Lomitapide
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From MedlinePlus, U.S. National Library of Medicine
Boxed warning
WARNING: RISK OF HEPATOTOXICITY JUXTAPID can cause elevations in transaminases. In the adult clinical trial, 10 (34%) of the 29 patients treated with JUXTAPID had at least one elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times the upper limit of normal (ULN). There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR), or alkaline phosphatase. In the pediatric clinical trial (5 to 17 years of age), 6 (14%) of the 43 patients experienced elevations in ALT and/or AST ≥ 3 times ULN.
No concomitant clinically meaningful elevations in total bilirubin or alkaline phosphatase were observed [see Warnings and Precautions (5.1) ]. JUXTAPID also increases hepatic fat, with or without concomitant increases in transaminases. The median absolute increase in hepatic fat in adult patients was 6% after both 26 and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy (MRS). The median absolute increase in hepatic fat in pediatric patients aged 5 to 17 years was 4% after 24 weeks and 104 weeks of treatment, from 3% at baseline, measured by nuclear magnetic resonance (NMR).
Hepatic steatosis associated with JUXTAPID treatment may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis [see Warnings and Precautions (5.1) ]. 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 JUXTAPID if the ALT or AST are ≥3 times ULN. Discontinue JUXTAPID for clinically significant liver toxicity [ see Dosage and Administration (2.7) and Warnings and Precautions (5.1) ].
Because of the risk of hepatotoxicity, JUXTAPID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the JUXTAPID REMS Program [see Warnings and Precautions (5.2) ]. Prescribe JUXTAPID only to patients with a clinical or laboratory diagnosis consistent with HoFH. The safety and effectiveness of JUXTAPID have not been established in patients with hypercholesterolemia who do not have HoFH [see Indications and Usage (1) ] . WARNING: RISK OF HEPATOTOXICITY See full prescribing information for complete boxed warning. JUXTAPID can cause elevations in transaminases ( 5.1 ).
Measure alanine and aspartate aminotransferases (ALT, AST), alkaline phosphatase, and total bilirubin before initiating treatment and then ALT and AST regularly as recommended ( 2.5 , 5.1 ). During treatment, adjust the dose of…
Dosing in kidney impairment
Recommended Dosage in Patients with Renal Impairment The recommended dosage of JUXTAPID in patients with end-stage renal disease (eGFR <15 mL/min/1.73m 2 ) receiving hemodialysis is described in Table 5. JUXTAPID has not been studied in patients with mild, moderate, or severe renal impairment, including those with end stage renal disease not receiving dialysis [see Use in Specific Populations ]. [See table below.]
| Age GROUP | MAXIMUM RECOMMENDED DAILY DOSAGE |
|---|---|
| 2 to 10 years | 15 mg |
| 11 to 17 years | 30 mg |
| 18 years and older | 40 mg |
Dosing in liver impairment
Prior to Initiation Before beginning treatment with JUXTAPID: Liver function tests: Measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin [see Warnings and Precautions ] ; Pregnancy testing: Obtain a negative pregnancy test in females of reproductive potential prior to initiating treatment with JUXTAPID [see Contraindications , Warnings and Precautions , and Use in Specific Populations (8.1 , 8.3) ] ; Dietary counseling: Initiate a low-fat diet supplying <20% of energy from fat or less than 30 grams of fat, whichever is less [see Warnings and Precautions ].
Recommended Dosage in Patients with Baseline Hepatic Impairment JUXTAPID is contraindicated in patients with moderate or severe hepatic impairment (based on Child-Pugh category B or C) and patients with active liver disease, including unexplained persistent elevations of serum transaminases [see Warnings and Precautions ] .
