Spravato (esketamine HCl)

Dosage of esketamine hydrochloride is expressed in terms of esketamine.

Esketamine hydrochloride is administered intranasally using a nasal spray device. The drug is intended for patient self-administration under the direct supervision of a healthcare provider. A treatment session consists of intranasal administration of esketamine and post-administration observation under supervision. Patients should be instructed on use of the nasal spray device and advised to read the patient instructions for use provided by the manufacturer. Following administration of each dose, patients must be monitored at the healthcare facility by a provider for at least 2 hours and then assessed for clinical stability and readiness to be discharged. Patients should not drive after the treatment session.

Esketamine nasal solution is commercially available in kits containing either 2 (56-mg dose kit) or 3 (84-mg dose kit) stoppered glass vials within a nasal spray device. Each nasal spray device delivers a total of 28 mg of esketamine and delivers 2 sprays containing 14 mg of esketamine per spray. Two devices should be used for a 56-mg dose and 3 devices should be used for an 84-mg dose. An indicator on the device displays one green dot for each spray remaining in the device. Prior to administration of esketamine nasal spray, a healthcare provider should confirm the number of nasal spray devices required for the dose and check that each device indicator displays 2 green dots. To prevent loss of the drug, esketamine nasal spray devices should not be primed before use.

Patients should be instructed to blow the nose to clear the nasal passages before the initial spray from the first device at each treatment session. During administration, patients should recline their head to about 45 degrees to help keep the solution inside the nose.

The patient should insert the tip of the device straight into one nostril; the nose rest should touch the skin between the nostrils. While holding the other nostril closed, the patient should concurrently inspire through the nose while pushing on the plunger to activate the spray. The patient should then sniff gently to keep the solution in the nose. This procedure should be repeated for the other nostril.

The procedure should then be repeated for each device until the full dose of esketamine nasal spray has been administered. Following administration of esketamine in each device (i.e., 2 sprays), the patient should rest in a comfortable position (preferably semi-reclined) for 5 minutes to allow the drug to be absorbed. Following use, each device should be checked by the healthcare provider to ensure that both sprays have been delivered; if a green dot appears in the device indicator, the patient should spray again into the second nostril. If liquid drips out of the nostril, the nose should be dabbed with a tissue.

Following use, esketamine nasal spray devices must be handled with adequate security and accountability, and disposal must be in accordance with the facility's procedures and federal, state, and local regulations for C-III drug products.

Store esketamine nasal spray at 20--25degreesC; excursions permitted from 15-30degreesC.

During and following administration of esketamine nasal spray at each treatment session, patients must be observed (i.e., for sedation, dissociation, respiratory status, and increased blood pressure). Patient observation should continue for at least 2 hours until the patient can safely leave the healthcare setting.

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Esketamine is metabolized principally by cytochrome P-450 (CYP) isoenzymes 2B6 and 3A4 and, to a lesser extent, by CYP2C9 and CYP2C19. The drug's major active metabolite, noresketamine, also is metabolized via CYP-mediated pathways.

In vitro, esketamine is a modest inducer of CYP2B6 and CYP3A4 and noresketamine weakly and reversibly inhibits CYP3A4. Esketamine and its major metabolites are unlikely to substantially inhibit other CYP isoenzymes or uridine diphosphate-glucuronosyltransferases (UGTs). Esketamine and its major metabolites do not induce CYP1A2 in vitro.

Esketamine is not a substrate for P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1, or OATP1B3 in vitro. The drug and its principal metabolites do not inhibit P-gp, BCRP, OATP1B1, OATP1B3, multidrug and toxin extrusion transporter (MATE) 1, MATE2K, organic cation transporter (OCT) 2, organic anion transporter (OAT) 1, or OAT3.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

N-Methyl-D-Aspartate (NMDA) Antagonists/Memantine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: N-methyl-D-aspartate (NMDA) antagonists act at the same receptor system as does memantine.(1,2)

CLINICAL EFFECTS: Concurrent use may result in more frequent and more pronounced side effects, especially CNS-related effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of memantine states that the concurrent use of memantine with N-methyl-D-aspartate (NMDA) antagonists such as amantadine or ketamine should be avoided.(1) The US manufacturer of memantine states that concurrent use should be approached with caution.(2)

DISCUSSION: Because N-methyl-D-aspartate (NMDA) antagonists act at the same receptor system as does memantine, concurrent use may result in more frequent and more pronounced side effects, especially CNS-related effects. Therefore, the UK manufacturer of memantine states that the concurrent use of memantine with NMDA antagonists such as amantadine or ketamine should be avoided.(1) The US manufacturer of memantine states that concurrent use should be approached with caution.(2) In a study in 52 healthy subjects, concurrent memantine (20 mg daily) and dextromethorphan/quinidine (30/30 mg daily) resulted in no changes in dextromethorphan or memantine levels. There was a slight increase in dizziness as measured by the dizziness visual analog scale (VAS) when compared to memantine alone but not the combination of dextromethorphan/quinidine alone. For other pharmacodynamic assessments, there was either no effect or improvement on some subscales.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Selected Sensitive Cyp2b6 Substrates/Lemborexant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lemborexant may induce the metabolism of CYP2B6 substrates.(1)

CLINICAL EFFECTS: Concurrent lemborexant may result in decreased levels of sensitive CYP2B6 substrates, which may result in a decrease in or failure of clinical response.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of lemborexant recommends close monitoring of patients who receive lemborexant with CYP2B6 substrates. Monitor patients receiving concurrent lemborexant for an adequate clinical response. The dosage of the CYP2B6 substrate may need to be adjusted.(1,2) An alternative agent may need to be selected.

