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Lomitapide

Pronunciation

(loe MI ta pide)

Index Terms

  • AEGR-733
  • BMS 201038
  • Lomitapide Mesylate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Juxtapid: 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 60 mg

Brand Names: U.S.

  • Juxtapid

Pharmacologic Category

  • Antilipemic Agent, Microsomal Triglyceride Transfer Protein (MTP) Inhibitor

Pharmacology

Lomitapide directly binds to and inhibits microsomal triglyceride transfer protein (MTP) which is located in the lumen of the endoplasmic reticulum. MTP inhibition prevents the assembly of apo-B containing lipoproteins in enterocytes and hepatocytes resulting in reduced production of chylomicrons and VLDL and subsequently reduces plasma LDL-C concentrations.

Distribution

Mean Vd: 985-1292 L

Metabolism

Primarily hepatic (extensive) through CYP3A4 to M1 and M3 (major [inactive in vitro] metabolites); CYP1A2, CYP2B6, CYP2C8, and CYP2C19 are also involved in metabolism to a minor degree.

Excretion

Urine (53% to 60%; major component: M1 metabolite); feces (33% to 35%; major component: parent drug)

Time to Peak

~6 hours

Half-Life Elimination

39.7 hours

Protein Binding

99.8% to plasma proteins

Special Populations: Renal Function Impairment

In patients with end-stage renal disease receiving dialysis, lomitapide exposure was increased by ~50% compared to healthy volunteers. The pharmacokinetics of lomitapide have not been evaluated in patients with mild to severe renal impairment not receiving dialysis; however, exposure exceeding 50% is possible.

Special Populations: Hepatic Function Impairment

In patients with mild hepatic impairment (Child-Pugh class A), lomitapide exposure was increased by ~50% compared to healthy volunteers. Lomitapide exposure was increased by 164% and Cmax was 361% higher in patients with moderate hepatic impairment compared to healthy volunteers.

Use: Labeled Indications

Homozygous familial hypercholesterolemia: Adjunct to a low-fat diet and other lipid-lowering treatments, including low-density lipoprotein (LDL) apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol, apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

Contraindications

Pregnancy; coadministration with moderate or strong CYP3A4 inhibitors; moderate or severe hepatic impairment (Child-Pugh class B or C) and patients with active liver disease, including unexplained persistent elevations of serum transaminases.

Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to lomitapide or any component of the formulation; known significant, chronic bowel disease (eg, inflammatory bowel disease, malabsorption); concomitant administration of simvastatin >20 mg daily (concomitant use with simvastatin 40 mg daily is permitted in patients previously tolerant of simvastatin 80 mg daily for ≥1 year without evidence of myotoxicity); galactose intolerance, Lapp-lactase deficiency, or glucose-galactose malabsorption

Dosing: Adult

Homozygous familial hypercholesterolemia (HoFH):

Note: Measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin prior to initiation and prior to any dose increase; obtain a negative pregnancy test in female patients of reproductive potential prior to beginning treatment. Maintenance dose should be individualized, taking into account patient characteristics such as goal of therapy and response to treatment. To reduce development of fat-soluble nutrient deficiency, administer daily supplements containing vitamin E 400 units, linoleic acid ≥200 mg, alpha-linolenic acid (ALA) ≥210 mg, eicosapentaenoic acid (EPA) ≥110 mg, and docosahexaenoic acid (DHA) ≥80 mg. Initiate and maintain a low-fat diet supplying <20% of energy from fat.

Oral: Initial: 5 mg once daily; after ≥2 weeks of therapy, may increase to 10 mg once daily, as tolerated; then at ≥4-week intervals, may increase to 20 mg once daily, then to 40 mg once daily, and finally to a maximum dose of 60 mg/day as tolerated.