Table 6 summarizes the dosage adjustment for patients with baseline mild hepatic impairment (Child-Pugh A) [see Use in Specific Populations ] . [See table below.]
| AGE GROUP | MAXIMUM RECOMMENDED DAILY DOSAGE |
|---|---|
| 2 to 10 years | 15 mg |
| 11 to 17 years | 30 mg |
| 18 years and older | 40 mg |
Preparation and administration
Administration Take JUXTAPID orally once daily with a glass of water, without food, at least 2 hours after the evening meal. Administration with food may increase the risk of gastrointestinal adverse reactions [see Warnings and Precautions ]. Swallow JUXTAPID capsules whole: If a patient is unable to swallow the intact capsule(s), open the capsule(s) and sprinkle the contents on 1 tablespoon of apple sauce or mashed banana.
For younger patients who require a smaller spoon for administration, sprinkle the capsule contents onto 1 tablespoon of apple sauce or mashed banana, and administer the entire amount using the smaller spoon. Administer JUXTAPID at least 4 hours before or 4 hours after administration of a bile acid sequestrant [see Drug Interactions ].
Drug interactions
Check lomitapide against a medication listLabel text (9 paragraphs)
7 DRUG INTERACTIONS CYP3A4 inhibitors increase exposure to lomitapide. Strong and moderate CYP3A4 inhibitors are contraindicated with JUXTAPID. Patients must avoid grapefruit juice ( 7.1 ). When administered with weak CYP3A4 inhibitors, the dose of JUXTAPID should be decreased by half. Follow the titration recommendations provided in the Full PI ( 7.2 ). Warfarin: Lomitapide increases plasma concentrations of warfarin. Monitor international normalized ratio (INR) regularly, especially with JUXTAPID dose adjustment ( 7.3 ). Simvastatin and lovastatin exposure increase with JUXTAPID. Limit dose when co-administered with JUXTAPID due to myopathy risk ( 7.4 ).
P-glycoprotein (P-gp) Substrates: Consider dose reduction of P-gp substrate because of possible increased absorption with JUXTAPID ( 7.5 ). Bile Acid Sequestrants: Separate JUXTAPID dosing by at least 4 hours ( 7.6 ).
7.1 Moderate and Strong CYP3A4 Inhibitors A strong CYP3A4 inhibitor has been shown to increase lomitapide exposure approximately 27-fold [see Clinical Pharmacology (12.3) ] . Concomitant use of strong CYP3A4 inhibitors with JUXTAPID is contraindicated. Concomitant use of moderate CYP3A4 inhibitors has not been studied, but concomitant use with JUXTAPID is contraindicated since lomitapide exposure will likely increase significantly in the presence of these inhibitors. Avoid food or drinks containing grapefruit during JUXTAPID treatment [see Contraindications (4) , Warnings and Precautions (5.6) , and Clinical Pharmacology (12.3) ] .
7.2 Weak CYP3A4 Inhibitors Weak CYP3A4 inhibitors can increase lomitapide exposure approximately 2-fold [see Clinical Pharmacology (12.3) ] . When administered with weak CYP3A4 inhibitors, the dose of JUXTAPID should be decreased by half. Careful titration of JUXTAPID may then be considered based on LDL-C response and safety/tolerability to half the maximum recommended dosage except when co-administered with oral contraceptives only, in which case the maximum recommended JUXTAPID dosage is approximately two thirds of the maximum recommended dosage (Table 3) [see Dosage and Administration (2.4) , Warnings and Precautions (5.6) , and Clinical Pharmacology (12.3) ] .
7.3 Warfarin Lomitapide increases plasma concentrations of both R(+)-warfarin and S(-)-warfarin by approximately 30% and increases the INR 22%. Patients taking warfarin should undergo regular monitoring of INR, particularly after any changes in JUXTAPID dosage. The dose of warfarin should be adjusted as clinically indicated [see Warnings and Precautions (5.8) ] .
7.4 Simvastatin and Lovastatin The risk of myopathy, including rhabdomyolysis, with simvastatin and lovastatin monotherapy is dose-related. Lomitapide approximately doubles the exposure of simvastatin; therefore, the recommended dose of simvastatin should be reduced by 50% when initiating JUXTAPID [see Clinical Pharmacology (12.3) ] . While taking JUXTAPID, limit simvastatin dosage to 20 mg daily (or 40 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year without evidence of muscle toxicity). Refer to the simvastatin prescribing information for simvastatin dosing recommendations. Interaction between lovastatin and lomitapide has not been studied.
