Dosing and uses of Juxtapid (lomitapide)
Adult dosage forms and strengths
capsule
- 5mg
- 10mg
- 20mg
- 30mg
- 40mg
- 60mg
Homozygous Familial Hypercholesterolemia
Indicated as an adjunct to a low-fat diet and other lipid lowering treatments, including LDL apheresis where available, to reduce LDL-C, TC, apo B, and non-HDL-C in patients with homozygous familial hypercholesterolemia
Initial: 5 mg PO qDay; may gradually increase dose based on tolerability and response, not to exceed 60 mg/day
Dose titration
- 5 mg/day, wait at least 2 weeks before increasing to 10 mg/day
- Wait at least 4 weeks before increasing dose to next dosage if on 10 mg/day, 20 mg/day, or 40 mg/day
- Not to exceed 60 mg/day
Dosage modifications
Coadministration with strong or moderate CYP3A4 inhibitors: Contraindicated
Coadministration with weak CYP3A4 inhibitors (including atorvastatin and oral contraceptives): Not to exceed 30 mg/day
Renal impairment
- End-stage renal disease (ESRD) receiving dialysis: Not to exceed 40 mg/day
- Mild, moderate, and severe renal impairment, including those with ESRD not yet receiving dialysis: Not studied; however, may increase lomitapide exposure >50%
Hepatic impairment
- Baseline moderate-to-severe (Child-Pugh B or C): Contraindicated
- Baseline mild (Child-Pugh A): Not to exceed 40 mg/day
Elevated ALT or AST ≥3x and <5x ULn
- Confirm elevation with a repeat measurement within 1 week
- If confirmed, reduce the dose and obtain additional liver-related tests if not already measured (eg, alkaline phosphatase, total bilirubin, INR)
- Repeat tests weekly and withhold dosing with signs of abnormal liver function (eg, increased bilirubin or INR), if transaminase levels >5x ULN, or if transaminase levels do not fall below 3x ULN within approximately 4 weeks
- In these cases of persistent or worsening abnormalities, also investigate to identify the probable cause
- If dosing resumed after transaminases resolve to <3x ULN, consider reducing the dose and monitor liver-related tests more frequently
Elevated ALT or AST ≥5x ULn
- Withhold dosing, obtain additional liver related tests if not already measured (eg, alkaline phosphatase, total bilirubin, INR), and investigate to identify the probable cause
- If transaminase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥2x ULN, or active liver disease, discontinue therapy and investigate to identify the probable cause
- If dosing resumed after transaminases resolve to <3x ULN, reduce the dose and monitor liver-related tests more frequently
Dosing Considerations
Because of hepatotoxicity risk, available only through a restricted access program
Because of lomitapide’s action in the small intestine, administer with daily supplements that contain vitamin E 400 IU, linoleic acid 200 mg, alpha-linolenic acid 210 mg, eicosapentaenoic acid 110 mg, and docosahexaenoic acid 80 mg to reduce the risk of developing a fat-soluble nutrient deficiency
Obtain baseline tests
- Before initiating, measure ALT, AST, alkaline phosphatase, and total bilirubin
- Obtain negative pregnancy test in women of reproductive potential
- Initiate a low-fat diet (ie, <20% of energy from fat)
Administration
Take once daily with a glass of water, without food, at least 2 hr after the evening meaL
Administration with food increases GI adverse effects
Swallow whole; do not crush, chew, open, or dissolve
Limitation of Use
The safety and effectiveness of lomitapide have not been established in patients with hypercholesterolemia who do not have homozygous familial hypercholesterolemia
The effect of lomitapide on cardiovascular morbidity and mortality has not been determined
Pediatric dosage forms and strengths
Safety and efficacy not established
Juxtapid (lomitapide) adverse (side) effects
>10%
Gastrointestinal disorders (93%)
Diarrhea (79%)
Nausea (65%)
Dyspepsia (38%)
Vomiting (34%)
Abdominal pain (34%)
Decreased weight (24%)
Chest pain (24%)
Constipation (21%)
Abdominal discomfort (21%)
Abdominal distension (21%)
Flatulence (21%)
Influenza (21%)
Increased ALT or AST (3-21%)
Nasopharyngitis (17%)
Fatigue (17%)
Gastroenteritis (14%)
Back pain (14%)
Pharyngolaryngeal pain (14%)
1-10%
GERD (10%)
Defecation urgency (10%)
Rectal tenesmus (10%)
Fever (10%)
Headache (10%)
Dizziness (10%)
Nasal congestion (10%)
Angina pectoris (10%)
Palpitations (10%)
Warnings
Black box warnings
Can cause elevations in hepatic transaminases; in a clinical trial, 10 (34%) of the 29 patients treated with lomitapide had at least 1 elevation in ALT or AST ≥3x ULn
Also increases hepatic fat (median increase 6%), with or without concomitant increases in transaminases, which may lead to progressive liver disease
Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment and then ALT and AST regularly as recommended
Adjust dose if the ALT or AST are ≥3x ULn
Discontinue for clinically significant liver toxicity
