ANEXATE AMPOULES

Israel - English - Ministry of Health

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Active ingredient:
FLUMAZENIL 0.1 MG/ML
Available from:
ROCHE PHARMACEUTICALS (ISRAEL) LTD
ATC code:
V03AB25
Pharmaceutical form:
SOLUTION FOR INJECTION
Administration route:
I.V
Manufactured by:
HOFFMANN LA ROCHE LTD, SWITZERLAND
Therapeutic group:
FLUMAZENIL
Therapeutic indications:
Benzodiazepine antagonist for reversal of benzodiazepine anasthesia, as well as for patients with benzodiazepine intoxication.
Authorization number:
064462532000
Authorization date:
2009-06-01

טמרופ ןולע הז עבקנ ע " י דרשמ תואירבה ונכותו קדבנ רשואו לע - בודי טסוגוא 2008

ANEXATE ®

FLUMAZENIL

Solution for injection or infusion

1. TRADE NAME OF THE MEDICINAL PRODUCT

Anexate ®

0.1mg/ml Ampoule

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml ampoule contains 500 microgramsof flumazenil (100 micrograms per ml).

Each 10ml ampoule contains 1000 microgramsof flumazenil (100 micrograms per ml).

For excipients,see 6.1.

3. PHARMACEUTICAL FORM

Solution for Injection or infusion.

A clear, almost colourless, sterile aqueous solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Anexateis indicated for reversal of the centrally sedative effects of benzodiazepine. It is

therefore used in anesthesia and intensive care in the following indications:

In anesthesia: termination of general anesthesia inducedandmaintainedwithbenzodiazepine

in inpatients.

Reversalofbenzodiazepine-inducedsedationin short diagnostic and therapeutic procedures

in both inpatients and outpatients.

As specific reversal of the central effects of benzodiazepine in the drug overdose (return to

spontaneous respiration and consciousness in order to render intubation unnecessary or

allow extubation).

4.2 Posologyand method of administration

Anexateisforslowintravenous injection or infusion. It should only be administered under the

supervision of an experienced physician.

Anexate may be used concurrently with other resuscitative procedures.

Adults

The recommended initial dose is 200 micrograms administered intravenously over 15 seconds.

Ifthedesiredlevelofconsciousness is not obtained within 60 seconds a further dose of 100

micrograms can be injected and repeated at 60-second intervals where necessary, up to a

maximum total dose of 1mg or in intensive caresituations,2mg.Theusualdoserequiredis

300 - 600 micrograms.

ANEXATE ® MoH approved Prescribing Information

Ampoules 0.1 mg/ml August 2008

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Ifdrowsinessrecurs,anintravenousinfusionof 100 - 400 micrograms per hour may be

employed. The rate of infusion should be individually adjusted to achieve the desiredlevelof

arousal.

The individually titrated, slow injections or infusions of Anexate should not produce withdrawal

symptoms, even in patients exposed to high doses of benzodiazepines and/or for long periods

of time. If, however, unexpected signs of overstimulation occur, an individually titrated dose of

diazepam (Valium) or midazolam (Hypnovel) should be given by slow intravenous injection.

If a significant improvement in consciousness or respiratory functionisnotobtainedafter

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

Elderly

No specific data are available on the use of Anexate in the elderly, but it should be

remembered that this population is more sensitive totheeffectsofbenzodiazepinesand

should be treated with due caution.

Children

There are insufficient data to make dosage recommendations for Anexateinchildren.It

should,therefore,beadministeredonlyifthe potential benefits to the patient outweigh the

possible risks.

Use in renal and hepatic insufficiency

No dosage adjustments are necessary in patients with renal impairment. However,since

flumazenil is primarily metabolised in the liver, careful titration of dosage isrecommendedin

patients with impaired hepatic function.

4.3 Contra-indications

Anexate is contra-indicated in patients with known hypersensitivity to flumazenil,

benzodiazepines or any of the excipients.

Anexateis contra-indicated in patients who have been given a benzodiazepine for control of

apotentially life-threatening condition (e.g. control of intracranial pressure or status

epilepticus).

In mixed intoxications with benzodiazepines and tricyclicand/or tetracyclic antidepressants, the

toxicity of the antidepressants can be masked by protective benzodiazepine effects. Inthe

presence of autonomic (anticholinergic), neurological (motor abnormalities) or cardiovascular

symptoms of severe intoxication with tricyclics/tetracyclics, Anexate should notbeusedto

reverse benzodiazepine effects.

