Juxtapid Drug Information

is indicated as an adjunct to a low-fat diet and exercise and other low density lipoprotein cholesterol (LDL-C) therapies to reduce LDL-C in adults and pediatric patients aged 2 years and older with homozygous familial hypercholesterolemia (HoFH). JUXTAPID is a microsomal triglyceride transfer protein inhibitor indicated as an adjunct to a low-fat diet and exercise and other low-density lipoprotein cholesterol (LDL-C) therapies, to reduce LDL-C in adult and pediatric patients aged 2 years and older with HoFH..

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. Adults with HoFH 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 . 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. Table 8: Adverse Reactions Reported in ≥10% of Patients in the Adult Clinical Trial ADVERSE REACTION N (%) Diarrhea 23 Nausea 19 Dyspepsia 11 Abdominal pain 10 Vomiting 10 Chest pain 7 Decreased weight 7 Abdominal discomfort 6 Abdominal distension 6 Constipation 6 Flatulence 6 Influenza 6 Fatigue 5 Increased ALT 5 Nasopharyngitis 5 Back pain 4 Gastroenteritis 4 Pharyngolaryngeal pain 4 Angina pectoris 3 Defecation urgency 3 Dizziness 3 Fever 3 Gastroesophageal reflux disease 3 Headache 3 Nasal congestion 3 Palpitations 3 Rectal tenesmus 3 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%). Pediatric Patients with HoFH Aged 5 to 17 years 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 . Table 9: Adverse Reactions Reported in ≥10% of Pediatric Patients Aged 5 to 17 Years ADVERSE REACTION N (%) Elevated transaminases Grouped terms composed of several similar terms 23 Abdominal pain 23 Diarrhea 22 Vomiting 12 Decreased appetite 6 Nausea 5 Transaminase Elevations 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. 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.

Table 10: Patient Incidence of Transaminase Elevations During the Clinical Trials ADULTS Upper limits of normal (ULN) ranged from 33 to 41 international units/L for ALT and 36 to 43 international units/L for AST. N (%) PEDIATRIC PATIENTS AGED 5 TO 17 YEARS ULN ranged from 21 to 55 international units/L for ALT and 24 to 60 international units/L for AST, based on age and gender. N (%) Total Patients 29 43 Maximum ALT ≥3 to <5 × ULN 6 3 ≥5 to <10 × ULN 3 2 ≥10 to <20 × ULN 1 0 ≥20 × ULN 0 0 Maximum AST ≥3 to <5 × ULN 5 3 ≥5 to <10 × ULN 1 0 ≥10 to <20 × ULN 0 0 ≥20 × ULN 0 0 Hepatic Steatosis 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.

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: Myalgia Skin reactions: Alopecia

Moderate and Strong

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

Weak

CYP3A4 Inhibitors Weak CYP3A4 inhibitors can increase lomitapide exposure approximately 2-fold . 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) .

Warfarin 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 .

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 . 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

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.

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.

Pregnancy Pregnancy Exposure 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. Risk Summary Based on findings from animal studies, JUXTAPID use is contraindicated in pregnancy since it may cause fetal harm.

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.

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

is contraindicated in the following conditions: Pregnancy . Concomitant administration of JUXTAPID with moderate or strong CYP3A4 inhibitors, as this can increase JUXTAPID exposure. 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 . Pregnancy. Concomitant use with strong or moderate CYP3A4 inhibitors.

Moderate or severe hepatic impairment or active liver disease including unexplained persistent abnormal liver function tests.

There is no specific treatment in the event of overdose of JUXTAPID. In the event of overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Liver-related tests should be monitored. Hemodialysis is unlikely to be beneficial given that lomitapide is highly protein-bound.