Ketamine Hcl (ketamine HCl)

Dosage of ketamine hydrochloride is expressed in terms of ketamine.

Ketamine hydrochloride usually is administered by slow (e.g., over 60 seconds) IV injection, IV infusion, or IM injection. Ketamine also has been used in IV patient-controlled analgesia (PCA), either as the sole analgesic or in combination with opioids to improve pain control and reduce opioid-related adverse effects. Ketamine also has been administered by oral+, intranasal+, rectal+, subcutaneous+, and intraosseous (IO)+ routes. Because of extensive first-pass metabolism, the bioavailability of ketamine following oral or rectal administration is limited (approximately 20-30%). Although ketamine has been administered epidurally+ or intrathecally+, there have been concerns about potential neurotoxicity with these routes, and some experts state it may be prudent to avoid neuraxial administration of the drug.

Some experts state that IV administration of ketamine is preferred to IM administration when access can be obtained readily. IM administration is associated with a higher rate of vomiting and longer recovery times compared with IV administration. In addition, IV access can permit convenient administration of additional doses for longer procedures and allow for rapid treatment of adverse effects (e.g., IV benzodiazepines for emergence reactions). In certain patients (e.g., severely agitated or uncooperative patients, young children), IM administration may be preferred.

Store ketamine hydrochloride injection at controlled room temperature between 20-25degreesC (excursions permitted between 15-30degreesC) and protect from light.

Ketamine has been reported to be compatible with several drugs when administered as additives, simultaneously in the same syringe, or when a Y-type administration set is used; specialized references should be consulted for more specific information.

Ketamine principally undergoes N-demethylation to the active metabolite norketamine. N-Demethylation of ketamine to norketamine is mediated principally by cytochrome P-450 (CYP) isoenzyme 2B6 and 3A4 and, to a lesser extent, by other CYP enzymes.

Ketamine, and its active norketamine metabolite, are principally metabolized by CYP3A4 with lesser involvement by CYP2B6 and CYP2C9.

There are no contraindication interactions for this drug.

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

Agents That May Cause Respiratory Depression/Sodium Oxybate

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

MECHANISM OF ACTION: Oxybate by itself may be associated with severe somnolence or respiratory depression. Concurrent use with other CNS depressants may further increase the risk for respiratory depression or loss of consciousness.(1-3)

CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for profound sedation, respiratory depression, coma, and/or death.(1,2) Fatalities have been reported.(3)

PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3)

PATIENT MANAGEMENT: Avoid use of concomitant opioids, benzodiazepines, sedating antidepressants, sedating antipsychotics, general anesthetics, or muscle relaxants, particularly when predisposing risk factors are present. If combination use is required, dose reduction or discontinuation of one or more CNS depressants should be considered. If short term use of an opioid or general anesthetic is required, consider interruption of sodium oxybate treatment.(1,2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)

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)

There are no moderate interactions for this drug.

*Patients in whom substantial blood pressure elevation would constitute a serious hazard.

*Known hypersensitivity to ketamine or any ingredient in the formulation.

*Some experts state that relative contraindications may include history of airway instability, tracheal surgery, or tracheal stenosis; active pulmonary infection or disease; known or suspected cardiovascular disease (e.g., angina, congestive heart failure (CHF), hypertension); CNS masses, abnormalities, or hydrocephalus; elevated intraocular pressure (IOP) (e.g., glaucoma, acute globe injury); and porphyria, hyperthyroidism, or concomitant thyroid replacement therapy.

• Acute decompensated heart failure
• Severe uncontrolled hypertension

• Cardiac decompensation
• Delirium
• Respiratory depression

• Acute cognitive impairment
• Alcohol intoxication
• Alcohol use disorder
• Increased cerebrospinal fluid pressure
• Ocular hypertension

The most common adverse reactions with ketamine are emergence reactions and elevated blood pressure and pulse.

