VA CFU Criteria Formulary Advisor Reference
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KETAMINE INJ,SOLN

Generic Name
KETAMINE INJ
Brand Names
KETALAR, KETAMINE HCL, KETAMINE HCL-0.9% NACL, KETAMINE HCL-NACL, KETAMINE HCL-WATER
Drug Class
GENERAL ANESTHETICS,OTHER
Formulary Status
Y
Copay Tier
N/A
Last Updated
2017-02-27

Clinical Criteria Summary

Document 411

Indication & Patient Population

  • Veterans with intractable/treatment-resistant neuropathic pain or Complex Regional Pain Syndrome (CRPS), centralized pain disorder
  • Must be under care of VHA Pain Specialists or Pain Management Teams (not VA Community Care)
  • Must be part of a comprehensive, multi-modal pain care plan

Inclusion Criteria

  • Failed adequate trials (unless contraindicated) of TCAs (amitriptylline, desipramine, nortriptyline), SNRIs (venlafaxine, duloxetine), and alpha-2-delta calcium channel blockers (gabapentin, pregabalin)
  • Evaluated and qualified by a pain management or interventional pain specialist with documented reasoning in the medical record
  • Cleared of mental health contraindications by a Mental Health Pain Provider with documentation in the medical record
  • Verbal informed consent provided by patient or legal representative
  • Adult accompaniment for transportation arranged, or safe transport method documented

Exclusion Criteria

  • Current or past history of schizophrenia, schizoaffective disorder, bipolar disorder, or decompensated psychiatric disorder
  • Dementia
  • Current or recent (within 7 days) delirium
  • Current uncontrolled hypertension (SBP >160 mm Hg or DBP >90 mm Hg)
  • Conditions where increased blood pressure would be hazardous
  • Severe cardiac decompensation
  • Myocardial ischemia/angina, recent MI (within 3 months)
  • Pregnant (positive test) or lack of birth control in women of childbearing potential
  • Positive urine drug screen or current/previous abuse of ketamine (patients prescribed opioids/benzodiazepines/barbiturates by VHA are eligible; acute intoxication/detoxification requires exclusion until addressed)
  • Allergy or previous serious adverse effects to ketamine
  • Recent infection or illness
  • Psychosis or decompensated psychiatric condition
  • Ketamine-related cystitis
  • Illicit drug use (cocaine, methamphetamine, marijuana)
  • Morbid obesity with BMI > 40
  • End-stage renal or hepatic disease
  • DM2 with HbA1c > 9.0 (unless demonstrated improvement in diabetic control per recent 2-week glucose diary)
  • Pulmonary HTN (mod-severe)

Screening & Pre-treatment Requirements

  • Screening completed no more than 30 days prior to first dose
  • Includes verbal informed consent, inclusion/exclusion criteria review, physical exam with vitals (BP, HR, RR, SpO2, weight), relevant labs, urine toxicology, and pregnancy screen
  • SBP >150 mm Hg or DBP >95 mm Hg at screening indicates higher risk; hypertension must be adequately treated prior to infusion
  • Cardiopulmonary/cerebrovascular disease, recent MI, symptomatic ischemic heart disease, dyspnea/wheezing, poor exercise capacity (<6 METs), or conditions increasing risk of acute cardiac demand/BP/respiratory depression require individual case-by-case risk/benefit consideration
  • Baseline HR <60 or >100 bpm requires case-by-case risk assessment
  • SpO2 at screening must be >94% after mild exertion
  • Other labs/screening determined per individual risk factors by prescribing psychiatrist
  • Medical clearance from PCP or specialist consults based on risk factors (prescribing provider responsibility)
  • History of substance abuse, alcohol use, smoking, medication misuse, positive UDS considered; length of sobriety factored in
  • Concurrent barbiturates/opioids/Scheduled meds may delay recovery; wean opioids as much as possible prior due to respiratory depression risk with benzodiazepine coadministration

Administration & Monitoring Requirements

  • Facility identifies private/semi-private location large enough for patient and personnel
  • Setting must provide immediate care capability with crash cart readily accessible
  • Must monitor cardiovascular (ECG, BP) and respiratory (SpO2, end-tidal CO2) functions
  • Capable of administering oxygen, medication, restraints for behavioral symptoms
  • Plan for rapid response to sustained CV alterations (ACLS or transfer)
  • High-risk patients treated at facilities equipped/staffed for CV/respiratory events
  • Infusion ordered by pain management/interventional pain specialist
  • Pre-medication/concurrent meds (e.g., IV lorazepam) ordered to prevent/manage adverse effects
  • ACLS-certified pain physician or anesthesiologist present at initiation, intermittently during, and at end; ACLS-certified nurse present during infusion
  • Ordering provider leaves after completion if stable; must return at end to evaluate and clear for discharge; ACLS provider remains until discharge

