Get your patient on Juxtapid - Lomitapide Mesylate capsule (Lomitapide Mesylate)

Before beginning treatment with JUXTAPID:

• Liver function tests: Measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin [see Warnings and Precautions (5.1) ] ;
• Pregnancy testing: Obtain a negative pregnancy test in females of reproductive potential prior to initiating treatment with JUXTAPID [see Contraindications (4) , Warnings and Precautions (5.3) , and Use in Specific Populations (8.1 , 8.3) ] ;
• Dietary counseling: Initiate a low-fat diet supplying <20% of energy from fat or less than 30 grams of fat, whichever is less [see Warnings and Precautions (5.5) ].

The recommended initiation dosage is

• 2 mg for patients aged 2 to 15 years.
• 5 mg for patients aged 16 years and older.

• Follow the titration schedule presented in Table 1 according to the patient's age. Select the dosage based on target LDL-C level recommended in current HoFH treatment guidance, safety, and tolerability.
• For pediatric patients, if a patient crosses over into the next age group, escalate the dosage of JUXTAPID to dosage recommended for the new age group.
• Measure transaminases prior to any dosage increase. If transaminases are abnormal, reduce or withhold dosing of JUXTAPID and monitor as recommended [see Warnings and Precautions (5.1) ] .

The maximum recommended dosage is:

• 20 mg for patients aged 2 to 10 years.
• 40 mg for patients aged 11 to 17 years.
• 60 mg for patients aged 18 years and older.

To reduce the risk of developing a fat-soluble nutrient deficiency due to JUXTAPID's mechanism of action in the small intestine [see Warnings and Precautions (5.4) ] , administer JUXTAPID with daily nutritional supplements. See Table 2 for nutritional supplementation recommendations according to age.

• Take JUXTAPID orally once daily with a glass of water, without food, at least 2 hours after the evening meal. Administration with food may increase the risk of gastrointestinal adverse reactions [see Warnings and Precautions (5.5) ].
• Swallow JUXTAPID capsules whole:
  • If a patient is unable to swallow the intact capsule(s), open the capsule(s) and sprinkle the contents on 1 tablespoon of apple sauce or mashed banana.
  • For younger patients who require a smaller spoon for administration, sprinkle the capsule contents onto 1 tablespoon of apple sauce or mashed banana, and administer the entire amount using the smaller spoon.
• Administer JUXTAPID at least 4 hours before or 4 hours after administration of a bile acid sequestrant [see Drug Interactions (7.6) ].

JUXTAPID is contraindicated with concomitant use of moderate and strong cytochrome P450 3A4 (CYP3A4) inhibitors [see Contraindications (4) and Drug Interactions (7.1) ].

• J UXTAPID Initiation in Patients Treated with a Stable Dosage of a Weak CYP3A4 Inhibitor:
  • Follow the recommended dosage and titration schedule described in Table 1. Consider target LDL-C level, safety, and tolerability when selecting a maintenance dosage.
  • Refer to the maximum recommended dose of JUXTAPID described in Table 3.

• Decrease the dosage of JUXTAPID by half.
• The dosage of JUXTAPID may be further titrated according to target LDL-C level, safety, and tolerability, not to exceed the maximum recommended dose of JUXTAPID described in Table 3.

• JUXTAPID Initiation in Patients Treated with a Stable Dosage of an Oral Contraceptive:
  • Follow the recommended dosage and titration schedule described in Table 1.
  • Consider target LDL-C level, safety, and tolerability when selecting a maintenance dosage, not to exceed the maximum recommended dose of JUXTAPID described in Table 3.
• Oral contraceptive Initiation in Patients Treated with a Stable Dosage of JUXTAPID:
  • Decrease the dose of JUXTAPID by one-third.
  • The dosage of JUXTAPID may be further titrated according to target LDL-C level, safety, and tolerability, not to exceed the maximum recommended dose of JUXTAPID described in Table 3.

Table 4 summarizes recommendations for dosage adjustment and monitoring for patients who develop elevated transaminases during treatment with JUXTAPID [see Warnings and Precautions (5.1) ].

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 times ULN, or active liver disease, discontinue treatment with JUXTAPID and investigate to identify the probable cause [see Warnings and Precautions (5.1) ] .

