Juxtapid (Lomitapide Mesylate)

JUXTAPID is contraindicated in the following conditions:

• Pregnancy
  [see

  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 use effective contraception during therapy with JUXTAPID and for two weeks after the final dose. If pregnancy is detected, discontinue JUXTAPID.

  and

  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to JUXTAPID during pregnancy. For additional information visit www.JUXTAPID.com or call the Global Lomitapide Pregnancy Exposure Registry (PER) at 1-877-902-4099. Healthcare professionals are encouraged to call the PER at 1-877-902-4099 to enroll patients who become pregnant during JUXTAPID treatment.

  Risk Summary

  Based on findings from animal studies, JUXTAPID use is contraindicated in pregnancy since it may cause fetal harm

  [see Contraindications (4), Warnings and Precautions (5.3)].

  Available human data are insufficient to draw conclusions about any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, in animal reproduction studies, lomitapide was teratogenic in rats at clinically relevant exposures and in ferrets at exposures estimated to be less than human therapeutic exposure at 60 mg when administered during organogenesis, based on AUC comparisons. Embryo-fetal lethality was observed in rabbits at 6-times the maximum recommended human dose (MRHD) of 60 mg based on body surface area. If pregnancy is detected, discontinue JUXTAPID.

  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

  Data

  Animal Data

  Oral gavage doses of 0.04, 0.4, or 4 mg/kg/day lomitapide given to pregnant rats from gestation day 6 through organogenesis were associated with fetal malformations at ≥2-times human exposure at the MRHD (60 mg) based on plasma AUC comparisons. Fetal malformations included umbilical hernia, gastroschisis, imperforate anus, alterations in heart shape and size, limb malrotations, skeletal malformations of the tail, and delayed ossification of cranial, vertebral and pelvic bones.

  Oral gavage doses of 1.6, 4, 10, or 25 mg/kg/day lomitapide given to pregnant ferrets from gestation day 12 through organogenesis were associated with both maternal toxicity and fetal malformations at exposures that ranged from less than the human exposure at the MRHD to 5-times the human exposure at the MRHD. Fetal malformations included umbilical hernia, medially rotated or short limbs, absent or fused digits on paws, cleft palate, open eye lids, low-set ears, and kinked tail.

  Oral gavage doses of 0.1, 1, or 10 mg/kg/day lomitapide given to pregnant rabbits from gestation day 6 through organogenesis were not associated with adverse effects at systemic exposures up to 3-times the MRHD of 60 mg based on body surface area comparison. Treatment at doses of ≥20 mg/kg/day, ≥6-times the MRHD, resulted in embryo-fetal lethality.

  Pregnant female rats given oral gavage doses of 0.1, 0.3, or 1 mg/kg/day lomitapide from gestation day 7 through termination of nursing on lactation day 20 were associated with malformations at systemic exposures equivalent to human exposure at the MRHD of 60 mg based on AUC. Increased pup mortality occurred at 4-times the MRHD.

  ]
  .
• Concomitant administration of JUXTAPID with moderate or strong CYP3A4 inhibitors, as this can increase JUXTAPID exposure
  [see

  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 24× ULN, AST 13× 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)].

  ,

  7.1 Moderate and Strong CYP3A4 Inhibitors

  A strong CYP3A4 inhibitor has been shown to increase lomitapide exposure approximately 27-fold

  [see Clinical Pharmacology (12.3)]

  . Concomitant use of strong CYP3A4 inhibitors (such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir, voriconazole) with lomitapide is contraindicated. Concomitant use of moderate CYP3A4 inhibitors (such as amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) has not been studied, but concomitant use with lomitapide is contraindicated since lomitapide exposure will likely increase significantly in the presence of these inhibitors.

  Patients must avoid grapefruit juice while taking JUXTAPID

  [see Contraindications (4), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)]

  .

  , and

  12.3 Pharmacokinetics

  Absorption

  Upon oral administration of a single 60-mg dose of JUXTAPID, the lomitapide t_maxis around 6 hours in healthy volunteers. The absolute bioavailability of lomitapide is approximately 7%. Lomitapide pharmacokinetics is approximately dose-proportional for oral single doses from 10-100 mg.

  Distribution

  The mean lomitapide volume of distribution at steady state is 985-1292 liters. Lomitapide is 99.8% plasma-protein bound.

