Summary Basis of Decision for Tomvi

Clinical Pharmacology

The production of sedation and hypnosis by etomidate is thought to occur through enhancement of the function of gamma-aminobutyric acid type A (GABA_A) receptors in the brain. Specifically, etomidate increases the potency with which GABA activates GABA_A receptors, and can directly activate the receptors in the absence of GABA. Etomidate interacts selectively with GABA_A receptors that contain β2 or β3 subunits.

Etomidate is a general anesthetic without analgesic activity. Intravenous injection produces anesthesia characterized by a rapid onset of action, usually within one minute. Duration of anesthesia is dose-dependent but relatively brief (approximately 7 minutes), with a quick recovery after regaining consciousness. The most characteristic effect of intravenous etomidate on the respiratory system is apnea.

Following intravenous administration, plasma concentrations of etomidate decrease rapidly for approximately 30 minutes. The concentration decreases more slowly after this point, with traces still detectable after 6 hours. Metabolites of etomidate, produced mainly through hydrolysis, are excreted even more slowly.

Etomidate is rapidly distributed to the brain and other tissues, and is rapidly metabolized to etomidate carboxylic acid in the plasma and liver. The primary route of elimination is in urine, with 75% of the administered dose eliminated after 24 hours, primarily as metabolites. Only 2% is excreted unchanged via the urine. The terminal half-life of approximately 3-5 hours reflects slow redistribution from the deep peripheral compartment.

Lower dosing may be required in geriatric patients, as reduced protein binding, decreased initial distribution volumes, and lower total clearance have been observed in this population.

The hypnotic effect of etomidate may be enhanced by neuroleptics, opioids, sedatives/hypnotics, and alcohol. Induction with etomidate may be accompanied by a transient reduction in peripheral resistance, which may enhance the hypotensive effect of other drugs.

When administered with intravenous fentanyl, the plasma clearance and volume of distribution of etomidate is decreased by a factor of 2 or 3, with no change in half-life. Therefore, when etomidate is co-administered with intravenous fentanyl, the dose of etomidate may need to be reduced.

Co-administration of etomidate with alfentanil has been reported to decrease the terminal half-life of etomidate to approximately 29 minutes. Caution should be used when both drugs are administered together as the concentration of etomidate may drop below the hypnotic threshold.

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

Clinical Efficacy

The New Drug Submission (NDS) for Tomvi was a Submission Relying on Third-Party Data (SRTD). Instead of original clinical data, the sponsor submitted evidence from medical literature to support the efficacy of etomidate (the medicinal ingredient in Tomvi) for the induction of general anesthesia and the supplementation of subpotent anesthetic agents during maintenance of anesthesia for short operative procedures. Three published studies were identified as pivotal by the sponsor: Miller et. al., 1978, Morison et. al., 1982, and Wu et. al., 2013. An additional 13 published studies were submitted as supportive evidence.

The study by Miller et. al. (1978) compared the anesthetic efficacy of etomidate and methohexitone, as measured by induction and recovery times. A total of 100 patients were enrolled in this double-blind, active-controlled study to undergo elective cystoscopy, and were pre-medicated with atropine prior to induction of anesthesia. For induction of anesthesia, patients were randomized to receive either 0.3 mg/kg etomidate (number of patients [n] = 50) or 1.5 mg/kg methohexitone (n = 50).

After administration of the assigned induction medication, patients received anesthesia consisting of halothane in nitrous oxide and oxygen, with all patients breathing spontaneously. Systemic arterial pressure and heart rate were monitored during the study, and recovery time was measured from the end of anesthesia to eye opening with a verbal command.

No statistically significant differences were observed in recovery time between patients who received etomidate (4.6±0.30 minutes) and those who received methohexitone (3.8±0.28 minutes). Additionally, no significant differences were observed between the two treatment groups with respect to heart rate or blood pressure.

