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Summary Basis of Decision (SBD)
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Juxtapid is located below.
Recent Activity for Juxtapid
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Juxtapid
Updated: 2014/09/04
The following table describes post-authorization activity for Juxtapid, a product which contains the medicinal ingredient lomitapide mesylate. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Numbers (DINs):
DIN 02420341 - 5 mg capsule
DIN 02420376 - 10 mg capsule
DIN 02420384 - 20 mg capsule
Post-Authorization Activity Table (PAAT)Activity/Submission Type, Control NumberDate SubmittedDecision and DateSummary of Activities(the most recent activities are listed first)NC # 1756982014/06/16Issued No Objection Letter 2014/08/29Level II (90 day) Notifiable Change (Safety Change) to modify the Product Monograph (PM) to re-classify the antiretroviral drug tipranavir/ritonavir as a strong cytochrome P450 (CYP) 3A4 inhibitor, instead of previously classified as a weak CYP 3A4 inhibitor. Consequently, use of tipranavir/ritonavir in combination with Juxtapid is now contraindicated.
A correction was also made under the Warnings and Precautions section of the PM regarding the number of patients which developed hepatic steatosis.
The submission was reviewed and a No Objection Letter was issued.Drug product (DINs 02420341, 02420376, 02420384) market notificationNot applicableDate of first sale: 2014/05/06The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the 
Food and Drug Regulations.NDS # 1603852012/11/21Issued NOC 2014/02/04Notice of Compliance issued for New Drug Submission.Summary Basis of Decision (SBD) for Juxtapid
Date SBD Issued: 2014/04/07
The following information relates to the original authorization of the new drug submission for Juxtapid.
Lomitapide mesylate
5 mg, 10 mg and 20 mg, capsule, oral
Drug Identification Numbers (DINs):
DIN 02420341 - 5 mg capsule
DIN 02420376 - 10 mg capsule
DIN 02420384 - 20 mg capsule
Aegerion Pharmaceuticals (Canada) Ltd.
New Drug Submission Control Number: 160385
On February 4, 2014, Health Canada issued a Notice of Compliance to Aegerion Pharmaceuticals Canada Inc. for the drug product Juxtapid.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Juxtapid is favourable as an adjunct to a low-fat diet and other lipid-lowering drugs, with or without LDL apheresis, to reduce low-density lipoprotein cholesterol (LDL-C) in adult patients with homozygous familial hypercholesterolemia (HoFH). Its use is limited to that of physicians experienced in the diagnosis and treatment of familial hypercholesterolemia.
What was approved?
Why was Juxtapid approved?
What steps led to the approval of Juxtapid?
What follow-up measures will the company take?
What post-authorization activity has taken place for Juxtapid?
What other information is available about drugs?
What was the scientific rationale for Health Canada's decision?
1. What was approved?
Juxtapid, a microsomal triglyceride transfer protein (MTP) inhibitor, is indicated as an adjunct to a low-fat diet and other lipid-lowering drugs, with or without LDL apheresis, to reduce low-density lipoprotein cholesterol (LDL-C) in adult patients with homozygous familial hypercholesterolemia (HoFH).
Juxtapid is contraindicated in:
patients with moderate or severe hepatic impairment;
patients with known significant chronic bowel disease;
with concomitant administration of >20 mg daily simvastatin (40 mg daily is allowed for patients who have previously tolerated simvastatin 80 mg daily for at least one year without evidence of muscle toxicity);
concomitant use with strong or moderate CYP 3A4 inhibitors, including HIV protease inhibitors, some macrolide antibiotics, some calcium channel blockers, and the anti-arrhythmic, dronedarone;
pregnancy;
patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency, or glucose-galactose malabsorption; and
patients who are hypersensitive to the drug product, or to any ingredient in the formulation or component of the container.
Juxtapid was approved for use under the conditions stated in the Juxtapid Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Juxtapid (5mg, 10mg and 20mg of lomitapide mesylate) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains gelatin, lactose white monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, red iron oxide (5 mg and 10 mg capsules only), silicon dioxide, sodium starch glycolate, titanium dioxide.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Juxtapid Product Monograph, approved by Health Canada and available through the Drug Product Database.
