Flumazenil (Systemic)


VA CLASSIFICATION
Primary: AD700
Secondary: CN303

Commonly used brand name(s): Anexate; Romazicon.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Benzodiazepine antagonist—

Indications

General considerations
Administering flumazenil to reverse the effects of benzodiazepines does not eliminate the need for monitoring and evaluating the patient and instituting needed interventions, e.g., establishing an airway, assisting ventilation, and supporting circulation {01}. Although flumazenil partially reverses benzodiazepine-induced hypoventilation, it should not be relied upon to provide complete {01} {02} {04} {06} or sustained {21} {22} reversal of hypoventilation, especially if the patient has also received an opioid analgesic {45}. Also, resedation may occur after initial recovery {01} {02} {04} {07} {08} {09} {11} {12} {13} {31} {32} {67}, although most patients remain more alert than they were before flumazenil administration {07} {08} {09} {11} {12} {13} {67}.

Before flumazenil is administered, the advantages of reversing benzodiazepine-induced sedation should be weighed against the possible disadvantages, especially in high-risk patients {02}. The risks of antagonizing the anticonvulsant effects of benzodiazepines {01} {15} {67} and/or of precipitating a withdrawal syndrome in physically dependent patients {01} {02} {05} {15} {67} must be considered because seizures may result {01}.

Accepted

Sedation, benzodiazepine-induced, reversal{61}—Flumazenil is indicated for partial or complete reversal of postprocedure residual sedation resulting from use of benzodiazepines for induction and/or maintenance of anesthesia, conscious sedation, or deep sedation {01} {02}. The benefits of reversing postprocedure residual sedation are more apparent in patients who are heavily sedated at the time of administration than in patients who are only mildly or moderately sedated {10} {16} {67}. Flumazenil facilitates patient management most significantly during the first hour following administration. After 1 hour, significant spontaneous recovery is also apparent in patients who have not received the medication {06} {11} {12} {67}. Flumazenil has been shown to speed recovery of patients who have received benzodiazepines concurrently with opioid analgesics {01} {04} {08} {10} {11} {12} {13} {14} {31} {67}, inhalation anesthetics {01} {11} {12} {13} {67}, or local {01} {07} {08} {09} {67}, regional {01} {07} {08} {09} {67}, spinal {04} {05} {07} {09} {67}, or topical {07} {08} {09} {67} anesthetics. However, its efficacy may be decreased when multiple anesthetic agents have been used or sedating medications are required postprocedure {01}.
—Flumazenil is indicated to reverse the effects of benzodiazepines used to sedate critical care patients {01}.

Toxicity, benzodiazepine (treatment)—Flumazenil is indicated for the management of benzodiazepine overdose {01} {02}. However, if the patient has been intubated flumazenil may be unnecessary and may complicate patient management by causing agitation {48}. In addition to reversing central nervous system (CNS) depression, flumazenil has been reported to reverse benzodiazepine-induced hypotension and bradycardia unresponsive to administration of intravenous fluids, atropine, and dopamine {18}. Flumazenil is most effective in intoxications caused by a benzodiazepine alone, although resedation occurs frequently {06} {15} {67}. Flumazenil may also be at least partially effective in treating mixed overdoses {04} {05} {15} {23} {67}, but its efficacy depends on the extent to which a benzodiazepine contributes to the intoxication {05}, especially if significant quantities of other sedating medications have been used concurrently {05} {06}. Flumazenil is not a substitute for other measures that may be necessary {01}, but in some clinical trials its use decreased the need for interventions such as gastric lavage {04} {05} {23}, urinary catheterization {04} {23}, and diagnostic tests {23}.
Extreme caution is recommended if flumazenil is considered for treating mixed overdoses in which medications with potential seizurogenic and/or arrhythmogenic activity {01} {04} {05} or unidentified medications {48} may have been taken. Reversal of the protective effect of the benzodiazepine in such cases has resulted in seizures and/or arrhythmias, usually in mixed overdoses with tricyclic antidepressants {01} {04} {05} {41}. Some emergency care physicians recommend that flumazenil not be used until after a diagnostic electrocardiogram and/or quantitative analytical testing has ruled out severe cyclic (tricyclic or tetracyclic) antidepressant overdosage {04}.

Note: Flumazenil does not reverse benzodiazepine-induced amnesia for events occurring prior to administration of the antagonist (retrograde amnesia) {04}. Although flumazenil may partially reverse amnesia for events occurring after it is given (anterograde amnesia), its effects on memory are less complete {01} {04} {06} {07} {13} {67}, less consistent {01} {07} {08} {09} {10} {11} {14} {67}, and of shorter duration {16} than its effects on sedation. Also, although flumazenil may reverse postprocedure psychomotor deficits associated with benzodiazepine administration {01} {10} {11} {12} {13} {14} {15} {16} {17} {67}, normal levels of performance may not be achieved {04} {11} {12} {67}.


Acceptance not established
Flumazenil has been used to reverse benzodiazepine-maintained anesthesia intraoperatively during spinal surgery, to arouse the patient temporarily for assessment of sensory and motor function {06} {19} {46}. Assessments could be performed within 1 or 2 minutes after administration of flumazenil {06} {19}. Postoperatively, the patients did not recall having been aroused {06} {19}. However, flumazenil has been used for this purpose in relatively few patients; more experience is needed before the risks and benefits of this procedure can be determined {62}.

Unaccepted
Flumazenil should not be administered in mixed overdoses if signs of severe cyclic (tricyclic or tetracyclic) antidepressant toxicity are present {01}. Instead, respiration and circulation should be supported until signs of cyclic antidepressant {49} toxicity have abated {01}.

Use of flumazenil for the treatment of benzodiazepine dependence is not recommended. Efficacy has not been established {01}.

Because of the unacceptably high risk of adverse effects, flumazenil should not be used to determine whether dependence on sedating benzodiazepines has occurred in critical care patients {01}.

