FLUMAZENIL

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Flumazenil is administered intravenously; however, ingestion of food during IV administration of flumazenil can increase the clearance of flumazenil by about 50%.
-Patient must have a patent airway and established IV access prior to administration of flumazenil.

IV Push
-May be administered undiluted or diluted in a syringe with 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection. Discard diluted injections after 24 hours.
-Inject over 15 to 30 seconds directly into the tubing of a free-flowing compatible IV infusion solution into a large vein to minimize injection site pain. Care should be taken to avoid extravasation because the drug may be irritating to perivascular tissue.
-Observe patient for at least 2 hours after administration for signs of resedation and hypoventilation.



Rectal Administration
-Rectal administration of flumazenil is not FDA-approved.
-The IV formulation has been administered rectally to children and adolescents using a short air-washed cannula. The drug was administered undiluted to patients without IV access to reverse midazolam sedation.


Other Administration Route(s)
Intranasal Administration
-Intranasal administration is not FDA-approved.
-Undiluted injection has been administered intranasally to reverse midazolam procedural sedation.
-Divide the dose into 2 equal doses and administer 1 dose to each nare. Administer in a syringe as drops. Dividing the dose should minimize the volume administered to each nare and increase absorption intranasally.
-Placing the patient into the Trendelenburg or the recovery position may further minimize the risk of aspiration.

Flumazenil has a much shorter duration of action than many of the benzodiazepines it is used to counteract. Resedation can occur. Patients having regained consciousness should not be discharged until the possibility of resedation has been eliminated. Resedation is least likely when flumazenil is used to reverse a low dose of short-acting benzodiazepine. It is most likely when a large single or cumulative benzodiazepine dose has been administered in the course of a long procedure along with neuromuscular blocking agents and anesthetics. In clinical studies, profound resedation occurred in 1% to 3% of patients.

Deaths have occurred in patients who have received flumazenil for a variety of clinical purposes; most deaths have occurred in patients with serious underlying illness or in patients who have ingested large amounts of non-benzodiazepine drugs (usually cyclic antidepressants) as part of an overdose.

Seizures (convulsions) are one of the most serious adverse reactions reported with flumazenil. Flumazenil administration can be associated with the onset of seizures in patients with hepatic impairment, patients previously using benzodiazepines to control seizures, patients who have become dependent on benzodiazepines, and patients who have taken large overdoses of drug mixtures. Six seizures were reported out of 446 patients treated with flumazenil during 2 clinical trials; 4 of the 6 patients had ingested large doses of cyclic antidepressants. Most flumazenil-associated seizures require treatment and have been successfully managed with benzodiazepines, phenytoin, or barbiturates; higher than usual benzodiazepine doses are required due to the presence of flumazenil. A retrospective review of flumazenil administration in poisoned children reported no cases of seizures in patients receiving flumazenil for alleged benzodiazepine and non-benzodiazepine poisonings.

Dermatologic and injection site-related adverse reactions were among the most common considered to be related to flumazenil administration in clinical trials (n = 1,875). When flumazenil was administered alone, injection site pain and hyperhidrosis were among the most common events (3% to 9%). In trials where flumazenil was used both alone and for the reversal of benzodiazepine effects, an injection site reaction, with thrombo-phlebitis, skin abnormality, and rash, was reported in 1% to 3% of patients. Rigors and shivering were reported in less than 1% of recipients during trials; however, the relationship to flumazenil administration is not known.

Nervous system related adverse reactions were among the most common considered to be related to flumazenil administration in clinical trials (n = 1,875). When flumazenil was administered alone, dizziness and headache were reported in 3% to 9% of patients. In trials where flumazenil was used both alone and for the reversal of benzodiazepine effects, dizziness (including vertigo and ataxia) was reported in 10% of patients. Agitation, anxiety, nervousness, tremor, and insomnia were reported in 3% to 9% of patients. Fatigue, asthenia, malaise, headache, emotional lability (including abnormal crying, depersonalization, euphoria, depression, dysphoria, and paranoia), and paresthesias (including abnormal sensations and hypoesthesia) were reported in 1% to 3% of patients. Adverse events that were observed infrequently (less than 1%) during trials, though deemed likely related to flumazenil and/or reversal of benzodiazepine effects include confusion, difficulty concentrating, delirium, convulsions, drowsiness, and stupor. Speech disorder, dysphonia, and thick tongue were also reported in less than 1% of recipients during trials; however, the relationship to flumazenil administration is not known. Fear and panic attacks, in patients with a history of panic disorders, have been reported in postmarketing surveillance.

