Lomitapide

Concomitant use of lomitapide with potent (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir, voriconazole) or moderate CYP3A4 inhibitors (e.g., aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) is contraindicated. If concomitant use with moderate or potent CYP3A4 inhibitors cannot be avoided, lomitapide therapy should be interrupted during the course of treatment with the CYP3A4 inhibitor.

Concomitant use of lomitapide with inhibitors of CYP3A4 may result in increased systemic exposure to lomitapide. When the potent CYP3A4 inhibitor ketoconazole (200 mg twice daily for 9 days) was administered concomitantly with lomitapide (60 mg once daily), peak plasma concentration and area under the plasma concentration-time curve (AUC) of lomitapide were increased by 15- and 27-fold, respectively. When the potent CYP3A4 inhibitor clarithromycin was added to lomitapide therapy in at least 1 patient, ALT and AST concentrations were increased to 24 and 13 times the upper limit of normal (ULN), respectively, within days of initiating the potent CYP3A4 inhibitor. Concomitant use of lomitapide with moderate inhibitors of CYP3A4 has not been studied; however, results of pharmacokinetic studies evaluating concomitant use of lomitapide with potent and weak CYP3A4 inhibitors suggest that moderate CYP3A4 inhibitors will likely increase lomitapide exposure.

Following concomitant use of lomitapide (10 mg once daily for 7 days) with fenofibrate (single 145-mg dose as micronized formulation), peak plasma concentration and AUC of fenofibric acid were decreased by 29 and 10%, respectively. Dosage adjustment of fenofibrate (as micronized formulation) is not required during concomitant use with lomitapide.

Following concomitant use of lomitapide (10 mg once daily for 7 days) with ezetimibe (single 10-mg dose), peak plasma concentration and AUC of ezetimibe were increased by 3 and 6%, respectively. Dosage adjustment of ezetimibe is not required during concomitant use with lomitapide.

For more Interactions (Complete) data for Lomitapide (18 total), please visit the HSDB record page.

Lomitapide is associated with a moderately high rate of serum aminotransferase elevations during therapy, levels above 3 times the upper limit of normal (ULN) occurring in 34% of patients. Aminotransferase elevations above 10 times ULN have also been reported which can necessitate drug discontinuation. Despite the frequency of ALT elevations, however, increases in serum bilirubin and alkaline phosphatase levels are rare and there have been no reports of clinically apparent acute liver injury with jaundice. Chronic therapy with lomitapide can be associated with fluctuations in serum aminotransferase levels and accumulation of liver fat. In some instances, the increase in liver fat is from baseline levels of

IDENTIFICATION AND USE: Lomitapide is a white to off-white powder. Lomitapide is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). HUMAN EXPOSURE AND TOXICITY: Very few data are available on the effects of overdose to lomitapide. The maximum dose administered to human subjects in clinical studies was 200 mg lomitapide, as a single dose, without adverse consequences. Lomitapide should not be used during pregnancy because lomitapide may cause fetal harm when administered to a pregnant woman. Lomitapide may also cause diarrhea and malabsorption in patients with rare hereditary disorders, including galactose intolerance, the Lapp lactase deficiency, and glucose-galactose malabsorption; therefore, use of lomitapide should be avoided in such patients. Lomitapide causes a risk of hepatotoxicity. Lomitapide can cause elevations in transaminases and hepatic steatosis. To what extent lomitapide-associated hepatic steatosis promotes the elevations in transaminases is unknown. Although cases of hepatic dysfunction or hepatic failure have not been reported, there is concern that lomitapide could induce steatohepatitis, which can progress to cirrhosis over several years. Therefore, it should not be administered to patients with moderate or severe hepatic impairment (Child-Pugh class B or C) or patients with active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations. Lomitapide did not exhibit genotoxic potential in a battery of studies, including an in vitro cytogenetics assay using primary human lymphocytes. ANIMAL STUDIES: 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 as low as 1.5 mg/kg/day and in females at as low as 7.5 mg/kg/day. Incidences of small intestinal carcinomas in males and combined adenomas and carcinomas in females were significantly increased at doses as low as 15 mg/kg/day. In 2 year studies in rats, there were no statistically significant drug-related increases in tumor incidences. Reproduction studies were conducted in rats, rabbits and ferrets. 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 greater than or equal to 2-times human exposure at the maximum recommended human dose (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. In rabbits, exposures up to 3 times the MRHD based on body surface area (BSA) (MRDH-BSA) from gestational day 6 through organogenesis were not associated with adverse effects. However, exposure equal to or greater than 6 times the MRHD-BSA resulted in embryo-fetal death. 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. Lomitapide did not exhibit genotoxic potential in a battery of studies, including the in vitro Bacterial Reverse Mutation (Ames) and an oral micronucleus study in rats.

/SIGNS AND SYMPTOMS/ The maximum dose administered to human subjects in clinical studies was 200 mg lomitapide, as a single dose, without adverse consequences.