Flumazenil is not recommended for treatment of hepatic encephalopathy {52} {63}. Although intravenously administered flumazenil has produced partial improvement of neurologic status in some patients, the beneficial effect was not sustained, and several patients became worse after treatment was discontinued {50}. One patient who received twice-daily administration of oral flumazenil in an attempt to prevent return of symptoms experienced a psychotic reaction that began 48 hours after treatment was started and resolved within 12 hours after the medication was discontinued {51}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Flumazenil is a 1,4-imidazobenzodiazepine derivative {04}. It is structurally related to benzodiazepine agonists {01}.
Molecular weight—
    303.29 {26}

pKa—
    1.78 {01}

Octanol:buffer partition coefficient
    14.1 {01}.

Mechanism of action/Effect:

Flumazenil selectively {07} {67} antagonizes or attenuates the effects of benzodiazepines in the CNS {01} {05} {07} {67} by competitively inhibiting their actions at the benzodiazepine binding site of the gamma aminobutyric acid (GABA)–benzodiazepine receptor complex {01} {02} {04} {05} {06} {07} {67}. Flumazenil does not antagonize the effects of CNS-active substances that act via other receptors {01} {02}. Also, flumazenil does not alter the pharmacokinetics of benzodiazepines {01} {02} {28}.

The extent to which flumazenil reverses the effects of a benzodiazepine depends on the dose and plasma concentration of both medications and on the effect being assessed {01}. Flumazenil reverses some components of benzodiazepine-induced hypoventilation {20} {21} {22} {45}, leading to at least partial improvement in respiratory function {20} {21} {22} {45} {47}. One study showed that midazolam's effect on respiration results primarily (but not exclusively) from a reduction in tidal volume, and that flumazenil completely reverses this effect {22}. However, several studies have shown that flumazenil may not affect other measures of respiratory function {22} {45}, especially measures that are independent of patient effort or wakefulness {45}. Also, amnesia is antagonized less consistently and less completely than psychomotor deficits {01} {04} {06} {07} {08} {09} {10} {11} {12} {13} {14} {16} {67}, which may be reversed less completely than sedation {04} {11} {12} {67}.


Other actions/effects:

Animal studies have shown that flumazenil may have some weak agonist or inverse agonist activity {01} {05} {28} {32} when given in high doses {59}. However, therapeutic doses of flumazenil have not produced clinically significant effects other than antagonism of administered benzodiazepines in humans {01} {04} {05} {28}.

Distribution:

Flumazenil is rapidly distributed into the brain {01} {05} {06}. Concentrations are highest in the cerebral cortex (which contains the largest number of benzodiazepine receptors) {01} {04}, intermediate in the inferior temporal lobe and cerebellum {01}, and lowest in white matter {01}.


Volume of distribution (Vol D):

Initially, 0.5 L per kg of body weight (L/kg) {01}. After redistribution, the apparent Vol D is approximately 1 L/kg {01} {32} (range, 0.77 to 1.6 L/kg) {01}. One study in children 5 to 9 years of age also reported a mean Vol D at steady-state of 1 ± 0.2 L/kg {53}. These values are not altered in patients with moderately impaired hepatic function, but are increased by approximately 37% in patients with severe hepatic function impairment {30}.


Protein binding:

Moderate (approximately 50% {01} {02} {04} {05} {28}, of which 66% is bound to albumin) {01}. Protein binding is reduced in patients with hepatic cirrhosis; in one study, the free fraction was increased from 55% in controls to 64 and 79% in patients with moderate and severe hepatic function impairment, respectively {02} {30}.

Biotransformation:

Hepatic {01} {02} {06} {28}; rapid {02} {06} and extensive {02}. Clearance is dependent on hepatic blood flow {01} {28}.

Half-life:


In plasma:

Distribution: 7 to 15 minutes {01}.

Elimination: Approximately 54 minutes (range, 41 to 79 minutes) in adults {01}. One study in children 5 to 9 years of age reported a mean elimination half-life of 35.3 ± 13.8 minutes {53}. Elimination is prolonged to about 1.3 hours and 2.5 hours in patients with moderate and severe hepatic function impairment, respectively {01}, but not affected by renal function impairment {01} {02} {32} or by hemodialysis beginning 1 hour after flumazenil administration {01} {32}. The elimination half-life in pediatric patients is shorter (mean 40 [range, 20 to 75] minutes) and more variable than in adult patients {01}.



In brain:

Elimination: 20 to 30 minutes {32}.


Onset of action:

Approximately 1 to 2 minutes {01} {06}.

Time to peak concentration:

In the CNS—Approximately 1 to 3 minutes {01}.

Peak serum concentration:

1-mg dose, infused over 5 minutes—24 (range, 11 to 43) nanograms per mL (nanograms/mL) (0.08 [range, 0.036 to 0.14] micromoles/L) {01}; substantially higher in patients with moderate, stable, alcoholic cirrhosis {29}. The concentration in the brain may be higher than the simultaneous plasma concentration {32}.

Therapeutic serum concentration

Dependent on the benzodiazepine being reversed and its concentration {54}. In patients receiving usual sedating doses of benzodiazepines, partial reversal generally occurs at flumazenil concentrations of 3 to 6 nanograms/mL (0.01 to 0.02 micromoles/L) and complete reversal usually occurs at concentrations of 12 to 28 nanograms/mL (0.036 to 0.09 micromoles/L). These concentrations are generally produced by doses of 100 to 200 mcg (0.1 to 0.2 mg) and 400 mcg (0.4 mg) to 1 mg, respectively {01}.

Time to peak effect:

6 to 10 minutes after completion of the injection {01} {06}.