Cardiovascular adverse reactions, including palpitations (3% to 9%) and peripheral vasodilation (resulting in sweating, flushing, and hot flashes; 1% to 3%), were reported during flumazenil clinical trials (n = 1,875). Two of the 446 adult patients who received flumazenil in clinical trials for the management of benzodiazepine overdose experienced cardiac arrhythmias, consisting of ventricular tachycardia and junctional tachycardia. Arrhythmia exacerbation (atrial, nodal, and ventricular extrasystoles), bradycardia, sinus tachycardia, hypertension, and chest pain (unspecified) were reported in less than 1% of recipients during trials; however, their relationship to flumazenil administration is not known.

Abnormal or blurred vision was reported in 3% to 9% of adult patients receiving flumazenil in clinical trials (n = 1,875) and was one of the most frequently reported adverse reactions. Visual field defects, diplopia, and increased tears or lacrimation were reported in 1% to 3% of patients. Abnormal hearing (including transient hearing loss or impairment, hyperacusis, and tinnitus) was reported in less than 1% of patients.

Gastrointestinal adverse reactions were among the most common considered to be related to flumazenil administration in clinical trials (n = 1,875). In trials where flumazenil was used both alone and for the reversal of benzodiazepine effects, vomiting (11%), xerostomia (3% to 9%), and nausea (1% to 3%) were reported. Hiccups were reported in less than 1% of recipients during trials; however, the relationship to flumazenil administration is not known.

Acute withdrawal symptoms may occur if flumazenil is administered to patients who are physically dependent on benzodiazepines. Slower titration rates and lower initial doses of flumazenil may help reduce the frequency of emergent confusion and agitation. Monitor patients for resedation if lower flumazenil doses are used.

Respiratory system related adverse reactions, such as dyspnea and hyperventilation, were reported in 3% to 9% of patients in clinical trials (n = 1,875) where flumazenil was used both alone and for the reversal of benzodiazepine effects.

Flumazenil has a much shorter duration of action than do many of the benzodiazepines it is used to counteract. Resedation can occur. Patients having regained consciousness should be monitored until the possibility of resedation has been eliminated.

Benzodiazepines are often used in combination with neuromuscular blocking agents. Whenever possible, the actions of the neuromuscular blocker should be allowed to wear off before administration of flumazenil to avoid arousing the patient while still in a paralyzed state.

Flumazenil is contraindicated in patients with a known flumazenil hypersensitivity or benzodiazepine hypersensitivity.

Flumazenil therapy has been associated with seizures. Seizures are most frequent in patients receiving long-term benzodiazepine therapy (benzodiazepine dependence). Use of flumazenil can precipitate signs of benzodiazepine withdrawal, which may precipitate seizures. Flumazenil is contraindicated in patients who have received a benzodiazepine for the control of life-threatening conditions such as the control of increased intracranial pressure and status epilepticus. Use flumazenil with caution in patients with head trauma as it may be capable of precipitating convulsions or altering cerebral blood flow in patients receiving benzodiazepines. It should be used only by practitioners prepared to manage such complications should they occur. Possible risk factors for seizures include: concurrent major sedative-hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, and myoclonic jerking or seizure activity prior to flumazenil administration in overdose cases. Flumazenil is contraindicated in the presence of serious concurrent cyclic antidepressant overdose or poisoning as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs and symptoms, and cardiovascular collapse at presentation. In such cases, withhold flumazenil, and allow the patient to remain sedated (with ventilatory and circulatory support as needed) until the signs of cyclic antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit for serious mixed-overdose patients other than reversing sedation; do not use in cases where seizures (from any cause) are likely. Most convulsions associated with flumazenil administration require treatment and have been successfully managed with benzodiazepines, phenytoin or fosphenytoin, or barbiturates. Because of the presence of flumazenil, higher than usual doses of benzodiazepines may be required. Use flumazenil cautiously in the intensive care setting where there is the possibility of unrecognized benzodiazepine dependence and in patients who have a history of substance abuse or alcoholism or who are known substance abusers. The use of flumazenil is not recommended in patients with a seizure disorder managed chronically with benzodiazepines because of possible precipitation of seizures when the benzodiazepine effect is withdrawn.

Use flumazenil with caution in patients being treated with a benzodiazepine for anxiety or panic disorder. Reversal of the benzodiazepine may precipitate an anxiety episode or panic attack. Careful titration of dosage is recommended in these patients.

The reversal of benzodiazepine-induced respiratory depression by flumazenil is short-lived since the effect of flumazenil typically wears off before the effect of the benzodiazepine. The benefit of flumazenil in the treatment of hypoventilation resulting from benzodiazepine administration has not been established. Constant monitoring of pulmonary function is necessary, depending on the type of benzodiazepine used. Patients with significant pulmonary disease who develop respiratory depression from benzodiazepines may require ventilatory support.

Patients with hepatic disease show reduced clearance of flumazenil, and if the initial dose is not clinically effective in sedation reversal, administer repeat doses at lower levels and less frequently.

