lomitapide

lomitapide

(lom-i- ta-pide ),

Juxtapid

(trade name)

Classification

Therapeutic: lipid lowering agents
Pharmacologic: temporary class
Pregnancy Category: X

Indications

Adjunctive treatment (with low-fat diet and other lipid-lowering treatments) to ↓ low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B) and non-high-density lipoprotein (non-HCL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

Action

Binds and inhibits microsomal transfer protein (MTP), inhibiting the synthesis of lipoproteins and further inhibiting synthesis of chylomicrons and VLDL.

Therapeutic effects

Decreased levels of LDL-C.

Pharmacokinetics

Absorption: 7% absorbed following oral administration.
Distribution: Unknown.
Protein Binding: 99.8%.
Metabolism and Excretion: Extensively metabolized by the liver, mostly via CYP 3A4, metabolites do not have lipid-lowering properties. 59.5% excreted in urine (mostly as metabolites), 33.4% in feces (mostly as parent drug).
Half-life: 39.7 hr

Time/action profile (lowering of LDL-C)

ROUTEONSETPEAKDURATION
POwithin 2 wk18 wkunknown

Contraindications/Precautions

Contraindicated in: Concurrent use of strong or moderate inhibitors of the CYP3A4 enzyme system; Moderate/severe hepatic impairment or active liver disease;Rare Hereditary Disorders of Galactose Intolerance (may result in diarrhea/malabsorption);Concurrent ingestion of grapefruit juice; Obstetric: Pregnancy (may cause fetal harm); Lactation: Discontinue breastfeeding or discontinue lomitapide.
Use Cautiously in: Females with reproductive potential ; Pediatric: safe use in children has not been established.

Adverse Reactions/Side Effects

Central nervous system

  • dizziness (most frequent)
  • headache (most frequent)

Cardiovascular

  • angina pectoris (most frequent)
  • chest pain (most frequent)
  • palpitations (most frequent)

Gastrointestinal

  • abdominal discomfort/pain (most frequent)
  • abdominal distention (most frequent)
  • constipation (most frequent)
  • (most frequent)
  • defecation urgency (most frequent)
  • diarrhea
  • dyspepsia (most frequent)
  • flatulence (most frequent)
  • gatrointestinal reflux (most frequent)
  • hepatotoxicity (most frequent)
  • nausea (most frequent)
  • rectal tenesmus (most frequent)
  • ↑ transaminases (most frequent)
  • vomiting (most frequent)

Metabolic

  • ↓ weight

Musculoskeletal

  • back pain (most frequent)

Miscellaneous

  • fever (most frequent)

Interactions

Drug-Drug interaction

Gastrointestinal adverse reactions may ↓ absorption of other orally administered medications. Concurrent use of moderate to strong or moderate CYP3A4 inhibitors including amprenavir, aprepitant, atazanavir, bocepravir, ciprofloxacin, clarithromycin, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinibindinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posiconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil and voriconazole ↑ blood levels and the risk of toxicity, concurrent use is contraindicated. Concurrent use of mild CYP3A4 inhibitors including alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, isoniazid, lapatinib, nilotinib, oral contraceptives , pazopanib, ranitidine, ranolazine, tipranavir/ritonavir, ticagrelor and zileuton ↑ blood levels and the risk of toxicity (daily dose of lomitapide should not exceed 30 mg). ↑ blood levels and risk of bleeding with warfarin. ↑ levels and risk of myopathy with lovastatin or simvastatin (statin dose may need to be lowered). May ↑ absorption and levels of p-glycoprotein (P-gp) substrates including aliskiren, ambisentan, colchicine, dabigatran etexilate, digoxine, everolimus, fexofenadine, imitanib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan and topotecan (dose reduction of P-gp substrate may be required). Absorption may be ↓ by bile acid sequestrants , including colesevelam and cholestyramine (separate doses by 4 hr). ↓ absorption of fat-soluble vitamins and fatty acids (supplementation with vitamin E, linoleic acid, alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid is recommended). Ginko and goldenseal↑ blood levels and the risk of toxicity (lomitapide dose should not exceed 30 mg/day).Grapefruit juice ↑ levels and the risk of toxicity (concurrent ingestion should be avoided).

Route/Dosage

Oral (Adults) 5 mg once daily initially, after 2 wk may be increased to 10 mg once daily, then may be increased at 4 wk intervals to 20 mg/day, then 40 mg/day up to 60 mg once daily as needed/tolerated; concurrent use of weak CYP3A4 inhibitors —daily dose should not exceed 30 mg.

Hepatic/Renal Impairment

Oral (Adults) End-stage renal disease on dialysis or mild hepatic impairment (Child–Pugh A)—daily dose should not exceed 40 mg; other modifications are required for ↑ transaminases.

