Generic drug: lomitapide
Brand name: Juxtapid
What is Juxtapid (lomitapide), and how does it work?
Juxtapid (lomitapide) is a prescription medicine used along with diet and other lipid-lowering treatments, including low-density lipoprotein (LDL) apheresis where available, in people with homozygous familial hypercholesterolemia (HoFH) to reduce:
- LDL ("bad") cholesterol
- total cholesterol
- a protein that carries "bad" cholesterol in the blood (apolipoprotein B)
- non-high-density lipoprotein cholesterol (non-HDL-C)
It is not known if Juxtapid can decrease problems from high cholesterol, such as heart attack, stroke, death or other health problems.
It is not known if Juxtapid is safe and effective in people with high cholesterol who do not have HoFH, including those with heterozygous familial hypercholesterolemia (HeFH).
What are the side effects of Juxtapid?
WARNING
RISK OF HEPATOTOXICITY
Juxtapid can cause elevations in transaminases. In the Juxtapid clinical
trial, 10 (34%) of the 29 patients treated with Juxtapid had at least one
elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
=3x upper limit of normal (ULN). There were no concomitant clinically meaningful
elevations of total bilirubin, international normalized ratio (INR), or alkaline
phosphatase.
Juxtapid also increases hepatic fat, with or without concomitant increases in
transaminases. The median absolute increase in hepatic fat was 6% after both 26
and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance
spectroscopy. Hepatic steatosis associated with Juxtapid treatment may be a risk
factor for progressive liver disease, including steatohepatitis and cirrhosis.
Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating
treatment and then ALT and AST regularly as recommended. During treatment,
adjust the dose of Juxtapid if the ALT or AST are =3x ULN. Discontinue Juxtapid
for clinically significant liver toxicity.
Because of the risk of hepatotoxicity, Juxtapid is available only through a
restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called
the Juxtapid REMS Program. Prescribe Juxtapid only to patients with a clinical
or laboratory diagnosis consistent with HoFH. The safety and effectiveness of
Juxtapid have not been established in patients with hypercholesterolemia who do
not have HoFH.
Juxtapid can cause serious side effects, including:
- problems absorbing certain nutrients. Juxtapid may decrease your
ability to absorb fat-soluble nutrients such as Vitamin E and fatty acids.
You should take supplements each day that contain fat-soluble vitamins.
People with bowel or pancreas problems may have an increased chance of not
being able to absorb these nutrients. - gastrointestinal symptoms. Diarrhea, nausea, vomiting, and stomach pain or discomfort are very common when taking
Juxtapid. Strictly following a low-fat diet may help lower the chance of having these symptoms. Stop taking Juxtapid and tell your doctor if you have severe diarrhea, especially if you also have lightheadedness, decreased urine output, or tiredness. - increased levels of certain blood thinners. Juxtapid can increase the level of the blood thinner, warfarin. If you take warfarin, your doctor should check your blood clotting times frequently, especially after your dose of
Juxtapid changes. - liver problems caused by certain drugs. Certain medicines can cause liver problems, including isotretinoin, acetaminophen, methotrexate, tetracyclines, and tamoxifen. If you take these medicines with
Juxtapid your doctor may do blood tests more often to check your liver.
The most common side effects of Juxtapid include:
- diarrhea
- nausea
- vomiting
- indigestion
- stomach cramping/pain
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Juxtapid. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What is the dosage for Juxtapid?
Initiation And Maintenance Of Therapy
Before beginning treatment with Juxtapid:
- Measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin;
- Obtain a negative pregnancy test in females of reproductive potential prior to initiating treatment with Juxtapid;
- Initiate a low-fat diet supplying <20% of energy from fat.
The recommended starting dosage of Juxtapid is 5 mg once daily, and the dose should be escalated gradually based on acceptable safety and tolerability. Transaminases should be measured prior to any increase in dose.
The maintenance dosage of Juxtapid should be individualized, taking into account patient characteristics such as goal of therapy and response to treatment, to a maximum of 60 mg daily as described in Table 1. Modify dosing for patients taking concomitant weak CYP3A4 inhibitors and for those with renal impairment or baseline hepatic impairment.
Monitor transaminases during treatment with Juxtapid as described in the prescribing information, and reduce or withhold dosing for patients who develop transaminase values =3x the upper limit of normal (ULN).
Table 1: Recommended Regimen for Titrating Dosage
DOSAGE
DURATION OF ADMINISTRATION BEFORE CONSIDERING INCREASE TO NEXT DOSAGE
5 mg daily
At least 2 weeks
10 mg daily
At least 4 weeks
20 mg daily
At least 4 weeks
40 mg daily
At least 4 weeks
60 mg daily
Maximum recommended dosage
- To reduce the risk of developing a fat-soluble nutrient deficiency due to Juxtapid's mechanism of action in the small intestine, patients treated with Juxtapid should take daily supplements that contain 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).
Administration
- Juxtapid should be taken once daily with a glass of water, without food, at least 2 hours after the evening meal because administration with food may increase the risk of gastrointestinal adverse reactions. Patients should swallow Juxtapid capsules whole. Capsules should not be opened, crushed, dissolved, or chewed.
Dosing With Cytochrome P450 3A4 Inhibitors
- Juxtapid is contraindicated with concomitant use of moderate and strong cytochrome P450 3A4 (CYP3A4) inhibitors.
- The recommended maximum dosage of Juxtapid is 30 mg daily with concomitant use of weak CYP3A4 inhibitors (such as alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, lapatinib, nilotinib, pazopanib, ranitidine, ranolazine, ticagrelor, zileuton). However, the recommended maximum dosage of Juxtapid is 40 mg daily with concomitant use of oral contraceptives.