The recommended dosage of JUXTAPID in patients with end-stage renal disease (eGFR <15 mL/min/1.73m ² ) receiving hemodialysis is described in Table 5. JUXTAPID has not been studied in patients with mild, moderate, or severe renal impairment, including those with end stage renal disease not receiving dialysis [see Use in Specific Populations (8.6) ].

JUXTAPID is contraindicated in 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 (5.6) ] . Table 6 summarizes the dosage adjustment for patients with baseline mild hepatic impairment (Child-Pugh A) [see Use in Specific Populations (8.7) ] .

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

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.

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.

There are no data on the presence of lomitapide in human or animal milk, effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions, including hepatotoxicity, advise patients that breastfeeding is not recommended during treatment with JUXTAPID.

Females of reproductive potential should have a negative pregnancy test before starting JUXTAPID.

Based on animal studies, JUXTAPID may cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective contraception during treatment with JUXTAPID and for two weeks after the final dose .

The use of JUXTAPID may result in reduced efficacy of oral contraceptives if vomiting or diarrhea occurs. Advise patients using oral contraceptives and who experience vomiting or diarrhea to use an effective alternative contraceptive method until 7 days after resolution of symptoms [see Drug Interactions (7.2) ].

The safety and effectiveness of JUXTAPID as an adjunct to other LDL-C lowering therapies for the treatment of HoFH have been established in pediatric patients aged 2 years and older. Use of JUXTAPID for this indication is supported by evidence from an open-label trial in adults; an open-label trial of 43 pediatric patients with HoFH aged 5 to 17 years old; and additional pharmacokinetic modeling and simulation data for pediatric patients aged 2 years and older. Adverse reactions reported in pediatric patients aged 5 to 17 years were similar to those reported in adults [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] .

The safety and effectiveness of JUXTAPID have not been established in pediatric patients younger than 2 years old.

Clinical trials of JUXTAPID did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. In general, dosing for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Patients with end-stage renal disease (eGFR <15 mL/min/1.73m ² ) receiving hemodialysis, lomitapide exposure increased approximately 50% compared with healthy volunteers [see Clinical Pharmacology (12.3) ] . The maximum recommended dosage of JUXTAPID in patients with end-stage renal disease receiving hemodialysis is lower than in those with normal renal function [see Dosage and Administration (2.6) ]. Effects of mild, moderate, and severe renal impairment, including those with end-stage renal disease not yet receiving dialysis, on lomitapide exposure have not been studied. However, it is possible that patients with renal impairment who are not yet receiving dialysis may experience increases in lomitapide exposure exceeding 50% [see Clinical Pharmacology (12.3) ] .

JUXTAPID is contraindicated in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment since the lomitapide exposure increased 164% compared with healthy volunteers [see Contraindications (4) and Clinical Pharmacology (12.3) ] . In adult patients with mild hepatic impairment (Child-Pugh A), lomitapide exposure increased approximately 50% compared with healthy volunteers [see Clinical Pharmacology (12.3) ] . The maximum recommended dosage of JUXTAPID in patients with mild hepatic impairment is lower than in those with normal hepatic function [see Dosage and Administration (2.7) ].

JUXTAPID can cause elevations in transaminases and hepatic steatosis in adults and pediatric patients, as described below [see Warnings and Precautions (5.2) ] . JUXTAPID may induce steatohepatitis, which can progress to cirrhosis over several years. Clinical trials of JUXTAPID for HoFH would have been unlikely to detect this adverse outcome given their size and duration [see Clinical Studies (14) ] .

Elevations in transaminases (ALT and/or AST) are associated with JUXTAPID.

In the 78-week adult clinical trial, 10 (34%) of the 29 patients with HoFH had at least one elevation in ALT or AST ≥3 times ULN, and 4 (14%) of the patients had at least one elevation in ALT or AST ≥5 times ULN. There were no concomitant or subsequent clinically meaningful elevations in bilirubin, INR, or alkaline phosphatase [see Adverse Reactions (6.1) ]. No patients discontinued prematurely because of elevated transaminases. Among the 19 patients who subsequently enrolled in the adult HoFH extension trial, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24 times ULN, AST 13 times ULN) that had several possible causes, including a drug-drug interaction between JUXTAPID and the strong CYP3A4 inhibitor clarithromycin [see Drug Interactions (7.1) ].

