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Juxtapid

Generic Name: Lomitapide Mesylate
Class: Antilipemic Agents, Miscellaneous
Chemical Name: N - (2,2,2 - Trifluoroethyl) - 9 - [4 - [4 - [[[4′ - (trifluoromethyl)[1,1′ - biphenyl] - 2 - yl]carbonyl]amino] - 1 - piperidinyl]butyl] - 9H - fluorene - 9 - carboxamide, methanesulfonate
Molecular Formula: C39H37F6N3O2•CH4O3S
CAS Number: 202914-84-9

Warning(s)

  • Hepatotoxicity
  • Increases in serum aminotransferase (ALT and/or AST) concentrations and/or hepatic steatosis reported; hepatic steatosis is a risk factor for progressive liver disease, including steatohepatitis and cirrhosis.1 (See Hepatotoxicity under Cautions.)

  • Monitor liver function laboratory tests prior to initiation of therapy, prior to any increase in dosage, and at recommended intervals during therapy.1 If hepatotoxicity occurs, interrupt therapy, reduce dosage, or discontinue lomitapide depending on severity and persistence of toxicity.1 (See Hepatotoxicity under Dosage and Administration.)

  • Restricted Distribution Program
  • Available only through the Juxtapid REMS program.1 4 (See REMS and also see Restricted Distribution Program under Dosage and Administration.)

REMS:

FDA approved a REMS for lomitapide to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of lomitapide and consists of the following: elements to assure safe use and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center (). Also see Restricted Distribution Program under Dosage and Administration.

Introduction

Antilipemic agent; microsomal triglyceride transfer protein (MTTP) inhibitor.1 3 5 6 7 8 9 10 11 12 14 15 16

Uses for Juxtapid

Dyslipidemias

Adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce LDL-cholesterol, total cholesterol, apolipoprotein B (apo B), and non-HDL-cholesterol concentrations in the management of homozygous familial hypercholesterolemia (designated an orphan drug by US FDA for use in this condition).1 2 3 7

Safety and efficacy not established in patients with hypercholesterolemia who do not have homozygous familial hypercholesterolemia.1

Effects on cardiovascular morbidity and mortality not established.1

Juxtapid Dosage and Administration

General

  • Begin low-fat diet (i.e., <20% of total calories from fat) prior to initiation of lomitapide therapy and continue this diet during treatment to reduce risk of adverse GI effects.1

  • Obtain liver function tests (i.e., ALT, AST, alkaline phosphatase, and total bilirubin concentrations) prior to initiation of therapy and at recommended intervals during therapy.1 (See Hepatotoxicity under Cautions.)

  • Supplement with 400 units of vitamin E and at least 200 mg of linoleic acid, 210 mg of alpha-linolenic acid, 110 mg eicosapentaenoic acid (EPA), and 80 mg of docosahexaenoic acid (DHA).1 (See Fat-soluble Vitamin and Fatty Acid Deficiency under Cautions.)

  • Exclude pregnancy before initiating therapy.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Restricted Distribution Program

  • Lomitapide can only be prescribed and dispensed by healthcare providers and pharmacies certified through the Juxtapid REMS program.1 4

  • Additional information available at 855-898-2743 or .1 4

Administration

Oral Administration

Administer orally once daily without food, ≥2 hours after evening meal.1

Swallow capsules whole with a glass of water; do not open, crush, dissolve, or chew.1

If a dose is missed, take next dose at regularly scheduled time.1 If therapy is interrupted for >1 week, contact healthcare provider prior to reinitiation of therapy.1

Dosage

Available as lomitapide mesylate; dosage expressed in terms of lomitapide.1

Adults

Dyslipidemias
Homozygous Familial Hypercholesterolemia
Oral

Initially, 5 mg once daily.1 Continue initial dosage for ≥2 weeks.1

After receiving initial dosage for ≥2 weeks, may increase dosage gradually (i.e., at intervals of ≥4 weeks) in stepwise manner (i.e., to 10, 20, 40, and then 60 mg daily) based on safety and tolerability.1

Maintenance dosage should be individualized, taking into account patient's goals and response to therapy.1 (See Prescribing Limits under Dosage and Administration.)

Dosage Modification
Oral
Hepatotoxicity

If hepatotoxicity occurs, reduce lomitapide dosage, or interrupt or permanently discontinue therapy and investigate probable cause.1 (See Table 1.)

