Summary Basis of Decision for Aptiom

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 Aptiom is located below.

Recent Activity for Aptiom

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Aptiom

Updated: 2024-06-28

The following table describes post-authorization activity for Aptiom, a product which contains the medicinal ingredient eslicarbazepine acetate. 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 found in Post-Authorization Activity Tables (PAATs).

 

For additional information about the drug submission process, refer to the  Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number (DIN):

  • DIN 02426862 - 200 mg eslicarbazepine acetate, tablet, oral administration
  • DIN 02426870 - 400 mg eslicarbazepine acetate, tablet, oral administration
  • DIN 02426889 - 600 mg eslicarbazepine acetate, tablet, oral administration
  • DIN 02426897 - 800 mg eslicarbazepine acetate, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

Drug product (DIN 02426862) market notification

Not applicable

Date of first sale: 2024-05-30

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

Drug product (DIN 02426889) market notification

Not applicable

Date of first sale: 2024-05-15

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

Drug product (DIN 02426870) market notification

Not applicable

Date of first sale: 2024-04-12

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

Drug product (DIN 02426897) market notification

Not applicable

Date of first sale: 2024-02-07

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 282495

2024-01-03

Issued NOC 2024-01-25

Submission filed to change the name of the drug sponsor from Sunovion Pharmaceuticals Canada Inc. to Sumitomo Pharma Canada, Inc. An NOC was issued.

NC # 226705

2019-04-09

Issued NOL

2019-07-11

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 section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 222182

2018-11-21

Issued NOC

2019-01-24

Submission filed as a Level I - Supplement to increase the size of the bottle labels. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 209753

2017-09-28

Issued NOC

2018-09-12

Submission filed as a Level I - Supplement for the extension of the indication for the treatment of partial-onset seizures to include monotherapy and adjunctive therapy in patients 4 years of age and older. Regulatory Decision Summary published.

SNDS # 208086

2017-08-01

Issued NOC

2018-06-25

Submission filed as a Level I - Supplement to seek a monotherapy indication for Aptiom in adult patients with partial-onset seizures. Regulatory Decision Summary published.

NC # 213953

2018-02-23

Issued NOL

2018-04-25

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 Adverse Reactions section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 210683

2017-10-27

Issued NOL

2018-02-02

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, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 203475

2017-03-03

Issued NOC

2018-02-02

Submission filed as a Level I - Supplement for an alternate site for a drug substance manufacturing facility. The information was reviewed and considered acceptable. An NOC was issued.

 

NC # 201472

2016-12-23

Issued NOL

2017-03-27

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, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 179303

2014-10-30

Cancellation Letter Received 2015-10-07

Submission filed as a Level I - Supplement for an expanded indication: use as monotherapy in the treatment of partial-onset seizures. The design of the two studies submitted was not considered adequate to support the expanded indication. A Notice of Deficiency was issued on 2015-07-23, and the submission was subsequently cancelled by the sponsor.

Drug product (DINs 02426862, 02426870, 02426889, 02426897) market notification

Not applicable

Date of first sale: 2014-08-07

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 165665

2013-06-12

Issued NOC 2014-07-08

Notice of Compliance issued for New Drug Submission.
 
Summary Basis of Decision (SBD) for Aptiom

Date SBD issued: 2014-08-29

The following information relates to the New Drug Submission for Aptiom.

Eslicarbazepine acetate, 200 mg, 400 mg, 600 mg, and 800 mg, tablets, oral

Drug Identification Number (DIN):

  • DIN 02426862 - 200 mg tablet
  • DIN 02426870 - 400 mg tablet
  • DIN 02426889 - 600 mg tablet
  • DIN 02426897 - 800 mg tablet

Sunovion Pharmaceuticals Canada Inc.

New Drug Submission Control Number: 165665

 

On July 8, 2014, Health Canada issued a Notice of Compliance to Sunovion Pharmaceuticals Canada Inc. for the drug product, Aptiom.

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 Aptiom is favourable as adjunctive therapy in the treatment of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy.

 

1 What was approved?

 

Aptiom, an antiepileptic agent, was authorized as adjunctive therapy in the treatment of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy.

There were insufficient numbers of elderly patients who completed partial-onset seizure controlled studies (number of patients = 12) to determine the safety and efficacy of Aptiom in this patient population. Caution should be exercised during dose titration, and age-associated decrease in renal clearance should be considered in elderly patients.