- When initiating a weak CYP3A4 inhibitor in a patient already taking Juxtapid 10 mg daily or more, decrease the dose of Juxtapid by half; patients taking Juxtapid 5 mg daily may continue with the same dosage.
- Careful titration of Juxtapid may then be considered according to LDL-C response and safety/tolerability to a maximum recommended dosage of 30 mg daily except when coadministered with oral contraceptives, in which case the maximum recommended lomitapide dosage is 40 mg daily.
Dose Modification Based On Elevated Transaminases
Table 2 summarizes recommendations for dose adjustment and monitoring for patients who develop elevated transaminases during therapy with Juxtapid.
Table 2: Dose Adjustment and Monitoring for Patients with Elevated Transaminases
ALT OR AST
TREATMENT AND MONITORING RECOMMENDATIONS*
≥3 and <5 ULN
- Confirm elevation with a repeat measurement within one week.
- If confirmed, reduce the dose and obtain additional liver-related tests if not already measured (such as alkaline phosphatase, total bilirubin, and INR).
- Repeat tests weekly and withhold dosing if there are signs of abnormal liver function (increase in bilirubin or INR), if transaminase levels rise above 5 ULN, or if transaminase levels do not fall below 3 ULN within approximately 4 weeks. In these cases of persistent or worsening abnormalities, also investigate to identify the probable cause.
- If resuming Juxtapid after transaminases resolve to <3 ULN, consider reducing the dose and monitor liver-related tests more frequently.
≥5 ULN
- Withhold dosing, obtain additional liver-related tests if not already measured (such as alkaline phosphatase, total bilirubin, and INR), and investigate to identify the probable cause.
- If resuming Juxtapid after transaminases resolve to <3 ULN, reduce the dose and monitor liver-related tests more frequently.
*Recommendations based on an ULN of approximately 30-40 international units/L.
- 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 treatment with Juxtapid and investigate to identify the probable cause.
Dosing In Patients With Renal Impairment
- Patients with end-stage renal disease receiving dialysis should not exceed 40 mg daily. There are no data available to guide dosing in other patients with renal impairment.
Dosing In Patients With Baseline Hepatic Impairment
- Patients with mild hepatic impairment (Child-Pugh A) should not exceed 40 mg daily.
What drugs interact with Juxtapid?
Moderate And Strong CYP3A4 Inhibitors
- A strong CYP3A4 inhibitor has been shown to increase lomitapide exposure
approximately 27-fold. - Concomitant use of strong CYP3A4 inhibitors (such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir, voriconazole) with lomitapide is contraindicated.
- Concomitant use of moderate CYP3A4 inhibitors (such as amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) has not been studied, but concomitant use with lomitapide is contraindicated since lomitapide exposure will likely increase significantly in the presence of these inhibitors.
- Patients must avoid grapefruit juice while taking Juxtapid.
Weak CYP3A4 Inhibitors
- Weak CYP3A4 inhibitors (such as alprazolam, amiodarone, amlodipine,
atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine,
fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, lapatinib,
nilotinib, pazopanib, ranitidine, ranolazine, ticagrelor, zileuton) can
increase lomitapide exposure approximately 2-fold. - When administered with weak CYP3A4 inhibitors, the dose of Juxtapid
should be decreased by half. - Careful titration of Juxtapid may then be considered based on LDL-C
response and safety/tolerability to a maximum recommended dosage of 30 mg
daily except when coadministered with oral contraceptives, in which case the
maximum recommended lomitapide dosage is 40 mg daily.
Warfarin
- Lomitapide increases plasma concentrations of both R(+)-warfarin and
S(-)-warfarin by approximately 30% and increased the INR 22%. Patients
taking warfarin should undergo regular monitoring of INR, particularly after
any changes in lomitapide dosage. The dose of warfarin should be adjusted as
clinically indicated.
Simvastatin And Lovastatin
- The risk of myopathy, including rhabdomyolysis, with simvastatin and
lovastatin monotherapy is dose related. Lomitapide approximately doubles the
exposure of simvastatin; therefore, the recommended dose of simvastatin
should be reduced by 50% when initiating Juxtapid. - While taking Juxtapid, limit simvastatin dosage to 20 mg daily (or 40 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year without evidence of muscle toxicity).
- Refer to the simvastatin prescribing information for simvastatin dosing recommendations.
- Interaction between lovastatin and lomitapide has not been studied.
- However, the metabolizing enzymes and transporters responsible for the disposition of lovastatin and simvastatin are similar, suggesting that
Juxtapid may increase the exposure of lovastatin; therefore, reducing the dose of lovastatin should be considered when initiating
Juxtapid.
P-glycoprotein Substrates
- Lomitapide is an inhibitor of P-glycoprotein (P-gp). Coadministration of lomitapide with P-gp substrates (such as aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan) may increase the absorption of P-gp substrates.
- Dose reduction of the P-gp substrate should be considered when used concomitantly with lomitapide.
Bile Acid Sequestrants
- Juxtapid has not been tested for interaction with bile acid sequestrants.
- Administration of Juxtapid and bile acid sequestrants should be separated by at least 4 hours since bile acid sequestrants can interfere with the absorption of oral medications.
Is Juxtapid safe to use while pregnant or breastfeeding?
- Based on findings from animal studies, Juxtapid use is contraindicated in pregnancy since it may cause fetal harm.
- There are no data on the presence of lomitapide in human or animal milk, effects on the breastfed infant or on milk production.
- Because of the potential for serious adverse reactions, including hepatotoxicity, advise patients that breastfeeding is not recommended during treatment with
Juxtapid.