Dosage adjustment for lomitapide with weak CYP3A inhibitors (eg, alprazolam, amiodarone, amlodipine, atorvastatin, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, ticagrelor): Initial: Decrease lomitapide dose by half to a minimum of 5 mg once daily when initiating a weak CYP3A inhibitor in a patient already receiving lomitapide; titrate based on response and tolerability; maximum dose: 30 mg/day.

Dosage adjustment for lomitapide with oral contraceptives: Initial: Decrease lomitapide dose by half to a minimum of 5 mg once daily when initiating an oral contraceptive in a patient already receiving lomitapide; titrate based on response and tolerability; maximum dose: 40 mg/day.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild to severe impairment (not receiving dialysis): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, it is possible that patients with renal impairment not receiving dialysis may experience increases in lomitapide exposure exceeding 50%.

End stage renal disease (ESRD; receiving dialysis): Maximum dose: 40 mg/day

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): Maximum dose: 40 mg/day

Moderate to severe impairment (Child-Pugh class B or C), active liver disease (including unexplained persistent transaminase elevations): Use is contraindicated.

Dosing: Adjustment for Toxicity

Hepatotoxicity: Note: If transaminases are abnormal, reduce or withhold dose; monitor as recommended. If transaminase elevations are accompanied by clinical symptoms of liver injury (eg, nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥2 times ULN, or active liver disease, discontinue use and investigate for probable cause.

AST or ALT ≥ 3 to <5 times ULN: Confirm measurement (within 1 week); once confirmed, reduce dose and obtain additional liver function tests (LFTs) (eg, alkaline phosphatase, total bilirubin, and INR); repeat tests weekly and withhold subsequent doses if signs of abnormal liver function (eg, increased bilirubin or INR), if transaminases rise to >5 times ULN, or if they do not fall to <3 times ULN within ~4 weeks; investigate for probable cause. If resuming after transaminase resolution to <3 times ULN, consider reducing dose and monitor LFTs more frequently.

AST or ALT ≥ 5 times ULN: Withhold doses, obtain additional LFTs (eg, alkaline phosphatase, total bilirubin, and INR); investigate for probable cause. If resuming after transaminase resolution to <3 times ULN, reduce dose and monitor LFTs more frequently.

Persistent or clinically significant transaminase elevations: Discontinue use.

Administration

Oral: Administer with water and without food; administer at least 2 hours after the evening meal since administration with food may increase risk of gastrointestinal adverse effects. Swallow capsules whole (do not open, crush, dissolve, or chew).

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Brief exposure up to 40°C (104°F) may be tolerated provided the mean temperature does not exceed 25°C (77°F); minimize this type of exposure. Protect from moisture.

Drug Interactions

Alcohol (Ethyl): May enhance the hepatotoxic effect of Lomitapide. Management: Advise patients to limit alcohol consumption to 1 drink per day while receiving lomitapide. Consider therapy modification

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Lomitapide. Management: Administer lomitapide at least 4 hours before or after administration of a bile acid sequestrant. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ciprofloxacin (Systemic): May increase the serum concentration of Lomitapide. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Lomitapide. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Lomitapide. Avoid combination

CYP3A4 Inhibitors (Weak): May increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Ethinyl Estradiol: May increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 40 mg/day. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Lovastatin: Lomitapide may increase the serum concentration of Lovastatin. Management: Consider reducing lovastatin doses during concomitant treatment with lomitapide, and monitor for signs and symptoms of muscle toxicity. Specific dosing recommendations are not presently available. Consider therapy modification

Mipomersen: Lomitapide may enhance the hepatotoxic effect of Mipomersen. Specifically, the risk of steatosis may be increased with this combination. Avoid combination

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Nilotinib: May increase the serum concentration of Lomitapide. Management: Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half with concurrent nilotinib; the lomitapide dose may then be increased to a max adult dose of 30 mg/day (patients on lomitapide 5 mg/day may continue that dose). Consider therapy modification