Table 1. Recommended Dosage Modifications for Hepatotoxicity1

ALT or AST Concentrations

Treatment and Monitoring Recommendations

3 to <5 times the ULN

Repeat ALT and AST measurement within 1 week; if ALT or AST concentration remains elevated, reduce dosage and obtain additional liver function tests (e.g., alkaline phosphatase, total bilirubin, INR) if not already measured1

Repeat liver function tests weekly; withhold lomitapide if signs of abnormal liver function (e.g., increased bilirubin concentrations or INR) are present, ALT or AST concentrations increase to >5 times the ULN, or ALT or AST concentrations do not decrease to <3 times the ULN within 4 weeks; investigate probable cause of persistent or worsening liver function abnormalities1

If therapy is resumed (after ALT or AST concentrations have decreased to <3 times the ULN), consider reducing lomitapide dosage and monitor liver function tests more frequently1

≥5 times the ULN

Withhold lomitapide, obtain additional liver function tests (e.g., alkaline phosphatase, total bilirubin, INR) if not already measured, and investigate probable cause1

If therapy is resumed (after ALT or AST concentrations have decreased to <3 times the ULN), reduce lomitapide dosage and monitor liver function tests more frequently1

Serum ALT or AST elevations accompanied by clinical symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), bilirubin concentration ≥2 times the ULN, or active liver disease

Discontinue lomitapide and investigate probable cause1

Concomitant Use with CYP3A4 Inhibitors

Concomitant use with moderate or potent CYP3A4 inhibitors is contraindicated.1 (See Interactions.)

Do not exceed lomitapide dosage of 30 mg daily when used concomitantly with weak CYP3A4 inhibitors.1

Prescribing Limits

Adults

Homozygous Familial Hypercholesterolemia
Oral

Maximum 60 mg daily.1

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Do not exceed 40 mg daily.1 (See Hepatic Impairment under Cautions.)

Moderate or severe hepatic impairment (Child-Pugh class B or C): Use is contraindicated.1

Renal Impairment

End-stage renal disease requiring dialysis: Do not exceed 40 mg daily.1 (See Renal Impairment under Cautions.)

Renal impairment or end-stage renal disease not requiring dialysis: Not studied.1

Geriatric Patients

Select dosage with caution because of possible age-related decreases in hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.1

Cautions for Juxtapid

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

Hepatotoxicity

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

Juxtapid Registry

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

Fetal/Neonatal Morbidity and Mortality

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.)

Fat-soluble Vitamin and Fatty Acid Deficiency

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

GI Effects

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

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 Hydroxymethylglutaryl CoA (HMG-CoA) Reductase Inhibitors (Statins)

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.)

Concomitant Use with Warfarin

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.)

Patients with Hereditary Disorders

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

Pregnancy

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

Lactation

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

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

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.)

Hepatic Impairment

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

Renal Impairment

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

Interactions for Juxtapid

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

Inhibits CYP3A41 5 6 but does not inhibit CYP isoenzymes 1A2, 2B6, 2C9, 2C19, 2D6, or 2E1.1

Does not induce CYP isoenzymes 1A2, 3A4, or 2B6.1

Inhibitor, but not a substrate, of P-glycoprotein (P-gp).1

Does not inhibit breast cancer resistance protein (BCRP).1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Moderate or potent CYP3A4 inhibitors: Possible increased exposure to lomitapide.1 Concomitant use contraindicated.1 If concomitant use cannot be avoided, interrupt lomitapide therapy during therapy with the CYP3A4 inhibitor.1 (See Specific Drugs and Foods under Interactions.)

Weak CYP3A4 inhibitors: Possible increased exposure to lomitapide.1 If used concomitantly, do not exceed lomitapide dosage of 30 mg daily.1 (See Specific Drugs and Foods under Interactions.)

Drugs Affected by P-glycoprotein Transport

Substrates of P-gp: Possible increased absorption of P-gp substrate.1 If used concomitantly, consider dosage reduction of P-gp substrate.1 (See Specific Drugs and Foods under Interactions.)

Hepatotoxic Drugs

Possible increased risk of hepatotoxicity.1 Use concomitantly with caution; more frequent monitoring of liver-related tests may be warranted.1 (See Specific Drugs and Foods under Interactions.)

