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Amidate

Generic Name: Etomidate
Class: General Anesthetics, Miscellaneous
VA Class: CN203
Chemical Name: 1-(1-Phenylethyl)-1H-imidazole-5-carboxylic acid ethyl ester
Molecular Formula: C14H16N2O2
CAS Number: 33125-97-2

Warning(s)

Special Alerts:

[Posted 04/27/2017]

AUDIENCE: Consumer, Surgery, Anesthesiology

ISSUE: FDA has approved previously announced label changes regarding the use of general anesthetic and sedation medicines in children younger than 3 years. These changes include:

  • A new Warning stating that exposure to these medicines for lengthy periods of time or over multiple surgeries or procedures may negatively affect brain development in children younger than 3 years.

  • Addition of information to the sections of the labels about pregnancy and pediatric use to describe studies in young animals and pregnant animals that showed exposure to general anesthetic and sedation drugs for more than 3 hours can cause widespread loss of nerve cells in the developing brain; and studies in young animals suggested these changes resulted in long-term negative effects on the animals' behavior or learning.

General anesthetic and sedation drugs are necessary for patients, including young children and pregnant women, who require surgery or other painful and stressful procedures. In the U.S., surgeries during the third trimester of pregnancy requiring general anesthesia are performed only when medically necessary and rarely last longer than 3 hours. FDA is advising that in these situations, pregnant women should not delay or avoid surgeries or procedures during pregnancy, as doing so can negatively affect themselves and their infants.

Similarly, surgeries or procedures in children younger than 3 years should not be delayed or avoided when medically necessary. Consideration should be given to delaying potentially elective surgery in young children where medically appropriate.

BACKGROUND: This is an update to the MedWatch alert “General Anesthetic and Sedation Drugs: Drug Safety Communication - New Warnings for Young Children and Pregnant Women”, available at: , issued on December 14, 2016.

RECOMMENDATION: Health care professionals should continue to follow their usual practices of patient counseling including discussing the benefits and risks of surgeries or procedures that require general anesthesia and sedation drugs. FDA will continue to monitor the use of these drugs in children and will update the public if additional information becomes available.

Parents, caregivers, and pregnant women should talk to their health care professionals if they have any questions or concerns about general anesthesia and sedation drugs.

[Posted 12/14/2016]

AUDIENCE: Consumer, Surgery, Anesthesiology

ISSUE: FDA is warning that repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children's brains.

Consistent with animal studies, recent human studies suggest that a single, relatively short exposure to general anesthetic and sedation drugs in infants or toddlers is unlikely to have negative effects on behavior or learning. However, further research is needed to fully characterize how early life anesthetic exposure affects children's brain development.

To better inform the public about this potential risk, FDA is requiring warnings to be added to the labels of general anesthetic and sedation drugs (see List of General Anesthetic and Sedation Drugs Affected by this Label Change). FDA will continue to monitor the use of these drugs in children and pregnant women and will update the public if additional information becomes available.

See the FDA Drug Safety Communication, available at: , for a data summary and listing of general anesthetic and sedation drugs affected by this label change.

BACKGROUND: Anesthetic and sedation drugs are necessary for infants, children, and pregnant women who require surgery or other painful and stressful procedures, especially when they face life-threatening conditions requiring surgery that should not be delayed. In addition, untreated pain can be harmful to children and their developing nervous systems.

FDA has been investigating the potential adverse effects of general anesthetic and sedation drugs on children's brain development since the first animal study on this topic was published in 1999. FDA held advisory committee meetings in 2007, 2011, and 2014. To coordinate and fund research in this area, FDA also formed a partnership with the International Anesthesia Research Society (IARS) called SmartTots (Strategies for Mitigating Anesthesia-Related neuroToxicity in Tots). More research is still needed to provide additional information about the safe use of these drugs in young children and pregnant women.

