Summary Basis of Decision for Carbaglu

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 Carbaglu is located below.

Recent Activity for Carbaglu

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 Carbaglu

Updated:

2020-09-24

The following table describes post-authorization activity for Carbaglu, a product which contains the medicinal ingredient carglumic acid. 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 Number (DIN):

  • DIN 02439360 - Carglumic acid, 200 mg, tablet, oral

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
Drug product (DIN 02439360) market notificationNot applicableDate of forst sale:
2020-03-17		The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 2295022019-07-08Issued NOC
2019-08-12		Submission filed to change the name of the drug sponsor from Orphan Europe SARL to Recordati Rare Diseases. An NOC was issued.
SNDS # 1982022016-09-08Issued NOC
2017-04-06		Submission filed as a Level I - Supplement to change the container closure system of the drug product. As a result of the SNDS, modifications were made to the Dosage Forms, Composition, and Packaging section of the PM. The submission was reviewed and considered acceptable, and an NOC was issued.
Drug product (DIN 02439360) market notificationNot applicableDate of first sale:
2015-09-08		The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 1713582014-01-14Issued NOC
2015-04-10		Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Carbaglu

Date SBD issued: 2015-06-08

The following information relates to the new drug submission for Carbaglu.

Carglumic acid, 200 mg, tablet, oral

Drug Identification Number (DIN):

  • 02439360

Orphan Europe S.A.R.L.

New Drug Submission Control Number: 171358

On April 10, 2015, Health Canada issued a Notice of Compliance to Orphan Europe S.A.R.L. for the drug product Carbaglu.

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 Carbaglu is favourable as

  • Maintenance therapy in pediatric and adult patients for chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). During maintenance therapy, the concomitant use of other ammonia lowering therapies and protein restriction may be reduced or discontinued based on plasma ammonia levels.
  • Adjunctive therapy in pediatric and adult patients for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme NAGS. During acute hyperammonemic episodes, concomitant administration of Carbaglu with other ammonia lowering therapies such as alternate pathway medications, hemodialysis, and dietary protein restriction are recommended.

1 What was approved?

Carbaglu contains the active ingredient carglumic acid which is an amino acid and a synthetic structural analogue of N-acetylglutamate (NAG). Carglumic acid acts as a replacement of NAG in patients that have a deficiency of the mitochondrial enzyme N-acetylglutamate synthase (NAGS). It activates carbamoyl phosphate synthetase1 (CPS1) in liver mitochondria and hence restores the urea cycle since the enzyme CPS1 is the first enzyme of the urea cycle that converts ammonia into urea.

Carbaglu was authorized for the following two indications.

  • Acute hyperammonemia in patients with NAGS deficiency:
    Carbaglu is indicated as an adjunctive therapy in pediatric and adult patients for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme NAGS. During acute hyperammonemic episodes, concomitant administration of Carbaglu with other ammonia lowering therapies such as alternate pathway medications, hemodialysis, and dietary protein restriction are recommended.
  • Maintenance therapy for chronic hyperammonemia in patients with NAGS deficiency:
    Carbaglu is indicated for maintenance therapy in pediatric and adult patients for chronic hyperammonemia due to the deficiency of the hepatic enzyme NAGS. During maintenance therapy, the concomitant use of other ammonia lowering therapies and protein restriction may be reduced or discontinued based on plasma ammonia levels.

Carbaglu is contraindicated for patients who have hypersensitivity to carglumic acid or to any ingredient in the formulation, and for patients who are breastfeeding. Carbaglu was approved for use under the conditions stated in the Carbaglu Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Carbaglu (200 mg carglumic acid) is presented as a tablet. In addition to the medicinal ingredient, carglumic acid, the tablet also contains croscarmellose sodium, hypromellose, microcrystalline cellulose, silica colloidal anhydrous, sodium laurilsulfate, and sodium stearyl fumarate.

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

2 Why was Carbaglu approved?

Health Canada considers that the benefit/risk profile of Carbaglu (carglumic acid) is favourable as

  • Maintenance therapy in pediatric and adult patients for chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). During maintenance therapy, the concomitant use of other ammonia lowering therapies and protein restriction may be reduced or discontinued based on plasma ammonia levels.
  • Adjunctive therapy in pediatric and adult patients for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme NAGS. During acute hyperammonemic episodes, concomitant administration of Carbaglu with other ammonia lowering therapies such as alternate pathway medications, hemodialysis, and dietary protein restriction are recommended.

