Lomitapide

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.

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; and initiate a low-fat diet supplying <20% of energy from fat ( 2.1 ). Initiate treatment at 5 mg once daily. Titrate dose based on acceptable safety/tolerability: increase to 10 mg daily after at least 2 weeks; and then, at a minimum of 4-week intervals, to 20 mg, 40 mg, and up to the maximum recommended dose of 60 mg daily ( 2.1 ). Due to reduced absorption of fat-soluble vitamins/fatty acids: Take daily vitamin E, linoleic acid, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) supplements ( 2.1 , 5.4 ). Take once daily, whole, with water and without food, at least 2 hours after evening meal ( 2.2 ). Patients with end-stage renal disease on dialysis or with baseline mild hepatic impairment should not exceed 40 mg daily ( 2.5 , 2.6 ). 2.1 Initiation and Maintenance of Therapy Before beginning treatment with JUXTAPID: Measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin [see Warnings and Precautions (5.1) ] ; Obtain a negative pregnancy test in females of reproductive potential prior to initiating treatment with JUXTAPID [see Contraindications (4) , Warnings and Precautions (5.3) , Use in Specific Populations (8.1 , 8.3) ] ; Initiate a low-fat diet supplying <20% of energy from fat [see Warnings and Precautions (5.5) ]. The recommended starting dosage of JUXTAPID is 5 mg once daily, and the dose should be escalated gradually based on acceptable safety and tolerability. Transaminases should be measured prior to any increase in dose [see Warnings and Precautions (5.1) ] . The maintenance dosage of JUXTAPID should be individualized, taking into account patient characteristics such as goal of therapy and response to treatment, to a maximum of 60 mg daily as described in Table 1. Modify dosing for patients taking concomitant weak CYP3A4 inhibitors and for those with renal impairment or baseline hepatic impairment [see Dosage and Administration (2.3) , (2.5) , and (2.6) ] . Monitor transaminases during treatment with JUXTAPID as described in Warnings and Precautions (5.1) , and reduce or withhold dosing for patients who develop transaminase values ≥3× the upper limit of normal (ULN) [see Dosage and Administration (2.4) ]. Table 1: Recommended Regimen for Titrating Dosage DOSAGE DURATION OF ADMINISTRATION BEFORE CONSIDERING INCREASE TO NEXT DOSAGE 5 mg daily At least 2 weeks 10 mg daily At least 4 weeks 20 mg daily At least 4 weeks 40 mg daily At least 4 weeks 60 mg daily Maximum recommended dosage To reduce the risk of developing a fat-soluble nutrient deficiency due to JUXTAPID's mechanism of action in the small intestine, patients treated with JUXTAPID should take daily supplements that contain 400 international units vitamin E and at least 200 mg linoleic acid, 210 mg alpha-linolenic acid (ALA), 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA) [see Warnings and Precautions (5.4) ]. 2.2 Administration JUXTAPID should be taken once daily with a glass of water, without food, at least 2 hours after the evening meal because administration with food may increase the risk of gastrointestinal adverse reactions [see Warnings and Precautions (5.5) ]. Patients should swallow JUXTAPID capsules whole. Capsules should not be opened, crushed, dissolved, or chewed. 2.3 Dosing with 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) ]. The recommended maximum dosage of JUXTAPID is 30 mg daily with concomitant use of 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). However, the recommended maximum dosage of JUXTAPID is 40 mg daily with concomitant use of oral contraceptives. When initiating a weak CYP3A4 inhibitor in a patient already taking JUXTAPID 10 mg daily or more, decrease the dose of JUXTAPID by half; patients taking JUXTAPID 5 mg daily may continue with the same dosage. Careful titration of JUXTAPID may then be considered according to 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 Drug Interactions (7.2) ] . 2.4 Dose Modification Based on Elevated Transaminases Table 2 summarizes recommendations for dose adjustment and monitoring for patients who develop elevated transaminases during therapy with JUXTAPID [see Warnings and Precautions (5.1) ]. Table 2: Dose Adjustment and Monitoring for Patients with Elevated Transaminases ALT OR AST T

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 (incidence ≥28%) are diarrhea, nausea, vomiting, dyspepsia, and abdominal pain ( 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. One single-arm, open-label, 78-week trial has been conducted in 29 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 30.7 years (range, 18 to 55 years), 16 (55%) patients were men, 25 (86%) patients were Caucasian, 2 (7%) were Asian, 1 (3%) was African American, and 1 (3%) was multi-racial [see Clinical Studies (14) ] . Five (17%) of the 29 patients with HoFH that participated in the clinical trial 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 HoFH clinical trial included diarrhea, nausea, vomiting, dyspepsia, and abdominal pain. Other common adverse reactions, reported by 5 to 7 (17-24%) 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 patients during the HoFH clinical trial are presented in Table 4. Table 4: Adverse Reactions Reported in ≥10% of Patients in the Clinical Trial in HoFH ADVERSE REACTION N (%) Gastrointestinal Disorders Diarrhea 23 (79) Nausea 19 (65) Dyspepsia 11 (38) Vomiting 10 (34) Abdominal pain 10 (34) Abdominal discomfort 6 (21) Abdominal distension 6 (21) Constipation 6 (21) Flatulence 6 (21) Gastroesophageal reflux disease 3 (10) Defecation urgency 3 (10) Rectal tenesmus 3 (10) Infections Influenza 6 (21) Nasopharyngitis 5 (17) Gastroenteritis 4 (14) Investigations Decreased weight 7 (24) Increased ALT 5 (17) General Disorders Chest pain 7 (24) Fatigue 5 (17) Fever 3 (10) Musculoskeletal Disorders Back pain 4 (14) Nervous System Disorders Headache 3 (10) Dizziness 3 (10) Respiratory Disorders Pharyngolaryngeal pain 4 (14) Nasal congestion 3 (10) Cardiac Disorders Angina pectoris 3 (10) Palpitations 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%). Transaminase Elevations During the HoFH clinical trial, 10 (34%) of 29 patients had at least one elevation in ALT and/or AST ≥3× ULN (see Table 5). No clinically meaningful elevations in total bilirubin or alkaline phosphatase were observed. Transaminases typically fell within one to four weeks of reducing the dose or withholding JUXTAPID. Table 5: Patient Incidence of Transaminase Elevations During the HoFH Clinical Trial N (%) Upper limits of normal (ULN) ranged from 33-41 international units/L for ALT and 36-43 international units/L for AST. Total Patients 29 Maximum ALT ≥3 to <5 × ULN 6 (21%) ≥5 to <10 × ULN 3 (10%) ≥10 to <20 × ULN 1 (3%) ≥20 × ULN 0 Maximum AST ≥3 to <5 × ULN 5 (17%) ≥5 to <10 × ULN 1 (3%) ≥10 to <20 × ULN 0 ≥20 × ULN 0 Among the 19 patients who enrolled in an extension study following the HoFH clinical trial, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24× ULN, AST 13× ULN) that had several possible causes, including a drug-drug interaction between JUXTAPID and the strong CYP3A4 inhibitor clarithromycin [see Drug Interactions (7.1) ]. Hepatic Steatosis Hepatic fat was prospectively measured using magnetic resonance spectroscopy (MRS) in all eligible patients during the HoFH clinical trial. After 26 weeks, the median absolute increase in hepatic fat from baseline was 6%, and the mean absolute

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 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 lomitapide with P-gp substrates (such as aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan) may increase the absorption of P-gp substrates. Dose reduction of the P-gp substrate should be considered when used concomitantly with lomitapide. 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