No

Antidote

For complete or partial reverse of the sedative effects of benzodiazepine in cases where

2. sedation has been produced with benzodiazepine for diagnostic and therapeutic procedures

3. management of benzodiazepine overdose

C

Hypersensitivity to flumazenil or benzodiazepines; patients given benzodiazepines for control of potentially life-threatening conditions (eg, control of intracranial pressure or status epilepticus); patients who are showing signs of serious cyclic-antidepressant overdosage

Risk of seizures = high-risk patients:

Patients on benzodiazepines for long-term sedation

Tricyclic antidepressant overdose patients

Concurrent major sedative-hypnotic drug withdrawal

Recent therapy with repeated doses of parenteral benzodiazepines

Myoclonic jerking or seizure activity prior to flumazenil administration

Hypoventilation: Does not reverse respiratory depression/hypoventilation or cardiac depression

Resedation: Occurs more frequently in patients where a large single dose or cumulative dose of a benzodiazepine is administered along with a neuromuscular blocking agent and multiple anesthetic agents

Flumazenil should be used with caution in the intensive care unit because of increased risk of unrecognized benzodiazepine dependence in such settings.

>10%: Gastrointestinal: Vomiting, nausea

1% to 10%:

Cardiovascular: Palpitations

Central nervous system: Headache, anxiety, nervousness, insomnia, abnormal crying, euphoria, depression, agitation, dizziness, emotional lability, ataxia, depersonalization, increased tears, dysphoria, paranoia

Endocrine & metabolic: Hot flashes

Gastrointestinal: Xerostomia

Local: Pain at injection site

Neuromuscular & skeletal: Tremor, weakness, paresthesia

Ocular: Abnormal vision, blurred vision

Respiratory: Dyspnea, hyperventilation

Miscellaneous: Diaphoresis

<1%: Bradycardia, tachycardia, chest pain, hypertension, arrhythmia, generalized convulsions, somnolence, confusion, speech disorder, abnormal hearing, hiccups, withdrawal syndrome, shivering

Use with caution in overdosage involving mixed drug overdose; toxic effects may emerge (especially with cyclic antidepressants) with the reversal of the benzodiazepine effect by flumazenil

For I.V. use only; compatible with D₅W, lactated Ringer's, or normal saline; once drawn up in the syringe or mixed with solution use within 24 hours; discard any unused solution after 24 hours

Competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil does not antagonize the CNS effect of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (ethanol, barbiturates, general anesthetics) and does not reverse the effects of opioids

Onset of action: 1-3 minutes; 80% response within 3 minutes

Peak effect: 6-10 minutes

Duration: Resedation occurs usually within 1 hour; duration is related to dose given and benzodiazepine plasma concentrations; reversal effects of flumazenil may wear off before effects of benzodiazepine

Distribution: 0.63-1.06 L/kg; Initial V_d: 0.5 L/kg; V_dss 0.77-1.6 L/kg

Protein binding: 40% to 50%

Half-life, adults: Alpha: 7-15 minutes; Terminal: 41-79 minutes

Elimination: Clearance dependent upon hepatic blood flow; hepatically eliminated, 0.2% unchanged in urine

Pediatric dosage (further studies are needed):

Pediatric dosage for reversal of conscious sedation: Intravenously through a freely running intravenous infusion into a large vein to minimize pain at the injection site.

Initial dose: 0.01 mg/kg over 15 seconds (maximum dose of 0.2 mg)

Repeat doses: 0.005-0.01 mg/kg (maximum dose of 0.2 mg) repeated at 1-minute intervals

Maximum total cumulative dose: 1 mg

Pediatric dosage for management of benzodiazepine overdose: Intravenously through a freely running intravenous infusion into a large vein to minimize pain at the injection site.

Initial dose: 0.01 mg/kg (maximum dose: 0.2 mg)

Repeat doses: 0.01 mg/kg (maximum dose of 0.2 mg) repeated at 1-minute intervals

Maximum total cumulative dose: 1 mg

In place of repeat bolus doses, follow-up continuous infusions of 0.005-0.01 mg/kg/hour have been used; further studies are needed

Adult dosage:

Adult dosage for reversal of conscious sedation: Intravenously through a freely running intravenous infusion into a large vein to minimize pain at the injection site.

Initial dose: 0.2 mg intravenously over 15 seconds

Repeat doses: If desired level of consciousness is not obtained, 0.2 mg may be repeated at 1-minute intervals.

Maximum total cumulative dose: 1 mg (usual dose 0.6-1 mg). In the event of resedation: Repeat doses may be given at 20-minute intervals with maximum of 1 mg/dose and 3 mg/hour

Adult dosage for suspected benzodiazepine overdose: Intravenously through a freely running intravenous infusion into a large vein to minimize pain at the injection site.

Initial dose: 0.2 mg intravenously over 30 seconds

Repeat doses: 0.5 mg over 30 seconds repeated at 1-minute intervals

Maximum total cumulative dose: 3 mg (usual dose 1-3 mg). Patients with a partial response at 3 mg may require additional titration up to a total dose of 5 mg. If a patient has not responded 5 minutes after cumulative dose of 5 mg, the major cause of sedation is not likely due to benzodiazepines.

In the event of resedation: May repeat doses at 20-minute intervals with maximum of 1 mg/dose and 3 mg/hour.

Resedation: Repeated doses may be given at 20-minute intervals as needed; repeat treatment doses of 1 mg (at a rate of 0.5 mg/minute) should be given at any time and no more than 3 mg should be given in any hour. After intoxication with high doses of benzodiazepines, the duration of a single dose of flumazenil is not expected to exceed 1 hour; if desired, the period of wakefulness may be prolonged with repeated low intravenous doses of flumazenil, or by an infusion of 0.1-0.4 mg/hour. Most patients with benzodiazepine overdose will respond to a cumulative dose of 1-3 mg and doses >3 mg do not reliably produce additional effects. Rarely, patients with a partial response at 3 mg may require additional titration up to a total dose of 5 mg. If a patient has not responded 5 minutes after receiving a cumulative dose of 5 mg, the major cause of sedation is not likely to be due to benzodiazepines.

Dosing in renal impairment: Not significantly affected by renal failure (Cl_cr <10 mL/minute) or hemodialysis beginning 1 hour after drug administration

Dosing in hepatic impairment: Initial dose of flumazenil used for initial reversal of benzodiazepine effects is not changed; however, subsequent doses in liver disease patients should be reduced in size or frequency

Monitor patients for return of sedation or respiratory depression

No information available to require special precautions

No effects or complications reported

Avoid driving or activities requiring alertness for 18-24 hours after drug use. Memory and judgment may be impaired for 24-48 hours. Avoid alcohol or other CNS depressants for 2-3 days after treatment. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Consult prescriber if breast-feeding.

Parenteral: For I.V. use only; administer via freely running I.V. infusion into larger vein to decrease chance of pain, phlebitis

Injection: 0.1 mg/mL (5 mL, 10 mL)

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