The safety and efficacy of Aptiom in paediatric patients have not been studied. Aptiom is not indicated for use in this population.

Aptiom is contraindicated for patients with a known hypersensitivity to Aptiom (eslicarbazepine acetate) or other carboxamide derivatives [for example (e.g.) carbamazepine, oxcarbazepine] or any of its components, and for patients with a history of, or presence of, second- or third-degree atrioventricular block. Aptiom was approved for use under the conditions stated in the Aptiom Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Aptiom (eslicarbazepine acetate) is presented as 200 mg, 400 mg, 600 mg and 800 mg tablets. In addition to the medicinal ingredient, eslicarbazepine acetate, the tablet contains croscarmellose sodium, magnesium stearate, and povidone.

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 Aptiom Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Aptiom approved?

 

Health Canada considers that the benefit/risk profile of Aptiom is favourable as adjunctive therapy in the treatment of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy.

Epilepsy is a chronic neurological disorder that affects 1-3 percent of the population worldwide. The main symptom of epilepsy is the recurrence of unprovoked seizure attacks. Seizures are abnormal electrical discharges in the brain that temporarily disrupt normal brain function. Classification of seizures includes generalized type, involving both sides of the brain, or partial-onset, which begins in one part of the brain and may spread to affect both sides. Aptiom is indicated as an adjunctive therapy for partial-onset seizures. There are currently many anti-epileptic drugs approved for the treatment of partial-onset seizures in Canada.

Due largely to incomplete response and insufficient adherence because of poor tolerability and emergence of adverse events, many patients receive more than one anti-epileptic drug to control their seizures.

Eslicarbazepine acetate, the medicinal ingredient of Aptiom, is a new active substance and is a third generation member of the dibenzazepine family of drugs, which includes the first and second generation members, carbamazepine and oxcarbazepine, respectively. Although the precise mechanism of action in humans is unknown, non-human data suggest that Aptiom may work by delaying the return of the inactivated sodium channels to the active state which reduces the repetitive neuronal firing.

Aptiom has been shown to be efficacious in the treatment of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy. The market authorization was based on three 12-week, randomized, double-blind, placebo-controlled, multicentre studies. In two of the three studies, the two key efficacy endpoints (the median percent reduction in seizure frequency from baseline to the maintenance phase, and the proportion of patients with ≥50% reduction in seizure frequency) were statistically significant for both the 800 mg and 1,200 mg doses, and similar to the effect size of most other anti-epileptic drugs. In the third study, the results were statistically significant for the 1,200 mg dose and numerically better than placebo for the 800 mg treatment arm, but not statistically significant.

Some of the most frequently reported adverse reactions in the controlled epilepsy studies were dizziness, somnolence, headache, nausea, diplopia, vomiting, fatigue, ataxia, vision blurred, and vertigo. The majority of adverse events in the Aptiom-treated patients were of mild to moderate intensity. Adverse events of special interest included cardiac-related events, hyponatremia, neurologic and opthalmological effects. These issues have been addressed through appropriate labelling in the Aptiom Product Monograph.

A Risk Management Plan (RMP) for Aptiom was submitted by Sunovion Pharmaceuticals Canada Inc. 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.

Overall, the therapeutic benefits seen in the pivotal studies are considered positive and the benefits of Aptiom therapy seem to outweigh the potential risks. Aptiom has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Aptiom 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 Aptiom?

 

Submission Milestones: Aptiom

Submission Milestone Date
Pre-submission meeting: 2012-09-05
Submission filed: 2013-06-12
Screening  
Screening Deficiency Notice issued: 2013-07-23
Response filed: 2013-07-31
Screening Acceptance Letter issued: 2013-09-11
Review  
Biopharmaceutics Evaluation complete: 2014-06-24
Quality Evaluation complete: 2014-06-25
Clinical Evaluation complete: 2014-07-04
Labelling Review complete: 2014-06-13
Notice of Compliance issued by Director General: 2014-07-08

 

The Canadian regulatory decision on the non-clinical and clinical review of Aptiom was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as an added reference.

