Romazicon Information
Romazicon (Flumazenil) Description
Romazicon (Flumazenil) is a benzodiazepine receptor antagonist. Chemically, flumazenil is ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a](1,4) benzodiazepine-3-carboxylate. Flumazenil has an imidazobenzodiazepine structure, a calculated molecular weight of 303.3, and the following structural formula:
Flumazenil is a white to off-white crystalline compound with an octanol:buffer partition coefficient of 14 to 1 at pH 7.4. It is insoluble in water but slightly soluble in acidic aqueous solutions. Romazicon (Flumazenil) is available as a sterile parenteral dosage form for intravenous administration. Each mL contains 0.1 mg of flumazenil compounded with 1.8 mg of methylparaben, 0.2 mg of propylparaben, 0.9% sodium chloride, 0.01% edetate disodium, and 0.01% acetic acid; the pH is adjusted to approximately 4 with hydrochloric acid and/or, if necessary, sodium hydroxide.
Romazicon (Flumazenil) Clinical Pharmacology
Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man.
Flumazenil does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids.
In animals pretreated with high doses of benzodiazepines over several weeks, Romazicon (Flumazenil) elicited symptoms of benzodiazepine withdrawal, including seizures. A similar effect was seen in adult human subjects.
Romazicon (Flumazenil) Clinical Trials
Romazicon (Flumazenil) has been administered in adults to reverse the effects of benzodiazepines in conscious sedation, general anesthesia, and the management of suspected benzodiazepine overdose. Limited information from uncontrolled studies in pediatric patients is available regarding the use of Romazicon (Flumazenil) to reverse the effects of benzodiazepines in conscious sedation only.
Romazicon (Flumazenil) was studied in four trials in 970 patients who received an average of 30 mg diazepam or 10 mg midazolam for sedation (with or without a narcotic) in conjunction with both inpatient and outpatient diagnostic or surgical procedures. Romazicon (Flumazenil) was effective in reversing the sedating and psychomotor effects of the benzodiazepine; however, amnesia was less completely and less consistently reversed. In these studies, Romazicon (Flumazenil) was administered as an initial dose of 0.4 mg IV (two doses of 0.2 mg) with additional 0.2 mg doses as needed to achieve complete awakening, up to a maximum total dose of 1 mg.
Seventy-eight percent of patients receiving flumazenil responded by becoming completely alert. Of those patients, approximately half responded to doses of 0.4 mg to 0.6 mg, while the other half responded to doses of 0.8 mg to 1 mg. Adverse effects were infrequent in patients who received 1 mg of Romazicon (Flumazenil) or less, although injection site pain, agitation, and anxiety did occur. Reversal of sedation was not associated with any increase in the frequency of inadequate analgesia or increase in narcotic demand in these studies. While most patients remained alert throughout the 3-hour postprocedure observation period, resedation was observed to occur in 3% to 9% of the patients, and was most common in patients who had received high doses of benzodiazepines (see ).
Romazicon (Flumazenil) was studied in four trials in 644 patients who received midazolam as an induction and/or maintenance agent in both balanced and inhalational anesthesia. Midazolam was generally administered in doses ranging from 5 mg to 80 mg, alone and/or in conjunction with muscle relaxants, nitrous oxide, regional or local anesthetics, narcotics and/or inhalational anesthetics. Flumazenil was given as an initial dose of 0.2 mg IV, with additional 0.2 mg doses as needed to reach a complete response, up to a maximum total dose of 1 mg. These doses were effective in reversing sedation and restoring psychomotor function, but did not completely restore memory as tested by picture recall. Romazicon (Flumazenil) was not as effective in the reversal of sedation in patients who had received multiple anesthetic agents in addition to benzodiazepines.
Eighty-one percent of patients sedated with midazolam responded to flumazenil by becoming completely alert or just slightly drowsy. Of those patients, 36% responded to doses of 0.4 mg to 0.6 mg, while 64% responded to doses of 0.8 mg to 1 mg.
Resedation in patients who responded to Romazicon (Flumazenil) occurred in 10% to 15% of patients studied and was more common with larger doses of midazolam (>20 mg), long procedures (>60 minutes) and use of neuromuscular blocking agents (see ).
Romazicon (Flumazenil) was studied in two trials in 497 patients who were presumed to have taken an overdose of a benzodiazepine, either alone or in combination with a variety of other agents. In these trials, 299 patients were proven to have taken a benzodiazepine as part of the overdose, and 80% of the 148 who received Romazicon (Flumazenil) responded by an improvement in level of consciousness. Of the patients who responded to flumazenil, 75% responded to a total dose of 1 mg to 3 mg.
