Data Sheet

Anexate
flumazenil 0.5 mg per 5 mL, solution for injection

Description

Benzodiazepine antagonist.

Anexate ampoules contain 0.5 mg flumazenil in 5 mL aqueous solution for intravenous (IV)
administration. Anexate is a colourless to almost-colourless, sterile, clear liquid stored in 5 mL glass
ampoules. Anexate ampoules are supplied in packs of five.

ATC code: V03AB25

Excipients
Disodium edetate, glacial acetic acid, sodium chloride, sodium hydroxide, sterile water for injections.

Clinical Particulars

Therapeutic Indications
Anexate is indicated for reversal of the centrally sedative effects of benzodiazepines. It should
therefore be used in anaesthesia and intensive care in the following indications:

In anaesthesia
Termination of general anaesthesia induced and maintained with benzodiazepines in
inpatients.
Reversal of benzodiazepine sedation in short diagnostic and therapeutic procedures in both
inpatients and outpatients.
Reversal of paradoxical reactions due to benzodiazepines.

In intensive care and in the management of unconsciousness of unknown

origin
For the diagnosis and/or management of benzodiazepine overdose due to self-poisoning or
accidental overdose.
As a diagnostic measure in unconsciousness of unknown origin to differentiate between
involvement of benzodiazepines, other medicines or drugs or brain damage.
Anexate may also be used for specific reversal of the central effects of benzodiazepines in
drug or medicine overdose (return to spontaneous respiration and consciousness in order to
render intubation unnecessary or allow extubation).

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Dosage and Administration

Anexate is recommended for intravenous (IV) use only and should be administered by an
anaesthesiologist or experienced physician.

For instructions on handling Anexate, see Pharmaceutical Particulars.

Dosage should be titrated for the intended effect. Since the duration of action of some
benzodiazepines may exceed that of Anexate, repeated doses may be required if sedation recurs
following awakening.

In anaesthesia
The recommended initial dose of Anexate is 0.2 mg administered IV over 15 seconds. If the desired
degree of consciousness is not obtained within 60 seconds, a second dose of 0.1 mg can be injected;
this may be repeated at 60-second intervals where necessary, up to a total dose of 1 mg. The usual
dose is 0.3-0.6 mg, but individual requirements may vary considerably, depending on the dose and
duration of effect of the benzodiazepine administered and patient characteristics.

In intensive care and in the management of unconsciousness of unknown

origin
The recommended initial dose of Anexate is 0.3 mg IV. If the desired level of consciousness is not
obtained within 60 seconds, Anexate may be injected repeatedly until the patient awakes or up to a
total dose of 2 mg. If drowsiness recurs, Anexate may be administered as one or more bolus IV doses
as above, or as an IV infusion of 0.1-0.4 mg per hour. The rate of infusion should be individually
adjusted to the desired level of arousal.

If a significant improvement in consciousness or respiratory function is not obtained after repeated

doses of Anexate, a non-benzodiazepine aetiology must be assumed.

In the intensive care unit, in patients treated with high doses of benzodiazepines and/or for long
periods of time, the individually titrated injections of Anexate, slowly administered, should not produce
withdrawal syndromes. If unexpected symptoms occur, diazepam or midazolam could be carefully
titrated intravenously according to patient response (see Warnings and Precautions).

Special dosage instructions

Children >1 year-of-age
For the reversal of conscious sedation induced with benzodiazepines in children above one year-of-
age, the recommended initial dose is 0.01 mg/kg (up to 0.2 mg) administered IV over 15 seconds. If
the desired level of consciousness is not obtained after waiting an additional 45 seconds, further
injections of 0.01 mg/kg (up to 0.2 mg) can be administered and repeated at 60 second intervals where
necessary (up to a maximum of four additional times) to a maximum total dose of 0.05 mg/kg or 1 mg,
whichever is lower. The dose should be individualised based on patient response. No data are
available on the safety and efficacy of repeated administration of Anexate to children for re-sedation.

Hepatic Impairment
Since Anexate is primarily metabolised in the liver, careful titration of dosage is recommended in
patients with impaired hepatic function.

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Contraindications

Anexate is contraindicated in patients with known hypersensitivity to the medicine.