N-acetylglutamate synthase (NAGS) deficiency, an inherited autosomal recessive metabolic disorder, is one of the rarest and most severe of the hereditary Urea Cycle Disorders (UCDs) with approximately 50 known cases worldwide. Patients with NAGS deficiency lack a specific liver enzyme (NAGS) that produces NAG (N-acetylglutamate) which activates carbamyl-phosphate synthetase 1 (CPS1) as the first and rate-limiting step of the urea cycle. These patients are unable to eliminate nitrogen waste (ammonia) resulting in hyperammonemia which results in acute cerebral edema with severe neurological compromise. At present, there is no drug therapy approved in Canada for the treatment of hyperammonemia due to NAGS deficiency. Carbaglu is an analogue of NAG and therefore stimulates CPS and activates the first step in the urea cycle.

Carbaglu has been shown to be efficacious in patients with NAGS deficiency. The pivotal data supporting safety and efficacy were based on a retrospective case series of 23 patients with NAGS deficiency exposed to Carbaglu for up to 21 years. Given the exceptionally rare nature of NAGS deficiency and the well-defined pathophysiology of the disease, these data, despite not being derived from rigorous and well-controlled investigations, are considered sufficient for supporting the efficacy and safety of this product. The results showed a decrease in the mean baseline plasma ammonia levels to normal levels within 3 days with longer term maintenance of normal ammonia levels attained for most patients. The patients who achieved the greatest efficacy from Carbaglu generally received an early diagnosis and used concomitant treatments, including ammonia scavengers, dietary protein restriction and hemodialysis, during acute hyperammonemic episodes. When treatment with Carbaglu was started early, acute hyperammonemic episodes usually resolved and patients exhibited normal neurologic development.

The most common adverse events observed with Carbaglu were infections, vomiting, abdominal pain, pyrexia, tonsillitis, anemia, ear infection, diarrhea, nasopharyngitis, and headache. The most common serious adverse events (SAEs) were vomiting, somnolence, and pneumonia. Ten patients experienced 30 non-fatal SAEs, the most common one being vomiting. There were two deaths in NAGS deficiency patients treated chronically with Carbaglu. The causes of death were multi-organ failure with encephalopathy in one patient and severe hyperammonemia following pneumonia in the second patient.

A Risk Management Plan (RMP) for Carbaglu was submitted by Orphan Europe S.A.R.L. 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.

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

Overall, the therapeutic benefits seen in the pivotal data are positive and the benefits of Carbaglu therapy are considered to outweigh the potential risks. Carbaglu 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 Carbaglu 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 the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Carbaglu?

The drug submission for Carbaglu was reviewed and accepted under the Priority Review Policy. Sufficient evidence was submitted demonstrating that Carbaglu provides an effective treatment for a disease or condition for which no drug is presently marketed in Canada.

Due to issues identified in the review of the chemistry and manufacturing information, a Notice of Non-Compliance (NON) was issued for Carbaglu on November 5, 2014. The major issue in the NON was the lack of adequate validation data from the release-testing laboratory. The sponsor submitted a response to the NON and all of the concerns that led to the NON were satisfactorily addressed. The reviews were completed and the submission was found to be in compliance with the Food and Drugs Act and Regulations. A Notice of Compliance was issued on April 10, 2015.

Submission Milestones: Carbaglu

Submission MilestoneDate
Pre-submission meeting:2012-11-23
Request for priority status
Filed2013-10-15
Approval issued by the Bureau of Metabolism, Oncology and Reproductive Sciences Division2013-11-15
Submission filed:2014-01-14
Screening 1
Screening Acceptance Letter issued2014-05-09
Review 1
Clinical Evaluation complete2014-11-07
Labelling Review complete2014-10-23
Notice of Non-Compliance (NON) issued by Director General (quality issues)2014-11-05
Response filed:2014-12-24
Screening 2
Screening Acceptance Letter issued2015-01-21

Review 2

Quality Evaluation complete2015-02-25
Clinical Evaluation complete2015-04-02
Notice of Compliance issued by Director General2015-04-10

The Canadian regulatory decision on the non-clinical and clinical review of Carbaglu 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?

In addition to requirements outlined in the Food and Drugs Act and Regulations, the sponsor has agreed to provide the results of a two-year carcinogenicity study that was initiated in 2013. The first draft of the report should be available in 2015.

5 What post-authorization activity has taken place for Carbaglu?

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 Carbaglu 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

Carglumic acid, the active ingredient in Carbaglu, is a synthetic structural analogue of N-acetylglutamate (NAG), which is the essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS1) in liver mitochondria. The enzyme CPS1 is the first enzyme of the urea cycle, which converts ammonia into urea. The protein NAG is the product of NAGS, a mitochondrial enzyme. Patients who have NAGS deficiency are unable to adequately activate CPS1. Carglumic acid acts as replacement for NAG in NAGS deficiency patients and activates CPS1, thereby activates the urea cycle which converts ammonia to urea.

