Summary Basis of Decision for Dotarem
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Dotarem is located below.
Recent Activity for Dotarem
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 Dotarem
Updated:
The following table describes post-authorization activity for Dotarem, a product which contains the medicinal ingredient gadoterate meglumine. 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 02459329 - 376.9 mg/mL, gadoterate meglumine, solution, intravenous)
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Summary Safety Review posted | Not applicable | Posted2018-05-01 | Summary Safety Review posted for gadolinium-based contrast agents. |
| SNDS # 205610 | 2017-05-12 | Issued NOC2018-04-24 | Submission filed as a Level I - Supplement to expand the indication of contrast enhancement during craial and spinal MRI investigations to children younger than 2 years of age. Regulatory Decision Summary published. |
| SNDS # 212858 | 2018-02-16 | Issued NOC2018-03-23 | Submission filed as a Level I - Supplement to update the safety information in the PM for Dotarem with respect to risk of brain deposition of gadolinium with repeated use of gadolinium-based contrast agents. As a result for the SNDS, modifications were made to the Warnings and Precautions, and Dosage and Administration sections of the PM. The submission was reviewed and considered acceptable, and an NOC was issued. |
| Drug product (DIN 02459329) market notification | Not applicable | Date of first sale:2017-09-22 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| SNDS # 204205 | 2017-04-28 | Issued NOC2017-06-09 | Submission filed as a Level I - Supplement to improve the safety information in the PM for Dotarem in response to Health Canada's class-labelling request for all gadolinium-based contrast agents with respect to gadolinium accumulation in brain. As a result for the SNDS, modifications were made to the Warnings and Precautions, 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 NOC was issued. |
| Information Update | Not applicable | Posted2017-01-06 | Information Update posted containing new safety information for the general public. |
| NDS # 186333 | 2015-07-31 | Issued NOC2016-11-25 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Dotarem
Date SBD issued: 2017-01-25
The following information relates to the new drug submission for Dotarem.
Gadoterate meglumine
376.9 mg/mL, solution, intravenous
Drug Identification Number (DIN):
- 02459329
Guerbet
New Drug Submission Control Number: 186333
On November 25, 2016, Health Canada issued a Notice of Compliance to Guerbet for the drug product Dotarem.
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 Dotarem is favourable in adults and pediatrics (2-18 years of age) for contrast enhancement during cranial and spinal MRI investigations.
1 What was approved?
Dotarem, a contrast enhancement agent for magnetic resonance imaging (MRI), was authorized in adults and pediatrics (2-18 years of age) for contrast enhancement during cranial and spinal MRI investigations.
No special precautions are required in elderly patients (>65 years old) unless renal function is impaired.
The safety and efficacy of Dotarem has been established in pediatric patients (2-18 years of age) for intravenous use for cranial and spinal MRI.
The safety and efficacy has not been established in children less than two years of age. Dotarem is not recommended for use in children less than two years of age.
Dotarem is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Dotarem was approved for use under the conditions stated in the Dotarem Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Dotarem (376.9 mg/mL gadoterate meglumine) is presented as a solution. In addition to the medicinal ingredient, the solution also contains water.
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 Dotarem Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Dotarem approved?
Health Canada considers that the benefit/risk profile of Dotarem is favourable in adults and pediatrics (2-18 years of age) for contrast enhancement during cranial and spinal MRI investigations.
Contrast-enhanced MRI is commonly performed for spine pathologies like infections, inflammatory diseases, degenerative diseases, and malignancies.
Dotarem contains the medicinal ingredient gadoterate meglumine which is a paramagnetic macrocyclic ionic gadolinium chelate that develops a magnetic moment when placed in a magnetic field. The magnetic moment enhances the relaxation rates of water protons in its vicinity, leading to an increase in signal intensity (brightness) of tissues.
There are currently eight gadolinium-based contrast agents (GBCAs) for contrast-enhanced MRI approved for marketing in Canada but only two are indicated for use in children less than two years old.