Duration of action:

Dependent on the doses and concentrations of the benzodiazepine being antagonized and of flumazenil {01} {06} {32}. In various clinical trials that assessed flumazenil's ability to reverse postprocedure residual sedation, the level of alertness achieved was maintained during the 3-hour observation period in 60 to 95% of the responders {07} {10} {11} {12} {13} {14}. Although up to 40% of the patients experienced partial resedation {07} {08} {09} {10} {11} {12} {13} {31} {67}, most retained an adequate level of alertness {07} {08} {09} {10} {11} {12} {13} {67}. Up to 3% of the patients experienced clinically significant resedation {01}, generally 1 to 2 hours after flumazenil administration {10} {11} {12} {13} {14} {67}. In a study that assessed flumazenil's ability to reverse much larger quantities (i.e., overdoses) of various benzodiazepines, resedation occurred in > 60% of the patients, generally 60 to 90 minutes after flumazenil administration {15} {67}.

Elimination:
    Renal—90 to 95% of a dose {01} {02}, primarily as metabolites (following hepatic metabolism) {01}. In adults, < 1% of a dose is eliminated in the urine as unchanged flumazenil {01}. However, in a study in children 5 to 9 years of age, 5.8 to 13.8% of a dose was eliminated in the urine as unchanged flumazenil {53}.
    Biliary/fecal—In adults: 5 to 10% of a dose {01} {02}.

Note: About 70% of a dose is excreted within 2 hours, and 86% of a dose is excreted within 4 hours, after administration {02}. Elimination is complete within 72 hours {01} {02}.
Plasma clearance in healthy adult subjects ranges from 0.7 to 1.3 (mean, 1) L per hour per kg of body weight {01} (L/hr/kg). Values in pediatric patients undergoing minor surgery are similar; a study in a small number of children 5 to 9 years of age reported a mean clearance rate of 1.2 L/hr/kg {53}.
Ingestion of food during an infusion has been shown to increase flumazenil clearance by 50%, probably by increasing hepatic blood flow {01}. The clinical significance of this effect is not known {64}. Clearance rates may be increased by approximately 25% in patients with chronic stable renal failure (with or without dialysis) {02}, but are not affected by hemodialysis beginning 1 hour after administration of flumazenil {01} or by advanced age {01}. However, clearance rates are decreased to approximately 40 to 60% of normal values in patients with moderate hepatic function impairment and to 25% of normal values in patients with severely impaired hepatic function {01}.



Precautions to Consider

Carcinogenicity

Studies have not been done {01}.

Mutagenicity

Flumazenil was not mutagenic in the Ames test (performed with 5 different test strains), assays in S. cerevisiae D7 and Chinese hamster cells, blastogenesis assays in peripheral human lymphocytes in vitro , and in a mouse micronucleus assay in vivo . Cytotoxic concentrations of flumazenil caused a slight increase in unscheduled DNA synthesis in rat hepatocyte culture, but no increase in DNA repair occurred in male mouse germ cells in an in vivo assay {01}.

Pregnancy/Reproduction
Fertility—
Flumazenil did not impair fertility in male or female rats given oral doses of 125 mg per kg of body weight (mg/kg) per day. This dose is considered, on the basis of area under the concentration-time curve (AUC) comparisons, to represent 120 times the human exposure provided by the maximum recommended intravenous dose of 5 mg {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}. However, after administration to a pregnant woman who took an overdose of diazepam, flumazenil (300 mcg [0.3 mg] intravenously) reversed tachycardia and occasional decelerations in the fetus as well as antagonizing sedation in the woman. Fetal cardiac abnormalities and maternal drowsiness recurred about 15 hours later and responded to a second dose of flumazenil {33}.

Studies in rats given up to 150 mg/kg per day orally from Day 6 to Day 15 of gestation and in rabbits given up to 150 mg/kg per day orally from Day 6 to Day 18 of gestation (120 to 600 times the human exposure provided by the maximum recommended intravenous dose of 5 mg, based on AUC comparisons) found no evidence of teratogenicity. Embryocidal effects (higher rates of preimplantation and postimplantation losses) occurred in rabbits given 50 mg/kg (200 times the human exposure to a 5-mg intravenous dose) but did not occur in rabbits given 15 mg/kg (60 times the human exposure to a 5-mg intravenous dose). Also, decreased survival during lactation, increased liver weight at weaning, delayed incisor eruption, and delayed ear opening (and, consequently, delayed appearance of the auditory startle response) were observed in offspring of rats given 125 mg/kg per day (120 times the human exposure to a 5-mg intravenous dose), but not in offspring of rats given 5 or 25 mg/kg per day (up to 24 times the human exposure to a 5-mg intravenous dose) {01}.

FDA Pregnancy Category C {01}.


Labor and delivery—

The safety of administering flumazenil to reverse the effects of benzodiazepines used during labor and delivery has not been established {01}.

Breast-feeding

It is not known whether flumazenil is distributed into breast milk {01}.

Pediatrics

Flumazenil has been administered to a limited number of pediatric patients up to 17 years of age {06}, including a neonate with apnea (born at 38 weeks' gestation) who had been exposed to diazepam in utero during the last 3 weeks of pregnancy {34} as well as children receiving the medication for reversal of benzodiazepine sedation or for treatment of benzodiazepine overdose {06}. One study showed a higher incidence of resedation in younger children (1 to 5 years of age) than in older children after reversal of benzodiazepine-induced conscious sedation with flumazenil {01} {68}. Mean time to resedation was 25 (range, 19 to 50) minutes {01}.

Flumazenil is not approved for use in neonates and infants {01}.