In the 104-week open-label trial in pediatric patients aged 5 to 17 years with HoFH exposed to JUXTAPID, 6 (14%) of the 43 patients with HoFH had at least one elevation in ALT and/or AST ≥3 times ULN, including 2 (5%) patients who had at least one elevation in ALT ≥5 times ULN. No patients discontinued treatment because of increased transaminases, although some patients required dose interruptions or reductions for management of liver transaminase elevations.

Before initiating JUXTAPID and during treatment, monitor transaminases as recommended in Table 7.

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 conducted in adults, 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 scheduled liver biopsies were not performed in the adult clinical trial.

In a phase 3 trial in pediatric patients, two patients (both aged 5 to 10 years) developed mild hepatic steatosis (as assessed by ultrasound), which resolved without specific medical interventions, other than the protocol specified follow-up ultrasounds and laboratory monitoring. Overall, the median absolute increase in hepatic fat was 4% after 24 weeks and 104 weeks, from 3% at baseline, measured by NMR. As with data from the adult patients, clinical pediatric 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.

Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. Drinking more than one alcoholic drink per day is not recommended for patients taking JUXTAPID.

Exercise caution when using JUXTAPID 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.

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).

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.

Given its mechanism of action in the small intestine, JUXTAPID may reduce the absorption of fat-soluble nutrients. In clinical trials of adult and pediatric patients with HoFH, patients were provided daily dietary supplements of vitamin E, linoleic acid, ALA, EPA, and DHA.

In the adult clinical trial, the median levels of serum vitamin E, ALA, linoleic acid, EPA, DHA, and arachidonic acid (AA) 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.

In the pediatric clinical trial, overall, mean serum vitamin E levels decreased from baseline to Week 104 as expected but were still within or above the upper limit of the reference range. Mean values of linoleic acid, ALA, EPA, AA, and DHA all remained within the normal range or above the upper limit of the reference range during the 104-week trial. Eicosatrienoic acid was below lower limit of normal throughout the trial and increased to a mean normal value by Week 104.

Patients treated with JUXTAPID should take daily nutritional supplements that contain the dosages of vitamin E and essential fatty acids recommended in Dosage and Administration (2.2) . 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.

Gastrointestinal adverse reactions were reported by 27 (93%) of 29 patients in the adult 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 adult 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 this trial for 4 (14%) patients.

Gastrointestinal adverse reactions were reported by 31 (72%) of the 43 patients in the pediatric clinical trial. Diarrhea occurred in 22 (51%) patients and was more frequently reported by patients 11 to 17 years of age compared to patients 5 to 10 years of age (57% and 45%, respectively). Abdominal pain occurred in 19 (44%) patients and was reported with similar incidences in patients 5 to 10 years of age and 11 to 17 years of age. Vomiting occurred in 12 (28%) patients and was more frequently reported by patients 5 to 10 years of age compared to patients 11 to 17 years of age (50% and 9% of patients, respectively). Gastrointestinal reactions contributed to the reasons for early discontinuation from the trial for 2 (5%) patients.

There have been post-marketing reports of severe diarrhea in adults treated with 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.

Absorption of concomitant oral medications may be affected in patients who develop diarrhea or vomiting.

To reduce the risk of gastrointestinal adverse reactions, instruct patients or their caregiver(s) to adhere to a low-fat diet supplying <20% of energy from fat or less than 30 grams of fat, whichever is less. Increase the dosage of JUXTAPID gradually. Individualize the maximum daily fat goal based on caloric needs due to age, growth, activity level, and tolerability. Monitor growth and weight loss in pediatric patients who are below the 10th percentile for height, weight, or BMI [see Dosage and Administration (2.1) and (2.2) ] .

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 adult patient with HoFH developed markedly elevated transaminases (ALT 24 times ULN, AST 13 times 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.

Avoid food or drinks containing grapefruit during JUXTAPID treatment.

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 half the maximum recommended dosage except when co-administered with oral contraceptives only, in which case the maximum recommended JUXTAPID dose is approximately two thirds the maximum recommended dose (Table 3) [see Dosage and Administration (2.4) and Drug Interactions (7.2) ].

