Flumazenil

(BAN, USAN, rINN)
Flumazenil Chemical formula
Synonyms: Flumatseniili; Flumazénil; Flumazenilis; Flumazenilum; Flumazepil; Ro-15-1788; Ro-15-1788/000. Ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4]benzodiazepine-3-carboxylate.
Cyrillic synonym: Флумазенил.

💊 Chemical information

Chemical formula: C15H14FN3O3 = 303.3.
CAS — 78755-81-4.
ATC — V03AB25.
ATC Vet — QV03AB25.

Pharmacopoeias.

In Eur. and US.

Ph. Eur. 6.2

(Flumazenil). A white or almost white crystalline powder. Very slightly soluble in water; freely soluble in dichloromethane; sparingly soluble in methyl alcohol.

USP 31

(Flumazenil). A white to off-white powder. Practically insoluble in water; slightly soluble in acidic aqueous solutions. Store in airtight containers.

💊 Adverse Effects and Precautions

The adverse effects experienced during use of flumazenil are generally due to the reversal of benzodiazepine effects and resemble benzodiazepine withdrawal symptoms. Nausea, vomiting, dizziness, blurred vision, headache, and flushing may occur. Anxiety, fear, and agitation have been reported after too rapid reversal of sedation. There have been reports of seizures, especially in epileptics. Transient increases in blood pressure and heart rate have been observed. Hypersensitivity reactions have occurred rarely. Patients who have received benzodiazepines for prolonged periods are particularly at risk of experiencing withdrawal symptoms and rapid injection of flumazenil should be avoided in such patients. Because of its short duration of action, patients given flumazenil to reverse benzodiazepine-induced sedation should be kept under close observation; further doses of flumazenil may be necessary. Flumazenil is contra-indicated in patients who are receiving benzodiazepines to control potentially life-threatening conditions and should not be given to epileptic patients who have been receiving benzodiazepines for a prolonged period to control seizures. In cases of mixed overdose, flumazenil may unmask adverse effects of other psychotropic drugs. In particular, it should not be used in the presence of severe intoxication with tricyclic and related antidepressants. Flumazenil should not be given to patients who have received neuromuscular blockers until the effects of neuromuscular blockade have fully cleared. Dosage should be adjusted individually; in high-risk or anxious patients, and after major surgery, it may be preferable to maintain some sedation during the early postoperative period. Flumazenil should be used with caution in patients with head injury since it may precipitate seizures or alter cerebral blood flow. Careful titration of dosage is recommended in hepatic impairment.
Heart block has also been reported4 after flumazenil use in a patient who had taken benzodiazepines, paracetamol, nifedipine, and atenolol. Death from refractory tonic-clonic seizures has been reported in a patient5 after the use of flumazenil for a mixed overdose with a benzodiazepine and a tricyclic antidepressant. Death from respiratory failure occurred in an 83-year-old woman after sedation with midazolam6 despite use of flumazenil, although some7 considered that this did not represent a failure by flumazenil to reverse the depressive effects on respiration of midazolam. Ventricular fibrillation followed by asystole and death has been reported in a patient given flumazenil during weaning from assisted ventilation (a period during which diazepam had been given).8
1. Short TG, et al. Ventricular arrhythmia precipitated by flumazenil. BMJ 1988; 296: 1070–1
2. Burr W, et al. Death after flumazenil. BMJ 1989; 298: 1713
3. Marchant B, et al. Flumazenil causing convulsions and ventricular tachycardia. BMJ 1989; 299: 860
4. Herd B, Clarke F. Complete heart block after flumazenil. Hum Exp Toxicol 1991; 10: 289
5. Haverkos GP, et al. Fatal seizures after flumazenil administration in a patient with mixed overdose. Ann Pharmacother 1994; 28: 1347–9
6. Lim AG. Death after flumazenil. BMJ 1989; 299: 858–9. Correction. ibid.: 1531
7. Birch BRP, Miller RA. Death after flumazenil? BMJ 1990; 300: 467–8
8. Katz Y, et al. Cardiac arrest associated with flumazenil. BMJ 1992; 304: 1415.

