Tools
Lomitapide
Indications
Homozygous familial hypercholesterolemia: Added to a diet with low fats and other drugs to reduce lipids, involving LDL apheresis to decrease low-density lipoprotein cholesterol (LDL-C), total cholesterol, apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients suffering from HoFH.[1][2]
Patients who suffer from HoFH might have arcus corneae, tendinous xanthomas, and xanthelasma and planar or tuberous xanthomas. Planar xanthomas are flat or somewhat elevated yellowish patches. Tuberous xanthomas are painless, hard nodules usually on the extensor joints’ surfaces.
Guidelines: Lomitapide might be beneficial in patients suffering from HoFH with inadequate responsiveness to the inhibitors of PCSK9 treatment.[3][4] Also, lomitapide might be useful in patients suffering from atherosclerotic cardiovascular disease (ASCVD) and baseline LDL-C ≥190 mg/dL who lack proper responding to statins (with or without inhibitors of PCSK9 or ezetimibe).[5][6][7][8]
Mechanism of Action
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Mechanism of Action
Lomitapide binds instantly to and suppresses microsomal triglyceride transfer protein (MTP) inside the endoplasmic reticulum lumen. Suppressing MTP hinders producing lipoproteins that contain apo-B in the hepatocytes and the enterocytes and leads to a decrease in generating very-low-density lipoprotein (VLDL) and chylomicrons and hence decreases the levels of LDL-C in plasma.[9]
Administration
Lomitapide is taken once per day; administered with water and without food minimally 2 hours following the night meal because taking it with food might raise the danger of gastrointestinal side effects; and wallowed as the entire capsules without opening, crushing, dissolving, or chewing.
Starting dose is 5 mg once per day; following 2 weeks or more of treatment, might be raised to 10 mg once per day, based on tolerance; next at periods of 4-weeks or greater, may be increased to 20 mg once per day, then to 40 mg once per day, and lastly to the highest dose of 60 mg per day based on tolerance.
Adverse Effects
The most frequently reported adverse effects include the following:
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Cardiovascular: Chest pain
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Central nervous system: Fatigue
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Gastrointestinal: Severe diarrhea and vomiting, nausea, dyspepsia, weight loss, severe abdominal pain, discomfort and distension, constipation, flatulence, and gastroenteritis.
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Hepatic: Elevated transaminases levels in serum and liver steatosis
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Infection: Influenza
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Neuromuscular and skeletal: Back pain
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Respiratory: Pharyngolaryngeal pain and nasopharyngitis[10]
Contraindications
Pregnancy; concomitant administration with moderate or potent inhibitors of CYP3A4; moderately or seriously deteriorated liver (Child-Pugh class B or C) and patients suffering from active hepatic disorders, involving unjustified lasting increases of transaminases in the serum.[11]
Hypersensitivity to lomitapide or other formula elements; identified critical, chronic disorders of the bowel such as malabsorption or inflammatory bowel disease; co-administration of daily simvastatin greater than 20 mg (co-administration with daily simvastatin of 40 mg daily is allowed for patients initially tolerant to daily simvastatin of 80 mg for a year or more with no indication of myotoxicity); intolerance to galactose, deficiency in Lapp-lactase, or malabsorption of glucose-galactose.[12]
Monitoring
Ask for hepatic and renal function tests (baseline alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin).
Before starting treatment, pregnancy test in females of child-bearing age.
In the first year, assess transaminases every month or before any rise in the dosage (whichever happens first), and afterward every three months minimally and before increasing the dose.
Check other medications that patients might be administering; adjusting doses or alternative treatments might be required.
Check signs of severe diarrhea or hepatic toxicity.
For Nurses
Assess abnormalities in the ordered labs and reports.
Monitor for and inform the patient to report severe diarrhea or any signs of hepatic toxicity, for example, loss of appetite, serious abdominal pain, jaundice, dark urine, or light-colored feces.
Toxicity
Lomitapide could elevate transaminases. In a clinical trial, 34% of patients showed an elevation in ALT or AST about three times the upper limit of normal (ULN), or even more. There were no significant clinically relevant elevations in alkaline phosphatase, total bilirubin, or the international normalized ratio (INR).[13][14]
Lomitapide can elevate liver fats. This can occur with or without related transaminases elevations. Following 26 and 78 weeks of therapy, the median absolute rise in liver fats, from a baseline of 1%, was 6% assessed through magnetic resonance spectroscopy (MRS). Lomitapide therapy-associated liver steatosis could be a risk factor for advanced liver disease, involving both steatohepatitis or cirrhosis.
Before starting therapy, assess AST, ALT, alkaline phosphatase, and total bilirubin and routinely AST and ALT as required afterward. During treatment, modify lomitapide dosage if the AST or ALT is three times the ULN or more. Stop lomitapide in case of clinically meaningful hepatic toxicity.
For the risk of liver toxicity, lomitapide is prescribed only via a controlled program below policy for assessing and mitigating risk. Prescribe lomitapide only to patients who are confirmed either clinically or by laboratory results to have HoFH. Lomitapide efficacy and safety remain unconfirmed in patients diagnosed with hypercholesterolemia other than HoFH.[15]
Enhancing Healthcare Team Outcomes
Dyslipidemia is a risk factor for atherosclerosis and could cause asymptomatic coronary artery or peripheral arterial diseases.
- Causes of dyslipidemia include sedentary living with diets rich in calories, saturated and trans fats, cholesterol, and/or familial (genetic) abnormalities in metabolizing fats.
- Diagnosis is by measuring serum lipid levels (assessing total cholesterol, TGs, and HDL cholesterol and quantified LDL cholesterol and VLDL).
- Screening exams should take place at 9 to 11 years old, then at 17 to 21 years old and 2 to 8 years old (for a significant family history of serious hyperlipidemia, premature coronary artery disease, or other risk factors); adults should have screening starting at 20 years of age, and then every five years.
- Total and HDL cholesterol are assessable while not fasting; however, most patients should have all lipids assessed during fasting, often for 12 hours, for optimal validity and precision.
- The American Heart Association and the American College of Cardiology recommend treatment for all patients in the four key risk groups and those who have raised lipid profiles and other risk factors combinations to decrease atherosclerotic cardiovascular disease risk.
- Management relies on the particular abnormalities in the lipid profile. However, it should always cover optimizing compliance, changing lifestyle (diet modification and physical activity), controlling diabetes and hypertension, quitting smoking, and sometimes in cases with an elevated risk of myocardial infarction or death because of coronary artery disease, low-dose of daily aspirin.
- Lomitapide is a microsomal triglyceride transfer protein inhibitor, which affects secreting TG-rich lipoproteins in the intestine and the liver. The dose starts low and step-by-step, raised almost bi-weekly. Patients should adhere to diets with less than 20% in fat calories.
- Lomitapide might lead to gastrointestinal side effects such as diarrhea, raised liver fats, and increased hepatic enzymes. Efficacy and safety in patients who lack homozygous familial hypercholesterolemia remain unproven.
- Apheresis is also a frequently used treatment in patients suffering from the HoFH who have limited or no response to medications.
- However, elevated HDL levels have links with lower cardiovascular risk, and it is unclear if therapies that raise the levels of HDL cholesterol would reduce cardiovascular events or death risks.
The above management activities are best accomplished by an interprofessional healthcare team that includes clinicians, specialists, mid-level practitioners, nurses, and pharmacists, all working collaboratively and sharing their findings with the other team members to drive optimal patient outcomes with the fewest adverse events. [Level 5]
References
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