Summary Basis of Decision for Juxtapid

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

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 decisions were 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:

2017-11-08

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 and to the list of abbreviations that are found in PAATs.

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
NC # 2043382017-03-31Issued NOL
2017-06-29		Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Adverse Reactions section of the PM based on post-market safety information. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 1986502016-09-26Issued NOC
2017-03-27		Submission filed as a Level I - Supplement for the addition of a new drug substance manufacture site as well as minor changes to the manufacturing process for this new site. Additionally, the drug substance re-test period has been extended from 1 year to 3 years. The information was reviewed and considered acceptable. An NOC was issued.
NC # 1949452016-07-09Issued NOL
2016-10-28		Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, Drug Interactions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 1756982014-06-16Issued No Objection Letter
2014-08-29		Level 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:
2014-05-06		The 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
2014-02-04		Notice 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 new drug submission for Juxtapid.

Lomitapide mesylate, 5 mg, 10 mg and 20 mg, capsule, oral

Drug Identification Number (DIN):

  • 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.

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: Juxtapid

Submission MilestoneDate
Submission filed:2012-11-21
Screening
Screening Deficiency Notice issued:2013-01-18
Response filed:2013-02-28
Screening Acceptance Letter issued:2013-04-12
Review
Biopharmaceutics Evaluation complete:2013-11-07
Quality Evaluation complete:2014-01-27
Clinical Evaluation complete:2013-12-16
Labelling Review complete:2014-01-24
Notice of Compliance issued by Director General:2014-02-04

For 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:

7 What was the scientific rationale for Health Canada's decision?
7.1 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 <0.001).

Observed values and changes from baseline to Weeks 26 and 56 in LDL-C for the 23 patients who completed the study through to Week 26 (the primary efficacy time point) were also reported. In this population, mean LDL-C decreased from 352 mg/dL (9.1 mmol/L) at baseline to 168 mg/dL (4.3 mmol/L) at the end of the Efficacy Phase (Week 26), a mean change of -185 mg/dL (4.8 mmol/L), representing a clinically meaningful and statistically significant mean percent change from baseline of -50% (p <0.001).

Results for the secondary efficacy endpoints of TC, apo B, triglycerides, non-HDL-C and VLDL-C were consistent in direction, magnitude of change, and significance with the primary endpoint of LDL-C. The percent decrease in Lp(a) was smaller than for the other apo B-containing lipoproteins, with a median percent change of -13% from baseline to Week 26, and not statistically significant.

For more information, refer to the Juxtapid Product Monograph, approved by Health Canada and available through the Drug Product Database.

Supportive Studies

The key supportive Phase II Study, UP1001, had a similar study design to the Phase III study as it was also an open-label, single-arm clinical trial designed to evaluate the safety and lipid-lowering effect of lomitapide in patients with HoFH using a dose escalation regimen. However, in contrast to Study UP1002/AEGR-733-005, which required patients to remain on their LLT, in Study UP1001, patients were required to stop all lipid-lowering treatments, including apheresis, within 4 weeks prior to the baseline visit and remain off these therapies throughout the study until completion of the 4-week follow-up assessment.

Clinical Safety

Overall, the evaluation of the safety of lomitapide is based on data from a total of 1,145 patients treated with lomitapide and/or a comparator agent across the Phase I, II, and III clinical development program. A total of 925 patients received oral lomitapide either as mono-therapy or co-administered with another therapy. Lomitapide was administered at dose levels ranging from 1 mg to 200 mg. The majority of patients, [that is (i.e.)], 959 of 1,145, were enrolled in placebo and/or active controlled trials.

Data from 20 of the 24 lomitapide studies have been pooled for safety analysis based on the population treated and study design. Four different study pools are summarised based on indication and type of study:

  • homozygous familial hypercholesterolemia (HoFH) population: Studies UP1001, and UP1002/AEGR-733-005.
  • Elevated LDL-C and other risk factors population: Studies AEGR-733-001, AEGR-733-003b, AEGR-733-004, AEGR-733-006, CV145-002, CV145-009, CV145-010.
  • Single-dose population: Studies AEGR-733-010, AEGR-733-017, CV145-001, CV145-003, CV145-006.
  • Multiple-dose, drug-drug interaction (DDI) or crossover studies: Studies AEGR-733-002, AEGR-733-013, AEGR-733-015, AEGR-733-018, AEGR-733-019, CV145-005

The most common reason for discontinuation from study treatment was an adverse event. The incidence of discontinuation due to AEs was higher in the Elevated LDL-C and Other Risk Factors pool (19%), even though these studies were of shorter duration than the HoFH studies, which had an AE discontinuation rate of 11%.

The most commonly reported treatment-emergent adverse events (TEAE) among patients with HoFH in Study UP1002/AEGR-733-005 were GI events, including diarrhea (79%), nausea (65%), vomiting (35%), dyspepsia (35%), abdominal discomfort (31%), abdominal pain (28%), and constipation, flatulence, and weight decreased (each 21%). All other AE were reported in less than 20% of patients in this study.

Similar results were observed in the Phase II trial, Study UP1001. The most commonly reported AE in that study was diarrhoea, occurring in 5 (83%) of 6 patients. Other commonly reported events were lung disorders, i.e., cold and flu-symptoms, and oropharyngeal pain (4 subjects each, 67%), and alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, and headache (3 subjects each, 50%).

