Romazicon

Antidotes, Systemic

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

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.[57223]

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.[53815] [53816]

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.[53813]

bradycardia / Rapid / 0-1.0
hearing loss / Delayed / 0-1.0
seizures / Delayed / Incidence not known
arrhythmia exacerbation / Early / Incidence not known
ventricular tachycardia / Early / Incidence not known

ataxia / Delayed / 3.0-10.0
palpitations / Early / 3.0-9.0
blurred vision / Early / 3.0-9.0
dyspnea / Early / 3.0-9.0
depression / Delayed / 1.0-3.0
euphoria / Early / 1.0-3.0
dysphoria / Early / 1.0-3.0
phlebitis / Rapid / 1.0-3.0
hot flashes / Early / 1.0-3.0
peripheral vasodilation / Rapid / 1.0-3.0
dysphonia / Delayed / 0-1.0
delirium / Early / 0-1.0
confusion / Early / 0-1.0
hypertension / Early / 0-1.0
sinus tachycardia / Rapid / 0-1.0
chest pain (unspecified) / Early / 0-1.0
hyperacusis / Delayed / 0-1.0
withdrawal / Early / Incidence not known

vomiting / Early / 11.0-11.0
vertigo / Early / 3.0-10.0
dizziness / Early / 3.0-10.0
anxiety / Delayed / 3.0-9.0
tremor / Early / 3.0-9.0
insomnia / Early / 3.0-9.0
headache / Early / 1.0-9.0
agitation / Early / 3.0-9.0
hyperhidrosis / Delayed / 3.0-9.0
xerostomia / Early / 3.0-9.0
hyperventilation / Early / 3.0-9.0
hypoesthesia / Delayed / 1.0-3.0
emotional lability / Early / 1.0-3.0
malaise / Early / 1.0-3.0
fatigue / Early / 1.0-3.0
asthenia / Delayed / 1.0-3.0
paresthesias / Delayed / 1.0-3.0
paranoia / Early / 1.0-3.0
injection site reaction / Rapid / 1.0-3.0
rash / Early / 1.0-3.0
flushing / Rapid / 1.0-3.0
diplopia / Early / 1.0-3.0
lacrimation / Early / 1.0-3.0
nausea / Early / 1.0-3.0
drowsiness / Early / 0-1.0
shivering / Rapid / 0-1.0
tinnitus / Delayed / 0-1.0
hiccups / Early / 0-1.0

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.[57223]

Romazicon

Rx

Parenteral benzodiazepine antagonist
Treats benzodiazepine overdose, reverses benzodiazepine-induced sedation, and antagonizes the actions of zolpidem
Does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants

Initially, 0.2 mg IV. The dose may be repeated after 45 seconds if the desired level of consciousness is not achieved, and subsequently at 1-minute intervals until a maximum of 4 doses have been administered (1 mg total over 5-minute period). If resedation occurs, repeat the regimen at 20-minute intervals, up to a maximum of 3 mg/hour.[57223]

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).[57223]

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).[53472] [57223]

NOTE: An intranasal formulation is not commercially available. Studies have administered the undiluted intravenous formulation intranasally.

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.[53813] 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.[53814]

NOTE: A rectal formulation is not commercially available. Studies have administered the undiluted intravenous formulation rectally.

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.[53815] 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.[53816]

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.[48525]

Initially, 0.2 mg IV. An additional dose of 0.3 mg IV may be given 30 seconds later if the desired level of consciousness is not achieved. Further doses of 0.5 mg may be administered at 1-minute intervals up to a maximum of 3 mg. In most patients, cumulative doses exceeding 3 mg have not been shown to provide additional benefit. However, some patients who exhibit a partial response to a cumulative dose of 3 mg may rarely require doses up to a total of 5 mg. Unresponsive sedation is unlikely to have been caused by benzodiazepines. If resedation occurs, repeat the dosage regimen every 20 minutes, up to a maximum of 3 mg/hour.[57223] Infusions of 0.1 to 0.4 mg per hour IV, adjusting rate to provide the desired level of arousal, have also been used.

