microsomal transfer protein inhibitors
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).
Binds and inhibits microsomal transfer protein (MTP), inhibiting the synthesis of lipoproteins and further inhibiting synthesis of chylomicrons and VLDL.
Decreased levels of LDL-C.
Absorption: 7% absorbed following oral administration.
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)
|PO||within 2 wk||18 wk||unknown|
- 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;
- OB: May cause fetal harm;
- Lactation: Discontinue breastfeeding or discontinue lomitapide.
Use Cautiously in:
- Rep: Women of reproductive potential
- Pedi: Safety and effectiveness not established.
Adverse Reactions/Side Effects
CNS: dizziness, headache
CV: angina, chest pain, palpitations
GI: HEPATOTOXICITY, abdominal discomfort/pain, abdominal distention, constipation, defecation urgency, diarrhea, dyspepsia, flatulence, gatrointestinal reflux, hepatotoxicity, ↑ liver enzymes, nausea, rectal tenesmus, vomiting
Metabolic: ↓ weight
MS: back pain
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- Gastrointestinal adverse reactions may ↓ absorption of other orally administered medications.
- Concurrent use of moderate or strong CYP3A4 inhibitors, including aprepitant, atazanavir, ciprofloxacin, clarithromycin, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posiconazole, ritonavir, saquinavir, tipranavir/ritonavir, verapamil and voriconazole , ↑ levels and the risk of toxicity, concurrent use contraindicated.
- Concurrent use of weak CYP3A4 inhibitors, including alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, isoniazid, lapatinib, nilotinib, oral contraceptives , pazopanib, ranitidine, ranolazine, ticagrelor and zileuton , ↑ levels and the risk of toxicity.
- ↑ levels and risk of bleeding with warfarin.
- ↑ levels and risk of myopathy with lovastatin or simvastatin (statin dose may need to be ↓).
- May ↑ absorption and levels of p-glycoprotein (P-gp) substrates including aliskiren, ambisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imitanib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan and topotecan (dose ↓ 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 ↑ levels and the risk of toxicity.
Grapefruit juice ↑ levels and the risk of toxicity (concurrent ingestion should be avoided).
PO (Adults): 5 mg once daily initially; after 2 wk may be ↑ to 10 mg once daily, then may be ↑ 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 (oral contraceptives)– If already taking lomitapide at a dose of ≥10 mg/day, ↓ dose by 50%. Do not exceed dose of 40 mg/day; Concurrent use of weak CYP3A4 inhibitors (alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, isoniazid, lapatinib, nilotinib, pazopanib, ranitidine, ranolazine, ticagrelor, or zileuton)– If already taking lomitapide at a dose of ≥10 mg/day, ↓ dose by 50%; Do not exceed dose of 30 mg/day.
Hepatic Renal Impairment
PO (Adults): End-stage renal disease on dialysis or mild hepatic impairment (Child–Pugh A)– Do not exceed 40 mg once daily; other modifications are required for ↑ transaminases.
Capsules: 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 60 mg
- 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: Obtain a negative pregnancy test in females with reproductive potential prior to starting therapy.
- 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 mo and before each dose increase. Measure AST and ALT prior to dose increases.
- 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.
- Diarrhea (Side Effects)
- 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).
- PO 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.
- 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.
- Rep: 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.
Decrease in LDL cholesterol, total cholesterol, apolipoprotein B, and non HDL cholesterol.
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