Reversal of sedation was associated with an increased frequency of symptoms of CNS excitation. Of the patients treated with flumazenil, 1% to 3% were treated for agitation or anxiety. Serious side effects were uncommon, but six seizures were observed in 446 patients treated with flumazenil in these studies. Four of these 6 patients had ingested a large dose of cyclic antidepressants, which increased the risk of seizures (see ).
Romazicon (Flumazenil) Individualization Of Dosage
The serious adverse effects of Romazicon (Flumazenil) are related to the reversal of benzodiazepine effects. Using more than the minimally effective dose of Romazicon (Flumazenil) is tolerated by most patients but may complicate the management of patients who are physically dependent on benzodiazepines or patients who are depending on benzodiazepines for therapeutic effect (such as suppression of seizures in cyclic antidepressant overdose).
In high-risk patients, it is important to administer the smallest amount of Romazicon (Flumazenil) that is effective. The 1-minute wait between individual doses in the dose-titration recommended for general clinical populations may be too short for high-risk patients. This is because it takes 6 to 10 minutes for any single dose of flumazenil to reach full effects. Practitioners should slow the rate of administration of Romazicon (Flumazenil) administered to high-risk patients as recommended below.
The risk of confusion, agitation, emotional lability, and perceptual distortion with the doses recommended in patients with benzodiazepine overdose (3 mg to 5 mg administered as 0.5 mg/min) may be greater than that expected with lower doses and slower administration. The recommended doses represent a compromise between a desirable slow awakening and the need for prompt response and a persistent effect in the overdose situation. If circumstances permit, the physician may elect to use the 0.2 mg/minute titration rate to slowly awaken the patient over 5 to 10 minutes, which may help to reduce signs and symptoms on emergence.
Romazicon (Flumazenil) has no effect in cases where benzodiazepines are not responsible for sedation. Once doses of 3 mg to 5 mg have been reached without clinical response, additional Romazicon (Flumazenil) is likely to have no effect.
Romazicon (Flumazenil) may cause benzodiazepine withdrawal symptoms in individuals who have been taking benzodiazepines long enough to have some degree of tolerance. Patients who had been taking benzodiazepines prior to entry into the Romazicon (Flumazenil) trials, who were given flumazenil in doses over 1 mg, experienced withdrawal-like events 2 to 5 times more frequently than patients who received less than 1 mg.
In patients who may have tolerance to benzodiazepines, as indicated by clinical history or by the need for larger than usual doses of benzodiazepines, slower titration rates of 0.1 mg/min and lower total doses may help reduce the frequency of emergent confusion and agitation. In such cases, special care must be taken to monitor the patients for resedation because of the lower doses of Romazicon (Flumazenil) used.
Romazicon (Flumazenil) Contraindications
Romazicon (Flumazenil) is contraindicated:
Romazicon (Flumazenil) Warnings
THE USE OF Romazicon (Flumazenil) HAS BEEN ASSOCIATED WITH THE OCCURRENCE OF SEIZURES.
THESE ARE MOST FREQUENT IN PATIENTS WHO HAVE BEEN ON BENZODIAZEPINES FOR LONG-TERM SEDATION OR IN OVERDOSE CASES WHERE PATIENTS ARE SHOWING SIGNS OF SERIOUS CYCLIC ANTIDEPRESSANT OVERDOSE.
PRACTITIONERS SHOULD INDIVIDUALIZE THE DOSAGE OF Romazicon (Flumazenil) AND BE PREPARED TO MANAGE SEIZURES.
The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations. Possible risk factors for seizures include: concurrent major sedative-hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, myoclonic jerking or seizure activity prior to flumazenil administration in overdose cases, or concurrent cyclic antidepressant poisoning.
Romazicon (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 Romazicon (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 Romazicon (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.
Most convulsions associated with flumazenil administration require treatment and have been successfully managed with benzodiazepines, phenytoin or barbiturates. Because of the presence of flumazenil, higher than usual doses of benzodiazepines may be required.
Patients who have received Romazicon (Flumazenil) for the reversal of benzodiazepine effects (after conscious sedation or general anesthesia) should be monitored for resedation, respiratory depression, or other residual benzodiazepine effects for an appropriate period (up to 120 minutes) based on the dose and duration of effect of the benzodiazepine employed.
