LOMITAPIDE
JUXTAPID CAPSULES
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 ].
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 ].
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 AND WARNINGS AND PRECAUTIONS ].
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 ]. 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 ].
DESCRIPTION
JUXTAPID CAPSULES CONTAIN LOMITAPIDE MESYLATE, A SYNTHETIC LIPID -LOWERING AGENT FOR ORAL ADMINISTRATION.
LOMITAPIDE MESYLATE IS A WHITE TO OFF-WHITE POWDER THAT IS SLIGHTLY SOLUBLE IN AQUEOUS SOLUTIONS OF PH 2 TO 5. LOMITAPIDE MESYLATE IS FREELY SOLUBLE IN ACETONE, ETHANOL , AND METHANOL; SOLUBLE IN 2-BUTANOL, METHYLENE CHLORIDE, AND ACETONITRILE; SPARINGLY SOLUBLE IN 1-OCTANOL AND 2-PROPANOL; SLIGHTLY SOLUBLE IN ETHYL ACETATE; AND INSOLUBLE IN HEPTANE.
EACH JUXTAPID CAPSULE CONTAINS LOMITAPIDE MESYLATE EQUIVALENT TO 5, 10, 20, 30, 40 OR 60 MG LOMITAPIDE FREE BASE AND THE FOLLOWING INACTIVE INGREDIENTS: PREGELATINIZED STARCH, SODIUM STARCH GLYCOLATE, MICROCRYSTALLINE CELLULOSE, LACTOSE MONOHYDRATE, SILICON DIOXIDE AND MAGNESIUM STEARATE. THE CAPSULE SHELLS OF ALL STRENGTHS CONTAIN GELATIN AND TITANIUM DIOXIDE; THE 5 MG, 10 MG AND 30 MG CAPSULES ALSO CONTAIN RED IRON OXIDE; AND THE 30 MG, 40 MG AND 60 MG CAPSULES ALSO CONTAIN YELLOW IRON OXIDE. THE IMPRINTING INK CONTAINS SHELLAC, BLACK IRON OXIDE, AND PROPYLENE GLYCOL.
INDICATIONS
INDICATIONS
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 (LDLC), 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.
DOSAGE
DOSAGE AND ADMINISTRATION
INITIATION AND MAINTENANCE OF THERAPY
BEFORE BEGINNING TREATMENT WITH JUXTAPID:
· MEASURE TRANSAMINASES (ALT, AST), ALKALINE PHOSPHATASE, AND TOTAL BILIRUBIN [SEE WARNINGS AND PRECAUTIONS ];
· OBTAIN A NEGATIVE PREGNANCY TEST IN FEMALES OF REPRODUCTIVE POTENTIAL [SEE WARNINGS AND PRECAUTIONS ]; AND,
· INITIATE A LOW-FAT DIET SUPPLYING <20% OF ENERGY FROM FAT [SEE WARNINGS AND PRECAUTIONS ].
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 ]. 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, AND]. MONITOR TRANSAMINASES DURING TREATMENT WITH JUXTAPID AS DESCRIBED IN WARNINGS AND PRECAUTIONS , AND REDUCE OR WITHHOLD DOSING FOR PATIENTS WHO DEVELOP TRANSAMINASE VALUES ?3X THE UPPER LIMIT OF NORMAL (ULN) [SEE DOSE MODIFICATION BASED ON ELEVATED TRANSAMINASES].