Concomitant use with other LDL-lowering agents known to increase hepatic fat not studied; therefore, such concomitant use not recommended.1

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Acetaminophen (>4 g daily for ≥3 days per week)

Possible increased risk of hepatotoxicity1

Use concomitantly with caution; more frequent monitoring of liver-related tests may be warranted1

Alcohol

Possible increased levels of hepatic fat; may induce or exacerbate liver injury1

Limit alcohol consumption to ≤1 alcohol-containing drink per day1

Aliskiren

Possible increased aliskiren absorption1

Consider reducing aliskiren dosage1

Alprazolam

Possible increased lomitapide exposure1

Do not exceed lomitapide dosage of 30 mg daily1

Ambrisentan

Possible increased ambrisentan absorption1

Consider reducing ambrisentan dosage1

Amiodarone

Possible increased lomitapide exposure; possible increased risk of hepatotoxicity1

Use concomitantly with caution and do not exceed lomitapide dosage of 30 mg daily; more frequent monitoring of liver function tests may be warranted1

Amlodipine

Possible increased lomitapide exposure1

Do not exceed lomitapide dosage of 30 mg daily1

Antidepressants, SSRIs (fluoxetine, fluvoxamine)

Possible increased lomitapide exposure1

Do not exceed lomitapide dosage of 30 mg daily1

Antidiabetic agents, dipeptidyl peptidase-4 (DPP-4) inhibitors (saxagliptin, sitagliptin)

Possible increased absorption of DPP-4 inhibitor1

Consider reducing dosage of DPP-4 inhibitor1

Antifungals, azoles (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)

Possible increased lomitapide exposure1

Ketoconazole: Substantial increases in peak plasma concentration and AUC of lomitapide

Posaconazole: Possible increased lomitapide exposure; possible increased posaconazole absorption1

Concomitant use contraindicated; if concomitant use is unavoidable, interrupt lomitapide therapy during antifungal treatment1

Antiretrovirals, HCV protease inhibitors (boceprevir, telaprevir)

Possible increased lomitapide exposure1

Concomitant use contraindicated1

Antiretrovirals, HIV protease inhibitors (atazanavir, darunavir/ritonavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir/ritonavir)

Possible increased lomitapide exposure1

Concomitant use contraindicated1

Aprepitant

Possible increased lomitapide exposure1

Concomitant use contraindicated; if concomitant use is unavoidable, interrupt lomitapide therapy during aprepitant treatment1

Bicalutamide

Possible increased lomitapide exposure1

Do not exceed lomitapide dosage of 30 mg daily1

Bile acid sequestrants

Possible decreased lomitapide absorption1

Administer lomitapide ≥4 hours apart from bile acid sequestrant1

Calcium-channel blocking agents, nondihydropyridine (diltiazem, verapamil)

Possible increased lomitapide exposure1

Concomitant use contraindicated1

Cilostazol

Possible increased lomitapide exposure1

Do not exceed lomitapide dosage of 30 mg daily1

Ciprofloxacin

Possible increased lomitapide exposure1

Concomitant use contraindicated; if concomitant use is unavoidable, interrupt lomitapide therapy during ciprofloxacin treatment1

Colchicine

Possible increased colchicine absorption1

Consider reducing colchicine dosage1

Conivaptan

Possible increased lomitapide exposure1

Concomitant use contraindicated; if concomitant use is unavoidable, interrupt lomitapide therapy during conivaptan treatment1

Crizotinib

Possible increased lomitapide exposure1

Concomitant use contraindicated1

Cyclosporine

Possible increased lomitapide exposure1

Do not exceed lomitapide dosage of 30 mg daily1

Dabigatran

Possible increased dabigatran absorption1

Consider reducing dabigatran dosage1

Digoxin

Possible increased digoxin absorption1

Consider reducing digoxin dosage1

Everolimus

Possible increased everolimus absorption1

Consider reducing everolimus dosage1

Ezetimibe

Slight increases in peak plasma concentration and AUC of total ezetimibe1 6

No dosage adjustment of ezetimibe required1

Fenofibrate (as micronized formulation)

Decreased peak plasma concentration and AUC of fenofibric acid1 6

No dosage adjustment of fenofibrate required1

Fexofenadine

Possible increased fexofenadine absorption1

Consider reducing fexofenadine dosage1

Ginkgo

Possible increased lomitapide exposure1

Do not exceed lomitapide dosage of 30 mg daily1

Goldenseal

Possible increased lomitapide exposure1

Do not exceed lomitapide dosage of 30 mg daily1

Grapefruit juice

Possible increased lomitapide exposure1

Avoid concomitant use1

Histamine H2-receptor antagonists (cimetidine, ranitidine)

Possible increased lomitapide exposure1

Do not exceed lomitapide dosage of 30 mg daily1

Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) (atorvastatin, lovastatin, rosuvastatin, simvastatin)

Atorvastatin: Increased peak plasma concentration and AUC of atorvastatin acid1 6

Lovastatin: Possible increased lovastatin exposure1

Rosuvastatin: Increased peak plasma concentration and AUC of rosuvastatin1 6

Simvastatin: Increased peak plasma concentrations and AUC of simvastatin and simvastatin acid1

