Spravato Esketamine Hydrochloride 28 mg/.2mL Solution
🆔 Identity & classification
Where does this data come from?
🏷️ RxNorm drug class
This medicine belongs to the Other general anesthetics class.
Where does this data come from?
🏭 Manufacturer & labeler
Where does this data come from?
🩺 Clinical
Esketamine nasal spray is used alone or in combination with another antidepressant, taken by mouth, to manage treatment-resistant depression (TRD; depression that does not improve with treatment) in adults. It is also used along with another antidepressant, taken by mouth, to treat depressive symptoms in adults with major depressive disorder (MDD) and suicidal thoughts or actions. Esketamine is in a class of medications called NMDA receptor antagonists. It works by changing the activity of certain natural substances in the brain.
Read the full MedlinePlus article ↗- No — Spravato cannot be taken at home, and that's a firm rule, not just a suggestion. Because it can cause heavy sedation, a dreamlike detachment from reality (called dissociation)...
- Why do I have to go to a clinic every time I use this? Can I take it at home?
- Dissociation is when you feel detached from yourself or your surroundings — time might feel distorted, things might look or sound different, or you might feel like you're watching...
- What does 'dissociation' actually feel like, and is it dangerous?
Patient education
Supplement & herbal interactions
Esketamine may be associated with lower levels of 1 nutrient — worth a chat with your pharmacist, not a cause for alarm.
Where does this data come from?
Ask a licensed pharmacist directly — free, answered by our team.
🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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UNII 2968PHW8QP
A weak organic acid derived from citrus fruits or made through fermentation. It works as a buffer to control pH, a preservative to extend shelf life, and a flavoring agent in medications.
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UNII 7FLD91C86K
Edetate disodium is a chemical compound that binds and removes certain metal ions. In medicines, it acts as a preservative and stabilizer by preventing metals like calcium from interfering with the product's shelf life and consistency.
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UNII 55X04QC32I
A strong alkaline chemical used to adjust and maintain the pH balance of liquid medicines. It helps keep the medicine stable and ensures it stays effective during storage.
3 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
Why might an inactive ingredient be missing?
Can inactive ingredients matter?
💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $431.228 | $1,293.68 / 3 vials |
| Medicaid paysCMS SDUD · 12 mo | $444.02 | $1,332.05 / 3 vials |
| Medicare drug plans payPart D · quarterly | No Part D plan price is available for this NDC in our data. | |
Where does this data come from?
🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Spravato 28 mg/.2mLthis 50458-0028-03 | Janssen | 1 kit | $431.228 | — | Availability likely | — |
Where does this data come from?
⏳ Availability & generic status
We did not find an FDA-approved generic match for this exact strength, form and route. Patent/protection dates below may affect future generic timing.
Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.
🛈 What do these terms mean?
- Patent
- Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
- Substance patent
- Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
- Formulation (product) patent
- Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
- Method-of-use patent
- A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
- Skinny label
- A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
- Exclusivity
- FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
- Paragraph IV
- A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
- RLD / RS
- Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
- TE / AB rating
- FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
- LOE (loss of exclusivity)
- The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.
Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.
| Patent | Type | Use code | Expires |
|---|---|---|---|
| US 8785500 ↗ | Method of use | U-2502 | Mar 5, 2033 |
| US 9592207 ↗ | Method of use | U-2502 | Mar 20, 2027 |
| US 11883526 ↗ | Method of use | U-4120 | Feb 18, 2040 |
| US 8785500 ↗ | Method of use | U-4112 | Mar 5, 2033 |
| US 9592207 ↗ | Method of use | U-4112 | Mar 20, 2027 |
| US 10869844 ↗ | Method of use | U-4113 | Sep 10, 2035 |
| US 10869844 ↗ | Method of use | U-4114 | Sep 10, 2035 |
| US 11173134 ↗ | Method of use | U-4115 | Sep 10, 2035 |
| US 11311500 ↗ | Method of use | U-4116 | Sep 10, 2035 |
| US 11311500 ↗ | Method of use | U-4117 | Sep 10, 2035 |
| US 11446260 ↗ | Method of use | U-4118 | Mar 14, 2034 |
| US 11173134 ↗ | Method of use | U-3536 | Sep 10, 2035 |
| US 11446260 ↗ | Method of use | U-4119 | Mar 14, 2034 |
| US 11883526 ↗ | Method of use | U-3812 | Feb 18, 2040 |
| US 11883526 ↗ | Method of use | U-3813 | Feb 18, 2040 |
| US 11311500 ↗ | Method of use | U-3034 | Sep 10, 2035 |
| US 11311500 ↗ | Method of use | U-3036 | Sep 10, 2035 |
| US 11311500 ↗ | Method of use | U-3035 | Sep 10, 2035 |
| US 11173134 ↗ | Method of use | U-3257 | Sep 10, 2035 |
| US 11446260 ↗ | Method of use | U-3444 | Mar 14, 2034 |
| US 11446260 ↗ | Method of use | U-3445 | Mar 14, 2034 |
| US 11446260 ↗ | Method of use | U-3446 | Mar 14, 2034 |
| US 10869844 ↗ | Method of use | U-3035 | Sep 10, 2035 |
| US 10869844 ↗ | Method of use | U-3034 | Sep 10, 2035 |
| US 10869844 ↗ | Method of use | U-3036 | Sep 10, 2035 |
| Code | What it grants | Expires |
|---|---|---|
| I-959 | New indication (3-year) | Jan 17, 2028 |
Is there a generic version of SPRAVATO 84 MG DOSE PACK?
The FDA approved a generic — why can’t I get it at my pharmacy yet?
Why do different websites show different generic release dates?
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What does a patent or protection date mean here?
What does “current Orange Book estimate” mean?
Can a generic come out before the last patent expires?
Can a generic come out after the listed dates?
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Where does this data come from?
🗺️ Medicaid utilization & spend
💊 Medicaid utilization by pack size
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
📦 Packaging — all sizes for this product
| Package NDC | Description | Per unit | Per pack | Marketing start | Status |
|---|---|---|---|---|---|
| 50458-0028-02 | 2 BLISTER PACK in 1 KIT (50458-028-02) / 1 VIAL, SINGLE-USE in 1 BLISTER PACK / .2 mL in 1 VIAL, SINGLE-USE (50458-028-00) | $426.30 / ea | $852.60 | 2019-03-05 | Active |
| 50458-0028-03 You're viewing this | 3 BLISTER PACK in 1 KIT (50458-028-03) / 1 VIAL, SINGLE-USE in 1 BLISTER PACK / .2 mL in 1 VIAL, SINGLE-USE (50458-028-00) | $431.23 / ea | $1,293.68 | 2019-03-05 | Active |
In Medicaid, this is the most-dispensed pack of this product — about 88% of fills over the last four reported quarters. See all packs ↓
Pack size FAQ
What quantity is in NDC 50458-0028-03?
What NDC number is used to bill for this package of Spravato Esketamine Hydrochloride 28 mg/.2mL Solution?
Prices are the latest CMS NADAC pharmacy acquisition cost per NDC; per-pack figures are per-unit × pack quantity, shown only when the pack is denominated in the same measure NADAC prices.
🧭 About this NDC listing & data coverage
Kit / multi-component package
This NDC identifies a kit — a package containing more than one component. Structured data (pricing, ingredients, equivalents) is often reported per component rather than for the kit NDC itself, which can make this page look thinner than the components' own pages.
What data is (and isn’t) available for this NDC — tap to expand
| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
| Package photos | ✓ Available |
| Inactive ingredients (structured) | ✓ Available |
| NADAC pharmacy acquisition price (CMS) | ✓ Available |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | — Not published for this NDC Most self-administered / retail products have no J-code — that is normal. |
| Medicaid utilization (CMS SDUD) | ✓ Available |
Questions about this listing
Is the NDC printed on the package the same as the 11-digit billing NDC?
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📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: SEDATION; DISSOCIATION; RESPIRATORY DEPRESSION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS WARNING: SEDATION; DISSOCIATION; RESPIRATORY DEPRESSION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Risk for sedation, dissociation, and respiratory depression after administration. Monitor patients for at least two hours after administration.
( 5.1 , 5.2 , 5.3 ) Potential for abuse and misuse. Consider the risks and benefits of prescribing SPRAVATO prior to using in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse.
( 5.4 ) SPRAVATO is only available through a restricted program called the SPRAVATO REMS. ( 5.5 ) Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors.
SPRAVATO is not approved for use in pediatric patients. ( 5.6 ) Sedation Patients are at risk for sedation after administration of SPRAVATO [see Warnings and Precautions (5.1) ]. Dissociation Patients are at risk for dissociative or perceptual changes after administration of SPRAVATO [see Warnings and Precautions (5.2) ].
Respiratory Depression Respiratory depression has been observed in postmarketing experience [see Warnings and Precautions (5.3) ] . Because of the risks of sedation, dissociation, and respiratory depression, patients must be monitored for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Abuse and Misuse SPRAVATO has the potential to be abused and misused.
Consider the risks and benefits of prescribing SPRAVATO prior to use in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse [see Warnings and Precautions (5.4) ] . Because of the risks of serious adverse outcomes resulting from sedation, dissociation, respiratory depression, abuse and misuse, SPRAVATO is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS [see Warnings and Precautions (5.5) ] .
Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. SPRAVATO is not approved for use in pediatric patients [see Warnings and Precautions (5.6) ] .
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE SPRAVATO is indicated for the treatment of: Treatment-resistant depression (TRD) in adults as monotherapy or in conjunction with an oral antidepressant Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior in conjunction with an oral antidepressant SPRAVATO is a non-competitive N -methyl D -aspartate (NMDA) receptor antagonist indicated for the treatment of: Treatment-resistant depression (TRD) in adults, as monotherapy or in conjunction with an oral antidepressant.
( 1 ) Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior in conjunction with an oral antidepressant. ( 1 ) Limitations of Use: The effectiveness of SPRAVATO in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use of SPRAVATO does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of SPRAVATO.
( 1 ) SPRAVATO is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO as an anesthetic agent have not been established. ( 1 ) Limitations of Use The effectiveness of SPRAVATO in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated [see Clinical Studies (14.2) ] .
Use of SPRAVATO does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of SPRAVATO. SPRAVATO is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO as an anesthetic agent have not been established.
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Administer SPRAVATO intranasally under the supervision of a healthcare provider. ( 2.1 ) Assess blood pressure prior to and after administration. ( 2.1 ) TRD: Evidence of therapeutic benefit should be evaluated at the end of the 4-week induction phase to determine need for continued treatment.
( 2.2 ) Depressive symptoms in MDD with acute suicidal ideation or behavior : Evidence of therapeutic benefit should be evaluated after 4 weeks to determine need for continued treatment. Treatment beyond 4 weeks has not been systematically evaluated. ( 2.3 ) See Full Prescribing Information for recommended dosage.
( 2.2 , 2.3 ) See Full Prescribing Information for important administration instructions. ( 2.4 )
2.1Important Considerations Prior to Initiating and During Therapy SPRAVATO must be administered under the direct supervision of a healthcare provider. A treatment session consists of nasal administration of SPRAVATO and post-administration observation under supervision. Respiratory Status Assessment During Treatment Monitor patients for changes in respiratory status for at least 2 hours (including pulse oximetry) at each treatment session [see Warnings and Precautions (5.3) ] .
Blood Pressure Assessment Before and After Treatment Assess blood pressure prior to dosing with SPRAVATO [see Warnings and Precautions (5.7) ] . If baseline blood pressure is elevated (e.g., >140 mmHg systolic, >90 mmHg diastolic), consider the risks of short term increases in blood pressure and benefit of SPRAVATO treatment [see Warnings and Precautions (5.7) ]. Do not administer SPRAVATO if an increase in blood pressure or intracranial pressure poses a serious risk [see Contraindications (4) ] .
After dosing with SPRAVATO, reassess blood pressure at approximately 40 minutes (which corresponds with the C max ) and subsequently as clinically warranted. If blood pressure is decreasing and the patient appears clinically stable for at least two hours, the patient may be discharged at the end of the post-dose monitoring period; if not, continue to monitor [see Warnings and Precautions (5.7) ]. Food and Liquid Intake Recommendations Prior to Administration Because some patients may experience nausea and vomiting after administration of SPRAVATO [see Adverse Reactions (6.1) ], advise patients to avoid food for at least 2 hours before administration and to avoid drinking liquids at least 30 minutes prior to administration.
Nasal Corticosteroid or Nasal Decongestant Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should administer these medications at least 1 hour before SPRAVATO [see Clinical Pharmacology (12.3) ].
2.2Treatment-Resistant Depression The recommended dosage of SPRAVATO for the treatment of TRD in adults as monotherapy or in conjunction with an oral antidepressant is shown in Table 1. Dosage adjustments should be made based on efficacy and tolerability. Evidence of therapeutic benefit should be evaluated at the end of the induction phase to determine need for continued treatment.
Table 1: Recommended Dosage for SPRAVATO for TRD Adults Induction Phase Weeks 1 to 4: Administer twice per week 56 mg or 84 mg Maintenance Phase Weeks 5 to 8 : Administer once weekly 56 mg or 84 mg Week 9 and after : Administer every 2 weeks or once weekly Dosing frequency should be individualized to the least frequent dosing to maintain remission/response. 56 mg or 84 mg
2.3Depressive Symptoms in Patients with Major Depressive Disorder with Acute Suicidal Ideation or Behavior Administer SPRAVATO in conjunction with an oral antidepressant (AD). The recommended dosage of SPRAVATO for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior is 84 mg twice per week for 4 weeks. Dosage may be reduced to 56 mg twice per week based on tolerability.
After 4 weeks of treatment with SPRAVATO, evidence of therapeutic benefit should be evaluated to determine need for continued treatm…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Nasal Spray: 28 mg of esketamine per device. Each nasal spray device delivers two sprays containing a total of 28 mg esketamine. Nasal Spray : 28 mg of esketamine per device. Each nasal spray device delivers two sprays containing a total of 28 mg of esketamine. ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS SPRAVATO is contraindicated in patients with: Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation [see Warnings and Precautions (5.7) ] History of intracerebral hemorrhage [see Warnings and Precautions (5.7) ] Hypersensitivity to esketamine, ketamine, or any of the excipients. Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation.
( 4 ) Intracerebral hemorrhage. ( 4 ) Hypersensitivity to esketamine, ketamine, or any of the excipients. ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Increases in Blood Pressure: Patients with cardiovascular and cerebrovascular conditions and risk factors may be at an increased risk of associated adverse effects. ( 5.7 ) Cognitive Impairment: SPRAVATO may impair attention, judgment, thinking, reaction speed and motor skills. ( 5.8 ) Impaired Ability to Drive and Operate Machinery: Do not drive or operate machinery until the next day after a restful sleep.
( 5.9 ) Embryo-fetal Toxicity: May cause fetal harm. Consider pregnancy planning and prevention in females of reproductive potential. ( 5.11 , 8.1 , 8.3 )
5.1Sedation SPRAVATO may cause sedation or loss of consciousness. In some cases, patients may display diminished or less apparent breathing. In clinical trials, 48% to 61% of SPRAVATO-treated patients developed sedation based on the Modified Observer's Assessment of Alertness/Sedation scale (MOAA/S) [see Adverse Reactions (6.1) ] , and 0.3% to 0.4% of SPRAVATO-treated patients experienced loss of consciousness (MOAA/S score of 0).
Because of the possibility of delayed or prolonged sedation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Dosage and Administration (2.5) ] . Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants [see Drug Interactions (7.1) ] . SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.5) ] .
5.2Dissociation The most common psychological effects of SPRAVATO were dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization (61% to 84% of SPRAVATO-treated patients developed dissociative or perceptual changes based on the Clinician-Administered Dissociative States Scale) [see Adverse Reactions (6.1) ] . Given its potential to induce dissociative effects, carefully assess patients with psychosis before administering SPRAVATO; treatment should be initiated only if the benefit outweighs the risk.
Because of the risks of dissociation, patients must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Dosage and Administration (2.5) ] . SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.5) ] .
5.3Respiratory Depression In post marketing experience, respiratory depression was observed with the use of SPRAVATO. In addition, there were rare reports of respiratory arrest [see Adverse Reactions (6.2) ] . Because of the risks of respiratory depression, patients must be monitored for changes in respiratory status by a healthcare provider for at least 2 hours (including pulse oximetry) at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Dosage and Administration (2.5) ] .
SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.5) ] .
5.4Abuse and Misuse SPRAVATO contains esketamine, a Schedule III controlled substance (CIII), and may be subject to abuse and diversion. Assess each patient's risk for abuse or misuse prior to prescribing SPRAVATO and monitor all patients receiving SPRAVATO for the development of these behaviors or conditions, including drug-seeking behavior, while on therapy. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of SPRAVATO.
Individuals with a history of drug abuse or dependence are at greater risk; therefore, use careful consideration prior to treatment of individuals with a history of substance use disorder and…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Sedation [see Warnings and Precautions (5.1) ] Dissociation [see Warnings and Precautions (5.2) ] Respiratory Depression [see Warnings and Precautions (5.3) ] Increase in Blood Pressure [see Warnings and Precautions (5.7) ] Cognitive Impairment [see Warnings and Precautions (5.8) ] Impaired Ability to Drive and Operate Machinery [see Warnings and Precautions (5.9) ] Ulcerative or Interstitial Cystitis [see Warnings and Precautions (5.10) ] Embryo-fetal Toxicity [see Warnings and Precautions (5.11) ] The most commonly observed adverse reactions (incidence ≥5% and at least twice that of placebo): TRD: dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, feeling drunk, and headache.
( 6 ) Treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior: dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Treatment-Resistant Depression In Conjunction with an Oral Antidepressant SPRAVATO was evaluated for safety in 1709 adults diagnosed with treatment-resistant depression (TRD) [see Clinical Studies (14.1) ] from five Phase 3 studies (3 short-term and 2 long-term studies) and one Phase 2 dose-ranging study.
Of all SPRAVATO-treated patients in the completed Phase 3 studies, 479 (30%) received at least 6 months of treatment, and 178 (11%) received at least 12 months of treatment. Adverse Reactions Leading to Discontinuation of Treatment In short-term studies in adults <65 years old (Study 1 pooled with another 4-week study), the proportion of patients who discontinued treatment because of an adverse reaction was 4.6% in patients who received SPRAVATO plus oral AD compared to 1.4% for patients who received placebo nasal spray plus oral AD.
For adults ≥65 years old, the proportions were 5.6% and 3.1%, respectively. In Study 2, a long-term maintenance study, the discontinuation rates because of an adverse reaction were similar for patients receiving SPRAVATO plus oral AD and placebo nasal spray plus oral AD in the maintenance phase, at 2.6% and 2.1%, respectively. Across all Phase 3 studies, adverse reactions leading to SPRAVATO discontinuation in more than 2 patients were (in order of frequency): anxiety (1.2%), depression (0.9%), blood pressure increased (0.6%), dizziness (0.6%), suicidal ideation (0.5%), dissociation (0.4%), nausea (0.4%), vomiting (0.4%), headache (0.3%), muscular weakness (0.3%), vertigo (0.2%), hypertension (0.2%), panic attack (0.2%) and sedation (0.2%).
Most Common Adverse Reactions The most commonly observed adverse reactions in patients treated with SPRAVATO plus oral AD (incidence ≥5% and at least twice that of placebo nasal spray plus oral AD) were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk. Table 3 shows the incidence of adverse reactions that occurred in patients treated with SPRAVATO plus oral AD at any dose and greater than patients treated with placebo nasal spray plus oral AD.
Table 3: Adverse Reactions Occurring in ≥2% of Adult TRD Patients Treated with SPRAVATO + Oral AD at Any Dose and at a Greater Rate than Patients Treated with Placebo Nasal Spray + Oral AD SPRAVATO + Oral AD (N=346) Placebo + Oral AD (N=222) Cardiac disorders Tachycardia The following terms were combined:…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS
7.1Central Nervous System Depressants Concomitant use with CNS depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation [see Warnings and Precautions (5.1) ] . Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants.
7.2Psychostimulants Concomitant use with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) may increase blood pressure [see Warnings and Precautions (5.7) ] . Closely monitor blood pressure with concomitant use of SPRAVATO with psychostimulants.
7.3Monoamine Oxidase Inhibitors (MAOIs) Concomitant use with monoamine oxidase inhibitors (MAOIs) may increase blood pressure [see Warnings and Precautions (5.7) ] . Closely monitor blood pressure with concomitant use of SPRAVATO with MAOIs.
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended. ( 8.2 )
8.1Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including SPRAVATO, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ . Risk Summary SPRAVATO is not recommended during pregnancy.
There are insufficient data on SPRAVATO use in pregnant women to draw conclusions about any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on published findings from pregnant animals treated with ketamine, the racemic mixture of arketamine and esketamine, SPRAVATO may cause fetal harm when administered to pregnant women (see Data ) . Advise pregnant women of the potential risk to an infant exposed to SPRAVATO in utero .
There are risks to the mother associated with untreated depression in pregnancy (see Clinical Considerations ). If a woman becomes pregnant while being treated with SPRAVATO, treatment with esketamine should be discontinued and the patient should be counseled about the potential risk to the fetus. Published studies in pregnant primates demonstrate that the administration of drugs that block N -methyl- D -aspartate (NMDA) receptors during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring.
There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans [see Use in Specific Populations (8.2) ] . In an embryo-fetal reproduction study in rabbits, skeletal malformations were noted at maternally toxic doses when ketamine was intranasally administered with a No Observed Adverse Effect Level (NOAEL) at estimated esketamine exposures 0.3 times the exposures at the maximum recommended human dose (MRHD) of 84 mg/day. In addition, intranasal administration of esketamine to pregnant rats during pregnancy and lactation at exposures that were similar to those at the MRHD resulted in a delay in sensorimotor development in pups during the preweaning period and a decrease in motor activity in the post-weaning period.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
Data Animal Data Based on published data, when female monkeys were treated intravenously with racemic ketamine at anesthetic dose levels in the third trimester of pregnancy, neuronal cell death was observed in the brains of their fetuses. This period of brain development translates into the third trimester of human pregnancy. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits.
Racemic ketamine was administered intranasally to pregnant rats during the period of organogenesis at doses of 15, 50, and 150 mg/kg/day. The No Observed Adverse Effect Leve…
🤰 Pregnancy ▾
8.1Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including SPRAVATO, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ . Risk Summary SPRAVATO is not recommended during pregnancy.
There are insufficient data on SPRAVATO use in pregnant women to draw conclusions about any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on published findings from pregnant animals treated with ketamine, the racemic mixture of arketamine and esketamine, SPRAVATO may cause fetal harm when administered to pregnant women (see Data ) . Advise pregnant women of the potential risk to an infant exposed to SPRAVATO in utero .
There are risks to the mother associated with untreated depression in pregnancy (see Clinical Considerations ). If a woman becomes pregnant while being treated with SPRAVATO, treatment with esketamine should be discontinued and the patient should be counseled about the potential risk to the fetus. Published studies in pregnant primates demonstrate that the administration of drugs that block N -methyl- D -aspartate (NMDA) receptors during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring.
There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans [see Use in Specific Populations (8.2) ] . In an embryo-fetal reproduction study in rabbits, skeletal malformations were noted at maternally toxic doses when ketamine was intranasally administered with a No Observed Adverse Effect Level (NOAEL) at estimated esketamine exposures 0.3 times the exposures at the maximum recommended human dose (MRHD) of 84 mg/day. In addition, intranasal administration of esketamine to pregnant rats during pregnancy and lactation at exposures that were similar to those at the MRHD resulted in a delay in sensorimotor development in pups during the preweaning period and a decrease in motor activity in the post-weaning period.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
Data Animal Data Based on published data, when female monkeys were treated intravenously with racemic ketamine at anesthetic dose levels in the third trimester of pregnancy, neuronal cell death was observed in the brains of their fetuses. This period of brain development translates into the third trimester of human pregnancy. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits.
Racemic ketamine was administered intranasally to pregnant rats during the period of organogenesis at doses of 15, 50, and 150 mg/kg/day. The No Observed Adverse Effect Level (NOAEL) for embryo-fetal toxicity in rats was the highest dose of 150 mg/kg/da…
🧒 Pediatric Use ▾
8.4Pediatric Use The safety and effectiveness of SPRAVATO in pediatric patients have not been established.
🧓 Geriatric Use ▾
8.5Geriatric Use Of the total number of patients in randomized, double-blind, placebo-controlled short-term clinical studies exposed to SPRAVATO, (N=2064), 238 (12%) were 65 years of age and older, and 29 (1%) were 75 years of age and older. No overall differences in the safety profile were observed between patients 65 years of age and older and patients younger than 65 years of age. The mean esketamine C max and AUC values were higher in elderly patients compared with younger adult patients [see Clinical Pharmacology (12.3) ] .
The efficacy of SPRAVATO for the treatment of TRD in geriatric patients was evaluated in a 4-week, randomized, double-blind study comparing flexibly-dosed intranasal SPRAVATO plus a newly initiated oral antidepressant compared to intranasal placebo plus a newly initiated oral antidepressant in patients ≥ 65 years of age. SPRAVATO was initiated at 28 mg twice weekly and could be titrated to 56 mg or 84 mg administered twice weekly. At the end of four weeks, there was no statistically significant difference between groups on the primary efficacy endpoint of change from baseline to Week 4 on the Montgomery-Åsberg Depression Rating Scale (MADRS).
🆘 Overdosage ▾
10 OVERDOSAGE Management of Overdosage There is no specific antidote for esketamine overdose. In the case of overdose, the possibility of multiple drug involvement should be considered. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222 or www.poison.org).
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N -methyl- D -aspartate (NMDA) receptor, an ionotropic glutamate receptor. The mechanism by which esketamine exerts its antidepressant effect is unknown. The major circulating metabolite of esketamine (noresketamine) demonstrated activity at the same receptor with less affinity.
12.2Pharmacodynamics Cardiac Electrophysiology The effect of SPRAVATO (84 mg nasal spray and 0.8 mg/kg esketamine intravenously infused over 40 minutes) on the QTc interval was evaluated in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy subjects. A large increase in heart rate (i.e., >10 bpm) was observed in both intranasal and intravenous esketamine treatment groups. The totality of evidence from the nonclinical and clinical data indicates a lack of clinically relevant QTc prolongation at the therapeutic dose of esketamine.
12.3Pharmacokinetics Esketamine exposure increases with dose from 28 mg to 84 mg. The increase in C max and AUC values was less than dose-proportional between 28 mg and 56 mg or 84 mg, but it was nearly dose proportional between 56 mg and 84 mg. No accumulation of esketamine in plasma was observed following twice a week administration.
Absorption The mean absolute bioavailability is approximately 48% following nasal spray administration. The time to reach maximum esketamine plasma concentration is 20 to 40 minutes after the last nasal spray of a treatment session. The inter-subject variability of esketamine ranges from 27% to 66% for C max and 18% to 45% for AUC ∞ .
The intra-subject variability of esketamine is approximately 15% for C max and 10% for AUC ∞ . Distribution The mean steady-state volume of distribution of esketamine administered by the intravenous route is 709 L. Protein binding of esketamine was approximately 43% to 45%.
The brain-to-plasma ratio of noresketamine is 4- to 6-times lower than that of esketamine. Elimination After C max was reached following intranasal administration, the decline in plasma esketamine concentrations was biphasic, with rapid decline for the initial 2 to 4 hours and a mean terminal half-life (t 1/2 ) that ranged from 7 to 12 hours. The mean clearance of esketamine is approximately 89 L/hour following intravenous administration.
The elimination of the major metabolite, noresketamine, from plasma is slower than esketamine. The decline of noresketamine plasma concentrations is biphasic, with rapid decline for the initial 4 hours and a mean terminal t 1/2 of approximately 8 hours. Metabolism Esketamine is primarily metabolized to noresketamine metabolite via cytochrome P450 (CYP) enzymes CYP2B6 and CYP3A4 and to a lesser extent CYP2C9 and CYP2C19.
Noresketamine is metabolized via CYP-dependent pathways and certain subsequent metabolites undergo glucuronidation. Excretion Less than 1% of a dose of nasal esketamine is excreted as unchanged drug in urine. Following intravenous or oral administration, esketamine-derived metabolites were primarily recovered in urine (≥ 78% of a radiolabeled dose) and to a lesser extent in feces (≤ 2% of a radiolabeled dose).
Specific Populations Exposures of esketamine in specific populations are summarized in Figure 1. No significant differences in the pharmacokinetics of SPRAVATO nasal spray were observed for sex and total body weight (>39 to 170 kg) based on population PK analysis. There is no clinical experience with SPRAVATO nasal spray in patients on renal dialysis or with severe (Child-Pugh class C) hepatic impairment.
Figure 1: Effect of Specific Populations on the Pharmacokinetics of Esketamine Figure 1 Drug Interaction Studies The effect of other drugs on the exposures of intranasally administered esketamine are summarized in Figure 2. The effect of SPRAVATO on the exposures of other drugs are summarized in Figure 3. Based on…
🧬 Mechanism of Action ▾
12.1Mechanism of Action Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N -methyl- D -aspartate (NMDA) receptor, an ionotropic glutamate receptor. The mechanism by which esketamine exerts its antidepressant effect is unknown. The major circulating metabolite of esketamine (noresketamine) demonstrated activity at the same receptor with less affinity.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING SPRAVATO ® nasal spray is available as an aqueous solution of esketamine hydrochloride in a stoppered glass vial within a nasal spray device. Each nasal spray device delivers two sprays containing a total of 28 mg of esketamine (supplied as 32.3 mg of esketamine hydrochloride). SPRAVATO is available in the following presentations: 56 mg Dose Kit: Unit-dose carton containing two 28 mg nasal spray devices (56 mg total dose) (NDC 50458-028-02).
84 mg Dose Kit: Unit-dose carton containing three 28 mg nasal spray devices (84 mg total dose) (NDC 50458-028-03). Within each kit, each 28 mg device is individually packaged in a sealed blister (NDC 50458-028-00). Storage Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] .
Disposal SPRAVATO nasal spray devices must be handled with adequate security, accountability, and proper disposal, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations.
📦 Storage and Handling ▾
Storage Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] .
📋 Description ▾
11 DESCRIPTION SPRAVATO ® contains esketamine hydrochloride, a non-competitive N -methyl- D -aspartate (NMDA) receptor antagonist. Esketamine is the S-enantiomer of racemic ketamine. The chemical name is (S) -2-(o-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride.
Its molecular formula is C 13 H 16 ClNO.HCl and its molecular weight is 274.2. The structural formula is: Esketamine hydrochloride is a white or almost white crystalline powder that is freely soluble in water and in methanol, and soluble in ethanol. SPRAVATO nasal spray is intended for nasal administration.
Esketamine hydrochloride is contained as a solution in a stoppered glass vial within the nasal spray device. Each device delivers two sprays with a total of 32.3 mg of esketamine hydrochloride (equivalent to 28 mg of esketamine) in 0.2 mL of a clear, colorless aqueous solution with a pH of 4.5. The inactive ingredients are citric acid monohydrate, edetate disodium, sodium hydroxide, and water for injection.
Chemical Structure
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Sedation, Dissociation, and Respiratory Depression Inform patients that SPRAVATO has potential to cause sedation, dissociative symptoms (including perception disturbances), dizziness, vertigo, anxiety, and respiratory depression. Advise patients that they will need to be observed by a healthcare provider until these effects resolve [see Boxed Warning , Warnings and Precautions (5.1 , 5.2 , 5.3) ] .
Potential for Abuse, Misuse, and Dependence Advise patients that SPRAVATO is a federally controlled substance because it can be abused or lead to dependence [see Warnings and Precautions (5.4) , Drug Abuse and Dependence (9) ]. SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) SPRAVATO is available only through a restricted program called the SPRAVATO REMS [see Warnings and Precautions (5.5) ] . Inform the patient of the following notable requirements: Patients treated in outpatient healthcare settings (e.g. medical offices and clinics) must be enrolled in the SPRAVATO REMS Program prior to administration.
SPRAVATO must be administered under the direct observation of a healthcare provider. Patients must be monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO . Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted [see Boxed Warning and Warnings and Precautions (5.6) ] .
Increases in Blood Pressure Advise patients that SPRAVATO can cause increases in blood pressure. Inform patients that after treatment sessions they should be advised that they may need to be observed by a healthcare provider until these effects resolve [see Warnings and Precautions (5.7) ] . Impaired Ability to Drive and Operate Machinery Caution patients that SPRAVATO may impair their ability to drive or operate machinery.
Instruct patients not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination such as driving a motor vehicle or operating machinery until the next day after a restful sleep. Advise patients that they will need someone to drive them home after each treatment session [see Warnings and Precautions (5.9) ] . Pregnancy Advise pregnant women and women of reproductive potential of the potential risk to a fetus.
Advise patients to notify their healthcare provider if they are pregnant or intend to become pregnant during treatment with SPRAVATO. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SPRAVATO during pregnancy [see Use in Specific Populations (8.1) ] . Lactation Advise women not to breastfeed during treatment with SPRAVATO [see Use in Specific Populations (8.2) ] .
💬 Medication Guide ▾
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 01/2025 MEDICATION GUIDE SPRAVATO ® (sprah vah toe) (esketamine) nasal spray, CIII What is the most important information I should know about SPRAVATO?
SPRAVATO can cause serious side effects, including: Sedation, dissociation, and respiratory depression . SPRAVATO may cause sleepiness (sedation), fainting, dizziness, spinning sensation, anxiety, or feeling disconnected from yourself, your thoughts, feelings, space and time (dissociation), and breathing problems (respiratory depression and respiratory arrest). Tell your healthcare provider right away if you feel like you cannot stay awake or if you feel like you are going to pass out.
Your healthcare provider must monitor you for serious side effects for at least 2 hours after taking SPRAVATO. Your healthcare provider will decide when you are ready to leave the healthcare setting. Abuse and misuse.
There is a risk for abuse and misuse with SPRAVATO, which may lead to physical and psychological dependence. Your healthcare provider should check you for signs of abuse, misuse, and dependence before and during treatment. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines, or street drugs.
Your healthcare provider can tell you more about the differences between physical and psychological dependence in drug addiction. SPRAVATO Risk Evaluation and Mitigation Strategy (REMS). Because of the risks for sedation, dissociation, respiratory depression, abuse and misuse, SPRAVATO is only available through a restricted program called the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) Program.
SPRAVATO can only be administered at healthcare settings certified in the SPRAVATO REMS Program. Patients treated in outpatient healthcare settings (such as medical offices and clinics) must be enrolled in the program. Increased risk of suicidal thoughts and actions.
Antidepressant medicines may increase suicidal thoughts and actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed . SPRAVATO is not for use in children. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions.
Some people may have a higher risk of having suicidal thoughts and actions. These include people who have (or have a family history of) depression or a history of suicidal thoughts and actions. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
Pay close attention to any changes, especially sudden changes, in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. Tell your healthcare provider right away if you have any new or sudden changes in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Tell your healthcare provider or get emergency help right away if you or your family member have any of the following symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying new or worse depression feeling very agitated or restless trouble sleeping (insomnia) acting aggressive, being angry, or violent an extreme increase in activity and talking (mania) suicide attempts new or worse anxiety panic attacks new or worse irritability acting on dangerous impulses other unusual changes in behavior or mood See “ What are the possible side effects of SPRAVATO? ” for more information about side effects.
What is SPRAVATO? SPRAVATO is a prescription medicine used: with or without an antidepressant taken by mouth, to treat adults with treatment-resistant depression (TRD). with an antidepressant taken by mouth, to treat depressive symptoms in adults with majo…