The study by Morison et. al. (1982) was double-blind and active-controlled, and compared the clinical efficacy and hemodynamic effects of 0.3 mg/kg etomidate (n = 24) and 75 µl/kg alfathesin (n = 24). Patients were pre-medicated with 1 µg/kg fentanyl, administered intravenously one minute prior to induction. Anesthesia was maintained with nitrous oxide and oxygen, with patients breathing spontaneously. Increments of either induction drug were injected at the discretion of the treating anesthetist, when deemed clinically necessary. A blinded observer assessed adverse reactions, including pain on injection, incidence of apnea, involuntary movements, and respiratory disturbances. Recovery was defined as the time from termination of anesthesia to eye opening, and patient recall of their date of birth. A scoring system was used to evaluate "street fitness". Post-operative adverse effects were assessed using two patient questionnaires, administered on post-operative day one and prior to leaving the hospital.

No statistically significant differences were observed between the treatment groups receiving etomidate and alfathesin with respect to times for loss of verbal responsiveness (50.9±1.8 seconds and 45.7±2.1 seconds, respectively), loss of eyelash reflex (77.3±5.7 seconds and 62.2±2.5 seconds), or duration of anesthesia (8.8±1.1 minute and 8.3±0.9 minute). Additionally, significant differences were not observed between the two treatment groups with respect to recovery times for eye opening (2.83±0.42 minute and 2.87±0.35 minute), giving date of birth (5.23±0.68 minute and 5.76±0.60 minute), or being "street fit" (3.30±0.15 hours and 3.25±0.15 hours).

Heart rate was lower in the etomidate treatment group than in the alfathesin treatment group at all time points (p = 0.006). Patients in the etomidate treatment group displayed a higher systolic blood pressure at 1 and 2 minutes (p<0.05) and a higher diastolic blood pressure up to 8 minutes, relative to patients treated with alfathesin (p = 0.002). Respiratory rate showed a progressive increase, which was similar in both groups. In the etomidate treatment group, minute volume increased progressively after the second minute. In the alfathesin treatment group, minute volume decreased following induction, returning to the preoperative value at 4 minutes and rising progressively thereafter. Minute volume was significantly higher in the etomidate treatment group than in the alfathesin treatment group at all time points (p = 0.015).

The study by Wu et. al. (2013) assessed the efficacy and safety of etomidate (0.2 mg/kg) and propofol (2 mg/kg) when used during surgical abortions. This study enrolled 240 healthy women, who were randomized into six treatment groups: each induction agent was assessed alone, combined with fentanyl (0.5 µg/kg), or combined with fentanyl and midazolam (0.02 mg/kg). If a patient had spontaneous movements that interfered with the surgical abortion, the initial dose was supplemented with a 1-2 mL bolus dose of 2 mg/kg propofol or 0.2 mg/kg etomidate (group-dependent).

Patients were monitored through electrocardiogram (ECG), non-invasive blood pressure monitoring, and pulse oximetry. Mean arterial pressure, heart rate, and oxygen saturation (SpO2) were recorded at five time points. Time to recovery (time to eye opening after anesthetic was stopped), time to obeying commands (time until patients could answer questions), and post-anesthesia care unit recovery time (time until attainment of a modified Aldrete score ≥9) were determined for all patients.

Recovery times were similar between the treatment groups for etomidate and propofol, and recovery times in the etomidate treatment groups were not affected by fentanyl or midazolam. A significantly greater decrease in oxygen saturation was seen in the propofol treatment groups compared to the etomidate treatment groups. Additionally, a larger decrease in mean arterial pressure was observed for all propofol treatment groups compared to the etomidate treatment groups, and the difference was found to be statistically significant.

Thirteen additional published studies were submitted in support of the efficacy of etomidate as an anesthetic induction agent. In many of the studies, the exact formulations of etomidate were not specified, and different combinations of medications were used. All of the studies were randomized controlled trials. Only eight of the studies were double-blind, and the remaining studies were either open-label or blinding was not specified. Most of the studies were conducted in patients scheduled for either elective surgery or electroconvulsive therapy.