The clinical pharmacology program evaluated the pharmacokinetics of carglumic acid in healthy male volunteers. The results support the use of Carbaglu for the specified indication.

Carglumic acid was well-tolerated with no major adverse events reported in the clinical pharmacology studies.

The pharmacokinetics have not been evaluated in geriatric patients, and the effects of renal and hepatic impairment on the pharmacokinetics of Carbaglu are unknown. There were also no clinical drug-interaction studies performed, and no conclusions could be drawn concerning the electrocardiographic safety of carglumic acid because of the shortcomings of the available clinical electrocardiogram data. Given that NAGS deficiency is considered a rare and life-threatening disease, and that Carbaglu is the only treatment available currently in Canada for the treatment of hyperammonia in NAGS deficient patients, this lack of information is considered acceptable. Appropriate warnings and precautions are in place in the approved Carbaglu Product Monograph to address the identified safety concerns.

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

Clinical Efficacy

The efficacy of Carbaglu in the treatment of hyperammonemia due to NAGS deficiency was evaluated in a retrospective review of the clinical course of 23 NAGS deficiency patients who received Carbaglu treatment for a median of 7.9 years (range 0.6 to 20.8 years).

As of the cut-off date for the data collection (December 31, 2007), there were 18 NAGS deficiency patients who were chronically and continuously being treated with Carbaglu. Fifteen of these patients had a molecular (DNA test confirmed) diagnosis for NAGS deficiency whereas DNA test reports were not available for the other 3 patients. Of the 15 patients, 1 had a heterozygous mutation, 14 a homozygous mutation and 3 were unconfirmed. By the cut-off date, there were also 5 patients who had discontinued Carbaglu. Two of these patients died and 3 were heterozygous and removed from treatment.

Efficacy was primarily evaluated by plasma ammonia levels. Mean and median values were provided for baseline, as well as for short-term (Days 1 to 7) and long-term (last available value on Carbaglu treatment) evaluation.

The very small number of patients precludes any meaningful statistical analysis. Mean results were further complicated by the differences in availability of results at each time-point given the retrospective nature of the data. The mean data provided limited information on the change in laboratory parameters over the course of treatment and statistical conclusions were limited to descriptive-based statements. Results from several laboratories, spanning 20 years in several countries, provided results for this retrospective assessment. Thus, weighted mean averages of all the laboratory normal ranges were determined for reference. The mean normal maximum level for plasma ammonia was defined as ≤50 µmol/L.

At baseline (defined as the value immediately before initiation of treatment), ammonia levels were available for 20 patients (1 patient had missing data for 'baseline' and two did not have any data prior to treatment). The mean baseline ammonia level was 218.9 µmol/L. Mean ammonia levels decreased from 218.9 µmol/L (range of 29 to 1,428 µmol/L) at baseline to 145.9 µmol/L (range of 25 to 1,190 µmol/L) on Day 1 of treatment and 64.7 µmol/L (range of 11 to 255 µmol/L) on Day 2 of treatment. By Day 3 of treatment, the mean plasma ammonia level was 43.3 µmol/L (within the mean normal range) and on Day 7, the value was 41.5 µmol/L. The long-term results showed a mean ammonia level of 51.9 µmol/L with a range of 7 to 419.0 µmol/l. Given the small sample size and the large variance in plasma ammonia levels, the mean data provided a general overview of response to treatment. Three patients did not fully respond to treatment and skewed the mean data. Two of these patients were on sub-therapeutic doses of Carbaglu and it is unclear what factors contributed to poor efficacy in the third patient due to insufficient data. Individual patient narratives were reviewed to provide a more detailed assessment.

From the individual narratives, it was observed that the patients who achieved the greatest efficacy from Carbaglu had the following factors:

  • early and correct diagnosis
  • sufficient dosing during acute and maintenance periods
  • compliance to treatment
  • use of concomitant treatments during acute hyperammonemic episodes.

Efficacy was supported in patients who were shown to have homozygous NAGS deficiencies with a dechallenge/rechallenge effect demonstrated for Carbaglu in a few cases.

Efficacy of the proposed initial dosing regimen of 100-250 mg/kg/day for acute hyperammonemia and between 10-100 mg/kg/day for maintenance of efficacy was supported by the findings of the retrospective case series.

