Romazicon Side Effects, and Drug Interactions - Flumazenil

Romazicon Side Effects, and Drug Interactions - Flumazenil

SIDE EFFECTS

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).

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.

*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 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.

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.

ROMAZICON 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 has a benzodiazepine-like structure it does not act as a benzodiazepine agonist in man and is not a controlled substance.

DRUG INTERACTIONS

Interaction with central nervous system depressants other than benzodiazepines has not been specifically studied; however, no deleterious interactions were seen when ROMAZICON 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 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 is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although ROMAZICON 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 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.

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 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 is planned (see PRECAUTIONS: Use in Drug-and Alcohol-Dependent Patients).