The risk of myopathy, including rhabdomyolysis, with simvastatin and lovastatin monotherapy is dose related. Lomitapide approximately doubles the exposure to simvastatin; therefore, it is recommended to reduce the dose of simvastatin by 50% when initiating JUXTAPID [see Clinical Pharmacology (12.3) ] . While taking JUXTAPID, limit simvastatin dosage to 20 mg daily (or 40 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year without evidence of muscle toxicity). Refer to the simvastatin prescribing information for additional dosing recommendations.

Interaction between lovastatin and lomitapide has not been studied. However, the metabolizing enzymes and transporters responsible for the disposition of lovastatin and simvastatin are similar, suggesting that JUXTAPID may increase the exposure of lovastatin; therefore, reducing the dose of lovastatin should be considered when initiating JUXTAPID.

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 adult 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) ] .

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.

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 adult 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 31 years (range, 18 to 55 years), 16 (55%) patients were male, 25 (86%) patients were White, 2 (7%) were Asian, 1 (3%) was Black or African American, and 1 (3%) was multi-racial [see Clinical Studies (14) ] .

Five (17%) of the 29 patients 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 clinical trial included diarrhea, nausea, vomiting, dyspepsia, and abdominal pain. Other common adverse reactions, reported by 5 to 7 (17 to 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 adult patients are presented in Table 8.

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%).

A single-arm, open label, multinational, 104-week trial was conducted in 43 pediatric patients with HoFH aged 5 to 17 years. Thirty-nine of the patients completed the trial. The dose of JUXTAPID was escalated from an age-dependent starting dose to a maximum tolerated dose (MTD) as applicable to the pediatric age group and based on acceptable safety and tolerability criteria, in addition to LDL-C goals [see Dosage and Administration (2) and Clinical Studies (14) ] .

During the adult clinical trial, 10 (34%) of 29 patients had at least one elevation in ALT and/or AST ≥3 times ULN (see Table 10 ). 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.

Among the 19 adult patients who enrolled in an extension trial following the adult clinical trial, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24 times ULN, AST 13 times ULN) that had several possible causes, including a drug-drug interaction between JUXTAPID and the strong CYP3A4 inhibitor clarithromycin [see Drug Interactions (7.1) ].

In the pediatric trial, 6 patients experienced elevations in ALT and/or AST ≥3 times ULN (see Table 10 ). No discontinuations occurred due to increased transaminases in the trial, although some patients required interrupting JUXTAPID or reducing the dose.

Hepatic fat was prospectively measured using magnetic resonance spectroscopy (MRS) in all eligible patients during the adult 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.

In the pediatric clinical trial, the median absolute increase in hepatic fat was 4% after 24 weeks and 104 weeks, from 3% at baseline, measured by NMR. Among the 19 patients with hepatic fat measured by NMR on at least one occasion during the trial, 8 (42%) patients exhibited an increase in hepatic fat to >10% including 1 (5%) patient with an increase to >20%. Data from pediatric patients with follow-up measurements after Week 104 suggest that hepatic fat accumulation is reversable after stopping treatment with JUXTAPID, but whether histological sequelae remain is unknown, especially after long term use.

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: Myalgia

Skin reactions: Alopecia

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 with JUXTAPID is contraindicated. Concomitant use of moderate CYP3A4 inhibitors has not been studied, but concomitant use with JUXTAPID is contraindicated since lomitapide exposure will likely increase significantly in the presence of these inhibitors.

Avoid food or drinks containing grapefruit during JUXTAPID treatment [see Contraindications (4) , Warnings and Precautions (5.6) , and Clinical Pharmacology (12.3) ] .

Weak CYP3A4 inhibitors can increase lomitapide exposure approximately 2-fold [see Clinical Pharmacology (12.3) ] . 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 half the maximum recommended dosage except when co-administered with oral contraceptives only, in which case the maximum recommended JUXTAPID dosage is approximately two thirds of the maximum recommended dosage (Table 3) [see Dosage and Administration (2.4) , Warnings and Precautions (5.6) , and Clinical Pharmacology (12.3) ] .

Lomitapide increases plasma concentrations of both R(+)-warfarin and S(-)-warfarin by approximately 30% and increases the INR 22%. Patients taking warfarin should undergo regular monitoring of INR, particularly after any changes in JUXTAPID dosage. The dose of warfarin should be adjusted as clinically indicated [see Warnings and Precautions (5.8) ] .

