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). Prescribe JUXTAPID only to patients with a clinical or laboratory
`diagnosis consistent with HoFH. The safety and effectiveness of
`JUXTAPID have not been established in patients with
`hypercholesterolemia who do not have HoFH (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).
`
` ----------------------- 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).
`
`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
`
`3
`
`Reference ID: 4537578
`
`• Patients with end-stage renal disease on dialysis or with baseline mild
`hepatic impairment should not exceed 40 mg daily (2.5, 2.6).
`
`
` --------------------- 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: 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, 8.1, 8.3).
`• 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 (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).
`
` ----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`
`•
`•
`
`Lactation: Breastfeeding not recommended (8.2).
`Pediatric Patients: Safety and effectiveness not established (8.4).
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`
`Revised: 12/2019
`
`4
`5
`
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1 Risk of Hepatotoxicity
`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
`
`

`

`10
`11
`12
`
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`OVERDOSAGE
`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
`PATIENT COUNSELING INFORMATION
`17
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`13
`
`6
`
`7
`
`8
`
`5.9 Risk of Malabsorption with Rare Hereditary
`Disorders of Galactose Intolerance
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing experience
`
`DRUG INTERACTIONS
`7.1 Moderate and Strong CYP3A4 Inhibitors
`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
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`
`
`Reference ID: 4537578
`
`

`

`
`
`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)]. Prescribe
`JUXTAPID only to patients with a clinical or laboratory diagnosis consistent with
`HoFH. The safety and effectiveness of JUXTAPID have not been established in patients
`with hypercholesterolemia who do not have HoFH [see Indications and Usage (1)].
`
`Reference ID: 4537578
`
`

`

`
`
`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, including those with heterozygous familial
`hypercholesterolemia (HeFH).
`
`• 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 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
`
`Reference ID: 4537578
`
`

`

`
`
`and Precautions (5.1), and reduce or withhold dosing for patients who develop transaminase
`values ≥3x the upper limit of normal (ULN) [see Dosage and Administration (2.4)].
`
`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, 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
`
`Reference ID: 4537578
`
`

`

`
`
`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
`≥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 (8.6)].
`
`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 (8.7)].
`
`Reference ID: 4537578
`
`

`

` 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 (8.7)].
`
`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: 4537578
`
`

`

`
`
`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)].
`
`Monitoring of Transaminases
`
`Before initiating JUXTAPID and during treatment, monitor transaminases as recommended in
`Table 3.
`
`Table 3: Recommendations for Monitoring Transaminases
`
`•
`
`RECOMMENDATIONS
`• 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)].
`• Measure liver-related tests (ALT and AST, at a minimum) prior to
`each increase in dose or monthly, whichever occurs first.
`• Measure liver-related tests (ALT and AST, at a minimum) at least
`every 3 months and before any increase in dose.
`If transaminases are abnormal, reduce or withhold dosing of
`JUXTAPID and monitor as recommended [see Dosage and
`Administration (2.4)].
`• 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 ≥2x
`ULN, or active liver disease, discontinue treatment with
`JUXTAPID and identify the probable cause.
`
`•
`
`•
`
` TIME
` Before initiating treatment
`
` During the first year
`
` After the first year
`
` At any time during treatment
`
`
`
`Reference ID: 4537578
`
`

`

`
`
`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.
`
`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
`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
`
`Reference ID: 4537578
`
`

`

`
`
`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 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
`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.
`
`There have been postmarketing reports of severe diarrhea with the use of JUXTAPID, including
`patients being hospitalized because of diarrhea-related complications such as volume depletion.
`Monitor patients who are more susceptible to complications from diarrhea, such as older patients
`and patients taking drugs that can lead to volume depletion or hypotension. Instruct patients to
`stop JUXTAPID and contact their healthcare provider if severe diarrhea occurs or if they
`experience symptoms of volume depletion such as lightheadedness, decreased urine output, or
`tiredness. In such cases, consider reducing the dose or suspending use of JUXTAPID.
`
`Reference ID: 4537578
`
`

`

`
`
`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,
`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.
`
`Grapefruit juice must be omitted from the diet while being treated with JUXTAPID.
`
`Weak CYP3A4 inhibitors can increase the exposure of lomitapide approximately 2-fold;
`therefore, when JUXTAPID is administered with weak CYP3A4 inhibitors, the dose of
`JUXTAPID should be decreased by half. Careful titration 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) and Drug Interactions
`(7.2)].
`
`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,
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`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.
`
`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
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`(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.
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`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