Flumazenil

Registered South African indications:

• Reversal of sedative effects of benzodiazepines

Registered South African contraindications

• Hypersensitivity to flumazenil or to any of the excipients
• 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)
• Safety of flumazenil during pregnancy and lactation has not been established

Contraindications registered in other jurisdictions

• Hypersensitivity to flumazenil or to any of the excipients
• Patients receiving benzodiazepines for control of a potentially life-threatening condition (e.g. control of intracranial pressure or status epilepticus)

• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (Recommendations in other jurisdictions)
• Moderate to severe hepatic impairment
• Elderly
• Children
• Patients with cardiac problems
• Rapid injection
• Patients treated with high-dose and/or long-term exposure to benzodiazepines
• Anxiety
  - Pre-operative anxiety
  - History of chronic or episodic anxiety
• Patients in which rapid awakening from sedation could be detrimental
• Epileptic patients treated with benzodiazepines for a prolonged period
• Severe brain injury
• Unstable intracranial pressure
• Mixed drug overdose, especially intoxication with benzodiazepines and cyclic antidepressants
• Treatment of benzodiazepine-dependence or long-term benzodiazepine-abstinence-syndromes
• History of panic disorder
• Alcoholism
• Patients on controlled sodium diet
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Complete or partial reversal of central sedative effects of benzodiazepines in anaesthesia
- Termination of hypnosedative effects in general anaesthesia induced and/or maintained with benzodiazepines in hospitalised patients
- Reversal of benzodiazepine sedation in short-term diagnostic and therapeutic procedures in ambulatory patients and hospitalised patients
- Reversal of conscious sedation induced with benzodiazepines in >1 year of age 

• IV: Initial: 0.2mg, given as an injection over 15sec; Then 0.1mg if response not achieved; Repeat 0.1mg dose at 60sec intervals if needed; Max total dose: 1mg

---

The usual dose is 300 to 600 micrograms, but may deviate depending on the patient's characteristics and the benzodiazepine used

---

Complete or partial reversal of central sedative effects of benzodiazepines in intensive care situations
- To restore spontaneous respiration
- For diagnosis and treatment of intoxications or overdose with only or mainly benzodiazepines

• IV: Initial: 0.3mg, given as an injection over 15sec; Then 0.1mg if response not achieved; Repeat 0.1mg dose at 60sec intervals if needed until patient awakes; Max total dose: 2mg

If re-sedation occurs

• IV: 0.3mg, given as an injection over 15sec

OR

• IV: 0.1-0.4mg/hr, as an infusion

---

Flumazenil must be administered intravenously by an anaesthetist or a doctor with experience in anesthesiology

---

 Flumazenil is not recommended for the treatment of benzodiazepine-dependence or for the treatment of long-term benzodiazepine-abstinence-syndromes

---

Dosage and rate of infusion should be adjusted individually to achieve the desired level of consciousness

---

If a significant improvement in consciousness or respiratory function is not obtained after repeated doses of flumazenil, a non-benzodiazepine aetiology must be assumed

---

Infusion should be discontinued every 6hrs to verify whether re-sedation occurs

---

To avoid withdrawal symptoms in patients treated for a long period of time with high doses of benzodiazepines in the intensive care unit, flumazenil dosage has to be titrated individually and the injection has to be administered slowly

---

Flumazenil must be diluted prior to infusion and should only be diluted with sodium chloride 9mg/ml (0.9%) solution, dextrose 50mg/ml (5%) solution or sodium chloride 4.5mg/ml (0.45%) + dextrose 25mg/ml (2.5%) solution. Compatibility between flumazenil and other solutions for injection has not been established

Paed. forms avail. in SA and covered in this monograph: inj

Reversal of conscious sedation induced with benzodiazepines 

Younger than 1 year

• Not established for use
  Flumazenil should only be administered in children <1 year if the potential benefits to the patient outweigh the possible risk

Older than 1 year

• IV: Initial: 0.01mg/kg (max 0.2mg), given as an injection over 15sec; Repeat dosage after additional 45sec if needed; Repeat dosage at intervals of 60sec (max 0.2mg) if needed (max: 4 doses); Max total dose: 0.05mg/kg or 1mg, whichever is lower

---

Flumazenil must be administered intravenously by an anaesthetist or a doctor with experience in anesthesiology