Dotarem has been shown to be efficacious as a contrast enhancement agent for adult and pediatric patients during cranial and spinal MRI investigations. The market authorization was based on two pivotal Phase III studies, DGD-44-050 and DGD-44-051. Study DGD-44-050 was a multicentre, randomized, double-blind, comparative study with 364 adult patients with known or suspected central nervous system (CNS) lesions. The efficacy co-primary endpoints in the study were also assessed in an open-label arm of 38 pediatric patients, with a representation of age groups from 2 to 17 years of age. Study DGD-44-051 is a blinded, centralized re-read of a previously conducted study (DGD-03-044, a multicenter, open label study) to determine the safety and efficacy of Dotarem in 151 patients presenting or suspected of cerebral or spinal tumors. For both studies, the three primary visualization endpoints were contrast enhancement, border delineation, and internal morphology. Patients received either Dotarem or Magnevist, a gadopentetate dimeglumine, each administered at a dose of 0.1 mmol/kg. Patients first underwent a baseline (pre-contrast) MRI examination followed by the assigned GBCA administration and a post-contrast MRI examination.
Study DGD-44-050 provided sufficient support for the approval of Dotarem's use for contrast enhancement of CNS lesions. The co-primary efficacy endpoint (lesion visualization score) was significantly higher (p<0.001) for the combined (paired) image than for the pre-contrast image in adults and pediatric subjects older than 2 years of age. Study DGD-44-051 demonstrated similar results. The percentage of patients with improved lesion visualization for paired images compared to pre-contrast images ranged from 60% to 97.8% for study DGD-44-050, and 67.6% to 97.3% for study DGD-44-051.
The representation of patients with spinal cord lesions was low in both pivotal studies. The results of subgroup analysis demonstrated that based on a limited number of patients, the lesion visualization score for each category was higher for paired images compared with pre-contract (unenhanced) images. The difference reached statistical significance for 2 out of 3 readers for contrast enhancement and internal morphology score. For border delineation, there was a trend toward better delineation for paired images compared to unenhanced images. Hence, Health Canada also granted the indication to contrast enhanced MRI of spinal lesions.
To support pediatric use, the sponsor submitted one pivotal study (DGD-44-050) and three supportive studies. All supportive studies were exploratory in nature. The efficacy outcome was evaluated in a descriptive subjective manner using non-validated scales. The main limitation of the submitted evidence was the low number of patients less than 2 years of age. In the three supportive studies, there were only 7 patients less than 2 years of age and in the pivotal study, there were no patients less than 2 years of age. The results of the pivotal study support the use of Dotarem in pediatric patients 2-18 years of age; however, based on the lack of conclusive evidence of efficacy of Dotarem in pediatric patients younger than 2 years of age, the indication was restricted to adults and pediatric patients older than 2 years of age (2-18 years of age).
In support of the proposed contrast-enhanced magnetic resonance angiography (CE-MRA) indication, two pivotal Phase III / Phase IV multicentre, open-label, comparative, non-randomized studies were submitted to evaluate the efficacy of Dotarem enhanced MRA compared to time-of-flight magnetic resonance angiography (TOF) MRA in the diagnosis of carotid and vertebral basilar arterial disease (re-reading of previously conducted studies). Patients with severe stenosis have been reported to experience a stroke at a rate of 24% after 18 months; therefore, detection of patients with severe stenosis of carotid arteries is paramount for stroke prevention.
The evidence presented was considered insufficient to support CE-MRA in adults. One of the two studies demonstrated that the co-primary efficacy endpoint was achieved; however, it only indicated that performance of Dotarem-enhanced MRA was better than that of TOF MRA from a technical perspective. It failed to detect all clinically significant stenotic lesions with an acceptable level of precision, especially, taking into consideration the potential use of CE-MRA for detection of stenotic lesions as a potential replacement for the more invasive computed tomographic angiography procedure. The sensitivity for detection of severe stenosis was demonstrated to be low for Dotarem MRA. More importantly, the sensitivity for detection of severe stenosis was evaluated on a very low number of segments with severe stenosis (35 out of 2,686 segments for one study and 41 out of 2,532 segments in the other) and at the patient level was higher for the comparator than for Dotarem in both studies; therefore, Health Canada did not grant the indication for CE-MRA at this time.