/SIGNS AND SYMPTOMS/ Juxtapid can cause elevations in transaminases and hepatic steatosis, ... . To what extent Juxtapid-associated hepatic steatosis promotes the elevations in transaminases is unknown. Although cases of hepatic dysfunction (elevated transaminases with increase in bilirubin or international normalized ratio (INR)) or hepatic failure have not been reported, there is concern that Juxtapid could induce steatohepatitis, which can progress to cirrhosis over several years.

/CASE REPORTS/ ... We report this ... case of long-term management of intractable near-fatal recurrent pancreatitis secondary to severe hypertriglyceridemia by a novel use of lomitapide, an inhibitor of microsomal triglyceride transfer protein, recently approved for treatment of familial homozygous hypercholesterolemia. The patient had been hospitalized many times for pancreatitis since age 15 years. Her serum triglyceride level averaged 3900 mg/dL while she received therapy with approved lipid drugs. She is homozygous for a coding mutation (P234L) in lipoprotein lipase, leaving her unable to metabolize triglycerides in chylomicrons and very low density lipoproteins (VLDL). Lomitapide reduces the secretion of chylomicrons and VLDL. Lomitapide, which was started when she was 44 years old after near-fatal pancreatitis, lowered her fasting triglyceride level from greater than 3000 mg/dL to a mean (SD) of 903 (870) mg/dL while she received 30 mg/d and to 524 (265) mg/dL while she received 40 mg/d; eliminated chronic abdominal pain; and prevented pancreatitis. However, fatty liver, present before treatment, progressed to steatohepatitis and fibrosis after 12 to 13 years. Lomitapide prevented pancreatitis in severe intractable hypertriglyceridemia but at a potential long-term cost of hepatotoxicity.

/GENOTOXICITY/ Lomitapide did not exhibit genotoxic potential in a battery of studies, including ... an in vitro cytogenetics assay using primary human lymphocytes ... .

/OTHER TOXICITY INFORMATION/ Microsomal triglyceride transfer protein (MTP) is one of the promising targets for the therapy of dyslipidemia and MTP inhibition can lead to robust plasma low-density lipoprotein cholesterol (LDL-C) reduction. Lomitapide, a small-molecule MTP inhibitor, was recently approved by the US FDA as an additional treatment for homozygous familial hypercholesterolemia (hoFH). However, liver-related side effects, including hepatic fat accumulation and transaminase elevations, are the main safety concerns associated with MTP inhibitors. Here, we review recent knowledge on the mechanisms underlying liver toxicity of MTP inhibitors. The contribution of altered levels of intracellular triglycerides, cholesteryl esters, and free cholesterols toward cellular dysfunction is specifically addressed. On this basis, therapies targeted to attenuate cellular lipid accumulation, to reduce risk factors for non-alcoholic fatty liver disease (NAFLD) (i.e., insulin resistance and oxidative stress) and to specifically inhibit intestinal MTP may be useful for ameliorating liver damage induced by MTP inhibitors. In particular, weight loss through lifestyle interventions is expected to be the most effective and safest way to minimize the undesirable side effects. Specific dietary supplementation might also have protective effects against hepatosteatosis. Despite that, to date, few clinical data support these therapeutic options in MTP inhibition-related liver damage, such proposed approaches may be further explored in the future for their use in preventing unwanted effects of MTP inhibitors.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In 2 year studies in rats, there were no statistically significant drug-related increases in tumor incidences.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ 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 > or = 1.5 mg/kg/day (> or = 2-times the MRHD at 60 mg based on AUC) and in females at > or = 7.5 mg/kg/day (> or = 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 > or = 15 mg/kg/day (> or = 23-times the human exposure at 60 mg based on AUC).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In rabbits, exposures up to 3 times the maximum recommended human dose (MRHD) based on body surface area (BSA) (MRDH-BSA) from gestational day 6 through organogenesis were not associated with adverse effects. However, exposure that were > or = 6 times the MRHD-BSA resulted in embryo-fetal death.

For more Non-Human Toxicity Excerpts (Complete) data for Lomitapide (8 total), please visit the HSDB record page.

Patients with end-stage renal disease receiving dialysis should not exceed 40 mg daily since lomitapide exposure in these patients increased approximately 50% compared with healthy volunteers. 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%.

Lomitapide mesylate is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C); patients with active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations; women who are pregnant; ... .

Juxtapid is contraindicated during pregnancy because Juxtapid may cause fetal harm when administered to a pregnant woman.

Lomitapide may cause diarrhea and malabsorption in patients with rare hereditary disorders, including galactose intolerance, the Lapp lactase deficiency, and glucose-galactose malabsorption; therefore, use of lomitapide should be avoided in such patients.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

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.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including lomitapide mesylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Lomitapide mesylate/

Table: Lomitapide Mesylate Preparations [Table#8204]

Oral: 5 mg, 10 mg, 20 mg capsules, Lojuxta