  Metabolism

  Lomitapide is metabolized extensively by the liver. The metabolic pathways include oxidation, oxidative N-dealkylation, glucuronide conjugation, and piperidine ring opening. Cytochrome P450 (CYP) 3A4 metabolizes lomitapide to its major metabolites, M1 and M3, as detected in plasma. The oxidative N-dealkylation pathway breaks the lomitapide molecule into M1 and M3. M1 is the moiety that retains the piperidine ring, whereas M3 retains the rest of the lomitapide molecule

  in vitro

  . CYPs 1A2, 2B6, 2C8, and 2C19 may metabolize lomitapide to a small extent to M1. M1 and M3 do not inhibit activity of microsomal triglyceride transfer protein

  in vitro

  .

  Excretion

  In a mass-balance study, a mean of 59.5% and 33.4% of the dose was excreted in the urine and feces, respectively. In another mass-balance study, a mean of 52.9% and 35.1% of the dose was excreted in the urine and feces, respectively. Lomitapide was not detectable in urine samples. M1 is the major urinary metabolite. Lomitapide is the major component in the feces. The mean lomitapide terminal half-life is 39.7 hours.

  Specific Populations

  Hepatic Impairment

  A single-dose, open-label study was conducted to evaluate the pharmacokinetics of 60 mg lomitapide in healthy volunteers with normal hepatic function compared with patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. In patients with moderate hepatic impairment, lomitapide AUC and C_maxwere 164% and 361% higher, respectively, compared with healthy volunteers. In patients with mild hepatic impairment, lomitapide AUC and C_maxwere 47% and 4% higher, respectively, compared with healthy volunteers. Lomitapide has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15)

  [see Dosage and Administration (2.6), Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.7)]

  .

  Renal Impairment

  A single-dose, open-label study was conducted to evaluate the pharmacokinetics of 60 mg lomitapide in patients with end-stage renal disease receiving hemodialysis compared with healthy volunteers with normal renal function. Healthy volunteers had estimated creatinine clearance >80 mL/min by the Cockcroft-Gault equation. Compared with healthy volunteers, lomitapide AUC_0-infand C_maxwere 40% and 50% higher, respectively, in patients with end-stage renal disease receiving hemodialysis. Effects of mild, moderate, and severe renal impairment as well as end-stage renal disease not yet on dialysis on lomitapide exposure have not been studied

  [see Dosage and Administration (2.5)and Use in Specific Populations (8.6)]

  .

  Drug Interactions

  [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.6), (5.7), (5.8), and Drug Interactions (7)].

  In vitro Assessment of Drug Interactions

  Lomitapide does not induce CYPs 1A2, 3A4, or 2B6. Lomitapide inhibits CYP3A4. Lomitapide does not inhibit CYPs 1A2, 2B6, 2C9, 2C19, 2D6, or 2E1. M1 and M3 do not induce CYPs 1A2, 3A4, or 2B6. M1 and M3 do not inhibit CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. Lomitapide is not a P-gp substrate. Lomitapide inhibits P-gp but does not inhibit breast cancer resistance protein (BCRP).

  Effects of other Drugs on Lomitapide

  Table 6 summarizes the effect of coadministered drugs on lomitapide AUC and C_max.

  Table 6: Effect of Coadministered Drugs on Lomitapide Systemic Exposure

  COADMINISTERED DRUG	DOSING OF COADMINISTERED DRUG	DOSING OF LOMITAPIDE	RATIO OF LOMITAPIDE EXPOSURE WITH/WITHOUT COADMINISTERED DRUG NO EFFECT = 1
  			AUC	Cmax
  BID = twice daily; QD = once daily
  ↑ = increase
  Contraindicated with lomitapide [see Contraindications (4)and Warnings and Precautions (5.6)]
  Ketoconazole	200 mg BID for 9 days	60 mg single dose	↑ 27	↑ 15
  Adjustment necessary when coadministered with lomitapide [see Dosage and Administration (2.3)and Warnings and Precautions (5.6)]
  			AUC	Cmax
  Atorvastatin	80 mg QD	20 mg single dose	↑2	↑2.1
  Ethinyl Estradiol (EE) / norgestimate	0.035 mg EE/ 0.25 mg norgestimate QD	20 mg single dose	↑1.3	↑1.4

  Effect of Lomitapide on other Drugs

  Table 7 summarizes the effects of lomitapide on the AUC and C_maxof coadministered drugs.

