Class: Central Nervous System Agents, Miscellaneous
VA Class: AD900
CAS Number: 78755-81-4
Brands: Romazicon
Introduction
Benzodiazepine antagonist.1
Uses for Flumazenil
Reversal of General Anesthesia
Used for complete or partial reversal of sedating and psychomotor effects of benzodiazepines (e.g., midazolam) used for induction or maintenance of general anesthesia.1
Does not completely restore memory and is not as effective in the reversal of sedation in patients who received multiple anesthetic agents in addition to benzodiazepines.1
Reversal of Conscious Sedation
Used for complete or partial reversal of sedating and psychomotor effects of benzodiazepines when these drugs are used for diagnostic or therapeutic procedures.1
Not as effective in completely and consistently reversing benzodiazepine-induced amnesia.1
Benzodiazepine Overdosage
Management of benzodiazepine overdosage;1 2 4 used as an adjunct to, not a replacement for, appropriate supportive and symptomatic measures (e.g., ventilatory and circulatory support).1 2
No known benefit other than reversal of benzodiazepine-induced sedation in seriously ill patients with multiple-drug overdosage.1 4
Should not be used in drug overdose cases where seizures (from any cause) are likely (e.g., cyclic depressant overdosage).1
Other Uses
Not recommended for management of benzodiazepine dependence† or protracted benzodiazepine abstinence syndrome†.1
Flumazenil Dosage and Administration
General
- Reversal of General Anesthesia and Conscious Sedation
To provide better control of sedation reversal while minimizing the risk of adverse effects, administer multiple small doses rather than large bolus doses.1
Repeat doses may be needed to prevent resedation.1 2
- Management of Benzodiazepine Overdosage
Secure airway and IV access prior to administration of the drug.1
Do not rush administration; awaken patients gradually.1
Repeat doses may be needed to prevent resedation.1 2
Administration
IV Administration
For solution and drug compatibility information, see Compatibility under Stability.
Recommended for IV use only.1
Administer into tubing of a freely running IV infusion into a large vein to minimize local irritation.1
Avoid extravasation into perivascular tissues.1 (See Local Effects under Cautions.)
Rate of Administration
Administer by rapid IV injection over 15–30 seconds.1
Dosage
Carefully titrate dosage using the smallest effective dosage.1 Dosages exceeding the minimally effective dose can complicate management of patients who are physically dependent on benzodiazepines or in whom the therapeutic benefit of the drugs is needed.1
Pediatric Patients
Reversal of Conscious Sedation
IV
Initially, 0.01 mg/kg (up to 0.2 mg) given over 15 seconds.1 If the desired consciousness level is not achieved after waiting 45 seconds, additional 0.01-mg/kg (up to 0.2 mg) doses may be administered at 1-minute intervals until an adequate response is achieved or a maximum of 4 additional doses is administered (i.e., maximum cumulative dose of 0.05 mg/kg or 1 mg, whichever is lower).1
Mean total dose in the pediatric clinical trial was 0.65 mg (range: 0.08–1 mg) with approximately 50% of children requiring the maximum of 5 injections.1 Safety and efficacy of repeated flumazenil administration in pediatric patients experiencing resedation have not been established.1
Adults
Reversal of General Anesthesia
IV
Initially, 0.2 mg given over 15 seconds.1 If the desired consciousness level is not achieved after waiting 45 seconds, additional 0.2-mg doses may be administered at 1-minute intervals until an adequate response is achieved or a maximum of 4 additional doses is administered (i.e., maximum cumulative dose of 1 mg during an initial 5-minute dosing period).1 Most patients respond to cumulative doses of 0.6–1 mg.1
If resedation occurs, the initial dosing regimen (i.e., up to 1 mg given in divided 0.2-mg doses at 1-minute intervals) may be administered no more frequently than every 20 minutes up to a maximum of 3 mg in any 1-hour period.1
In clinical situations where resedation is not yet apparent but must be prevented, initial dosing regimen may be repeated at 30 and 60 minutes despite the current absence of manifestations of recurrence.b
Reversal of Conscious Sedation
IV
Initially, 0.2 mg given IV over 15 seconds.1 If the desired consciousness level is not achieved after waiting 45 seconds, additional 0.2-mg doses may be administered at 1-minute intervals until an adequate response is achieved or a maximum of 4 additional doses is administered (i.e., maximum cumulative dose of 1 mg during an initial 5-minute dosing period).1 Most patients respond to cumulative doses of 0.6–1 mg.1