TABLE 1: RECOMMENDED REGIMEN FOR TITRATING DOSAGE
DOSAGE DURATION OF ADMINISTRATION BEFORE CONSIDERING INCREASE TO NEXT DOSAGE
5 MG DAILY AT LEAST 2 WEEKS
10 MG DAILY AT LEAST 4 WEEKS
20 MG DAILY AT LEAST 4 WEEKS
40 MG DAILY AT LEAST 4 WEEKS
60 MG DAILY MAXIMUM RECOMMENDED DOSAGE
TO REDUCE THE RISK OF DEVELOPING A FAT-SOLUBLE NUTRIENT DEFICIENCY DUE TO JUXTAPID'S MECHANISM OF ACTION IN THE SMALL INTESTINE , PATIENTS TREATED WITH JUXTAPID SHOULD TAKE DAILY SUPPLEMENTS THAT CONTAIN 400 INTERNATIONAL UNITS VITAMIN E AND AT LEAST 200 MG LINOLEIC ACID, 210 MG ALPHA-LINOLENIC ACID (ALA ), 110 MG EICOSAPENTAENOIC ACID (EPA ), AND 80 MG DOCOSAHEXAENOIC ACID (DHA ) [SEE WARNINGS AND PRECAUTIONS ].
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 ]. PATIENTS SHOULD SWALLOW JUXTAPID CAPSULES WHOLE. CAPSULES SHOULD NOT BE OPENED, CRUSHED, DISSOLVED, OR CHEWED.
DOSING WITH CYTOCHROME P450 3A4 INHIBITORS
JUXTAPID IS CONTRAINDICATED WITH CONCOMITANT USE OF MODERATE AND STRONG CYTOCHROME P450 3A4 (CYP3A4) INHIBITORS [SEE CONTRAINDICATIONS AND DRUG INTERACTIONS ].
THE RECOMMENDED MAXIMUM DOSAGE OF JUXTAPID IS 30 MG DAILY WITH CONCOMITANT USE OF WEAK CYP3A4 INHIBITORS (SUCH AS ALPRAZOLAM , AMIODARONE , AMLODIPINE , ATORVASTATIN , BICALUTAMIDE, CILOSTAZOL , CIMETIDINE , CYCLOSPORINE, FLUOXETINE , FLUVOXAMINE, GINKGO, GOLDENSEAL, ISONIAZID, LAPATINIB, NILOTINIB, PAZOPANIB, RANITIDINE , RANOLAZINE, TICAGRELOR, ZILEUTON). HOWEVER, THE RECOMMENDED MAXIMUM DOSAGE OF JUXTAPID IS 40 MG DAILY WITH CONCOMITANT USE OF ORAL CONTRACEPTIVES.
WHEN INITIATING A WEAK CYP3A4 INHIBITOR IN A PATIENT ALREADY TAKING JUXTAPID 10 MG DAILY OR MORE, DECREASE THE DOSE OF JUXTAPID BY HALF; PATIENTS TAKING JUXTAPID 5 MG DAILY MAY CONTINUE WITH THE SAME DOSAGE. CAREFUL TITRATION OF JUXTAPID MAY THEN BE CONSIDERED ACCORDING TO LDL-C RESPONSE AND SAFETY/TOLERABILITY TO A MAXIMUM RECOMMENDED DOSAGE OF 30 MG DAILY EXCEPT WHEN COADMINISTERED WITH ORAL CONTRACEPTIVES, IN WHICH CASE THE MAXIMUM RECOMMENDED LOMITAPIDE DOSAGE IS 40 MG DAILY [SEE DRUG INTERACTIONS ].
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 ].
TABLE 2: DOSE ADJUSTMENT AND MONITORING FOR PATIENTS WITH ELEVATED TRANSAMINASES
ALT OR AST TREATMENT AND MONITORING RECOMMENDATIONS*
?3X AND <5X ULN · 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.
?5X ULN · 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 ].
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 ].
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 ].
