Drug Safety-related Labeling Changes (SrLC)

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JUXTAPID (NDA-203858)

(LOMITAPIDE MESYLATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/25/2026 (SUPPL-27)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

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)].

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5 Warnings and Precautions

5.1 Risk of Hepatotoxicity

Extensive changes; please refer to label for complete information

5.4 Reduced Absorption of Fat-Soluble Vitamins and Serum Fatty Acids

Additions and/or revisions underlined:

Given its mechanism of action in the small intestine, JUXTAPID may reduce the absorption of fat-soluble nutrients. In clinical trials of adult and pediatric patients with HoFH, patients were provided daily dietary supplements of vitamin E, linoleic acid, ALA, EPA, and DHA.

In the adult clinical trial, the median levels of serum vitamin E, ALA, linoleic acid, EPA, DHA, and arachidonic acid (AA) decreased from baseline to Week 26 but remained above the lower limit of the reference range. Adverse clinical consequences of these reductions were not observed with JUXTAPID treatment of up to 78 weeks.

In the pediatric clinical trial, overall, mean serum vitamin E levels decreased from baseline to Week 104 as expected but were still within or above the upper limit of the reference range. Mean values of linoleic acid, ALA, EPA, AA, and DHA all remained within the normal range or above the upper limit of the reference range during the 104-week trial. Eicosatrienoic acid was below lower limit of normal throughout the trial and increased to a mean normal value by Week 104.

Patients treated with JUXTAPID should take daily nutritional supplements that contain the dosages of vitamin E and essential fatty acids recommended in Dosage and Administration (2.2). Patients with chronic bowel or pancreatic diseases that predispose to malabsorption may be at increased risk for deficiencies in these nutrients with use of JUXTAPID.

5.5 Gastrointestinal Adverse Reactions

Additions and/or revisions underlined:

Gastrointestinal adverse reactions were reported by 27 (93%) of 29 patients in the adult clinical trial.

…

Gastrointestinal adverse reactions of severe intensity were reported by 6 (21%) of 29 patients in the adult clinical trial, with the most common being diarrhea (4 patients, 14%); vomiting

(3 patients, 10%); and abdominal pain, distension, and/or discomfort (2 patients, 7%). Gastrointestinal reactions contributed to the reasons for early discontinuation from this trial for 4 (14%) patients.

Gastrointestinal adverse reactions were reported by 31 (72%) of the 43 patients in the pediatric clinical trial. Diarrhea occurred in 22 (51%) patients and was more frequently reported by patients 11 to 17 years of age compared to patients 5 to 10 years of age (57% and 45%, respectively). Abdominal pain occurred in 19 (44%) patients and was reported with similar incidences in patients 5 to 10 years of age and 11 to 17 years of age. Vomiting occurred in 12 (28%) patients and was more frequently reported by patients 5 to 10 years of age compared to patients 11 to 17 years of age (50% and 9% of patients, respectively). Gastrointestinal reactions contributed to the reasons for early discontinuation from the trial for 2 (5%) patients.

There have been post-marketing reports of severe diarrhea in adults treated with JUXTAPID, including patients being hospitalized because of diarrhea-related complications such as volume depletion.

…

To reduce the risk of gastrointestinal adverse reactions, instruct patients or their caregiver(s) to adhere to a low-fat diet supplying <20% of energy from fat or less than 30 grams of fat, whichever is less. Increase the dosage of JUXTAPID gradually. Individualize the maximum daily fat goal based on caloric needs due to age, growth, activity level, and tolerability. Monitor growth and weight loss in pediatric patients who are below the 10th percentile for height, weight, or BMI [see Dosage and Administration (2.1) and (2.2)].

5.6 Concomitant Use of CYP3A4 Inhibitors

Additions and/or revisions underlined:

…

In the JUXTAPID clinical trials, one adult patient with HoFH developed markedly elevated transaminases (ALT 24 times ULN, AST 13 times ULN) within days of initiating the strong CYP3A4 inhibitor clarithromycin. If treatment with moderate or strong CYP3A4 inhibitors is unavoidable, JUXTAPID should be stopped during the course of treatment.

Avoid food or drinks containing grapefruit during JUXTAPID treatment.

Weak CYP3A4 inhibitors can increase the exposure of lomitapide approximately 2-fold; therefore, when …

Careful titration 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 dose is approximately two thirds the maximum recommended dose (Table 3) [see Dosage and Administration (2.4) and Drug Interactions (7.2)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

7 Drug Interactions

7.2 Weak CYP3A4 Inhibitors

Additions and/or revisions underlined:

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)].

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

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.

8.4 Pediatric Use

Newly added information

The safety and effectiveness of JUXTAPID as an adjunct to other LDL-C lowering therapies for the treatment of HoFH have been established in pediatric patients aged 2 years and older. Use of JUXTAPID for this indication is supported by evidence from an open-label trial in adults; an open-label trial of 43 pediatric patients with HoFH aged 5 to 17 years old; and additional pharmacokinetic modeling and simulation data for pediatric patients aged 2 years and older.