4.4 Special warnings and special precautions for use

Inviewof the short duration of action of Anexate and the possible need for repeat doses, the

patientshouldremainundercloseobservation until all possible central benzodiazepine effects

have subsided.

The use of Anexate is not recommended inepileptic patients who have been receiving

benzodiazepine treatment for a prolonged period. AlthoughAnexateexertsaslightintrinsic

anticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine

agonist can give rise to convulsions in epileptic patients.

ANEXATE ® MoH approved Prescribing Information

Ampoules 0.1 mg/ml August 2008

_________________________________________________________________________

3

Anexateshouldbe used with caution in patients with head injury as it may be capable of

precipitating convulsions or altering cerebral blood flow inpatientsreceiving

benzodiazepines.

Benzodiazepines have a dependence potential when used chronically. Symptoms such as

depression, nervousness, rebound insomnia, irritability, sweating and diarrhoea mayarise

followingabrupt cessation of benzodiazepines in patients treated with high doses and/or for

prolonged periods of time. Rapid injection of Anexateinsuchpatientsmaytriggerthese

withdrawal symptoms, even in patients who stopped taking the benzodiazepine in the weeks

preceding Anexate administration (depending on the half-life of the benzodiazepine used) and

shouldthereforebeavoided.There is also a possibility of mild and transient withdrawal

reactions occurring even after a short period of administration of benzodiazepines.

WhenAnexateisused with neuromuscular blocking agents, it should not be injected until

the effects of neuromuscular blockade have been fully reversed.

In high-risk patients, theadvantagesofcounteracting the central nervous system depression

associated with benzodiazepines should be weighed against the drawbacks ofrapid

awakening.

ThedosageofAnexate should be adjusted individually to the needs of patients suffering from

pre-operative anxiety or having a history of chronicorepisodic anxiety. In anxious patients,

particularly those with coronary heart disease, it is preferable to maintain a degreeofsedation

throughout the early post-operative period rather than bring about complete arousal.

Thepainfeltbypatientsinthepost-operative period must be taken into account. Following a

major intervention, it is preferable to maintain a moderate degree of sedation.

Anexateis not recommended either as a treatment for benzodiazepine dependence or for

the management of protracted benzodiazepine abstinence syndromes.

4.5 Interaction with other medicaments and other forms of interaction

Anexate blocks the central effects of benzodiazepines by competitive interactionatthe

receptor level; the effects of non-benzodiazepines acting via the benzodiazepine receptor,

such as zopiclone, are also blockedbyAnexate. However, Anexate is ineffective when

unconsciousness is due to other substances.

Interactionwithothercentral nervous system depressants has not been observed. However,

particularcaution is necessary when using Anexate in cases of intentional overdosage since

the toxic effects of other psychotropic drugs(especiallytricyclicantidepressants)taken

concurrently may increase with the subsidence of the benzodiazepine effect.

The pharmacokinetics of benzodiazepines are unaltered in thepresenceofAnexateandvice

versa.

4.6 Pregnancyand lactation

Like other benzodiazepine compounds, Anexate is expected to cross the placentaandtoenter

into breast milk, although the total quantities involved would be small. There has been little

humanusagebut animal studies have shown no teratogenic potential. The established

medicalprinciple of only administering drugs in early pregnancy when considered absolutely

necessary should therefore be observed.

Emergency use of Anexate during lactation is not contra-indicated.

ANEXATE ® MoH approved Prescribing Information

Ampoules 0.1 mg/ml August 2008

_________________________________________________________________________

4

4.7 Effects on abilityto drive and use machines

Patientswhohavereceived Anexate to reverse the effects of benzodiazepine sedation should

be warned not to drive, to operate machinery or to engage in any otherphysicallyormentally

demanding activity for at least 24 hours, since the effect of the benzodiazepine may return.

4.8 Undesirable effects

Anexateisgenerallywelltolerated.In post-operative use, nausea and/or vomiting are

occasionally observed, particularly if opiateshavealso been employed. Flushing has also

been noted. If patients are awakened too rapidly, they may become agitated, anxious or

fearful. Very rarely, seizures have been reported,particularly in patients known to suffer from

epilepsy or severe hepatic impairment, particularlyafterlong-termtreatmentwith

benzodiazepines or in cases of mixed drug overdose. Transient increases in bloodpressure

and heart rate may occur on awakening in intensive care patients.