However, the metabolizing enzymes and transporters responsible for the disposition of lovastatin and simvastatin are similar, suggesting that JUXTAPID may increase the exposure of lovastatin; therefore, reducing the dose of lovastatin should be considered when initiating JUXTAPID.
7.5 P-glycoprotein Substrates Lomitapide is an inhibitor of P-glycoprotein (P-gp). Coadministration of JUXTAPID with P-gp substrates may increase the absorption of P-gp substrates. Dose reduction of the P-gp substrate should be considered when used concomitantly with JUXTAPID.
7.6 Bile Acid Sequestrants JUXTAPID has not been tested for interaction with bile acid sequestrants. Administration of JUXTAPID and bile acid sequestrants should be separated by at least 4 hours since bile acid sequestrants can interfere with the absorption of oral medications.
Contraindications
4 CONTRAINDICATIONS JUXTAPID is contraindicated in the following conditions: Pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1) ] . Concomitant administration of JUXTAPID with moderate or strong CYP3A4 inhibitors, as this can increase JUXTAPID exposure [see Warnings and Precautions (5.6) , Drug Interactions (7.1) , and Clinical Pharmacology (12.3) ]. Patients with moderate or severe hepatic impairment (based on Child-Pugh category B or C) and patients with active liver disease, including unexplained persistent elevations of serum transaminases [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7) ] . Pregnancy ( 4 ).
Concomitant use with strong or moderate CYP3A4 inhibitors ( 4 ). Moderate or severe hepatic impairment or active liver disease including unexplained persistent abnormal liver function tests ( 4 ).
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Pregnancy Exposure There is a registry that monitors pregnancy outcomes in women exposed to JUXTAPID during pregnancy. For additional information visit www.JUXTAPID.com or call the Lomitapide Observational Worldwide Exposure Registry (LOWER) at 1-877-902-4099. Healthcare professionals are encouraged to call the LOWER at 1-877-902-4099 to enroll patients who become pregnant during JUXTAPID treatment. Risk Summary Based on findings from animal studies, JUXTAPID use is contraindicated in pregnancy since it may cause fetal harm [see Contraindications (4) , Warnings and Precautions (5.3) ].
Available human data are insufficient to draw conclusions about any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, in animal reproduction studies, lomitapide was teratogenic in rats at clinically relevant exposures and in ferrets at exposures estimated to be less than human therapeutic exposure at 60 mg when administered during organogenesis, based on AUC comparisons. Embryo-fetal lethality was observed in rabbits at 6-times the maximum recommended human dose (MRHD) of 60 mg based on body surface area. If pregnancy is detected, discontinue JUXTAPID.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Oral gavage doses of 0.04, 0.4, or 4 mg/kg/day lomitapide given to pregnant rats from gestation day 6 through organogenesis were associated with fetal malformations at ≥2-times human exposure at the MRHD (60 mg) based on plasma AUC comparisons.
Fetal malformations included umbilical hernia, gastroschisis, imperforate anus, alterations in heart shape and size, limb malrotations, skeletal malformations of the tail, and delayed ossification of cranial, vertebral and pelvic bones. Oral gavage doses of 1.6, 4, 10, or 25 mg/kg/day lomitapide given to pregnant ferrets from gestation day 12 through organogenesis were associated with both maternal toxicity and fetal malformations at exposures that ranged from less than the human exposure at the MRHD to 5-times the human exposure at the MRHD.
Fetal malformations included umbilical hernia, medially rotated or short limbs, absent or fused digits on paws, cleft palate, open eye lids, low-set ears, and kinked tail. Oral gavage doses of 0.1, 1, or 10 mg/kg/day lomitapide given to pregnant rabbits from gestation day 6…
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
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