Summary

• In clinical studies SPRAVATO has been reported to cause somnolence, sedation, dissociative symptoms, perception disturbances, dizziness, vertigo, and anxiety.¹
• Before SPRAVATO administration, instruct patients not to engage in potentially hazardous activities, such as driving a motor vehicle or operating machinery until the next day after a restful sleep.¹
• Two studies were conducted to assess the effects of SPRAVATO on the ability to drive.¹ The effects of SPRAVATO 84 mg were comparable to placebo (PBO) at 6 hours and 18 hours post-dose. However, two SPRAVATO-treated patients in one of the studies discontinued the driving test at 8 hours post-dose because of SPRAVATO-related adverse reactions.^2,3
  • The mean standard deviation of the lateral position (SDLP) was evaluated in patients with major depressive disorder (MDD) the next day after a single 84-mg dose of SPRAVATO, and on the same day after SPRAVATO dosing compared to PBO. The same day testing was repeated biweekly for 3 weeks.³
    • No statistically significant difference was found in standard deviation of speed (SDS) between SPRAVATO and PBO.
    • In part A, the upper limit of the two-sided 95% confidence interval (CI) of the mean difference between SPRAVATO and PBO was 0.58 cm, which was not statistically significant (P=0.572).
    • In part B, the upper limit of the two-sided 95% CI of the mean difference between SPRAVATO and PBO on day 11 was 1.81 cm, on day 18 it was 2.20 cm and on day 25 it was 1.71 cm, which was not statistically significant (day 11, P=0.493; day 18, P=0.686; day 25, P=0.451).

Clinical Data

Driving Study 8 Hours After SPRAVATO Administration in Healthy Volunteers

van de Loo et al (2017)² conducted a single-center, randomized, double-blind, double-dummy, three-way crossover, PBO-controlled study to evaluate the effects of SPRAVATO nasal spray on driving performance in 26 healthy men and women, between 21 and 60 years of age.

Study Design/Methods

There was a 21-day screening phase in which participant eligibility was determined. This was followed by a three-way crossover, double-blind, single-dose treatment phase and then a 7-10-day follow-up phase after administration of the last dose. There was a 6-day washout period between test days.

On each testing day, subjects received one of three treatments: (1) SPRAVATO 84 mg nasal spray and oral PBO, (2) intranasal PBO and oral mirtazapine 30 mg, or (3) intranasal and oral PBO. Driving performance was assessed 8 hours after treatment administration in a 100-km on-road driving test. Mirtazapine was used as an active control, as it is known to have effects on driving.  The prespecified noninferiority margin for SDLP was +2.4 cm (relative to PBO). A driving instructor with access to dual controls accompanied study participants during each driving test for safety purposes.

Eligibility criteria required a driver’s license for ≥3 years, driving ≥5000 km in the past year, driving a car regularly, body mass index (BMI) 18-30 kg/m², weight ≥45 kg, normal visual acuity, no mental or physical disease, and no use of psychoactive medication known to affect driving ability.

Results

The primary outcome measure, the mean SDLP, which indicates weaving of the car, was evaluated in healthy volunteers during a 100-km, on-road driving test 8 hours after administration of a single 84-mg dose of SPRAVATO vs PBO. The prespecified noninferiority margin for SDLP was +2.4 cm (relative to PBO) to indicate clinically relevant impairment.  The upper limit of the two-sided 95% CI of the mean difference between SPRAVATO and PBO was +0.86 cm, indicating that SPRAVATO was noninferior to PBO, and that there were no significant differences in driving performance between participants receiving SPRAVATO nasal spray and PBO 8 hours earlier.²

Two subjects did not complete the study; therefore, results were analyzed in 24 subjects. Mean SDLP (standard error [SE]) were 17.1 cm (0.92), 19.38 cm (0.91), and 17.25 cm (0.92) after SPRAVATO, mirtazapine, and PBO, respectively. The upper limit of the two-sided 95% CI of the mean difference between SPRAVATO and PBO was +0.86 cm, below the prespecified noninferiority threshold of +2.4 cm. The upper limit of the two-sided 95% CI of the mean difference between mirtazapine and PBO was +3.15 cm. There were no significant differences from PBO with regard to the SDS, mean lateral position (MLP), and mean speed (MS) (see Table: Driving Test Results).

Two subjects did not complete driving assessments after administration of SPRAVATO due to adverse events. One of these subjects also declined the driving test with mirtazapine due to ongoing nausea and dizziness.

On-Road Driving Study After SPRAVATO Administration in Patients With MDD

Dijkstra et al (2022)³ conducted a 2-part study. Part A, a single-blind, double-dummy, randomized, 3-period, cross-over, PBO-controlled study evaluated the effects of a single 84mg dose of SPRAVATO nasal spray on next day driving, 18±2 hours post-treatment. An ethanol-containing beverage was used as a positive control. Part B, an open-label, PBOcontrolled study, evaluated the effect of repeated administration 84-mg dose of SPRAVATO on same-day driving, 6±0.5 hours post-treatment biweekly for 3 weeks.

Study Design/Methods

Key Eligibility Criteria

Male and female patients aged 22-60 years (BMI, 18-32 kg/m²) with MDD without persistent depressive disorder (PDD)/dysthymia and with no use of medication known to cause sedation were included. All patients were required to have a valid driver's license and must have driven regularly in the year prior to screening. See Figure: Study Design.

Results

In total, 25 patients completed part A and 23 patients completed part B of the study. The primary outcome measure was SDLP. The prespecified noninferiority margin for SDLP of +2.4 cm (relative to PBO) was used to indicate clinically relevant driving impairment.

In part A, the SDLP after administration of single 84-mg dose of SPRAVATO nasal spray was similar to PBO. The upper limit of the two-sided 95% CI of the mean difference between single-dose SPRAVATO and PBO was 0.58 cm, which was not statistically significant (P=0.572). See Table: Next-Day On-Road Driving Test Results.

In part B, the difference in least mean square SDLP (upper limit of the 2-sided 95% CI [cm]) evaluated on day 11 vs day 1 was -0.96 cm (1.81), on day 18 it was -0.56 cm (2.20), and on day 25 it was -1.05 cm (1.71), which was not statistically significant (day 11, P=0.493; day 18, P=0.686; day 25, P=0.451). See Table: Same-Day On-Road Driving Test Results.

No statistically significant difference was found in SDS, MLP, and MS between SPRAVATO and PBO. The subjective assessments of driving quality and mental effort to perform the driving test were not statistically significant between the treatments and PBO in both parts of the study.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 20 November 2024.