Geriatrics


Flumazenil was found to be safe and effective in geriatric patients in clinical trials {07} {08} {09} {10} {11} {12} {13} {14} {35} {67}, which included patients up to 91 years of age {07} {08} {10} {67}. Other studies have shown that the pharmacokinetics of flumazenil are not altered, and no adjustment of dosage is needed, in geriatric patients {01}. However, particularly careful monitoring of the patient may be needed because benzodiazepine-induced sedation tends to be deeper and more prolonged in geriatric patients than in younger adults {35}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Benzodiazepines, chronic use of    (the risk of precipitating withdrawal symptoms and of other adverse effects, including those associated with reversal of the therapeutic effects of a benzodiazepine, is increased when flumazenil is administered to patients taking a benzodiazepine chronically {01})


Seizurogenic medications, especially:
» Cyclic (tricyclic or tetracyclic) antidepressants    (high risk of seizures, especially in a mixed overdose with a seizurogenic medication and a benzodiazepine, because flumazenil reverses the anticonvulsant, as well as the sedative, effects of benzodiazepines {01} {04} {05} {15} {41} {67})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Head injury, severe    (flumazenil may induce seizures and/or alter cerebral blood flow in patients with head injury {01}; flumazenil significantly increased intracranial pressure in patients with severe head injuries when intracranial pressure was not well controlled [but not when intracranial pressure was adequately controlled] {32}; it should not be used in cases of severe head injury with known or suspected increases in intracranial pressure or poor compliance in intracranial vessels {32})


» Overdose, cyclic (tricyclic or tetracyclic) antidepressant    (flumazenil may induce seizures)


» Status epilepticus    (flumazenil may worsen status epilepticus by antagonizing the effects of a benzodiazepine used to control the seizures {01})


Risk-benefit should be considered when the following medical problems exist
Anxiety, chronic or episodic, history of or
Anxiety, existing or
Panic disorder    (reversal of benzodiazepines may cause anxiety {01} {02} and has precipitated panic attacks in susceptible patients; {01} {04} careful titration of dosage to clinical response is recommended, especially in patients with cardiac disease {02})


» Benzodiazepine tolerance or dependence    (For patients who may be tolerant to or dependent on benzodiazepines [including patients who have received only a few days of high-dose treatment with benzodiazepines in the intensive care unit], a slower rate of administration and lower total doses should be used to minimize the risk of adverse effects {01}. An alternate plan to manage the cases of patients who may be tolerant to or dependent on benzodiazepines should be considered {01}.)


Cardiac disease, especially with increased left ventricular end-diastolic pressure    (although studies in patients with cardiac disease undergoing cardiac catheterization or surgery have not shown that administration of flumazenil produces significant alterations in cardiac function or evidence of ischemia {24} {36}, caution is recommended if the patient has displayed significant preprocedure nervousness because stress and/or anxiety associated with abrupt reversal of benzodiazepines has led to increased blood pressure in some patients, especially after cardiac surgery {04}; also, flumazenil has increased left ventricular end-diastolic pressure in some patients with coronary artery disease who received the medication to reverse benzodiazepine-induced sedation after cardiac catheterization; although the increases generally represented a return to presedation values, caution is recommended in patients with pre-existing increases in left ventricular end-diastolic pressure {36})


Drug abuse or history of, especially:
» Benzodiazepine abuse or chronic use    (risk of precipitating withdrawal symptoms, including seizures, since the patient may be dependent on benzodiazepines; benzodiazepine-dependent patients receiving flumazenil have had seizures before awakening; also, flumazenil administration may complicate treatment for withdrawal from alcohol, barbiturates, and sedatives to which cross-tolerance may exist {01})


Hepatic function impairment    (clearance of flumazenil is decreased to 40 to 60% of normal in patients with mild to moderate hepatic function impairment, and to 25% of normal in patients with severely impaired hepatic function; although no alteration of initial dosage is necessary, a reduction in the size or frequency of subsequent doses may be needed {01})


» Hypersensitivity to benzodiazepines or to flumazenil{02}
» Seizure disorders, especially if treated with benzodiazepines    (high risk of precipitating seizures {01} {02} {04} {05} {06})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Electrocardiographic determinations    (may be advisable to detect QRS prolongation, a possible sign of cyclic [tricyclic or tetracyclic] antidepressant toxicity, prior to flumazenil administration in overdose situations, especially when mixed overdosage with a cyclic antidepressant is suspected {04})


» Oxygenation, determined via pulse oximetry{56}    (monitoring for an adequate period of time, depending on the dose and duration of action of the benzodiazepine being antagonized, is essential following flumazenil administration because benzodiazepine-induced hypoventilation may not be completely antagonized or may recur {01} {06} {32} {37} {45}; it cannot be assumed that residual respiratory depression is not present in an alert patient {32} {37}; ventilatory assistance and/or supplemental oxygen {65} may be required {01})


» Patient alertness    (monitoring for at least 1 to 2 hours {55} following flumazenil administration is essential, although more prolonged monitoring may be needed {32} {54}, depending on the dose {01} {32} and the duration of action {01} {04} {05} of the benzodiazepine being antagonized {01} {04} {05} {32} and whether other CNS depressants have been or are being given {01}; resedation requiring additional treatment may occur, especially after initial reversal of the effects of large quantities of a benzodiazepine {01} {15} {32} or of a benzodiazepine with a long elimination half-life or active metabolites {52}; patients who do not show signs of resedation within 2 hours after postprocedure administration of 1 mg of flumazenil are not likely to experience severe resedation at a later time {01}; however, resedation may occur 3 to 5 hours {05} or longer {06} {33} [15 hours, in 1 reported case] {33} after reversal of an overdose)


» Vital signs    (monitoring of blood pressure, heart rate, and respiratory rate is recommended so that supplemental treatment can be instituted as required {65})




