Drugs List

Therapeutic Indications

Uses

Flumazenil is used for the complete or partial reversal of the central sedative effects of benzodiazepines. It may therefore be used in the following situations:

- Termination of general anaesthesia induced and/or maintained with benzodiazepines.

- Reversal of benzodiazepine sedation in short diagnostic and therapeutic procedures.

- For the specific reversal of central effects of benzodiazepines, to allow return to spontaneous respiration and consciousness, in patients in intensive care.

- For the diagnosis and treatment of intoxication or overdose with only or mainly benzodiazepines.

- The reversal of conscious sedation induced by benzodiazepines in children over 1 year old.

Administration

For slow intravenous injection or infusion.

Handling

For single use only. Any unused portion should be discarded.

Reconstitution

For intravenous infusion
Flumazenil solution may be diluted with one of the following intravenous solutions:
-Sodium chloride Infusion 0.9%
-Glucose Infusion 5%

Flumazenil infusion should be administered within 3 hours of preparation.

Chemical and physical in-use stability after dilution has been demonstrated for 24 hours at room temperature.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 degrees C, unless dilution has taken place in controlled and validated aseptic conditions.

Incompatibilities

The medicinal product must not be mixed with other medicinal products except for those mentioned in Administration - Reconstitution section.

Contraindications

Patients given benzodiazepines for control of potentially life-threatening conditions (e.g. control of intracranial pressure or status epilepticus)

In mixed intoxications with benzodiazepines and tricyclic and/or tetracyclic antidepressants as the toxicity of the antidepressants can be masked by protective benzodiazepine effects. In the presence of autonomic (anticholinergic), neurological (motor abnormalities) or cardiovascular symptoms of severe intoxication with tricyclics/tetracyclics, flumazenil should not be used to reverse benzodiazepine effects.

Precautions and Warnings

To be administered under the supervision of an experienced physician.

Flumazenil specifically reverses benzodiazepines. Therefore if the patient does not wake up, another aetiology should be considered.

Monitor patients closely until all possible central benzodiazepine effects have subsided since flumazenil has a short duration of action and repeated doses may be needed. ECG, pulse, oximetry, patient alertness, heart rate, respiratory rate and blood pressure should be monitored.

No specific data are available on the use of flumazenil in the elderly, but it should be remembered that this population is more sensitive to the effects of benzodiazepines and should be treated with due caution.

Children under 18 years - use of flumazenil for indications other than reversal of conscious sedation is not recommended.
There are insufficient data to make dosage recommendations for flumazenil in children under 1 year. It should therefore be administered only if the potential benefits to the patient outweigh the possible risks.

Since flumazenil is primarily metabolised in the liver, careful titration of dosage is recommended in hepatic impairment.

Use with caution in epileptic patients who have been receiving benzodiazepine treatment for prolonged periods. Although flumazenil 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.

Flumazenil 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. In patients with severe brain damage (and/or unstable intracranial pressure), flumazenil, used to reverse the effects of benzodiazepines, may cause an increase in intracranial pressure.

Pregnancy - see Pregnancy section

Breastfeeding - see Lactation section

Rapid injection of flumazenil should be avoided. In patients with high dose and/or long-term exposure to benzodiazepines ending at any time within the weeks preceding flumazenil administration, rapid injection has led to withdrawal symptoms, including palpitations, agitation, anxiety, emotional lability as well as mild confusion and sensory distortions

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

In high risk patients, the advantages of counteracting the central nervous system depression associated with benzodiazepines should be weighed against the drawbacks of rapid awakening.

Due to the increased frequency of benzodiazepine tolerance and dependence in patients with alcoholism and other drug dependencies, flumazenil should be used with caution in this population.

Adjust the dose of flumazenil individually in patients suffering from pre-operative anxiety or having a history of chronic or episodic anxiety. May provoke panic attacks in patients with a history of panic disorders. In anxious patients, particularly those with coronary heart disease, it is preferable to maintain a degree of sedation throughout the early post-operative period rather than bring about complete arousal.

The pain felt by patients in the post-operative period must be taken into account. Following a major intervention, it is preferable to maintain a moderate degree of sedation.

Flumazenil is not recommended to treat benzodiazepine dependence or to manage benzodiazepine withdrawal symptoms.

Patients who have received flumazenil to reverse the effects of benzodiazepine sedation should be warned not to drive, to operate machinery or to engage in any other physically or mentally demanding activity for at least 24 hours, since the effect of the benzodiazepine may return.

Formulations contain sodium - This should be considered when treating patients with controlled sodium intake.

