Drug Interactions of SPRAVATO - General

SUMMARY  

• Concomitant use with central nervous system (CNS) depressants (benzodiazepines, opioids, alcohol) may increase sedation; therefore, closely monitoring for sedation is recommended with concomitant use of SPRAVATO and CNS depressants.¹
• Concomitant use with psychostimulants (amphetamines, methylphenidate, modafinil, armodafinil) may increase blood pressure; therefore, closely monitoring blood pressure is recommended with concomitant use of SPRAVATO and psychostimulants.¹
• Concomitant use with monoamine oxidase inhibitors (MAOIs) may increase blood pressure; therefore, closely monitoring blood pressure is recommended with concomitant use of SPRAVATO and MAOIs.¹
• (ESK) is primarily metabolized by cytochrome P450 (CYP)2B6 and CYP3A4.²
• ESK is not a substrate of transporters P glycoprotein-1, breast cancer resistance protein (BCRP), organic anion transporter (OATP)1B1, or OATP1B3. Neither ESK nor its major circulating phase-1 metabolites were found to be relevant inhibitors of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, organic cation transporter 2 (OCT2), multidrug and toxin extrusion (MATE)1, or MATE2K transporters.²
• Dose adjustment of SPRAVATO is not warranted in patients taking an inhibitor of hepatic enzymes CYP2B6 or CYP3A4, an inducer of hepatic enzymes CYP3A4 or CYP2B6.²
• A pharmacokinetic (PK) study assessed the effects of co-administration of a nasal decongestant (oxymetazoline), administered 1 hour prior to SPRAVATO dosing, and a nasal corticosteroid (mometasone furoate). No significant differences in the PK of SPRAVATO were observed.^2,3
• Administration of SPRAVATO did not affect the PK of oral bupropion, but slightly lowered maximum serum concentration (C_max) and area under the curve (AUC) of oral midazolam.²
• Repeated SPRAVATO administration is not expected to influence ethinyl estradiol exposure from combination oral contraceptives.²
• A real-world PK study in patients with treatment-resistant depression (TRD) found a higher serum SPRAVATO concentration and area under the plasma concentration-time curve from time zero to 72 hours (AUC_0-72) among patients receiving antidepressants known to inhibit CYP isoforms (eg, fluoxetine, paroxetine, duloxetine, and venlafaxine/desvenlafaxine) than among patients receiving antidepressants with minimal CYP inhibition. ⁴

Phase 1 PK studies

As described in the studies below, co-administration of a CYP inducer, CYP3A4 inhibitor, CYP2B6 inhibitor, intranasal corticosteroid, or intranasal decongestant showed no evidence of significant impact on the PK of SPRAVATO.

Midazolam and Bupropion

An open-label (OL), multiple-dose, parallel-group study evaluated the induction potential of repeated SPRAVATO on CYP3A4 and CYP2B6 using midazolam (CYP3A4 substrate) and bupropion (CYP2B6 substrate), respectively. Cohort 1 (n=13) received oral midazolam 6 mg on day 1 and 17 and SPRAVATO 84 mg on day 2, 5, 9, 12, and 16. Cohort 2 received bupropion 150 mg on day 1 and 19 and SPRAVATO 84 mg on day 4, 7, 11, 14, and 18.⁵

Based on geometric mean ratios (GMRs), repeated dosing of SPRAVATO after midazolam administration resulted in midazolam C_max, AUC up to the last measurable concentration (AUC_last), and total drug exposure across time (AUC_∞) being approximately 11%, 18%, and 16% lower, respectively, compared to that seen with midazolam administration alone. C_max of 1-hydroxymidazolam was unaffected, but AUC_last and AUC_∞, were reduced by approximately 14%.⁵

The plasma and urinary PK of bupropion and its metabolite, hydroxybupropion, were not affected by multiple administrations of SPRAVATO.⁵

Rifampin

An OL, 2-period, fixed sequence study evaluated the effects of oral rifampin, a potent CYP inducer, on the PK of SPRAVATO in healthy White subjects (n=16). Subjects were administered SPRAVATO 56 mg on day 1 of period 1, rifampin 600 mg daily on day -6 to -1 of period 2, and SPRAVATO 56 mg on day 1 of period 2. There was a washout period of 8-10 days between both SPRAVATO doses.⁵

Based on GMRs, C_max, AUC_last, and AUC_∞ of SPRAVATO were 17%, 31% and 28% lower in subjects pretreated with rifampin than in subjects treated with SPRAVATO alone.⁵

Clarithromycin

An OL study evaluated the effects of clarithromycin, a potent CYP3A4 inhibitor, on SPRAVATO PK. Subjects (n=18) received clarithromycin 500 mg twice daily on days -3 to day 2 followed by SPRAVATO 84 mg on day 1.⁵