Anexate is contraindicated in patients who have been given a benzodiazepine for control of a
potentially life-threatening condition (e.g. control of intracranial pressure or status epilepticus).

Warnings and Precautions

General
Particular caution is necessary when using Anexate in cases of mixed-substance overdose since the
toxic effects (such as convulsions and cardiac dysrhythmias) of other medicines taken in overdose
(especially cyclic antidepressants) may emerge with the reversal of benzodiazepine effects by Anexate.

The use of Anexate is not recommended in epileptic patients who have been receiving benzodiazepine
treatment for a prolonged period. Although Anexate 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.

Patients who have received Anexate for the reversal of benzodiazepine effects should be monitored for
resedation, respiratory depression or other residual benzodiazepine effects for an appropriate period
based on the dose and duration of effect of the benzodiazepine employed. As patients with underlying
hepatic impairment may experience delayed benzodiazepine effects, an extended observation period
may be required.

When Anexate is used with neuromuscular-blocking agents, it should not be injected until the effects of
neuromuscular blockade have been fully reversed.

Anexate 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.

Rapid injection of Anexate should be avoided in patients with high dose and/or long-term exposure to
benzodiazepines ending at any time within the weeks preceding Anexate administration as it may
produce withdrawal symptoms, including agitation, anxiety, emotional lability as well as mild confusion
and sensory distortions (see Dosage and Administration).

Anexate is not recommended either as a treatment for benzodiazepine dependence or for the
management of protracted benzodiazepine abstinence syndromes.

Anexate should be used with caution for the reversal of conscious sedation in children below the age of
one year, for the management of overdose in children, for resuscitation of the newborn and for reversal
of the sedative effects of benzodiazepines used for induction of general anaesthesia in children, as
experience is limited (see Dosage and Administration).

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Ability to Drive and Use Machines
Patients should be warned against engaging in hazardous activities requiring complete mental
alertness (such as operating dangerous machinery or driving a motor vehicle) during the first
24 hours after administration, since the effect of the originally ingested or administered benzodiazepine
(for example, sedation) may occur.

Interactions with other Medicinal Products and other Forms

of Interaction
Anexate blocks the central effects of benzodiazepines by competitive interaction at the receptor level.
The effects of non-benzodiazepine agonists at benzodiazepine receptors, such as zopiclone,
triazolopyridazines and others, are also blocked by Anexate.

The pharmacokinetics of benzodiazepine agonists are unaltered in the presence of Anexate and vice
versa.

There is no pharmacokinetic interaction between ethanol and flumazenil.

Use in Special Populations

Pregnancy
Although in-vitro and animal studies using high doses of Anexate have not shown evidence of
mutagenicity, teratogenicity or impairment of fertility, the safety of Anexate in human pregnancy has not
been established. Therefore, the benefits of medication during pregnancy should be weighed against
possible risks to the foetus.

Nursing Mothers
Parenteral administration of Anexate in emergencies is not contraindicated during lactation.

Paediatric Use
See Warnings and Precautions; General

Hepatic Impairment
See Dosage and Administration; Special Dosing Instructions and Warnings and Precautions; General.

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Undesirable Effects

Post-Marketing
Anexate is well tolerated in adults and children. In adults, Anexate is well tolerated even at doses
exceeding those recommended.

Hypersensitivity reactions, including anaphylaxis, have been observed.

Complaints such as feelings of anxiety, palpitations and fear have been infrequently observed after
rapid injection of Anexate. These adverse effects usually do not necessitate special treatment.

Seizures have been reported in patients known to suffer from epilepsy or severe hepatic impairment,
particularly after long-term treatment with benzodiazepines or in cases of mixed-substance overdose.

In cases of mixed-substance overdose, particularly with cyclic antidepressants, toxic effects (such as
convulsions and cardiac dysrhythmias) may emerge with the reversal of benzodiazepine effects by
Anexate.

Withdrawal symptoms may occur following rapid injection of Anexate in patients with long-term
exposure to benzodiazepines ending at any time within the weeks preceding Anexate administration.

Anexate has been reported to provoke panic attacks in patients with a history of panic disorders.