RECOMMENDATION: Health care professionals should balance the benefits of appropriate anesthesia in young children and pregnant women against the potential risks, especially for procedures that may last longer than 3 hours or if multiple procedures are required in children under 3 years. Discuss with parents, caregivers, and pregnant women the benefits, risks, and appropriate timing of surgery or procedures requiring anesthetic and sedation drugs.

Parents and caregivers should discuss with their child's health care professional the potential adverse effects of anesthesia on brain development, as well as the appropriate timing of procedures that can be delayed without jeopardizing their child's health. Pregnant women should have similar conversations with their health care professionals. Also talk with them about any questions or concerns.

For more information visit the FDA website at: and .

Introduction

Sedative and hypnotic agent.1 2

Uses for Amidate

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Induction Anesthesia

Induction of general anesthesia.1 2 3 4 5

Induction results in dose-related hypnotic effects (progressing from light sleep to unconsciousness).1 2 3 4 5 6 9

Particularly useful in patients with compromised cardiopulmonary function because of its minimal hemodynamic effects and decreased respiratory depressant effects relative to other IV anesthetics (barbiturates, propofol).1 2

Carefully weigh the potential benefits of the drug’s hemodynamic effects against the possible risks of very frequent transient skeletal muscle movements associated with etomidate therapy.1 2

Maintenance Anesthesia

Maintenance anesthesia to supplement subpotent anesthetic agents (e.g., nitrous oxide and oxygen) during short-term surgical procedures (e.g., dilatation and curettage, cervical conization).1 2

Amidate Dosage and Administration

General

Premedication

  • Premedication generally includes benzodiazepines (to relieve anxiety, induce light anesthesia, and produce anterograde amnesia), barbiturates (to relieve anxiety and provide sedation), and/or opiate agonists (to relieve pain), and sometimes anticholinergic agents (e.g., atropine, scopolamine) to suppress vagal reflexes and inhibit secretions.1 2 9 10

Administration

IV Administration

Administer undiluted by direct IV injection.1 2

Do not administer by prolonged IV infusion.1 2 (See Decreased Plasma Cortisol Concentrations under Cautions.)

Should be administered only by individuals experienced in the administration of general anesthetics and in the management of possible complications associated with these agents.1 2

Limited data indicate that inadvertent intra-arterial administration of etomidate injections does not appear to be associated with tissue necrosis distant from the injection site; however, intra-arterial use of the drug is not recommended.1 2 9

Use the larger veins of the forearm, rather than the smaller, distal hand or wrist veins to minimize pain at injection site.1 2

To prevent needlestick injuries, do not recap, bend, or break needles by hand.1 2

Rate of Administration

For induction of anesthesia, administer by rapid (over 30–60 seconds) IV injection in children >10 years of age and adults.1 2

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Because individual response is variable, adjust dosage according to individual requirements and response, age, physical and clinical status, underlying pathologic conditions (e.g., shock, intestinal obstruction, malnutrition, anemia, burns, advanced malignancy, ulcerative colitis, uremia, alcoholism), and the type and amount of premedication or concomitant medication(s).1 2 9 Titrate dosage according to clinical effect.9

Pediatric Patients

Induction Anesthesia
IV

Children >10 years of age: 0.3 mg/kg (0.2–0.6 mg/kg).1 2 9

Maintenance Anesthesia
IV

Use smaller increments than those used for induction.1 2

Adults

Induction Anesthesia
IV

0.3 mg/kg (0.2–0.6 mg/kg).1 2 9

Maintenance Anesthesia
IV

Use smaller increments than those used for induction.1 2

Special Populations

Geriatric Patients

Geriatric patients may require lower dosages than younger patients because of pharmacokinetic differences.2

Cautions for Amidate

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Known hypersensitivity to etomidate.1 2

Warnings/Precautions

Warnings

Decreased Plasma Cortisol Concentrations

Decreased plasma concentrations of cortisol (which usually persist for 6–8 hours and are unresponsive to stimulation by corticotropin [ACTH]) may occur with 0.3-mg/kg induction doses.1 2 3 4 5 6

Because of the danger of prolonged suppression of endogenous cortisol and aldosterone secretion from the adrenal cortex, the manufacturers and some clinicians recommend that etomidate not be administered as a continuous IV infusion.1 2 6

Although decreased plasma concentrations of cortisol have not been associated with changes in vital signs or increased mortality rate, concern exists in patients undergoing severe stress;1 2 consider administration of exogenous corticosteroids in such patients.1 2

General Precautions

Musculoskeletal Effects

Transient skeletal muscle movements occur frequently (32%; range 23–63%).1 2

Most are mild to moderate in severity, although disturbing movements occur occasionally.1 2

Disturbing movements have been classified as myoclonic (74%), tonic (10%), ocular (9%), and averting movements (7%).1 2

Movements may be bilateral (of arms, legs, shoulders, neck, chest wall, trunk, and/or all extremities, with one or more muscle groups predominating), with EEG suggesting that they are manifestations of cortical disinhibition in the absence of evidence of seizure activity.1 2 Alternatively, muscle movements may be unilateral, or predominate on one side, or a mixture of bilateral and unilateral types.1 2

Administration of 0.1 mg of IV fentanyl immediately before induction may minimize incidence of skeletal muscle movements. 1 2 10

Labor and Delivery

Since safety of the drug during labor and delivery has not been fully elucidated, use is not recommended during labor and delivery, including cesarean section.1 2

Specific Populations

Pregnancy

Category C.1 2

Lactation

Not known whether IV etomidate is distributed into milk.1 2 Use with caution.1 2

Pediatric Use

Safety and efficacy of etomidate for induction anesthesia or maintenance anesthesia (to supplement subpotent anesthetic agents during surgical procedures) in children <10 years of age have not been established.1 2 10

Geriatric Use

Cardiac depression (decreased heart rate and cardiac index) and decreased mean arterial BP may occur in geriatric patients, especially those with hypertension.2

Since geriatric patients may have decreased renal function, monitor renal function and select dosage carefully.2 (See Special Populations under Dosage and Administration and see Renal Impairment under Cautions.)

Renal Impairment

Substantially excreted by the kidneys.2 The risk of severe adverse reactions may be increased in patients with impaired renal function.2

Common Adverse Effects

Injection site pain, eye movement, skeletal muscle movements (e.g., myoclonic, averting, tonic, eye). 1 2 3 4 9

Interactions for Amidate

Specific Drugs

Drug

Interaction

Comments

CNS depressants (e.g., anesthetics, sedatives, hypnotics, opiate agonists)

Additive pharmacologic effect1 2 10

Consider dosage reduction1 2 10

Neuromuscular blocking agents

Etomidate does not alter usual dosage requirements of neuromuscular blocking agents1 2

Amidate Pharmacokinetics

Absorption

Onset

Following IV administration, rapid onset of action;1 2 3 4 5 6 loss of consciousness occurs usually within 1 minute.1 2 4 9

Duration

Dose dependent.1 2 Following IV administration of average doses (0.3 mg/kg), duration of hypnosis is short (about 3–5 minutes).1 2 Recovery from anesthesia is at least as fast as with thiopental (no longer commercially available in the US),1 2 but slower than that associated with propofol.9

Plasma Concentrations

Minimal hypnotic plasma concentrations are at least 0.23 mcg/mL.1 2

Distribution

Extent

Rapidly distributed from blood into CNS with substantial tissue uptake.3 4

Elimination

Metabolism

Rapidly metabolized in the liver, principally by hydrolysis, to etomidate carboxylic acid,1 2 3 4 8 which appears to be pharmacologically inactive.4

Elimination Route

Excreted in urine (75%) within 24 hours, mainly (about 80%) as the carboxylic acid metabolite;1 2 4 13 and 10% of a dose are excreted in feces and bile, respectively.4

Half-life

About 1.25–5 hours.1 2 3 4 8

Special Populations

Elimination half-life approximately doubled in patients with cirrhosis and esophageal varices.1 2

Stability

Storage

Parenteral

Injection

15–30°C.1 2

Do not use the injection unless the solution is clear and the container undamaged.1 2

Discard unused portion.1 2

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Drug Compatibility
Y-Site CompatibilityHID

Compatible

Alfentanil HCl

Atracurium besylate

Atropine sulfate

Ephedrine sulfate

Fentanyl citrate

Lidocaine HCl

Lorazepam

Midazolam HCl

Mivacurium chloride

Morphine sulfate

Pancuronium bromide

Phenylephrine HCl

Succinylcholine chloride

Sufentanil citrate

Incompatible

Ascorbic acid injection

Vecuronium bromide

Actions

  • Structurally unrelated to other currently available IV anesthetics.6

  • Enhances the activity of GABA, the principal inhibitory neurotransmitter in the CNS,6 7 by interacting with the GABAA receptor complex.6 7

  • Capable of producing all levels of CNS depression—from light sleep to deep coma—depending on the dosage.9

  • Has no analgesic activity.1 2 4

  • Substantial changes on the EEG appear to occur following induction doses.3 4 9 The EEG changes are indicative of the various stages of anesthesia and appear to be similar to those occurring following induction of anesthesia with barbiturates.3 4

  • May decrease cerebral blood flow and intracranial pressure.1 3 9

  • Causes minimal hemodynamic changes9 and is associated with a decreased incidence and severity of cardiovascular effects compared with other IV anesthetic agents.3 4 5 6 10

  • Minor increases in cardiac index and slight decreases in heart rate, systemic vascular resistance, and arterial BP reported.9

  • Equivalent induction doses of etomidate cause less respiratory depression than propofol or barbiturates.9

  • Increases in carbon dioxide tension (PCO2) reported.1 2

  • Usually reduces intraocular pressure (IOP).1 2

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Etomidate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV use

2 mg/mL (20 and 40 mg)*

Amidate (with propylene glycol 35% v/v; available as single-use ampuls, Abboject syringes, and vials)

Hospira

Etomidate Injection (with propylene glycol 35% v/v; available as preservative-free single-use vials)

Bedford

AHFS DI Essentials. © Copyright 2017, Selected Revisions April 27, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Bedford Laboratories. Etomidate injection prescribing information. Bedford, OH; 2004 Mar.

2. Abbott. Amidate (etomidate) injection prescribing information. North Chicago, IL; 1999.

3. Batjer HH. Cerebral protective effects of etomidate: experimental and clinical aspects. Cerebrovasc Brain Metab Rev. 1993; 5:17-32. [PubMed 8452760]

4. Giese JL Stanley TH. Etomidate: a new intravenous anesthetic induction agent. Pharmacotherapy. 1983; 3:251-8. [PubMed 6359080]

5. Preziosi P, Vacca M. Adrenocortical suppression and other endocrine effects of etomidate: minireview. Life Sci. 1988; 42:477- 89. [PubMed 3276997]

6. Carmichael FJ, Haas DA. General Anesthetics. In: Kalant H and Roschlau WH, eds. Principles of Medical Pharmacology. 6th edition. New York: Oxford University Press; 1998:278-92.

7. Hales TG, Olsen RW. Basic pharmacology of intravenous induction agents. In: Bowdle TA, Horita A, Kharasch ED. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:295-306.

8. Henthorn TK. Pharmacokinetics of intravenous induction agents. In: Bowdle TA, Horita A, Kharasch ED. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:307-9.

9. Fragen RJ. Clinical pharmacology and applications of intravenous anesthetic induction agents. In: Bowdle TA, Horita A, Kharasch ED. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:319-36.

10. Abbott Laboratories, North Chicago, IL: Personal communication.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:647-8.

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