Regulatory Decision Summary for Dotarem

 

One pivotal study was submitted to support the use of Dotarem for contrast enhancement during cranial and spinal MRI investigations in pediatrics (from term neonates). The overall quality of images was considered "good" for 26 subjects (92.9%) and "fair" for 2 subjects (7.1%) with pre-contrast images while it was "good" for all subjects with pre + post-contrast images.

 

Lesions were identified in 15 subjects with pre-contrast images and in 16 subjects with pre + post-contrast images. The same number of lesions was detected with pre- and pre-post images for 27 subjects while for one subject, 2 lesions were only identified with pre- + post-contrast images (none identified on pre-contrast images). The lesion visualization based on 3 co-endpoints was improved at lesion and at patient level.

 

 

The population PK study demonstrated that PK parameters after a single intravenous injection of 0.1 mmol/kg in pediatric subjects aged less than 2 years was similar to that observed in adults with a median clearance of 0.06 versus 0.10 L/h/kg BW and T1/2 of 1.35 h versus 1.6 h. Since Dotarem is extensively excreted in urine, the main factor modifying individual pharmacokinetic behavior is the renal maturity as exemplified in the population pharmacokinetic model. There is uncertainty about the effect of severe renal insufficiency on PK behavior of Dotarem as subjects with eGFR <30 mL/min/1.73 m² were not included in the study. The efficacy and safety of Dotarem is expected to be similar to that in the adult population due to similarity in PK parameters of adults.

 

 

In the pivotal study, the only ADR reported in children below age 2 years old was rash. The most common AEs were pyrexia (11.5% of patients), vomiting (3.8%), and leukopenia (3.8%). The incidence and distribution of ADEs in pediatric population below 2 years of age differ from that reported in adult population and older children. In the adult population the most frequent ADRs were nausea (0.8%), headache (0.4%) and injection site pain (0.3%). The most frequent ADRs in older children were headache (1.4%) and nausea/vomiting (1.4%). The possibility of similar ADRs reported in the adult population (nausea, headache) cannot be excluded considering children of very young age are not able to express certain complaints (especially given the fact that children of young age are often sedated for the procedure); therefore, all AEs reported in this population are included in the label regardless of their causality. No NSF cases in children less than 2 years of age have been reported after Dotarem-enhanced MRI.

 

 

The safety of Dotarem in neonatal and juvenile animals was demonstrated to be safe when administered at the proposed dose.

 

 

Overall, the risk-benefit profile of Dotarem in the pediatric population is considered favorable.