Regulatory Decision Summary for DOTAREM

Health Canada considers that the benefits of Dotarem outweigh its potential risks only for certain indications and conditions of use as described below.

In support of contrast-enhanced MRI of lesions of the central nervous system (CNS), two phase Phase III clinical trials were submitted. Both studies were a Phase III/IV, multicenter, double-blind, randomized, comparative trial which evaluated the safety and efficacy of Dotarem in MRI in patients with CNS lesions. Study DGD-44-050 provided sufficient support for the approval of Dotarem 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 patients older than two years of age.

The representation of patients with spinal cord lesions was low in both pivotal studies. However, 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-contrast images. The difference reached statistical significance for two out of three 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, 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. The main limitation of these studies was the low number of patients less than two years of age. In the three supportive studies, there were only seven patients less than two years of age that were included and no patients less than two years of age were included in the pivotal study (DGD-44-050). The results of the pivotal study support the proposed indication in pediatric patients 2-18 years of age; however, based on the limited data and lack of conclusive evidence of efficacy of Dotarem in pediatric patients younger than 2 years of age, Dotarem was approved only for pediatric patients 2-18 years of age.

In support of the contrast-enhanced magnetic resonance angiography (CE-MRA) indication, two pivotal Phase III / Phase IV multicenter, open-label, comparative, nonrandomized studies were submitted to evaluated 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 end point 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 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, the most frequently reported adverse events assessed as related to Dotarem were nausea, headache, injection site pain, injection site coldness, feeling cold and hypotension. Overall, the safety profile based on data reported from clinical trials was favorable with the exception of the pediatric population below age of 2 years where the safety profile of Dotarem could not be determined due to the low number of patients.

The major risk associated with gadolinium-based contrast agents is the occurrence of Nephrogenic Systemic Fibrosis (NSF), which is deemed to be a class effect and class-labelling for NSF was introduced in 2007 by Health Canada. Dotarem was assessed by the European Medicines Agency as having a low risk in terms of NSF causation. No NSF case was reported in the Dotarem clinical trials and in post-marketing studies focused on renally-impaired patients. The potential risks and current uncertainties are labelled in the Product Monograph. Overall, Health Canada considers that the anticipated benefits of Dotarem for contrast enhancement during cranial and spinal MRI investigations in adults and pediatrics (2-18 years of age) outweigh its potential risks under the conditions of use described in the Product Monograph.

For more information on Health Canadas decision, please view the Summary Basis of Decision.