This is because Romazicon (Flumazenil) has not been established in patients as an effective treatment for hypoventilation due to benzodiazepine administration. In healthy male volunteers, Romazicon (Flumazenil) is capable of reversing benzodiazepine-induced depression of the ventilatory responses to hypercapnia and hypoxia after a benzodiazepine alone. However, such depression may recur because the ventilatory effects of typical doses of Romazicon (Flumazenil) (1 mg or less) may wear off before the effects of many benzodiazepines. The effects of Romazicon (Flumazenil) on ventilatory response following sedation with a benzodiazepine in combination with an opioid are inconsistent and have not been adequately studied. The availability of flumazenil does not diminish the need for prompt detection of hypoventilation and the ability to effectively intervene by establishing an airway and assisting ventilation.
Overdose cases should always be monitored for resedation until the patients are stable and resedation is unlikely.
Romazicon (Flumazenil) Precautions
Romazicon (Flumazenil) may be expected to improve the alertness of patients recovering from a procedure involving sedation or anesthesia with benzodiazepines, but should not be substituted for an adequate period of postprocedure monitoring. The availability of Romazicon (Flumazenil) does not reduce the risks associated with the use of large doses of benzodiazepines for sedation.
Patients should be monitored for resedation, respiratory depression (see ) or other persistent or recurrent agonist effects for an adequate period of time after administration of Romazicon (Flumazenil) .
Resedation is least likely in cases where Romazicon (Flumazenil) is administered to reverse a low dose of a short-acting benzodiazepine (
Profound resedation was observed in 1% to 3% of adult patients in the clinical studies. In clinical situations where resedation must be prevented in adult patients, physicians may wish to repeat the initial dose (up to 1 mg of Romazicon (Flumazenil) given at 0.2 mg/min) at 30 minutes and possibly again at 60 minutes. This dosage schedule, although not studied in clinical trials, was effective in preventing resedation in a pharmacologic study in normal volunteers.
The use of Romazicon (Flumazenil) to reverse the effects of benzodiazepines used for conscious sedation has been evaluated in one open-label clinical trial involving 107 pediatric patients between the ages of 1 and 17 years. This study suggested that pediatric patients who have become fully awake following treatment with flumazenil may experience a recurrence of sedation, especially younger patients (ages 1 to 5). Resedation was experienced in 7 of 60 patients who were fully alert 10 minutes after the start of Romazicon (Flumazenil) administration. No patient experienced a return to the baseline level of sedation. Mean time to resedation was 25 minutes (range: 19 to 50 minutes) (see ). The safety and effectiveness of repeated flumazenil administration in pediatric patients experiencing resedation have not been established.
Romazicon (Flumazenil) should be used with caution in the ICU because of the increased risk of unrecognized benzodiazepine dependence in such settings. Romazicon (Flumazenil) may produce convulsions in patients physically dependent on benzodiazepines (see and ).
Administration of Romazicon (Flumazenil) to diagnose benzodiazepine-induced sedation in the ICU is not recommended due to the risk of adverse events as described above. In addition, the prognostic significance of a patient's failure to respond to flumazenil in cases confounded by metabolic disorder, traumatic injury, drugs other than benzodiazepines, or any other reasons not associated with benzodiazepine receptor occupancy is unknown.
Romazicon (Flumazenil) is intended as an adjunct to, not as a substitute for, proper management of airway, assisted breathing, circulatory access and support, internal decontamination by lavage and charcoal, and adequate clinical evaluation.
Necessary measures should be instituted to secure airway, ventilation and intravenous access prior to administering flumazenil. Upon arousal, patients may attempt to withdraw endotracheal tubes and/or intravenous lines as the result of confusion and agitation following awakening.
Romazicon (Flumazenil) should be used with caution in patients with alcoholism and other drug dependencies due to the increased frequency of benzodiazepine tolerance and dependence observed in these patient populations.
Romazicon (Flumazenil) is not recommended either as a treatment for benzodiazepine dependence or for the management of protracted benzodiazepine abstinence syndromes, as such use has not been studied.
The administration of flumazenil can precipitate benzodiazepine withdrawal in animals and man. This has been seen in healthy volunteers treated with therapeutic doses of oral lorazepam for up to 2 weeks who exhibited effects such as hot flushes, agitation and tremor when treated with cumulative doses of up to 3 mg doses of flumazenil.
Similar adverse experiences suggestive of flumazenil precipitation of benzodiazepine withdrawal have occurred in some adult patients in clinical trials. Such patients had a short-lived syndrome characterized by dizziness, mild confusion, emotional lability, agitation (with signs and symptoms of anxiety), and mild sensory distortions. This response was dose-related, most common at doses above 1 mg, rarely required treatment other than reassurance and was usually short lived. When required, these patients (5 to 10 cases) were successfully treated with usual doses of a barbiturate, a benzodiazepine, or other sedative drug.
Practitioners should assume that flumazenil administration may trigger dose-dependent withdrawal syndromes in patients with established physical dependence on benzodiazepines and may complicate the management of withdrawal syndromes for alcohol, barbiturates and cross-tolerant sedatives.