Dosing & Infusion Protocol

  • Dose: 0.5 mg/kg IV infusion over 4 hours using an infusion pump
  • For BMI >30 kg/m2, calculate dose using ideal body weight (Men = 50 kg + [2.3 kg x each inch >5 feet]; Women = 45.5 kg + [2.3 kg x each inch >5 feet])
  • T-2 days or sooner: UDS and pregnancy tests collected, meds reviewed, consent obtained
  • T-60 min: IV line started, vitals (sitting/standing BP, sitting/standing pulse, RR, SpO2) taken, BPI baseline administered
  • T-0 min: Administer ketamine if vitals acceptable and screens negative
  • T+10, 20, 30, 40, 80, 110 min: Vitals and cognitive status check as indicated
  • T+240 min: Vitals, Pain NRS (or other pain scale)

Parameters for Stopping Infusion

  • BP must remain <180 mm Hg systolic and <110 mm Hg diastolic at all times
  • SBP drop >10 mm Hg accompanied by increased HR or distress requires stopping
  • HR must remain below age-adjusted max: 20 yrs <140 bpm, 30 yrs <133, 40 yrs <126, 50 yrs <119, 60 yrs <112; for ≥65 yrs, individualize based on exercise capacity/risk factors
  • Stop for: pallor/cyanosis/poor perfusion symptoms; respiratory symptoms (SOB, wheezing); chest/jaw/arm pain suggesting cardiac involvement; patient's desire to stop

Repeat Schedules & Discontinuation Criteria

  • May be repeated daily for up to 4 hours and up to 5 days (excluding weekends) per pain physician discretion based on response
  • "Booster" sessions may be given no more frequently than every 3 months, individualized
  • Alternative: Every other day x 3 days (M-W-F) for 1-2 weeks; failure to respond results in discontinuation
  • Taper and discontinue in interest of safety; time frame undefined/individualized
  • Discontinue if patient wishes for any reason
  • Discontinue if infusion stopped >1 time due to exceeding BP or HR thresholds
  • Discontinue after 4 to 6 infusions without adequate response (defined as ≥50% decline in NRS pain score from baseline)
  • Discontinue when dosing cannot be spaced to minimum of 1 dose per week by second month of treatment

Outcomes Monitoring

  • Monitor at baseline, 1-2 weeks post-infusion, and monthly
  • Track: Brief Pain Inventory (BPI), number/dosing regimens of opioid (MEDD) and non-opioid pain meds

Document 438

Indication & Purpose

  • Treatment of acute behavioral agitation in VHA Emergency Departments (ED) and Urgent Care Centers (UCC).
  • Indicated for non-procedural sedation.

Patient Selection (Inclusion Criteria)

  • Patients who are extremely combative and at immediate risk of causing physical harm to medical staff, the public, or themselves.
  • Patients who have failed de-escalation techniques and one or more rapid tranquilization medications (e.g., benzodiazepines, droperidol, haloperidol, olanzapine, ziprasidone).
  • Ketamine is determined to be a preferred first-line agent.

Contraindications

  • Hypersensitivity to ketamine or any excipient.

Precautions

  • Active psychosis.
  • Pregnancy.
  • Elevated intracranial or intraocular pressure.
  • Severe cardiovascular disease: acute coronary syndrome, decompensated heart failure, severe valvular disease, active cardiac dysthymias.
  • Pulmonary hypertension.
  • Severe hepatic dysfunction.

Dosing & Pharmacokinetics

  • Intramuscular dosing: 1-3 mg/kg (Ideal Body Weight).
  • If administered shortly after another sedating agent, dose at the lower end of the range.
  • Onset: 5 minutes.
  • Duration: Up to 60 minutes.
  • Half-life: 2 to 3 hours.
  • IM ketamine may have significant variation in clinical effect between individuals; caution advised.

