Lomitapide Mesylate

Contraindications

• Moderate or severe hepatic impairment (Child-Pugh class B or C).1

• Active liver disease, including unexplained, persistent elevations in serum aminotransferase concentrations.1

• Pregnancy.1

• Concomitant use with moderate or potent CYP3A4 inhibitors.1

Warnings/Precautions

Warnings

Increases in serum aminotransferase (ALT and/or AST) concentrations reported; persistent and severe (≥10 times the ULN) elevations also reported.1 3 4 7 No concomitant or subsequent clinically meaningful elevations in bilirubin, INR, or alkaline phosphatase concentrations.1 3 Serum aminotransferase concentrations typically declined within 1–4 weeks following reduction in lomitapide dosage or interruption of therapy.1 3

Hepatic steatosis, with or without concomitant increases in serum aminotransferase concentrations, reported.1 3 4 7 May be reversible following discontinuance of therapy; however, not known whether histologic sequelae remain, particularly after long-term therapy.1 Hepatic steatosis is a risk factor for progressive liver disease, including steatohepatitis and cirrhosis.1 Long-term consequences of hepatic steatosis associated with lomitapide therapy unknown.1 3 11 However, there is concern that lomitapide-induced hepatic steatosis could result in steatohepatitis, which can progress to cirrhosis over several years.1

Hepatic dysfunction (elevated aminotransferase concentrations with increases in bilirubin concentrations or INR) or hepatic failure not reported.1

Perform liver function tests (i.e., ALT, AST, alkaline phosphatase, and total bilirubin concentrations) prior to initiation of therapy; evaluate and manage abnormal concentrations before initiating therapy.1 During first year of therapy, perform liver function tests (or, at a minimum, ALT and AST concentrations) prior to each increase in dosage or monthly, whichever occurs first.1 After first year of therapy, perform liver-related tests at least every 3 months and prior to any increase in dosage.1 If elevations in aminotransferase concentrations occur, reduce lomitapide dosage; if persistent or clinically relevant elevations are observed, interrupt or permanently discontinue therapy and investigate probable cause.1 (See Hepatotoxicity under Dosage and Administration.)

Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury.1 Advise patients to limit alcohol consumption to ≤1 alcohol-containing drink per day.1

Exercise caution when used concomitantly with other potentially hepatotoxic drugs.1 Concomitant use with other LDL-lowering agents known to increase hepatic fat not recommended.1 (See Hepatotoxic Drugs under Interactions.)

Other Warnings and Precautions

A registry has been established to monitor and evaluate the long-term effects of lomitapide.1 Information available at 877-902-4099 or at .1

May cause fetal harm; teratogenicity demonstrated in animals.1

Exclude pregnancy prior to initiation of therapy.1 Advise women of childbearing potential to use an effective method of contraception during therapy.1 If oral contraceptives are used, do not exceed lomitapide dosage of 30 mg daily.1 If incomplete absorption of oral contraceptives occurs (e.g., resulting from lomitapide-induced vomiting and diarrhea), may need to use additional contraceptive methods.1

If used during pregnancy or if patient becomes pregnant during therapy, discontinue therapy and apprise of potential fetal hazard.1 (See Advice to Patients.)

May reduce absorption of fat-soluble vitamins and serum fatty acids1 8 and increase risk of developing fat-soluble nutrient deficiency.1 Patients predisposed to malabsorption (e.g., those with chronic bowel or pancreatic diseases) may be at increased risk.1

Manufacturer recommends use of supplements containing 400 units of vitamin E and at least 210 mg of alpha-linolenic acid, 200 mg of linoleic acid, 110 mg of EPA, and 80 mg of DHA during therapy.1

Adverse GI effects, including diarrhea, nausea, dyspepsia, and vomiting frequently observed.1 8 12 Abdominal pain, abdominal discomfort, abdominal distention, constipation, and flatulence also reported.1 Absorption of concomitantly used oral medications may be affected in patients who develop diarrhea or vomiting during therapy.1

To reduce to risk of adverse GI effects, increase dosage gradually and instruct patients to adhere to a low-fat diet (i.e., <20% of total calories from fat) and to take lomitapide without food (≥2 hours after evening meal).1 11

Concomitant use with CYP3A4 inhibitors may increase exposure to lomitapide.1

Concomitant use with moderate or potent CYP3A4 inhibitors is contraindicated.1 (See Contraindications under Cautions.) If used concomitantly with a weak CYP3A4 inhibitor, do not exceed lomitapide dosage of 30 mg daily.1 (See Specific Drugs and Foods under Interactions.)

