`
`
`
`
`
`
`
`
`
` • T ake 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).
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMAT ION
`
`
`
` These highlights do not include all the inf ormation needed to use
` JUXTAPID saf ely an d ef f ectively. S ee f u ll p rescrib in g in f ormation f or
`
`
` JUXTAPID.
`
`
`JUXTAPID® (lomitap id e) cap su les, f or 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).
`
`
`
`
`
`• Measu re alanine and aspartate aminotransf erases (AL T , AS T),
`
`
`alkaline phosphatase, and total bilirubin bef ore initiating treatment
`
`and then ALT and AST regu larly as recommen d ed (2.4, 5.1).
`
`
`
`Du rin g treatmen t, ad ju st th e d ose of JUXT APID if the ALT or AST
`
`
`
`
`
`
`is ≥3 times th e u p p er limit of n ormal (ULN) (2. 4, 5. 1).
`
`
`
`
`
`
`Discontinue JUXT APID f or clinically signif icant liver tox icity (2.4,
`
`
`
`5.1).
`
`JUXTAPID in creases h ep atic f at (h ep atic steatosis) with or with ou t
`
`
`
`
`
`con comitan t in creases in tran samin ases (5.1).
`
`
`
`
`Hepatic steatosis associated with JUXT APID may be a risk f actor
`
`
`
`
`
`•
`f or p rogressive liver d isease, in clu d in g steatoh ep atitis an d cirrh osis
`(5. 1).
`
`Becau se of th e risk of h ep atotox icity, JUXT APID is available only
`
`
`
`
`th rou gh a restricted p rogram called th e JUXT APID REMS Program
`
`
`
`
`
`
`(5.2). Prescribe JUXTAPID only to patients with a clinical or laboratory
`
`
`
`
`
`diagnosis consistent with HoFH. The saf ety and ef f ectiveness of
`
`
`JUXTAPID have not been established in patients with
`
`
`hypercholesterolemia who do not have HoFH (1).
`
`
`
` ------------------------------RE CE NT MAJOR CHANGE S-----------------------------­
`
`
`
` 05/2016
` Boxed W arning
` Indications and Usage (1.1)
`
` 05/2016
`
`
` 05/2016
`
` Dosage and Administration (2. 1)
`
` 05/2016
`
` W arnings and Precautions (5.1)
`
` 05/2016
`
` W arnings and Precautions (5.5)
`
`
` -------------------------------INDICATIONS AND US AGE -----------------------------­
`
`
` JUXT AP ID 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 (T C), apolipoprotein B (apo B), and non-high­
`
`
`
`
` density lipoprotein cholesterol (non-HDL-C ) in patients with homozygous
`
` familial hypercholesterolemia (HoF H) (1).
`
`
` .Limitations of Use
`
`
`• T he safety and effectiveness of JUXT AP ID have not been established in
`
`
`
`
`
`
`
`
` patients with hypercholesterolemia who do not have HoFH, including those
`
`
`
` with heterozygous familial hypercholesterolemia (HeFH) (1).
`
`
`• T he effect of JUXT AP ID on cardiovascular morbidity and mortality has not
`
`
`
`
`
`
` been determined (1).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` --------------------------DOS AGE AND ADMINIS T RAT ION ------------------------­
`
` • Before treatment, measure ALT , AS T , 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. T itrate 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: T ake daily
`
`
`
`
`
` vitamin E, linoleic acid, alpha-linolenic acid (ALA), eicosapentaenoic acid
`
`
`
`
` (EPA), and docosahexaenoic acid (DHA) supplements (2. 1, 5. 4).
`
`
`
`
`
`
`
`
`
`
`
`FULL PRE S CRIBING INFORMAT ION: CONT E NT S *
`
`
`
`WARNING: RIS K OF HE PAT OT OXICIT Y
`
`
`INDICAT IONS AND US AGE
`1
`
`
`
`1.1 Homozygous Familial Hypercholesterolemia