The secondary efficacy outcomes generally showed a positive impact on growth development with the change (z-score) from baseline to last follow-up for height being +0.5 and for weight +1.9. Among the 13 patients with available data, 9 patients were under a protein-restricted diet at baseline and 4 were on an unrestricted diet; whereas at the last reported measurement, there were only 2 patients on a protein restricted diet and 11 patients on an unrestricted diet. With respect to neurologic and psychomotor status, the data showed that at the long-term evaluation, 5 of the 7 patients who presented their affected neurological status at baseline, had normal neurological status at the last follow-up. There were no patients who had normal neurological status at baseline who deteriorated in status at the last follow-up visit. Hepatic status was assessed in 10 patients who presented both baseline and long-term follow-up data. There were two patients with affected hepatic status at baseline with no change at the long-term visit for hepatic status.

Overall, the efficacy data based on the retrospective case series of 23 patients with NAGS deficiency were sufficient to support the approval of Carbaglu for the recommended indication. The efficacy results showed a decrease in the mean baseline plasma ammonia levels to normal ammonia levels within 3 days, and demonstrated a longer-term maintenance of normal ammonia levels for most patients.

Indication

The New Drug Submission for Carbaglu was filed with the following indication, "Carbaglu is indicated for the treatment of hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency".

Health Canada recommended the following indication to accurately reflect the pivotal data and to ensure safe and effective use of the product.

  • Acute hyperammonemia in patients with NAGS deficiency:
    Carbaglu is indicated as an adjunctive therapy in pediatric and adult patients for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). During acute hyperammonemic episodes, concomitant administration of Carbaglu with other ammonia lowering therapies such as alternate pathway medications, hemodialysis, and dietary protein restriction are recommended.
  • Maintenance therapy for chronic hyperammonemia in patients with NAGS deficiency:
    Carbaglu is indicated for maintenance therapy in pediatric and adult patients for chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). During maintenance therapy, the concomitant use of other ammonia lowering therapies and protein restriction may be reduced or discontinued based on plasma ammonia levels.

In the majority of cases (18/23), the patients were on a previous treatment for hyperammonemia (ammonia scavengers, amino acid supplementation, hemodialysis). In many cases, some of these treatments were used concomitantly during the hyperammonemic crisis acute period and were gradually withdrawn. The majority of patients were on sodium benzoate (16 patients, 69.6%), followed by arginine (14 patients, 60.9%), carnitine (10 patients, 43.5%), phenylbutyrate (7 patients, 30.4%), citrulline (5 patients, 21.7%), hemodialysis (4 patients, 17.4%) or non-specified amino acid (1 patient, 4.3%). Given the potential for serious consequences stemming from hyperammonemia, it is crucial that ammonia levels are reduced as quickly as possible and thus it is prudent to use concomitant treatments to achieve this goal. Therefore, the proposed indication was revised to include a statement recommending concomitant treatment in acute hyperammonemic episodes and that individual monitoring of plasma ammonia levels will determine whether concomitant treatments may be reduced or discontinued in the maintenance period.

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

Clinical Safety

The clinical safety evaluation was based on retrospective data from the 23 patients exposed to Carbaglu that formed the study population described in the Clinical Efficacy section. As NAGS deficiency is an extremely rare disease, the sample size was small but the patients were exposed to Carbaglu for chronic periods of time providing exposure data of ≤10 years for 8 of the patients and ≤5 years for 14 of the patients. There were only 2 patients who were treated for less than a year (these patients had both started Carbaglu within the year prior to the end of the study period). The maximum exposure to Carbaglu was 21 years. In addition to the retrospective case series, a clinical safety report provided data on a broader patient base including patients who did not have NAGS deficiency but contributed information on long-term safety. In total, there were 143 patients exposed to Carbaglu over the report period (January 1, 1991 to December 31, 2007) including 99 patients exposed over a longer term and 44 patients exposed only short term (including 15 healthy volunteers). Finally, Periodic Safety Update Report data were submitted covering a 3-year period with 19 NAGS deficiency patients exposed to Carbaglu in total (overlapping with the 23 patients from the retrospective case series). Overall, there were 61 patients exposed through clinical studies (including patients with other conditions such as organic acidemias).

In the retrospective cases series, there were two patients who died while being treated with Carbaglu. One was an 11 year old girl who had been treated with Carbaglu for approximately 11 years and the cause of death was hyperammonemic crisis following pneumonia. The other death was a 9 year old girl who was treated for 9 years and the cause of death was multi-organ failure and encephalopathy. In both cases, sub-therapeutic treatment appeared to have contributed to an exacerbation of the underlying medical condition.