Pregnancy and Lactation

Pregnancy

Flumazenil should only be administered in early pregnancy when considered absolutely necessary. The indication is such that Briggs (2011) suggests that the benefit to the mother will far outweigh the unknown embryo/fetal risk.

Like other benzodiazepine compounds, flumazenil is expected to cross the placenta, although the total quantities involved would be small.

There has been little human usage but animal studies have shown no teratogenic potential.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Manufacturers advise that the emergency use of flumazenil during breastfeeding is not contraindicated.

Like other benzodiazepine compounds, flumazenil is expected to enter into breast milk, although the total quantities involved would be small. The very short half-life (mean 54 mins) will mitigate this transfer also IV flumazenil has been used directly in neonates therefore flumazenil should not be withheld during breastfeeding. However due to potential adverse effects in the nursing infant (similar to those seen in treated adults), consideration should be given to suspending breastfeeding for 24 hours to allow drug elimination from the mother to occur.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Nausea
Vomiting
Flushing
Agitation
Anxiety
Fear
Seizures
Cardiac arrhythmias
Palpitations
Increased blood pressure (transient)
Hypersensitivity reactions
Panic attack
Withdrawal symptoms
Confusion
Hallucinations
Emotional lability
Insomnia
Somnolence
Vertigo
Headache
Tremor
Dry mouth
Hyperventilation
Speech disturbances
Paraesthesia
Hearing disturbances
Diplopia
Strabismus
Increased lacrimation
Tachycardia
Dizziness
Bradycardia
Extrasystoles
Hypotension
Postural hypotension
Dyspnoea
Cough
Nasal congestion
Chest pain
Hiccups
Sweating
Fatigue
Local pain (injection site)
Shivering
Crying
Aggression in children
Aggressive reaction
Chills
Increased heart rate
Sensory disturbances

Presentation

Parenteral formulations of flumazenil.

Drugs List

Therapeutic Indications

Uses

Flumazenil is used for the complete or partial reversal of the central sedative effects of benzodiazepines. It may therefore be used in the following situations:

- Termination of general anaesthesia induced and/or maintained with benzodiazepines.

- Reversal of benzodiazepine sedation in short diagnostic and therapeutic procedures.

- For the specific reversal of central effects of benzodiazepines, to allow return to spontaneous respiration and consciousness, in patients in intensive care.

- For the diagnosis and treatment of intoxication or overdose with only or mainly benzodiazepines.

- The reversal of conscious sedation induced by benzodiazepines in children over 1 year old.

Dosage

To be administered under the supervision of an experienced physician.

Flumazenil may be used concurrently with other resuscitative procedures.

Adults

Children

Neonates

Administration

For slow intravenous injection or infusion.

Handling

For single use only. Any unused portion should be discarded.

Reconstitution

For intravenous infusion
Flumazenil solution may be diluted with one of the following intravenous solutions:
-Sodium chloride Infusion 0.9%
-Glucose Infusion 5%

Flumazenil infusion should be administered within 3 hours of preparation.

Chemical and physical in-use stability after dilution has been demonstrated for 24 hours at room temperature.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 degrees C, unless dilution has taken place in controlled and validated aseptic conditions.

Incompatibilities

The medicinal product must not be mixed with other medicinal products except for those mentioned in Administration - Reconstitution section.

Contraindications

Patients given benzodiazepines for control of potentially life-threatening conditions (e.g. control of intracranial pressure or status epilepticus)

In mixed intoxications with benzodiazepines and tricyclic and/or tetracyclic antidepressants as the toxicity of the antidepressants can be masked by protective benzodiazepine effects. In the presence of autonomic (anticholinergic), neurological (motor abnormalities) or cardiovascular symptoms of severe intoxication with tricyclics/tetracyclics, flumazenil should not be used to reverse benzodiazepine effects.

Precautions and Warnings

To be administered under the supervision of an experienced physician.

Flumazenil specifically reverses benzodiazepines. Therefore if the patient does not wake up, another aetiology should be considered.

Monitor patients closely until all possible central benzodiazepine effects have subsided since flumazenil has a short duration of action and repeated doses may be needed. ECG, pulse, oximetry, patient alertness, heart rate, respiratory rate and blood pressure should be monitored.

No specific data are available on the use of flumazenil in the elderly, but it should be remembered that this population is more sensitive to the effects of benzodiazepines and should be treated with due caution.

Children under 18 years - use of flumazenil for indications other than reversal of conscious sedation is not recommended.
There are insufficient data to make dosage recommendations for flumazenil in children under 1 year. It should therefore be administered only if the potential benefits to the patient outweigh the possible risks.

Since flumazenil is primarily metabolised in the liver, careful titration of dosage is recommended in hepatic impairment.

