Juxtapid

Boxed Warning 02/2026 Indications and Usage ( 1 ) 02/2026 Dosage and Administration ( 2 ) 02/2026 Warnings and Precautions ( 5.1 , 5.4 , 5.5 ) 02/2026

1 INDICATIONS AND USAGE JUXTAPID is a microsomal triglyceride transfer protein inhibitor indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH) ( 1 ). Limitations of Use The safety and effectiveness of JUXTAPID have not been established in patients with hypercholesterolemia who do not have HoFH, including those with heterozygous familial hypercholesterolemia (HeFH) ( 1 ). The effect of JUXTAPID on cardiovascular morbidity and mortality has not been determined ( 1 ). 1.1 Homozygous Familial Hypercholesterolemia JUXTAPID is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). Limitations of Use The safety and effectiveness of JUXTAPID have not been established in patients with hypercholesterolemia who do not have HoFH, including those with heterozygous familial hypercholesterolemia (HeFH). The effect of JUXTAPID on cardiovascular morbidity and mortality has not been determined.

2 DOSAGE AND ADMINISTRATION Before treatment, measure ALT, AST, alkaline phosphatase, and total bilirubin; obtain a negative pregnancy test in females of reproductive potential; initiate a low-fat diet supplying <20% of energy from fat or less than 30 grams of fat, whichever is less. ( 2.1 ). The recommended initiation dosage is ( 2.2 ): 2 mg for patients aged 2 to 15 years. 5 mg for patients aged 16 years and older. Follow the titration schedule presented in Table 1 according to the patient's age. Select the dosage based on the recommended target LDL-C, safety, and tolerability ( 2.2 ). For pediatric patients, if a patient crosses over into the next age category, escalate the dose of JUXTAPID up to the maximum recommended dose applicable for the new age group ( 2.2 ). Measure transaminases prior to any dosage increase. If transaminases are abnormal, reduce or withhold dosing of JUXTAPID and monitor as recommended ( 5.1 ). Table 1: Recommended JUXTAPID Dosage and Titration Schedule Age group (years) JUXTAPID Dose 2 mg 5 mg 10 mg 20 mg 40 mg 60 mg W:Weeks; ---: Not a recommended dosage; 1 Maximum recommended dosage. 2 to 10 W 0 to 8 W 9 to 12 W 13 to 16 W 17 and beyond 1 --- --- 11 to 15 W 0 to 4 W 5 to 8 W 9 to 12 W 13 to 16 17 and beyond 1 --- 16 to 17 --- W 0 to 4 W 5 to 8 W 9 to 12 13 and beyond 1 --- 18 and older --- W 0 to 2 W 3 to 6 W 7 to 10 W 11 to 14 15 and beyond 1 Due to reduced absorption of fat-soluble vitamins/fatty acids: Take daily vitamin E [400 international units (IU) for patients aged 9 years and older, or 200 IU for patients aged 2 to 8 years old] and linoleic acid (200 mg), alpha-linolenic acid (210 mg), eicosapentaenoic acid (110 mg), and docosahexaenoic acid (80 mg) supplements ( 2.2 ). Take orally once daily, whole, with water and without food, at least 2 hours after evening meal. If unable to swallow intact capsule, patients may sprinkle capsule contents onto a tablespoon of apple sauce or mashed banana ( 2.3 ). Refer to the Full PI for dosage modifications based on elevated transaminases ( 2.5 ); in patients with end-stage renal disease on dialysis require dose adjustment ( 2.6 ), and in patients with baseline mild hepatic impairment require dose adjustment ( 2.7 ). 2.1 Prior to Initiation Before beginning treatment with JUXTAPID: Liver function tests: Measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin [see Warnings and Precautions (5.1) ] ; Pregnancy testing: Obtain a negative pregnancy test in females of reproductive potential prior to initiating treatment with JUXTAPID [see Contraindications (4) , Warnings and Precautions (5.3) , 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 (5.5) ]. 2.2 Recommended Dosage Initiation Dosage The recommended initiation dosage is 2 mg for patients aged 2 to 15 years. 5 mg for patients aged 16 years and older. Dosage Titration Follow the titration schedule presented in Table 1 according to the patient's age. Select the dosage based on target LDL-C level recommended in current HoFH treatment guidance, safety, and tolerability. For pediatric patients, if a patient crosses over into the next age group, escalate the dosage of JUXTAPID to dosage recommended for the new age group. Measure transaminases prior to any dosage increase. If transaminases are abnormal, reduce or withhold dosing of JUXTAPID and monitor as recommended [see Warnings and Precautions (5.1) ] . Table 1: Recommended JUXTAPID Dosage and Titration Schedule Age Group JUXTAPID Dosage and Titration Schedule 2 mg 5 mg 10 mg 20 mg 40 mg 60 mg 2 to 10 years Weeks 0 to 8 Weeks 9 to 12 Weeks 13 to 16 Weeks 17 and beyond Maximum recommended dosage. Select the dosage based on target LDL-C level recommended in current HoFH treatment guidance, safety and tolerability. Not recommended Not recommended 11 to 15 years Weeks 0 to 4 Weeks 5 to …

3 DOSAGE FORMS AND STRENGTHS Capsules: 2 mg: Grey/grey hard gelatin capsule printed with black ink "A733" and "2 mg" 5 mg: Orange/orange hard gelatin capsule printed with black ink "A733" and "5 mg" 10 mg: Orange/white hard gelatin capsule printed with black ink "A733" and "10 mg" 20 mg: White/white hard gelatin capsule printed with black ink "A733" and "20 mg" 30 mg: Orange/yellow hard gelatin capsule printed with black ink "A733" and "30 mg" Capsules: 2 mg, 5 mg, 10 mg, 20 mg, and 30 mg ( 3 ).

