Esketamine Nasal Spray

Esketamine nasal spray (Spravato) is FDA-approved for two distinct conditions in adults:

• Treatment-resistant depression (TRD): Spravato nasal spray is used when depression has not responded adequately to other antidepressants. It can be used alone or alongside an oral antidepressant.
• Depressive symptoms in major depressive disorder (MDD) with acute suicidal ideation or behavior: Spravato nasal spray is used together with an oral antidepressant to treat depressive symptoms in adults who are experiencing active suicidal thoughts or behaviors. Note: it has not been proven to prevent suicide or reduce suicidal ideation or behavior directly.

Spravato is not approved for use in children or teens, and is not approved as an anesthetic agent.

Esketamine is the active ingredient in Spravato. It works by blocking the NMDA receptor — a key receptor in the brain that responds to a chemical messenger called glutamate. By blocking this receptor, esketamine is thought to alter signaling pathways involved in mood regulation, though the exact mechanism behind its antidepressant effect is not fully understood. Its main metabolite (breakdown product) in the body, noresketamine, also acts on the same receptor but with less potency.

Spravato nasal spray is always given in a certified healthcare setting — never at home. For treatment-resistant depression, it is typically given twice a week during an initial induction phase, then reduced to once weekly, and later potentially every two weeks during maintenance, based on how you respond. For MDD with acute suicidal ideation or behavior, it is given twice a week for 4 weeks; use beyond 4 weeks has not been fully studied for this use. Dosing frequency is individualized by your prescriber.

• Avoid food for at least 2 hours before your dose and avoid liquids for at least 30 minutes before
• If you use a nasal corticosteroid or decongestant on a dosing day, use it at least 1 hour before Spravato
• If you miss sessions and your depression symptoms worsen during maintenance, your provider may temporarily increase the frequency again
• Do not drive or operate machinery until the next day after a restful night's sleep — arrange a ride home every time

The most commonly reported side effects with Spravato include:

• Dissociation — feeling detached from yourself or your surroundings, with altered perceptions of time or space (very common, reported in up to 84% of patients in trials)
• Sedation or heavy drowsiness (reported in roughly half to two-thirds of patients)
• Dizziness or vertigo
• Nausea or vomiting
• Increased blood pressure
• Numbness or reduced sensation (hypoesthesia)
• Headache
• Feeling drunk or euphoric
• Anxiety or lethargy

Serious reactions to act on immediately include difficulty breathing or very slow breathing, extreme or prolonged sedation, loss of consciousness, signs of a hypertensive crisis (chest pain, sudden severe headache, vision changes, seizures), new or worsening suicidal thoughts, and signs of bladder problems such as pain or urgency with urination.

• Sedation and loss of consciousness: Spravato commonly causes significant drowsiness and has rarely caused loss of consciousness. You are monitored for at least 2 hours after every dose for this reason.
• Dissociation: Most patients experience some degree of detachment from reality, altered perceptions, or derealization during treatment. Patients with psychosis require careful evaluation before starting Spravato.
• Respiratory depression: Slowed or difficult breathing — and in rare cases, respiratory arrest — has occurred. Breathing and oxygen levels are monitored at every session.
• Blood pressure increases: Spravato raises blood pressure after each dose. People with high blood pressure, heart disease, or cerebrovascular disease need careful monitoring. Seek emergency care for chest pain, sudden severe headache, or vision changes.
• Abuse and misuse: Spravato is a Schedule III controlled substance with real potential for abuse. It is only available through the Spravato REMS program at certified healthcare settings.
• Suicidal thoughts in young adults: Antidepressants can increase the risk of suicidal thoughts or behavior in patients 24 and younger. All patients should be closely monitored, especially early in treatment.
• Cognitive impairment: Spravato temporarily affects attention, thinking, reaction time, and coordination around the time of the dose. Do not drive the same day.
• Bladder problems: Urinary symptoms (frequent urination, urgency, pain) were more common with Spravato than placebo. Long-term ketamine misuse has caused serious bladder damage; report any urinary changes to your provider.
• Pregnancy risk: Based on animal studies, Spravato may harm a developing fetus. It is not recommended during pregnancy, and breastfeeding is not recommended during treatment.

Spravato can interact with several types of drugs in clinically important ways:

• CNS depressants (benzodiazepines, opioids, alcohol): Using these together with Spravato increases the risk of dangerous sedation. Close monitoring is required if these are used together.
• Psychostimulants (amphetamines, methylphenidate, modafinil, armodafinil): These can further raise blood pressure when combined with Spravato. Blood pressure must be closely monitored.
• MAOIs (monoamine oxidase inhibitors): A type of older antidepressant that can also significantly raise blood pressure when used with Spravato. Close blood pressure monitoring is required.

This is not a complete list of interactions. Always talk with your doctor or pharmacist before starting, stopping, or changing any medication.

• Do not use if you have aneurysmal vascular disease (including in the aorta, brain, or peripheral blood vessels), arteriovenous malformation, or a history of intracerebral hemorrhage (bleeding in the brain)
• Do not use if you are allergic to esketamine, ketamine, or any ingredient in Spravato
• Tell your provider about any history of high blood pressure, heart disease, or stroke — blood pressure rises with each dose
• Tell your provider if you have a history of psychosis — Spravato's dissociative effects may worsen psychotic symptoms
• Tell your provider about any history of substance use disorder — Spravato has abuse potential as a controlled substance
• Moderate liver (hepatic) impairment: Drug levels may be higher and last longer; longer post-dose monitoring may be needed. Spravato is not recommended for severe liver impairment.
• Older adults (65+): Drug levels tend to be higher in older patients; no overall difference in safety was seen in clinical trials, but monitoring applies equally
• Children and teens: Safety and effectiveness have not been established; Spravato is not approved for pediatric patients
• Pregnancy: Spravato is not recommended during pregnancy — animal studies suggest risk of fetal harm. Effective contraception should be considered during treatment.
• Breastfeeding: Esketamine passes into breast milk and breastfeeding is not recommended during treatment due to potential neurotoxicity in infants

There is no specific antidote for an esketamine overdose. If an overdose is suspected, the possibility of multiple drugs being involved should be considered. Contact the Poison Control Center immediately at 1-800-222-1222 or visit www.poison.org for the most current guidance.

Spravato can raise heart rate noticeably (by more than 10 beats per minute) after each dose. Studies do not suggest it causes clinically meaningful changes to the heart's electrical rhythm (QTc interval) at therapeutic doses. Blood pressure also rises after dosing and is a required monitoring point at every treatment session.

After nasal administration, about 48% of the dose reaches the bloodstream (bioavailability), with peak blood levels occurring roughly 20 to 40 minutes after the last spray of a session. Esketamine is then broken down rapidly over the first 2 to 4 hours, with a terminal half-life (the time for blood levels to fall by half) of about 7 to 12 hours. It is primarily metabolized in the liver by enzymes CYP2B6 and CYP3A4 into its main metabolite, noresketamine, with less than 1% of the original drug excreted unchanged in urine. Drug levels tend to be higher in older adults and in people with moderate liver impairment, which may require longer post-dose monitoring in those groups.

Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) .