In terms of safety, in clinical studies, the most frequently reported adverse events assessed as related to Dotarem were nausea, headache, injection site pain, injection site coldness, feeling cold, and hypotension. No adverse drug reaction occurred at a rate greater than 1%. Most adverse reactions were mild in severity and transient in nature.
The major risk associated with GBCA injections is the occurrence of nephrogenic systemic fibrosis (NSF). The development of NSF is considered a potential class-related effect of all GBCAs although mainly reported with linear GBCAs compared to macrocyclics. A Serious Warnings and Precautions Box has been included in the Product Monograph for Dotarem stating that GBCAs increase the risk for NSF in patients with acute or chronic severe renal insufficiency. No unconfounded cases of NSF were reported in the Dotarem clinical studies and in in the post-marketing studies focused on renally-impaired patients.
A Risk Management Plan (RMP) for Dotarem was submitted by Guerbet 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.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Dotarem has been deemed acceptable.
Overall, the therapeutic benefits seen in the pivotal studies are promising and the benefits of Dotarem therapy are considered to outweigh the potential risks. Dotarem 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 Dotarem Product Monograph to address the identified safety concerns. Further evaluation will take place upon the submission of the requested studies after they become available.
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 Dotarem?
Submission Milestones: Dotarem
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2015-07-31 |
| Screening | |
| Screening Deficiency Notice issued: | 2015-09-16 |
| Response filed: | 2015-11-04 |
| Screening Acceptance Letter issued: | 2015-12-17 |
| Review | |
| Quality Evaluation complete: | 2016-11-23 |
| Clinical Evaluation complete: | 2016-11-23 |
| Labelling Review complete: | 2016-11-24 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2016-11-25 |
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.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Gadoterate meglumine, the medicinal ingredient in Dotarem, is a paramagnetic molecule that develops a magnetic moment when placed in a magnetic field. The magnetic moment enhances the relaxation rates of water protons in its vicinity, leading to an increase in signal intensity (brightness) of tissues.
The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data supports the use of Dotarem for the specified indication.
The elimination of Dotarem was similar to that of other drugs of this class: i.e., gadolinium-based contrast agents (GBCAs). There was rapid distribution to the central compartment with primary renal elimination. The elimination of Dotarem 0.1 mmol/kg dose was evaluated in patients with moderate to severe renal failure (creatinine clearance 30-60 mL/min and 10-30 mL/min, respectively) compared to healthy subjects. The difference in pharmacokinetic parameters was significant between groups (patients with moderate renal insufficiency compared to healthy volunteers and patients with severe renal insufficiency compared to healthy volunteers). In terms of urinary elimination, healthy subjects eliminated almost all the active ingredient in the urine within 24 hours. The elimination of the active ingredient continued for 48 and 72 hours for patients with moderate and severe renal insufficiency, respectively. Appropriate warnings are properly labelled in the Dotarem Product Mongraph.
For further details, please refer to the Dotarem Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical development programme for Dotarem included efficacy data for adults and children.
Clinical Efficacy in Adults
The clinical efficacy of Dotarem as a contrast agent for magnetic resonance imaging (MRI) of the brain and spine in adults was based primarily on two pivotal studies, DGD-44-050 and DGD-44-051.
Study DGD-44-050 was a multicentre, randomized, double-blind, comparative study conducted to determine the safety and efficacy of Dotarem in patients with known or suspected central nervous system (CNS) lesions. In this study, 364 adult patients were randomized at a 2:1 ratio to receive either Dotarem or gadopentetate dimeglumine, each administered at a dose of 0.1 mmol/kg. Among the patients, 38 pediatric patients aged 2-17 years were also enrolled and received Dotarem, at the same dose of 0.1 mmol/kg. Patients first underwent a baseline (pre-contrast) magnetic resonance imaging (MRI) examination followed by the assigned GBCA administration and a post-contrast MRI examination.