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Simvastatin: Lomitapide may increase the serum concentration of Simvastatin. Management: Reduce the recommended simvastatin dose by 50%. Generally, limit the maximum adult simvastatin dose to 20 mg/day. A 40 mg/day dose can be considered in patients who previously received 80 mg/day for at least a year without evidence of muscle toxicity. Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tipranavir: May increase the serum concentration of Lomitapide. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Warfarin: Lomitapide may increase the serum concentration of Warfarin. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Chest pain (24%)

Central nervous system: Fatigue (17%)

Gastrointestinal: Diarrhea (79%; severe: 14%), nausea (65%), dyspepsia (38%), vomiting (34%; severe: 10%), abdominal pain (34%; severe: 7%), weight loss (24%), abdominal discomfort (21%; severe: 7%), abdominal distension (21%; severe: 7%), constipation (21%), flatulence (21%), gastroenteritis (14%)

Hepatic: Liver steatosis (increase in hepatic fat >5%: 78%; >20% fat increase: 13%), increased serum transaminases (≥3 times upper limit of normal: 34%; ≥5 times upper limit of normal: 14%)

Infection: Influenza (21%)

Neuromuscular & skeletal: Back pain (14%)

Respiratory: Nasopharyngitis (17%), pharyngolaryngeal pain (14%)

1% to 10%:

Cardiovascular: Angina pectoris (10%), palpitations (10%)

Central nervous system: Dizziness (10%), headache (10%)

Gastrointestinal: Bowel urgency (10%), gastroesophageal reflux disease (10%), rectal tenesmus (10%)

Hepatic: Hepatotoxicity (severe: 10%)

Respiratory: Nasal congestion (10%)

Miscellaneous: Fever (10%)

<1% (Limited to important or life-threatening): Alopecia, myalgia

ALERT: U.S. Boxed Warning

Risk of hepatotoxicity:

Lomitapide can cause elevations in transaminases. In the clinical trial, 34% of patients had at least 1 elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 3 times the upper limit of normal (ULN) or higher. There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR), or alkaline phosphatase.

Lomitapide also increases hepatic fat, with or without concomitant increases in transaminases. The median absolute increase in hepatic fat was 6% after both 26 and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy (MRS). Hepatic steatosis associated with lomitapide treatment may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis.

Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment and then ALT and AST regularly as recommended. During treatment, adjust the dose of lomitapide if the ALT or AST is 3 times the ULN or higher. Discontinue lomitapide for clinically significant liver toxicity.

Because of the risk of hepatotoxicity, lomitapide is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Juxtapid REMS program. Prescribe lomitapide only to patients with a clinical or laboratory diagnosis consistent with homozygous familial hypercholesterolemia (HoFH). The safety and effectiveness of lomitapide have not been established in patients with hypercholesterolemia who do not have HoFH.

Warnings/Precautions

Concerns related to adverse effects:

• Gastrointestinal events: Significant gastrointestinal events (eg, diarrhea, nausea, dyspepsia, vomiting) occur commonly during treatment. Severe diarrhea, leading to volume depletion requiring hospitalization, has been reported. Monitor patients susceptible to complications from diarrhea (eg, elderly, coadministration with drugs causing volume depletion or hypotension). Consider dosage reduction or withholding dose if severe diarrhea or symptoms of volume depletion (eg, lightheadedness, decreased urine output, tiredness) occur. Absorption of other oral medications may be affected in patients with diarrhea or vomiting. Adhering to a low-fat diet (<20% of energy from fat) and gradual titration of dosage may reduce the risk of gastrointestinal adverse events.