Interaction with central nervous system depressants other than benzodiazepines has not been specifically studied; however, no deleterious interactions were seen when Romazicon (Flumazenil) was administered after narcotics, inhalational anesthetics, muscle relaxants and muscle relaxant antagonists administered in conjunction with sedation or anesthesia.
Particular caution is necessary when using Romazicon (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) may emerge with the reversal of the benzodiazepine effect by flumazenil (see ).
The use of Romazicon (Flumazenil) is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although Romazicon (Flumazenil) exerts a slight intrinsic anticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients.
Romazicon (Flumazenil) blocks the central effects of benzodiazepines by competitive interaction at the receptor level. The effects of nonbenzodiazepine agonists at benzodiazepine receptors, such as zopiclone, triazolopyridazines and others, are also blocked by Romazicon (Flumazenil) .
The pharmacokinetics of benzodiazepines are unaltered in the presence of flumazenil and vice versa.
There is no pharmacokinetic interaction between ethanol and flumazenil.
The effects of Romazicon (Flumazenil) may wear off before a long-acting benzodiazepine is completely cleared from the body. In general, if a patient shows no signs of sedation within 2 hours after a 1-mg dose of flumazenil, serious resedation at a later time is unlikely. An adequate period of observation must be provided for any patient in whom either long-acting benzodiazepines (such as diazepam) or large doses of short-acting benzodiazepines (such as >10 mg of midazolam) have been used (see ).
Because of the increased risk of adverse reactions in patients who have been taking benzodiazepines on a regular basis, it is particularly important that physicians query patients or their guardians carefully about benzodiazepine, alcohol and sedative use as part of the history prior to any procedure in which the use of Romazicon (Flumazenil) is planned (see ).
The safety and effectiveness of Romazicon (Flumazenil) have been established in pediatric patients 1 year of age and older. Use of Romazicon (Flumazenil) in this age group is supported by evidence from adequate and well-controlled studies of Romazicon (Flumazenil) in adults with additional data from uncontrolled pediatric studies including one open-label trial.
The use of Romazicon (Flumazenil) to reverse the effects of benzodiazepines used for conscious sedation was evaluated in one uncontrolled clinical trial involving 107 pediatric patients between the ages of 1 and 17 years. At the doses used, Romazicon (Flumazenil) 's safety was established in this population. Patients received up to 5 injections of 0.01 mg/kg flumazenil up to a maximum total dose of 1.0 mg at a rate not exceeding 0.2 mg/min.
Of 60 patients who were fully alert at 10 minutes, 7 experienced resedation. Resedation occurred between 19 and 50 minutes after the start of Romazicon (Flumazenil) administration. None of the patients experienced a return to the baseline level of sedation. All 7 patients were between the ages of 1 and 5 years. The types and frequency of adverse events noted in these pediatric patients were similar to those previously documented in clinical trials with Romazicon (Flumazenil) to reverse conscious sedation in adults. No patient experienced a serious adverse event attributable to flumazenil.
The safety and efficacy of Romazicon (Flumazenil) in the reversal of conscious sedation in pediatric patients below the age of 1 year have not been established (see ).
The safety and efficacy of Romazicon (Flumazenil) have not been established in pediatric patients for reversal of the sedative effects of benzodiazepines used for induction of general anesthesia, for the management of overdose, or for the resuscitation of the newborn, as no well-controlled clinical studies have been performed to determine the risks, benefits and dosages to be used. However, published anecdotal reports discussing the use of Romazicon (Flumazenil) in pediatric patients for these indications have reported similar safety profiles and dosing guidelines to those described for the reversal of conscious sedation.
The risks identified in the adult population with Romazicon (Flumazenil) use also apply to pediatric patients. Therefore, consult the , and sections when using Romazicon (Flumazenil) in pediatric patients.
Of the total number of subjects in clinical studies of flumazenil, 248 were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
The pharmacokinetics of flumazenil have been studied in the elderly and are not significantly different from younger patients. Several studies of Romazicon (Flumazenil) in subjects over the age of 65 and one study in subjects over the age of 80 suggest that while the doses of benzodiazepine used to induce sedation should be reduced, ordinary doses of Romazicon (Flumazenil) may be used for reversal.
Romazicon (Flumazenil) Adverse Reactions
Deaths have occurred in patients who received Romazicon (Flumazenil) in a variety of clinical settings. The majority of deaths occurred in patients with serious underlying disease or in patients who had ingested large amounts of non-benzodiazepine drugs (usually cyclic antidepressants), as part of an overdose.