`
`DOS AGE AND ADMINIS T RAT ION
`
`
`2.1 Initiation and Maintenance of T herapy
`
`
`2.2 Administration
`
`
`
`2.3 Dosing with Cytochrome P450 3A4 Inhibitors
`
`
`
`
`
`2.4 Dose Modification Based on Elevated T ransaminases
`
`
`2
`
`Reference ID: 3934821
`
`
`
`
` ------------------------DOS AGE FORMS AND S T RENGTHS-----------------------­
`
`
`
` Capsules: 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg (3).
` ----------------------------------CONT RAINDICAT IONS --------------------------------­
`
`
` • Pregnancy (4).
`
`
`
`
`
`
`
`
` • Concomitant use with strong or moderate C YP 3A4 inhibitors (4).
`
` • Moderate or severe hepatic impairment or active liver disease including
`
`
`
` unexplained persistent abnormal liver function tests (4).
`
`
`
`
`
`
`
`
` --------------------------WARNINGS AND PRE CAUT IONS -------------------------­
`
`
` • Embryo-Fetal T oxicity: Females of Reproductive Potential should have a
`
`
`
` negative pregnancy test before starting JUXT AP ID 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).
`
`
`
`
`
`
`
`
`
` ----------------------------------ADVERS E RE ACT IONS---------------------------------­
` Most common adverse reactions (incidence ≥28%) are diarrhea, nausea,
`
`
`
`
` vomiting, dyspepsia, and abdominal pain (6. 1).
`
`
`
`
` T o rep ort S US PE CT E D ADVERS E REACTIONS , con tact Aegerion
` Ph armaceu ticals at 1-855-303-2347 or FDA at 1-800-FDA-1088 or
`
`
` www.f da.gov/medwatch.
`
`
` ----------------------------------DRUG INT ERACT IONS---------------------------------­
`
`
`
`
`
`
`
`
`
`
` • C YP 3A4 inhibitors increase exposure to lomitapide. Strong and moderate
`
`
`
` C YP 3A4 inhibitors are contraindicated with JUXT AP ID. Patients must
`
`
` avoid grapefruit juice (4, 5.6, 7.1).
`
`
`
`
` • W hen administered with weak CYP3A4 inhibitors, the dose of JUXT AP ID
`
` should be decreased by half. T he dosage of JUXT AP ID may then be up­
`
`
`
`
` titrated to a maximum recommended dosage of 30 mg daily (2. 3, 5. 6, 7. 2).
`
`
`
`
`
` • W arfarin: Lomitapide increases plasma concentrations of warfarin. Monitor
`
`
`
`
` international normalized ratio (INR) regularly, especially with JUXT AP ID
`
`
`
`
`
` dose adjustment (5.8, 7.3).
`
`
`
`
` • Simvastatin and lovastatin exposure increase with JUXT AP ID. Limit dose
`
`
` when co-administered with JUXT AP ID 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 JUXT AP ID (7. 5).
`
`
` • Bile Acid S equestrants: Separate JUXT AP ID dosing by at least 4 hours
`
`
`
`
`
`
` (7.6).
`
`
`
`
`
`
`
`
`
` --------------------------US E IN S PE CIFIC POPULATIONS-------------------------­
`
`
`
`
`•
`
`•
`
`
`
`
` Nursing Mothers: Discontinue drug or nursing (8.3).
` Pediatric Patients: S afety and effectiveness not established (8. 4).
`
`
`
`
`
`
`
`
`
`
`
` S ee 17 f or PATIE NT COUNS EL ING INFORMATION and Medication
` Guide
`
`
`
`
`
`
`
`
`Revised : 05/2016
`
`
`3
`
`4
`
`5
`
`
`
`
`2.5 Dosing in Patients with Renal Impairment
`
`
`
`
`2.6 Dosing in Patients with Baseline Hepatic Impairment
`
`DOS AGE FORMS AND S T RE NGT HS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRE CAUTIONS
`
`
`
`5.1 Risk of Hepatotoxicity
`
`
`
`
`5.2 JUXT AP ID REMS P rogram
`
`
`5.3 Embryo-Fetal T oxicity
`
`
`5.4 Reduced Absorption of Fat-Soluble Vitamins and
`
`Serum Fatty Acids
`
`