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 ).

6 ADVERSE REACTIONS The following important adverse reactions have been observed and are discussed in detail in other sections of the label: Risk of hepatotoxicity [see Warnings and Precautions (5.1) ] Reduced absorption of fat-soluble vitamins, and serum fatty acids [see Warnings and Precautions (5.4) ] Gastrointestinal adverse reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions in adult patients (incidence ≥10%) are diarrhea, nausea, dyspepsia, vomiting, and abdominal pain (6.1). Most common adverse reactions in pediatric patients aged 5 to 17 years old (incidence ≥15%) are abdominal pain, alanine aminotransferase increased, aspartate aminotransferase increased, diarrhea, and vomiting ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Chiesi Farmaceutici S.p.A. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults with HoFH One single-arm, open-label, 78-week trial has been conducted in 29 adult patients with HoFH, 23 of whom completed at least one year of treatment. The initial dosage of JUXTAPID was 5 mg daily, with titration up to 60 mg daily during an 18-week period based on safety and tolerability. In this trial, the mean age was 31 years (range, 18 to 55 years), 16 (55%) patients were male, 25 (86%) patients were White, 2 (7%) were Asian, 1 (3%) was Black or African American, and 1 (3%) was multi-racial [see Clinical Studies (14) ] . Five (17%) of the 29 patients discontinued treatment due to an adverse reaction. The adverse reactions that contributed to treatment discontinuations included diarrhea (2 patients; 7%) and abdominal pain, nausea, gastroenteritis, weight loss, headache, and difficulty controlling INR on warfarin (1 patient each; 3%). The most common adverse reactions were gastrointestinal, reported by 27 (93%) of 29 patients. Adverse reactions reported by ≥8 (28%) patients in the clinical trial included diarrhea, nausea, vomiting, dyspepsia, and abdominal pain. Other common adverse reactions, reported by 5 to 7 (17 to 24%) patients, included weight loss, abdominal discomfort, abdominal distension, constipation, flatulence, increased ALT, chest pain, influenza, nasopharyngitis, and fatigue. The adverse reactions reported in at least 10% of adult patients are presented in Table 8. Table 8: Adverse Reactions Reported in ≥10% of Patients in the Adult Clinical Trial ADVERSE REACTION N (%) Diarrhea 23 (79) Nausea 19 (65) Dyspepsia 11 (38) Abdominal pain 10 (34) Vomiting 10 (34) Chest pain 7 (24) Decreased weight 7 (24) Abdominal discomfort 6 (21) Abdominal distension 6 (21) Constipation 6 (21) Flatulence 6 (21) Influenza 6 (21) Fatigue 5 (17) Increased ALT 5 (17) Nasopharyngitis 5 (17) Back pain 4 (14) Gastroenteritis 4 (14) Pharyngolaryngeal pain 4 (14) Angina pectoris 3 (10) Defecation urgency 3 (10) Dizziness 3 (10) Fever 3 (10) Gastroesophageal reflux disease 3 (10) Headache 3 (10) Nasal congestion 3 (10) Palpitations 3 (10) Rectal tenesmus 3 (10) Adverse reactions of severe intensity were reported by 8 (28%) of 29 patients, with the most common being diarrhea (4 patients, 14%), vomiting (3 patients, 10%), increased ALT or hepatotoxicity (3 patients, 10%), and abdominal pain, distension, and/or discomfort (2 patients, 7%). Pediatric Patients with HoFH Aged 5 to 17 years A single-arm, open label, multinational, 104-week trial was conducted in 43 pediatric patients with HoFH aged 5 to 17 years. Thirty-nine of the patients completed the trial. The dose of JUXTAPID was escalated from an age-dependent starting dose to a maximum tolerated dose (MTD) as applicable to the pediatric age group and based on acceptable safety and tolerability criteria, in addition to LDL-C goals [ …