HOW SUPPLIED
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”
STORAGE AND HANDLING
5 MG CAPSULES:
ORANGE/ORANGE HARD GELATIN CAPSULE PRINTED WITH BLACK INK “A733” AND “5 MG”
BOTTLES OF 28 NDC 76431-105-01
10 MG CAPSULES
ORANGE/WHITE HARD GELATIN CAPSULE PRINTED WITH BLACK INK “A733” AND “10 MG”
BOTTLES OF 28 NDC 76431-110-01
20 MG CAPSULES
WHITE/WHITE HARD GELATIN CAPSULE PRINTED WITH BLACK INK “A733” AND “20 MG”
BOTTLES OF 28 NDC 76431-120-01
30 MG CAPSULES
ORANGE/YELLOW HARD GELATIN CAPSULE PRINTED WITH BLACK INK “A733” AND “30 MG”
BOTTLES OF 28 NDC 76431-130-01
40 MG CAPSULES
YELLOW/WHITE HARD GELATIN CAPSULE PRINTED WITH BLACK INK “A733” AND “40 MG”
BOTTLES OF 28 NDC 76431-140-01
60 MG CAPSULES
YELLOW/YELLOW HARD GELATIN CAPSULE PRINTED WITH BLACK INK “A733” AND “60 MG”
BOTTLES OF 28 NDC 76431-160-01
STORAGE
STORE AT 20°C TO 25°C (68°F TO 77°F); EXCURSIONS PERMITTED BETWEEN 15°C AND 30°C (BETWEEN 59°F AND 86°F). BRIEF EXPOSURE TO TEMPERATURES UP TO 40°C (104°F) MAY BE TOLERATED PROVIDED THE MEAN KINETIC TEMPERATURE DOES NOT EXCEED 25°C (77°F); HOWEVER, SUCH EXPOSURE SHOULD BE MINIMIZED. KEEP CONTAINER TIGHTLY CLOSED AND PROTECT FROM MOISTURE.
MANUFACTURED FOR: AEGERION PHARMACEUTICALS, INC., CAMBRIDGE, MA 02142. REVISED: JUL 2017
SIDE EFFECTS
SIDE EFFECTS
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 ]
· REDUCED ABSORPTION OF FAT-SOLUBLE VITAMINS, AND SERUM FATTY ACIDS [SEE WARNINGS AND PRECAUTIONS ]
· GASTROINTESTINAL ADVERSE REACTIONS [SEE WARNINGS AND PRECAUTIONS ]
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 ].
FIVE (17%) OF THE 29 PATIENTS WITH HOFH THAT PARTICIPATED IN THE CLINICAL TRIAL DISCONTINUED TREATMENT DUE TO AN ADVERSE REACTION. THE ADVERSE REACTIONS THAT CONTRIBUTED TO TREATMENT DISCONTINUATIONS INCLUDED DIARRHEA (2 PATIENTS; 7%) AND ABDOMINAL PAIN, NAUSEA, GASTROENTERITIS , WEIGHT LOSS, HEADACHE, AND DIFFICULTY CONTROLLING INR ON WARFARIN (1 PATIENT EACH; 3%).
THE MOST COMMON ADVERSE REACTIONS WERE GASTROINTESTINAL, REPORTED BY 27 (93%) OF 29 PATIENTS. ADVERSE REACTIONS REPORTED BY ?8 (28%) PATIENTS IN THE HOFH CLINICAL TRIAL INCLUDED DIARRHEA, NAUSEA, VOMITING, DYSPEPSIA , AND ABDOMINAL PAIN. OTHER COMMON ADVERSE REACTIONS, REPORTED BY 5 TO 7 (17-24%) PATIENTS, INCLUDED WEIGHT LOSS, ABDOMINAL DISCOMFORT, ABDOMINAL DISTENSION, CONSTIPATION, FLATULENCE , INCREASED ALT, CHEST PAIN, INFLUENZA , NASOPHARYNGITIS, AND FATIGUE.
THE ADVERSE REACTIONS REPORTED IN AT LEAST 10% OF PATIENTS DURING THE HOFH CLINICAL TRIAL ARE PRESENTED IN TABLE 4.
