Juxtapid

1 INDICATIONS AND USAGE JUXTAPID is indicated as an adjunct to a low-fat diet and exercise and other low density lipoprotein cholesterol (LDL-C) therapies to reduce LDL-C in adults and pediatric patients aged 2 years and older with homozygous familial hypercholesterolemia (HoFH). JUXTAPID is a microsomal triglyceride transfer protein inhibitor indicated as an adjunct to a low-fat diet and exercise and other low-density lipoprotein cholesterol (LDL-C) therapies, to reduce LDL-C in adult and pediatric patients aged 2 years and older with HoFH. ( 1 ).

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 …

5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. Discontinue JUXTAPID if pregnancy detected ( 5.3 ). Gastrointestinal adverse reactions occur in 93% of adult and 72% of pediatric patients and could affect absorption of concomitant oral medications ( 5.5 ). 5.1 Risk of Hepatotoxicity JUXTAPID can cause elevations in transaminases and hepatic steatosis in adults and pediatric patients, as described below [see Warnings and Precautions (5.2) ] . JUXTAPID may induce steatohepatitis, which can progress to cirrhosis over several years. Clinical trials of JUXTAPID for HoFH would have been unlikely to detect this adverse outcome given their size and duration [see Clinical Studies (14) ] . Elevation of Transaminases Elevations in transaminases (ALT and/or AST) are associated with JUXTAPID. In the 78-week adult clinical trial, 10 (34%) of the 29 patients with HoFH had at least one elevation in ALT or AST ≥3 times ULN, and 4 (14%) of the patients had at least one elevation in ALT or AST ≥5 times ULN. There were no concomitant or subsequent clinically meaningful elevations in bilirubin, INR, or alkaline phosphatase [see Adverse Reactions (6.1) ]. No patients discontinued prematurely because of elevated transaminases. Among the 19 patients who subsequently enrolled in the adult HoFH extension trial, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24 times ULN, AST 13 times ULN) that had several possible causes, including a drug-drug interaction between JUXTAPID and the strong CYP3A4 inhibitor clarithromycin [see Drug Interactions (7.1) ]. In the 104-week open-label trial in pediatric patients aged 5 to 17 years with HoFH exposed to JUXTAPID, 6 (14%) of the 43 patients with HoFH had at least one elevation in ALT and/or AST ≥3 times ULN, including 2 (5%) patients who had at least one elevation in ALT ≥5 times ULN. No patients discontinued treatment because of increased transaminases, although some patients required dose interruptions or reductions for management of liver transaminase elevations. Monitoring of Transaminases Before initiating JUXTAPID and during treatment, monitor transaminases as recommended in Table 7. Table 7: Recommendations for Monitoring Transaminases TIME RECOMMENDATIONS 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 [see Contraindications (4) ] . 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 >1 and <3 times ULN, no dose modification is required. Continue routine monitoring of liver-related tests (once monthly during the first year of treatment and every 3 months thereafter). If transaminases are ≥3 times ULN, reduce or withhold dosing of JUXTAPID and monitor as recommended [see Dosage and Administration (2.5) ]. 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 ≥2 times ULN, or active liver disease, discontinue treatment with JUXTAPID and identify the probable cause. Hepatic Steatosis JUXTAPID increases hepatic fat,…

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 ).

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 …

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.

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 […