2. Why was Juxtapid approved?
Health Canada considers that the benefit/risk profile of Juxtapid (lomitapide) is favourable. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor. The inhibition of MTP leads to diminished production of low-density lipoprotein cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia (HoFH), a very rare, life-threatening, inherited disease. The disease is generally caused by mutations in both alleles of the low-density lipoprotein receptor (LDL-R) gene, which results in a very substantial accumulation of low density lipoprotein cholesterol (LDL-C) in the blood. The prevalence of homozygosity for LDL-R mutations has been historically reported to be only 1:1,000,000.
The most commonly reported adverse events during treatment with lomitapide in HoFH patients were gastrointestinal (GI) disorders, which were reported in 93% of patients during the first 26 weeks of treatment, and at a lower incidence in the safety phase of the pivotal trial at 74%, suggesting that the incidence of these adverse events may be reduced once maximum tolerated dose is established. These GI effects are entirely expected due to the mechanism of action of lomitapide, which, at the level of the intestine, results in pharmacologic disruption of normal fat absorption from the intestinal lumen, leading to malabsorption of dietary fat.
Based on its mechanism of action, noteworthy increases in hepatic fat content may be expected in all patients treated with lomitapide at clinically relevant doses. The extent of such increases varies from patient to patient and is not directly dose-related, although higher sustained doses generally predispose the patient to increased hepatic fat accumulation. This effect appears to be reversible over a period of a number of weeks, or a few months, upon discontinuation of lomitapide treatment. In the clinical development program, there was no evidence of progression of hepatic steatosis to steatohepatitis, with or without associated hepatic fibrosis. There were no cases of cirrhosis or hepatic failure observed clinically.
Hepatic transaminase elevations were noted with lomitapide use, at a substantially increased frequency over controls. Increases in hepatic fat content with lomitapide treatment were associated with clinically relevant increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in a minority of patients. These elevations of hepatic transaminases generally responded well to downward dose adjustment of lomitapide, if necessary, and were not associated with concomitant increases in serum bilirubin.
A Risk Management Plan (RMP) for Juxtapid was submitted by Aegerion Pharmaceuticals Canada Ltd. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. As part of pharmacovigilance measures to be instituted, a worldwide registry of patients to be treated with lomitapide is to be created and maintained for at least ten years.
Overall, the therapeutic benefit of Juxtapid therapy is favourable, and outweighs potential risks, when used as directed. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Juxtapid Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of Sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to Section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3. What steps led to the approval of Juxtapid?
Submission Milestones: JuxtapidSubmission MilestoneDatePre-submission meeting:2012/08/02Submission filed:2012/11/21ScreeningScreening Deficiency Notice issued:2013/01/18Response filed:2013/02/28Screening Acceptance Letter issued:2013/04/12ReviewBiopharmaceutics Evaluation complete:2013/11/07Quality Evaluation complete:2014/01/27Clinical Evaluation complete:2013/12/16Labelling Review complete:2014/01/24Notice of Compliance issued by Director General:2014/02/04For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4. What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
5. What post-authorization activity has taken place for Juxtapid?
Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.
The PAAT for Juxtapid is found above.
For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.
6. What other information is available about drugs?
Up to date information on drug products can be found at the following links:
See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
See the Patent Register for patents associated with medicinal ingredients, if applicable.
See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7. What was the scientific rationale for Health Canada's decision?
Clinical Basis for Decision
Clinical Pharmacology
Lomitapide has been developed as an adjunctive treatment for patients with homozygous familial hypercholesterolemia (HoFH), a very rare, life-threatening inherited disease. The disease is generally caused by mutations in both alleles of the low-density lipoprotein receptor (LDL-R) gene which leads to an accumulation of low-density lipoprotein cholesterol (LDL-C) in the blood. The prevalence of homozygosity for LDL-R mutations has been historically reportred to be 1:1,000,000, based on frequency of mutations in the LDL-R gene.
Lomitapide is a potent, selective inhibitor of microsomal triglyceride transfer protein (MTP), an intracellular lipid-transfer protein that is found in the lumen of the endoplasmic reticulum and is responsible for binding and shuttling individual lipid molecules between membranes. Since MTP plays a key role in the assembly of apolipoprotein B (apo B)-containing lipoproteins in the liver and intestines, inhibition of MTP impairs the synthesis of very low density lipoprotein cholesterol (VLDL-C) and chylomicrons. The inhibition of the synthesis of VLDL leads to reduced levels of plasma low density lipoprotein cholesterol (LDL-C). Lomitapide has a mechanism of action that differs from those of other classes of lipid lowering agents (e.g., statins, bile acid sequestrants, cholesterol absorption inhibitors). This distinct mechanism appears to be complementary to that of other lipid-lowering agents.