---

Dose should be individualised based on the patient's response

---

No data available on safety and efficacy of repeated administration of flumazenil to children for re-sedation

---

Children previously sedated with midazolam should be monitored at least 2 hours after flumazenil administration because of the potential for re-sedation and respiratory depression. In case of other sedating benzodiazepines, the monitoring time must be adjusted according to their expected duration

Pregnancy 

South African recommendations

• Contraindicated

Recommendations in other jurisdictions

• Caution
• Emergency use of flumazenil during pregnancy is not contraindicated
• Flumazenil should only be used during pregnancy if the possible benefit to the patient outweighs the potential risks to the foetus

Breastfeeding 

South African recommendations

• Contraindicated

Recommendations in other jurisdictions

• Caution
• It is not known whether flumazenil is excreted in human milk. For this reason, breastfeeding should be interrupted for 24 hours when flumazenil is used during breastfeeding
• Emergency use of flumazenil during breastfeeding is not contraindicated

Fertility

• Although studies in animals have not shown evidence of embryotoxicity or teratogenicity, the possible risk to humans caused by flumazenil during pregnancy has not been determined

Renal Impairment 

• No dose adjustment recommended 

Hepatic Impairment

• Caution; dose adjustment recommended
  Since flumazenil is primarily metabolised in the liver, careful titration of dosage is recommended in patients with impaired hepatic function

Elderly

• Caution; no dose adjustment recommended
  In the absence of data on the use of flumazenil in elderly patients, it should be noted that this population is generally more sensitive to the effects of medicinal products and should be treated with due caution

Porphyria

• Possibly porphyrinogenic (PSP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Anxiety  
• Emotional lability  
• Insomnia  
• Somnolence  
• Fear  
• Withdrawal symptoms  
  - Agitation  
  - Anxiety  
  - Emotional lability  
  - Confusion 
  - Sensory distortions  
  - Tachycardia  
  - Dizziness  
  - Sweating  
• Panic attacks  
• Abnormal crying  
• Agitation  
• Aggressive reactions  
• Vertigo  
• Headache  
• Tremor  
• Hyperventilation  
• Speech disorder  
• Paresthesia  
• Seizures  

Cardiovascular Disorders

• Palpitations  
• Tachycardia  
• Bradycardia  
• Extrasystole  
• Flushing  
• Hypotension  
• Orthostatic hypotension  
• Transient increase in blood pressure (on awakening)  

Respiratory Disorders

• Dyspnoea  
• Cough  
• Nasal congestion  
• Chest pain  

Gastrointestinal Disorders

• Dry mouth  
• Nausea and vomiting  
• Hiccups  

Skin and Subcutaneous Tissue Disorders

• Sweating  
• Injection site pain  

Immune, Blood and Lymphatic System Disorders

• Allergic reactions  
• Severe hypersensitivity reactions including anaphylaxis  
• Shivering  

Sensory Disorders

• Diplopia  
• Strabismus  
• Increased lacrimation  
• Abnormal hearing  

• Benzodiazepines
• Non-benzodiazepine agonists acting via the benzodiazepine receptor
• Zopiclone
• Triazolopyridazine  
• Psychotropic agents  
• Tricyclic antidepressants  

• ECG
• Pulse oximetry
• Vital signs
• Blood pressure
• Respiratory function

Additional observations

• Re-sedation
• Respiratory depression
• Benzodiazepine withdrawal
• Other residual effects of benzodiazepines for at least 2 hours

Flumazenil, an imidazobenzodiazepine, is a benzodiazepine antagonist which, by competitive interaction, blocks the effects of substances acting via the benzodiazepine-receptor. According to experiments in animals, the effects of substances, which are not acting via the benzodiazepine-receptor (like barbiturates, GABA-mimetics and adenosine-receptor agonists), are not blocked by flumazenil. Non-benzodiazepine-agonists, like cyclopyrrolones (zopiclone) and triazolopyridazines, are blocked by flumazenil. The hypnosedative effects of benzodiazepines are blocked rapidly (within 1-2 minutes) after intravenous administration. Flumazenil has possibly a slight agonistic, anticonvulsive effect.

Injection (per 5ml) 0.5mg

• Anexate (Pharmaco) originator

Injection (per 10ml) 1mg

• Anexate (Pharmaco) originator