` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
`
`
`
` JUXTAPID safely and effectively. See full prescribing information for
` JUXTAPID.
`
`
`JUXTAPID® (lomitapide) capsules, for oral use
`
`
`
`Initial U.S. Approval: 2012
`
`
`
`
`•
`
`
`•
`
`
`
`
`
`WARNING: RISK OF HEPATOTOXICITY
`
`
`
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`JUXTAPID can cause elevations in transaminases (5.1).
`
`
`• Measure alanine and aspartate aminotransferases (ALT, AST),
`
`
`
`alkaline phosphatase, and total bilirubin before initiating treatment
`and then ALT and AST regularly as recommended (2.4, 5.1).
`
`
`
`
`
`
`
`During treatment, adjust the dose of JUXTAPID if the ALT or AST
`is ≥3 times the upper limit of normal (ULN) (2.4, 5.1).
`
`
`
`
`
`
`
`
`
`
`
`Discontinue JUXTAPID for clinically significant liver toxicity (2.4,
`5.1).
`
`JUXTAPID increases hepatic fat (hepatic steatosis) with or without
`
`
`
`concomitant increases in transaminases (5.1).
`
`
`• Hepatic steatosis associated with JUXTAPID may be a risk factor
`
`
`
`
`
`for progressive liver disease, including steatohepatitis and cirrhosis
`
`(5.1).
`
`Because of the risk of hepatotoxicity, JUXTAPID is available only
`
`
`
`through a restricted program called the JUXTAPID REMS Program
`
`
`
`(5.2).
`
`
`
`
` ---------------------------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 (1).
`
`
`
`• The effect of JUXTAPID on cardiovascular morbidity and mortality has not
`
`
`
`
`
` been determined (1).
`
`
`
`
`
`
`
` -----------------------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
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: RISK OF HEPATOTOXICITY
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Homozygous Familial Hypercholesterolemia
`
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Initiation and Maintenance of Therapy
`
`
`
`2.2 Administration
`
`
`2.3 Dosing with Cytochrome P450 3A4 Inhibitors
`
`
`2.4 Dose Modification Based on Elevated Transaminases
`
`
`2.5 Dosing in Patients with Renal Impairment
`
`
`
`2.6 Dosing in Patients with Baseline Hepatic Impairment
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Hepatotoxicity
`
`
`
`3
`
`4
`
`5
`
`
`Reference ID: 3738536
`
`
`
`
` ---------------------DOSAGE FORMS AND STRENGTHS---------------------
` Capsules: 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg (3).
`
`
`
`
`
` ------------------------------ CONTRAINDICATIONS -----------------------------
`
`
`
` • 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).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` -----------------------WARNINGS AND PRECAUTIONS ----------------------
` • Embryo-Fetal Toxicity: Females of Reproductive Potential should have a
`
`
`
`
`
` negative pregnancy test before starting JUXTAPID and use contraception
`
`
`
`
` during treatment (5.3).
` • Gastrointestinal adverse reactions occur in 93% of patients and could affect
`
`
`
`
`
`
`
` absorption of concomitant oral medications (5.5).
`
`
`
`
`
`
`
`
`
` ------------------------------ADVERSE REACTIONS -----------------------------
` Most common adverse reactions (incidence ≥28%) are diarrhea, nausea,
`
`
`
`
` vomiting, dyspepsia, and abdominal pain (6.1).
`
`
`
`
`
` To report SUSPECTED ADVERSE REACTIONS, contact Aegerion
`
` Pharmaceuticals at 1-855-303-2347 or FDA at 1-800-FDA-1088 or
`
`
`
`
`
` www.fda.gov/medwatch.
`
` ------------------------------DRUG INTERACTIONS------------------------------
`
`
`
`
`
`
`
`
`
` • CYP3A4 inhibitors increase exposure to lomitapide. Strong and moderate
`
`
`
` CYP3A4 inhibitors are contraindicated with JUXTAPID. Patients must
`
`
`
` avoid grapefruit juice. Do not exceed 30 mg daily of JUXTAPID when used
`
`
`
` concomitantly with weak CYP3A4 inhibitors, including atorvastatin and
`
`
`
` oral contraceptives (2.3, 4, 5.6, 7.1, 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).
`
`
`
`
`
`
`
`
`
`
`
`
`
` -----------------------USE IN SPECIFIC POPULATIONS ----------------------
`
`
`
`
`
`
`
`
`•
`
`•
`
` Nursing Mothers: Discontinue drug or nursing (8.3).
