Lomitapide

Caution should be exercised when Lojuxta is used with other medicinal products 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 lomitapide with other hepatotoxic medicine is unknown. More frequent monitoring of liver-related tests may be warranted.

Medicinal products that induce CYP3A4 would be expected to increase the rate and extent of metabolism of lomitapide. CYP3A4 inducers exert their effect in a time-dependent manner, and may take at least 2 weeks to reach maximal effect after introduction. Conversely, on discontinuation, CYP3A4 induction may take at least 2 weeks to decline.

Co-administration of a CYP3A4 inducer is expected to reduce the effect of lomitapide. Any impact on efficacy is likely to be variable. When co-administering CYP3A4 inducers (i.e. aminoglutethimide, nafcillin, non-nucleoside reverse transcriptase inhibitors, phenobarbital, rifampicin, carbamazepine, pioglitazone, glucocorticoids, modafinil and phenytoin) with lomitapide, the possibility of a drug-drug interaction affecting efficacy should be considered. The use of St. John's Wort should be avoided with lomitapide.

It is recommended to increase the frequency of LDL-C assessment during such concomitant use and consider increasing the dose of lomitapide to ensure maintenance of the desired level of efficacy if the CYP3A4 inducer is intended for chronic use. On withdrawal of a CYP3A4 inducer, the possibility of increased exposure should be considered and a reduction in the dose of lomitapide may be necessary.

Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. In the Phase 3 study, 3 of 4 patients with ALT elevations > 5x ULN reported alcohol consumption beyond the limits recommended in the protocol. The use of alcohol during lomitapide treatment is not recommended.

Lomitapide inhibits P-gp in vitro, and may increase the absorption of P-gp substrates. Coadministration of lomitapide with P-gp substrates (such as aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan) may increase the absorption of P gp substrates. Dose reduction of the P gp substrate should be considered when used concomitantly with lomitapide.

Weak CYP3A4 inhibitors are expected to increase the exposure of lomitapide when taken simultaneously. When administered with atorvastatin, the dose of lomitapide should either be taken 12 hours apart or be decreased by half. The dose of lomitapide should be administered 12 hours apart from any other weak CYP3A4 inhibitor.

Patients with end-stage renal disease receiving dialysis should not exceed 40 mg daily.

Patients with mild hepatic impairment (Child-Pugh A) should not exceed 40 mg daily.

Lomitapide increases the plasma concentrations of warfarin. Increases in the dose of lomitapide may lead to supratherapeutic anticoagulation, and decreases in the dose may lead to subtherapeutic anticoagulation. Difficulty controlling INR contributed to early discontinuation from the Phase 3 study for one of five patients taking concomitant warfarin. Patients taking warfarin should undergo regular monitoring of the INR, especially after any changes in the dose of lomitapide. The dose of warfarin should be adjusted as clinically indicated.

Lomitapide increases plasma concentrations of statins. Patients receiving lomitapide as adjunctive therapy to a statin should be monitored for adverse events that are associated with the use of high doses of statins. Statins occasionally cause myopathy. In rare cases, myopathy may take the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and can lead to fatality. All patients receiving lomitapide in addition to a statin should be advised of the potential increased risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness. Doses of simvastatin >40 mg should not be used with lomitapide.

Effects on lomitapide levels

Lomitapide has not been tested for interaction with bile acid sequestrants (resins such as colesevelam and cholestyramine).

Recommendation concerning co-administration with lomitapide

Because bile acid sequestrants can interfere with the absorption of oral medicines, bile acid sequestrants should be taken at least 4 hours before or at least 4 hours after lomitapide.

Lomitapide is contraindicated during pregnancy. There are no reliable data on its use in pregnant women. Animal studies have shown developmental toxicity (teratogenicity, embryotoxicity). The potential risk for humans is unknown.

It is not known whether lomitapide is excreted into human milk. Because of the potential for adverse effects based on findings in animal studies with lomitapide, a decision should be made whether to discontinue breast-feeding or discontinue the medicinal product, taking into account the importance of the medicinal product to the mother.

Use in women of child-bearing potential

Before initiating treatment in women of child-bearing potential, the absence of pregnancy should be confirmed, appropriate advice on effective methods of contraception provided, and effective contraception initiated. Patients taking oestrogen-based oral contraceptives should be advised about possible loss of effectiveness due to diarrhoea and/or vomiting. Additional contraceptive measures should be used until resolution of symptoms.

Fertility

No adverse effects on fertility were observed in male and female rats administered lomitapide at systemic exposures (AUC) estimated to be 4 to 5 times higher than in humans at the maximum recommended human dose.

Lomitapide has minor influence on the ability to drive and use machines.

Summary of the safety profile

The most serious adverse reactions during treatment were liver aminotransferase abnormalities.

The most common adverse reactions were gastrointestinal effects. Gastrointestinal adverse reactions were reported by 27 (93%) of 29 patients in the Phase 3 clinical study. Diarrhoea 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. Gastrointestinal adverse reactions occurred more frequently during the dose escalation phase of the study and decreased once patients established the maximum tolerated dose of lomitapide.

Gastrointestinal adverse reactions of severe intensity were reported by 6 (21%) of 29 patients in the Phase 3 clinical study, with the most common being diarrhoea (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 study for 4 (14%) patients.

The most commonly reported adverse reactions of severe intensity were diarrhoea (4 subjects, 14%), vomiting (3 patients, 10%), and abdominal distension and ALT increased (2 subjects each, 7%).

Tabulated list of adverse reactions

Frequency of the adverse reactions is defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 1 lists all adverse reactions reported across the 35 patients treated in the Phase 2 Study UP1001 and in the Phase 3 Study UP1002/AEGR-733-005 or its extension study AEGR-733-012.

Table 1. Frequency of adverse reactions in HoFH patients:

Table 2 lists all adverse reactions for subjects who received lomitapide monotherapy (N=291) treated in Phase 2 studies in subjects with elevated LDL-C (N=462).

Table 2. Frequency of adverse reactions in elevated LDL-C patients: