lomitapide 40 MG Oral Capsule [Juxtapid]

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 ).

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 8 Weeks 9 to 12 Weeks 13 to 16 Weeks 17 and beyond Not recommended 16 to l7 years Not recommended Weeks 0 to 4 Weeks 5 to 8 Weeks 9 to 12 Weeks 13 and beyond Not recommended 18 years and older Not recommended Weeks 0 to 2 Weeks 3 to 6 Weeks 7 to 10 Weeks 11 to 14 Week 15 and beyond Maximum Recommended Dosage The maximum recommended dosage is: 20 mg for patients aged 2 to 10 years. 40 mg for patients aged 11 to 17 years. 60 mg for patients aged 18 years and older. Nutritional Supplementation To reduce the risk of developing a fat-soluble nutrient deficiency due to JUXTAPID's mechanism of action in the small intestine [see Warnings and Precautions (5.4) ] , administer JUXTAPID with daily nutritional supplements. See Table 2 for nutritional supplementation recommendations according to age. Table 2: Nutritional Supplementation Recommendations for Adult and Pediatric Patients Aged 2 Years and Older Receiving JUXTAPID Age Group Vitamin E Essential Fatty Acids 2 to 8 years 200 International Units (IU) (134 mg d-alpha-tocopherol or 90 mg dl-alpha-tocopherol) Linoleic acid: 200 mg Alpha-linolenic acid (ALA): 210 mg Eicosapentaenoic acid (EPA): 110 mg Docosahexaenoic acid (DHA): 80 mg 9 years and older 400 IU (268 mg d-alpha-tocopherol or 180 mg dl-alpha-tocopherol) 2.3 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 (5.5) ]. 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 (7.6) ]. 2.4 Dosage Modifications for Cytochrome P450 3A4 Inhibitors Moderate or Strong Cytochrome P450 3A4 Inhibitors JUXTAPID is contraindicated with concomitant use of moderate and strong cytochrome P450 3A4 (CYP3A4) inhibitors [see Contraindications (4) and Drug Interactions (7.1) ]. Weak CYP3A4 Inhibitors (With or Without Oral Contraceptives) J UXTAPID Initiation in Patients Treated with a Stable Dosage of a Weak CYP3A4 Inhibitor: Follow the recommended dosage and titration schedule described in Table 1. Consider target LDL-C level, safety, and tolerability when selecting a maintenance dosage. Refer to the maximum recommended dose of JUXTAPID described in Table 3. Weak CYP3A4 Inhibitor Initiation in Patients Treated with a Stable Dosage of JUXTAPID: Decrease the dosage of JUXTAPID by half. The dosage of JUXTAPID may be further titrated according to target LDL-C level, safety, and tolerability, not to exceed the maximum recommended dose of JUXTAPID described in Table 3. Concomitant Oral contraceptive use Only JUXTAPID Initiation in Patients Treated with a Stable Dosage of an Oral Contraceptive: Follow the recommended dosage and titration schedule described in Table 1. Consider target LDL-C level, safety, and tolerability when selecting a maintenance dosage, not to exceed the maximum recommended dose of JUXTAPID described in Table 3. Oral contraceptive Initiation in Patients Treated with a Stable Dosage of JUXTAPID: Decrease the dose of JUXTAPID by one-third. The dosage of JUXTAPID may be further titrated according to target LDL-C level, safety, and tolerability, not to exceed the maximum recommended dose of JUXTAPID described in Table 3. Table 3: Recommended Maximum JUXTAPID Dosage with Concomitant Weak CYP3A4 inhibitor or an Oral Contraceptive Age group Maximum JUXTAPID Dosage Weak CYP3A4 inhibitor Oral Contraceptive Oral contraceptives are not indicated before menarche. 2 to 10 years 10 mg 15 mg 11 to 17 years 20

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, with or without concomitant increases in transaminases. Hepatic steatosis is a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. The long-term consequences of hepatic steatosis associated with JUXTAPID treatment are unknown. During the HoFH clinical trial conducted in adults, the median absolute increase in hepatic fat was 6% after both 26 weeks and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy (MRS) [see Adverse Reactions (6.1) ]. Clinical data suggest that hepatic fat accumulation is reversible after stopping treatment with JUXTAPID, but whether histological sequelae remain is unknown, especially after long-term use; protocol scheduled liver biopsies were not performed in the adult clinical trial. In a phase 3 trial in pediatric patients, two patients (both aged 5 to 10 years) developed mild hepatic steatosis (as assessed by ultrasound), which resolved without specific medical interventions, other than the protocol specified follow-up ultrasounds and laboratory monitoring. Overall, the median absolute increase in hepatic fat was 4% after 24 weeks and 104 weeks, from 3% at baseline, measured by NMR. As with data from the adult patients, clinical pediatric data suggest that hepatic fat accumulation is reversible after stopping treatment with JUXTAPID, but whether histological sequelae remain is unknown, especially after long term use. Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. Drinking more than one alcoholic drink per day is not recommended for patients taking JUXTAPID. Exercise caution when using JUXTAPID with other medications known to have potential for hepatotoxicity, such as isotretinoin, amiodarone, acetaminophen (>4 g/day for ≥3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant administration of JUXTAPID with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted. JUXTAPID has not been studied concomitantly with other LDL-lowering agents that can also increase hepatic fat. Therefore, the combined use of such agents is not recommended. 5.2 JUXTAPID REMS Program Because of the risk of hepatotoxicity associated with JUXTAPID therapy, JUXTAPID is available through a restricted program under the REMS. Under the JUXTAPID REMS, only certified healthcare providers and pharmacies may prescribe and distribute JUXTAPID. Further information is available at www.JUXTAPIDREMSProgram.com or by telephone at 1-85-JUXTAPID (1-855-898-2743). 5.3 Embryo-Fetal Toxicity 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. 5.4 Reduced Absorption of Fat-Soluble Vitamins and Serum Fatty Acids 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 bu

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 ).

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.