TABLE 4: ADVERSE REACTIONS REPORTED IN ?10% OF PATIENTS IN THE CLINICAL TRIAL IN HOFH
ADVERSE REACTION N (%)
GASTROINTESTINAL DISORDERS
DIARRHEA 23 (79)
NAUSEA 19 (65)
DYSPEPSIA 11 (38)
VOMITING 10 (34)
ABDOMINAL PAIN 10 (34)
ABDOMINAL DISCOMFORT 6 (21)
ABDOMINAL DISTENSION 6 (21)
CONSTIPATION 6 (21)
FLATULENCE 6 (21)
GASTROESOPHAGEAL REFLUX DISEASE3 (10)
DEFECATION URGENCY 3 (10)
RECTAL TENESMUS 3 (10)
INFECTIONS
INFLUENZA 6 (21)
NASOPHARYNGITIS 5 (17)
GASTROENTERITIS 4 (14)
INVESTIGATIONS
DECREASED WEIGHT 7 (24)
INCREASED ALT 5 (17)
GENERAL DISORDERS
CHEST PAIN 7 (24)
FATIGUE 5 (17)
FEVER 3 (10)
MUSCULOSKELETAL DISORDERS
BACK PAIN 4 (14)
NERVOUS SYSTEM DISORDERS
HEADACHE 3 (10)
DIZZINESS 3 (10)
RESPIRATORY DISORDERS
PHARYNGOLARYNGEAL PAIN 4 (14)
NASAL CONGESTION 3 (10)
CARDIAC DISORDERS
ANGINA PECTORIS 3 (10)
PALPITATIONS 3 (10)
ADVERSE REACTIONS OF SEVERE INTENSITY WERE REPORTED BY 8 (28%) OF 29 PATIENTS, WITH THE MOST COMMON BEING DIARRHEA (4 PATIENTS, 14%), VOMITING (3 PATIENTS, 10%), INCREASED ALT OR HEPATOTOXICITY (3 PATIENTS, 10%), AND ABDOMINAL PAIN, DISTENSION, AND/OR DISCOMFORT (2 PATIENTS, 7%).
TRANSAMINASE ELEVATIONS
DURING THE HOFH CLINICAL TRIAL, 10 (34%) OF 29 PATIENTS HAD AT LEAST ONE ELEVATION IN ALT AND/OR AST ?3X ULN (SEE TABLE 5). NO CLINICALLY MEANINGFUL ELEVATIONS IN TOTAL BILIRUBIN OR ALKALINE PHOSPHATASE WERE OBSERVED. TRANSAMINASES TYPICALLY FELL WITHIN ONE TO FOUR WEEKS OF REDUCING THE DOSE OR WITHHOLDING JUXTAPID.
TABLE 5: PATIENT INCIDENCE OF TRANSAMINASE ELEVATIONS DURING THE HOFH CLINICAL TRIAL
N (%)
TOTAL PATIENTS 29
MAXIMUM ALT
?3 TO <5 X ULN 6 (21%)
?5 TO <10 X ULN 3 (10%)
?10 TO <20 X ULN 1 (3%)
?20 X ULN 0
MAXIMUM AST
?3 TO <5 X ULN 5 (17%)
?5 TO <10 X ULN 1 (3%)
?10 TO <20 X ULN 0
?20 X ULN 0
UPPER LIMITS OF NORMAL (ULN) RANGED FROM 33-41 INTERNATIONAL UNITS/L FOR ALT AND 36-43 INTERNATIONAL UNITS/L FOR AST.
AMONG THE 19 PATIENTS WHO ENROLLED IN AN EXTENSION STUDY FOLLOWING THE HOFH CLINICAL TRIAL, ONE DISCONTINUED BECAUSE OF INCREASED TRANSAMINASES THAT PERSISTED DESPITE SEVERAL DOSE REDUCTIONS, AND ONE TEMPORARILY DISCONTINUED BECAUSE OF MARKEDLY ELEVATED TRANSAMINASES (ALT 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].