Anyside-effectsassociated with Anexate usually subside rapidly without the need for special

treatment.

Excessive and/or rapidly injected doses of Anexate mayinducebenzodiazepinewithdrawal

symptomssuchas anxiety attacks, tachycardia, dizziness and sweating in patients on long-

termand/orhighdosebenzodiazepine treatment ending at any time within the weeks

preceding Anexate administration (depending on the half-life of the benzodiazepineused).

Such symptoms may be treated by slow intravenous injection of diazepam or midazolam(see

section4.2 Posology and method of administration). There is also a possibilityofmildand

transient withdrawal reactions occurring even after a short period of administrationof

benzodiazepines.

Anexate has been reported to provoke panic attacks in patientswithahistoryofpanic

disorders.

Hypersensitivity reactions (includinganaphylaxis) have occurred very rarely.

4.9 Overdose

Even when given intravenously at doses of 100mg,no symptoms of overdosage attributableto

Anexate have been observed.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Anexate, an imidazobenzodiazepine, is a specific competitiveinhibitorof substances which act

via the benzodiazepine receptors, specifically blocking their centraleffects.Thehypnotic-

sedativeeffectsoftheagonistarerapidly reversed by Anexate and may then reappear

gradually within a few hours, depending on the half-life and dose ratio of the agonistand

antagonist.

5.2 Pharmacokinetic properties

The pharmacokinetics of flumazenil are dose-proportional within and above the therapeutic

range (up to 100mg).

Distribution

ANEXATE ® MoH approved Prescribing Information

Ampoules 0.1 mg/ml August 2008

_________________________________________________________________________

5

Flumazenil, a weak lipophilic base, is about 50% bound to plasmaproteins.Albumin

accounts for two thirds of plasma protein binding. Flumazenilisextensivelydistributedinthe

extravascular space. Plasma concentrationsofflumazenil 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 metaboliteisthemain

metaboliteinplasma (free form) and urine (free form and its glucuronide). This main

metabolite showed no benzodiazepine agonist or antagonistactivityinpharmacological

tests.

Elimination

Flumazenilis almost completely (99%) eliminated by nonrenal routes. Practically no

unchangedflumazenil is excreted in the urine, suggesting complete metabolic degradation

of the drug. Elimination of radiolabelled drug is essentially completewithin72hours,with90

- 95% of the radioactivity appearing in urine and 5 - 10% inthefaeces.Eliminationisrapid,

asshownbyashortelimination 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 a50%increasein

clearance, most likely due to the increased hepatic blood flow that accompanies a meal.

Pharmacokinetics in special populations

In patients with impaired liver function, theelimination half-life of flumazenil is longer and the

totalbody clearance lower than in healthy subjects. The pharmacokinetics of flumazenil are

not significantly affected in the elderly, by gender, haemodialysis or renal failure.

5.3 Preclinical safetydata

Therearenopreclinicaldataof relevance to the prescriber which are additional to that

already included in other sections of the Prescribing Information.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium Edetate

Glacial Acetic Acid

Sodium Chloride

Sodium Hydroxide

Water for Injections

6.2 Incompatibilities

None stated.

6.3 Shelf life

Unopened: 5 years.

The product should be used immediately after opening.

ANEXATE ® MoH approved Prescribing Information

Ampoules 0.1 mg/ml August 2008

_________________________________________________________________________

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6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

Clear glass 5ml ampoules. Cartons of 5 or 25.

Clear glass 10 ml ampoules. Cartons of 5 or 25.

6.6 Instructions for use

Anexateampoulesolution may be diluted with Sodium Chloride Intravenous Infusion BP or

Dextrose 5% Intravenous Infusion BP. Chemicalandphysicalstabilityhasbeendemonstrated

for 24 hours at room temperature.

Anexate infusion should be administered within 3 hours of preparation.

Nopreparations other than those recommended should be added to the Anexate ampoule or

mixed with the Anexate infusion solution.

For single use only. Discard any unused contents.

7. MARKETING AUTHORISATION HOLDER

Roche Pharmaceuticals (Israel) Ltd., P.O. Box 7543, Petach-Tikva 49170.

8. MARKETING AUTHORISATION NUMBER

MoH number 64.46.25320

Medicine: keep out of reach of children

Manufacturer: F. Hoffmann-La Roche Ltd., Basel, Switzerland

1101ANEX0808

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