Study DGD-44-051 was a blinded centralized re-read of a previously conducted study (DGD-03-044). This study was a multicentre, open-label, study conducted in Europe to determine the safety and efficacy of Dotarem in 151 patients presenting or suspected of cerebral or spinal tumors. Dotarem administration was performed in the same manner as in Study DGD-44-050.
These two studies included a total of 396 adult patients who received Dotarem, out of which 388 could be analysed for efficacy. The mean age of Dotarem adult patients was similar in both studies, 53.2 years and 53.9 years (range 18 to 85 years). Study DGD-44-050 enrolled more female patients (53.5%), and the racial and ethnic representations were 84% Caucasian, 11% Asian, 4% Black, and 1% other. Study DGD-44-051 enrolled more male patients (55.6%); the majority of patients were Caucasian (97%), 1% were Black and 2% of other ethnicities.
The primary efficacy analysis compared paired (pre-+ post-contrast) images to pre-contrast images for adults who received Dotarem for three parameters of anatomy visualization (border delineation, internal morphology and contrast enhancement). For each of these parameters there was a pre-defined 3-point scoring scale: unevaluable (0); seen but imperfectly (1); or seen completely/perfectly (2). Lesion counting (up to five largest representative lesions per patient) was also reflected within each component of patient-level visualization score as the patient "paired" and "pre" scores were calculated as the sum of all lesion scores for "paired" and "pre" assessments, respectively. Mean scores (mean of all patients "paired" scores and mean of all patients "pre" scores) were computed. The efficacy of Dotarem was expected to be demonstrated for at least 2 out of 3 readers independently meeting a statistically significant positive difference between the mean "paired" score and the mean "pre" score for each co-primary endpoint.
The evaluation of the primary endpoint demonstrated statistically significant (p<0.001) superiority of paired images over pre-contrast (unenhanced) images for lesion visualization for all three readers in both studies.
In study DGD-44-505, the mean differences between the pre and pair modalities for all three readers were as follows:
- For border delineation, the scores were 2.26, 2.92, and 1.15.
- For internal morphology, the scores were 2.75, 2.77, and 1.54.
- For contrast enhancement, the scores were 3.13, 3.76, and 2.99.
All differences were statistically significant (p<0.001). Dotarem-enhanced MRI demonstrated to be superior to the unenhanced MRI on the lesion visualization score. The results of the study are supportive for the use of Dotarem as a contrast enhancement agent for CNS lesions in adult patients.
Study DGD-44-051demonstrated similar results for all three readers:
- For the border delineation, the scores were 1.05, 0.77, and 1.28.
- For the internal morphology, the scores were 1.14, 0.94, and 1.74.
- For the contrast enhancement, the scores were 2.06, 2.10, and 2.21.
The results of post-hoc analysis demonstrated that based on a limited number of patients (<10 patients) with spinal lesions; the lesion visualization score for each category was higher for paired images compared with pre-contrast (unenhanced) images. The difference reached statistical significance for 2 out of 3 readers for the contrast enhancement scores and internal morphology scores. For the border delineation scores, there was a trend towards better delineation for the paired images compared to the pre-contrast images. Overall, the results support the use of Dotarem as a contrast enhancement agent for MRI investigations of spinal lesions. Extension of the indication to contrast-enhanced MRI of spinal lesions was granted.
Clinical Efficacy in Children
The clinical efficacy of Dotarem as a contrast agent for magnetic resonance imaging (MRI) of the brain and spine in children was based primarily on one pivotal, multicentre, randomized, double-blind, comparative study, DGD-44-050. In the pivotal study, 38 children (ages 2 to 17 years of age) received the Dotarem dose of 0.1 mmol/kg. None of the pediatric patients received Magnevist.
The primary efficacy analysis compared paired (pre-+ post-contrast) images to pre-contrast images for the patients who received Dotarem for three parameters of anatomy visualization (border delineation, internal morphology and contrast enhancement). The efficacy of Dotarem was expected to be demonstrated for at least 2 out of 3 readers independently meeting a statistically significant positive difference between the mean "paired" score and the mean "pre" score for each co-primary endpoint.