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 (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 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.

Lomitapide is an inhibitor of P-glycoprotein (P-gp). Coadministration of JUXTAPID with P-gp substrates may increase the absorption of P-gp substrates. Dose reduction of the P-gp substrate should be considered when used concomitantly with JUXTAPID.

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.

JUXTAPID directly binds and inhibits microsomal triglyceride transfer protein (MTP), which resides in the lumen of the endoplasmic reticulum, thereby preventing the assembly of apo B-containing lipoproteins in enterocytes and hepatocytes. This inhibits the synthesis of chylomicrons and VLDL. The inhibition of the synthesis of VLDL leads to reduced levels of plasma LDL-C.

At a concentration 23 times the C _max of the maximum recommended dose, lomitapide does not prolong QTc to any clinically relevant extent.

Lomitapide pharmacokinetics is approximately dose-proportional for oral single doses from 10 to 100 mg. Following the maximum recommended dose of 60 mg daily in patients ≥18 years old, the steady state exposure (i.e., AUC _tau with tau=24 hours) and C _max were predicted to be 116.34 ng/mL∙h (with 90% prediction interval of 41.7 to 362.6 ng/mL∙h) and 5.74 ng/mL (2.00 to 17.9 ng/mL) respectively (see Table 11 ).

The absolute bioavailability of lomitapide is approximately 7%. Upon oral administration of a single 60-mg dose of JUXTAPID, the lomitapide t _max is around 6 hours in healthy volunteers.

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

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 .

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.

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of 60 mg lomitapide in healthy adult volunteers with normal hepatic function compared with adult patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. In patients with moderate hepatic impairment, lomitapide AUC and C _max were 164% and 361% higher, respectively, compared with healthy volunteers. In patients with mild hepatic impairment, lomitapide AUC and C _max were 47% and 4% higher, respectively, compared with healthy volunteers. Lomitapide has not been studied in patients with severe hepatic impairment (Child-Pugh score 10 to 15) [see Dosage and Administration (2.7) , Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.7) ] .

A single-dose, open-label study in adults was conducted to evaluate the pharmacokinetics of 60 mg lomitapide in patients with end-stage renal disease receiving hemodialysis compared with healthy adult 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-inf and C _max were 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 (2.6) and Use in Specific Populations (8.6) ] .

Predicted lomitapide exposures under the maximum dosage levels (i.e., 20 and 40 mg) for pediatric patients in each age group are presented in Table 11.

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).

Table 12 summarizes the effect of co-administered drugs on lomitapide AUC and C _max .

Table 13 summarizes the effects of lomitapide on the AUC and C _max of co-administered drugs.

In a 2-year dietary carcinogenicity study in mice, lomitapide was administered at doses of 0.3, 1.5, 7.5, 15, or 45 mg/kg/day. There were statistically significant increases in the incidences of liver adenomas and carcinomas in males at doses ≥1.5 mg/kg/day (≥2-times the MRHD at 60 mg based on AUC) and in females at ≥7.5 mg/kg/day (≥10-times the human exposure at 60 mg based on AUC). Incidences of small intestinal carcinomas in males and combined adenomas and carcinomas in females were significantly increased at doses ≥15 mg/kg/day (≥23-times the human exposure at 60 mg based on AUC).

In a 2-year carcinogenicity study in rats, lomitapide was administered by oral gavage for up to 99 weeks at doses of 0.25, 1.7, or 7.5 mg/kg/day in males and 0.03, 0.35, or 2.0 mg/kg/day in females. While the design of the study was suboptimal, there were no statistically significant drug-related increases in tumor incidences at exposures up to 6-times (males) and 8-times (females) higher than human exposure at the MRHD based on AUC.

Lomitapide did not exhibit genotoxic potential in a battery of studies, including the in vitro Bacterial Reverse Mutation (Ames) assay, an in vitro cytogenetics assay using primary human lymphocytes, and an oral micronucleus study in rats.

Lomitapide had no effect on fertility in rats at doses up to 5 mg/kg/day at systemic exposures estimated to be 4-times (females) and 5-times (males) higher than in humans at 60 mg based on AUC.

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.