Serious Adverse Reactions
Deaths have occurred in patients who received ROMAZICON 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 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 ROMAZICON 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 ROMAZICON 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 , injection site reaction (thrombophlebitis, skin abnormality, rash)
Cardiovascular System: cutaneous vasodilation (sweating, flushing, hot flushes)
Digestive System: nausea, vomiting (11%)
Nervous System: agitation (anxiety, nervousness, dry mouth, tremor, palpitations, insomnia, dyspnea, hyperventilation), dizziness (vertigo, ataxia) (10%), emotional lability (crying abnormal, depersonalization, euphoria, increased tears, depression, dysphoria, paranoia)
Special Senses: abnormal vision (visual field defect, diplopia), paresthesia (sensation abnormal, hypoesthesia)
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 administration and/or reversal of benzodiazepine effects:
Nervous System: confusion (difficulty concentrating, delirium), convulsions (see WARNINGS), 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 ROMAZICON 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, 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.
Additional Adverse Reactions Reported During Postmarketing Experience
The following events have been reported during postapproval use of ROMAZICON.
Nervous System: Fear, panic attacks in patients with a history of panic disorders.
Withdrawal symptoms may occur following rapid injection of ROMAZICON in patients with long-term exposure to benzodiazepines.