HEPATIC STEATOSIS
HEPATIC FAT WAS PROSPECTIVELY MEASURED USING MAGNETIC RESONANCE SPECTROSCOPY (MRS) IN ALL ELIGIBLE PATIENTS DURING THE HOFH CLINICAL TRIAL. AFTER 26 WEEKS, THE MEDIAN ABSOLUTE INCREASE IN HEPATIC FAT FROM BASELINE WAS 6%, AND THE MEAN ABSOLUTE INCREASE WAS 8% (RANGE, 0% TO 30%). AFTER 78 WEEKS, THE MEDIAN ABSOLUTE INCREASE IN HEPATIC FAT FROM BASELINE WAS 6%, AND THE MEAN ABSOLUTE INCREASE WAS 7% (RANGE, 0% TO 18%). AMONG THE 23 PATIENTS WITH EVALUABLE DATA, ON AT LEAST ONE OCCASION DURING THE TRIAL, 18 (78%) EXHIBITED AN INCREASE IN HEPATIC FAT >5% AND 3 (13%) EXHIBITED AN INCREASE >20%. DATA FROM INDIVIDUALS WHO HAD REPEAT MEASUREMENTS AFTER STOPPING JUXTAPID SHOW THAT HEPATIC FAT ACCUMULATION IS REVERSIBLE, BUT WHETHER HISTOLOGICAL SEQUELAE REMAIN IS UNKNOWN.
POSTMARKETING EXPERIENCE
THE FOLLOWING ADVERSE REACTIONS HAVE BEEN IDENTIFIED DURING POST-APPROVAL USE OF JUXTAPID. BECAUSE THESE REACTIONS ARE REPORTED VOLUNTARILY FROM A POPULATION OF UNCERTAIN SIZE, IT IS NOT POSSIBLE TO RELIABLY ESTIMATE THEIR FREQUENCY OR ESTABLISH A CAUSAL RELATIONSHIP TO JUXTAPID EXPOSURE.
MUSCULOSKELETAL DISORDERS: MYALGIA
SKIN REACTIONS: ALOPECIA
DRUG INTERACTIONS
DRUG INTERACTIONS
MODERATE AND STRONG CYP3A4 INHIBITORS
A STRONG CYP3A4 INHIBITOR HAS BEEN SHOWN TO INCREASE LOMITAPIDE EXPOSURE APPROXIMATELY 27FOLD [SEE CLINICAL PHARMACOLOGY ]. CONCOMITANT USE OF STRONG CYP3A4 INHIBITORS (SUCH AS BOCEPREVIR, CLARITHROMYCIN, CONIVAPTAN, INDINAVIR, ITRACONAZOLE, KETOCONAZOLE , LOPINAVIR/RITONAVIR, MIBEFRADIL, NEFAZODONE, NELFINAVIR, POSACONAZOLE, RITONAVIR, SAQUINAVIR, TELAPREVIR, TELITHROMYCIN, TIPRANAVIR/RITONAVIR, VORICONAZOLE) WITH LOMITAPIDE IS CONTRAINDICATED. CONCOMITANT USE OF MODERATE CYP3A4 INHIBITORS (SUCH AS AMPRENAVIR, APREPITANT, ATAZANAVIR, CIPROFLOXACIN , CRIZOTINIB, DARUNAVIR/RITONAVIR, DILTIAZEM, ERYTHROMYCIN , FLUCONAZOLE , FOSAMPRENAVIR, IMATINIB, VERAPAMIL ) HAS NOT BEEN STUDIED, BUT CONCOMITANT USE WITH LOMITAPIDE IS CONTRAINDICATED SINCE LOMITAPIDE EXPOSURE WILL LIKELY INCREASE SIGNIFICANTLY IN THE PRESENCE OF THESE INHIBITORS.
PATIENTS MUST AVOID GRAPEFRUIT JUICE WHILE TAKING JUXTAPID [SEE CONTRAINDICATIONS , WARNINGS AND PRECAUTIONS , AND CLINICAL PHARMACOLOGY ].