If resedation occurs, the initial dosing regimen (i.e., up to 1 mg given in divided 0.2-mg doses at 1-minute intervals) may be administered no more frequently than every 20 minutes up to a maximum of 3 mg in any 1-hour period.1
In clinical situations where resedation is not yet apparent but must be prevented, initial dosing regimen may be repeated at 30 and 60 minutes despite the current absence of manifestations of recurrence.b
Management of Benzodiazepine Overdosage
IV
Initially, 0.2 mg given IV over 30 seconds; if the desired consciousness level is not achieved after waiting 30 seconds, an additional 0.3-mg dose may be administered over 30 seconds.1 If an adequate response still is not achieved, further additional 0.5-mg doses may be administered over 30 seconds at 1-minute intervals up to a cumulative dose of 3 mg.1
Usual cumulative doses: 1–3 mg; higher doses do not reliably produce additional benefit.1 However, some patients who exhibit a partial response after a 3-mg cumulative dose rarely may require additional doses up to a total of 5 mg.1 If no response is observed within 5 minutes after administration of an initial 5-mg cumulative dose, the major cause of sedation may not be a benzodiazepine and additional doses are unlikely to provide any beneficial effect.1
If resedation occurs, the initial dosing regimen (i.e., up to 1 mg given in divided 0.5-mg doses at 1-minute intervals) may be repeated no more frequently than every 20 minutes up to a maximum dose of 3 mg in any 1-hour period.1
Prescribing Limits
Pediatric Patients
Reversal of Conscious Sedation
IV
Initially, maximum 0.2 mg given over 15 seconds.1 If the desired consciousness level is not achieved after waiting 45 seconds, maximum 0.2 mg doses may be administered at 1-minute intervals until an adequate response is achieved or a maximum of 4 additional doses is administered (i.e., maximum cumulative dose of 0.05 mg/kg or 1 mg, whichever is lower).1
Adults
Reversal of General Anesthesia
IV
Maximum cumulative dose of 1 mg during an initial 5-minute dosing period (i.e., initially, maximum 0.2-mg followed by a maximum of 4 additional 0.2-mg doses administered at 1-minute intervals).1
If resedation occurs, maximum 1 mg given in divided 0.2-mg doses at 1-minute intervals may be administered no more frequently than every 20 minutes up to a maximum of 3 mg in any 1-hour period.1
Reversal of Conscious Sedation
IV
Maximum cumulative dose of 1 mg during an initial 5-minute dosing period (i.e., initially, maximum 0.2-mg followed by a maximum of 4 additional 0.2-mg doses administered at 1-minute intervals).1
If resedation occurs, maximum 1 mg given in divided 0.2-mg doses at 1-minute intervals may be administered no more frequently than every 20 minutes up to a maximum of 3 mg in any 1-hour period.1
Management of Benzodiazepine Overdosage
IV
For initial treatment, the usual maximum cumulative dose is 3 mg (i.e., maximum 1 mg given in divided 0.5-mg doses administered over 30 seconds at 1-minute intervals).1 Patients who exhibit a partial response after a 3-mg cumulative dose rarely may require additional doses up to a total of 5 mg.1
If resedation occurs, maximum 1 mg given in divided 0.5-mg doses at 1-minute intervals; doses may be repeated no more frequently than every 20 minutes up to a maximum dose of 3 mg in any 1-hour period.1
Special Populations
Hepatic Impairment
No initial dose adjustments necessary but repeat doses should be reduced in size or frequency.1
Patients Tolerant to Benzodiazepines
Use of lower total doses and slower titration rates of 0.1 mg/minute may help reduce the frequency of emergent confusion and agitation.1 In such cases, special care must be taken to monitor the patients for resedation because of the lower doses used.1
Patients Physically Dependent on Benzodiazepines
The manufacturer makes no specific dosage recommendations for patients who are physically dependent on benzodiazepines.1
Consult scientific literature for specific information.1
Cautions for Flumazenil
Contraindications
Patients receiving a benzodiazepine for control of a potentially life-threatening condition (e.g., control of intracranial pressure or status epilepticus).1
Patients exhibiting manifestations of serious cyclic antidepressant overdosage.1 (See Seizures under Cautions.)
Known hypersensitivity to flumazenil or benzodiazepines or any ingredient in the formulation.1
Warnings/Precautions
Warnings
Seizures
Possible onset of seizures; individualize doses and be prepared to manage seizures.1
Seizures occur most frequently in patients receiving benzodiazepines for long-term sedation or in patients with manifestations of serious cyclic antidepressant overdose.1 Other risk factors include major sedative-hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, myoclonic jerking or seizure activity prior to flumazenil administration in overdose cases, or concurrent cyclic antidepressant poisoning.1
Use not recommended in patients with manifestations of serious cyclic antidepressant poisoning (e.g., twitching, rigidity, focal seizure, wide QRS, ventricular dysrhythmia, heart block, mydriasis, dry mucosa, hypoperistalsis, cardiovascular collapse).b (See Contraindications under Cautions.) Flumazenil has no known benefit in seriously ill, mixed-overdose patients (except to reverse sedation) and use not recommended in patients where seizures are likely to occur.1
Most seizures require treatment with anticonvulsants (e.g., barbiturates, benzodiazepines, phenytoin).1 If benzodiazepines are used, higher dosages than usual may be required.1
Hypoventilation
May not fully reverse postoperative airway problems or ventilatory insufficiency associated with benzodiazepine administration; facilities and equipment for immediate ventilatory support should be readily available for any patient receiving the drug.1 Monitor patients for respiratory depression.1
General Precautions
Return of Sedation
Possible return of sedation; monitor patients carefully for an adequate period of time (i.e., up to 2 hours) for signs of resedation, respiratory depression, or other residual benzodiazepine effects.1 1 Repeat doses in adult (but not pediatric) patients when necessary.1 (See Adults under Dosage and Administration.)
Resedation most likely to occur with use of large single or cumulative dose of a benzodiazepine (e.g., midazolam dosages >10 mg) in the course of a long procedure (e.g., >60 minutes) along with neuromuscular blocking agents and multiple anesthetic agents.1 3
Withdrawal Reactions
Possible precipitation of dose-dependent manifestations of withdrawal (e.g., seizures) in patients with established physical dependence on benzodiazepines; use only if the potential benefits of using the drug outweigh the risks of precipitated seizures.1
Assume that flumazenil administration may complicate the management of withdrawal syndromes for alcohol, barbiturates, and cross-tolerant sedatives.1
Intensive Care Setting
Use with caution; possible increased risk of seizures due to increased risk of unrecognized benzodiazepine dependence in this setting.1
Use in an intensive care setting to define CNS depression as being benzodiazepine induced is not recommended; risk of precipitating potentially serious manifestations of withdrawal (e.g., seizures) in cases of unrecognized benzodiazepine dependence greater than prognostic value of such therapy.1
Head Injury
Risk of precipitating seizures or altering cerebral blood flow in cases of unrecognized benzodiazepine dependence; use with caution and only by clinicians who are prepared to manage such complications.1
Panic Disorders
Possible provocation of panic attacks in patients with a history of panic disorder.1
Local Effects
Possible local pain or inflammation at injection site following extravasation; administer into a freely running IV infusion into a large vein.1
Pulmonary Disease
Not recommended as primary treatment of patients with serious lung disease who experience serious respiratory depression secondary to benzodiazepines; administer appropriate ventilatory support instead.1 (See Hypoventilation under Cautions.)
Cardiovascular Disease
Use of flumazenil alone had no clinically important effects on cardiovascular parameters when administered to patients with stable ischemic heart disease to reverse the effects of benzodiazepines.1
Drug and Alcohol Dependence
Possible increased frequency of benzodiazepine tolerance and dependence in patients dependent on other drugs or alcohol; use with caution.b
Specific Populations
Pregnancy
Category C.1
Not recommended during labor and delivery since the effects on neonates are not known.1
Lactation
Not known whether flumazenil is distributed into milk.1 Caution is advised if flumazenil is used.1
Pediatric Use
Safety and efficacy not established in infants <1 year of age for the reversal of conscious sedation.1
Safety and efficacy not established in children <18 years of age for management of benzodiazepine overdosage, for neonatal resuscitation, nor for reversal of sedation when benzodiazepines are used for induction of general anesthesia.1
No substantial differences in safety and efficacy relative to adults for the reversal of conscious sedation.1 Risks associated with flumazenil use in the adult population also apply to pediatric patients.1
Geriatric Use
No substantial differences in safety or efficacy relative to younger adults, but increased sensitivity to flumazenil cannot be ruled out.1
Hepatic Impairment
Systemic clearance of flumazenil may be decreased.1 (See Special Populations under Pharmacokinetics.) Dose adjustments may be necessary.1 (See Hepatic Impairment under Dosage and Administration.)
Common Adverse Effects
Dizziness, injection site pain, increased sweating, headache, and abnormal or blurred vision.1
Interactions for Flumazenil
Extensively metabolized in the liver, but the precise enzymes responsible are unknown.1
Specific Drugs
Drug | Interaction | Comment |
|---|---|---|
Alcohol | Pharmacokinetic interaction not observedb | |
Anesthetics, inhalational | No deleterious interactions observed when flumazenil was administered after inhalation anesthetics1 | |
Benzodiazepines | Pharmacokinetic interaction unlikely1 May precipitate dose-dependent manifestations of withdrawal in patients with established physical dependence on benzodiazepines1 | Concomitant use contraindicated1 |
Cyclic antidepressants | Increased risk of seizures1 | Concomitant use contraindicated1 |
Neuromuscular blocking agents | Do not administer until the effects of neuromuscular blockade have been fully reversed1 | |
Nonbenzodiazepine hypnotics | Flumazenil blocks the effects of nonbenzodiazepine hypnoticsb | |
Opiate agonists | No deleterious interactions observed when flumazenil was administered after opiates1 | |
Skeletal muscle relaxants | No deleterious interactions observed when flumazenil was administered after skeletal muscle relaxants1 |
Flumazenil Pharmacokinetics
Absorption
Onset
Reversal of benzodiazepine-induced effects usually is evident within 1–2 minutes following completion of IV injection, with an 80% response occurring within 3 minutes, and the peak effect occurring at 6–10 minutes.1
Duration
Duration and degree of reversal of benzodiazepine-induced effects appear to be related to the dose of flumazenil and plasma concentrations of benzodiazepine.1 b
Food
Ingestion of food during an IV infusion of the drug results in a 50% increase in clearance, most likely because of the increased hepatic blood flow that accompanies a meal.1
Distribution
Extent
Extensively distributed in extravascular space.b
Plasma Protein Binding
Approximately 50%1 (mainly albumin).b
Elimination
Metabolism
Completely (99%) metabolized in the liver.1 b
Elimination Route
Principally by hepatic metabolism and is dependent on hepatic blood flow; <1% of the administered dose excreted in urine as unchanged drug.1
Half-life
Terminal half-life is approximately 0.7–1.3 hours.1
Special Populations
In patients with mild to moderate or severe hepatic impairment, clearance is reduced to 40–60 or 25% of that of patients with normal hepatic function, respectively.1
In children 1–17 years of age, half-life of flumazenil is more variable (averaging 40 minutes; range: 20–75 minutes) than that in adults.1 b
Stability
Storage
Parenteral
Injection
15–30°C.1
Discard unused solution 24 hours after initial entry into a syringe or mixture with any of the compatible solutions.1
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral
Solution CompatibilityHID 1
Compatible |
|---|
Dextrose 5% in water |
Lactated Ringer’s |
Sodium chloride 0.9% |
Drug Compatibility
Compatible |
|---|
Aminophylline |
Cimetidine HCl |
Dobutamine HCl |
Dopamine HCl |
Famotidine |
Heparin sodium |
Lidocaine HCl |
Procainamide HCl |
Ranitidine HCl |
ActionsActions
Antagonizes CNS effects (e.g., sedation, impaired recall, psychomotor impairment, respiratory depression) of benzodiazepines by competitively inhibiting the activity of the drugs at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex.1
Does not antagonize the CNS effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (e.g., barbiturates, alcohol, general anesthetics) and does not reverse the effects of opioids.1
Advice to Patients
Risk of impaired memory and judgment.1
Risk of increased adverse effects in regular users of benzodiazepines; importance of informing clinicians of history of benzodiazepine, alcohol, and/or sedative use prior to use of flumazenil.1
Importance of avoiding activities that require complete alertness, and not operating hazardous machinery or a motor vehicle until at least 18–24 hours after discharge and it is certain that no residual sedative effects of the benzodiazepine remain.1
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV use | 0.1 mg/mL (0.5 and 1 mg)* | Flumazenil Injection (with parabens) | Abraxis, Apotex, Baxter, Bedford, Sabex, Sicor |
Romazicon (with parabens) | Roche |
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
1. Roche Laboratories, Inc. Romazicon (flumazenil) prescribing information. Nutley, NJ; 2000 May.
2. Weinbroum AA, Flaishon R, Sorkine P et al. A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose. Drug Saf. 1997; 17:181-96. [PubMed 9306053]
3. Shannon M, Albers G, Burkhart K et al for the Flumazenil Pediatric Study Group. Safety and efficacy of flumazenil in the reversal of benzodiazepine-induced conscious sedation. J Pediatr. 1997; 131:582-6. [IDIS 397529] [PubMed 9386663]
4. Mathieu-Nolf M, Babé MA, Coquelle-Couplet V et al. Flumazenil use in an emergency department: a survey. J Toxicol Clin Toxicol. 2001; 39:15-20. [IDIS 464895] [PubMed 11327221]
HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:735-6.
b. Roche Laboratories, Inc. Romazicon (flumazenil) prescribing information. Nutley, NJ; 2003 Dec.
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