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 Aptiom?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorisation 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 Adcetris 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

In humans, the pharmacological activity of Aptiom is primarily exerted through its active metabolite, eslicarbazepine. The precise mechanism(s) by which eslicarbazepine exerts its anticonvulsant actions are not fully characterized. However, in vitro electrophysiological studies indicate that eslicarbazepine may stabilize the inactivated state of voltage-gated sodium channels, preventing/delaying their return to the activated state resulting in an inhibition of repetitive neuronal firing. In addition, eslicarbazepine may inhibit T-type calcium channels which may further contribute to its anticonvulsant effects.

Aptiom is rapidly metabolized by hydrolytic first-pass metabolism to its major active metabolite, eslicarbazepine, which is mainly excreted through the renal system. Instructions for dose adjustment and monitoring for renal and hepatic impairment, as well as elderly patients, have been added to the Aptiom Product Monograph. This drug has not been studied systematically in patients under 18 years of age and is not recommended for use in this population.

Aptiom has been shown to interact with certain anti-epileptic drugs (AEDs) and non-AEDs. Instructions for monitoring and/or dose adjustment based on drug interactions have been added to the Aptiom Product Monograph.

For further details, please refer to the Aptiom Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Three Phase III, 12-week, randomized, double-blind, placebo-controlled, fixed-dose, multicentre studies (Studies 301, 302, 304) were submitted to support the efficacy of Aptiom (eslicarbazepine acetate) as adjunctive therapy in the treatment of partial-onset seizures in adult patients with epilepsy. The total number of Aptiom-treated patients was 992 (placebo: 418). Patients had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 AEDs. Overall, 69% of the patients used two concomitant AEDs and 28% used one concomitant AED. The most commonly used AEDs were carbamazepine (50%), lamotrigine (24%), valproic acid (21%), and levetiracetam (18%). Oxcarbazepine was not allowed as a concomitant AED. Aptiom patients had a mean duration of epilepsy of 22 years (range 1 to 70 years) and a mean [Standard Deviation (SD)] baseline seizure frequency of 15 (22) per28 days. Similarly, placebo patients had a mean duration of epilepsy of 22 years (range 1 to 65 years) and a mean (SD) baseline seizure frequency of 15 (18) per 28 days.

Studies 301 and 302 compared doses of Aptiom 400, 800, and 1,200 mg, once daily with placebo. Study 304 compared doses of Aptiom 800 and 1,200 mg once daily with placebo. In all three studies, following an 8-week baseline phase to establish baseline seizure frequency prior to randomization, patients were randomized and titrated to the randomized dose. For all three studies, the titration phase lasted 2 weeks and was followed by a maintenance phase that lasted 12 weeks, during which patients were to remain on a stable dose of Aptiom. Among patients randomized to and who received Aptiom in the three studies, 89% in the 400 mg dose group, 82% in the 800 mg dose group, and 71% in the 1,200 mg dose group completed the studies (placebo: 87%).

The three studies (Studies 301, 302, and 304) had the same key efficacy endpoints:

  • Median percent reduction in seizure frequency from baseline to the maintenance phase.
  • Proportion of patients with a ≥50% reduction in seizure frequency from baseline to the maintenance phase.

In Studies 301 and 302, the results of the two key efficacy endpoints were statistically and clinically significant for both the 800 mg and 1,200 mg doses, and similar to the effect size of most other AEDs. In Study 304, the results were statistically and clinically significant for the 1,200 mg dose and numerically better than placebo, but not statistically significant for the 800 mg dose.

In Study 301, the largest percent decrease in median seizure frequency was in the Aptiom 1,200 mg/day group (39%), followed by the 800 mg/day group (36%); both statistically significantly better than placebo (15%). For the 400 mg/day group the percent decrease was 26%. The responder rates (patients with a ≥50% reduction in seizure frequency from baseline to the maintenance phase) for the 400 mg/day group, the 800 mg/day group, and the 1,200 mg/day group were 24%, 33% and 42.5%, respectively compared to placebo at 19%. The 1,200 mg/day group had the highest responder rate.

During the 12-week maintenance period, the proportion of seizure-free patients in the intent-to-treat (ITT) population was highest in the 1,200 mg/day group (8%), followed by the 800 mg/day group (4%). The proportion of seizure-free patients in the placebo arm was 2%. The 1,200 mg/day group was only marginally statistically superior to placebo (p = 0.0426). These results are generally expected and are in line with those observed with other AEDs.