`

`
`
`
`
`
`
`
` 10
`
` 11
`
` 12
`
`
`
` 13
`
`
`
` 8.4 P ediatric Use
`
`
`
` 8.5 Geriatric Use
`
`
` 8.6 F emales of Reproductive P otential
`
`
`
` 8.7 Renal Impairment
`
`
`
` 8.8 Hepatic Impairment
`
` OVE RDOS AGE
`
`
` DES CRIPT ION
` CLINICAL PHARMACOLOGY
`
`
`
` 12.1 Mechanism of Action
`
`
` 12.2 P harmacodynamics
`
`
`
` 12.3 P harmacokinetics
`
`
` NONCL INICAL T OXICOL OGY
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
` CLINICAL S T UDIE S
`
`
` 14
`
` HOW S UPPL IED / S TORAGE AND HANDLING
`
` 16
`
`
` 17
` PATIE NT COUNS EL ING INFORMAT ION
` *Sections or subsections omitted from the full prescribing information are not
`
`
`
` listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 W arfarin
`
`
`
`
` 5.9 Risk of Malabsorption with Rare Hereditary
`
`
`
` Disorders of Galactose Intolerance
`
`
`
` ADVE RS E RE ACT IONS
`
` 6.1 Clinical T rials Experience
`
`
` DRUG INTE RACT IONS
`
` 7.1 Moderate and Strong CYP3A4 Inhibitors
`
`
`
`
` 7.2 Weak CYP3A4 Inhibitors
`
`
`
` 7.3 W arfarin
`
`
`
`
` 7.4 Simvastatin and Lovastatin
`
`
` 7.5 P-glycoprotein Substrates
`
`
`
` 7.6 Bile Acid S equestrants
`
`
`
` US E IN S PE CIFIC POPULAT IONS
`
`
`
` 8.1 P regnancy
`
`
` 8.3 Nursing Mothers
`
`
`
`
`
`
`
`
`
`
`
`
` 6
`
`
`
` 7
`
`
`
` 8
`
`Reference ID: 3934821
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`
` WARNING: RISK OF HEPATOTOXICITY
`
`
`
`
`
`
`JUXTAPID can caus e e levations in trans aminas e s . In the JUXTAPID clinical trial, 10
`
`
`
`
`
`(34%) of the 29 patie nts tre ate d with JUXTAPID had at le as t one e levation in alanine
`
`
`
`
`
`aminotrans fe ras e (ALT) or as partate aminotrans fe ras e (AST) ≥3 x uppe r limit of normal
`
`
`
`
`
`
`
`
`
`(ULN). The re we re no concomitant clinically me aningful e le vations of total bilirubin,
`
`
`inte rnational normalize d ratio (INR), or alk aline phos phatas e [see Warnings and
`
`
`
`
`
`Precautions (5.1)].
`
`
`JUXTAPID als o incre as e s hepatic fat, with or without concomitant incre as e s in
`
`
`
`
`
`trans aminas e s . The me dian abs olute incre as e in he patic fat was 6% afte r both 26 and 78
`
`
`
`
`
`
`we e k s of tre atme nt, from 1% at bas e line , me as ured by magne tic re s onance s pectroscopy.
`
`
`He patic s te atosis as sociated with JUXTAPID tre atme nt may be a ris k factor for
`
`
`
`
`progre s s ive live r dis ease, including s te atohepatitis and cirrhos is [see Warnings and
`
`
`Precautions (5.1)].
`
`
`M e as ure ALT, AST, alk aline phos phatas e , and total bilirubin be fore initiating tre atme nt
`
`
`and the n ALT and AST re gularly as re comme nde d. During tre atme nt, adjus t the dos e of
`
`
`
`
`JUXTAPID if the ALT or AST are ≥3x ULN. Dis continue JUXTAPID for clinically
`
`
`
`
`
`
`
`s ignificant live r toxicity [see Dosage and Administration (2.4) and Warnings and
`
`
`
`
`Precautions (5.1)].
`
`
`
`B e caus e of the ris k of he patotoxicity, JUXTAPID is available only through a re s tricte d
`
`
`
`
`program unde r a Ris k Evaluation and M itigation Strate gy (REM S) calle d the JUXTAPID
`
`REM S Program [see Warnings and Precautions (5.2)]. Pre s cribe JUXTAPID only to
`
`
`
`
`
`
`patie nts with a clinical or laboratory diagnos is cons is tent with HoFH. The s afe ty and
`e ffe ctive ness of JUXTAPID have not be e n e stablis hed in patie nts with
`
`hype rchole s terolemia who do not have HoFH [see Indications and Usage (1)].
`
`
`
`
`
`
`
`
`
`Reference ID: 3934821
`
`