Studies of in vitro metabolism of lomitapide in microsomes and hepatocytes, as well as data from two clinical pharmacology studies, have shown that the drug is extensively metabolised. In vitro data demonstrated that lomitapide is primarily metabolised by CYP 3A4. The pharmacological activity of lomitapide and its two, primary metabolites, M1 and M3, were examined in vitro using vesicles incorporating bovine MTP to allow assessment of triglyceride transfer by fluorescence imaging. Lomitapide was confirmed to be a potent inhibitor of the triglyceride transfer activity of MTP with a half maximal inhibitory concentration (IC50) value of 15.5 nM. The two primary metabolites were not found to have pharmacodynamics activity at clinically relevant concentrations.
For further details, please refer to the Juxtapid Product Monograph, approved by Health Canada and available through the Drug Product Database.
Drug-Drug Interactions
Drug interaction studies revealed a major interaction with the strong CYP 3A4 inhibitor, ketoconazole, with which a 27-fold increase in lomitapide plasma exposure was seen. Accordingly, lomitapide use is contraindicated with all strong or moderate CYP 3A4 inhibitors, including ketoconazole. Grapefruit juice should also be avoided with lomitapide treatment. With weak inhibitors of CYP 3A4, such as atorvastatin, oral contraceptives, and the herbal preparations, gingko, goldenseal, and peppermint oil, the maximum recommended dose of Juxtapid is lowered by half to 30 mg daily. Lomitapide is an inhibitor of P-glycoprotein (P-gp), but is not a P-gp substrate itself. Dose reduction of P-gp substrates should be considered when used concomitantly with lomitapide. All of these observations have been appropriately captured in the Juxtapid Product Monograph. No QT effects were seen in a dedicated thorough QT study.
Clinical Efficacy
The pivotal study, UP1002/AEGR-733-005, is a Phase III, open-label, single-arm clinical trial, designed to evaluate both the efficacy and long-term safety of lomitapide in patients with homozygous familial hypercholesterolemia (HoFH), at an individually-determined maximum tolerated dose, up to 60 mg, given once daily, in addition to other lipid-lowering drugs with or without LDL apheresis.
The demographic characteristics of the 29 patients with HoFH treated in the Phase III study had a mean age of 30.7 years and ranged from 18 to 55 years. Just over half the patients were male [16 of 29 (55%)] and the majority were Caucasian [25 of 29 (86%)].
The mean percent change from baseline in low-density lipoprotein cholesterol (LDL-C) after 26 weeks of treatment was the primary efficacy endpoint. The secondary endpoints were total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apo B). These lipid and lipoprotein parameters were measured in fasting blood samples at baseline, and serially over the course of treatment.
Of the 29 patients enrolled in Study UP1002/AEGR-733-005, 23 completed the study through Week 56, with 6 patients withdrawing prematurely prior to the primary efficacy assessment at Week 26. The patient population for the primary efficacy analysis was the intent-to-treat (ITT) population. Standard statistical testing was performed for the efficacy analyses, with a paired t-test performed to test the hypothesis of no percent change from baseline within the treatment group. Missing data due to patient withdrawal were imputed using a last-observation-carried-forward (LOCF) method to the primary endpoint.
Efficacy results focus primarily on the intent-to-treat (ITT) population, and secondarily on the completer (per-protocol) populations. All patients who completed the Efficacy Phase of Study UP1002/AEGR-733-005 through Week 26, also completed the Safety Phase through Week 56. Thus, patients in the Week 26 and Week 56 Completer populations are identical. As such, results for the Efficacy Phase of the trial focus on the ITT analysis, while results for the Completer population present data from both the Efficacy and Safety Phases.
Treatment with lomitapide titrated to each patient's maximum tolerated dose, to a pre-specified limit of 60 mg daily, taken concurrently with other lipid-lowering therapies and a low-fat diet for 26 weeks, substantially and significantly reduced LDL-C levels in patients with HoFH. In the ITT population, mean LDL-C decreased from 336 mg/dL (8.7 mmol/L) at baseline to 190 mg/dL (4.9 mmol/L) at the end of the Efficacy Phase (Week 26/LOCF), a mean change of -146.9 mg/dL (3.8 mmol/L), representing a clinically meaningful and statistically significant mean percent change from baseline of - 40% (p