DISCUSSION: In a study, lemborexant (10 mg dose) decreased the concentration maximum (Cmax) and area-under-curve (AUC) of a S-bupropion by 49.9% and 45.5%, respectively.(1) Sensitive CYP2B6 substrates linked to this monograph include: bupropion and esketamine.(3,4)

Selected Sensitive Cyp2b6 Substrates/Midostaurin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Midostaurin may induce the metabolism of CYP2B6 substrates.(1)

CLINICAL EFFECTS: Concurrent midostaurin may result in decreased levels of sensitive CYP2B6 substrates, which may result in a decrease in clinical response.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent midostaurin for an adequate clinical response. The dosage of the CYP2B6 substrate may need to be adjusted.(1,2) An alternative agent may need to be selected.

DISCUSSION: In a study, multiple doses of midostaurin (50 mg twice daily) decreased the area-under-curve (AUC) of a single dose of bupropion by 48% and of bupropion's metabolite, hydroxybupropion by 65%.(1) Sensitive CYP2B6 substrates linked to this monograph include: bupropion and esketamine.(3,4)

*Aneursymal vascular disease (including that affecting the thoracic and abdominal aorta and intracranial and peripheral arterial vessels) or arteriovenous malformation.

*History of intracerebral hemorrhage.

*Hypersensitivity to esketamine, ketamine, or any excipient in the formulation.

• Arterial aneurysm
• Arteriovenous malformation
• Intracerebral hemorrhage
• Lactation

• Acute myocardial infarction
• Cardiac arrhythmia
• Chronic heart failure
• Drug abuse
• History of drug abuse
• Hypertension
• Hyperthyroidism
• Intracranial hypertension
• Pregnancy
• Suicidal ideation
• Valvular heart disease

• Child-pugh class B hepatic impairment
• Disease of liver
• Psychotic disorder

Adverse effects reported in at least 5% of patients with treatment-resistant depression receiving intranasal esketamine and at an incidence at least twice that of placebo include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, vomiting, drunk feeling, and headache.

Adverse effects reported in at least 5% of patients (and at least twice that of placebo) with major depressive disorder receiving esketamine for the treatment of depressive symptoms with acute suicidal ideation or behavior include dissociation, dizziness, sedation, increased blood pressure, hypoesthesia, vomiting, euphoric mood, and vertigo.

More Frequent

• Depersonalization
• Dissociation
• Hypertension

Rare or Very Rare

• Cystitis
• Respiratory depression
• Suicidal ideation
• Unconsciousness

More Frequent

• Acute cognitive impairment
• Dizziness
• Feeling of alcohol intoxication
• Hypoesthesia
• Lethargy
• Nausea
• Sedation
• Symptoms of anxiety
• Vertigo
• Vomiting

Less Frequent

• Altered mental status
• Constipation
• Diarrhea
• Dysarthria
• Dysgeusia
• Dysuria
• Euphoria
• Headache disorder
• Hyperhidrosis
• Increased urinary frequency
• Insomnia
• Muscle weakness
• Nasal pain
• Pain in oropharynx
• Pharyngitis
• Tachycardia
• Tremor
• Urinary urgency
• Xerostomia

Rare or Very Rare

• Accidental fall
• Hypotension
• Panic disorder
• Sialorrhea

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Safety and efficacy of esketamine nasal spray have not been established in pediatric patients.

Increased risk of suicidality has been observed in children and adolescents receiving antidepressants for major depressive disorder and other indications in short-term studies.

Results of animal studies indicate that repeated or prolonged use of drugs that block NMDA receptors, including ketamine and esketamine, in children younger than approximately 3 years of age potentially may adversely affect brain development. The clinical relevance of these findings to humans treated with esketamine nasal solution at the recommended clinical dosage is not known.

Data on esketamine use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, based on published findings from pregnant animals exposed to ketamine, esketamine may cause fetal harm. Esketamine is not recommended for use during pregnancy. If a patient becomes pregnant while being treated with esketamine, treatment with esketamine should be discontinued and the patient should be counseled on the potential risk to the fetus.

In an embryo-fetal reproduction study in rabbits, skeletal malformations were noted at maternally toxic doses when esketamine was intranasally administered with a NOAEL at estimated esketamine exposures 0.3 times the exposures at the MRHD of 84 mg/day. Intranasal administration of esketamine to rats during pregnancy and lactation at exposures similar to the MRHD resulted in a delay in sensorimotor development in pups during the pre-weaning period and a decrease in motor activity in the post-weaning period.

A pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to antidepressants, including esketamine. For more information, patients or their clinicians may contact the National Pregnancy Registry for Antidepressants at 844-405-6185 or visit https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregi stry/antidepressants/.

Esketamine is distributed into milk in humans. It is not known if the drug has any effect on the nursing infant or on milk production.

Studies in juvenile animals demonstrate that administration of drugs that block NMDA receptors (including ketamine) during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. The window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend to approximately 3 years of age in humans.

Because of the potential for neurotoxicity in nursing infants, the manufacturer states that breast-feeding during esketamine therapy is not recommended.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In short-term trials in the clinical development program for esketamine nasal spray in treatment-resistant depression, 12% of patients were 65 years of age or older and 1% were 75 years of age or older. No overall differences in the safety profile of esketamine were observed between geriatric patients and younger adults.

Higher peak plasma concentrations and systemic exposure of esketamine have been observed in geriatric patients compared with younger adults.

In a double-blind, placebo-controlled trial of 4 weeks' duration in patients 65 years of age or older with treatment-resistant depression, a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) total score was observed with esketamine treatment (initial dosage of 28 mg intranasally twice weekly then titrated to 56 or 84 mg twice weekly) in conjunction with a newly initiated oral antidepressant at the end of 4 weeks. However, the difference in the reduction in the MADRS total score between the esketamine and placebo groups did not achieve statistical significance in this study.