholipids) into apo B-48, resulting in inhibition of chylomicron synthesis and, subsequently, inhibition of fat absorption in the intestines.

• Inhibition of MTTP in hepatocytes prevents incorporation of endogenous lipids into apo B-100, resulting in inhibition of VLDL-cholesterol synthesis (a precursor of LDL-cholesterol) and, subsequently, inhibition of LDL-cholesterol synthesis in the liver.

• Because of lomitapide's mechanism of action, neutral lipids not used in the formation of chylomicrons and VLDL-cholesterol are expected to accumulate in the intestines and liver, resulting in adverse GI and hepatic effects (e.g., diarrhea, nausea, hepatic steatosis). (See Hepatotoxicity and also GI Effects under Cautions.)

• No clinically important prolongation of QT_c interval.

Advice to Patients

• Importance of informing patients that a registry has been established to monitor and evaluate the long-term effects of lomitapide; importance of encouraging patients to participate in this voluntary registry.

• Importance of educating patients regarding the Juxtapid REMS restricted distribution program for obtaining lomitapide. (See REMS and also see Restricted Distribution Program under Dosage and Administration.)

• Importance of taking lomitapide capsules whole and not opening, crushing, dissolving, or chewing the capsules.

• Risk of hepatotoxicity. Importance of obtaining liver-related laboratory tests prior to initiation of therapy, prior to any increase in dosage, and at recommended intervals during therapy. Importance of limiting alcohol consumption to ≤1 alcohol-containing drink per day. Importance of immediately reporting symptoms suggestive of liver injury (e.g., nausea, vomiting, or abdominal pain that is severe or persistent or changes in character; fever; jaundice; lethargy; flu-like symptoms).

• Risk of fetal harm. Importance of excluding pregnancy with a negative pregnancy test before starting lomitapide. Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise women of reproductive potential to use effective contraception to prevent pregnancy during lomitapide therapy. If pregnancy occurs, importance of discontinuing lomitapide and immediately notifying a clinician.

• Importance of taking daily supplements containing 400 units of vitamin E and at least 210 mg of alpha-linolenic acid, 200 mg of linoleic acid, 110 mg of EPA, and 80 mg of DHA.

• Risk of adverse GI reactions. Importance of taking lomitapide without food (≥2 hours after the evening meal) and adhering to a low-fat diet to reduce the risk of adverse GI effects. Importance of consulting a clinician if diarrhea or vomiting occurs during lomitapide therapy.

• Importance of avoiding grapefruit juice during lomitapide therapy.

• If a dose is missed, importance of administering the next dose at the regularly scheduled time. If therapy is interrupted for >1 week, importance of contacting a clinician before reinitiating therapy.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., ginkgo, goldenseal), as well as any concomitant illnesses (e.g., renal disease, hepatic disease).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of lomitapide is restricted. (See Restricted Distribution Program under Dosage and Administration.)

Reload page with references included

Frequently asked questions

• What is the mechanism of action for Juxtapid (lomitapide)?
• Is Juxtapid FDA-approved as a high cholesterol treatment?

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