`
`
`
`
`
` Pediatric Patients: Safety and effectiveness not established (8.4).
`
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide
`
`
`
`Revised: 4/2015
`
`5.2 JUXTAPID REMS Program
`
`
`
`
`5.3 Embryo-Fetal Toxicity
`
`
`5.4 Reduced Absorption of Fat-Soluble Vitamins and
`
`
`Serum Fatty Acids
`
`
`5.5 Gastrointestinal Adverse Reactions
`
`
`5.6 Concomitant Use of CYP3A4 Inhibitors
`
`
`5.7 Risk of Myopathy with Concomitant use of
`
`
`
`
`
`Simvastatin or Lovastatin
`
`5.8 Risk of Supratherapeutic or Subtherapeutic
`
`
`Anticoagulation with Warfarin
`
`5.9 Risk of Malabsorption with Rare Hereditary
`
`
`
`
`Disorders of Galactose Intolerance
`
`
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`DRUG INTERACTIONS
`
`7.1 Moderate and Strong CYP3A4 Inhibitors
`
`
`
`
`6
`
`
`7
`
`
`
`
`
`
`
` 11
`
` 12
`
`
`
` 13
`
` DESCRIPTION
`
` CLINICAL PHARMACOLOGY
`
`
` 12.1 Mechanism of Action
`
`
` 12.2 Pharmacodynamics
`
`
`
` 12.3 Pharmacokinetics
`
`
` NONCLINICAL TOXICOLOGY
`
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
` CLINICAL STUDIES
`
`
` 14
`
` HOW SUPPLIED / STORAGE AND HANDLING
`
` 16
`
`
` 17
` PATIENT COUNSELING INFORMATION
` *Sections or subsections omitted from the full prescribing information are not
`
`
` listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 7.2 Weak CYP3A4 Inhibitors
`
`
` 7.3 Warfarin
`
`
`
`
` 7.4 Simvastatin and Lovastatin
`
`
` 7.5 P-glycoprotein Substrates
`
`
`
` 7.6 Bile Acid Sequestrants
`
`
` USE IN SPECIFIC POPULATIONS
`
`
`
` 8.1 Pregnancy
`
`
` 8.3 Nursing Mothers
`
`
` 8.4 Pediatric Use
`
`
`
` 8.5 Geriatric Use
`
`
`
` 8.6 Females of Reproductive Potential
`
`
` 8.7 Renal Impairment
`
`
`
` 8.8 Hepatic Impairment
`
` OVERDOSAGE
`
`
`
`
`
`
`
`
`
`
` 8
`
`
`
` 10
`
`Reference ID: 3738536
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` WARNING: RISK OF HEPATOTOXICITY
`
`
`
`
`
`
` JUXTAPID can cause elevations in transaminases. In the JUXTAPID clinical trial, 10
`
`
`
`
`(34%) of the 29 patients treated with JUXTAPID had at least one elevation in alanine
`
`
`
`aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3x upper limit of normal
`
`
`
`(ULN). There were no concomitant clinically meaningful elevations of total bilirubin,
`
`international normalized ratio (INR), or alkaline phosphatase [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 was 6% after both 26 and 78
`
`weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy.
`
`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)].
`
`
`Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment
`
`
`
`
`
`and then ALT and AST regularly as recommended. During treatment, adjust the dose of
`JUXTAPID if the ALT or AST are ≥3x ULN. Discontinue JUXTAPID for clinically
`
`
`
`
`
`significant liver toxicity [see Dosage and Administration (2.4) and Warnings and Precautions
`
`
`
`
`(5.1)].
`
`Because of the risk of hepatotoxicity, JUXTAPID is available only through a restricted
`
`
`
`
`program under a Risk Evaluation and Mitigation Strategy (REMS) called the JUXTAPID
`
`
`
`REMS Program [see Warnings and Precautions (5.2)].
`
`
`
`
`
`
`Reference ID: 3738536
`
`
`
`
`
`
`
` 1 INDICATIONS AND USAGE
`
`
`
`
` 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.
`
` • The effect of JUXTAPID on cardiovascular morbidity and mortality has not been
`
`
`
` determined.
