Regulatory Decision Summary for Tomvi

The primary goal of a drug used for the induction of general anesthesia is to rapidly, reliably and safely produce a reversible state of sedation/hypnosis for the patient undergoing a painful or anxiety provoking procedure or operation. A variety of agents are currently indicated for use in induction of anesthesia in Canada, including benzodiazepines (e.g. midazolam), opiates (e.g. fentanyl, remifentanil), propofol, and ketamine. Each agent and class of agents has disadvantages, such as excessive sedation with benzodiazepines in elderly patients or patients with hepatic or renal impairment, negative ionotropic and hypotensive effects with propofol, and the increases in heart rate and blood pressure seen with ketamine.

Etomidate (Tomvi) is an imidazole derivative that acts directly on the gamma-aminobutyric acid type A (GABAA) receptor complex, blocking neuro-excitation and producing anesthesia. Etomidate has been market-authorized as an anesthetic induction agent in Europe, the United States, and other jurisdictions for several decades, and is frequently released through the Health Canada Special Access Programme (SAP).

This New Drug Submission (NDS) was assessed through the Submission Relying on Third-Party Data (SRTD) regulatory pathway. In the NDS, the sponsor provided evidence from the medical literature demonstrating the effectiveness of Tomvi for induction of general anesthesia and supplementation of subpotent anesthetic agents during maintenance of anesthesia for short operative procedures. Evidence of efficacy was based primarily on 3 published studies identified by the sponsor as pivotal, supplemented by an additional 13 published studies considered supportive.

In the studies reviewed, a single dose of intravenous etomidate in the range of 0.2-0.4 mg/kg allowed for a short induction time (less than a minute) and maintenance of anesthesia for a short duration, with rapid recovery of eye opening and consciousness. The time for return to consciousness varied between studies and was influenced by co-administration of other medications, but generally ranged from 4 to 10 minutes. Etomidate administration resulted in stable hemodynamics in patients with reduced cardiac ejection fraction who required intubation for elective cardiopulmonary bypass surgery or for cardioversion. In the submitted studies, etomidate was also utilized in a number of short operative procedures, including surgical abortion, cataract extraction, minor urological or gynecological surgery, cervical dilation, superficial orthopedic surgery, as well as for induction prior to anesthesia for general surgery, emergency intubation and electroconvulsive therapy. Overall, for these procedures, etomidate provided rapid onset of hypnosis with predictable effects and a rapid return to consciousness and time to street fitness.

With respect to the safety of etomidate, in addition to roughly four decades of clinical experience with the use of the active pharmaceutical ingredient, the sponsor submitted evidence of safety from a total of 41 small, randomized, active-controlled studies of variable quality.

Overall, the most common adverse events (AEs) seen with etomidate were transient injection site pain, transient skeletal muscle movement, and post-operative nausea and vomiting. Transient skeletal muscle movements, often classified as myoclonus, were reported in a majority of the submitted articles. The addition of fentanyl or fentanyl plus midazolam prior to induction with etomidate generally reduced the incidence of these muscle movements, and pre-treatment with a central nervous system depressant also reduced myoclonus. Additional AEs included hemodynamic alterations, including both elevations and reductions of mean blood pressure and heart rate, as well as short periods of apnea. Notably, etomidate also affects adrenocortical function, causing reductions in serum cortisol concentrations and an impaired response to exogenous adrenocorticotropic hormone (ACTH) administration, as well as increased epinephrine, norepinephrine, and beta-endorphin levels and decreased aldosterone concentrations.

The possible clinical consequences of transient adrenal suppression seen with a single induction dose of etomidate is uncertain and a potential safety concern. Specifically, concerns have been raised regarding the safety of single dose etomidate in critically ill patients, including patients with sepsis. Health Canada reviewed the available data relating to the issue, including a 2015 Cochrane meta-analysis of 7 randomized controlled trials. Overall, no statistically significant difference in mortality could be demonstrated between etomidate and several comparator induction agents, although a modest numerical trend suggesting increased risk was observed. As a precaution, a "Serious Warnings and Precautions" box was added to the Tomvi Product Monograph (PM) describing the adrenal suppression seen with induction doses of etomidate and the uncertainty regarding mortality risk in critically ill patients including those with sepsis, and advising caution in the use of the drug in this population.

A Risk Management Plan (RMP) was submitted and reviewed by the Marketed Health Products Directorate (MHPD) and was considered acceptable.

Overall, the benefit risk assessment of Tomvi is considered favorable for use by suitably qualified health care providers for induction of general anesthesia or supplementation of subpotent anesthetic agents during anesthesia for short operative procedures, under the proposed conditions of use.

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