Serious adverse events have occurred in all clinical settings, and convulsions are the most common serious adverse events reported. Romazicon (Flumazenil) administration has been associated with the onset of convulsions in patients with severe hepatic impairment and in patients who are relying on benzodiazepine effects to control seizures, are physically dependent on benzodiazepines, or who have ingested large doses of other drugs (mixed-drug overdose) (see ).
Two of the 446 patients who received Romazicon (Flumazenil) in controlled clinical trials for the management of a benzodiazepine overdose had cardiac dysrhythmias (1 ventricular tachycardia, 1 junctional tachycardia).
The following adverse reactions were considered to be related to Romazicon (Flumazenil) administration (both alone and for the reversal of benzodiazepine effects) and were reported in studies involving 1875 individuals who received flumazenil in controlled trials. Adverse events most frequently associated with flumazenil alone were limited to dizziness, injection site pain, increased sweating, headache, and abnormal or blurred vision (3% to 9%).
Body as a Whole:
indicates reaction in 3% to 9% of cases.
Cardiovascular System:
Digestive System:
Nervous System:
Special Senses:
All adverse reactions occurred in 1% to 3% of cases unless otherwise marked.
Observed percentage reported if greater than 9%.
The following adverse events were observed infrequently (less than 1%) in the clinical studies, but were judged as probably related to Romazicon (Flumazenil) administration and/or reversal of benzodiazepine effects:
Special Senses:
The following adverse events occurred with frequencies less than 1% in the clinical trials. Their relationship to Romazicon (Flumazenil) administration is unknown, but they are included as alerting information for the physician.
Body as a Whole:
Cardiovascular System:
Digestive System:
Nervous System:
Not included in this list is operative site pain that occurred with the same frequency in patients receiving placebo as in patients receiving flumazenil for reversal of sedation following a surgical procedure.
The following events have been reported during postapproval use of Romazicon (Flumazenil) .
Nervous System:
Withdrawal symptoms may occur following rapid injection of Romazicon (Flumazenil) in patients with long-term exposure to benzodiazepines.
Romazicon (Flumazenil) Drug Abuse And Dependence
Romazicon (Flumazenil) acts as a benzodiazepine antagonist, blocks the effects of benzodiazepines in animals and man, antagonizes benzodiazepine reinforcement in animal models, produces dysphoria in normal subjects, and has had no reported abuse in foreign marketing.
Although Romazicon (Flumazenil) has a benzodiazepine-like structure it does not act as a benzodiazepine agonist in man and is not a controlled substance.
Romazicon (Flumazenil) Overdosage
There is limited experience of acute overdose with Romazicon (Flumazenil) .
There is no specific antidote for overdose with Romazicon (Flumazenil) . Treatment of an overdose with Romazicon (Flumazenil) should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
Intravenous bolus administration of doses ranging from 2.5 to 100 mg (exceeding those recommended) of Romazicon (Flumazenil) , when administered to healthy normal volunteers in the absence of a benzodiazepine agonist, produced no serious adverse reactions, severe signs or symptoms, or clinically significant laboratory test abnormalities. In clinical studies, most adverse reactions to flumazenil were an extension of the pharmacologic effects of the drug in reversing benzodiazepine effects.
Reversal with an excessively high dose of Romazicon (Flumazenil) may produce anxiety, agitation, increased muscle tone, hyperesthesia and possibly convulsions. Convulsions have been treated with barbiturates, benzodiazepines and phenytoin, generally with prompt resolution of the seizures (see ).
Romazicon (Flumazenil) Dosage And Administration
Romazicon (Flumazenil) is recommended for intravenous use only. It is compatible with 5% dextrose in water, lactated Ringer's and normal saline solutions. If Romazicon (Flumazenil) is drawn into a syringe or mixed with any of these solutions, it should be discarded after 24 hours. For optimum sterility, Romazicon (Flumazenil) should remain in the vial until just before use. As with all parenteral drug products, Romazicon (Flumazenil) should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
To minimize the likelihood of pain at the injection site, Romazicon (Flumazenil) should be administered through a freely running intravenous infusion into a large vein.
Romazicon (Flumazenil) How Supplied
5 mL multiple-use vials containing 0.1 mg/mL flumazenil — boxes of 10 (NDC 0004-6911-06); 10 mL multiple-use vials containing 0.1 mg/mL flumazenil — boxes of 10 (NDC 0004-6912-06).
Romazicon (Flumazenil)
Romazicon (Flumazenil) Principal Display Panel - Ml Vial Carton
NDC 0004-6911-06
5 mL Multiple-Use Vials (0.1 mg/mL)
10 Vials(5 mL Size)