Overdosage

There is very limited experience of acute overdose in humans with Anexate.

There is no specific antidote for overdose with Anexate. Treatment of an overdose with Anexate
should consist of general supportive measures including monitoring of vital signs and observation of
the clinical status of the patient.

Even when given at doses exceeding those recommended, no symptoms of overdosage were
observed. For withdrawal symptoms attributable to the agonist, see Dosage and Administration.

Pharmacological Properties and Effects

Pharmacodynamic Properties
Mechanism of action
Anexate, an imidazobenzodiazepine derivative, is a benzodiazepine antagonist. It competitively inhibits
agents that act via benzodiazepine receptors, specifically blocking their central nervous effects. In
animal experiments, the effects of compounds showing affinity for benzodiazepine receptors were
blocked. In healthy volunteers, IV Anexate has been shown to antagonise the sedation, amnesia and

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psychomotor impairment produced by benzodiazepine agonists. Hypnotic-sedative benzodiazepine
effects are rapidly reversed by Anexate after IV injection (1-2 minutes) and may then reappear
gradually within the next few hours depending on the half-life and dose ratio of the agonist and
antagonist.

Anexate may possess some weak intrinsic agonistic (e.g. anticonvulsant) activity.

In animals pre-treated with high doses of benzodiazepines over several weeks, Anexate elicited
symptoms of benzodiazepine withdrawal, including seizures. A similar effect was seen in adult human
subjects.

Pharmacokinetic Properties
Absorption
The pharmacokinetics of flumazenil are dose-proportional within and above the therapeutic range (up
to 100 mg).

Distribution
Flumazenil, a weak lipophilic base, is about 50% bound to plasma proteins. Albumin accounts for two-
thirds of plasma protein binding. Flumazenil is extensively distributed in the extravascular space.
Plasma concentrations of flumazenil decrease with a half-life of 4-11 minutes during the distribution
phase. The volume of distribution at steady state is 0.9-1.1 L/kg.

Metabolism
Flumazenil is extensively metabolised in the liver. The carboxylic acid metabolite is the main
metabolite in plasma (free form) and urine (free form and its glucuronide). This main metabolite shows
no benzodiazepine agonist or antagonist activity in pharmacological tests.

Elimination
Flumazenil is almost completely (99%) eliminated by non-renal routes. Practically no unchanged
flumazenil is excreted in the urine, suggesting complete metabolic degradation of the medicine.
Elimination of radiolabelled substance is essentially complete within 72 hours, with 90-95% of the
radioactivity appearing in urine and 5-10% in the faeces. Elimination is rapid, as shown by a short
elimination half-life of 40-80 minutes. The total plasma clearance of flumazenil is 0.8-1.0 L/hr/kg and
can be attributed almost entirely to hepatic clearance.

Ingestion of food during an intravenous infusion of flumazenil results in a 50% increase in clearance,
most likely due to the increased hepatic blood flow that accompanies a meal.

Pharmacokinetics in special populations

In patients with impaired liver function, the elimination half-life of flumazenil is longer (1.3 hours in
moderate impairment and 2.4 hours in severely impaired patients) and the total body clearance is
lower than in healthy subjects. The pharmacokinetics of flumazenil are not significantly affected in the
elderly, by gender, haemodialysis or renal failure.

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The elimination half-life in children over one year of age is more variable than in adults, averaging 40
minutes and generally ranging from 20-75 minutes. Clearance and volume of distribution, normalised
for body weight, are in the same range as is seen in adults.

Pharmaceutical Particulars

Storage
Store below 30C.

The shelf-life of Anexate is 5 years. This medicine should not be used after the expiry date (EXP)
shown on the pack.

Special Instructions for Use, Handling and Disposal

When Anexate is drawn into a syringe or diluted with normal saline, lactated Ringers or 5% dextrose, it
should be discarded after 24 hours (see Dosage and Administration).

For optimum sterility, Anexate should remain in the ampoule until just before use.

Medicine Classification

Prescription medicine.

Name and Address

Roche Products (New Zealand) Limited

PO Box 109113, Newmarket
Auckland 1149
New Zealand

Customer enquiries: 0800 656 464

Date of Preparation

02 April 2014

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