Ketamine Nasal Spray

Overview of Ketamine Nasal Spray

Dosage Strength of Ketamine Nasal Spray

100 mg/mL (10 mg/Spray) 15 mL Nasal Spray Bottle

General Information

Ketamine, C13H16ClNO, is a synthetic racemic mixture of R-ketamine and S-ketamine (esketamine).123 Ketamine is a derivative of phencyclidine (PCP) and is considered a DEA Schedule III controlled substance.41

Ketamine was first FDA approved in 1970 under the brand name Ketalar, and is commonly used as an anaesthetic for both pediatric and adult surgical procedures.567

Ketamine is not FDA approved for depression, but esketamine (S-ketamine), the S(+) enantiomer of ketamine, is. In 2019, the FDA approved Spravato (esketamine) nasal spray, in conjunction with an oral antidepressant medication, to treat adults with treatment-resistant depression and depressive symptoms in adults with major depressive disorder (MDD) with suicidal thoughts or actions.8 Esketamine nasal spray is only available with a prescription and through a restricted Risk Evaluation and Mitigation Strategy program that is strictly implemented and monitored by a licensed healthcare provider. Esketamine nasal spray is not FDA approved as an anesthetic agent.9

Mechanism of Action

Ketamine is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist.10 Inhibition of NMDA receptors on GABA neurons results in disinhibition of dopaminergic neurons and therefore increased dopamine release.11

Ketamine is an opioid receptor agonist and an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activator.12 It is a transport inhibitor of the D-serine receptor and an HCN1 receptor inhibitor.131415

Ketamine increases the number of serotonin 1B receptors.16 It is an uptake inhibitor of norepinephrine, serotonin, and Dopamine receptors.13

Ketamine may increase levels of brain-derived neurotrophic factor (BDNF) via synaptogenesis that occurs through increased glutamate levels.14

Pharmacokinetics

Ketamine is hydrophilic and lipophilic, which allows for a diverse range of administration routes.17 Ketamine can be administered orally, intravenously (IV), intramuscularly, rectally, sublingually, and intranasally.18192021 It’s lipophilic nature allows it to readily cross the blood-brain barrier.22

Intranasal esketamine bioavailability is approximately 48%. After nasal administration, plasma levels of esketamine peak in about 40 minutes.232425

Esketamine is metabolized primarily to noresketamine. It is also metabolized to dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites.23 Esketamine metabolism is driven by hepatic microsomal enzymes, cytochrome P450 (CYP)2B6 and CYP3A4.1726

Esketamine has a biphasic half-life. A rapid decline occurs in the initial two to four hours after administration, and its terminal half-life is between seven and 12 hours.23

Indications

Esketamine nasal spray must be administered under the supervision of a healthcare provider in a certified doctor’s office or clinic. However, it is self-administered by the patient. It is indicated for use in conjunction with an oral antidepressant medication.8

The dosage of ketamine will depend on the efficacy and tolerability for each patient. The recommended dosage for esketamine nasal spray is 56 mg the first day. For the first four weeks of treatment, 56 mg or 84 mg are administered twice weekly. During weeks five through eight, 56 mg or 84 mg are administered once weekly. This may vary depending on each patient. Week nine and beyond, esketamine nasal spray should be administered weekly or every two weeks--the least frequent dosing needed in order to maintain response and/or remission.9

If you miss a treatment session, contact your doctor right away to schedule a new appointment. If you miss a treatment and if your depression becomes worse, your doctor may need to adjust your dose and/or treatment schedule.

Patients should not drive or operate heavy machinery until the following day, after a night of restful sleep.8

Esketamine nasal spray may cause nausea and/or vomiting. Patients should avoid eating two hours before administration and should avoid drinking liquids 30 minutes before administration.9

Patients who require the use of nasal corticosteroid or decongestant should administer these medications at least one hour before administering esketamine nasal spray.9

Contraindications / Precautions

Ketamine is identified as a Schedule III controlled substance under the Controlled Substances Act and therefore has a low to moderate risk of psychological and physical dependence.927 Physicians should carefully analyze an individuals risk of substance dependency, including alcohol, before prescribing and administering intranasal ketamine and should continuously monitor patients for signs of psychological and physical dependence throughout the treatment course.

