"FDA is recommending health care professionals discontinue prescribing and dispensing prescription combination drug products that contain more than 325 milligrams (mg) of acetaminophen per tablet, capsule or other dosage unit. There are no"...
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.
Risk of 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.
Return of Sedation
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 WARNINGS) 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 ( < 10 mg midazolam). It is most likely in cases where a large single or cumulative dose of a benzodiazepine has been given in the course of a long procedure along with neuromuscular blocking agents and multiple anesthetic agents.
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 PRECAUTIONS: Pediatric Use).
The safety and effectiveness of repeated flumazenil administration in pediatric patients experiencing resedation have not been established.
Use in the ICU
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 INDIVIDUALIZATION OF DOSAGE and WARNINGS).
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.
Use in Benzodiazepine Overdosage
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 head injury 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.
Use With Neuromuscular Blocking Agents
ROMAZICON (flumazenil) should not be used until the effects of neuromuscular blockade have been fully reversed.
Use in Psychiatric Patients
ROMAZICON (flumazenil) has been reported to provoke panic attacks in patients with a history of panic disorder.
Pain on Injection
To minimize the likelihood of pain or inflammation at the injection site, ROMAZICON (flumazenil) should be administered through a freely flowing intravenous infusion into a large vein. Local irritation may occur following extravasation into perivascular tissues.
Use in Respiratory Disease
The primary treatment of patients with serious lung disease who experience serious respiratory depression due to benzodiazepines should be appropriate ventilatory support (see PRECAUTIONS) rather than the administration of ROMAZICON. Flumazenil is capable of partially reversing benzodiazepine-induced alterations in ventilatory drive in healthy volunteers, but has not been shown to be clinically effective.
Use in Cardiovascular Disease
ROMAZICON (flumazenil) did not increase the work of the heart when used to reverse benzodiazepines in cardiac patients when given at a rate of 0.1 mg/min in total doses of less than 0.5 mg in studies reported in the clinical literature. Flumazenil alone had no significant effects on cardiovascular parameters when administered to patients with stable ischemic heart disease.
Use in Liver Disease
The clearance of ROMAZICON (flumazenil) is reduced to 40% to 60% of normal in patients with mild to moderate hepatic disease and to 25% of normal in patients with severe hepatic dysfunction (see CLINICAL PHARMACOLOGY: Pharmacokinetics). While the dose of flumazenil used for initial reversal of benzodiazepine effects is not affected, repeat doses of the drug in liver disease should be reduced in size or frequency.
Use in Drug- and Alcohol-Dependent Patients
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 WARNINGS).
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.
Use in Ambulatory Patients
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 INDIVIDUALIZATION OF DOSAGE).
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 PRECAUTIONS: Use in Drug- and Alcohol-Dependent Patients).
No specific laboratory tests are recommended to follow the patient's response or to identify possible adverse reactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies in animals to evaluate the carcinogenic potential of flumazenil have been conducted.
No evidence for mutagenicity was noted in the Ames test using five different tester strains. Assays for mutagenic potential in S. cerevisiae D7 and in Chinese hamster cells were considered to be negative as were blastogenesis assays in vitro in peripheral human lymphocytes and in vivo in a mouse micronucleus assay. Flumazenil caused a slight increase in unscheduled DNA synthesis in rat hepatocyte culture at concentrations which were also cytotoxic; no increase in DNA repair was observed in male mouse germ cells in an in vivo DNA repair assay.
Impairment of Fertility
A reproduction study in male and female rats did not show any impairment of fertility at oral dosages of 125 mg/kg/day. From the available data on the area under the curve (AUC) in animals and man the dose represented 120x the human exposure from a maximum recommended intravenous dose of 5 mg.
Pregnancy Category C
There are no adequate and well-controlled studies of the use of flumazenil in pregnant women. Flumazenil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Flumazenil has been studied for teratogenicity in rats and rabbits following oral treatments of up to 150 mg/kg/day. The treatments during the major organogenesis were on days 6 to 15 of gestation in the rat and days 6 to 18 of gestation in the rabbit. No teratogenic effects were observed in rats or rabbits at 150 mg/kg; the dose, based on the available data on the area under the plasma concentration-time curve (AUC) represented 120x to 600x the human exposure from a maximum recommended intravenous dose of 5 mg in humans. In rabbits, embryocidal effects (as evidenced by increased preimplantation and postimplantation losses) were observed at 50 mg/kg or 200x the human exposure from a maximum recommended intravenous dose of 5 mg. The no-effect dose of 15 mg/kg in rabbits represents 60x the human exposure.
An animal reproduction study was conducted in rats at oral dosages of 5, 25, and 125 mg/kg/day of flumazenil. Pup survival was decreased during the lactating period, pup liver weight at weaning was increased for the high-dose group (125 mg/kg/day) and incisor eruption and ear opening in the offspring were delayed; the delay in ear opening was associated with a delay in the appearance of the auditory startle response. No treatment-related adverse effects were noted for the other dose groups. Based on the available data from AUC, the effect level (125 mg/kg) represents 120x the human exposure from 5 mg, the maximum recommended intravenous dose in humans. The no-effect level represents 24x the human exposure from an intravenous dose of 5 mg.
Labor and Delivery
The use of ROMAZICON (flumazenil) to reverse the effects of benzodiazepines used during labor and delivery is not recommended because the effects of the drug in the newborn are unknown.
Caution should be exercised when deciding to administer ROMAZICON (flumazenil) to a nursing woman because it is not known whether flumazenil is excreted in human milk.
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 CLINICAL PHARMACOLOGY: Pharmacokinetics in Pediatric Patients).
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 CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS 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.
Last reviewed on RxList: 10/23/2007
This monograph has been modified to include the generic and brand name in many instances.
Additional Romazicon Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.