Flumazenil

Pharmacologic Category

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.

* See Dosage and Administration in AHFS Essentials for additional information.

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: Renal Impairment: Adult

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: Adult

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

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)

Dosing: Renal Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer’s labeling; adult pharmacokinetic data suggests drug not significantly affected by renal failure (CrCl <10 mL/minute) or hemodialysis.

Dosing: Hepatic Impairment: Pediatric

Initial reversal dose: Use normal dose; repeat doses should be decreased in size or frequency

Calculations

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.

* See Uses in AHFS Essentials for additional information.

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.

Administration: Injectable Detail

pH: ~4 (solution in vial)

Administration: Pediatric

Parenteral: For IV use only; administer by rapid IV injection over 15-30 seconds via a freely running IV infusion into larger vein (to decrease chance of pain, phlebitis). Children: Do not exceed 0.2 mg/minute. In adults for repeat doses, the following is suggested: Do not exceed 0.2 mg/minute for reversal of general anesthesia and do not exceed 0.5 mg/minute for reversal of benzodiazepine overdose.

Dietary Considerations

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

Storage/Stability

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.

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

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.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness

• Nausea

• Vomiting

• Blurred vision

• Dry mouth

• Headache

• Sweating a lot

• Anxiety

• Tremors

• Trouble sleeping

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• 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 an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Medication Safety Issues

Sound-alike/look-alike issues:

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.

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.

* See Cautions in AHFS Essentials for additional information.

Warnings: Additional Pediatric Considerations

Pediatric patients (especially 1 to 5 years of age) may experience resedation; these patients may require repeat bolus doses or continuous infusion.

Pregnancy Risk Factor

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).

Breast-Feeding Considerations

It is not known if flumazenil is excreted in breast milk. The manufacturer recommends that caution be used if administering to breast-feeding women.

Briggs' Drugs in Pregnancy & Lactation

Flumazenil

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

* See Cautions in AHFS Essentials for additional information.

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

There are no known significant interactions.

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.

Advanced Practitioners Physical Assessment/Monitoring

Assess level of consciousness frequently. Monitor vital signs and airway closely. Observe continually for resedation, respiratory depression, seizure activity, or other residual benzodiazepine effects.

Nursing Physical Assessment/Monitoring

Dosage Forms: US

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)

Dosage Forms: Canada

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

Solution, Intravenous:

Generic: 0.1 mg/mL (5 mL)

Anatomic Therapeutic Chemical (ATC) Classification

V03AB25

Generic Available (US)

Yes

Pricing: US

Solution (Flumazenil Intravenous)

0.5 mg/5 mL (per mL): $1.56 - $1.63

1 mg/10 mL (per mL): $1.56 - $7.49

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

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

Pharmacodynamics/Kinetics

Note: Follows a two compartment open model; Clearance and Vd per kg are similar for children and adults, but children display more variability

Onset of action: 1-2 minutes; 80% response within 3 minutes

Peak effect: 6-10 minutes

Duration: 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

Distribution: Initial Vd: 0.5 L/kg; Vdss: 0.9-1.1 L/kg

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

Metabolism: Hepatic; dependent upon hepatic blood flow

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

Excretion: Feces; urine (<1% as unchanged drug)

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

Pharmacodynamics/Kinetics: Additional Considerations

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

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Dental Health Professional Considerations

Sedation: Patients should be monitored for at least 1 hour following administration of flumazenil to ensure full recovery. Flumazenil should only be used in an emergency situation and not as a means of hastening recovery from conscious sedation. When used to hasten recovery, emergence can be sudden and unpleasant. Flumazenil should be used with caution in patients routinely taking benzodiazepines for other therapeutic uses, withdrawal symptoms will be induced.

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).

Effects on Bleeding

No information available to require special precautions

Related Information

Moderate Sedation

Index Terms

Romazicon

FDA Approval Date

December 20, 1991

References

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Brand Names: International

Anexat (RU); Anexate (AE, AT, AU, BE, BF, BG, BH, BJ, CH, CI, CN, CY, DE, EE, EG, ES, ET, GH, GM, GN, GR, HK, HR, HU, ID, IE, IQ, IR, IT, JO, JP, KE, KR, KW, LK, LR, LU, LY, MA, ML, MR, MU, MW, MY, NE, NG, NL, NO, NZ, OM, PH, PK, RO, SA, SC, SD, SI, SK, SL, SN, SY, TH, TN, TR, TW, TZ, UG, VN, YE, ZA, ZM, ZW); Antabenz (MY); Antadona (MX); Antadone (CR, DO, GT, HN, NI, PA, SV); Anzenil (PH); Fadaflumaz (AR); Flumage (AR); Flumil (PY, UY); Flunexate (JO, LB); Flunexil (BR); Flunil (KR); Fluoxem (CL); Lai Yi (CN); Lanexat (BB, BM, BR, BS, BZ, CL, CO, CR, DO, EC, GT, GY, HN, JM, MX, NI, PA, PE, PY, SE, SR, SV, TT, UY, VE)

Last Updated 8/28/20

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