(loe MI ta pide)
- BMS 201038
- Lomitapide Mesylate
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Juxtapid: 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 60 mg
Brand Names: U.S.
- Antilipemic Agent, Microsomal Triglyceride Transfer Protein (MTP) Inhibitor
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.
Mean Vd: 985-1292 L
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.
Urine (53% to 60%; major component: M1 metabolite); feces (33% to 35%; major component: parent drug)
Time to Peak
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).
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
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.
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.
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).
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.
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. Monitor therapy
Ciprofloxacin (Systemic): May increase the serum concentration of Lomitapide. Avoid combination
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. 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. 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. Monitor therapy
Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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. Avoid combination
HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone. Monitor therapy
Idelalisib: May increase the serum concentration of CYP3A4 Substrates. 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. 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
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Simeprevir: May increase the serum concentration of CYP3A4 Substrates. 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. 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. 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. Monitor therapy
Warfarin: Lomitapide may increase the serum concentration of Warfarin. Monitor therapy
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%), increased serum transaminases (17%; severe: 10%)
Neuromuscular & skeletal: Back pain (14%)
Respiratory: Nasopharyngitis (17%), pharyngolaryngeal pain (14%)
Miscellaneous: Influenza (21%)
1% to 10%:
Cardiovascular: Angina pectoris (10%), palpitation (10%)
Central nervous system: Dizziness (10%), fever (10%), headache (10%)
Gastrointestinal: Frequent bowel movement (10%), gastroesophageal reflux disease (10%), rectal tenesmus (10%)
Hepatic: Hepatotoxicity (severe: 10%)
Respiratory: Nasal congestion (10%)
<1% (Limited to important or life-threatening): Abnormal pulmonary function test, anemia, cough, decreased appetite, dehydration, early satiety, eructation, eye swelling, gait disturbance, gastroenteritis, hematemesis, hematuria, hepatomegaly, hyperhidrosis, hypersensitivity, increase neutrophil, increased appetite, increased gamma-glutamyl transferase, increased serum bilirubin, increased white blood cell count, joint swelling, lower gastrointestinal hemorrhage, myalgia, myocardial infarction, pain in extremity, paresthesia, pharyngeal lesion, prolonged prothrombin time, proteinuria, pyrexia, rsinusitis, skin rash, somnolence, transiet ischemic attack, xeroderma
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).
• 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.
• 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.
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
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.
• 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, loss of strength and energy, flatulence, constipation, heartburn, weight loss, back pain, rhinitis, pharyngitis, flu-like symptoms, 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 signs, severe diarrhea, severe dizziness, passing out, urinary retention, change in amount of urine passed, severe fatigue, severe nausea, severe vomiting or severe abdominal pain (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.