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Flumazenil

Pronunciation

Pronunciation

(FLOO may ze nil)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous:

Romazicon: 1 mg/10 mL (10 mL [DSC])

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

Brand Names: U.S.

  • Romazicon [DSC]

Pharmacologic Category

  • Antidote

Pharmacology

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

Distribution

Initial Vd: 0.5 L/kg; Vdss: 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)

Special Populations: Hepatic Function Impairment

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

Use: Labeled Indications

Benzodiazepine antagonist; reverses sedative effects of benzodiazepines used in conscious sedation and general anesthesia; 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 are showing signs of serious cyclic-antidepressant overdosage

Dosing: Adult

Reversal of conscious sedation and general anesthesia: IV:

Initial dose: 0.2 mg over 15 seconds

Repeat doses (maximum: 4 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 total dose: 0.6-1 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.

Suspected 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: 1-3 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 cumulative dose of 5 mg, the major cause of sedation is not likely due to benzodiazepines. 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

Reversal of benzodiazepine when used in conscious sedation: Children ≥1 year: IV:

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

Repeat doses (maximum: 4 doses): If desired level of consciousness is not obtained, 0.01 mg/kg (maximum: 0.2 mg) repeated at 1-minute intervals

Maximum total cumulative dose: 1 mg or 0.05 mg/kg (whichever is lower)

Mean total dose: 0.65 mg (range: 0.08-1 mg)

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer’s labeling; however, pharmacokinetics are not significantly affected by renal failure (CrCl <10 mL/minute) or hemodialysis.

Dosing: Hepatic Impairment

Initial reversal: No dosage adjustment necessary. Repeat doses: Reduce dose or frequency.

Administration

IV: Administer in freely-running IV into large vein. Inject over 15 seconds for reversal of conscious sedation and general anesthesia and over 30 seconds for benzodiazepine overdose.

Dietary Considerations

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

Compatibility

Stable in D5W, LR, NS.

Storage

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

Drug Interactions

Hypnotics (Nonbenzodiazepine): Flumazenil may diminish the sedative effect of Hypnotics (Nonbenzodiazepine). Exceptions: Ramelteon; Suvorexant; Tasimelteon. Monitor therapy

Adverse Reactions

>10%: Gastrointestinal: Vomiting (11%)

1% to 10%:

Cardiovascular: Palpitation (3% to 9%), flushing (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%), abnormal crying (1% to 3%), depersonalization (1% to 3%), depression (1% to 3%), dysphoria (1% to 3%), emotional lability (1% to 3%), euphoria (1% to 3%), fatigue (1% to 3%), headache (1% to 3%), malaise (1% to 3%), paranoia (1% to 3%)

Endocrine & metabolic: Hot flashes (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%), rash (1% to 3%), skin abnormality (1% to 3%), thrombophlebitis (1% to 3%)

Neuromuscular & skeletal: Hypoesthesia (1% to 3%), paresthesia (1% to 3%), weakness (1% to 3%), tremor

Ocular: Blurred vision (3% to 9%), abnormal vision (1% to 3%), lacrimation (1% to 3%)

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

Miscellaneous: Diaphoresis (1% to 3%)

<1% (Limited to important or life-threatening): Abnormal hearing, altered blood pressure increased/decreased, arrhythmia, bradycardia, chest pain, confusion, coldness sensation, delirium, difficulty concentrating, dysphonia, fear, generalized seizure, hiccups, hyperacusis, hypertension, junctional tachycardia, panic attacks, rigors, seizure, shivering, somnolence, stupor, tachycardia, thick tongue, tinnitus, transient hearing impairment, ventricular tachycardia, withdrawal syndrome

ALERT: U.S. Boxed Warning

Seizures:

The use of flumazenil has been associated with the occurrence of seizures. These are most frequent in patients who have been on benzodiazepines for long-term sedation or in overdose cases where patients are showing signs of serious cyclic antidepressant overdose. Practitioners should individualize the dosage of flumazenil and be prepared to manage seizures.

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: [U.S. 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, and other residual effects of benzodiazepines for at least 2 hours and until the patient is stable and resedation is unlikely.

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

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, nausea, vomiting, blurred vision, dry mouth, application site pain or irritation, headache, sweating a lot, anxiety, tremors, or insomnia. Have patient report immediately to prescriber seizures, difficulty breathing, slow breathing, shallow breathing, fast breathing, tachycardia, arrhythmia, bradycardia, severe headache, angina, loss of strength and energy, vision changes, mood changes, change in balance, or burning or numbness feeling (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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