Adverse reactions reported in pediatric patients aged 5 to 17 years were similar to those reported in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

The safety and effectiveness of JUXTAPID have not been established in pediatric patients younger than 2 years old.

8.6 Renal Impairment

Additions and/or revisions underlined:

Patients with end-stage renal disease (eGFR <15 mL/min/1.73m2) receiving hemodialysis, lomitapide exposure increased approximately 50% compared with healthy volunteers [see Clinical Pharmacology (12.3)]. The maximum recommended dosage of JUXTAPID in patients with end-stage renal disease receiving hemodialysis is lower than in those with normal renal function [see Dosage and Administration (2.6)].

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8.7 Hepatic Impairment

JUXTAPID is contraindicated in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment since the lomitapide exposure increased 164% compared with healthy volunteers [see Contraindications (4) and Clinical Pharmacology (12.3)]. In adult patients with mild hepatic impairment (Child-Pugh A), lomitapide exposure increased approximately 50% compared with healthy volunteers [see Clinical Pharmacology (12.3)]. The maximum recommended dosage of JUXTAPID in patients with mild hepatic impairment is lower than in those with normal hepatic function [see Dosage and Administration (2.7)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

See FDA-approved labeling (Medication Guide)

Patients or their caregiver(s) should be informed that a registry for patients taking JUXTAPID has been established to monitor and evaluate the long-term effects of JUXTAPID. Patients or their caregiver(s) are encouraged to participate in the registry and should be informed that their participation is voluntary. For information regarding the registry program visit www.JUXTAPID.com or call 1-877-902-4099.

Advise patients of the following:

Risk of Hepatotoxicity [see Warnings and Precautions (5.1)]

• JUXTAPID can cause both elevations in transaminases and hepatic steatosis. Discuss with patients or their caregiver(s) about the importance of monitoring of liver-related tests before taking JUXTAPID, prior to each dose escalation, and periodically thereafter.

• Advise patients of the potential for increased risk of liver injury if alcohol is consumed while taking JUXTAPID. It is recommended that patients taking JUXTAPID limit consumption to not more than one alcoholic drink per day.

• JUXTAPID is commonly associated with nausea, vomiting, and abdominal pain. Advise patients or their caregiver(s) to promptly report these symptoms if they increase in severity, persist, or change in the character, as they might reflect liver injury. Patients or their caregiver(s) should also report any other symptoms of possible liver injury, including fever, jaundice, lethargy, or flu-like symptoms.

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JUXTAPID. Dietary Supplements [see Warnings and Precautions (5.4)]

• Inform patients or their caregiver(s) that JUXTAPID may reduce the absorption of fat-soluble nutrients. Instruct patients or their caregiver(s) to take daily nutritional supplements that contain the dosages of vitamin E and essential fatty acids recommended in the Dosage and Administration Section (2.2).

Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.5)]

• Inform patients or their caregiver(s) that gastrointestinal adverse reactions are common with JUXTAPID. These include, but are not limited to, diarrhea, nausea/vomiting, abdominal pain/discomfort, flatulence, and constipation. Advise patients or their caregiver(s) to adhere to low-fat diet supplying <20% of energy from fat or less than 30 grams of fat, whichever is less, to reduce the risk of gastrointestinal adverse reactions.

• Instruct patients or their caregiver(s) to stop JUXTAPID and contact their healthcare provider if severe diarrhea occurs or if they experience symptoms of volume depletion such as lightheadedness, decreased urine output, or tiredness.

• Inform patients or their caregiver(s) that taking JUXTAPID with food may adversely impact gastrointestinal tolerability; therefore, they should take JUXTAPID at least 2 hours after the evening meal, swallowing each capsule whole, with water. Inform patients or their caregiver(s) that if the patient is unable to swallow the intact capsule(s), the capsule(s) can be opened and the contents sprinkled on 1 tablespoon of apple sauce or mashed banana, which are fat free. For younger patients who require a smaller spoon for administration, inform the patient or their caregiver(s) to sprinkle the capsule content onto 1 tablespoon of apple sauce or mashed banana and administer the entire amount using the smaller spoon.

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Drug Interactions [see Warnings and Precautions (5.6, 5.7) and Drug Interactions (7)]

• Instruct patients or their caregiver(s) to avoid food or drinks containing grapefruit during JUXTAPID treatment.

• Because multiple drug-drug interactions have been described with JUXTAPID, advise patients or their caregiver(s) to tell their healthcare provider(s) about all medications, nutritional supplements, and vitamins that they are taking or may be taking while taking JUXTAPID.

• Advise patients taking simvastatin or lovastatin that JUXTAPID may cause myopathy. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever.

Missed Doses

• If a dose of JUXTAPID is missed, the normal dose should be taken at the usual time the next day. If dosing is interrupted for more than a week, tell patients or their caregiver(s) to contact their healthcare provider before restarting treatment.