Effects on mental function.

Although flumazenil is considered to lack agonist properties, a study1 in healthy subjects found that intravenous flumazenil resulted in impairment of some measures of cognition and alertness. A severe acute psychotic disorder, which developed during treatment with flumazenil in a patient with hepatic encephalopathy, resolved when flumazenil was discontinued.2
1. Neave N, et al. Dose-dependent effects of flumazenil on cognition, mood, and cardio-respiratory physiology in healthy volunteers. Br Dent J 2000; 189: 668–74
2. Seebach J, Jost R. Flumazenil-induced psychotic disorder in hepatic encephalopathy. Lancet 1992; 339: 488–9.

💊 Pharmacokinetics

Flumazenil is well absorbed from the gastrointestinal tract but undergoes extensive first-pass hepatic metabolism and has a systemic bioavailability of about 20%. It is about 50% bound to plasma proteins. After intravenous administration it is extensively metabolised in the liver to the inactive carboxylic acid form, which is excreted mainly in the urine. The elimination half-life is about 40 to 80 minutes. In patients with hepatic impairment the clearance of flumazenil is decreased with a resultant prolongation of half-life.
1. Klotz U, et al. Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man. Eur J Clin Pharmacol 1984; 27: 115–17
2. Roncari G, et al. Pharmacokinetics of the new benzodiazepine antagonist Ro 15-1788 in man following intravenous and oral administration. Br J Clin Pharmacol 1986; 22: 421–8
3. Breimer LTM, et al. Pharmacokinetics and EEG effects of flumazenil in volunteers. Clin Pharmacokinet 1991; 20: 491–6
4. Jones RDM, et al. Pharmacokinetics of flumazenil and midazolam. Br J Anaesth 1993; 70: 286–92
5. Roncari G, et al. Flumazenil kinetics in the elderly. Eur J Clin Pharmacol 1993; 45: 585–7.

💊 Uses and Administration

Flumazenil is a benzodiazepine antagonist that acts competitively at CNS benzodiazepine receptors. It is used in anaesthesia and intensive care to reverse benzodiazepine-induced sedation; it may also be used to treat benzodiazepine overdosage (but see warnings in Precautions, above, and under Benzodiazepine Antagonism: Overdosage, below). Flumazenil should be given by slow intravenous injection or infusion. The usual initial dose for the reversal of benzodiazepine-induced sedation is 200 micrograms, followed at intervals of 60 seconds by further doses of 100 to 200 micrograms if required, to a maximum total dose of 1 mg or occasionally 2 mg (usual range, 0.3 to 1 mg); each dose should be given over 15 seconds, and further doses should only be given if an adequate response has not occurred 45 seconds after completion of the injection. If drowsiness recurs an intravenous infusion may be used, at a rate of 100 to 400 micrograms/hour, adjusted according to response. Alternatively, further doses of up to 1 mg, in boluses of 200 micrograms as above, may be given at 20-minute intervals to a maximum of 3 mg in one hour. Patients at risk from the effects of benzodiazepine reversal, such as those dependent on benzodiazepines, should receive smaller bolus injections of 100 micrograms. The dose for children is 10 micrograms/kg, repeated at 60-second intervals up to a maximum of 50 micrograms/kg or 1 mg, whichever is lower; doses are given intravenously over 15 seconds, with further doses if an adequate response has not occurred 45 seconds after completion of the injection, as for adults. The usual initial dose for the management of benzodiazepine overdose is 200 micrograms given intravenously over 30 seconds. A further dose of 300 micrograms can be given after another 30 seconds and can be followed by doses of 500 micrograms at one-minute intervals if required, to a total dose of 3 mg or occasionally 5 mg. If a dose of up to 5 mg produces no response then further doses are unlikely to be effective. If symptoms of intoxication recur, repeated doses may be given at 20-minute intervals; not more than 1 mg should be given at any one time and not more than 3 mg in one hour. As before a slower rate of administration may be used for ‘at risk’ patients. If signs of overstimulation occur during the use of flumazenil, then diazepam or midazolam may be given by slow intravenous injection. Flumazenil labelled with carbon-11 has been used for studying GABA receptors by positron emission tomography.
1. Brogden RN, Goa KL. Flumazenil: a reappraisal of its pharmacological properties and therapeutic efficacy as a benzodiazepine antagonist. Drugs 1991; 42: 1061–89
2. Hoffman EJ, Warren EW. Flumazenil: a benzodiazepine antagonist. Clin Pharm 1993; 12: 641–56
3. Krenzelok EP. Judicious use of flumazenil. Clin Pharm 1993; 12: 691–2
4. Seger DL. Flumazenil—treatment or toxin. J Toxicol Clin Toxicol 2004; 42: 209–16.