Flumazenil does not consistently reverse benzodiazepine-induced amnesia. Health care providers should discuss with patients or their guardians that although the patient may feel alert at the time of discharge, the sedative effects of the benzodiazepine may recur. The patient should be advised to use caution when performing activities requiring coordination and concentration (e.g., riding a bicycle or operating a vehicle) during the first 24 hours after discharge and it is certain no residual sedative effects of the benzodiazepine remain. Patients should also be advised not to take any alcohol or non-prescription drugs during the first 24 hours after flumazenil administration or if the effects of the benzodiazepine persist.

Description: Flumazenil is a parenteral benzodiazepine antagonist. It is an imidazobenzodiazepine derivative. Flumazenil is used in pediatrics for reversal of procedural sedation induced with benzodiazepines and for treating a suspected benzodiazepine overdose. Flumazenil will also antagonize the sedative actions of zolpidem and eszopiclone. Flumazenil is administered by rapid IV injection because it is highly irritating, and care should be taken to avoid extravasation. In pediatric patients, the intravenous formulation has also been administered intranasally and rectally; these routes of administration are not FDA-approved. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants and is contraindicated in patients showing signs of cyclic antidepressant toxicity. Flumazenil is FDA-approved in pediatric patients age 1 to 17 years for reversal of procedural sedation induced with benzodiazepines, although it is used off-label in patients as young as infants for this indication; it is used off-label for treating suspected benzodiazepine overdose in pediatric patients as young as neonates.

For sedation reversal when sedation is secondary to benzodiazepine therapy:
Intravenous dosage:
Infants*: Data are limited. Doses of 10 to 30 mcg/kg/dose IV bolus (Max: 200 mcg/dose) or 100 to 200 mcg/dose IV bolus have been administered. Doses may be repeated if the desired level of consciousness is not achieved; FDA-approved labeling in children and adolescents recommends repeat dosing every 1 minute up to a maximum total cumulative dose of 50 mcg/kg (Max: 1 mg).
Children and Adolescents: 10 mcg/kg/dose IV bolus (Max: 200 mcg/dose) administered over 15 seconds. The dose may be repeated after 45 seconds if the desired level of consciousness is not achieved, and subsequently at 1-minute intervals (maximum of 4 additional times) up to a maximum total cumulative dose of 50 mcg/kg (Max: 1 mg).
Intranasal dosage*:
NOTE: An intranasal formulation is not commercially available. Studies have administered the undiluted intravenous formulation intranasally.
Children: A pharmacokinetic study in 11 children (2 to 6 years) who received general anesthesia for dental procedures showed that a dose of 40 mcg/kg administered nasally provides similar pharmacokinetic parameters as to those seen after 20 mcg/kg/dose IV of flumazenil. The authors recommend dividing the dose equally between both nostrils to minimize the risk of aspiration and maximize absorption. In another study, a 14 kg 3-year old girl become oversedated after receiving anesthesia with intranasal midazolam and sufentanil for a dental procedure; 200 mcg of flumazenil intranasally (administered as 100 mcg/nare) and intranasal naloxone reversed the sedation.
Rectal dosage*:
NOTE: A rectal formulation is not commercially available. Studies have administered the undiluted intravenous formulation rectally.
Children and Adolescents: Doses of 20 to 40 mcg/kg rectally have been administered to 6 patients without IV access who received rectal midazolam for procedural sedation. Consciousness was regained between 8 and 15 minutes in all patients. In another case report, a dose of 40 mcg/kg led to consciousness in 3 minutes in a 1-year old girl who received oral midazolam for procedural sedation.