MEDICATION GUIDE

Extensive changes; please refer to label for complete information

12/20/2019 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

Embryo-Fetal Toxicity

(New subsection added)

Based on findings from animal studies, JUXTAPID use is contraindicated in pregnancy since it may cause fetal harm [see Contraindications (4), Use in Specific Populations (8.1, 8.3)]. In animal reproduction studies in rats and ferrets, embryonic death and fetal malformations were observed at clinically relevant exposures. Females of reproductive potential should have a negative pregnancy test before starting JUXTAPID. Advise females of reproductive potential to use effective contraception during therapy with JUXTAPID and for two weeks after the final dose. If pregnancy is detected, discontinue JUXTAPID.

8 Use in Specific Populations

Females and Males of Reproductive Potential

(PLLR Conversion, as below)

Pregnancy Testing

Females of reproductive potential should have a negative pregnancy test before starting JUXTAPID.

Contraception

Based on animal studies, JUXTAPID may cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with JUXTAPID and for two weeks after the final dose.

The use of JUXTAPID may result in reduced efficacy of oral contraceptives if vomiting or diarrhea occurs. Advise patients using oral contraceptives and who experience vomiting or diarrhea to use an effective alternative contraceptive method until 7 days after resolution of symptoms [see Drug Interactions (7.2)].

Lactation

(PLLR Conversion, as below)

Risk Summary

There are no data on the presence of lomitapide in human or animal milk, effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions, including hepatotoxicity, advise patients that breastfeeding is not recommended during treatment with JUXTAPID.

Pregnancy

(PLLR Conversion, as below)

(Additions and/or revisions underlined)

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient counseling information

(Additions and/or revisions underlined)

·       JUXTAPID is contraindicated in pregnancy since it may cause fetal harm. Advise females who become pregnant to discontinue JUXTAPID and inform their healthcare provider of a known or suspected pregnancy.

·       Advise females of reproductive potential to use effective contraception during treatment with JUXTAPID and for two weeks after the final dose. 

·       Advise patients who are taking oral contraceptives and experience vomiting or diarrhea while taking JUXTAPID to use an effective alternative contraceptive method until 7 days after resolution of symptoms .

Lactation [see Use in Specific Populations (8.2)]

• Advise females not to breastfeed during treatment with JUXTAPID.

07/28/2017 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(new subsection added)

The following adverse reactions have been identified during post-approval use of JUXTAPID. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to JUXTAPID exposure.

Musculoskeletal disorders: Myalgia

Skin reactions: Alopecia

05/23/2016 (SUPPL-15)

Approved Drug Label (PDF)

Boxed Warning

(addition to 4th paragraph)

• 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.

5 Warnings and Precautions

Risk of Hepatotoxicity

Monitoring of Transaminases

• Before initiating JUXTAPID and during treatment, monitor transaminases as recommended in Table 3.

Table 3: Recommendations for Monitoring Transaminases

• Before initiating treatment
  • Measure ALT, AST, alkaline phosphatase, and total bilirubin.
  • If abnormal, consider initiating JUXTAPID only after an appropriate work-up and the baseline abnormalities have been explained or resolved.
  • JUXTAPID is contraindicated in patients with moderate or severe hepatic impairment, or active liver disease, including unexplained persistent elevations of serum transaminases.
• During the first year
  • Measure liver-related tests (ALT and AST, at a minimum) prior to each increase in dose or monthly, whichever occurs first.
  • After the first year
  • Measure liver-related tests (ALT and AST, at a minimum) at least every 3 months and before any increase in dose
• At any time during treatment
  • If transaminases are abnormal, reduce or withhold dosing of JUXTAPID and monitor as recommended.
  • Discontinue JUXTAPID for persistent or clinically significant elevations.
  • If transaminase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin =2x ULN, or active liver disease, discontinue treatment with JUXTAPID and identify the probable cause.

6 Adverse Reactions

Gastrointestinal Adverse Reactions (addition as 3rd paragaraph of section)

• There have been postmarketing reports of severe diarrhea with the use of JUXTAPID, including patients being hospitalized because of diarrhea-related complications such as volume depletion. Monitor patients who are more susceptible to complications from diarrhea, such as older patients and patients taking drugs that can lead to volume depletion or hypotension. Instruct patients to stop JUXTAPID and contact their healthcare provider if severe diarrhea occurs or if they experience symptoms of volume depletion such as lightheadedness, decreased urine output, or tiredness. In such cases, consider reducing the dose or suspending use of JUXTAPID.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MG - Now available; please refer to label.

 

PCI - Gastrointestinal Adverse Reactions (bullet addition to this section)

• Instruct the patient to stop JUXTAPID and contact their healthcare provider if severe diarrhea occurs or if they experience symptoms of volume depletion such as lightheadedness, decreased urine output, or tiredness.