Administration, Monitoring & Personnel Requirements

  • Facilities must develop and operationalize a procedure for administering IM ketamine in the ED/UCC.
  • Facility is responsible for monitoring the patient during and after injection(s).
  • Must be capable of administering oxygen, medication, and/or restraints to manage potentially dangerous behavioral symptoms.
  • Bag Mask Valve (BVM) device and airway rescue equipment must be immediately available.
  • Plan required to rapidly address sustained alterations in cardiovascular function, including advanced cardiac life support or transfer to a hospital capable of acute cardiovascular care.
  • A Licensed Independent Practitioner (LIP) with at least Out of Operating Room Airway Management (OOORAM) Level 2 privileges must be immediately available at the bedside.
  • Patient must be directly observed by clinical staff for at least 30 minutes after receiving IM ketamine.
  • Non-invasive blood pressure monitoring, cardiac monitoring, continuous pulse oximetry, and respiratory rate monitoring recommended as practical.
  • ED/UCC LIP responsible for ensuring patient appropriateness, documenting risk/benefits/alternatives in the medical record.
  • ED/UCC RN may administer under an appropriate order from an ED/UCC LIP per state licensure requirements.
  • Facilities must participate in ongoing VA MedSAFE Medication Use Evaluation (MUE).

Exclusions

  • Does not apply to deep sedation, acute pain management outside of sedation, securing an endotracheal airway (e.g., rapid sequence intubation), or care of mechanically ventilated patients.

Document 439

Indication

  • Acute pain
  • Intractable pain
  • Clinically indicated when conventional modes of treatment have failed or ketamine is determined to be a more suitable agent
  • Opioid-tolerant patients as an adjunct to opioid therapy for acute pain
  • Patients on partial opioid or opioid antagonist therapy with acute tissue trauma related pain

Contraindications

  • Hypersensitivity to ketamine or any excipient

Precautions & Warnings

  • Active or history of psychosis
  • Patients for whom significant elevations in blood pressure would constitute a serious hazard
  • Myocardial ischemia
  • Pregnancy or lactation
  • Consider IVPB and lower dosing for older patients or patients with comorbidities to mitigate adverse effects

Dosing & Administration

  • Intravenous (IV)
  • Initial dose: 0.1 to 0.3 mg/kg Ideal Body Weight (IBW)
  • Administer via IVPB over 10-15 minutes (preferred) or slow IV push over 5 minutes
  • Maximum single dose: 30 mg
  • IV Compatibility: Dextrose 5% in Water (D5W), Normal Saline (NS), or Sterile Water for Injection
  • Additional dosing: Repeat IV dose via IVPB/slow IV push OR start continuous infusion at 0.15 to 0.2 mg/kg/hr
  • Titrate every 30 minutes until pain is relieved
  • Total dose should not exceed 1 mg/kg IBW
  • Intramuscular (IM) (when IV access not available)
  • Initial dose: 0.35 to 0.7 mg/kg IM
  • Additional dosing: Repeat IM dose OR, if IV access established, repeat via IV dosing OR start continuous infusion at 0.15 to 0.2 mg/kg/hr
  • Titrate every 30 minutes until pain is relieved
  • Total dose should not exceed 1 mg/kg IBW

Monitoring, Equipment, & Personnel Requirements

  • Bag Mask Valve (BVM) device must be available immediately at the bedside
  • Licensed Independent Practitioner (LIP) with Out of Operating Room Airway Management (OOORAM) privileges must be available in ED/UC to immediately respond to the bedside
  • Monitoring recommended during and for at least 15 minutes after administration: non-invasive blood pressure, cardiac monitoring, continuous pulse oximetry, respiratory rate
  • LIP responsible for ensuring patient appropriateness, obtaining informed consent, and attending to patient in event of adverse effect
  • RN responsible for patient monitoring activities and may administer medication under appropriate order from ED/UCC LIP consistent with applicable state licensure requirements

Adverse Effects (at Sub-Dissociative Doses)

  • Common: dizziness, sedation, sense of unreality, nausea
  • Rare: excess sedation, respiratory compromise
  • Adverse effects requiring additional management were rare in adults in ED SDK clinical trials; dizziness and perceptual changes attenuated with 15-minute infusion vs IV push

Scope & Exclusions

  • Does not apply to deep sedation, securing an endotracheal airway (e.g., rapid sequence intubation), or care of mechanically ventilated patients
  • Facilities may exercise flexibility to modify protocol as necessary to operationalize parenteral (IV or IM) ketamine for treating acute pain

Document 643

Indication & Patient Population

  • Management of treatment-refractory pain (nociceptive, neuropathic) when first-line therapies fail or are contraindicated.
  • For non-sedation purposes in VHA Hospice or Palliative Care under the care or direction of a palliative care team (or locally identified expert).
  • Applicable for inpatient or Community Living Center (CLC) settings.

Contraindications

  • Hypersensitivity to ketamine or any excipient.

Precautions

  • Active psychosis, delirium, or inability to report side effects.
  • Patients for whom significant elevations in blood pressure would constitute a serious hazard.
  • Patients with or at risk of increased intracranial pressure.
  • Unstable cardiovascular disease.
  • Consider lower dosing for older patients or patients with comorbidities to mitigate adverse effects.