In Study 302, there was a significant reduction in median seizure frequency of patients treated with various doses of Aptiom at the maintenance period, compared to placebo. However, the 800 mg/day group (33%) demonstrated slightly more reduction in seizure frequency compared to the 1,200 mg/day group (28%). The reduction in seizure frequency of the placebo-patients was unusually low compared to Studies 301 and 304, as well as compared to the placebo response in controlled studies of other AEDs. The responder rates were similar [35.6% versus (vs.) 35.8%] for the 800 mg/day and 1,200 mg/day groups. Both of these values were statistically significantly better than placebo (18%) and clinically meaningful. There was little difference between placebo and the 400 mg/day group (18% vs. 20%).

Over the 12-week maintenance period, the proportion of seizure-free patients increased dose-dependently with the highest proportion in the 1,200 mg/day group (5%). The 400 mg/day and 800 mg/day groups recorded seizure-free values of 1% and 3%, respectively (placebo: 2%). None of these differences were statistically significant. These results are in line with studies of other AEDs in adjunctive treatment with this type of patient population.

Study 304 had a similar design to Studies 301 and 302 but this study tested the efficacy and safety of only two doses of Aptiom (800 mg/day and 1,200 mg/day, not the 400 mg/day dose). In this study, some patients used a diary design similar to that used in Studies 301 and 302, and most patients used a diary design in which patients were required to enter a seizure record, including a zero if applicable. Overall, data in Study 304 demonstrated superior efficacy of Aptiom 1,200 mg over placebo in the treatment of patients with partial-onset seizures. The 800 mg/day group did not show statistically significant improvement over placebo. However, based on these data and previous data from Studies 301 and 302, the 800 mg/day dose is still considered a viable and likely effective maintenance dose.

Overall, the efficacy of Aptiom in the treatment of partial-onset seizures in adult patients with epilepsy was established in three placebo-controlled studies. For more information, refer to the Aptiom Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

A total of 1,021 patients received various doses of Aptiom (400 mg, 800 mg, and 1,200 mg) in the three Phase III, placebo-controlled studies (Studies 301, 302, and 304 described in the Clinical Efficacy section). Dizziness, somnolence, nausea, vomiting, and diplopia were among the most common adverse events (AEs) reported in these studies. Other AEs of interest included ataxia, blurred vision, rash, fatigue, and tremors. Some events [for example (e.g.), dizziness, rash, and diplopia] increased in frequency in a dose-dependent fashion. Serious AEs in the Aptiom treatment groups included dizziness and disturbances in gait (2% vs. placebo: 0%), somnolence (0.3% vs. placebo: 0%), and vision-related events (0.7% vs. placebo: 0%). Events leading to discontinuation included dizziness and disturbance in gait (9% vs. placebo: 0.7%), somnolence (3% vs. placebo: 0.7%), and vision-related events (4% vs. placebo: 0.2%).

The adverse event/safety profile of the open-label studies appeared to be similar to that of the controlled epilepsy studies with the exception of decreased diastolic pressure, which was not observed in the controlled studies.

As of March 30, 2014, the worldwide exposure to Aptiom was approximately 44,000 patient-years. Review of the available post-marketing data did not reveal any new safety concerns. Some of the notable post-marketing events that were observed in patients receiving Aptiom included hyponatremia, dizziness, partial seizures, fatigue, vertigo, rash, diplopia, pruritus, and nausea. These events have been included in the Aptiom Product Monograph.

Safety Topics of Special Interest

Dizziness and Somnolence

Dizziness and somnolence had a median time to onset of approximately 3-6 days and increased dose-dependently. In the Phase III controlled studies, dizziness was reported in the 400 mg, 800 mg, and 1,200 mg treatment groups at approximately 16%, 20%, and 28%, respectively (placebo: 9%). Somnolence occurred at approximately 11% and 18% in the 800 mg and 1,200 mg treatment groups, respectively (placebo: 8%). Dizziness and somnolence were among the AEs that most frequently led to discontinuation. The Product Monograph for Aptiom addresses these events.