Side/Adverse Effects

Note: Flumazenil caused no serious adverse effects when administered in large intravenous doses to volunteers who had not received a benzodiazepine agonist. Many side/adverse effects are caused by abrupt reversal of the effects of benzodiazepines {02}.
Reversal of the effects of benzodiazepines in physically dependent patients may precipitate a withdrawal syndrome with symptoms ranging from anxiety, headache, and/or emotional lability to seizures, depending on the degree of dependence. Other possible signs and symptoms of benzodiazepine withdrawal include hypertension {49}, dizziness, involuntary movements, irritability, muscle tension, palpitations, panic, paresthesias, perceptual disturbances, sweating, tachycardia, and tinnitus {02} {05} {38} {39}. The risk of precipitating a withdrawal syndrome is increased with flumazenil doses higher than 1 mg {01} and/or rapid administration {02}. Severe symptoms, especially seizures, may be more likely to occur in patients who have been receiving long-term benzodiazepine therapy, especially for seizure disorders {01} {04} {05} {06} {38}. However, benzodiazepine dependence resulting in an increased risk of seizures {01} {38} or other withdrawal symptoms {38} may develop after relatively short exposure {01} (3 to 5 days) {38} when a benzodiazepine is used to provide continuous sedation in critical care patients {01} {38}.
In addition to the side/adverse effects reported below, arrhythmias including atrial, nodal, and ventricular extrasystoles, bradycardia, and tachycardia; hypertension; and chest pain have been reported (frequencies of occurrence less than 1%). Arrhythmias have been reported mostly in mixed overdoses with potentially arrhythmogenic medications, including chloral hydrate {04} {05} {06} and tricyclic antidepressants {01} {04} {05} {15} {23} {41}. Also, complete heart block occurred in a patient who overdosed on temazepam, atenolol, and nifedipine {40}. It has been proposed that arrhythmias may occur in association with hypoxic seizures after other medications taken together with a benzodiazepine in an overdose have sensitized the myocardium to such complications {06}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent (3 to 9%) {01}
    
Agitation (anxiety; dry mouth; dyspnea; hyperventilation; insomnia; nervousness; palpitations; tremor)
    
headache

Incidence less frequent (1 to 3%) {01}
    
Emotional lability (crying; depersonalization; dysphoria; euphoria; mental depression; paranoia)
    
hypertension
    
resedation, severe
    
skin rash
Note: Anxiety and emotional lability, in addition to being symptoms of benzodiazepine withdrawal, may reflect reversal of the anxiolytic effects for which a benzodiazepine may have been prescribed {38}.
Overall resedation rates of 3 to 9% and 10 to 15% were reported in clinical studies in which flumazenil was used to reverse conscious sedation and deep sedation or anesthesia, respectively, although substantially higher rates of partial resedation have been reported in individual studies {31}. Resedation severe enough to be considered clinically significant occurred less frequently {01}. Resedation may occur in 40 {52} to > 60% {06} {15} {67} of patients being treated for an overdose. The risk of resedation in critical care patients receiving flumazenil for reversal of prolonged sedation is also high {01}. Clinically significant resedation is more likely to occur when large or repeated doses of a benzodiazepine have been administered, especially during a long procedure during which multiple anesthetics have been used {01}, after initial reversal of a long-acting benzodiazepine {01} {04} {05}, and in overdose situations {05} {15} {32}.



Incidence rare (less than 1%)
    
Hallucinations{02}
    
hives or itching of skin{02}
    
seizures without other signs or symptoms of withdrawal{01}
Note: The risk of seizures is increased in benzodiazepine-dependent patients, in patients with seizure disorders {04} {05} (especially if a benzodiazepine is being used for long-term treatment {01} {02} {41} or for control of a convulsive episode), {41} in patients treated for a mixed overdose with a cyclic (tricyclic or tetracyclic) antidepressant {01} {02} {41} or other potentially seizurogenic medication, {41} and in patients who are undergoing withdrawal from nonbenzodiazepine sedative-hypnotic agents. {41}





Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (3 to 11% {01}, unless otherwise specified)
    
Blurred vision or other vision disturbance
    
dizziness, possibly with ataxia and/or vertigo
    
drowsiness, residual or re-emergent —incidence up to 40 to 60%
    
nausea
    
pain at injection site
    
vomiting

Incidence less frequent (1 to 3%) or rare (less than 1%) {01}
    
Fatigue, possibly with asthenia and malaise
    
flushing or hot flashes
    
hearing disturbances
    
thrombophlebitis at injection site





General Dosing Information
Flumazenil administration is not a substitute for interventions such as establishing an airway, assisting ventilation, and supporting circulation. Equipment and medications needed to institute such measures should be available for immediate use {65}.

Equipment required for patient management, such as endotracheal tubes and intravenous access lines, should be securely in place before flumazenil is given. Some patients become confused and agitated when aroused and may attempt to remove them {01}.

Preparation for managing seizures should be made prior to flumazenil administration, especially when flumazenil is used to reverse long-term or high-dose use of a benzodiazepine for sedation in critical care patients or to treat a mixed overdose in which a potentially seizurogenic medication may have been ingested {01}.

Flumazenil is to be administered intravenously. To minimize injection pain, it should be injected into a large vein through a freely flowing intravenous infusion. Extravasation may result in local irritation and should be avoided {01}.

To allow control over the rate and degree of reversal {01} while avoiding complications associated with too-rapid awakening {02} or other adverse effects {01}, it is recommended that flumazenil be administered as a series of small injections rather than as a single dose {01} {02}.

Dosage must be individualized according to the needs of the patient and clinical circumstances {01} {02}. Doses higher than the minimally effective dose are tolerated well by most patients, but administration of more flumazenil than is necessary increases the risk of adverse effects resulting from reversal of a benzodiazepine's therapeutic effects and may complicate the management of physically dependent patients {01}. For patients who may be tolerant to or dependent on benzodiazepines (including patients who have received only a few days of high-dose treatment with benzodiazepines in the intensive care unit), a slower rate of administration and lower total doses should be used to minimize the risk of adverse effects {01}. An alternate plan to manage the cases of patients who may be tolerant to or dependent on benzodiazepines should be considered {01}.