Dosing & Administration

  • Continuous Infusion: Initial dose 0.1 to 0.2 mg/kg/hr of Ideal Body Weight (IBW) via continuous IV or SQ infusion. Titrate no sooner than every 12 hours; max titration increment 0.1 mg/kg/hr. Recommended maximum dose 0.5 mg/kg/hr IBW. Duration typically ranges from 1 to 5 days; consider titrating to effect/max tolerated dose and continuing for an additional 48 hours, then discontinue.
  • IVPB or SQ Bolus: Initial dose 0.1 to 0.3 mg/kg (IVPB administered over 30 minutes). Additional doses may be repeated if effective or converted to alternate route; frequency not to exceed q8hr dosing. May increase dose up to 0.5 mg/kg; maximum total daily dose not to exceed 1 mg/kg IBW.
  • Oral Administration: Test/initial dose 10 mg PO once, then 5-10 mg PO q8h based on response. Initial titration 5 to 10 mg per dose per 24 hours. Maximum dose 400 mg/day (e.g., 100 mg q6h). Parenteral to oral conversion: Calculate total 24-hour parenteral dose and replace at 2/3rds of that amount.
  • Consider using actual body weight if less than IBW to calculate dose.

Monitoring Requirements

  • Check vital signs, pain, affect, and psychomimetic adverse effects at baseline, at 1 hour after infusion starts or first dose/dose increase, then with each shift change.
  • Repeat initial monitoring process after each dose change.
  • Palliative care team may adjust monitoring as needed if vital signs assessment is not consistent with patient goals.
  • Alert provider if: Systolic BP change > 20 mmHg or HR change < or > 20 beats/min; Respiratory rate < 12 breaths/min or persistent shallow breathing/apnea; O2 saturation <90% or RASS score -2 or below.

Adverse Effects & Management

  • Common: Dizziness, sedation, sense of unreality, nausea. Manage with lower doses or slower routes; educate patient to report bothersome effects.
  • Uncommon: Increase in blood pressure.
  • Rare: Excess sedation, respiratory compromise.
  • Psychomimetic side effects: Add benzodiazepine or haloperidol (lorazepam commonly used) and decrease ketamine dose to previously tolerated dose.
  • Increased secretions/lacrimation/salivation: Manage with anticholinergic agent (glycopyrrolate, atropine ophthalmic drops, or scopolamine patch).
  • Discontinuation/Withdrawal: Hyperalgesia and allodynia reported after abrupt discontinuation after 3 weeks. If used >10 days, safely taper over 48-72 hours. Monitor for withdrawal signs including nausea, dizziness, diarrhea, depression, anxiety, and schizophrenic-type behaviors.

Additional Clinical Considerations & Scope

  • Consider decreasing opioids by 15-50% at initiation due to opioid-sparing effect; may need to continue taper if excessive respiratory depression or hemodynamic instability occur.
  • IV formulation may be drawn up directly for oral administration but is very bitter; administer with sweet liquid (e.g., fruit juice, cola).
  • Does not apply to primary sedation, securing an endotracheal airway (e.g., rapid sequence intubation), mechanically ventilated patients, topical-oral ketamine for mucositis, or outpatient oral use.
  • Dosing, duration, and route flexibility allowed per facility operational needs; must be individualized under guidance of providers experienced in palliative and hospice medicine.

Document 789

Indications & Patient Selection

  • Treatment for treatment-resistant major depressive disorder (TRD) or severe suicidal ideation
  • Meets one of the following:
  • Remission not achieved from 2 antidepressant trials (including an augmentation strategy) in the current episode of depression AND 4 total adequate antidepressant trials in the patient’s lifetime
  • Hospitalized with TRD with acute suicidal ideation/behavior
  • Must meet ALL additional criteria:
  • Moderate to severe depressive symptomatology (PHQ-9 > 15 within the last 30 days)
  • Antidepressant trials considered unsuccessful if no response to at least 6 weeks of an antidepressant at half maximum dose or greater
  • Evaluated and documented by a VA psychiatrist or VA licensed Mental Health care provider (CPP, NP, PA) as qualifying for ketamine treatment
  • Signed informed consent from patient or legal representative
  • Agreement to remain monitored post-administration, refrain from driving/operating machinery, and avoid making major financial/legal decisions for the remainder of the day
  • Adult accompaniment for transportation OR documented safe transport method arranged
  • For women of childbearing potential: Pregnancy excluded prior to administration; provided contraceptive counseling on risks vs. benefits

