Juxtapid (lomitapide)

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.

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

• 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

• 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.

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.

• 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.