The effects of a neuromuscular blocking agent, if used during surgery or for facilitating assisted ventilation in an intensive care patient, should be reversed completely before flumazenil is administered {01} {32}. Neuromuscular blocking agents should not be used without adequate sedation because the respiratory paralysis they induce is highly distressing to aware patients {27}.

Postprocedure analgesic requirements are not increased in patients who have received flumazenil, but awake patients may report pain, and require earlier treatment, than patients who have not received the reversal agent {42}.

Because psychomotor and memory deficits may persist after sedation has been completely reversed, patients receiving flumazenil following an outpatient procedure should be advised not to resume normal activities for at least 18 to 24 hours after discharge {01} {02} {32}. Also, postprocedure instructions should be given to the patient in writing or given to a responsible caretaker {01}.

For treatment of adverse effects
Recommended treatment consists of the following

   • For seizures—Benzodiazepines are usually recommended for treatment of seizures, but higher than usual doses may be needed after flumazenil has been administered {01}. Therefore, the risk of substantial resedation after the effects of flumazenil have subsided must be considered {49}. Administration of a barbiturate or phenytoin instead of a benzodiazepine should be considered {01}.
   • For CNS effects possibly associated with benzodiazepine withdrawal, e.g., anxiety and emotional lability—Signs and symptoms are usually mild and short-lived and may not require treatment. If severe, continuing symptoms occur, administration of a barbiturate, benzodiazepine, or other sedative may be required {01}.


Parenteral Dosage Forms

FLUMAZENIL INJECTION

Usual adult dose
Benzodiazepine antagonist


Reversal of benzodiazepine-induced sedation:
Intravenous, 200 mcg (0.2 mg), administered over fifteen seconds, initially. If the desired response has not been attained after forty-five seconds to one minute {66}, additional 200-mcg (0.2-mg) doses may be administered over fifteen seconds at one-minute intervals, up to a maximum cumulative dose of 1 mg. Most patients require 600 mcg (0.6 mg) to 1 mg {01}.

If resedation occurs, additional flumazenil may be administered at a rate of 200 mcg (0.2 mg) per minute, up to a total cumulative dose of 1 mg. This dose may be repeated at twenty-minute intervals, up to a maximum of 3 mg in a one-hour period {01}.



Treatment of benzodiazepine overdose:
Intravenous, 200 mcg (0.2 mg), administered over thirty seconds, initially. If the desired response has not been obtained after thirty seconds to one minute {66}, 300 mcg (0.3 mg) may be administered over thirty seconds. If necessary, additional doses of 500 mcg (0.5 mg) may be administered over thirty seconds at one-minute intervals, up to a maximum cumulative dose of 3 mg {01}. Most patients respond to a cumulative dose of 1 to 3 mg {01} {43}. Higher doses do not reliably produce additional benefit {01}, but patients who have responded partially to 3 mg may obtain additional benefit from a total dose of 4 {43} or 5 mg {01} {43}; occasional patients have required as much as 8 mg to achieve full reversal {43}. If no response is attained after a cumulative dose of 5 mg, it can be assumed that a benzodiazepine was not responsible for the overdose and that further administration of flumazenil is not likely to be helpful {01}. If resedation occurs, additional doses of up to a total of 1 mg of flumazenil may be administered at a rate of 500 mcg (0.5 mg) per minute. This dose may be repeated at twenty-minute intervals, up to a maximum of 3 mg in a one-hour period {01}. Alternatively, flumazenil may be administered as an intravenous infusion at a rate adjusted to provide the desired level of arousal, generally 100 to 400 mcg (0.1 to 0.4 mg) per hour {02}.



Note: The dosage should be titrated to produce the desired degree of arousal. Complete reversal may not be needed or desirable in certain circumstances {49}.
For patients who may be tolerant to or dependent on benzodiazepines (including patients who have received only a few days of high-dose treatment with benzodiazepines in the intensive care unit), a slower rate of administration (100 mcg [0.1 mg] per minute) and lower total doses may be required to minimize the risk of adverse effects {01}.
The recommended one-minute interval between doses may not be sufficiently long for high-risk patients {01}.
No adjustment of initial dosage is required for patients with significant hepatic function impairment, but a reduction in the size and/or frequency of subsequent doses is recommended {01}.
To prevent resedation after initial reversal, up to 1 mg of flumazenil may be administered intravenously at a rate of 200 mcg (0.2 mg) per minute thirty minutes and possibly sixty minutes later {01}.


Usual adult prescribing limits
For reversal of benzodiazepine-induced sedation
Not more than 1 mg at any one time or 3 mg per hour {01}.


Usual pediatric dose
Reversal of benzodiazepine-induced sedation
Intravenously, 10 mcg (0.01 mg) per kg of body weight (maximum 200 mcg [0.2 mg]) administered over fifteen seconds, initially. If the desired response has not been attained after forty-five seconds to one minute {66}, additional 10-mcg-per-kg-of-body-weight (maximum 200 mcg [0.2 mg]) doses may be administered over fifteen seconds at one-minute intervals, up to a maximum of five doses.

Note: The mean total dose administered to pediatric patients in pre-approval clinical trials was 0.65 (range, 0.08 to 1) mg. About fifty percent of the pediatric patients required the maximum five doses of flumazenil {01}.
Although not approved in the product labeling, flumazenil has been used to manage overdoses of benzodiazepines in pediatric patients {58}. Some investigators have administered flumazenil by intravenous infusion at a rate of 5 to 10 mcg (0.005 to 0.01 mg) per kg of body weight per hour to pediatric patients {06}.



Reversal of benzodiazepine-induced sedation
The maximum cumulative dose is 1 mg.

Usual geriatric dose
See Usual adult dose.

