5.5 Gastrointestinal Adverse Reactions Gastrointestinal adverse reactions were reported by 27 (93%) of 29 patients in the HoFH 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 HoFH 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 the trial for 4 (14%) patients.

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

To reduce the risk of gastrointestinal adverse events, patients should adhere to a low-fat diet supplying <20% of energy from fat and the dosage of JUXTAPID should be increased gradually [see Dosage and Administration (2.1) and (2.2)].

5.6 Concomitant Use of CYP3A4 InhibitorsCYP3A4 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 24x ULN, AST 13x 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 increase the exposure of lomitapide approximately 2-fold; therefore, JUXTAPID dosage should not exceed 30 mg daily when it is used concomitantly with these inhibitors, including atorvastatin and oral contraceptives [see Dosage and Administration (2.3) and Drug Interactions (7.2)].

5.7 Risk of Myopathy with Concomitant Use of Simvastatin or LovastatinThe 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 Subt