Flumazenil

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Generic: 0.5 mg/5 mL (5 mL); 1 mg/10 mL (10 mL)

Pharmacology

Mechanism of Action

Competitively inhibits the activity at the benzodiazepine receptor 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

Pharmacokinetics/Pharmacodynamics

Distribution

Initial V_d: 0.5 L/kg; V_dss: 0.9-1.1 L/kg

Metabolism

Hepatic; dependent upon hepatic blood flow

Excretion

Feces; urine (<1% as unchanged drug)

Clearance: Dependent upon hepatic blood flow; Adults: 0.8-1 L/hour/kg

Onset of Action

1-2 minutes; 80% response within 3 minutes; Peak effect: 6-10 minutes

Duration of Action

Resedation occurs after ~1 hour (range: 19-50 minutes); duration related to dose given and benzodiazepine plasma concentrations; reversal effects of flumazenil may wear off before effects of benzodiazepine

Half-Life Elimination

Children: Terminal: 20-75 minutes (mean: 40 minutes)

Adults: Alpha: 4-11 minutes; Terminal: 40-80 minutes

Moderate hepatic dysfunction: 1.3 hours

Severe hepatic impairment: 2.4 hours

Protein Binding

~50% (~67% of which is bound to albumin)

Use in Specific Populations

Special Populations: Hepatic Function Impairment

Moderate: Mean total clearance decreased 40% to 60%. Severe: Mean total clearance decreased 75%.

Use: Labeled Indications

Benzodiazepine reversal when used in conscious sedation or general anesthesia: Complete or partial reversal of the sedative effects of benzodiazepines used in conscious sedation and general anesthesia.

Management of benzodiazepine overdose: Treatment of benzodiazepine overdose.

Contraindications

Hypersensitivity to flumazenil, benzodiazepines, or any component of the formulation; patients given benzodiazepines for control of potentially life-threatening conditions (eg, control of intracranial pressure or status epilepticus); patients who may have ingested or are showing signs of cyclic-antidepressant overdosage.

Dosage and Administration

Dosing: Adult

Benzodiazepine reversal when used in conscious sedation or general anesthesia: IV:

Initial dose: 0.2 mg over 15 seconds

Repeat doses (maximum: 4 doses): If the desired level of consciousness is not obtained, 0.2 mg may be repeated at 1-minute intervals.

Maximum total cumulative dose: 1 mg (usual total dose: 0.6 to 1 mg). In the event of resedation: Repeat doses may be given at 20-minute intervals as needed at 0.2 mg per minute to a maximum of 1 mg total dose and 3 mg in 1 hour.

Management of benzodiazepine overdose: IV:

Initial dose: 0.2 mg over 30 seconds; if the desired level of consciousness is not obtained 30 seconds after the dose, 0.3 mg can be given over 30 seconds

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

Maximum total cumulative dose: 3 mg (usual total dose: 1 to 3 mg).

Patients with a partial response at 3 mg may require (rare) additional titration up to a total dose of 5 mg (although doses >3 mg do not reliably produce additional effects). If a patient has not responded 5 minutes after a cumulative dose of 5 mg, the major cause of sedation is not likely due to benzodiazepines or may be due to exposure to additional CNS depressants (eg, opioids). In the event of resedation, repeat doses may be given at 20-minute intervals if needed, at 0.5 mg per minute to a maximum of 1 mg total dose and 3 mg in 1 hour.

Dosing: Geriatric

Refer to adult dosing. No differences in safety or efficacy have been reported; however, increased sensitivity may occur in some elderly patients.

Dosing: Pediatric

Benzodiazepine reversal when used in conscious sedation or general anesthesia: Infants, Children, and Adolescents: IV: Initial dose: 0.01 mg/kg (maximum dose: 0.2 mg) given over 15 seconds; may repeat 0.01 mg/kg (maximum dose: 0.2 mg) after 45 seconds, and then every minute to a maximum total cumulative dose of 0.05 mg/kg or 1 mg, whichever is lower; usual total dose: 0.08 to 1 mg (mean: 0.65 mg)

Suspected benzodiazepine overdose: Limited data available: Infants, Children, and Adolescents: Initial dose: 0.01 mg/kg (maximum dose: 0.2 mg) with repeat doses of 0.01 mg/kg (maximum dose: 0.2 mg) given every minute to a maximum total cumulative dose of 1 mg; as an alternative to repeat bolus doses, follow up continuous infusions of 0.005-0.01 mg/kg/hour have been used (Clark 1995; Richard 1991; Roald 1989; Sugarman 1994)

Administration

IV: Administer in freely-running IV into large vein.

Management of benzodiazepine overdose: Administer over 30 seconds.

Reversal of benzodiazepine when used in conscious sedation: Administer over 15 seconds.

Dietary Considerations

Avoid alcohol for the first 24 hours after administration or as long as the effects of benzodiazepines exist.

Storage

Store at 20°C to 25°C (68°F to 77°F). Once drawn up in the syringe or mixed with D5W, LR, or NS, use within 24 hours. Discard any unused solution after 24 hours.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

>10%: Gastrointestinal: Vomiting (11%)

1% to 10%:

Cardiovascular: Palpitation (3% to 9%), flushing (1% to 3%), thrombophlebitis (1% to 3%), vasodilation (1% to 3%)

Central nervous system: Ataxia (10%), dizziness (10%), vertigo (10%), agitation (3% to 9%), anxiety (3% to 9%), insomnia (3% to 9%), nervousness (3% to 9%), depersonalization (1% to 3%), depression (1% to 3%), dysphoria (1% to 3%), emotional lability (1% to 3%; including crying), euphoria (1% to 3%), fatigue (1% to 3%), headache (1% to 3%), hypoesthesia (1% to 3%), malaise (1% to 3%), paranoia (1% to 3%), paresthesia (1% to 3%)

Dermatologic: Dermatological disease (skin abnormality: 1% to 3%), diaphoresis (1% to 3%), skin rash (1% to 3%)

Endocrine & metabolic: Hot flash (1% to 3%)

Gastrointestinal: Xerostomia (3% to 9%), nausea (1% to 3%)

Local: Pain at injection site (3% to 9%), injection site reaction (1% to 3%)

Neuromuscular & skeletal: Weakness (1% to 3%), tremor

Ophthalmic: Blurred vision (3% to 9%), lacrimation (1% to 3%), visual disturbance (1% to 3%)

Respiratory: Dyspnea (3% to 9%), hyperventilation (3% to 9%)

<1%, postmarketing, and/or case reports: Atrial tachycardia (paroxysmal), auditory disturbance, bradycardia, cardiac arrhythmia, chest pain, confusion, decreased blood pressure, delirium, drowsiness, fear, hiccups, hyperacusis, hypertension, increased blood pressure, lack of concentration, panic attack, reversible hearing loss, rigors, seizure (including generalized), sensation of cold, shivering, stupor, tachycardia, tinnitus, tongue edema, ventricular tachycardia, voice disorder, withdrawal syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Amnesia: Does not consistently reverse amnesia; patient may not recall verbal instructions after procedure.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving) for 24 hours after discharge.
• Resedation: Occurs more frequently in patients where a large single dose or cumulative dose of a benzodiazepine has been administered along with a neuromuscular-blocking agent and multiple anesthetic agents.
• Respiratory depression: Should not rely upon to reverse respiratory depression/hypoventilation. Flumazenil is not a substitute for evaluation of oxygenation. Establishing an airway and assisting ventilation, as necessary, is always the initial step in overdose management.
• Seizures: [US Boxed Warning]: Benzodiazepine reversal may result in seizures; seizures may occur more frequently in patients on benzodiazepines for long-term sedation or following tricyclic antidepressant overdose. Dose should be individualized and practitioners should be prepared to manage seizures. Seizures may also develop in patients with concurrent major sedative-hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, myoclonic jerking or seizure activity prior to flumazenil administration. Use with caution in patients relying on a benzodiazepine for seizure control.

Disease-related concerns:

• Head injury: Use with caution in patients with a head injury; may alter cerebral blood flow or precipitate convulsions in patients receiving benzodiazepines.
• Hepatic impairment: Use with caution in patients with hepatic dysfunction; repeated doses of the drug should be reduced in frequency or amount.
• Panic disorder: Use with caution in patients with a history of panic disorder; may provoke panic attacks.

Special populations:

• Drug/alcohol dependence: Use caution in drug and ethanol-dependent patients; these patients may also be dependent on benzodiazepines.
• Intensive care patients: Should be used with caution in the intensive care unit because of increased risk of unrecognized benzodiazepine dependence in such settings.

Other warnings/precautions:

• Appropriate use: Should not be used to diagnose benzodiazepine-induced sedation. Reverse neuromuscular blockade before considering use. Flumazenil does not antagonize the CNS effects of other GABA agonists (such as ethanol, barbiturates, or general anesthetics); nor does it reverse opioids. Not recommended for treatment of benzodiazepine dependence.
• Overdose use: Use with caution in patients with mixed drug overdoses; toxic effects of other drugs taken may emerge once benzodiazepine effects are reversed.

Monitoring Parameters

Monitor for return of sedation, respiratory depression, benzodiazepine withdrawal, and other residual effects of benzodiazepines for at least 2 hours and until the patient is stable and resedation is unlikely.

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

Teratogenic effects were not seen in animal reproduction studies. Embryocidal effects were seen at large doses. Use during labor and delivery is not recommended. In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).

Patient Education

What is this drug used for?

• It is used to reverse the effects of some drugs.
• It is used to treat side effects after benzodiazepine (eg, alprazolam, diazepam, and lorazepam) overdose.

Frequently reported side effects of this drug

• Dizziness
• Nausea
• Vomiting
• Blurred vision
• Dry mouth
• Headache
• Sweating a lot
• Anxiety
• Tremors
• Trouble sleeping

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Shortness of breath
• Seizures
• Fast breathing
• Abnormal heartbeat
• Behavioral changes
• Agitation
• Mood changes
• Change in balance
• Severe injection site redness, burning, pain, swelling, or irritation
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.