Ketamine is contraindicated in patients with schizophrenia. Ketamine may increase symptoms of psychosis and may exacerbate the symptoms of schizophrenia.14

Intranasal ketamine is contraindicated for patients with severe hepatic impairment.23

Esketamine nasal spray causes a temporary increase of blood pressure and is therefore contraindicated in patients with hypertension. Esketamine nasal spray is contraindicated in patients with conditions that, with an increase in blood pressure, pose a serious health risk, including aneurysmal vascular disease, history of intracerebral hemorrhage, and arteriovenous malformation).828299

Ketamine is a controlled substance that has the potential for dependence (physical and psychological) and abuse.41 Patients with a history of drug and/or alcohol abuse should not use ketamine. Physicians should assess patients for the risk of abuse and misuse before prescribing esketamine nasal spray. Physicians should monitor patients for signs of abuse throughout the treatment program.

Esketamine nasal spray is not for use in children. Patients who are allergic to ketamine, esketamine, or any of the excipients should not take esketamine nasal spray. Patients should avoid the use of alcohol with ketamine.9

Pregnancy / Breastfeeding

Ketamine use during pregnancy can harm the fetus. One study noted the effects of ketamine on a newborn baby whose mother was suspected of continuing to abuse ketamine during pregnancy. Researchers found high levels of ketamine in the newborn’s hair and observed low birth weight, general hypotonia, moderate cerebral dysfunction, intrauterine growth retardation, and poor reflex responses in the newborn.30 A study conducted on rats showed that ketamine administered to pregnant rats impaired neuronal development in pups (offspring).31 Women who are planning a pregnancy or who are pregnant should not take esketamine nasal spray.9 Women who are breastfeeding should not take ketamine.8

Interactions

The use of intranasal esketamine in conjunction with psychostimulants monoamine oxidase inhibitors (MAOIs) may increase blood pressure.23 Physicians should closely monitor blood pressure in patients who are taking psychostimulants, including amphetamines, methylphenidate, stimulant weight-loss medications, modafanil, and armodafinil, as well as patients taking MAOIs including tranylcypromine, phenelzine, isocarboxazid, and selegiline.932

Intranasal esketamine may increase the sedative effects of central nervous system (CNS) depressants. Physicians should closely monitor for sedation in patients who are taking CNS depressants, including benzodiazepines, opioids, and alcohol.923

Benzodiazepines may reduce the antidepressant effect of ketamine.26

Adverse Reactions / Side Effects

The most common symptoms associated with esketamine nasal spray include dizziness, nausea, sedation, lethargy, disassociation, vertigo, hypoesthesia, anxiety, increased blood pressure, vomiting, and feeling drunk.89 Physicians should closely monitor patients for at least two hours following administration.

Ketamine increases blood pressure and heart rate.733 Physicians should monitor blood pressure before administration and for at least two hours following administration.

In some cases, antidepressant agents increase the risk of suicidal thoughts and actions in young adults, especially during the initial treatment period. Esketamine nasal spray may increase suicidal thoughts and actions, especially in patients with a history (or family history) of depression.349 Physicians should closely monitor patients for worsening of depressive symptoms.

Ketamine is a controlled substance that has the potential for dependence (physical and psychological) and abuse.1 Physicians should assess patients for the risk of abuse and misuse before prescribing esketamine nasal spray. Physicians should monitor patients for signs of abuse throughout the treatment program.

This is not an all inclusive list of the side effects of esketamine nasal spray. Side effects are typically felt shortly after administering esketamine nasal spray and generally resolve the same day.

Chronic misuse of ketamine has been associated with impaired cognitive processing speed, verbal fluency, verbal learning, verbal memory, and visual recognition memory.35

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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