`

`
`
`
`
` 1 INDICATIONS AND USAGE
`
`
`
`
` 1.1 Homozygous Familial Hype rchole s terolemia
`
` JUXTAPID is indicated as an adjunct to a low-fat diet and other lipid-lower in g treatments,
`
`
`
`
`
`
`
`
`
` includin g LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL­
` C), total cholesterol (TC), apolipoprote in B (apo B), and non-high-dens it y 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, includin g those with heterozygous familial
`
`hypercholesterolemia (HeFH).
`
`
`
`
`
`
`
` • The effect of JUXTAP ID on cardiovascular morbidity and mortality has not been
`
`
` determined.
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
`
`
`2.1
` Initiation and M ainte nance of The rapy
`
` Before beginning treatment with JUXTAPID:
`
`
`
`
`
` • Measure transaminases (ALT, AST), alkaline phosphatase, and total bilirub in [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 JUXTAP ID is 5 mg once daily, and the dose should be
` escalated gradually based on acceptable safety and tolerabilit y. Transaminases should be
`
`
`
`
`
`
`
`measured prior to any increase in dose [see Warnings and Precautions (5.1)]. The maintenance
`
`
`
` dosage of JUXTAP ID should be individua lize d, 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 CYP 3A4 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 JUXTAP ID as described in Warnings
`
`
`
`
`
`
`Reference ID: 3934821
`
`

`

`
`
` 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: Re comme nde d Re gime n for Titrating Dos age
`
`
`DURAT ION OF ADMINIS T RAT ION BEFORE
`
` CONS IDERING INCREAS E TO NEXT DOSAGE
`
`
`
` A t leas t 2 weeks
`
`
` A t leas t 4 weeks
`
` A t leas t 4 weeks
`
` A t leas t 4 weeks
`
` Maximum recommen ded d osage
`
`
` DOSAGE
`
` 5 mg d aily
`
`
`
` 10 mg d aily
`
`
` 20 mg d aily
`
` 40 mg d aily
`
`
` 60 mg d aily
`
`
`
`
`
`
`
`
` 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 JUXTAP ID should take daily
`
`
`
`
`
`
`
` supplements that contain 400 international units vitamin E and at least 200 mg linole ic acid,
`
`
`
`
`
`
`
` 210 mg alpha-lino len ic acid (ALA), 110 mg eicosapentaenoic acid (EP A), and 80 mg
`
`
`
`
`
` docosahexaenoic acid (DHA) [see Warnings and Precautions (5.4)].
`
`
`
`
`
`
`
`
` 2.2 Adminis tration
`
`
`
`
`
`
`
`
` 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)]. P atients should swallow JUXTAPID
`
`
`
`
` capsules whole. Capsules should not be opened, crushed, dissolved, or chewed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.3 Dos ing with Cytochrome P450 3A4 Inhibitors
`
` JUXTAPID is contraindicated with concomitant use of moderate and strong cytochrome P 450
`
`
`
`
`
`
`
` 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 CYP 3A4 inhibit ors (such as alprazolam, amiodarone, amlodip ine , atorvastatin,
`
`
`
`
` bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine , ginkgo, goldenseal,
`
`
`
`
` isoniazid, lapatinib, nilotin ib , pazopanib, ranitidine, ranolazine, ticagrelor, zileuton). However,
`
`
`
` the recommended maximum dosage of JUXTAPID is 40 mg daily with concomitant use of oral
`
`
`
`
`
`
` contraceptives.
`
`
`
`
` When initiatin g a weak CYP 3A4 inhibit or in a patient already taking JUXTAPID 10 mg daily or
`
`
`
`
`
`
`
` more, decrease the dose of JUXTAP ID by half; patients taking JUXTAP ID 5 mg daily may
` continue with the same dosage. Careful titration of JUXTAPID may then be considered
`
`
`
`
`
`
` according to LDL-C response and safety/tolerabilit y to a maximum recommended dosage of
`
`
`
`
`
`Reference ID: 3934821
`
`

