Flumazenil (Page 5 of 7)

Pregnancy

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.

Teratogenic Effects

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.

Nonteratogenic Effects

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 5mg.

Labor and Delivery

The use of 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.

Nursing Mothers

Caution should be exercised when deciding to administer flumazenil to a nursing woman because it is not known whether flumazenil is excreted in human milk.

Pediatric Use

The safety and effectiveness of flumazenil have been established in pediatric patients 1 year of age and older. Use of flumazenil in this age group is supported by evidence from adequate and well-controlled studies of flumazenil in adults with additional data from uncontrolled pediatric studies including one open-label trial.

The use of 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, 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 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 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 flumazenil to reverse conscious sedation in adults. No patient experienced a serious adverse event attributable to flumazenil.

The safety and efficacy of 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 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 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 flumazenil use also apply to pediatric patients. Therefore, consult the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections when using flumazenil in pediatric patients.

Geriatric Use

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 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 flumazenil may be used for reversal.

ADVERSE REACTIONS:

Serious Adverse Reactions

Deaths have occurred in patients who received 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. 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 WARNINGS).

Two of the 446 patients who received flumazenil in controlled clinical trials for the management of a benzodiazepine overdose had cardiac dysrhythmias (1 ventricular tachycardia, 1 junctional tachycardia).

Adverse Events in Clinical Studies

The following adverse reactions were considered to be related to 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: fatigue (asthenia, malaise), headache, injection site pain* and injection site reaction (thrombophlebitis, skin abnormality, rash)

Cardiovascular System: cutaneous vasodilation (sweating, flushing, hot flushes)

Digestive System: nausea and vomiting (11%)

Nervous System: agitation (anxiety, nervousness, dry mouth, tremor, palpitations, insomnia, dyspnea, hyperventilation)*, dizziness (vertigo, ataxia) (10%) and emotional lability (crying abnormal, depersonalization, euphoria, increased tears, depression, dysphoria, paranoia)

Special Senses: abnormal vision (visual field defect, diplopia) and paresthesia (sensation abnormal, hypoesthesia)

All adverse reactions occurred in 1% to 3% of cases unless otherwise marked.

*indicates reaction in 3% to 9% of cases.

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 flumazenil administration and/or reversal of benzodiazepine effects:

Nervous System: confusion (difficulty concentrating, delirium), convulsions (see WARNINGS) and somnolence (stupor)

Special Senses: abnormal hearing (transient hearing impairment, hyperacusis, tinnitus)

The following adverse events occurred with frequencies less than 1% in the clinical trials. Their relationship to flumazenil administration is unknown, but they are included as alerting information for the physician.

Body as a Whole: rigors, shivering

Cardiovascular System: arrhythmia (atrial, nodal, ventricular extrasystoles), bradycardia, tachycardia, hypertension and chest pain

Digestive System: hiccup

Nervous System: speech disorder (dysphonia, thick tongue)

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.

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