What are the contraindications for esketamine nasal spray?

Contraindications for Esketamine Nasal Spray

Esketamine nasal spray is absolutely contraindicated in patients with aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels), arteriovenous malformation, history of intracerebral hemorrhage, or hypersensitivity to esketamine, ketamine, or any excipients. 1

Absolute Contraindications (FDA-Mandated)

The FDA drug label explicitly lists three absolute contraindications that preclude esketamine use under any circumstances:

• Aneurysmal vascular disease affecting any major vessel including thoracic aorta, abdominal aorta, intracranial vessels, or peripheral arterial vessels 1
• Arteriovenous malformation at any anatomic location 1
• History of intracerebral hemorrhage 1
• Hypersensitivity to esketamine, ketamine, or any formulation excipients 1

These contraindications exist because esketamine causes transient but significant cardiovascular stimulation, with mean maximum systolic/diastolic blood pressure increases of 13.3/8.7 mmHg in adults aged 18-64 years and 16.0/9.5 mmHg in elderly patients (≥65 years), reaching peak values within approximately 40 minutes of dosing. 2

Relative Contraindications and High-Risk Populations

Cardiovascular Disease

Patients with established cardiovascular disease require extreme caution and were excluded from pivotal clinical trials. 2 Specifically:

• Uncontrolled hypertension (>140/>90 mmHg) represents a relative contraindication, as adverse events related to increased blood pressure occurred in 11.6% of esketamine-treated patients versus 3.9% with placebo (OR 3.2) 2
• History of hypertensive crisis was an exclusion criterion in clinical development 2
• Clinically significant ECG abnormalities precluded enrollment in safety studies 2

Among patients without baseline hypertension, 2.1% required initiation of new antihypertensive medication during esketamine treatment. 2 Three serious cardiovascular adverse events related to blood pressure increase occurred during clinical trials, including one fatal event (acute cardiac failure, though considered unrelated). 2

Respiratory Considerations

While no respiratory depression events occurred in phase 3 trials, postmarketing surveillance identified 50 cases meeting criteria for respiratory depression, with 8 having stronger association with esketamine use. 3 The estimated incidence is approximately 1 case per 20,000 treatment sessions. 3

Monitoring for respiratory depression symptoms, including pulse oximetry, is mandatory within the postdose observation period. 3 Symptoms are manageable and resolve with minor supportive measures. 3

Clinical Context: When Esketamine Should NOT Be Used

Inappropriate Patient Selection

Esketamine is explicitly NOT indicated for initial treatment of depression and should never be used as first-line therapy. 4, 5 The American Psychiatric Association and American College of Physicians mandate that esketamine be reserved exclusively for adults with treatment-resistant depression who have failed at least 2 adequate antidepressant trials of different mechanisms of action at appropriate doses for at least 4 weeks each. 4, 5

Patients who have not met this threshold of treatment resistance should be considered inappropriate candidates, representing a clinical contraindication to use. 4

Monitoring Requirements as Practical Contraindications

The requirement for blood pressure monitoring due to hypertensive effects, along with mandatory monitoring for dissociative symptoms, sedation, and potential respiratory depression, means that settings unable to provide this level of surveillance represent practical contraindications to esketamine administration. 4

The FDA mandates ongoing surveillance for abuse and misuse potential throughout treatment, as well as assessment for development of substance use disorder. 4 Facilities without capacity for this monitoring should not administer esketamine.

Common Pitfalls to Avoid

• Do not assume normal baseline cardiovascular status eliminates risk: Even patients without hypertension history may require new antihypertensive medications (2.1% incidence). 2
• Do not overlook vascular imaging history: Specifically inquire about any prior imaging showing aneurysms or arteriovenous malformations, even if asymptomatic. 1
• Do not confuse treatment-resistant depression with treatment-refractory depression: The specific definition requires documented failure of 2 adequate trials with <25% improvement on validated scales. 4
• Do not administer without capacity for immediate intervention: The transient nature of adverse effects (BP peaks at ~40 minutes, returns to baseline by ~1.5 hours) requires on-site monitoring capability. 2