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
` Initiation and Maintenance of Therapy
`
`
`2.1
`
`
`
` 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 [see Warnings and
`
`
` Precautions (5.3)]; and,
`
`
`
`
`•
`
`
` 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 CYP3A4 inhibitors, renal impairment, or
`
` baseline hepatic impairment [see Dosage and Administration (2.3), (2.5), and (2.6)]. Dose
`
`
` adjustments are also required for patients who develop transaminase values ≥3x the upper limit
`
` of normal (ULN) during treatment with JUXTAPID [see Dosage and Administration (2.4)].
`
`
`
`
`
`
`
`
`
`Reference ID: 3738536
`
`
`
`
`
` Table 1: Recommended Regimen for Titrating Dosage
`
`DURATION OF ADMINISTRATION BEFORE
`
`
` CONSIDERING INCREASE TO NEXT DOSAGE
`
`
`
` At least 2 weeks
`
`
`
` At least 4 weeks
`
`
` At least 4 weeks
`
`
` At least 4 weeks
`
` Maximum recommended dosage
`
` DOSAGE
`
` 5 mg daily
`
`
` 10 mg daily
`
` 20 mg daily
`
` 40 mg daily
`
` 60 mg daily
`
`
`
` 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, oral contraceptives, pazopanib, ranitidine, ranolazine, ticagrelor,
`
` zileuton) [see Drug Interactions (7.2)].
`
`
`
`
`Reference ID: 3738536
`
`
`
`
`
`
`
` 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
`
`≥3x and <5x ULN
`
`
`
`
`
`≥5x ULN
`
` TREATMENT AND MONITORING RECOMMENDATIONS*
`
`• Confirm elevation with a repeat measurement within one week.
`
`
`
`
`
`If confirmed, reduce the dose and obtain additional liver-related tests if not
`
`
`
`
`•
`already measured (such as alkaline phosphatase, total bilirubin, and INR).
`
`
`• Repeat tests weekly and withhold dosing if there are signs of abnormal liver
`
`
`
`
`function (increase in bilirubin or INR), if transaminase levels rise above 5x ULN,
`
`
`or if transaminase levels do not fall below 3x ULN within approximately 4 weeks.
`
`
`
`In these cases of persistent or worsening abnormalities, also investigate to identify
`
`
`the probable cause.
`
`If resuming JUXTAPID after transaminases resolve to <3x ULN, consider
`
`
`
`reducing the dose and monitor liver-related tests more frequently.
`
`
`
`
`
`
`
`
`• Withhold dosing, obtain additional liver-related tests if not already measured
`
`
`
`(such as alkaline phosphatase, total bilirubin, and INR), and investigate to identify
`
`the probable cause.
`
`
`If resuming JUXTAPID after transaminases resolve to <3x ULN, reduce the dose
`
`
`
`
`and monitor liver-related tests more frequently.
`
`
`*Recommendations based on an ULN of approximately 30-40 international units/L.
`
`
`•
`
`
`•
`
`
` 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 investigate to
` identify the probable cause [see Warnings and Precautions (5.1)].
`
`
`
`
`
` 2.5 Dosing in Patients with Renal Impairment
`
` Patients with end-stage renal disease receiving dialysis should not exceed 40 mg daily. There are
`
`
`
` no data available to guide dosing in other patients with renal impairment [see Use in Specific
`
`
` Populations (8.7)].
`
`
`
`
`
` 2.6 Dosing in Patients with Baseline Hepatic Impairment
`
` Patients with mild hepatic impairment (Child-Pugh A) should not exceed 40 mg daily [see Use
`
` in Specific Populations (8.8)].
`
`
`
`
`
`Reference ID: 3738536
`
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
` 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”
`
`
` 40 mg: Yellow/white hard gelatin capsule printed with black ink “A733” and “40 mg”
`
`
` 60 mg: Yellow/yellow hard gelatin capsule printed with black ink “A733” and “60 mg”
`
`
`
`
`
`
`
`
`
` 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 (8.8)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`
` 5.1 Risk of Hepatotoxicity
`
` JUXTAPID can cause elevations in transaminases and hepatic steatosis, as described below [see
`
` Warnings and Precautions (5.2)]. To what extent JUXTAPID-associated hepatic steatosis
`
`
` promotes the elevations in transaminases is unknown. Although cases of hepatic dysfunction
`
` (elevated transaminases with increase in bilirubin or INR) or hepatic failure have not been
`
`
`
`
` reported, there is concern that JUXTAPID could induce steatohepatitis, which can progress to
`
`
` cirrhosis over several years. The clinical studies supporting the safety and efficacy of
`
`
` JUXTAPID in 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 (alanine aminotransferase [ALT] and/or aspartate aminotransferase
`
`
`
` [AST]) are associated with JUXTAPID. In the clinical trial, 10 (34%) of the 29 patients with
` HoFH had at least one elevation in ALT or AST ≥3x ULN, and 4 (14%) of the patients had at
`
`
`
`
` least one elevation in ALT or AST ≥5x ULN. There were no concomitant or subsequent
`
`
`
`Reference ID: 3738536
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`
`
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` clinically meaningful elevations in bilirubin, INR, or alkaline phosphatase [see Adverse
`
` Reactions (6.1)].