Concomitant use with certain statins that are metabolized by CYP3A4 (e.g., simvastatin, lovastatin) may result in increased exposure to the statin and possible increased risk of myopathy, including rhabdomyolysis.1 5 (See Specific Drugs and Foods under Interactions.)

Increases in lomitapide dosage may lead to supratherapeutic anticoagulation with warfarin, and decreases in lomitapide dosage may lead to subtherapeutic anticoagulation.1 Monitor INR regularly, especially following any changes to lomitapide dosage, and adjust warfarin dosage as clinically indicated.1 (See Specific Drugs and Foods under Interactions.)

Possible diarrhea and malabsorption in patients with rare hereditary disorders, including galactose intolerance, the Lapp lactase deficiency, and glucose-galactose malabsorption; avoid use in such patients.1

Specific Populations

Category X.1 (See Contraindications and also Fetal/Neonatal Morbidity and Mortality under Cautions.)

Pregnancy registry at 877-902-4099 or to monitor pregnancy outcomes in women who have been exposed to lomitapide.1

Not known whether distributed into human milk; discontinue nursing or the drug.1

Safety and efficacy not established in pediatric patients.1

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 Other reported clinical experience has not identified differences in responses between geriatric and younger patients.1 Select dosage with caution.1 (See Geriatric Patients under Dosage and Administration.)

Increased systemic exposure in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 (See Special Populations under Pharmacokinetics.) Not studied in patients with severe hepatic impairment (Child-Pugh class C).1

Do not exceed lomitapide dosage of 40 mg daily in patients with mild hepatic impairment (Child-Pugh class A).1

Use contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1

Increased systemic exposure in patients with end-stage renal disease undergoing dialysis; do not exceed lomitapide dosage of 40 mg daily.1 (See Special Populations under Pharmacokinetics.)

Not studied in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease not requiring dialysis.1

Common Adverse Effects

Diarrhea,1 3 nausea,1 3 dyspepsia,1 3 vomiting,1 3 abdominal pain,1 3 weight loss,1 3 chest pain,1 3 abdominal discomfort,1 3 abdominal distention,1 3 constipation,1 3 flatulence,1 3 influenza,1 3 nasopharyngitis,1 3 increased ALT,1 3 fatigue,1 3 gastroenteritis,1 3 back pain,1 3 pharyngolaryngeal pain,1 3 gastroesophageal reflux disease,1 3 defecation urgency,1 3 rectal tenesmus,1 3 fever,1 3 headache,1 3 dizziness,1 3 nasal congestion,1 3 angina pectoris,1 3 palpitations.1 3

Absorption

Bioavailability

Absolute bioavailability is approximately 7%.1

Peak plasma concentrations attained in about 6 hours following oral administration.1 5

Pharmacokinetics are approximately dose proportional over single-dose range of 10–100 mg.1

Special Populations

In patients with mild hepatic impairment (Child-Pugh class A), peak plasma concentration and AUC are increased by 4 and 47%, respectively, compared with individuals with normal hepatic function.1 (See Hepatic Impairment under Dosage and Administration.)

In patients with moderate hepatic impairment (Child-Pugh class B), peak plasma concentration and AUC are increased by 361 and 164%, respectively, compared with individuals with normal hepatic function.1 (See Contraindications under Cautions.)

In patients with end-stage renal disease undergoing dialysis, peak plasma concentration and AUC are 50 and 40% higher, respectively, compared with individuals with normal renal function.1 (See Renal Impairment under Dosage and Administration.)