More Frequent

• Hypertension
• Tachycardia

Less Frequent

• Bradycardia
• Hypotension

Rare or Very Rare

• Abnormal hepatic function tests
• Acquired dilation of bile duct
• Acute kidney injury
• Anaphylaxis
• Apnea
• Cardiac arrhythmia
• Cholestasis
• Cholestatic hepatitis
• Cystitis
• Drug-induced hepatitis
• Hematuria
• Hepatic fibrosis
• Hepatocellular damage
• Hydronephrosis
• Increased cerebrospinal fluid pressure
• Laryngismus
• Respiratory depression
• Secondary sclerosing cholangitis
• Urinary tract obstruction
• Viral infection

More Frequent

• Acute cognitive impairment
• Delirium
• Hallucinations
• Tremor

Less Frequent

• Agitation
• Behavioral disorders
• Diplopia
• Dream disorder
• Drowsy
• Erythema
• Hypertonia
• Memory impairment
• Tachypnea
• Vomiting

Rare or Very Rare

• Accidental fall
• Anorexia
• Dysuria
• Increased urinary frequency
• Injection site sequelae
• Muscle spasm
• Nausea
• Nystagmus
• Ocular hypertension
• Skin rash
• Urinary urge incontinence

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Although the manufacturer states that safety and efficacy of ketamine have not been established in patients younger than 16 years of age, the drug has been used widely in pediatric patients+ in a variety of clinical settings for anesthesia, procedural sedation and analgesia, postoperative analgesia, and chronic pain management. Ketamine frequently is used in children to facilitate painful procedures in the emergency department and is considered a drug of choice for this use. Ketamine may be particularly useful in pediatric patients because the drug may be administered IM.

Repeated or prolonged use of general anesthetics and sedation drugs, including ketamine, in children <3 years of age or during the third trimester of pregnancy may adversely affect neurodevelopment. In animals, use of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity leads to widespread neuronal apoptosis in the brain and long-term deficits in cognition and behavior when used for longer than 3 hours; however, the clinical relevance to humans is unknown.

Ketamine may be preferred for induction of anesthesia in children with congenital heart disease with right-to-left shunt+ because of its sympathomimetic effects and hemodynamic stability.

Ketamine generally should not be used in infants younger than 3 months of age because of the potential increased risk of airway complications (e.g., airway obstruction, laryngospasm, apnea) thought to be due to age-specific differences in airway reactivity and anatomy.

There are no adequate and well-controlled studies of ketamine in pregnant women. Although ketamine has been used for induction of anesthesia during vaginal delivery and caesarean sections, the manufacturer states that the drug is not recommended for use during pregnancy or delivery because safety has not been established. Some neonates exposed to ketamine at maternal IV doses of 1.5 mg/kg or higher during delivery have experienced respiratory depression and low Apgar scores requiring resuscitation. Marked increases in maternal blood pressure and uterine tone have been observed following administration of IV ketamine doses greater than 2 mg/kg.

In animal reproduction studies using IM ketamine doses approximately 0.3-0.6 times the usual human IM dose of 10 mg/kg (based on body surface area), developmental delays, skeletal hypoplasia, and increased fetal resorptions were observed.

Based on animal data, repeated or prolonged use of general anesthetics and sedation drugs, including ketamine, during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus. The clinical relevance of these animal findings to humans is not known; the potential risk of adverse neurodevelopmental effects should be considered and discussed with pregnant women undergoing procedures requiring general anesthetics and sedation drugs.

It is not known whether ketamine is distributed into milk. Because the drug should be undetectable in plasma approximately 11 hours after administration, nursing after this time period should not expose the infant to clinically relevant amounts of ketamine.

The manufacturer recommends that dosages in geriatric patients should generally be started on the lower end of the dosing range to accommodate any underlying hepatic, renal, or cardiac dysfunction and any comorbidities or other drug therapy.

While reported clinical experience to date has not revealed age-related differences in response to ketamine when used as an anesthetic agent, clinical studies have not included sufficient numbers of patients >=65 years of age to determine whether geriatric patients respond differently than younger adults. When ketamine is used as an anesthetic agent in geriatric patients, the dosage should be selected carefully, usually starting at the low end of the dosing range, because of the greater frequency of age-related decreases in hepatic, renal, and/or cardiac function, and of concomitant disease or other drug therapy.