Because of hepatotoxicity risk, available only through a restricted access program
Contraindications
Pregnancy; negative pregnancy test required before initiating in women of reproductive potential; must use effective contraception during therapy
Coadministration with moderate or strong CYP3A4 inhibitors (strong inhibitors increases lomitapide exposure by 27-fold); if treatment with moderate or strong inhibitors is unavoidable, discontinue lomitapide during the course of treatment; grapefruit juice must be omitted from the diet while being treated
Moderate or severe hepatic impairment (based on Child-Pugh category B or C) or active liver disease, including unexplained persistent elevations of serum transaminases
Cautions
Risk of elevated transaminases and hepatic steatosis (see Contraindications, Black box warnings)
Has not been studied concomitantly with other LDL-lowering agents that can also increase hepatic fat; therefore, the combined use of such agents is not recommended
Safety and efficacy not established in patients with hypercholesterolemia who do not have HoFH, including those with heterozygous familial hypercholesterolemia
May cause embryo-fetal toxicity (see Contraindications)
Reduces absorption of fat-soluble vitamins and serum fatty acids; Daily dietary supplements required (see Dosing Considerations)
High incidence of GI adverse effects (eg, diarrhea, nausea, dyspepsia, vomiting)
Avoid use in patients with rare, hereditary galactose intolerance (eg, Lapp lactase deficiency, glucose-galactose malabsorption); use of lomitapide in these patients may result in diarrhea and malabsorption
Coadministration with CYP3A4 inhibitors (see Contraindications and Dosage modifications)
Lomitapide increases plasma concentrations of warfarin and may lead to supratherapeutic anticoagulation; caution when initiating, increasing, or decreasing lomitapide dose if coadministered with warfarin
Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating therapy; if level is abnormal, consider initiating therapy only after an appropriate work-u p and the baseline abnormalities have been explained or resolved
During first year, measure liver elated tests (A LT and AST, at a minimum) prior to each increase in dose or monthly, whichever occurs first; after first year, measure liver-related tests (ALT and AST, at a minimum) at least every 3 months and before any increase in dose
There have been postmarketing reports of severe diarrhea with therapy, including patients being hospitalized because of diarrhea-related complications such as volume depletion; monitor patients who are more susceptible to complications from diarrhea, such as older patients and patients taking drugs that can lead to volume depletion or hypotension
Instruct patients to stop therapy and contact their healthcare provider if severe diarrhea occurs or if they experience symptoms of volume depletion such as lightheadedness, decreased urine output, or tiredness; in such cases, consider reducing the dose or suspending therapy
Caution with use in elderly patients because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy
Coadministration with simvastatin or lovastatin
- Risk of myopathy (including rhabdomyolysis) with simvastatin and lovastatin
- Lomitapide ~doubles simvastatin exposure
- Reduce simvastatin dose by 50% and do not exceed 20 mg/day (or 40 mg/day in those previously tolerating 80 mg/day) when initiating lomitapide
- Interaction between lovastatin and lomitapide has not been studied; however, the metabolizing enzymes and transporters responsible for elimination of lovastatin and simvastatin are similar, suggesting increased lovastatin exposure
- Reduce lovastatin dose when initiating lomitapide
Pregnancy and lactation
Pregnancy category: X
Pregnancy exposure registry: 1-877-902-4099
Lactation: Unknown whether distributed in breast milk; because of the potential for tumorigenicity shown in a 2-year mouse study, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Juxtapid (lomitapide)
Mechanism of action
Directly binds and inhibits microsomal triglyceride transfer protein (MTP), which resides in the lumen of the endoplasmic reticulum, thereby preventing apo B-containing lipoproteins assembly in enterocytes and hepatocytes
This inhibits the synthesis of chylomicrons and VLDL; inhibition of VLDL synthesis leads to reduced LDL-C plasma levels
Absorption
Bioavailability: 7%
Peak Plasma Time: 6 hr
Distribution
Protein Bound: 99.8%
Vdss: 985-1292 L
Metabolism
Metabolized extensively by the liver
Metabolic pathways include oxidation, oxidative N-dealkylation, glucuronide conjugation, and piperidine ring opening
CYP3A4 metabolizes lomitapide to its major inactive metabolites M1 and M3
CYPs 1A2, 2B6, 2C8, and 2C19 may metabolize lomitapide to a small extent to M1
Elimination
Half-life:39.7 hr
Excretion: 59.5% urine; 33.4% feces