Strength(s) usually available
U.S.—


100 mcg (0.1 mg) per mL (Rx) [Romazicon{01} (methylparaben 1.8 mg per mL) (propylparaben 0.2 mg per mL) (sodium chloride 0.9%) (edetate disodium 0.01%) (acetic acid 0.01%)]

Canada—


100 mcg (0.1 mg) per mL (Rx) [Anexate{02} (edetate disodium 0.1 mg per mL) (sodium chloride) (glacial acetic acid) (sodium hydroxide)]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), {01} unless otherwise specified by manufacturer.

Preparation of dosage form:
Flumazenil injection may be diluted with 5% dextrose injection {01} {02}, 0.9% sodium chloride injection {01} {02}, 0.45% sodium chloride and 2.5% dextrose injecton {02}, or lactated Ringer's injection {01}.

Stability:
Infusion solutions prepared with 5% dextrose injection, 0.9% sodium chloride injection, or 0.45% sodium chloride and 2.5% dextrose injection are stable for up to 24 hours at room temperature {02}. Flumazenil injections that have been drawn into a syringe or mixed with intravenous infusion solutions should be discarded after 24 hours {01}.

One study has shown that stability of 20 mcg per mL (mcg/mL) of flumazenil in 5% dextrose injection is maintained for 12 hours at 23 °C (73 to 74 °F) when admixed with 3.2 mcg/mL of dopamine hydrochloride and for 24 hours when admixed with 2 mg per mL (mg/mL) of aminophylline, 2 mg/mL of dobutamine, 2.4 mg/mL of cimetidine, 0.08 mg/mL of famotidine, 50 USP Units per mL of heparin sodium, 4 mg/mL of lidocaine hydrochloride, 4 mg/mL of procainamide hydrochloride, or 0.3 mg/mL of ranitidine. Whether flumazenil affected the stability of the other medications was not determined {44}.



