"The U.S. Food and Drug Administration today approved Kynamro (mipomersen sodium) injection as an addition to lipid-lowering medications and diet to treat patients with a rare type of high cholesterol called homozygous familial hypercholesterolemi"...
The following important adverse reactions have been observed and are discussed in detail in other sections of the label:
- Risk of hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Reduced absorption of fat-soluble vitamins, and serum fatty acids [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal adverse reactions [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
One single-arm, open-label, 78-week trial has been conducted in 29 patients with HoFH, 23 of whom completed at least one year of treatment. The initial dosage of JUXTAPID was 5 mg daily, with titration up to 60 mg daily during an 18-week period based on safety and tolerability. In this trial, the mean age was 30.7 years (range, 18 to 55 years), 16 (55%) patients were men, 25 (86%) patients were Caucasian, 2 (7%) were Asian, 1 (3%) was African American, and 1 (3%) was multi-racial [see Clinical Studies].
Five (17%) of the 29 patients with HoFH that participated in the clinical trial discontinued treatment due to an adverse reaction. The adverse reactions that contributed to treatment discontinuations included diarrhea (2 patients; 7%) and abdominal pain, nausea, gastroenteritis, weight loss, headache, and difficulty controlling INR on warfarin (1 patient each; 3%).
The most common adverse reactions were gastrointestinal, reported by 27 (93%) of 29 patients. Adverse reactions reported by ≥ 8 (28%) patients in the HoFH clinical trial included diarrhea, nausea, vomiting, dyspepsia, and abdominal pain. Other common adverse reactions, reported by 5 to 7 (17-24%) patients, included weight loss, abdominal discomfort, abdominal distension, constipation, flatulence, increased ALT, chest pain, influenza, nasopharyngitis, and fatigue.
The adverse reactions reported in at least 10% of patients during the HoFH clinical trial are presented in Table 3.
Table 3: Adverse Reactions Reported in ≥ 10% of
Patients in the Clinical Trial in HoFH
|Adverse Reaction||N (%)|
|Abdominal pain||10 (34)|
|Abdominal discomfort||6 (21)|
|Abdominal distension||6 (21)|
|Gastroesophageal reflux disease||3 (10)|
|Defecation urgency||3 (10)|
|Rectal tenesmus||3 (10)|
|Decreased weight||7 (24)|
|Increased ALT||5 (17)|
|Chest pain||7 (24)|
|Back pain||4 (14)|
|Nervous System Disorders|
|Pharyngolaryngeal pain||4 (14)|
|Nasal congestion||3 (10)|
|Angina pectoris||3 (10)|
|Adverse Reaction||N (%)|
Adverse reactions of severe intensity were reported by 8 (28%) of 29 patients, with the most common being diarrhea (4 patients, 14%), vomiting (3 patients, 10%), increased ALT or hepatotoxicity (3 patients, 10%), and abdominal pain, distension, and/or discomfort (2 patients, 7%).
During the HoFH clinical trial, 10 (34%) of 29 patients had at least one elevation in ALT and/or AST ≥ 3x ULN (see Table 4). No clinically meaningful elevations in total bilirubin or alkaline phosphatase were observed. Transaminases typically fell within one to four weeks of reducing the dose or withholding JUXTAPID.
Table 4: Patient Incidence
of Transaminase Elevations During the HoFH Clinical Trial
|≥ 3 to < 5 x ULN||6 (21%)|
|≥ 5 to < 10 x ULN||3 (10%)|
|≥ 10 to < 20 x ULN||1 (3%)|
|≥ 20 x ULN||0|
|≥ 3 to < 5 x ULN||5 (17%)|
|≥ 5 to < 10 x ULN||1 (3%)|
|≥ 10 to < 20 x ULN||0|
|≥ 20 x ULN||0|
Upper limits of normal (ULN) ranged from 33-41 international units/L for ALT and 36-43 international units/L for AST.
Among the 19 patients who enrolled in an extension study following the HoFH clinical trial, one discontinued because of increased transaminases that persisted despite several dose reductions, and one temporarily discontinued because of markedly elevated transaminases (ALT 24x ULN, AST 13x ULN) that had several possible causes, including a drug-drug interaction between JUXTAPID and the strong CYP3A4 inhibitor clarithromycin [see DRUG INTERACTIONS].
Hepatic fat was prospectively measured using magnetic resonance spectroscopy (MRS) in all eligible patients during the HoFH clinical trial. After 26 weeks, the median absolute increase in hepatic fat from baseline was 6%, and the mean absolute increase was 8% (range, 0% to 30%). After 78 weeks, the median absolute increase in hepatic fat from baseline was 6%, and the mean absolute increase was 7% (range, 0% to 18%). Among the 23 patients with evaluable data, on at least one occasion during the trial, 18 (78%) exhibited an increase in hepatic fat > 5% and 3 (13%) exhibited an increase > 20%. Data from individuals who had repeat measurements after stopping JUXTAPID show that hepatic fat accumulation is reversible, but whether histological sequelae remain is unknown.
Read the Juxtapid (lomitapide capsules) Side Effects Center for a complete guide to possible side effects
Moderate And Strong CYP3A4 Inhibitors
A strong CYP3A4 inhibitor has been shown to increase lomitapide exposure approximately 27fold [see CLINICAL PHARMACOLOGY]. Concomitant use of strong CYP3A4 inhibitors (such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, 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.
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 [see CLINICAL PHARMACOLOGY]. 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 [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
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 [see WARNINGS AND PRECAUTIONS].
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 [see CLINICAL PHARMACOLOGY]. 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.
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.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/25/2016
Additional Juxtapid Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.