For reversal of benzodiazepine toxicity* in suspected overdose:
Intravenous dosage:
Neonates: Data are limited. 5 to 20 mcg/kg/dose IV bolus has been used. Doses may be repeated every minute up to a maximum total cumulative dose of 50 mcg/kg. As an alternative to repeat bolus doses, continuous infusions of 10 to 20 mcg/kg/hour IV have been used. In a full term infant on day 12 of life experiencing myoclonic jerks of the extremities approximately 1 hour after initiation of a midazolam infusion, a single dose of 7.8 mcg/kg IV bolus led to cessation of the myoclonic jerks within 5 minutes of the dose of flumazenil.
Infants, Children, and Adolescents: Data are limited. 5 to 10 mcg/kg/dose IV bolus (Max: 200 mcg/dose) has been used. In younger children, a dose of 10 to 20 mcg/kg/dose IV bolus (Max: 200 mcg/dose) has also been suggested. Doses may be repeated every minute up to a maximum total cumulative dose of 50 mcg/kg (Max: 1 mg). As an alternative to repeat bolus doses, continuous infusions of 5 to 10 mcg/kg/hour IV have been used.
-in neonates exposed to maternally ingested benzodiazepines in utero:
Intravenous dosage:
Neonates: 10 mcg/kg IV bolus followed by a continuous IV infusion of 10 mcg/kg/hour for 24 hours led to facial and limb movements and spontaneous respiration in a 32 week gestational age hypotonic neonate born without spontaneous respiration. On day 2, the rate of flumazenil infusion was decreased to 5 mcg/kg/hour and to 3.8 mcg/kg/hour on days 3 through 5, after which time the infusion was stopped. Prior to delivery, the mother had received diazepam, phenytoin, and thiopental for seizures and eclampsia without resolution, requiring an emergency cesarean section.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established. However, single doses of 20 mcg/kg IV have been used off-label; doses may be repeated as necessary up to a total cumulative dose of 50 mcg/kg IV. Alternatively, 20 mcg/kg/hour via continuous IV infusion has been used off-label.
-Infants
Safety and efficacy have not been established. However, single doses of 30 mcg/kg IV (Max: 200 mcg/dose) have been used off-label; doses may be repeated as necessary up to a total cumulative dose of 50 mcg/kg IV (Max: 1 mg). Alternatively, 10 mcg/kg/hour via continuous IV infusion has been used off-label.
-Children
Single doses of 10 mcg/kg IV (Max: 200 mcg/dose); doses may be repeated as necessary up to a total cumulative dose of 50 mcg/kg IV (Max: 1 mg). Alternatively, 10 mcg/kg/hour via continuous IV infusion has been used off-label.
-Adolescents
Single doses of 10 mcg/kg IV (Max: 200 mcg/dose); doses may be repeated as necessary up to a total cumulative dose of 50 mcg/kg IV (Max: 1 mg). Alternatively, 10 mcg/kg/hour via continuous IV infusion has been used off-label.

Patients with Hepatic Impairment Dosing
Initial doses for reversal of benzodiazepine effects are not altered; however, subsequent doses should be reduced in size or frequency, although specific recommendations are not available.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Flumazenil antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil has a high affinity for the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Flumazenil competes with benzodiazepines at this receptor for binding. Because binding is competitive and flumazenil has a much shorter duration of action than do most benzodiazepines, it is possible for the effects of flumazenil to dissipate sooner than the effects of the benzodiazepine.

While flumazenil reverses benzodiazepine-induced sedation, it has no proven effectiveness in the treatment of hypoventilation induced by benzodiazepines. Any beneficial effects on ventilatory response from flumazenil use can be outlived by the effects of the benzodiazepines. Prompt detection of hypoventilation with suitable ventilatory support is essential, especially in reversal of acute benzodiazepine overdosage. Abrupt awakening following flumazenil administration may be associated with dysphoria, agitation, and possibly increased adverse effects. If administered to patients who have received a benzodiazepine chronically, abrupt interruption of benzodiazepine agonism by flumazenil can induce benzodiazepine withdrawal including seizures. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.

Pharmacokinetics: Flumazenil is administered intravenously. The drug is widely distributed in the extravascular space with a steady-state Vd of 0.9 to 1.1 L/kg. In adults, the initial distribution half-life is 4 to 11 minutes. Flumazenil is a weak lipophilic base. Protein binding is approximately 50% with albumin accounting for two-thirds of plasma protein binding. Flumazenil is 99% metabolized to the inactive de-ethylated free acid and its glucuronide conjugate; less than 1% of the drug is excreted unchanged in the urine. Excretion is about 90% to 95% renal, mainly as metabolites, with 5% to 10% appearing in the feces, and excretion is essentially complete within 72 hours. The terminal half-life in adults is 40 to 80 minutes.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intravenous Route
Food in the GI tract increases the rate of clearance by about 50%, probably because of increased hepatic blood flow associated with digestion. The drug rapidly enters the central nervous system with an onset of action of 1 to 2 minutes after injection. Peak concentrations are proportional to dosage; 80% response will be reached within 3 minutes, with peak effect occurring at 6 to 10 minutes.

Other Route(s)
Intranasal Route
After administration of 40 mcg/kg intranasally to children, the Cmax was 67.8 ng/mL with a Tmax of 2 minutes and a half-life of 122 minutes.


-Special Populations
Pediatrics
Children and Adolescents
In children, the volume of distribution of flumazenil is approximately 1 L/kg (range 0.7 to 1.6 L/kg). Clearance and volume of distribution, normalized for body weight, are in the same range as values observed in adults, although there is more variability in pediatric patients. The elimination half-life is more variable, averaging 40 minutes (range: 20 to 75 minutes).

Hepatic Impairment
Decreased hepatic blood flow or severe hepatic dysfunction radically alter the clearance of flumazenil. In patients with moderate liver dysfunction, the clearance is decreased to 40% to 60% of normal values with a prolonged half-life of 1.3 hours. In patients with severe liver dysfunction, clearance is decreased to 25% of normal value with a half-life of 2.4 hours.

Renal Impairment
The pharmacokinetics of flumazenil are not significantly affected by renal impairment.