`

`
`
`
`
`
`
`
` 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 Dos e M odification B as e d on Ele vated Trans aminas e s
`
`
`
`
`
`
` 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: Dos e Adjus tme nt and M onitoring for Patie nts with Ele vate d Trans aminas e s
`
`
`
`
`
`
`
`
`
`
`
`
` ALT OR AS T
`
` ≥3x an d <5x ULN
`
`
`
`
`
` ≥5x ULN
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
` TREAT MENT AND MONIT ORING RECOMME NDAT IONS *
`
`
` • Co n firm elev atio n wit h a rep eat meas urement with in o ne week.
`
`
`
`
` If confirmed, reduce the dose and obtain additional liver-related tests if not
`
`
`•
` already meas u red (s uch as alkaline phosphatase, total bilirubin, and INR).
`
`
` • Rep eat tes ts weekly an d with hold d osing if t h ere are s ig ns o f abno rmal liv er
`
`
`
`
` function (increase in bilirubin or INR), if trans aminase levels ris e above 5x ULN,
`
`
`
`
` or if trans aminase levels do not fall below 3x ULN within approximately 4 weeks .
`
`
`
`
`
`
`
` In th es e cases o f p ersis tent o r wors enin g ab normalities , als o in v est igate t o id entify
`
` the pro bable cause.
`
`
`
`
` If res u min g JUXTA PID after tran samin ases res olve to <3x ULN, co ns id er
`
` reducing the dose and monitor liver-related tests mo re frequently.
`
`
`• W ithhold dosing, obtain additional liver-related tests if not already measured
`
`
`
`
` (s uch as alkaline phosphatase, total bilirubin, and INR), and investigate to identify
`
`
` the pro bable cause.
` If res u min g JUXTA PID after tran samin ases res olve to <3x ULN, redu ce th e d ose
`
`
` 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 JUXTAP ID and investigate to
`
`
`
`
`
`
`
`
`
` identify the probable cause [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`
` 2.5 Dos ing in Patie nts with Re nal Impairme nt
`
` P atients 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 Dos ing in Patie nts with B as e line Hepatic Impairme nt
`
` P atients with mild hepatic impairment (Child-P ugh A) should not exceed 40 mg daily [see Use
`
`
`
`
` in Specific Populations (8.8)].
`
`
`
`
`
`
`
`
`
`Reference ID: 3934821
`
`

`

`
`
`
`
`
`
` 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 :
`
`
` • P regnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
`
`
`
`
`
`
` • Concomitant administration of JUXTAPID with moderate or strong CYP 3A4 inhibitors , as
`
`
`
`
`
`
`
`
` this can increase JUXTAPID exposure [see Warnings and Precautions (5.6), Drug
`
`
`
`
`
` Interactions (7.1), and Clinical Pharmacology (12.3)].
`
`
` • P atients with moderate or severe hepatic impairment (based on Child-P ugh 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 Ris k of He patotoxicity
`
` 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: 3934821
`
`

`

`
`
`
` clinically meaningful elevations in bilirub in, 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 CYP 3A4 inhibit or clarithromycin [see
`
`
`
` Drug Interactions (7.1)].
`
`
`
`
`
`
`
` Monitoring of Transaminases
`
`Before initiating JUXTAP ID and during treatment, monitor transaminases as recommended in
`
`
`
`
`
`Table 3.
`
`
`
`Table 3: Re co mme ndations for M o nitoring Trans aminas e s
`
`
`
`
`
`
`•
`
`
`
` RE CO MME NDAT IO NS
`
` • Meas ure A LT, A ST, alkaline phosphatase, and total bilirubin.
`
`
` If abnormal, cons ider initiating JUXTAPID only after an
`
`•
` appropriate work-u p and the b aselin e ab normalities h ave been
`
`
`
` explained or res olved.
`
`
`
` JUXTA PID is co n train d icat ed in p atien ts with mo d erate or s ev ere
`
` h ep atic imp airment, o r active liver d is ease, inclu ding un explain ed
` p ers is tent elev atio ns o f s erum t ran samin ases [see Contraindications
`
`
`
` (4)].
`
` • Meas ure liv er-relat ed tests (A LT and A ST, at a min imum) prior to
`
`
` each in crease in dose or monthly, whichever occurs firs t.
`
`
`
`• Meas ure liv er-relat ed tests (A LT and A ST, at a min imum) at leas t
`
`
`
`ev ery 3 months and before any increase in dose.
`
`
`
`
`
` If trans aminases are abnormal, reduce or withhold dosing of
`
`
` JUXTAPID and monitor as recommended [see Dosage and
`
`
` Administration (2.4)].
`
`
` • Dis co n t in ue JUXTAPID fo r p ers ist en t o r clin ically s ig n ifican t
`
` elev atio n s.
`
`
` If trans amin ase elevation s are accomp an ied b y clin ical s y mp toms of
` liver injury (s uch as nausea, vomiting, abdomin al p ain, fev er,
`
`
` jau n d ice, leth argy , flu -like s ymptoms), increases in bilirubin ≥2x
`
`
`
`
`
` ULN, o r active liver d is eas e, d iscontin ue treatment with
`
`
`
` JUXTAPID and identify the probable cause.
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`
` TIME
`
` Befo re in it iatin g treatmen t
`
`
`
`
`
`
` During the firs t year
`
`A ft er th e firs t y ear
`
`
`At any time during treatment
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3934821
`
`