`
`
`
` During the 78-week HoFH clinical trial, no patients discontinued prematurely because of
` elevated transaminases. Among the 19 patients who subsequently enrolled in the HoFH
`
`
`
` extension study, one discontinued because of increased transaminases that persisted despite
`
`
`
` several dose reductions, and one temporarily discontinued because of markedly elevated
`
`
` transaminases (ALT 24x ULN, AST 13x ULN) that had several possible causes, including a
`
`
` drug-drug interaction between JUXTAPID and the strong CYP3A4 inhibitor clarithromycin [see
`
`
`
` Drug Interactions (7.1)].
`
`
`
`
`
`
`
`
`
`
` Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiation of treatment with
` JUXTAPID [see Dosage and Administration (2.1)]. JUXTAPID is contraindicated in patients
`
`
`
` with moderate or severe hepatic impairment, or active liver disease, including unexplained
`
`
`
` persistent elevations of serum transaminases. If the baseline liver-related tests are abnormal, one
`
`
`
`
` may consider initiating JUXTAPID after an appropriate work-up and the baseline abnormalities
`
`
`
` are explained or resolved. 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,
`
`
`
`
` do these tests at least every 3 months and before any increase in dose. Modify the dose of
`
`
`
`
` JUXTAPID if elevations of transaminases are observed and discontinue JUXTAPID for
`
`
`
`
` persistent or clinically significant elevations [see Dosage and Administration (2.4)].
`
`
`
`
`
`
`
` 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.
` 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, 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 liver biopsies were not
`
`
`
` performed in the HoFH clinical trial.
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`
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`Reference ID: 3738536
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`Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. It is
`
`
`recommended that patients taking JUXTAPID should not consume more than one alcoholic
`
`
`
`
`
`drink per day.
`
`
`Caution should be exercised when JUXTAPID is used 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
`
`
`
`JUXTAPID may cause fetal harm when administered to a pregnant woman based on findings of
`
`
`teratogenicity in rats and ferrets [see Use in Specific Populations (8.1)]. Females of reproductive
`
`
`
`potential should have a negative pregnancy test before starting JUXTAPID and should use
`
`
`
`effective contraception during therapy with JUXTAPID [see Use in Specific Populations (8.6)].
`
`
`If oral contraceptives are used, the maximum recommended dosage of JUXTAPID is 30 mg
`
`
`
`
`daily [see Dosage and Administration (2.3) and Drug Interactions (7.2)].
`
`
`
`
`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 the HoFH clinical trial, patients were provided daily dietary supplements
`
`
`
`of vitamin E, linoleic acid, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and
`
`docosahexaenoic acid (DHA). In this trial, the median levels of serum vitamin E, ALA, linoleic
`
`
`acid, EPA, DHA, and arachidonic acid 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. Patients treated with JUXTAPID
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`
`
`Reference ID: 3738536
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`
`
`
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`should take daily supplements that contain 400 international units vitamin E and at least 200 mg
`linoleic acid, 210 mg ALA, 110 mg EPA, and 80 mg DHA [see Dosage and Administration
`
`
`
`
`(2.1)]. 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
`
`
`
`Gastrointestinal adverse reactions were reported by 27 (93%) of 29 patients in the HoFH clinical
`trial. Diarrhea occurred in 79% of patients, nausea in 65%, dyspepsia in 38%, and vomiting in
`
`
`
`34%. Other reactions reported by at least 20% of patients include abdominal pain, abdominal
`
`
`discomfort, abdominal distension, constipation, and flatulence [see Adverse Reactions (6)].
`
`
`
`
`Gastrointestinal adverse reactions of severe intensity were reported by 6 (21%) of 29 patients in
`
`
`
`
`
`the HoFH 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 the trial for 4
`
`(14%) patients.