In the retrospective case series, 10 patients experienced 30 non-fatal serious adverse event (SAEs). The most common SAE was vomiting which was reported by 6 different patients, with the SAEs pneumonia and somnolence each occurring in 2 patients. The majority of SAEs were considered to have resolved/recovered with 3 not resolved (abnormal behavior, psychomotor hyperactivity, paraplegia), and 9 unknown. The majority of the adverse events (AEs) came from the System Organ Class (SOC) Gastrointestinal Disorders (25 AEs), followed by Infections and Infestations (23 AEs), and Nervous System Disorders (17 AEs).The most common AEs (occurring in ≥13% of patients) were infections, vomiting, abdominal pain, pyrexia, tonsillitis, anemia, ear infection, diarrhea, nasopharyngitis, and headache. The drug was withdrawn because of one AE (poor acceptance), which was considered to be related to Carbaglu, but the drug was reintroduced a few days later without the AE occurring again.

In the clinical safety report, there were 40 AEs reported of which 29 were serious and 11 were non-serious. The most common AEs (≥2 patients) were as follows (in order of most frequent) vomiting (4 non-serious, 7 serious), ear infections (6 non-serious, 2 serious), pyrexia (4 non-serious, 3 serious), nasopharyngitis (6 non-serious), headache (5 non-serious, 1 serious), diarrhea (3 non-serious, 2 serious), abdominal pain (3 non-serious, 1 serious), tonsillitis (4 non-serious), convulsion (4 serious), anemia (3 non-serious, 1 listed as hypochromic anemia), asthenia (2 non-serious, 1 serious), hyperammonemia (1 non-serious, 2 serious), infection (3 non-serious), pneumonia (2 serious), sepsis (2 serious), decreased hemogloblin (2 non-serious), decreased weight (2 non-serious), anorexia (2 non-serious), decreased appetite (2 non-serious), coma (2 serious), somnolence (2 serious), perinatal brain damage (2 serious), dry skin (2 non-serious), rash (2 non-serious), shock (2 serious), aggravated condition (2 serious), and drug ineffective (2 non-serious).

Periodic safety update report (PSUR) data showed that over a 3-year period, there were 19 NAGS deficiency patients exposed to Carbaglu with 61 patients in total exposed through clinical studies (including patients with other conditions such as organic acidemias). The most frequently observed individual adverse drug reaction (ADR) was vomiting with 4 serious cases and 1 non-serious case. The Post-Market Adverse Drug Reaction section in the Carbaglu Product Monograph lists the majority of the SAEs observed in this reporting period. In addition, based on follow-up data on 13 individual case safety reports from previous PSURs, restrictive cardiomyopathy and Ewing's sarcoma have also been added to the Carbaglu Product Monograph Post-Market Adverse Drug Reaction section and are being closely monitored by the sponsor.

Overall, the safety data supports the approval of Carbaglu for the recommended indication. Appropriate warnings and precautions are in place in the approved Carbaglu Product Monograph to address the identified safety concerns.

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

7.2 Non-Clinical Basis for Decision

The results of the non-clinical studies as well as the potential risks to humans have been included in the Carbaglu Product Monograph. In view of the intended use of Carbaglu 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 Carbaglu Product Monograph to address the identified safety concerns.

In the animal toxicity studies, carglumic acid was secreted in the milk of lactating rats which led to reductions in pup survival and offspring growth. Based on this finding, use of Carbaglu is contraindicated in women who are breastfeeding.

Carcinogenicity studies were not submitted. However, the sponsor has agreed to provide the results of a 2-year carcinogenicity study that was initiated in 2013. The first draft of the report should be available in 2015. Given the life-threatening condition of the intended patient population, a post-marketing carcinogenicity study is considered acceptable.

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

7.3 Quality Basis for Decision

The drug submission for Carbaglu previously received a Notice of Non-Compliance (NON). The sponsor failed to provide validation data from the release-testing laboratory for the assay, related substances, and dissolution methods. Given that evidence of fully validated analytical methods used to control the quality of the proposed commercial product is considered critical in order to meet the requirements of C.08.002(2)(f) of the Food and Drug Regulations, issuance of a NON was recommended. In response to the NON, the sponsor provided adequate information and sufficient evidence to address all of the issues identified in the NON, and the drug submission was again accepted into review.

The Chemistry and Manufacturing information submitted for Carbaglu 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.

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.

Details concerning the starting material of L-Glutamic Acid were provided. Certification and letters of attestation confirming that this material is not from a bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) affected country/area have been provided for this product indicating that it is considered to be safe for human use.

Report a problem or mistake on this page
Please select all that apply:
Date modified: