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FLUMAZENIL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Flumazenil, an imidazobenzodiazepine derivative, is a benzodiazepine antagonist.

Specific Substances

    1) Flumazenilum
    2) Flumazepil
    3) Ro-15-1788
    4) Ro-15-1788/000
    5) Ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate
    6) Molecular Formula: C15-H14-F-N3-O3
    7) CAS 78755-81-4

Available Forms Sources

    A) FORMS
    1) Flumazenil is available as 0.1 mg/mL solution for injection (Prod Info flumazenil intravenous injection, 2013).
    B) USES
    1) ADULTS: Flumazenil is indicated for the complete or partial reversal of benzodiazepine-induced sedation after general anesthesia, diagnostic or therapeutic procedures, and the management of benzodiazepine overdose (Prod Info flumazenil intravenous injection, 2013).
    2) CHILDREN (age 1- to 17-years-old): Flumazenil is used to reverse benzodiazepine-induced conscious sedation (Prod Info flumazenil intravenous injection, 2013).
    3) BENZODIAZEPINE REVERSAL
    a) CHLORDIAZEPOXIDE TOXICITY: Continuous infusion flumazenil was successfully used to treat a case of chlordiazepoxide toxicity in a 67 year old man with chronic alcoholism. The patient was admitted to the hospital for detoxification and treated with oral chlordiazepoxide for symptoms of withdrawal. He became sedated on day 3 of chlordiazepoxide treatment after receiving 250 mg of chlordiazepoxide on day 1 and 400 mg on day 2. Chlordiazepoxide was discontinued on day 3; however, his mental status continued to deteriorate and he developed respiratory depression and atrial fibrillation. On day 5 the patient was obtunded, unresponsive, and toxic levels of chlordiazepoxide were detected at 17.5 mcg/mL (therapeutic range: 1 to 3 mcg/mL). He was admitted to the intensive care unit and treated with 3 separate trial doses of flumazenil 1 mg IV over a period for 4 to 5 days. Each challenge resulted in some short-term improvement, which was not maintained. Starting on day 10 of admission, he received 3 courses of continuous IV flumazenil at 0.5 to 1 mg/hour over a 9-day period. Twelve days after the flumazenil was discontinued he was discharged (Maxa et al, 2003).
    4) NON-BENZODIAZEPINE REVERSAL
    a) BACLOFEN TOXICITY: Two adults being treated for tetanus developed CNS and respiratory depression one hour after receiving intrathecal baclofen injections (1 mg and 400 mcg). Both had immediate improvement in level of consciousness and ventilation after treatment with flumazenil 0.5 mg as an IV bolus. Institution of a flumazenil infusion at 0.1 mg/hour resulted in reappearance of tonic spasms 13 hours later with resultant respiratory failure in one of the patients. The second patient had no recurrence of spasms despite an 18 hour infusion of flumazenil at 0.1 mg/hour (Saissy et al, 1992).
    1) Flumazenil 0.25 mg had no effect in a 21-year-old man with coma after ingesting 240 mg of baclofen (Roberge et al, 1994).
    2) A 30-year-old woman with cerebral palsy on chronic therapy with diazepam and baclofen developed profound CNS depression 6 hours after ingesting 50 tablets of both diazepam (2 mg) and baclofen (10 mg). She was treated with 0.5 mg of flumazenil and developed a tonic clonic seizure within 30 seconds, which resolved after intravenous administration of 30 mg of diazepam. The authors speculated that the flumazenil unmasked the proconvulsant effects of baclofen (Chern & Kwan, 1996).
    b) CARBAMAZEPINE TOXICITY: Flumazenil 50 mg IV was reported to reverse coma in a 35-year-old woman with a negative plasma toxicology screen for benzodiazepines and a carbamazepine level of 27.8 mg/L (Zuber et al, 1988).
    c) CARISOPRODOL TOXICITY: A 52-year-old woman who was reportedly taking her carisoprodol tablets in an erratic fashion (an estimated 35 extra tablets were taken over a 13 day period) developed stupor (aroused with stimulation) along with confusion and garbled speech. Drug screen was positive for carisoprodol (serum level 7.4 mcg/mL) and meprobamate (serum level 30.7 mcg/mL) only. The patient received naloxone with no noticeable improvement; clinical symptoms improved within minutes of flumazenil (0.2 mg IV) administration. A second dose reversed all symptoms of intoxication (Roberge et al, 2000).
    d) CHLORZOXAZONE TOXICITY: The successful use of IV flumazenil (0.1 mg followed by 0.25 mg 30 minutes later) was reported after chlorzoxazone overdose (chlorzoxazone levels 39 mcg/mL) in a patient with coma. The patient did have a positive benzodiazepine drug screen, but the levels were subtherapeutic or therapeutic and probably not a direct cause of the patient's coma. The authors suggested that chlorzoxazone may interact with benzodiazepine receptors, making flumazenil potentially useful in overdose (Roberge et al, 1998).
    e) GABAPENTIN TOXICITY: Flumazenil was effectively used to treat gabapentin toxicity in an 83-year-old, hemodialysis-dependent man with end-stage renal disease. Two weeks following surgery for above-the-knee amputation, gabapentin 200 mg was ordered after each dialysis treatment for phantom limb pain. Approximately 4 hours after ingesting the first dose of gabapentin, the patient became comatose. Spontaneous limb movement returned after he was treated with a trial dose of flumazenil 0.2 mg IV. A second infusion of flumazenil 0.3 mg IV was administered and within 15 minutes the patient was responsive and speaking clearly (Butler et al, 2003).
    f) METHAMPHETAMINE-DEPENDANCY: In a 12-week, open-label, single-group study, 50 methamphetamine-dependent patients (18 to 65 years of age), who used methamphetamine within 7 days of study entry, received flumazenil, hydroxyzine, and gabapentin for 4 weeks and then they were followed for an additional 8 weeks. Overall, this treatment program was associated with significant reductions in frequency of thoughts about methamphetamine use, level of discomfort/disturbance from thoughts about use, short-term or long-term desire/intensity of cravings, intensity of cravings when in the presence of environmental cues to use, and time preoccupied by thoughts of methamphetamine use (Urschel et al, 2007).
    g) PROMETHAZINE TOXICITY: Flumazenil 0.5 mg IV was associated with reversal of CNS depression in a patient who inadvertently received 200 mg of promethazine IV (Plant & MacLeod, 1994). Routine use is NOT recommended.
    5) CONTRAINDICATIONS
    a) TRICYCLIC ANTIDEPRESSANTS: Flumazenil should not be used in patients with serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, seizure), dysrhythmias (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), or cardiovascular collapse at presentation (Prod Info flumazenil intravenous injection, 2013; Thomson et al, 2006).
    b) Flumazenil should not be used in patients who are benzodiazepine dependent or who have been given benzodiazepines for control of a life-threatening condition(Prod Info flumazenil intravenous injection, 2013; Thomson et al, 2006).
    c) There is no known benefit of treatment with flumazenil in a mixed drug overdose patient who is in critical condition. Flumazenil should NOT be used in cases where seizures are likely, from any cause (Prod Info flumazenil intravenous injection, 2013; Thomson et al, 2006).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Flumazenil is a benzodiazepine antagonist used to reverse benzodiazepine activity in the setting of benzodiazepine overdose, general anesthesia, or procedural sedation.
    B) PHARMACOLOGY: Flumazenil is an imidazobenzodiazepine derivative that selectively antagonizes the effects of benzodiazepines in the CNS by competitively inhibiting their actions at the benzodiazepine binding site of the GABA-benzodiazepine receptor complex.
    C) TOXICOLOGY: Flumazenil has been associated with precipitation of seizures in patients who are benzodiazepine dependent, have a history of seizures, and who have co-ingested a benzodiazepine and another medication that causes seizures (eg, tricyclic antidepressants or cocaine).
    D) EPIDEMIOLOGY: Flumazenil overdose is extremely rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects with therapeutic use of flumazenil are dizziness, nausea, vomiting, diaphoresis, headache, blurred vision, anxiety, and injection site pain. Seizures may occur, especially in patients who are benzodiazepine-dependent, have an underlying seizure disorder, or who have ingested other medications associated with precipitation of seizures.
    2) RARE: Rarely, dysrhythmias, bradycardia, tachycardia, hypotension, hypertension, confusion, somnolence, shivering, rigors, or increased muscle tone may occur. Dysrhythmias are more common in patients who have also taken other medications known to cause dysrhythmias (eg, tricyclic antidepressants).
    F) WITH POISONING/EXPOSURE
    1) Overdose in a patient who does not chronically use benzodiazepines is not expected to cause adverse effects. Overdose (or therapeutic use) in a patient who is chronically using benzodiazepines may precipitate withdrawal or seizures.
    0.2.20) REPRODUCTIVE
    A) Flumazenil is in FDA pregnancy category C.

Laboratory Monitoring

    A) Monitor vital signs.
    B) Monitor serum electrolytes in patients with seizures or recurrent vomiting.
    C) Flumazenil concentrations are not widely available or clinically useful.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treatment with benzodiazepines or barbiturates for seizure control may be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: Acute toxicity usually follows therapeutic intravenous administration. Gastrointestinal decontamination is not necessary.
    2) HOSPITAL: Acute toxicity usually follows therapeutic intravenous administration. Gastrointestinal decontamination is not necessary.
    D) AIRWAY MANAGEMENT
    1) Patients who develop seizures or status epilepticus may require intubation for airway management.
    E) ANTIDOTE
    1) There is no specific antidote for flumazenil toxicity. High-dose benzodiazepines or barbiturates may be required to control seizures following flumazenil administration.
    F) SEIZURES
    1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    G) ENHANCED ELIMINATION
    1) There is no role for hemodialysis.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no role for home management.
    2) OBSERVATION CRITERIA: A majority of patients who receive flumazenil will already be at a healthcare facility. Approximately 10% to 33% of patients who receive flumazenil for reversal of benzodiazepine effects from general anesthesia or procedural sedation will have resedation. The time course of resedation is poorly described in the literature at this time.
    3) ADMISSION CRITERIA: Patients who develop severe signs and symptoms after receiving flumazenil such as seizures, dysrhythmias, hypotension, or tachycardia should be admitted to a hospital. Any patient with recurrent seizures, status epilepticus, recurrent dysrhythmias, or refractory hypotension should be admitted to an ICU.
    4) CONSULT CRITERIA: Contact a medical toxicologist or your local poison center for any patient with suspected severe adverse effects after receiving flumazenil (eg, seizures, dysrhythmias, hypotension).
    I) PITFALLS
    1) Flumazenil should not be administered to patients who have a history of seizures, who have received benzodiazepines for current treatment of seizures, who have also ingested a substance that is proarrhythmogenic or that is known to provoke seizures, who use benzodiazepines chronically, or patients who have ECG findings concerning for tricyclic antidepressant toxicity (QRS prolongation, QT prolongation, terminal rightward axis). Patients treated with flumazenil for benzodiazepine induced sedation will often have recurrent CNS depression and require careful monitoring.
    J) PHARMACOKINETICS
    1) Flumazenil is well-absorbed from the gastrointestinal tract but has poor systemic bioavailability (20%) due to a large first-pass effect. When given IV, time to peak concentration is 3 minutes. Serum levels then rapidly decline and are typically below detectable limits within 4 to 6 hours of administration. Flumazenil is 40% to 50% protein bound in the serum, with a volume of distribution of 0.63 to 1.6 L/kg. Flumazenil undergoes extensive hepatic metabolism; there are no active metabolites. Less than 1% of the drug is excreted renally in the unchanged form. The elimination half-life is 40 to 80 minutes.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause seizure activity.

Range Of Toxicity

    A) TOXICITY: The toxic dose of flumazenil has not been established.
    B) THERAPEUTIC DOSE: ADULTS: The initial flumazenil dose for benzodiazepine overdose is 0.2 mg IV over 30 seconds. If the desired response is not obtained after waiting an additional 30 seconds, a dose of 0.3 mg can be administered over 30 seconds. Additional doses of 0.5 mg can be given over 30 seconds at 1-minute intervals up to a total cumulative dose of 3 mg. Rarely, patients who exhibit a partial response after 3 mg may require additional titration of flumazenil up to a cumulative dose of 5 mg. If the patient has not responded after receiving a cumulative dose of 5 mg, the major cause of sedation is most likely not due to benzodiazepines and additional flumazenil is unlikely to produce additional effects. If resedation occurs, repeat doses may be administered at 20-minute intervals as needed. For retreatment, no more than 1 mg should be given at one time (administered as 0.5 mg/minute); no more than 3 mg should be given within 1 hour.

Clinical Effects

Summary Of Exposure

    A) USES: Flumazenil is a benzodiazepine antagonist used to reverse benzodiazepine activity in the setting of benzodiazepine overdose, general anesthesia, or procedural sedation.
    B) PHARMACOLOGY: Flumazenil is an imidazobenzodiazepine derivative that selectively antagonizes the effects of benzodiazepines in the CNS by competitively inhibiting their actions at the benzodiazepine binding site of the GABA-benzodiazepine receptor complex.
    C) TOXICOLOGY: Flumazenil has been associated with precipitation of seizures in patients who are benzodiazepine dependent, have a history of seizures, and who have co-ingested a benzodiazepine and another medication that causes seizures (eg, tricyclic antidepressants or cocaine).
    D) EPIDEMIOLOGY: Flumazenil overdose is extremely rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects with therapeutic use of flumazenil are dizziness, nausea, vomiting, diaphoresis, headache, blurred vision, anxiety, and injection site pain. Seizures may occur, especially in patients who are benzodiazepine-dependent, have an underlying seizure disorder, or who have ingested other medications associated with precipitation of seizures.
    2) RARE: Rarely, dysrhythmias, bradycardia, tachycardia, hypotension, hypertension, confusion, somnolence, shivering, rigors, or increased muscle tone may occur. Dysrhythmias are more common in patients who have also taken other medications known to cause dysrhythmias (eg, tricyclic antidepressants).
    F) WITH POISONING/EXPOSURE
    1) Overdose in a patient who does not chronically use benzodiazepines is not expected to cause adverse effects. Overdose (or therapeutic use) in a patient who is chronically using benzodiazepines may precipitate withdrawal or seizures.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) In clinical trials, abnormal vision (visual field defect and diplopia) occurred in 1% to 3% (n= 1875) of patients treated with flumazenil (Prod Info Romazicon(R), flumazenil, 2000).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) In clinical trials, abnormal hearing (transient hearing impairment, hyperacusis, and tinnitus) has occurred in less than 1% of patients (n=1875) receiving flumazenil (Prod Info Romazicon(R), flumazenil, 2000).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) VASODILATATION
    1) WITH THERAPEUTIC USE
    a) In clinical trials, cutaneous vasodilation (sweating, flushing, and hot flashes) was frequently reported with flumazenil (S Sweetman , 2001; Prod Info Romazicon(R), flumazenil, 2000).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has also been reported rarely (S Sweetman , 2001; Winckler et al, 1988).
    C) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) In clinical trials, dysrhythmias (atrial, nodal, ventricular extrasystoles), bradycardia, and tachycardia have occurred in less than 1% of patients (n=1875) receiving flumazenil (S Sweetman , 2001; Prod Info Romazicon(R), flumazenil, 2000; Marchant et al, 1989; Winckler et al, 1988).
    b) In several patients, dysrhythmias, sometimes preceded by tonic-clonic (grand mal) seizures, and occasionally fatal, have been reported (S Sweetman , 2001; Burr et al, 1989; Marchant et al, 1989; Short et al, 1988). Patients developing significant ventricular dysrhythmias after flumazenil administration have generally taken toxic doses of drugs known to cause dysrhythmias (e.g. chloral hydrate, tricyclic antidepressants).
    c) Dysrhythmias have been reported in 2 patients (n=1875) receiving flumazenil for a benzodiazepine overdose (1 ventricular tachycardia, 1 junctional tachycardia) (Prod Info Romazicon, 2000).
    d) CASE REPORT - Ventricular dysrhythmia, precipitated by flumazenil, was reported in 30-year-old female after taking an overdose of an unknown quantity of oxazepam and chloral hydrate (Short et al, 1988).
    e) CASE REPORT: The use of flumazenil in an elderly patient was associated with transient complete heart block, followed by bradycardia (30 to 50 beats/minute) and first degree heart block which reversed with atropine (Herd & Clarke, 1991).
    D) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In clinical trials, hypertension was reported in less than 1% of patients (n=1875) receiving flumazenil (S Sweetman , 2001; Prod Info Romazicon(R), flumazenil, 2000).
    E) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) In clinical trials, chest pain was reported in less than 1% of patients (n=1875) receiving flumazenil (Prod Info Romazicon(R), flumazenil, 2000).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Dizziness is a frequently reported central nervous system adverse effect (10%). Other frequently reported effects include fatigue, headache, agitation, emotional lability, and paresthesia. Central nervous system toxicities (confusion, convulsion, somnolence, shivering and rigors) have been reported in less than 1% of patients (S Sweetman , 2001; Prod Info Romazicon(R), flumazenil, 2000).
    b) A higher incidence of central nervous system side effects has been reported in one study of 61 patients treated with flumazenil; 6 experienced chills, anxiety, and vomiting developed in 3 patients (Winckler et al, 1988). In another study, 2 of 15 patients experienced anxiety immediately following the injection of flumazenil (Breimer et al, 1988).
    c) Dizziness, headaches, and shivering have also been reported (Zuurmond et al, 1989; (Riishede et al, 1988; Merry et al, 1988).
    d) Panic attacks may be precipitated by flumazenil in patients with a history of panic disorder (Prod Info Romazicon(R), 1998; (Nutt et al, 1990; Woods et al, 1991; Maddock, 1998).
    2) WITH POISONING/EXPOSURE
    a) Reversal of benzodiazepine-induced sedation with high doses of flumazenil may cause agitation, anxiety, increased muscle tone, hyperesthesia and possibly convulsions. (S Sweetman , 2001; Prod Info Romazicon(R), flumazenil, 2000).
    B) SEDATED
    1) WITH THERAPEUTIC USE
    a) In patients who responded to flumazenil for general anesthesia reversal, 10% to 15% experienced resedation. It was more commonly seen in patients receiving larger doses of midazolam (greater than 20 mg), having longer procedures (greater than 60 minutes), and those receiving neuromuscular blockers (Prod Info Romazicon(R), flumazenil, 2000).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been reported following the use of flumazenil (S Sweetman , 2001; Prod Info Romazicon(R), flumazenil, 2000; Chern & Kwan, 1996; Haverkos et al, 1994; Burr et al, 1989). In several patients, dysrhythmias, sometimes preceded by tonic-clonic (grand mal) seizures, and occasionally fatal, have been reported (S Sweetman , 2001; Burr et al, 1989; Marchant et al, 1989; Short et al, 1988). Patients developing significant ventricular dysrhythmias after flumazenil administration have generally taken toxic doses of drugs known to cause dysrhythmias (e.g. chloral hydrate, tricyclic antidepressants).
    b) INCIDENCE
    1) Seizures are most frequently observed 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 (Prod Info Romazicon(R), flumazenil, 2000).
    2) ADULTS: In a review of data from The California Poison Control System (CPCS) between 1999 and 2008, 904 cases involving flumazenil use were identified for individuals 18 years of age or older. Seizure development was documented In 13 (1.4%) of the 904 cases. In 9 of those 13 cases, seizures occurred immediately after flumazenil administration. One death occurred. Further analysis showed that seizure development was significantly associated with pro-convulsant drug exposure (OR 3.41;95% CI 1.13 to 10.72) (Kreshak et al, 2012).
    3) PEDIATRIC: In a review of data from The California Poison Control System (CPCS) between 1999 and 2008, 83 cases involving flumazenil use were identified in children less than or equal to 12 years of age. Out of these 83 cases, 68 (81.9%) were reportedly associated with benzodiazepine exposure and 12 (14.5%) were exposed to a proconvulsant drug. Among the 83 cases identified, no seizures occurred in association with flumazenil use (Kreshak et al, 2012a).
    c) POSSIBLE RISK FACTORS
    1) Concurrent major sedative-hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, myoclonic jerking or seizure activity before the flumazenil administration in overdose cases, or concurrent cyclic anti-depressant poisoning (Prod Info Romazicon(R), flumazenil, 2000).
    2) One study reviewed 43 cases of seizures associated with the administration of flumazenil. In the majority of cases, the patients had an underlying cause to account for the seizure. In some cases, the seizure occurred as a result of reversing the anticonvulsant effect of a benzodiazepine administered previously to control a seizure episode. Seizures also appear to have been related to benzodiazepine withdrawal symptoms induced by flumazenil (Spivey, 1992).
    3) Substantial risk of seizures exists for patients presenting in coma with suspected drug overdose (Gueye et al, 1996).
    d) CASE REPORTS
    1) A 30-year-old woman developed a tonic-clonic seizure within 30 seconds of receiving flumazenil 0.5 mg intravenously for the treatment of a mixed baclofen and diazepam overdose. The woman with cerebral palsy but no seizure disorder ingested 50 tablets of both baclofen 10 mg and diazepam 2 mg. The authors hypothesized that the flumazenil may have unmasked a proconvulsant effect (similar to that of tricyclic antidepressants) of the baclofen (Chern & Kwan, 1996).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are common adverse effects reported with flumazenil occurring in approximately 11% of patients (n=1875) (S Sweetman , 2001; Prod Info Romazicon(R), flumazenil, 2000) Zuurmond et al, 1988; (Riishede et al, 1988; Breimer et al, 1988; Winckler et al, 1988; Wolff, 1988).
    B) HICCOUGHS
    1) WITH THERAPEUTIC USE
    a) Hiccups have been reported infrequently (Prod Info ROMAZICON(R) injection, 2007; Dunton et al, 1988).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) INJECTION SITE PAIN
    1) WITH THERAPEUTIC USE
    a) Pain on injection (Prod Info Romazicon(R), flumazenil, 2000; Claeys et al, 1988; Dunton et al, 1988) and at the site of the surgical wound (Breimer et al, 1988) have been reported following flumazenil administration. In addition, injection site reactions including thrombophlebitis, skin abnormality, and rash have been reported (Prod Info Romazicon(R), flumazenil, 2000).
    B) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Sweating has been reported rarely following flumazenil administration (Winckler et al, 1988).
    b) In clinical trials, cutaneous vasodilation (sweating, flushing, and hot flashes) was frequently reported with flumazenil (S Sweetman , 2001; Prod Info Romazicon(R), flumazenil, 2000).

Reproductive

    3.20.1) SUMMARY
    A) Flumazenil is in FDA pregnancy category C.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) US Food and Drug Administration Pregnancy Category C (Prod Info Romazicon(R), flumazenil, 2000).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) Monitor serum electrolytes in patients with seizures or recurrent vomiting.
    C) Flumazenil concentrations are not widely available or clinically useful.
    4.1.2) SERUM/BLOOD
    A) Monitor serum electrolytes in patients with seizures or recurrent vomiting.
    B) Flumazenil concentrations are not widely available or clinically useful.
    4.1.4) OTHER
    A) OTHER
    1) Monitor vital signs.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients who develop severe signs and symptoms after receiving flumazenil such as seizures, dysrhythmias, hypotension, or tachycardia should be admitted to a hospital. Any patient with recurrent seizures, status epilepticus, recurrent dysrhythmias, or refractory hypotension should be admitted to an ICU.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no role for home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Contact a medical toxicologist or your local poison center for any patient with suspected severe adverse effects after receiving flumazenil (eg, seizures, dysrhythmias, hypotension).
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) A majority of patients who receive flumazenil will already be at a healthcare facility. Approximately 10% to 33% of patients who receive flumazenil for reversal of benzodiazepine effects from general anesthesia or procedural sedation will have resedation. The time course of resedation is poorly described in the literature at this time.

Monitoring

    A) Monitor vital signs.
    B) Monitor serum electrolytes in patients with seizures or recurrent vomiting.
    C) Flumazenil concentrations are not widely available or clinically useful.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Acute toxicity usually follows therapeutic intravenous administration. Gastrointestinal decontamination is not necessary.

Range Of Toxicity

Summary

    A) TOXICITY: The toxic dose of flumazenil has not been established.
    B) THERAPEUTIC DOSE: ADULTS: The initial flumazenil dose for benzodiazepine overdose is 0.2 mg IV over 30 seconds. If the desired response is not obtained after waiting an additional 30 seconds, a dose of 0.3 mg can be administered over 30 seconds. Additional doses of 0.5 mg can be given over 30 seconds at 1-minute intervals up to a total cumulative dose of 3 mg. Rarely, patients who exhibit a partial response after 3 mg may require additional titration of flumazenil up to a cumulative dose of 5 mg. If the patient has not responded after receiving a cumulative dose of 5 mg, the major cause of sedation is most likely not due to benzodiazepines and additional flumazenil is unlikely to produce additional effects. If resedation occurs, repeat doses may be administered at 20-minute intervals as needed. For retreatment, no more than 1 mg should be given at one time (administered as 0.5 mg/minute); no more than 3 mg should be given within 1 hour.

Therapeutic Dose

    7.2.1) ADULT
    A) CONSCIOUS SEDATION REVERSAL
    1) INITIAL DOSE: The recommended dose is 0.2 mg administered intravenously over 15 seconds. If adequate anesthesia reversal does not occur after waiting an additional 45 seconds, this dose may be repeated at 1-minute intervals as needed, up to a maximum of 4 additional times. MAX DOSE: 1 mg (Prod Info flumazenil intravenous injection, 2013).
    2) RESEDATION: repeat doses may be administered at 20-minute intervals as needed. For retreatment, no more than 1 mg should be given at one time (given as 0.2 mg/minute). MAX DOSE: 3 mg in an hour (Prod Info flumazenil intravenous injection, 2013).
    B) GENERAL ANESTHESIA REVERSAL
    1) INITIAL DOSE: The recommended dosage is 0.2 mg administered intravenously over 15 seconds. If adequate anesthesia reversal does not occur after waiting an additional 45 seconds, this dose may be repeated at 1-minute intervals as needed, up to a maximum of 4 additional times. MAX DOSE: 1 mg (Prod Info ROMAZICON(R) IV injection, 2004).
    2) RESEDATION: repeat doses may be administered at 20-minute intervals as needed. For retreatment, no more than 1 mg should be given at one time (given as 0.2 mg/minute), and no more than 3 mg should be given within one hour (Prod Info flumazenil intravenous injection, 2013).
    C) BENZODIAZEPINE OVERDOSE
    1) INITIAL DOSE: The recommended initial flumazenil dose is 0.2 mg administered intravenously over 30 seconds. If the desired response is not obtained after waiting an additional 30 seconds, a dose of 0.3 mg can be administered over 30 seconds. Additional doses of 0.5 mg can be given over 30 seconds at 1-minute intervals up to a total cumulative dose of 3 mg. Rarely, patients who exhibit a partial response after 3 mg may require additional titration of flumazenil up to a cumulative dose of 5 mg. If the patient has not responded after receiving a cumulative dose of 5 mg, the major cause of sedation is most likely not due to benzodiazepines and additional flumazenil is unlikely to produce additional effects (Prod Info flumazenil intravenous injection, 2013).
    2) RESEDATION: repeat doses may be administered at 20-minute intervals as needed. For retreatment, no more than 1 mg should be given at one time (given as 0.5 mg/minute); no more than 3 mg should be given within one hour (Prod Info flumazenil intravenous injection, 2013).
    3) CHLORDIAZEPOXIDE TOXICITY: Continuous infusion flumazenil was successfully used to treat a case of chlordiazepoxide toxicity in a 67 year old man with chronic alcoholism. The patient was admitted to the hospital for detoxification and treated with oral chlordiazepoxide for symptoms of withdrawal. He became sedated on day 3 of chlordiazepoxide treatment after receiving 250 mg of chlordiazepoxide on day 1 and 400 mg on day 2. Chlordiazepoxide was discontinued on day 3; however, his mental status continued to deteriorate and he developed respiratory depression and atrial fibrillation. On day 5 the patient was obtunded, unresponsive, and toxic levels of chlordiazepoxide were detected at 17.5 mcg/mL (therapeutic range: 1 to 3 mcg/mL). He was admitted to the intensive care unit and treated with 3 separate trial doses of flumazenil 1 mg IV over a period for 4 to 5 days. Each challenge resulted in some short-term improvement, which was not maintained. Starting on day 10 of admission, he received 3 courses of continuous IV flumazenil at 0.5 to 1 mg/hour over a 9-day period. Twelve days after the flumazenil was discontinued he was discharged (Maxa et al, 2003).
    D) NON-BENZODIAZEPINE OVERDOSE
    1) BACLOFEN TOXICITY: Two adults being treated for tetanus developed CNS and respiratory depression one hour after receiving intrathecal baclofen injections (1 mg and 400 mcg). Both had immediate improvement in level of consciousness and ventilation after treatment with flumazenil 0.5 mg as an IV bolus. Institution of a flumazenil infusion at 0.1 mg/hour resulted in reappearance of tonic spasms 13 hours later with resultant respiratory failure in one of the patients. The second patient had no recurrence of spasms despite an 18 hour infusion of flumazenil at 0.1 mg/hour (Saissy et al, 1992).
    2) CARBAMAZEPINE TOXICITY: Flumazenil 50 mg IV was reported to reverse coma in a 35-year-old woman with a negative plasma toxicology screen for benzodiazepines and a carbamazepine level of 27.8 mg/L (Zuber et al, 1988).
    3) CARISOPRODOL TOXICITY: A 52-year-old woman who was reportedly taking her carisoprodol tablets in an erratic fashion (an estimated 35 extra tablets were taken over a 13 day period) developed stupor (aroused with stimulation) along with confusion and garbled speech. Drug screen was positive for carisoprodol (serum level 7.4 mcg/mL) and meprobamate (serum level 30.7 mcg/mL) only. The patient received naloxone with no noticeable improvement; clinical symptoms improved within minutes of flumazenil (0.2 mg IV) administration. A second dose reversed all symptoms of intoxication (Roberge et al, 2000).
    4) CHLORZOXAZONE TOXICITY: The successful use of IV flumazenil (0.1 mg followed by 0.25 mg 30 minutes later) was reported after chlorzoxazone overdose (chlorzoxazone levels 39 mcg/mL) in a patient with coma. The patient did have a positive benzodiazepine drug screen, but the levels were subtherapeutic or therapeutic and probably not a direct cause of the patient's coma. The authors suggested that chlorzoxazone may interact with benzodiazepine receptors, making flumazenil potentially useful in overdose (Roberge et al, 1998).
    5) GABAPENTIN TOXICITY: Flumazenil was effectively used to treat gabapentin toxicity in an 83-year-old, hemodialysis-dependent man with end-stage renal disease. Two weeks following surgery for above-the-knee amputation, gabapentin 200 mg was ordered after each dialysis treatment for phantom limb pain. Approximately 4 hours after ingesting the first dose of gabapentin, the patient became comatose. Spontaneous limb movement returned after he was treated with a trial dose of flumazenil 0.2 mg IV. A second infusion of flumazenil 0.3 mg IV was administered and within 15 minutes the patient was responsive and speaking clearly (Butler et al, 2003).
    6) PROMETHAZINE TOXICITY: Flumazenil 0.5 mg IV was associated with reversal of CNS depression in a patient who inadvertently received 200 mg of promethazine IV (Plant & MacLeod, 1994). Routine use is NOT recommended.
    7.2.2) PEDIATRIC
    A) DISEASE STATE
    1) CONSCIOUS SEDATION REVERSAL: The usual dosage in children 1 year or older is 0.01 mg/kg (up to 0.2 mg) administered intravenously over 15 seconds. If adequate anesthesia reversal does not occur after waiting an additional 45 seconds, further injections of 0.01 mg/kg (up to 0.2 mg) may be repeated at 1-minute intervals as needed, up to 4 times. MAX DOSE: 0.05 mg/kg or 1 mg, whichever is lower (Prod Info flumazenil intravenous injection, 2013).
    a) The safety and efficacy of administering repeated doses in the case of resedation or has not been established.
    b) The safety and efficacy of flumazenil have not been established in pediatric patients less than a year of age for reversal of sedative effects of benzodiazepines after conscious sedation (Prod Info flumazenil intravenous injection, 2013).
    2) GENERAL ANESTHESIA REVERSAL OR BENZODIAZEPINE OVERDOSE: The safety and efficacy of flumazenil have not been established in pediatric patients for reversal of sedative effects of benzodiazepines after general anesthesia or for the management of benzodiazepine overdose (Prod Info flumazenil intravenous injection, 2013).

Minimum Lethal Exposure

    A) The toxic dose of flumazenil has not been established (Prod Info ROMAZICON(R) injection, 2007).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ADULT
    a) Reversal of central nervous system depression: 10 to 20 mcg/liter (Klotz et al, 1985)
    b) Plasma concentrations above this level are achieved with intravenous doses of 2.5 mg but are maintained only for 1 to 2 hours (Klotz et al, 1984).
    c) Following oral flumazenil 200 mg, peak plasma concentrations of 143 to 439 nanograms/mL occur (Brogden & Goa, 1988; Roncari et al, 1986).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 4 gm/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) 1300 mg/kg (RTECS , 2001)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 1360 mg/kg (RTECS , 2001)
    4) LD50- (ORAL)RAT:
    a) 4200 mg/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Flumazenil is an imidazobenzodiazepine derivative that selectively antagonizes the effects of benzodiazepines in the CNS by competitively inhibiting their actions at the benzodiazepine binding site of the GABA-benzodiazepine receptor complex (Prod Info flumazenil intravenous injection, 2013).
    B) In healthy human volunteers, intravenous flumazenil has been shown to antagonize sedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines (Prod Info flumazenil intravenous injection, 2013).

Physicochemical

Physical Characteristics

    A) Flumazenil is a white to off-white crystalline compound; insoluble in water and slightly soluble in acidic aqueous solutions (Prod Info Romazicon(R), flumazenil, 2000).

Molecular Weight

    A) 303.3 (Prod Info Romazicon(R), flumazenil, 2000)

References

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