`

`
`
`
`
` Hepatic Steatosis
`
`
`
`
`
`
`
`
` JUXTAPID increases hepatic fat, with or without concomitant increases in transaminases.
` Hepatic steatosis is a risk factor for progressive liver disease, includin g 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 JUXTAP ID, 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.
`
`
`
`
`
`
`
` JUXTAP ID 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 REM S Program
`
`
`
`
`
`
`
` Because of the risk of hepatotoxicity associated with JUXTAP ID 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.JUXTAPIDREMSP rogram.com or by telephone at 1-85­
`
`
`
`
`
`
` JUXTAPID (1-855-898-274 3).
`
`
`
`
`
`
` 5.3 Embryo-Fe tal 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)].
`
`
`
`
`
`Reference ID: 3934821
`
`

`

`
`
` Oral contraceptives are weak CYP 3A4 inhibit ors [see Dosage and Administration (2.3) and
`
`
`
`
` Drug Interactions (7.2)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5.4 Re duce d Abs orption of Fat-Soluble Vitamins and Se rum 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, linole ic acid, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and
`
`
`
`
`
` docosahexaenoic acid (DHA). In this trial, the median levels of serum vitamin E, ALA, linole ic
`
`
`
`
`
`
`
`
`
` acid, EP A, 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. P atients treated with JUXTAP ID
`
`
`
` should take daily supplements that contain 400 international units vitamin E and at least 200 mg
`
`
`
`
`
`
` linoleic acid, 210 mg ALA, 110 mg EP A, and 80 mg DHA [see Dosage and Administration
`
`
`
`
`
`
` (2.1)]. P atients 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 Gas trointe s tinal Adve rs e 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 JUXTAP ID, including
`
`
`
`
`
`
`
`
`
`patients being hospitalized because of diarrhea-related complications such as volume depletion.
`
` Monitor patients who are more susceptible to complicatio ns from diarrhea, such as older patients
`
`
`
`
`
`
`
`
`
`
`and patients taking drugs that can lead to volume depletion or hypotension. Instruct patients to
` stop JUXTAP ID 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 JUXTAP ID.
`
`
`
`
`
`
`
`
`Reference ID: 3934821
`
`

`

`
`
`
`
` 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 Us e of CYP3A4 Inhibitors
`
` CYP 3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing
`
`
`
`
`
`
`
`
`
` exposure approximately 27-fold. Concomitant use of moderate or strong CYP 3A4 inhibit ors with
` JUXTAPID is contraindicated [see Drug Interactions (7.1)]. In the JUXTAP ID clinical trials,
`
`
`
`
`
`
` one patient with HoFH developed markedly elevated transaminases (ALT 24x ULN, AST 13x
`
`
`
`
`
` ULN) within days of initiating the strong CYP 3A4 inhibit or clarithromycin. If treatment with
`
`
` moderate or strong CYP 3A4 inhibitors is unavoidable, JUXTAPID should be stopped during the
`
`
`
`
`
` course of treatment.
`
`
`
`
`
` Grapefruit juice must be omitted from the diet while being treated with JUXTAP ID.
`
`
`
`
`
`
`
`
`
`
`
` Weak CYP 3A4 inhibitors can increase the exposure of lomitapide approximately 2-fold;
`
`
`
`
`
`
` therefore, when JUXTAPID is administered with weak CYP 3A4 inhibit ors, the dose of
`
`
`
`
`
` JUXTAP ID 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 Ris k of M yopathy with Concomitant Us e of Simvas tatin or Lovas tatin
`
`
`
`
` The risk of myopathy, including rhabdomyolys is , 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, l