Exclusion Criteria

  • Current or history of schizophrenia, schizoaffective disorder, or bipolar disorder
  • Dementia
  • Current or recent (within 30 days) delirium
  • Current uncontrolled hypertension (SBP >140 mm Hg or DBP >90 mm Hg)
  • Severe cardiac decompensation (Class IV heart failure or unstable angina)
  • Severe hepatic impairment (Child-Pugh class C)
  • Uncontrolled seizures
  • History of non-response to ketamine or esketamine
  • Pregnant (positive pregnancy test) or lack of birth control method in women of childbearing potential
  • Breastfeeding
  • Current or previous abuse of ketamine or esketamine
  • Clinical evidence for current substance misuse (except tobacco)
  • Current moderate or severe substance use disorder (SUD)
  • Allergy or previous serious adverse effects to ketamine or esketamine

Screening & Referral Requirements

  • Screening completed no more than 60 days prior to first dose acceptance/administration
  • Required screening components: Signed informed consent, psychiatric examination (including inclusion/exclusion criteria assessment), PHQ-9 depression rating scale, cognitive status evaluation (e.g., M-ACE), suicide risk assessment (C-SSRS at intake/initial evaluation and within 24 hours of discharge/clinically indicated; CSRE if first ever or updated clinically indicated), physical examination with vitals (BP, HR), relevant laboratory measures, urine toxicology, pregnancy screens
  • Medical clearance/consultation based on individual risk factors is the responsibility of the prescribing provider
  • Concurrent psychoactive substance use/abuse history must be evaluated; patients in recovery warned of relapse risk; close monitoring/random monitored urine drug testing recommended if treatment is chosen
  • CNS depressants (benzodiazepines, non-benzodiazepine hypnotics, naltrexone) may attenuate antidepressant effects; allow adequate washout time prior to administration

Administration & Monitoring Parameters

  • Facility must provide a private setting with crash cart access, capability for immediate care, monitoring of cardiovascular (ECG, BP) and respiratory function (O2 sat or end-tidal CO2), management of dangerous behavioral symptoms (oxygen, medications, restraints), and plan for sustained CV alterations/advanced cardiac life support
  • High-risk patients must be treated at equipped/staffed facilities
  • Ordering provider: VA psychiatrist or VA licensed Mental Health care provider (CPP, NP, PA)
  • Required personnel during infusion: ACLS certified physician/nurse and ordering provider (ordering provider may leave once stable; must return 120 minutes after start to clear for discharge; ACLS provider remains until discharge)
  • Dosing: 0.5 mg/kg IV infusion over 40 minutes (range 0.5–1 mg/kg). For BMI >30 kg/m2, calculate dose using ideal body weight
  • Monitoring schedule during infusion: Vitals at T+10, 20, 30, 40 min; check for resolution of sedation/dissociation/adverse effects at T+80 and T+120 min
  • Parameters to stop infusion: BP must remain <180 mm Hg systolic and <110 mm Hg diastolic. Stop if SBP drops >10 mm Hg with increased HR or distress. Heart rate must remain below age-adjusted maximum (e.g., 20 yrs <140, 30 yrs <133, 40 yrs <126, 50 yrs <119, 60 yrs <112; ≥65 yrs individualized). Stop for pallor/cyanosis/poor perfusion, respiratory symptoms (SOB/wheezing), chest/jaw/arm pain, or patient desire to stop

Infusion Schedule & Duration

  • Repeat no less than 2 days apart and not more frequently than twice a week for 4 weeks
  • After 4 weeks: Once a week to once every 3 weeks, with goal of extending interval (usually monthly)
  • Long-term maintenance may be used but requires regular clinical review/re-evaluation

Discontinuation Criteria

  • Discontinue if patient wishes for any reason
  • Discontinue if infusion stopped >1 time due to exceeding BP or HR thresholds
  • Discontinue if no response after 4 weeks (adequate response defined as ≥50% decline in PHQ-9 from baseline)
  • Discontinue if pronounced or slow-to-correct cognitive impairment or repeated dissociative symptoms
  • Discontinue when dosing cannot be spaced to a minimum of 1 dose per week by the second month

Longitudinal Monitoring

  • PHQ-9 completed prior to each IV ketamine dose
  • PHQ-9 and cognitive evaluation (e.g., M-ACE) at end of induction phase, every 6 months, and at end of treatment course
  • Suicide risk monitored via CSRE and C-SSRS Screener
  • C-SSRS required at intake/initial evaluation and within 24 hours of discharge/discontinuation; CSRE at intake if first ever or updated clinically indicated

Source Documents

Document 411 Document 438 Document 439 Document 643 Document 789