Atorvastatin: Do not exceed lomitapide dosage of 30 mg daily; no dosage adjustment of atorvastatin required1

Lovastatin: Consider reducing lovastatin dosage when lomitapide is initiated1

Rosuvastatin: No dosage adjustment of rosuvastatin required1

Simvastatin: Reduce simvastatin dosage by 50% when lomitapide is initiated; during concomitant use, do not exceed simvastatin dosage of 20 mg daily (or 40 mg daily in patients who have received the 80-mg daily dosage for ≥1 year without evidence of adverse muscular effects)1

Imatinib

Possible increased lomitapide exposure and possible increased imatinib absorption1

Concomitant use contraindicated1

Isoniazid

Possible increased lomitapide exposure1

Do not exceed lomitapide dosage of 30 mg daily1

Isotretinoin

Possible increased risk of hepatotoxicity1

Use concomitantly with caution; more frequent monitoring of liver function tests may be warranted1

Lapatinib

Possible increased lomitapide exposure; possible increased lapatinib absorption1

Do not exceed lomitapide dosage of 30 mg daily; consider reducing lapatinib dosage1

Macrolides (clarithromycin, erythromycin, telithromycin)

Possible increased lomitapide exposure1

Clarithromycin: Substantially increased ALT and AST concentrations1

Concomitant use contraindicated; if concomitant use is unavoidable, interrupt lomitapide therapy during anti-infective treatment1

Maraviroc

Possible increased maraviroc absorption1

Consider reducing maraviroc dosage1

Methotrexate

Possible increased risk of hepatotoxicity1

Use concomitantly with caution; more frequent monitoring of liver function tests may be warranted1

Nefazodone

Possible increased lomitapide exposure1

Concomitant use contraindicated1

Niacin, extended-release

Increased peak plasma concentrations and AUC of nicotinic acid and nicotinuric acid1 6

No dosage adjustment of extended-release niacin required1

Nilotinib

Possible increased lomitapide exposure; possible increased nilotinib absorption1

Do not exceed lomitapide dosage of 30 mg daily; consider reducing nilotinib dosage1

Oral contraceptives

Possible increased lomitapide exposure1

Ethinyl estradiol and norgestimate: Decreased peak plasma concentration and AUC of ethinyl estradiol; increased peak plasma concentration and AUC of 17-deacetyl norgestimate

Do not exceed lomitapide dosage of 30 mg daily; no dosage adjustment of oral contraceptive required1

Pazopanib

Possible increased lomitapide exposure1

Do not exceed lomitapide dosage of 30 mg daily1

Ranolazine

Possible increased lomitapide exposure; possible increased ranolazine absorption1

Do not exceed lomitapide dosage of 30 mg daily; consider reducing ranolazine dosage1

Sirolimus

Possible increased sirolimus absorption1

Consider reducing sirolimus dosage1

Tamoxifen

Possible increased risk of hepatotoxicity1

Use concomitantly with caution; more frequent monitoring of liver function tests may be warranted1

Tetracyclines

Possible increased risk of hepatotoxicity1

Use concomitantly with caution; more frequent monitoring of liver function tests may be warranted1

Ticagrelor

Possible increased lomitapide exposure1

Do not exceed lomitapide dosage of 30 mg daily1

Tolvaptan

Possible increased tolvaptan absorption1

Consider reducing tolvaptan dosage1

Topotecan

Possible increased topotecan absorption1

Consider reducing topotecan dosage1

Warfarin

Increased plasma concentrations of R- and S-warfarin; increased INR1

Monitor INR regularly, particularly following adjustments in lomitapide dosage; adjust warfarin dosage as clinically indicated1

Zileuton

Possible increased lomitapide exposure1

Do not exceed lomitapide dosage of 30 mg daily1

Juxtapid Pharmacokinetics

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

Stability

Storage

Oral

Capsules

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

Actions

  • 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

Advice to Patients

  • 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of lomitapide is restricted.1 (See Restricted Distribution Program under Dosage and Administration.)

Lomitapide Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

5 mg (of lomitapide)

Juxtapid

Aegerion

10 mg (of lomitapide)

Juxtapid

Aegerion

20 mg (of lomitapide)

Juxtapid

Aegerion

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Aegerion Pharmaceuticals, Inc. Juxtapid (lomitapide mesylate) capsules prescribing information. Cambridge, MA; 2014 Aug.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website (http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm). Accessed 2014 Jun 3.

3. Cuchel M, Meagher EA, du Toit Theron H et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013; 381:40-6. [PubMed 23122768]

4. Juxtapid (lomitapide) risk evaluation and mitigation strategy (REMS). From FDA website. Accessed 2014 Jun 3.

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