WEAK CYP3A4 INHIBITORS
WEAK CYP3A4 INHIBITORS (SUCH AS ALPRAZOLAM , AMIODARONE , AMLODIPINE , ATORVASTATIN , BICALUTAMIDE, CILOSTAZOL , CIMETIDINE , CYCLOSPORINE, FLUOXETINE , FLUVOXAMINE, GINKGO, GOLDENSEAL, ISONIAZID, LAPATINIB, NILOTINIB, PAZOPANIB, RANITIDINE , RANOLAZINE, TICAGRELOR, ZILEUTON) CAN INCREASE LOMITAPIDE EXPOSURE APPROXIMATELY 2-FOLD [SEE CLINICAL PHARMACOLOGY ]. WHEN ADMINISTERED WITH WEAK CYP3A4 INHIBITORS, THE DOSE OF JUXTAPID SHOULD BE DECREASED BY HALF. CAREFUL TITRATION OF JUXTAPID MAY THEN BE CONSIDERED BASED ON LDL -C RESPONSE AND SAFETY/TOLERABILITY TO A MAXIMUM RECOMMENDED DOSAGE OF 30 MG DAILY EXCEPT WHEN COADMINISTERED WITH ORAL CONTRACEPTIVES, IN WHICH CASE THE MAXIMUM RECOMMENDED LOMITAPIDE DOSAGE IS 40 MG DAILY [SEE DOSAGE AND ADMINISTRATION , WARNINGS AND PRECAUTIONS , AND CLINICAL PHARMACOLOGY ].
WARFARIN
LOMITAPIDE INCREASES PLASMA CONCENTRATIONS OF BOTH R(+)-WARFARIN AND S(-)-WARFARIN BY APPROXIMATELY 30% AND INCREASED THE INR 22%. PATIENTS TAKING WARFARIN SHOULD UNDERGO REGULAR MONITORING OF INR, PARTICULARLY AFTER ANY CHANGES IN LOMITAPIDE DOSAGE. THE DOSE OF WARFARIN SHOULD BE ADJUSTED AS CLINICALLY INDICATED [SEE WARNINGS AND PRECAUTIONS ].
SIMVASTATIN AND LOVASTATIN
THE RISK OF MYOPATHY , INCLUDING RHABDOMYOLYSIS , WITH SIMVASTATIN AND LOVASTATIN MONOTHERAPY IS DOSE RELATED. LOMITAPIDE APPROXIMATELY DOUBLES THE EXPOSURE OF SIMVASTATIN; THEREFORE, THE RECOMMENDED DOSE OF SIMVASTATIN SHOULD BE REDUCED BY 50% WHEN INITIATING JUXTAPID [SEE CLINICAL PHARMACOLOGY ]. WHILE TAKING JUXTAPID, LIMIT SIMVASTATIN DOSAGE TO 20 MG DAILY (OR 40 MG DAILY FOR PATIENTS WHO HAVE PREVIOUSLY TOLERATED SIMVASTATIN 80 MG DAILY FOR AT LEAST ONE YEAR WITHOUT EVIDENCE OF MUSCLE TOXICITY). REFER TO THE SIMVASTATIN PRESCRIBING INFORMATION FOR SIMVASTATIN DOSING RECOMMENDATIONS.
INTERACTION BETWEEN LOVASTATIN AND LOMITAPIDE HAS NOT BEEN STUDIED. HOWEVER, THE METABOLIZING ENZYMES AND TRANSPORTERS RESPONSIBLE FOR THE DISPOSITION OF LOVASTATIN AND SIMVASTATIN ARE SIMILAR, SUGGESTING THAT JUXTAPID MAY INCREASE THE EXPOSURE OF LOVASTATIN; THEREFORE, REDUCING THE DOSE OF LOVASTATIN SHOULD BE CONSIDERED WHEN INITIATING JUXTAPID.
