Lomitapide Mesylate

5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. Discontinue JUXTAPID if pregnancy detected ( 5.3 ). Gastrointestinal adverse reactions occur in 93% of adult and 72% of pediatric patients and could affect absorption of concomitant oral medications ( 5.5 ). 5.1 Risk of Hepatotoxicity 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) ] . Elevation of Transaminases 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. Monitoring of Transaminases Before initiating JUXTAPID and during treatment, monitor transaminases as recommended in Table 7. Table 7: 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 >1 and <3 times ULN, no dose modification is required. Continue routine monitoring of liver-related tests (once monthly during the first year of treatment and every 3 months thereafter). If transaminases are ≥3 times ULN, reduce or withhold dosing of JUXTAPID and monitor as recommended [see Dosage and Administration (2.5) ]. 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 times 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 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. 5.2 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 1-85-JUXTAPID (1-855-898-2743). 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. 5.4 Reduced Absorption of Fat-Soluble Vitamins and Serum Fatty Acids 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. 5.5 Gastrointestinal Adverse Reactions 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) ] . 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 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) ]. 5.7 Risk of Myopathy with Concomitant Use of Simvastatin or Lovastatin 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. 5.8 Risk of Supratherapeutic or Subtherapeutic Anticoagulation with Warfarin 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) ] . 5.9 Risk of Malabsorption with Rare Hereditary Disorders of Galactose Intolerance 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.