Administration of clarithromycin before SPRAVATO resulted in geometric mean increases in C_max, AUC_last, and AUC_∞ by 11%, 6%, and 4%, respectively, compared to SPRAVATO alone.⁵

Ticlopidine

An OL, 2-period, fixed-sequence study evaluated the effect of ticlopidine, a CYP2B6 inhibitor, on the PK of SPRAVATO. Subjects (n=16) received SPRAVATO 56 mg in period 1, ticlopidine 250 mg twice daily from day -9 to 1, and SPRAVATO 56 mg on day 1 in period 2.⁵

Ticlopidine administration before SPRAVATO resulted in geometric mean increases in C_max, AUC_last, AUC_∞ by approximately 2%, 33%, and 29% compared to SPRAVATO administration alone.⁵

Oxymetazoline and Mometasone Nasal Spray

Zannikos et al (2023)³ conducted a single-center, OL PK study to characterize the effects of coadministration of oxymetazoline or mometasone on the PK of SPRAVATO nasal spray in patients with allergic rhinitis or healthy subjects, respectively.

Twenty-two patients with a history of moderate allergic rhinitis were enrolled in cohort 1, a 2-way crossover study, and were exposed to pollen prior to randomization to one of two treatment sequences to trigger symptoms of allergic rhinitis. Both sequences had 2 periods separated by a 5- to 10-day washout interval. Period 1 of one sequence involved administration of SPRAVATO 56 mg. Period 2 of the same sequence involved 2 sprays of oxymetazoline 0.05% solution in each nostril 1 hour before another dose of SPRAVATO 56 mg. This was reversed in the treatment scheme for the other sequence.

Twenty-four healthy subjects were enrolled in cohort 2, a 2-period fixed sequence study, and received SPRAVATO 56 mg on day 1 of period 1, mometasone 200 μg nasal suspension (2 sprays of 50 μg/spray mometasone suspension in each nostril) from day 1 to day 16 of period 2, and SPRAVATO 56 mg on day 16 of period 2, 1 hour after administration of mometasone.

The 90% confidence intervals for the GMRs of C_max, AUC_last, and AUC_∞ were contained within the bioequivalence range between 0.80-1.25 for when SPRAVATO was administered after oxymetazoline or mometasone treatment compared with when SPRAVATO was administered alone.

Ethinyl Estradiol

A physiologically based PK modeling (PBPK) analyses indicated that repeated SPRAVATO administration is not expected to influence ethinyl estradiol exposure from combination oral contraceptives.²

REAL-WORLD PK Study

Alborghetti et al (2025)⁴ conducted a real-world PK study to evaluate the influence of concomitant antidepressants on SPRAVATO exposure in patients with TRD. Fifty-three adult patients receiving intranasal SPRAVATO 56 mg were stratified according to concomitant antidepressant therapy and potential CYP2B6/CYP3A4 inhibition. Serum and salivary SPRAVATO concentrations were measured at baseline, 20 minutes, 7 hours, 24 hours, and 72 hours after SPRAVATO administration. The serum SPRAVATO concentrations at
20 minutes, 7 hours, and 24 hours following administration, as well as AUC_₀-₇₂ values across antidepressant treatment groups, are shown in the figure below (See Figure: Effect of Concomitant Antidepressant Therapy on Serum SPRAVATO Concentrations and AUC₀-₇₂ in Patients with TRD)

Patients receiving antidepressants known to inhibit CYP metabolism (fluoxetine, paroxetine, duloxetine, or venlafaxine/desvenlafaxine) demonstrated higher serum SPRAVATO concentrations at 20 minutes following administration compared with patients who received antidepressants with minimal CYP inhibition (sertraline, citalopram, escitalopram, or vortioxetine). Significant differences persisted at 7 hours in patients treated with fluoxetine or paroxetine compared with those treated with antidepressants with minimal effects on CYP metabolism or vortioxetine, but were no longer observed at 24 hours. The AUC_0-72 value of SPRAVATO was also significantly higher in patients receiving fluoxetine/paroxetine than in patients receiving sertraline/citalopram/escitalopram, vortioxetine, or tricyclic antidepressants/mirtazapine/trazodone. Increased serum SPRAVATO concentrations and AUC₀-₇₂ were not associated with differences in depressive outcomes assessed 1 month after treatment initiation. However, higher serum SPRAVATO concentrations at 20 minutes were positively correlated with increases in systolic blood pressure.

The limitations of the study included small sample sizes, use of multiple antidepressants, lack of pharmacogenomic assessment of CYP450 variants, absence of cognitive assessments, and inclusion of a European White-only study population. Additional concomitant medications, including valproate, atorvastatin, oxcarbazepine, and prednisone, were used by some patients.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 24 July 2026.

A PBPK simulation model study described the PK of SPRAVATO and drugdrug interactions of SPRAVATO with other drugs. The findings of this simulation model were found to be in concordance with those of the phase 1 PK studies described in this response.⁶