For all 3 readers, mean scores for each endpoint were higher for "paired" (contrast-enhanced + unenhanced images) relative to "pre" (unenhanced) mean scores according to descriptive statistics.
Based on the results of the pivotal study DGD-44-050, the efficacy of Dotarem for use for the contrast-enhanced MRI of CNS lesion was established in children 2-17 years of age. No conclusions about efficacy of the drug in children younger than 2 years of age could be made.
Three supportive studies were submitted that were deemed exploratory with respect to diagnostic contribution in terms of lesion characterization and sequence specification. The efficacy outcome was evaluated in a descriptive subjective manner using non-validated scales. In the three supportive studies, there were only 7 patients less than 2 years of age.
Furthermore, in support of the use of Dotarem-enhanced MRI for CNS imaging in pediatric patients younger than 2 years of age, the sponsor submitted 7 prospective post-marketing studies. The primary objective of all of the studies was an assessment of the safety of Dotarem. The efficacy in the proposed population was assessed as secondary efficacy endpoints and in terms of effect on image quality, non-validated scales were used. The main conclusion from the supportive studies and post-market observational studies is that the safety of Dotarem-enhanced MRI based on limited data appears to be good.
Indication
During the original filing of this New Drug Submission (NDS), the proposed indications by the sponsor were the following.
In adults and pediatrics (0 - <18 years of age):
- contrast enhancement during brain (intracranial), spinal and associated tissues MRI investigations to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity.
In adults:
- contrast-enhanced magnetic resonance angiography (CE-MRA) of supra-aortic extra-cranial arteries to detect clinically significant steno-occlusive vascular disease.
Upon review, it was considered that there was a lack of efficacy and safety data to support the use of Dotarem for patients less than 2 years of age. Also, the efficacy of Dotarem in certain populations such as patients with stroke and other non-tumoral conditions was not established with certainty due to the fact that a limited number of patients with these conditions were included in the study population of the pivotal studies. As a result, Health Canada recommended the following indication to accurately reflect the pivotal data:
Dotarem is recommended in adults and pediatrics (2-18 years of age) for contrast enhancement during cranial and spinal MRI investigations.
Overall Analysis of Efficacy
The efficacy of Dotarem for contrast-enhanced MRI investigation of CNS (brain and spine) in adults and children age 2-18 years was established. The results of the pivotal studies demonstrated superior efficacy of Dotarem in terms of statistical significance on the lesion visualization score compared to unenhanced MRI.
For more information, refer to the Dotarem Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Dotarem was evaluated from safety data derived from 50 clinical studies that included data separately for adults and paediatrics and post-marketing surveillance data. Overall, the safety database included data from 2,822 patients. The majority of patients (62.9%) were 18-65 years old, 21.3% were 65-75 years old, 10.8% were 75 years or older, 2% were 6-12 years old, 1.5% of patients were 12-18 years old, 1.2% of patients were 2-6 years old, and 0.2% or 7 patients under 2 years of age. A total of 271 patients out of 2,822 patients experienced 349 post-injection adverse events (AEs). One-hundred and thirteen patients experienced 153 AEs which were assessed as related to Dotarem. Twenty-seven patients (1.0%) experienced 38 serious adverse events (SAEs). Two SAEs were considered possibly related to Dotarem: hypersensitivity (moderate intensity, resolved without treatment); and renal failure (mild intensity, resolved with sequelae). Twelve fatal events were reported in 8 patients. None of the AEs that led to death were assessed as related to Dotarem.
Overall, the most frequently reported AEs assessed as related to Dotarem were nausea (16 AEs in 16 patients), headache (12 AEs in 12 patients), injection site pain (12 AEs in 12 patients), injection site coldness (7 AEs in 6 patients), feeling cold (5 AEs in 4 patients) and hypotension (5 AEs in 3 patients). Burning sensation, somnolence and rash were each reported once in 4 patients. A total of 7 patients less than 2 years old were administered with Dotarem. Of these 7 patients, one patient (14.3%) experienced one AE (vomiting) post-injection, which was assessed as not related to Dotarem.