P-GLYCOPROTEIN SUBSTRATES
LOMITAPIDE IS AN INHIBITOR OF P-GLYCOPROTEIN (P-GP). COADMINISTRATION OF LOMITAPIDE WITH P-GP SUBSTRATES (SUCH AS ALISKIREN, AMBRISENTAN, COLCHICINE , DABIGATRAN ETEXILATE, DIGOXIN , EVEROLIMUS, FEXOFENADINE , IMATINIB, LAPATINIB, MARAVIROC, NILOTINIB, POSACONAZOLE, RANOLAZINE, SAXAGLIPTIN, SIROLIMUS , SITAGLIPTIN , TALINOLOL, TOLVAPTAN, TOPOTECAN) MAY INCREASE THE ABSORPTION OF P-GP SUBSTRATES. DOSE REDUCTION OF THE P-GP SUBSTRATE SHOULD BE CONSIDERED WHEN USED CONCOMITANTLY WITH LOMITAPIDE.
BILE ACID SEQUESTRANTS
JUXTAPID HAS NOT BEEN TESTED FOR INTERACTION WITH BILE ACID SEQUESTRANTS. ADMINISTRATION OF JUXTAPID AND BILE ACID SEQUESTRANTS SHOULD BE SEPARATED BY AT LEAST 4 HOURS SINCE BILE ACID SEQUESTRANTS CAN INTERFERE WITH THE ABSORPTION OF ORAL MEDICATIONS.
WARNINGS & PRECAUTIONS
WARNINGS
INCLUDED AS PART OF THE PRECAUTIONS SECTION.
PRECAUTIONS
RISK OF HEPATOTOXICITY
JUXTAPID CAN CAUSE ELEVATIONS IN TRANSAMINASES AND HEPATIC STEATOSIS, AS DESCRIBED BELOW [SEE JUXTAPID REMS PROGRAM]. 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 ].
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 CLINICALLY MEANINGFUL ELEVATIONS IN BILIRUBIN, INR, OR ALKALINE PHOSPHATASE [SEE ADVERSE REACTIONS ].
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 ].
MONITORING OF TRANSAMINASES
BEFORE INITIATING JUXTAPID AND DURING TREATMENT, MONITOR TRANSAMINASES AS RECOMMENDED IN TABLE 3.
TABLE 3: RECOMMENDATIONS FOR MONITORING TRANSAMINASES
TIME RECOMMENDATIONS
BEFORE INITIATING TREATMENT · MEASURE ALT, AST, ALKALINE PHOSPHATASE, AND TOTAL BILIRUBIN. · IF ABNORMAL, CONSIDER INITIATING JUXTAPID ONLY AFTER AN APPROPRIATE WORK-UP AND THE BASELINE ABNORMALITIES HAVE BEEN EXPLAINED OR RESOLVED. · JUXTAPID IS CONTRAINDICATED IN PATIENTS WITH MODERATE OR SEVERE HEPATIC IMPAIRMENT, OR ACTIVE LIVER DISEASE , INCLUDING UNEXPLAINED PERSISTENT ELEVATIONS OF SERUM TRANSAMINASES [SEE CONTRAINDICATIONS ].
DURING THE FIRST YEAR · MEASURE LIVER-RELATED TESTS (ALT AND AST, AT A MINIMUM) PRIOR TO EACH INCREASE IN DOSE OR MONTHLY, WHICHEVER OCCURS FIRST.
AFTER THE FIRST YEAR · MEASURE LIVER-RELATED TESTS (ALT AND AST, AT A MINIMUM) AT LEAST EVERY 3 MONTHS AND BEFORE ANY INCREASE IN DOSE.
AT ANY TIME DURING TREATMENT · IF TRANSAMINASES ARE ABNORMAL, REDUCE OR WITHHOLD DOSING OF JUXTAPID AND MONITOR AS RECOMMENDED [SEE DOSAGE AND ADMINISTRATION ].
· 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.
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 ]. 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.
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 1-85JUXTAPID (1-855-898-2743).