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.[50838] [53472] [53473]

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.[50838] [53472] [53473] 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.[53776]

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.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Alprazolam: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Amitriptyline: (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially tricyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
Amoxapine: (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially cyclic antidepressants like amoxapine) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
Benzodiazepines: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Chlordiazepoxide: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Chlordiazepoxide; Amitriptyline: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants. (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially tricyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
Chlordiazepoxide; Clidinium: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Clobazam: (Major) Flumazenil and benzodiazepines are pharmacologic opposites. The use of flumazenil is not indicated in epileptic patients receiving benzodiazepines. The antagonistic action of flumazenil may precipitate seizures in epileptic patients receiving benzodiazepines such as clobazam.
Clomipramine: (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially tricyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
Clonazepam: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Clorazepate: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Desipramine: (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially tricyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
Diazepam: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Doxepin: (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially tricyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
Estazolam: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Eszopiclone: (Major) Flumazenil, a benzodiazepine antagonist, can reverse the sedative/hypnotic effects of eszopiclone. Flumazenil and eszopiclone are pharmacological opposites, thus, this represents a pharmacodynamic interaction and not a pharmacokinetic one.
Flurazepam: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Imipramine: (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially tricyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
Lorazepam: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Maprotiline: (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially cyclic antidepressants like maprotiline) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
Midazolam: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Nalmefene: (Minor) Based on available animal data, an adverse interaction from the coadministration of these 2 drugs is not expected, but physicians should remain aware of the potential risk of seizures from agents in these classes. Preclinical studies have shown that both flumazenil and nalmefene can induce seizures in animals. The coadministration of both flumazenil and nalmefene produced fewer seizures than expected in a study in rodents, based on the expected effects of each drug alone. In humans, nalmefene has been administered in outpatient settings, both in trials in conscious sedation and in the emergency management of overdose following a wide variety of agents. No deleterious interactions have been observed.
Nortriptyline: (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially tricyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
Oxazepam: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Perphenazine; Amitriptyline: (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially tricyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
Protriptyline: (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially tricyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
Quazepam: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Remimazolam: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Temazepam: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Triazolam: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor 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. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause 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 has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Tricyclic antidepressants: (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially tricyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
Trimipramine: (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially tricyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
Zaleplon: (Major) Flumazenil, a benzodiazepine antagonist, can reverse the sedative/hypnotic effects of zaleplon. Flumazenil and zaleplon are pharmacological opposites.
Zolpidem: (Major) Flumazenil, a benzodiazepine antagonist, can reduce the sedative hypnotic effects of zolpidem. Flumazenil and zolpidem are pharmacological opposites and should not be used together therapeutically.

Flumazenil/Romazicon Intravenous Inj Sol: 0.1mg, 1mL

5 mg IV total cumulative dose for suspected benzodiazepine overdose. If patient unresponsive at this dose, cause of sedation not likely to be benzodiazepine. Max dose for reversal of conscious sedation is 1 mg IV.

5 mg IV total cumulative dose for suspected benzodiazepine overdose. If patient unresponsive at this dose, cause of sedation not likely to be benzodiazepine. Max dose for reversal of conscious sedation is 1 mg IV.

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.

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.

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.

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.

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.[57223]
 
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 after 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.[57223]

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 and an initial distribution half-life of 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.[57223]
 
Affected cytochrome P450 isoenzymes: none

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.

According to the FDA-approved labeling, caution is advised when administering flumazenil to a woman who is breast-feeding.[57223] It is not known if flumazenil is excreted into breast milk; however, the low molecular weight of the drug and moderate protein binding suggest that transfer into breast milk is possible. Even for single-dose use for endoscopy, experts are unclear on the impact on the nursing infant.[46776] However, because flumazenil is used to reverse the effects of benzodiazepines in conscious sedation or overdose, treatment should not be withheld in a woman who is breast-feeding if the drug is clinically indicated. Although data are very limited, flumazenil has been used in newborns to reverse the effects of direct or in utero exposure to benzodiazepines and no adverse effects have been reported.[48525] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.