Benzodiazepine antagonism.

Flumazenil is a specific benzodiazepine antagonist that binds competitively with benzodiazepine receptors, reversing the centrally mediated effects of benzodiazepines. Its effects are evident within a few minutes of intravenous injection, even after substantial doses of benzodiazepines, and last for up to 3 hours depending on the dose and on the characteristics of the benzodiazepine intoxication. In patients who have received benzodiazepines for prolonged periods, flumazenil may precipitate withdrawal symptoms. SEDATION. Flumazenil reduces sedation and amnesia following the use of benzodiazepines for induction or maintenance of general anaesthesia, and in patients undergoing minor surgery or diagnostic procedures who are given benzodiazepines for conscious sedation.1 Sedation may recur, particularly if long-acting benzodiazepines have been used, and there have been reports of increased analgesic requirements and anxiety following the use of flumazenil. Although flumazenil may antagonise the obvious effects of sedation, higher cognitive functions may still be impaired2,3 and the patient may be unfit to be discharged safely unaccompanied. Flumazenil is usually given intravenously but reversal of sedation has also been reported4 with oral use. Although experience with flumazenil in children is limited, it appears to be well tolerated and effective when used to reverse conscious sedation.5 Flumazenil has also been used in intensive care to reverse sedation and assist in weaning from mechanical ventilation, but is not routinely recommended. OVERDOSAGE. Flumazenil may be used as an adjunct in the management of benzodiazepine overdose including overdose involving multiple agents. However, its use may unmask the effects of other intoxicants,6 and since benzodiazepine overdose is rarely lethal and may even protect against the toxicity of other drugs, flumazenil should be used with great caution in mixed overdose, particularly when involving tricyclic antidepressants.7 Repeated doses of flumazenil may be required to maintain consciousness depending on the benzodiazepine responsible and the magnitude of the overdose; continuous infusion has also been used.8,9
1. Brogden RN, Goa KL. Flumazenil: a reappraisal of its pharmacological properties and therapeutic efficacy as a benzodiazepine antagonist. Drugs 1991; 42: 1061–89
2. Sanders LD, et al. Reversal of benzodiazepine sedation with the antagonist flumazenil. Br J Anaesth 1991; 66: 445–53
3. Girdler NM, et al. A randomised crossover trial of post-operative cognitive and psychomotor recovery from benzodiazepine sedation: effects of reversal with flumazenil over a prolonged recovery period. Br Dent J 2002; 192: 335–9
4. Girdler NM, et al. A randomised, controlled trial of cognitive and psychomotor recovery from midazolam sedation following reversal with oral flumazenil. Anaesthesia 2002; 57: 868–76
5. Shannon M, et al. Safety and efficacy of flumazenil in the reversal of benzodiazepine-induced conscious sedation. J Pediatr 1997; 131: 582–6
6. Weinbroum AA, et al. A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose. Drug Safety 1997; 17: 181–96
7. Hoffman RS, Goldfrank LR. The poisoned patient with altered consciousness: controversies in the use of a ‘coma cocktail’. JAMA 1995; 274: 562–9
8. Brammer G, et al. Continuous intravenous flumazenil infusion for benzodiazepine poisoning. Vet Hum Toxicol 2000; 42: 280–1
9. Chern C-H, et al. Continuous flumazenil infusion in preventing complications arising from severe benzodiazepine intoxication. Am J Emerg Med 1998; 16: 238–41.