Vision-related Adverse Events

In the Phase III controlled studies, there was a dose-dependent increase in the frequency of vision-related AEs (e.g., diplopia, blurred vision; 12%, 16%, and 17% in the 400 mg, 800 mg, and 1,200 mg treatment groups, respectively; placebo: 6%). Of the total, 0.7% was determined to be serious (placebo: 0%). These events also led to patient withdrawal in 4% of the patients (placebo: 0.2%). An initial increased frequency of these vision-related events (e.g., diplopia) may occur during the titration period, in the elderly, as well as with concomitant carbamazepine use. A warning statement about these events has been added to the Aptiom Product Monograph.

Cardiac-related Events

Aptiom has been shown to be associated with adose- and concentration-dependent increase in heart rate.It can also cause adose- and concentration-dependent prolongation of the PR interval. In the three Phase III, controlled studies (301, 302, and 304), 5 patients had a study-end PR interval value of >220 ms that was not present at baseline (placebo: none). Furthermore, a total of 7 patients had a study end PR interval value of 201 to 220 ms which was not present at baseline (placebo: one). Aptiom should not be used in patients with a history of, or presence of, second or third degree heart block.

Hyponatremia (Low blood sodium levels)

Other AEDs, especially those in the same pharmacological class as Aptiom, can cause hyponatremia (blood sodium levels ≤135 mmol/L). In the three Phase III, controlled studies, 1.1% of Aptiom-treated patients had clinically significant hyponatremia (blood sodium levels <125 mmol/L). Most cases occurred within the first 8 weeks of treatment with some occurring as early as 3 days post-treatment. Plasma sodium values as low as 110, 111, and 113 mmol/L were reported. Hypochloremia (low blood chloride levels) was also reported in the controlled studies. The majority of the Aptiom-treated patients who had low chloride values (≤90 mEq/L) also had sodium values ≤130 mEq/L (placebo: none). Both hyponatremia and hypochloremia appear to be dose-dependent. These issues are addressed in the Aptiom Product Monograph.

Overall, Aptiom demonstrated an acceptable safety profile for the specified indication and target population. Based on the data currently available to Health Canada, all safety issues have been labelled properly and all known risks can be managed at this time. Appropriate warnings and precautions are in place in the Aptiom Product Monograph.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The safety pharmacology and toxicology programs conducted with eslicarbazepine acetate are considered to be sufficient to support the indication of adjunctive therapy in the treatment of partial-onset seizures in adults. The species selection (mouse, dog and rabbit) for the safety assessment was appropriate from a drug metabolism point of view. The dose selection in the toxicology studies was generally limited by clinical tolerance and adverse effects were noted at eslicarbazepine exposures in the blood that were at or below therapeutic levels. The findings in these studies were generally similar to other drugs of this class (Trileptal and carbamazepine) and/or monitored in the clinical studies.

In pregnant mice, rats, and rabbits, eslicarbazepine acetate demonstrated developmental toxicity, abnormalities that included teratogenicity, embryo lethality, and fetal growth retardation, at clinically relevant doses and eslicarbazepine exposures in the blood that were lower than therapeutic levels. Therefore Aptiom should not be used during pregnancy or by individuals who may become pregnant unless the anticipated benefit justifies the potential risk to the fetus.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Aptiom Product Monograph. In view of the intended use of Aptiom, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product. Appropriate warnings and precautionary measures are in place in the Aptiom Product Monograph to address the identified safety concerns.

For more information, refer to the Aptiom 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 Aptiom 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 is considered acceptable.

Proposed limits of drug-related impurities are considered adequately qualified that is within International Conference on Harmonisation (ICH) limits and/or qualified from toxicological studies.

Comparative bioavailability studies were evaluated and considered to adequately bridge the clinical trial formulations for the 400 mg and 800 mg strengths with the corresponding strengths of the proposed commercial formulation. Based on compositional proportionality and similarity of dissolution profiles of the 600 mg commercial formulation and the 800 mg commercial formulation, a biowaiver for the 600 mg strength was considered to be supported. The sponsor also presented data to support comparable bioavailability of the 200 mg commercial formulation and the 800 mg commercial formulation. This supporting data combined with the long half-life of the drug substance and the specific proposed use of the 200 mg strength tablet were considered acceptable to support the 200 mg strength.

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

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. There are no excipients obtained from sources that are at risk of transmitting bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE). A letter of attestation confirming that the materials are not from a BSE/TSE affected country/area has been provided for this product indicating that it is considered to be safe for human use.

 

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