Use with caution in epileptic patients who have been receiving benzodiazepine treatment for prolonged periods. Although flumazenil 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.

Flumazenil 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. In patients with severe brain damage (and/or unstable intracranial pressure), flumazenil, used to reverse the effects of benzodiazepines, may cause an increase in intracranial pressure.

Pregnancy - see Pregnancy section

Breastfeeding - see Lactation section

Rapid injection of flumazenil should be avoided. In patients with high dose and/or long-term exposure to benzodiazepines ending at any time within the weeks preceding flumazenil administration, rapid injection has led to withdrawal symptoms, including palpitations, agitation, anxiety, emotional lability as well as mild confusion and sensory distortions

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

In high risk patients, the advantages of counteracting the central nervous system depression associated with benzodiazepines should be weighed against the drawbacks of rapid awakening.

Due to the increased frequency of benzodiazepine tolerance and dependence in patients with alcoholism and other drug dependencies, flumazenil should be used with caution in this population.

Adjust the dose of flumazenil individually in patients suffering from pre-operative anxiety or having a history of chronic or episodic anxiety. May provoke panic attacks in patients with a history of panic disorders. In anxious patients, particularly those with coronary heart disease, it is preferable to maintain a degree of sedation throughout the early post-operative period rather than bring about complete arousal.

The pain felt by patients in the post-operative period must be taken into account. Following a major intervention, it is preferable to maintain a moderate degree of sedation.

Flumazenil is not recommended to treat benzodiazepine dependence or to manage benzodiazepine withdrawal symptoms.

Patients who have received flumazenil to reverse the effects of benzodiazepine sedation should be warned not to drive, to operate machinery or to engage in any other physically or mentally demanding activity for at least 24 hours, since the effect of the benzodiazepine may return.

Formulations contain sodium - This should be considered when treating patients with controlled sodium intake.

Pregnancy and Lactation

Pregnancy

Flumazenil should only be administered in early pregnancy when considered absolutely necessary. The indication is such that Briggs (2011) suggests that the benefit to the mother will far outweigh the unknown embryo/fetal risk.

Like other benzodiazepine compounds, flumazenil is expected to cross the placenta, although the total quantities involved would be small.

There has been little human usage but animal studies have shown no teratogenic potential.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Manufacturers advise that the emergency use of flumazenil during breastfeeding is not contraindicated.

Like other benzodiazepine compounds, flumazenil is expected to enter into breast milk, although the total quantities involved would be small. The very short half-life (mean 54 mins) will mitigate this transfer also IV flumazenil has been used directly in neonates therefore flumazenil should not be withheld during breastfeeding. However due to potential adverse effects in the nursing infant (similar to those seen in treated adults), consideration should be given to suspending breastfeeding for 24 hours to allow drug elimination from the mother to occur.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Effects on Ability to Drive and Operate Machinery

Patients who have received flumazenil to reverse the effects of benzodiazepine sedation should be warned not to drive, to operate machinery or to engage in any other physically or mentally demanding activity for at least 24 hours, since the effect of the benzodiazepine may return.

Counselling

Patients who have received flumazenil to reverse the effects of benzodiazepine sedation should be warned not to drive, to operate machinery or to engage in any other physically or mentally demanding activity for at least 24 hours, since the effect of the benzodiazepine may return.

Side Effects

Nausea
Vomiting
Flushing
Agitation
Anxiety
Fear
Seizures
Cardiac arrhythmias
Palpitations
Increased blood pressure (transient)
Hypersensitivity reactions
Panic attack
Withdrawal symptoms
Confusion
Hallucinations
Emotional lability
Insomnia
Somnolence
Vertigo
Headache
Tremor
Dry mouth
Hyperventilation
Speech disturbances
Paraesthesia
Hearing disturbances
Diplopia
Strabismus
Increased lacrimation
Tachycardia
Dizziness
Bradycardia
Extrasystoles
Hypotension
Postural hypotension
Dyspnoea
Cough
Nasal congestion
Chest pain
Hiccups
Sweating
Fatigue
Local pain (injection site)
Shivering
Crying
Aggression in children
Aggressive reaction
Chills
Increased heart rate
Sensory disturbances

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Shelf Life and Storage

Storage requirements vary according to brand.

Further Information

Last Full Review Date: November 2012

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Summary of Product Characteristics: Flumazenil 0.1mg/ml solution for injection/infusion. Consilient Health Ltd. Revised March 2016.
Summary of Product Characteristics: Flumazenil 0.1mg/ml injection. Hameln Pharmaceuticals Ltd. Revised September 2010.
Summary of Product Characteristics: Flumazenil 0.1mg/ml injection. Actavis UK Ltd. Revised October 2011.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 21 August 2017