Frequency and distribution of AEs in different age groups was analysed. The AE trend could not be analysed in patients less than 2 years of age, in patients between age 2 and 6 years and in patients between age 12 and 17 years due to the low frequency of AEs (1-2 AEs). The most frequent related AE in the 6-12 age group was headache (3.5%) followed by dizziness and vomiting, no SAE was reported. The most frequent related AEs in the 18-65 age group was injection site pain (0.6%) followed by headache and nausea (0.5% each), injection site coldness (0.3%), feeling cold, burning sensation, somnolence, feeling hot, dysgeusia and rash (0.2% each). Two SAEs (hypersensitivity and renal failure) in 2 patients were assessed as related to Dotarem. In patients age 65-75, the most frequent related AE was nausea (0.5%) followed by hypotension, injection site pain, blood creatinine increased and hypertension (0.3% each); no SAE related to Dotarem was reported. In patients older than 75 years of age, the most frequent related AE was nausea (1%); all other AEs occurred as a single event; no SAE related to Dotarem was reported.
In clinical studies where imaging of the CNS was performed in adults, 1,188 patients were dosed with Dotarem and included in the pooled safety report. The majority of the population were Caucasian ethnicity, younger than 65 years of age; only 252 patients (21.5%) were older than 65 years of age. Slightly more males than females were included in the report (52.1 % vs. 47.9%). Out of 113 reported AEs, 55 AEs (3.6%) were assessed to be related to Dotarem. There were 10 SAEs reported in 7 patients (0.6%) who received Dotarem. All these SAEs were assessed as non-related to Dotarem administration. The most common related AEs were nausea (0.8%), headache (0.4%) and injection site pain (0.3%). The frequency of the most common AEs was similar to that in overall adult population.
In adult patients for cervical magnetic resonance angiogram (MRA) imaging (a type of MRI scan), 450 patients were dosed with Dotarem. The most common related AE was headache (0.4%) and nausea (0.7%). The frequency of the most common AEs was similar to that in the overall adult population.
Among the 164 patients with renal disorders who received Dotarem, 56 AEs were reported in 22 patients (13.4%) post Dotarem administration. Fifteen AEs reported in 10 patients (6.1%) were assessed as related to Dotarem. The most common AEs were hypotension and somnolence (3 patients each).
The frequency and distribution of the most common AEs in special populations (i.e., patients with allergy, with hepatic insufficiency, with cardiac disease, with diabetes) were similar to that in the overall population.
The safety of Dotarem-enhanced MRI in children 2-18 years of age appears to be good. In the pivotal study DGD-44-050 (n = 364), 38 pediatric patients (2-18 years old) were enrolled. Ten pediatric patients (26.3%) experienced at least 1 AE with Dotarem, all but 1 were mild or moderate in severity. The only treatment-emergent adverse event (TEAE) reported in more than 1 patient was headache which occurred in 2 patients (5.3%). Nausea and vomiting were each reported in 1 patient each and both were considered related, and 1 patient experienced application site erythema.
From 8 clinical studies that included 140 pediatric patients (7 patients aged <24 months, 33 aged 2-5 years, 57 aged 6-11 years and 43 aged 12-17 years) who received Dotarem, a total of 14 AEs were reported post-Dotarem injection in 9 patients (6.4%), out of which 10 AEs reported in 6 patients (4.3%) were assessed as related to Dotarem. The most frequent adverse reactions (ADRs) were headache (2 patients, 1.4%) and nausea/vomiting (2 patients, 1.4%); other ADRs (that is [i.e.], dizziness, asthenia, injection site urticarial, hematuria, pruritis) were recorded in one patient each (0.7%). Most AEs were mild in severity and transient in nature, and all patients recovered without treatment. The major known risk associated with gadolinium-based contrast agents is the risk of developing nephrogenic systemic fibrosis (NSF). At the time of this drug submission, no cases of NSF were reported in children under the age of 6.