  Table 7: Effect of Lomitapide on the Systemic Exposure of Coadministered Drugs

  COADMINISTERED DRUG	DOSING OF COADMINISTERED DRUG	DOSING OF LOMITAPIDE	CHANGE OF COADMINISTERED DRUG EXPOSURE WITH / WITHOUT LOMITAPIDE
  				AUC	Cmax
  QD = once daily; INR = international normalized ratio; ↑ = increase; ↓ = decrease
  Dosage adjustment necessary when coadministered with lomitapide
  SimvastatinLimit 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.	40 mg single dose	60 mg QD × 7 days	Simvastatin	↑ 99%	↑ 102%
  			Simvastatin acid	↑ 71%	↑ 57%
  	20 mg single dose	10 mg QD × 7 days	Simvastatin	↑ 62%	↑65%
  			Simvastatin acid	↑ 39%	↑ 35%
  WarfarinPatients taking warfarin should undergo regular monitoring of the INR, especially after any changes in lomitapide dosage.	10 mg single dose	60 mg QD × 12 days	R(+) warfarin	↑ 28%	↑ 14%
  			S(-) warfarin	↑ 30%	↑ 15%
  			INR	↑ 7%	↑ 22%
  No dosing adjustments required for the following:
  Atorvastatin	20 mg single dose	60 mg QD × 7 days	Atorvastatin acid	↑ 52%	↑63%
  	20 mg single dose	10 mg QD × 7 days	Atorvastatin acid	↑ 11%	↑19%
  Rosuvastatin	20 mg single dose	60 mg QD × 7 days	Rosuvastatin	↑ 32%	↑ 4%
  	20 mg single dose	10 mg QD × 7 days	Rosuvastatin	↑ 2%	↑ 6%
  Fenofibrate, micronized	145 mg single dose	10 mg QD × 7 days	Fenofibric acid	↓ 10%	↓29%
  Ezetimibe	10 mg single dose	10 mg QD × 7 days	Total ezetimibe	↑ 6%	↑ 3%
  Extended release niacin	1000 mg single dose	10 mg QD × 7 days	Nicotinic acid	↑ 10%	↑ 11%
  			Nicotinuric acid	↓ 21%	↓ 15%
  Ethinyl estradiol	0.035 mg QD × 28 days	50 mg QD × 8 days	Ethinyl estradiol	↓ 8%	↓ 8%
  Norgestimate	0.25 mg QD × 28 days	50 mg QD × 8 days	17-Deacetyl norgestimate	↑ 6%	↑ 2%

  ].
• 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

  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 ≥3× ULN, and 4 (14%) of the patients had at least one elevation in ALT or AST ≥5× ULN. There were no concomitant or subsequent 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 24× ULN, AST 13× ULN) that had several possible causes, including a drug-drug interaction between JUXTAPID and the strong CYP3A4 inhibitor clarithromycin

  [see Drug Interactions (7.1)].

  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 (4)] .
  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 (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 ≥2× ULN, or active liver disease, discontinue treatment with JUXTAPID and identify the probable cause.

  Hepatic Steatosis

  JUXTAPID increases hepatic fat, with or without concomitant increases in transaminases. Hepatic steatosis is a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. The long-term consequences of hepatic steatosis associated with JUXTAPID treatment are unknown. During the HoFH clinical trial, the median absolute increase in hepatic fat was 6% after both 26 weeks and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy (MRS)

  [see Adverse Reactions (6.1)].

  Clinical data suggest that hepatic fat accumulation is reversible after stopping treatment with JUXTAPID, but whether histological sequelae remain is unknown, especially after long-term use; protocol liver biopsies were not performed in the HoFH clinical trial.

  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.

  and

  8.7 Hepatic Impairment

  Patients with mild hepatic impairment (Child-Pugh A) should not exceed 40 mg daily since the lomitapide exposure in these patients increased approximately 50% compared with healthy volunteers. JUXTAPID is contraindicated in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment since the lomitapide exposure in patients with moderate hepatic impairment increased 164% compared with healthy volunteers

  [see Contraindications (4)and Clinical Pharmacology (12.3)]

  .

  ]
  .