Collectively, the evidence presented in the pivotal and supportive studies supports that a single 0.2-0.4 mg/kg dose of intravenous etomidate allows for a rapid anesthetic induction time (less than one minute) and a short duration of action, with prompt recovery of eye opening and consciousness. The range for return to consciousness varied between studies and with co-administration of other medications, but generally ranged from 4-10 minutes. Etomidate displays a relatively stable cardiovascular and respiratory profile. Overall, etomidate provided effective rapid onset of hypnosis with predictable effects, rapid return to consciousness and time to "street fitness", and a favourable hemodynamic and respiratory profile.

Indication

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

Clinical Safety

The clinical safety review of etomidate was based on post-market safety data derived from approximately four decades of clinical use in Europe, the United States, and other jurisdictions. The sponsor also cited data from the pivotal studies (described in the Clinical Efficacy section), and submitted an additional 41 small, randomized controlled studies of varying quality in support of the safety of etomidate.

Based on these collective sources, the most common adverse effects of etomidate include muscular movements due to myoclonus, coughing, brief periods of apnea, injection site pain, and adrenal suppression. Several strategies have been employed in clinical practice and reported in medical literature to lessen coughing and myoclonus, as well as to lessen injection site pain.

In the study by Miller et. al. (1978), two patients who were treated with etomidate and three patients treated with methohexitone reported pain on injection. Myoclonus was observed in 11 patients treated with etomidate, and none of the patients treated with methohexitone.

In the study by Morison et. al. (1982), statistically significant differences between treatment groups were reported for injection pain (10/24 patients who received etomidate and 0/24 patients who received alfathesin) and vomiting (9/24 patients who received etomidate and 2/24 patients who received alfathesin). Apnea and involuntary movements were also observed in both treatment groups, but the differences in frequency were not statistically significant. Following hospital discharge, the two treatment groups displayed comparable rates of vomiting, drowsiness, pain at the intravenous injection site the morning after surgery, and the rated quality of anesthesia.

In the study by Wu et. al. (2013), the adverse events monitored were injection site pain, myoclonus, and post-operative nausea and vomiting. Injection site pain was significantly more common in patients who received propofol, while myoclonus and post-operative nausea and vomiting were more common in patients who received etomidate. The study authors concluded that etomidate had a favourable safety profile relative to propofol for first-trimester surgical abortions, and low doses of fentanyl and midazolam reduced myoclonus, nausea and vomiting associated with etomidate.

A Serious Warnings and Precautions box in the Product Monograph highlights the risk of adrenal suppression associated with Tomvi and its use in critically ill patients. Studies have demonstrated a transient lack of response to stimulation of the adrenal glands following administration of a single bolus of etomidate, peaking approximately 6-12 hours after administration. Resumption of normal cortisol production generally occurs 20‑24 hours post-dose. There is no evidence for any adverse effects on non-critically ill patients. However, the question of whether adrenal suppression may affect critically ill patients, including those with septic shock, has been a topic of debate.

At the time of authorization, the Cochrane Collaboration (2015) was the most recent systematic review and meta-analysis to examine the issue of adrenal suppression in critically ill patients. The results did not demonstrate a statistically significant increased risk of mortality in this population. Eight trials were examined in the systematic review. Seven of these trials, which collectively included 772 critically ill patients, were included in a meta-analysis. Based on the results of this analysis, there was no statistically significant increased risk of mortality between patients who received etomidate and those who received other induction agents for emergency intubation (odds ratio 1.17; 95% confidence interval [CI] 0.86 to 1.60). The evidence on which this conclusion was based is considered to be of moderate quality according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework.

The results of the meta-analysis indicated a need for further randomized controlled trials in order to definitively determine whether etomidate is associated with an increased risk of morbidity or mortality in critically ill patients with certain subsets of shock, such as sepsis and trauma. Health Canada recommends that caution should be exercised when considering use of an induction dose of etomidate in patients with critical illness, including sepsis.

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