Cardiac Effects
Cardiac safety of Dotarem was assessed in a randomized, double-blind, cross-over, placebo-controlled Phase IIb study. The study was conducted in accordance with International Council for Harmonisation (ICH) E14 Guideline. The study demonstrated non-inferiority of Dotarem to placebo in terms of maximal increase in QT. The non-inferiority was demonstrated for both, male and female populations. The non-inferiority of Dotarem to placebo in terms of maximal increase in QTcB and QTcF was demonstrated in all subjects and separately, in female subjects.
In an electrocardiographic safety study with Dotarem, there was no clinically significant difference between Dotarem and placebo in QT, QTcF and QTcB parameters. The same absence of significant difference between Dotarem and placebo was observed in both male and female populations, separately. Overall, the results of the study demonstrated that Dotarem administered at cumulative dose of 0.3 mmol/kg as an intravenous bolus injection has no effect on QT and QTc; no arrhythmogenic potential was demonstrated. No potential for QT prolongation was demonstrated in non-clinical studies.
Nephrogenic Systemic Fibrosis
The major risk associated with gadolinium-based contrast agents (GBCAs) is the occurrence of nephrogenic systemic fibrosis (NSF). This safety concern is considered to be a class-related effect of all GBCAs, although the level of risk differs between agents (linear versus macrocyclic GBCAs). Dotarem has not been associated with any unconfounded cases of confirmed NSF. Class labelling for NSF was introduced in 2007 by Health Canada. Nephrogenic systemic fibrosis condition has been reported with use of GBCAs in patients with severe renal insufficiency. The effect of mild to moderate renal deficiency and the use of GBCAs and the occurrence of NSF is presently unknown. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA, the degree of renal function impairment at the time of exposure, and the use of linear GBCAs. The risk of NSF is stated within a Serious Warnings and Precautions box in the Dotarem Product Monograph. Appropriate warnings and precautions are in place in the Dotarem Product Monograph to address this safety concern.
Overall Analysis of Safety
The safety profile of Dotarem, as a contrast enhancement agent during cranial and spinal MRI investigations, in terms of frequency and distribution of AEs, is considered acceptable in patients two years old and older. The risks associated with the administration of Dotarem (i.e., risk of NSF, hypersensitivity) are well-known and sufficiently covered in the Dotarem Product Monograph, along with the means of prevention.
For more information, refer to the Dotarem Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical program for Dotarem (gadoterate meglumine) included studies on the safety pharmacology, pharmacokinetics, and toxicity of gadoterate meglumine. Dotarem is designed and intended to be used as a diagnostic aid for magnetic resonance imaging and its pharmacologic activity is intended to be as weak as possible. Because of the weak pharmacological activity, no in vivo pharmacodynamic studies were submitted.
Nephrogenic systemic fibrosis (NSF) development is considered a potential class-related effect of all GBCAs, including Dotarem. The administration of gadoterate meglumine to rats and dogs with normal renal functions, as well as gadoterate meglumine to rats with impaired renal functions, did not elicit clinical signs or microscopic lesions (skin/kidneys) which would present as NSF. Regardless of these negative findings, the use of Dotarem should be avoided in patients with acute and chronic renal failure, unless the diagnostic information is essential and not available with noncontrast-enhanced magnetic resonance imaging (MRI), and it should be used in accordance to the established clinical practices in patients with renal insufficiencies.
Non-clinical data showed that gadoterate meglumine was excreted into the milk of lactating goats. Although the total amount of gadoterate meglumine excreted in the milk was less than 0.1% of the administered dose, breast-feeding should be suspended for at least 24 hours after dosing of Dotarem. In studies with pregnant rats, small amounts of gadoterate meglumine were also observed in fetal tissue (approximately 5% of the maternal plasma concentration).
The results of the non-clinical studies as well as the potential risks to humans have been included in the Dotarem Product Monograph. In view of the intended use of Dotarem, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Dotarem 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 Dotarem 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 3 years is acceptable when the product is stored between 15°C and 30°C.
Proposed limits of drug-related impurities are considered adequately qualified: i.e., within International Council for Harmonisation (ICH) limits and/or qualified from toxicological studies.
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.
The excipients used in the dug product formulation are not of animal or human origin.