Revised: 12/14/98



References
  1. Romazicon package insert (Roche—US), Rev 9/98, Rec 11/98.
  1. Anexate product monograph (Hoffmann-La Roche—Canada), Rev 6/94, Rec 10/95.
  1. Hold.
  1. Brogden RN, Goa KL. Flumazenil. A reappraisal of its pharmacological properties and therapeutic efficacy as a benzodiazepine antagonist. Drugs 1991; 42: 1061-89.
  1. Votey SR, Bosse GM, Bayer MJ, et al. Flumazenil: A new benzodiazepine antagonist. Ann Emerg Med 1991; 20: 181-8.
  1. Sugarman JM, Paul RI. Flumazenil: a review. Pediatr Emerg Care 1994; 10: 37-43.
  1. The Flumazenil in Intravenous Conscious Sedation with Midazolam Multicenter Study Group I. Reversal of central nervous system effects by flumazenil after intravenous conscious sedation with midazolam: report of a multicenter study. Clin Ther 1992; 14: 861-77.
  1. The Flumazenil in Intravenous Conscious Sedation with Midazolam Multicenter Study Group II. Reversal of central benzodiazepine effects by intravenous flumazenil after conscious sedation with midazolam and opioids: a multicenter clinical study. Clin Ther 1992; 14: 878-94.
  1. The Flumazenil in Intravenous Conscious Sedation with Diazepam Multicenter Study Group I. Reversal of central benzodiazepine effects by flumazenil after conscious sedation produced by intravenous diazepam. Clin Ther 1992; 14: 895-909.
  1. The Flumazenil in Intravenous Conscious Sedation with Diazepam Multicenter Study Group II. Reversal of central benzodiazepine effects by flumazenil after intravenous conscious sedation with diazepam and opioids: report of a double-blind multicenter study. Clin Ther 1992; 14: 910-23.
  1. The Flumazenil in General Anesthesia in Hospitalized Patients Study Group I. Effect of intravenous flumazenil on reversal of the central effects of midazolam used with short-acting opioids for general anesthesia in hospitalized patients: report of a multicenter, double-blind clinical study. Clin Ther 1992; 14: 924-38.
  1. The Flumazenil in General Anesthesia in Hospitalized Patients Study Group II. Reversal of the central effects of midazolam by intravenous flumazenil after general anesthesia and use of a long-acting opioid in hospitalized patients: report of a multicenter double-blind clinical study. Clin Ther 1992; 14: 939-53.
  1. The Flumazenil in General Anesthesia in Outpatients Study Group II. Reversal of the central effects of midazolam by intravenous flumazenil after general anesthesia in outpatients premedicated with an opioid and a muscle relaxant: report of a multicenter double-blind clinical study. Clin Ther 1992; 14: 954-65.
  1. The Flumazenil in General Anesthesia in Outpatients Study Group I. Reversal of the central effects of midazolam by intravenous flumazenil after general anesthesia in outpatients: a multicenter double-blind clinical study. Clin Ther 1992; 14: 966-77.
  1. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. Treatment of benzodiazepine overdose with flumazenil. Clin Ther 1992; 14: 978-95.
  1. Glass PS, Jhaveri RM, Ginsberg B, et al. Evaluation of flumazenil for reversing the effects of midazolam-induced conscious sedation or general anesthesia. South Med J 1993; 86: 1238-47.
  1. Philip BK, Simpson TH, Hauch MA, et al. Flumazenil reverses sedation after midazolam-induced general anesthesia in ambulatory surgery patients. Anesth Analg 1990; 71: 371-6.
  1. Coates W, Evans TC, Jehle D, et al. Flumazenil for the reversal of refractory benzodiazepine-induced shock. Clin Toxicol 1991; 29: 537-42.
  1. Elder I, Lieberman N, Shiber R, et al. Use of flumazenil for intraoperative arousal during spine fusion. Anesth Analg 1992; 75: 580-3.
  1. Blouin RT, Conard PF, Perreault S, et al. The effect of flumazenil on midazolam-induced depression of the ventilatory response to hypoxia during isohypercarbia. Anesthesiology 1993; 78: 635-41.
  1. Flögel CM, Ward DS, Wada DR, et al. The effects of large-dose flumazenil on midazolam-induced ventilatory depression. Anesth Analg 1993; 77: 1207-14.
  1. Gross JB, Weller RS, Conard P. Flumazenil antagonism of midazolam-induced ventilatory depression. Anesthesiology 1991; 179-85.
  1. Höjer J, Baehrendtz S, Matell G, et al. Diagnostic utility of flumazenil in coma with suspected poisoning: a double blind, randomised, controlled study. Br Med J 1990; 301: 1308-11.
  1. Geller E, Halpern P, Chernilas J, et al. Cardiorespiratory effects of antagonism of diazepam sedation with flumazenil in patients with cardiac disease. Anesth Analg 1991; 72: 207-11.
  1. Ghoneim MM, Block RI, Sum Ping ST, et al. The intractions of midazolam and flumazenil on human memory and cognition. Anesthesiology 1993; 79: 1183-92.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 316.
  1. Anesthesiology Panel meeting, 10/93.
  1. Nilsson A. Pharmacokinetics of benzodiazepines and their antagonists. Ballière's Clinical Anesthesiology 1991; 5: 615-34.
  1. Janssen U, Walker S, Maier K, et al. Flumazenil disposition and elimination in cirrhosis. Clin Pharmacol Ther 1989; 46: 317-23.
  1. Pomier-Layrargues G, Giguere JF, Lavoie J, et al. Pharmacokinetics of benzodiazepine antagonist Ro 15-1788 in cirrhotic patients with moderate or severe liver dysfunction. Hepatology 1989; 10: 969-72.
  1. Ghouri AF, Ruiz MAR, White PF. Effect of flumazenil on recovery after midazolam and propofol sedation. Anesthesiology 1994; 81: 333-9.
  1. Geller E, Halpern P. Benzodiazepine antagonists. Int Anesthesiol Clin 1991; 29: 69-81.
  1. Stahl MM, Saldeen P, Vinge E. Reversal of fetal benzodiazepine intoxication using flumazenil. Br J Obstet Gynaecol 1993; 100: 185-8.
  1. Richard P, Autret E, Bardol J, et al. The use of flumazenil in a neonate. J Toxicol Clin Toxicol 1991; 29: 137-40.
  1. Katz JA, Fragen RJ, Dunn KL. Flumazenil reversal of midazolam sedation in the elderly. Reg Anesth 1991; 16: 247-52.
  1. Marty J, Nitenberg A, Philip I, et al. Coronary and left ventricular hemodynamic responses following reversal of flunitrazepam-induced sedation with flumazenil in patients with coronary artery disease. Anesthesiology 1991; 74: 71-6.
  1. Lim AG. Death after flumazenil. Br Med J 1989; 299: 858-9.
  1. Schauben JL. Flumazenil and precipitated benzodiazepine withdrawal reaction. Curr Ther Res Clin Exp 1992; 52: 152-9.
  1. Lopez A, Rebollo J. Benzodiazepine withdrawal syndrome after a benzodiazepine antagonist. Crit Care Med 1990; 18: 1480-1.
  1. Herd B, Clarke F. Complete heart block after flumazenil. Hum Exp Toxicol 1991; 10: 289.
  1. Spivey WH. Flumazenil and seizues: analysis of 43 cases. Clin Ther 1992; 14: 292-305.
  1. Olsen KM, Pablo CS, Ackerman BH. Postoperative analgesic requirements following flumazenil administration. DICP Ann Pharmacother 1990; 24: 1159-63.
  1. Spivey WH, Roberts JR, Derlet RW. A clinical trial of escalating doses of flumazenil for reversal of suspected benzodiazepine overdose in the emergency department. Ann Emerg Med 1993; 22: 1813-21.
  1. Olsen KM, Gurley BJ, Davis GA, et al. Stability of flumazenil with selected drugs in 5% dextrose injection. Am J Hosp Pharm 1993; 50: 1907-12.
  1. Shalansky SJ, Naumann TL, Englander FA. Effect of flumazenil on benzodiazepine-induced respiratory depression. Clin Pharm 1993; 12: 483-7.
  1. Reviewers' responses to monograph draft 10/94.
  1. Panel comments, draft 10/94.
  1. Panelist comment, draft 10/94.
  1. Panelist comment, draft 10/94.
  1. Howard CD, Seifert CF. Flumazenil in the treatment of hepatic encephalopathy. Ann Pharmacother 1993; 27: 46-7.
  1. Seebach J, Jost R. Flumazenil-induced psychotic disorder in hepatic encephalopathy [letter]. Lancet 1992; 339: 488-9.
  1. Panelist comment, draft 10/94.
  1. Jones RD, Chan K, Roulson CJ, et al. Pharmacokinetics of flumazenil and midazolam. Br J Anaesth 1993; 70: 286-92.
  1. Panelist comment, draft 10/94.
  1. Anesthesiology Panel meeting 10/16/94 and Panelist comments, draft 10/94.
  1. Anesthesiology Panel meeting 10/16/94.
  1. Reviewers' responses to monograph draft 10/94
  1. Panelist comment, draft 10/94.
  1. Panelist comment, draft 10/94.
  1. Panelist comment, draft 10/94.
  1. Reviewers' responses to monograph revision 12/94.
  1. Reviewers' responses to monograph revision 12/94.
  1. Reviewers' responses to monograph revision 12/94.
  1. Panelist comment, monograph revision 12/94.
  1. Panelist comment, monograph revision 12/94.
  1. Reviewers' responses to monograph revision 12/94.
  1. Miller RD, supplemental section editor. U.S. clinical trials of flumazenil, a benzodiazepine antagonist. Clin Ther 1992; 14: 860-995.
  1. Shannon M, Alders G, Burkhart K, et al. Safety and efficacy of flumazenil in the reversal of benzodiazepine-induced conscious sedation. The Flumazenil Pediatric Study Group. J Pediatr 1997; 131: 582-6.
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