`
`
`
`Absorption of concomitant oral medications may be affected in patients who develop diarrhea or
`
`vomiting.
`
`
`
`
`To reduce the risk of gastrointestinal adverse events, patients should adhere to a low-fat diet
`
`
`
`
`
`
`supplying <20% of energy from fat and the dosage of JUXTAPID should be increased gradually
`
`[see Dosage and Administration (2.1) and (2.2)].
`
`
`
`5.6 Concomitant Use of CYP3A4 Inhibitors
`
`
`
`
`CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing
`
`exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with
`
`JUXTAPID is contraindicated [see Drug Interactions (7.1)]. In the JUXTAPID clinical trials,
`
`
`
`
`
`
`
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`one patient with HoFH developed markedly elevated transaminases (ALT 24x ULN, AST 13x
`
`
`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.
`
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`
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`Grapefruit juice must be omitted from the diet while being treated with JUXTAPID.
`
`
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`Weak CYP3A4 inhibitors increase the exposure of lomitapide approximately 2-fold; therefore,
`
`
`
`JUXTAPID dosage should not exceed 30 mg daily when it is used concomitantly with these
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`Reference ID: 3738536
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`inhibitors, including atorvastatin and oral contraceptives [see Dosage and Administration (2.3)
`
`
`
`and Drug Interactions (7.2)].
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`
`
`5.7 Risk of Myopathy with Concomitant Use of Simvastatin or Lovastatin
`
`
`
`
`
`
`The risk of myopathy, including rhabdomyolysis, with simvastatin and lovastatin monotherapy is
`
`dose related. Lomitapide approximately doubles the exposure to simvastatin; therefore, it is
`
`
`recommended to reduce the dose of simvastatin 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 additional 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.
`
`
`5.8 Risk of Supratherapeutic or Subtherapeutic Anticoagulation with Warfarin
`
`
`
`
`
`JUXTAPID increases the plasma concentrations of warfarin. Increases in the dose of JUXTAPID
`
`
`
`may lead to supratherapeutic anticoagulation, and decreases in the dose of JUXTAPID may lead
`
`
`
`to subtherapeutic anticoagulation. Difficulty controlling INR contributed to early discontinuation
`
`
`from the HoFH clinical trial for one of five patients taking concomitant warfarin. Patients taking
`
`
`
`
`warfarin should undergo regular monitoring of the INR, especially after any changes in
`
`
`
`JUXTAPID dosage. The dose of warfarin should be adjusted as clinically indicated [see Drug
`
`
`
`
`Interactions (7.3)].
`
`
`5.9 Risk of Malabsorption with Rare Hereditary Disorders of Galactose Intolerance
`
`
`
`
`
`Patients with rare, hereditary problems of galactose intolerance, the Lapp lactase deficiency, or
`
`
`glucose-galactose malabsorption should avoid JUXTAPID as this may result in diarrhea and
`
`malabsorption.
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`Reference ID: 3738536
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`
`
`
`
`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)]
`
`
`
`
`
`
`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 3.
`
`
`Reference ID: 3738536
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`
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`
`
`
`
`
`
`
`
` Table 3: Adverse Reactions Reported in ≥10% of Patients in the Clinical Trial in HoFH
`
`
`
`
` ADVERSE REACTION
`
`Gastrointestinal Disorders
`
`Diarrhea
`
`
`
`
`Nausea
`
`
`Dyspepsia
`
`
`Vomiting
`
`
`
`Abdominal pain
`
`
`
`Abdominal discomfort
`
`
`
`Abdominal distension
`
`
`Constipation
`
`
`Flatulence
`
`
`
`Gastroesophageal reflux disease
`
`
`
`Defecation urgency
`
`
`
`Rectal tenesmus
` Infections
`
`
` Influenza
`
`
`
`Nasopharyngitis
`
`
`Gastroenteritis
`
` Investigations
` Decreased weight
`
`
`
`Increased ALT
`General Disorders
`
`
`
`
`Chest pain
`
`
`Fatigue
`
`
`Fever
`
`Musculoskeletal Disorders
`
`
`
`Back pain
`Nervous System Disorders
`
`
`
`Headache
`
`
`Dizziness
`Respiratory Disorders
`
`
`
`
`Pharyngolaryngeal pain
`
`
`
`Nasal congestion
`Cardiac Disorders
`