Hepatic encephalopathy.

Flumazenil has been tried in hepatic encephalopathy because of the suspected role of benzodiazepine-like agonists in the pathogenesis of the disorder.1,2However, benefits have generally been modest, and a metaanalysis3 concluded that flumazenil did produce short-term improvement of hepatic encephalopathy but had no effect on recovery or survival; it might be considered for patients with chronic liver disease and hepatic encephalopathy but routine clinical use was not recommended.
1. Grimm G, et al. Improvement of hepatic encephalopathy treated with flumazenil. Lancet 1988; ii: 1392–4
2. Basile AS, et al. The pathogenesis and treatment of hepatic encephalopathy: evidence for the involvement of benzodiazepine receptor ligands. Pharmacol Rev 1991; 43: 27–71
3. Als-Nielsen B, et al. Benzodiazepine receptor antagonists for hepatic encephalopathy. Available in The Cochrane Database of Systematic Reviews; Issu
2. Chichester: John Wiley; 2004 (accessed 04/10/05).

Non-benzodiazepine antagonism.

Although flumazenil is a specific benzodiazepine antagonist, it may also block the effects of other drugs that act via the benzodiazepine receptor, such as zopiclone and zolpidem. In a double-blind study1 in healthy subjects, flumazenil rapidly antagonised clinical sedation induced by zolpidem, and a rapid response to flumazenil has been reported2 in a patient who presented in a coma following mixed overdosage with zolpidem, alcohol, and prothipendyl. There have also been reports of flumazenil reversing coma associated with antihistamines,3 carisoprodol,4 gabapentin,5 and promethazine.6 Although reversal of alcohol-induced sedation has also been suggested, a controlled study7 found no effect with flumazenil at a dose comparable to that used for benzodiazepine overdosage.
1. Patat A, et al. Flumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypnotic. Clin Pharmacol Ther 1994; 56: 430–6
2. Lheureux P, et al. Zolpidem intoxication mimicking narcotic overdose: response to flumazenil. Hum Exp Toxicol 1990; 9: 105–7
3. Lassaletta A, et al. Reversal of an antihistamine-induced coma with flumazenil. Pediatr Emerg Care 2004; 20: 319–20
4. Roberge RJ, et al. Flumazenil reversal of carisoprodol (Soma) intoxication. J Emerg Med 2000; 18: 61–4
5. Butler TC, et al. Flumazenil and dialysis for gabapentin-induced coma. Ann Pharmacother 2003; 37: 74–6
6. Plant JR, MacLeod DB. Response of a promethazine-induced coma to flumazenil. Ann Emerg Med 1994; 24: 979–82
7. Lheureux P, Askenasi R. Efficacy of flumazenil in acute alcohol intoxication: double blind placebo-controlled evaluation. Hum Exp Toxicol 1991; 10: 235–9.

💊 Preparations

USP 31: Flumazenil Injection.

Proprietary Preparations

Arg.: Fadaflumaz; Flumage; Flumanovag; Flumazen; Fluxifarm; Lanexat†; Austral.: Anexate; Austria: Anexate; Belg.: Anexate; Braz.: Flumazen; Flumazil; Lanexat; Canad.: Anexate; Chile: Lanexat; Cz.: Anexate; Denm.: Lanexat; Fin.: Lanexat; Fr.: Anexate; Ger.: Anexate; Gr.: Anexate; Demoxate; Flumexate; Hong Kong: Anexate; Hung.: Anexate; Indon.: Anexate; Irl.: Anexate; Israel: Anexate; Ital.: Anexate; Malaysia: Anexate; Mex.: Lanexat; Neth.: Anexate; Norw.: Anexate; NZ: Anexate; Philipp.: Anexate; Pol.: Anexate; Port.: Anexate; S.Afr.: Anexate; Singapore: Anexate; Spain: Anexate; Swed.: Lanexat; Switz.: Anexate; Thai.: Anexate; Turk.: Anexate; UK: Anexate; USA: Romazicon; Venez.: Lanexat.
Published November 11, 2018.