Availability

Capsules: 5 mg, 10 mg, 20 mg

Nursing implications

Nursing assessment

  • Monitor for signs and symptoms of hepatotoxicity (nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms, increases in bilirubin ≥2 x upper limit of normal, active liver disease) periodically during therapy. If symptoms occur, discontinue therapy and investigate cause.
  • Lab Test Considerations: Measure ALT, AST, alkaline phosphatase, and total bilirubin prior to starting, prior to each dose increase or monthly during first year, then at least every 3 months and before each dose increase. Measure AST and ALT prior to dose increases. Dose is gradually increased based on safety and tolerability; if patient is taking 5 mg daily for at least 2 wks, may increase to 10 mg daily; if taking 10 mg daily for at least 4 wks, may increase to 20 mg daily; if taking 20 mg daily for at least 4 wks, may increase to 40 mg/day ; if taking 40 mg daily for at least 4 wks, may increase to 60 mg/day.
    • If ALT or AST ≥3 x upper limit of normal and <5 x upper limit of normal, confirm elevation with repeat measure within 1 wk. If confirmed, reduce dose and obtain additional liver-related tests (alkaline phosphatase, total bilirubin, INR). Repeat tests weekly and withhold dosing if signs of abnormal liver function (↑ bilirubin or INR), if transaminase levels ↑ >5 x upper limit of normal, or if transaminase levels do not fall <3 x upper limit of normal within 4 wks. Investigate probable cause. If resuming lomitapide after transaminase resolves to <3 x upper limit of normal, consider ↓ dose and monitor liver tests more frequently. If ALT or AST ≥5 x upper limit of normal, withhold dosing, obtain additional liver tests (alkaline phosphatase, total bilirubin, INR) and investigate probable cause. If resuming lomitapide after transaminase resolves to <3 x upper limit of normal, ↓ dose and monitor liver tests more frequently.
    • Obtain a negative pregnancy test in females with reproductive potential prior to starting therapy.

Potential Nursing Diagnoses

Diarrhea (Side Effects)

Implementation

  • Lomitapide is only available from health care professionals and pharmacies called the Juxtapid REMS Program because of risk of hepatotoxicity. Information is available at www.JUXTAPIDREMSProgram.com or by calling 1-85-JUXTAPID (1-855-898-2743).
  • Oral: Administer with a glass of water, without food, at least 2 hr after evening meal; food may increase GI adverse reactions. Swallow capsules whole; do not open, crush, dissolve, or chew.
    • If oral contraceptives are used, maximum recommended dose of lomitapide is 30 mg/day.
    • Daily supplements containing 400 international units vitamin E, and at least 200 mg linoleic acid, 210 mg alpha-linolenic acid (ALA), 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA) should be included with therapy. Lomitapide reduces absorption of fat-soluble vitamins and serum fatty acids.
    • Colesevelam and cholestyramine must be taken 4 hrs before or 4 hr after lomitapide.

Patient/Family Teaching

  • Instruct patient to take lomitapide as directed, along with daily supplements. Omit messed doses and take next daily dose as scheduled; if >1 wk missed notify health care professional. Do not stop lomitapide without consulting health care professional.
  • Advise patient to avoid grapefruit juice during therapy.
  • Caution patient that alcohol increases risk of liver injury. Limit alcohol to not more than 1 alcoholic drink per day. Advise patient to notify health care professional if signs and symptoms of liver injury occur.
  • Inform patient that GI adverse reactions are common (diarrhea, nausea, vomiting, abdominal pain/discomfort, flatulence, constipation. Strict adherence to a low-fat diet (<20% of total calories from fat) and taking at least 2 hrs after evening meal may minimize reactions.
  • Advise female patient to use effective contraception and avoid breastfeeding during therapy. If oral contraceptive is used, and additional method of contraception should be used. If pregnancy occurs notify health care professional immediately. Encourage pregnant patients to enroll in Global Lomitapide Pregnancy Exposure Registry (PER) by calling 1-877-902-4099.

Evaluation/Desired Outcomes

  • Decrease in LDL cholesterol, total cholesterol, apolipoprotein B, and non HDL cholesterol.
References in periodicals archive ?
Aegerion) announced that its patient enrollment has begun in Japan in a clinical trial of lomitapide as an adjunct treatment to reduce low-density lipoprotein cholesterol in Japanese patients with homozygous familial hypercholesterolemia (HoFH).
The same is true for the antilipemic agent lomitapide (Juxtapid).
In addition, as part of Aegerion's post-marketing commitment to both the FDA and the EMA, the Company will conduct an observational cohort study to generate more data on the long-term safety profile of lomitapide, the patterns of use and compliance and the long-term effectiveness of controlling LDL-C levels.
8, 2013 /PRNewswire/ -- Stuart Needleman, President and Chief Operating Officer, Aptuit LLC, announced that Aptuit and Aegerion Pharmaceuticals, Cambridge, Massachusetts, have signed a long-term supply agreement for commercial quantities of the active pharmaceutical ingredient (API) lomitapide.
Researchers at the Perelman School of Medicine at the University of Pennsylvania, who led the study, revealed that lomitapide, a first-in-class microsomal triglyceride transfer protein (MTP) inhibitor, substantially and stably reduced LDL cholesterol (the "bad" cholesterol) in patients with the orphan disease homozygous familial hypercholesterolemia (HoFH).
The single-arm, open label trial is designed to evaluate the efficacy and long-term safety of lomitapide for the treatment of patients with homozygous familial hypercholesterolemia (HoFH).
Lomitapide is designed to treat the disease by limiting secretions of cholesterol and triglycerides from the intestines and liver.
7,932,268 for lomitapide for "Methods for Treating Disorders or Diseases Associated with Hyperlipidemia and Hypercholesterolemia While Minimizing Side Effects" by the United States Patent and Trademark Office.
com/research/grn7nf/aegerion) has announced the addition of the "Aegerion lomitapide - how much leniency will FDA grant this orphan product?
Beer, Chief Executive Officer of Aegerion, discussing business strategy and objectives related to the company's lead product candidate, lomitapide.
The trial, titled "Phase III Study of Microsomal Triglyceride Transfer Protein Inhibitor (MTP-I) Lomitapide in Subjects with Homozygous Familial Hypercholesterolemia (HoFH)," was a 56-week assessment of the efficacy and safety of Aegerion Pharmaceuticals' MTP-I lomitapide in adults with HoFH.
Aegerion) announced that it has received orphan drug designation from Japan's Ministry of Labour, Health and Welfare for lomitapide which is used in the treatment of homozygous familial hypercholesterolemia (HoFH).