• Hepatotoxicity: [US Boxed Warning]: May cause transaminase elevations; elevations in ALT or AST ≥3 times upper limit of normal occurred during clinical trials (no clinically meaningful concomitant bilirubin, INR, or alkaline phosphatase elevation was observed). Lomitapide also increases hepatic fat, with or without concomitant transaminase elevations. Hepatic steatosis associated with lomitapide (reversible upon discontinuation) may be a risk factor for progressive liver disease including steatohepatitis and cirrhosis. Monitor hepatic function (ALT, AST, alkaline phosphatase and total bilirubin) prior to treatment; monitor ALT and AST regularly as recommended during treatment; dosage adjustment, withholding dose or discontinuation may be necessary; transaminases typically reduce within 1 to 4 weeks after reducing the dose or discontinuation. Discontinue use with persistent or clinically significant elevations. Alcohol ingestion may increase the risk of hepatic steatosis and induce or exacerbate liver injury; alcohol consumption should be limited to ≤1 drink/day. Use caution when administered concomitantly with other hepatotoxic medications (eg, acetaminophen [>4 g/day for ≥3 days/week], amiodarone, isotretinoin, methotrexate, tetracyclines, tamoxifen); may require more frequent monitoring of liver function tests. Concomitant administration with other LDL-lowering agents that also have the potential to increase hepatic fat is not recommended (has not been studied).

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with mild (Child-Pugh class A) hepatic impairment due to increased drug exposure; a reduced dose is recommended. Use is contraindicated in patients with moderate to severe (Child-Pugh class B or C) impairment or active liver disease including unexplained persistent elevations of serum transaminases. If abnormal liver function tests have been explained or resolved, consideration may be given to initiation of lomitapide. Monitor liver function as recommended.

• Renal impairment: Use with caution in patients with mild to severe renal impairment including end-stage renal disease (ESRD) not receiving dialysis (has not been studied); drug exposure may significantly increase. Use with caution in patients with ESRD receiving dialysis; a reduced dose is recommended.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Lactose: Contains lactose; avoid use in patients with hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption; may result in diarrhea and malabsorption.

Other warnings/precautions:

• Fat-soluble vitamins: Lomitapide may reduce the absorption of fat-soluble nutrients (eg, vitamin E, linoleic acid, alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid); supplementation is recommended. Patients with chronic bowel or pancreatic diseases predisposed to malabsorption are at increased risk for deficiency.

• Limitations of use: [US Boxed Warning]: Prescribe lomitapide only to patients with a clinical or laboratory diagnosis consistent with HoFH. Safety and effectiveness have not been established in patients with hypercholesterolemia who do not have HoFH, including those with heterozygous familial hypercholesterolemia. The effect of lomitapide on cardiovascular morbidity and mortality has not been determined.

• REMS program: [US Boxed Warning]: Due to the risk for hepatotoxicity, access is restricted through a REMS program (Juxtapid REMS program). Only certified healthcare providers and pharmacies may prescribe and dispense lomitapide.

Monitoring Parameters

ALT, AST, alkaline phosphatase, total bilirubin at baseline; pregnancy test in females of reproductive potential prior to initiation of therapy. Measure transaminases prior to any increase in dose or monthly (whichever occurs first) during the first year, and then at least every 3 months and prior to dosage increases (also see Dosage Adjustment for Toxicity)

Pregnancy Risk Factor

X

Pregnancy Considerations

Adverse effects have been observed in animal reproduction studies using doses lower than equivalent human doses. Use is contraindicated in pregnant women. Discontinue immediately if pregnancy occurs during treatment. Women of reproductive potential should have a negative pregnancy test prior to therapy and effective contraception must be used during treatment. Dose adjustment may be required for women using oral contraceptives.

Health care providers are encouraged to enroll women exposed to lomitapide during pregnancy in the Global Lomitapide Pregnancy Exposure Registry by calling 1-877-902-4099.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal cramps, bloating, loss of strength and energy, flatulence, constipation, heartburn, weight loss, back pain, rhinitis, pharyngitis, dizziness, or headache. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), angina, abnormal heartbeat, bruising, bleeding, flu-like symptoms, severe diarrhea, persistent diarrhea, or signs of dehydration (dry skin, dry mouth, dry eyes, increased thirst, tachycardia, dizziness, fast breathing, or confusion) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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