7 DRUG INTERACTIONS CYP3A4 inhibitors increase exposure to lomitapide. Strong and moderate CYP3A4 inhibitors are contraindicated with JUXTAPID. Patients must avoid grapefruit juice ( 4 , 5.6 , 7.1 ). When administered with weak CYP3A4 inhibitors, the dose of JUXTAPID should be decreased by half. The dosage of JUXTAPID may then be up-titrated to a maximum recommended dosage of 30 mg daily ( 2.3 , 5.6 , 7.2 ). Warfarin: Lomitapide increases plasma concentrations of warfarin. Monitor international normalized ratio (INR) regularly, especially with JUXTAPID dose adjustment ( 5.8 , 7.3 ). Simvastatin and lovastatin exposure increase with JUXTAPID. Limit dose when co-administered with JUXTAPID due to myopathy risk ( 5.7 , 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 (such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir, voriconazole) with lomitapide is contraindicated. Concomitant use of moderate CYP3A4 inhibitors (such as amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) has not been studied, but concomitant use with lomitapide is contraindicated since lomitapide exposure will likely increase significantly in the presence of these inhibitors. Patients must avoid grapefruit juice while taking JUXTAPID [see Contraindications (4) , Warnings and Precautions (5.6) , and Clinical Pharmacology (12.3) ] . 7.2 Weak CYP3A4 Inhibitors Weak CYP3A4 inhibitors (such as alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, lapatinib, nilotinib, pazopanib, ranitidine, ranolazine, ticagrelor, zileuton) 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 a maximum recommended dosage of 30 mg daily except when coadministered with oral contraceptives, in which case the maximum recommended lomitapide dosage is 40 mg daily [see Dosage and Administration (2.3) , 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 increased the INR 22%. Patients taking warfarin should undergo regular monitoring of INR, particularly after any changes in lomitapide 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 …

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended ( 8.2 ). 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 through organogenesis were not associated with adverse effects at systemic exposures up to 3-times the MRHD of 60 mg based on body surface area comparison. Treatment at doses of ≥20 mg/kg/day, ≥6-times the MRHD, resulted in embryo-fetal lethality. Pregnant female rats given oral gavage doses of 0.1, 0.3, or 1 mg/kg/day lomitapide from gestation day 7 through termination of nursing on lactation day 20 were associated with malformations at systemic exposures equivalent to human exposure at the MRHD of 60 mg based on AUC. Increased pup mortality occurred at 4-times the MRHD. 8.2 Lactation 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. 8.3 Females and Males of Reproductive Potential 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 …

12.1 Mechanism of Action JUXTAPID directly binds and inhibits microsomal triglyceride transfer protein (MTP), which resides in the lumen of the endoplasmic reticulum, thereby preventing the assembly of apo B-containing lipoproteins in enterocytes and hepatocytes. This inhibits the synthesis of chylomicrons and VLDL. The inhibition of the synthesis of VLDL leads to reduced levels of plasma LDL-C.

11 DESCRIPTION JUXTAPID capsules contain lomitapide mesylate, a synthetic lipid-lowering agent for oral administration. The chemical name of lomitapide mesylate is N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4'a-(trifluoromethyl)[1,1'-biphenyl]-2-yl]carbonyl]amino]-1-piperidinyl]butyl]-9 H -fluorene-9-carboxamide, methanesulfonate salt. Its structural formula is: The empirical formula for lomitapide mesylate is C 39 H 37 F 6 N 3 O 2 ∙ CH 4 O 3 S and its molecular weight is 789.8. Lomitapide mesylate is a white to off-white powder that is slightly soluble in aqueous solutions of pH 2 to 5. Lomitapide mesylate is freely soluble in acetone, ethanol, and methanol; soluble in 2-butanol, methylene chloride, and acetonitrile; sparingly soluble in 1-octanol and 2-propanol; slightly soluble in ethyl acetate; and insoluble in heptane. Each JUXTAPID capsule contains lomitapide mesylate equivalent to 2, 5, 10, 20, or 30 mg lomitapide free base and the following inactive ingredients: pregelatinized starch, sodium starch glycolate, microcrystalline cellulose, lactose monohydrate, silicon dioxide and magnesium stearate. The capsule shells of all strengths contain gelatin and titanium dioxide; the 2 mg capsules contain black iron oxide; the 5 mg, 10 mg and 30 mg capsules also contain red iron oxide; and the 30 mg capsules also contain yellow iron oxide. The imprinting ink contains shellac, black iron oxide, and propylene glycol. Chemical Structure

10 OVERDOSAGE There is no specific treatment in the event of overdose of JUXTAPID. In the event of overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Liver-related tests should be monitored. Hemodialysis is unlikely to be beneficial given that lomitapide is highly protein-bound.

16 HOW SUPPLIED / STORAGE AND HANDLING How Supplied JUXTAPID strengths are available as follows: Capsule Strength Description Package Configuration NDC Number 2 mg Grey/grey hard gelatin capsule printed with black ink "A733" and "2 mg" Bottles of 28 capsules 10122-402-28 5 mg Orange/orange hard gelatin capsule printed with black ink "A733" and "5 mg" Bottles of 28 capsules 10122-405-28 10 mg Orange/white hard gelatin capsule printed with black ink "A733" and "10 mg" Bottles of 28 capsules 10122-410-28 20 mg White/white hard gelatin capsule printed with black ink "A733" and "20 mg" Bottles of 28 capsules 10122-420-28 30 mg Orange/yellow hard gelatin capsule printed with black ink "A733" and "30 mg" Bottles of 28 capsules 10122-430-28 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F). Brief exposure to temperatures up to 40°C (104°F) may be tolerated provided the mean kinetic temperature does not exceed 25°C (77°F); however, such exposure should be minimized. Keep container tightly closed and protect from moisture.