There were no deaths reported during either Study UP1002/AEGR-733-005 or Study UP1001. Serious adverse events (SAEs) were reported in 3 (10%) of 29 up to 56-weeks in Study UP1002/AEGR-733-005, and 1 (17%) of 6 patients in the 16-week study, UP1001. None of the SAEs were considered to be related to study treatment by investigators.

The majority of these serious events were related to the subject's underlying cardiovascular disease, including acute coronary syndrome and angina pectoris (1 patient), and coronary artery arteriosclerosis (1 patient), or was related to a prior cardiac surgery, i.e., post-operative seroma, breast mass (1 patient). No patients in Study UP1002/AEGR-733-005 experienced a SAE after the Week 56 data cut-off, through September 8, 2011. In the long-term extension study, AEGR-733-012, 3 of 18 patients had experienced at least 1 SAE through the cut-off date cited above, including arteriovenous fistula, hypovolemic shock, reflux esophagitis, lower respiratory tract infection, hospitalisation for anticoagulation, and transfusion. All SAEs were assessed by investigators as not related to or unlikely to be related to study treatment.

Five of the HoFH patients (17%) experienced AEs leading to treatment discontinuation, with all five in Study UP1002/AEGR-733-005. All but one of these discontinuations due to AE was related to a GI disorder. One patient discontinued due to abdominal pain, nausea, and diarrhea, while 2 discontinued due to diarrhea, gastroenteritis, and headache. All of these reported GI events leading to treatment discontinuation were considered to be treatment related. None of these AEs leading to treatment discontinuation were serious and all were assessed as moderate in severity.

No patient experienced a SAE or had an AE leading to discontinuation after the Week 56 data cut-off date, through September 8, 2011. Following sponsor review of additional information available from the ongoing extension study, one patient in Study AEGR-733-012 was noted to have been discontinued from treatment due to an ALT elevation > 5× upper limit of normal (ULN) which was complicated by alcohol intake.

In conclusion, in the pivotal study, UP1002/AEGR-733-005, lomitapide was observed to lower LDL-C by approximately 40% at 26 weeks in the 29 patients enrolled, using the last-observation-carried-forward method in an intention-to-treat (ITT) analysis. Of the 23 patients that completed the initial 26 week course of treatment, called the Efficacy Phase of the pivotal study, all of them also completed the extension, so-called, Safety Phase of the trial of up to 56 weeks of total treatment duration. In terms of LDL-C response, mean change at Week 56 was reported as a 44% decrease from baseline, and 38% at Week 78 in a continuation of the pivotal study.

Lomitapide was also seen to lower other lipid parameters at Week 26, including total cholesterol (TC), apolipoprotein B (apo B), and triglycerides (TG) in patients with HoFH.

In addition, appropriate warnings and precautions are in place in the approved Juxtapid Product Monograph to address the identified all safety concerns.

For more information, refer to the Juxtapid Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

In order to support the clinical use of lomitapide, a comprehensive set of non-clinical studies were conducted using in vitro assays and in vivo in a variety of animal models. Pharmacological evaluation determined that lomitapide was effective in the inhibition of MTP, leading to dose-dependent reductions in total cholesterol, very low-density lipoprotein and low-density lipoprotein.

In the repeated dose studies, the most important effect observed was lipid accumulation in the liver and small intestine as a consequence of the pharmacological effect of lomitapide. This was seen at plasma exposures comparable to the intended human therapeutic exposure. Multifocal hemorrhage and extramedullar hematopoiesis, as well as increases in activated partial thromboplastin time (aPTT) and prothrombin time (PT) were observed in rats, most likely caused by vitamin K deficiency due to inhibited absorption of fat-soluble vitamins, since no hemorrhages were observed in vitamin-supplemented animals.

A standard package of genotoxicity assays did not elicit mutagenic or genotoxic potential for lomitapide. However, in the mouse carcinogenicity study, occurrence of hepatocellular adenoma and carcinoma were observed, without apparent wide-scale lipid accumulation in the liver. In the small intestine of mice, lipid vacuolation was observed, as well as increased epithelial carcinoma. In the rat carcinogenicity study, there was no clear increase in occurrence of liver tumours but there was a tendency to an increase when adenoma and carcinoma at the high dose when both males and females were totalled. In the small intestine, lipid vacuolation was observed but without an increase in the number of tumours. However, since the risk of tumour development with lomitapide cannot be completely excluded, further monitoring of tumour formation will be conducted by the sponsor in a prospective observational cohort study with an emphasis on small bowel, hepatic and colorectal tumours.

Although there were no major effects on fertility in either male or female rats, lomitapide was shown to be teratogenic in rats and ferrets, without any reasonable safety margin based on planned human exposure. Accordingly, lomitapide is contraindicated in pregnancy.

Overall, the non-clinical pharmacodynamics, pharmacokinetics, safety pharmacology and toxicology support the clinical use of lomitapide in patients with HoFH, if prescribed by physicians experienced in the diagnosis and treatment of familial hypercholesterolemia.

For more information, refer to the Juxtapid Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Juxtapid has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is considered acceptable when the capsules are packaged in 100 mL high density polyethylene (HDPE) bottles with an induction seal and 38 mm child-resistant (CR) closures, stored between 15°C to 30°C in a tightly closed container and protected from moisture.

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

Two excipients are of animal origin, lactose monohydrate and the gelatin used in the production of the capsule shells. However, no potential of bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) impacts are anticipated.

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