Distribution

Extent

Not known whether lomitapide distributes into human milk.1 (See Lactation under Cautions.)

Plasma Protein Binding

99.8%.1

Elimination

Metabolism

Metabolized in the liver, principally by CYP3A4;1 5 also may be metabolized to a small extent by CYP isoenzymes 1A2, 2B6, 2C8, and 2C19.1

Elimination Route

Excreted in urine (53–60%) as metabolites and in feces (33–35%) mainly as unchanged drug.1 5

Half-life

Approximately 40 hours.1 5

Storage

Oral

20–25°C (may be exposed to 15–30°C).1 Minimize exposure to temperatures up to 40°C.1 Keep container tightly closed and protect from moisture.1

• Binds directly to and inhibits MTTP in enterocytes and hepatocytes.1 3 5 6 7 8 9 10 11 12 17

• Inhibition of MTTP in enterocytes prevents incorporation of dietary lipids (e.g., triglycerides, cholesteryl esters, phospholipids) into apo B-48, resulting in inhibition of chylomicron synthesis and, subsequently, inhibition of fat absorption in the intestines.1 3 5 6 7 8 9 10 11 12 16 17

• Inhibition of MTTP in hepatocytes prevents incorporation of endogenous lipids into apo B-100, resulting in inhibition of VLDL-cholesterol synthesis (a precursor of LDL-cholesterol) and, subsequently, inhibition of LDL-cholesterol synthesis in the liver.1 3 5 6 7 8 9 10 11 12 16 17

• Because of lomitapide's mechanism of action, neutral lipids not used in the formation of chylomicrons and VLDL-cholesterol are expected to accumulate in the intestines and liver, resulting in adverse GI and hepatic effects (e.g., diarrhea, nausea, hepatic steatosis).3 7 8 9 11 12 16 (See Hepatotoxicity and also GI Effects under Cautions.)

• No clinically important prolongation of QTc interval.1

• Importance of informing patients that a registry has been established to monitor and evaluate the long-term effects of lomitapide; importance of encouraging patients to participate in this voluntary registry.1

• Importance of educating patients regarding the Juxtapid REMS restricted distribution program for obtaining lomitapide.1 4 (See REMS and also see Restricted Distribution Program under Dosage and Administration.)

• Importance of taking lomitapide capsules whole and not opening, crushing, dissolving, or chewing the capsules.1

• Risk of hepatotoxicity.1 Importance of obtaining liver-related laboratory tests prior to initiation of therapy, prior to any increase in dosage, and at recommended intervals during therapy.1 Importance of limiting alcohol consumption to ≤1 alcohol-containing drink per day.1 Importance of immediately reporting symptoms suggestive of liver injury (e.g., nausea, vomiting, or abdominal pain that is severe or persistent or changes in character; fever; jaundice; lethargy; flu-like symptoms).1

• Risk of fetal harm.1 Importance of excluding pregnancy with a negative pregnancy test before starting lomitapide.1 Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise women of reproductive potential to use effective contraception to prevent pregnancy during lomitapide therapy.1 If pregnancy occurs, importance of discontinuing lomitapide and immediately notifying a clinician.1

• Importance of taking daily supplements containing 400 units of vitamin E and at least 210 mg of alpha-linolenic acid, 200 mg of linoleic acid, 110 mg of EPA, and 80 mg of DHA.1

• Risk of adverse GI reactions.1 Importance of taking lomitapide without food (≥2 hours after the evening meal) and adhering to a low-fat diet to reduce the risk of adverse GI effects.1 Importance of consulting a clinician if diarrhea or vomiting occurs during lomitapide therapy.1

• Importance of avoiding grapefruit juice during lomitapide therapy.1

• If a dose is missed, importance of administering the next dose at the regularly scheduled time.1 If therapy is interrupted for >1 week, importance of contacting a clinician before reinitiating therapy.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., ginkgo, goldenseal), as well as any concomitant illnesses (e.g., renal disease, hepatic disease).1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)