Flumazenil

V03A - All other therapeutic products ATC V03AB25 Small molecule approved 1991 Parenteral Black-box warning

JFDA label: Flunexate IV Amp

⚠ Black-Box Warning

Seizures:

Mechanism of Action

Allosteric Antagonist of GABA-A receptor; anion channel — GABA-A receptor; anion channel allosteric antagonist

Target	Action	Gene / class
GABA-A receptor; anion channel efficacy	ALLOSTERIC ANTAGONIST

Indications

Approved

Benzodiazepine reversal when used in conscious sedation or general anesthesia
Management of benzodiazepine overdose

Contraindications

Source: Lexicomp

Hypersensitivity to flumazenil, benzodiazepines, or any component of the formulation Absolute
patients given benzodiazepines for control of potentially life-threatening conditions (eg, control of intracranial pressure or status epilepticus) Absolute
patients who may have ingested or are showing signs of cyclic-antidepressant overdosage Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (4)

Common flushing · Palpitation · thrombophlebitis · vasodilatation

Nervous system disorders (18)

Common agitation · anxiety · Ataxia · depersonalization · depression · dizziness · dysphoria · emotional lability · euphoria · fatigue · headache · hypoesthesia · insomnia · malaise · nervousness · paranoia · paresthesia · vertigo

Metabolism and nutrition disorders (1)

Common Hot flash

Gastrointestinal disorders (2)

Common nausea · Xerostomia

Skin and subcutaneous tissue disorders (3)

Common Dermatological disease · diaphoresis · skin rash

Musculoskeletal and connective tissue disorders (2)

Common tremor · Weakness

Eye disorders (3)

Common Blurred vision · lacrimation · visual disturbance

General disorders and administration site conditions (2)

Common injection site reaction · Pain at injection site

Other (1)

Very Common Gastrointestinal: Vomiting

Respiratory, thoracic and mediastinal disorders (2)

Common Dyspnea · hyperventilation

Dosing

Source: Lexicomp

Benzodiazepine reversal when used in conscious sedation or general anesthesia: IV: Initial dose: 0.2 mg over 15 seconds Repeat doses (maximum: 4 doses): If the desired level of consciousness is not obtained, 0.2 mg may be repeated at 1-minute intervals. Maximum total cumulative dose: 1 mg (usual total dose: 0.6 to 1 mg). In the event of resedation: Repeat doses may be given at 20-minute intervals as needed at 0.2 mg per minute to a maximum of 1 mg total dose and 3 mg in 1 hour. Management of benzodiazepine overdose: IV: Initial dose: 0.2 mg over 30 seconds; if the desired level of consciousness is not obtained 30 seconds after the dose, 0.3 mg can be given over 30 seconds Repeat doses: 0.5 mg over 30 seconds repeated at 1-minute intervals Maximum total cumulative dose: 3 mg (usual total dose: 1 to 3 mg). Patients with a partial response at 3 mg may require (rare) additional titration up to a total dose of 5 mg (although doses >3 mg do not reliably produce additional effects). If a patient has not responded 5 minutes after a cumulative dose of 5 mg, the major cause of sedation is not likely due to benzodiazepines or may be due to exposure to additional CNS depressants (eg, opioids). In the event of resedation, repeat doses may be given at 20-minute intervals if needed, at 0.5 mg per minute to a maximum of 1 mg total dose and 3 mg in 1 hour.

(For additional information see "Flumazenil: Pediatric drug information") Reversal of benzodiazepine when used in conscious sedation: Children ≥1 year and Adolescents: IV: Initial dose: 0.01 mg/kg (maximum dose: 0.2 mg) given over 15 seconds Repeat doses (maximum: 4 doses): If the desired level of consciousness is not obtained, 0.01 mg/kg (maximum dose: 0.2 mg) repeated at 1-minute intervals Maximum total cumulative dose: 1 mg or 0.05 mg/kg (whichever is lower) Mean total dose: 0.65 mg (range: 0.08 to 1 mg)

Refer to adult dosing. No differences in safety or efficacy have been reported; however, increased sensitivity may occur in some elderly patients.

No dosage adjustment provided in manufacturer's labeling; however, pharmacokinetics are not significantly affected by renal failure (CrCl

Initial reversal: No dosage adjustment necessary. Repeat doses: Reduce dose or frequency.

Warnings & Precautions

Source: Lexicomp

Amnesia

Does not consistently reverse amnesia; patient may not recall verbal instructions after procedure.

CNS depression

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving) for 24 hours after discharge.

Resedation

Occurs more frequently in patients where a large single dose or cumulative dose of a benzodiazepine has been administered along with a neuromuscular-blocking agent and multiple anesthetic agents.

Respiratory depression

Should not rely upon to reverse respiratory depression/hypoventilation. Flumazenil is not a substitute for evaluation of oxygenation. Establishing an airway and assisting ventilation, as necessary, is always the initial step in overdose management.

Seizures

Benzodiazepine reversal may result in seizures; seizures may occur more frequently in patients on benzodiazepines for long-term sedation or following tricyclic antidepressant overdose. Dose should be individualized and practitioners should be prepared to manage seizures. Seizures may also develop in patients with concurrent major sedative-hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, myoclonic jerking or seizure activity prior to flumazenil administration. Use with caution in patients relying on a benzodiazepine for seizure control. Disease-related concerns:

Head injury

Use with caution in patients with a head injury; may alter cerebral blood flow or precipitate convulsions in patients receiving benzodiazepines.

Hepatic impairment

Use with caution in patients with hepatic dysfunction; repeated doses of the drug should be reduced in frequency or amount.

Panic disorder

Use with caution in patients with a history of panic disorder; may provoke panic attacks. Special populations:

Drug/alcohol dependence

Use caution in drug and ethanol-dependent patients; these patients may also be dependent on benzodiazepines.

Intensive care patients

Should be used with caution in the intensive care unit because of increased risk of unrecognized benzodiazepine dependence in such settings. Other warnings/precautions:

Appropriate use

Should not be used to diagnose benzodiazepine-induced sedation. Reverse neuromuscular blockade before considering use. Flumazenil does not antagonize the CNS effects of other GABA agonists (such as ethanol, barbiturates, or general anesthetics); nor does it reverse opioids. Not recommended for treatment of benzodiazepine dependence.

Overdose use

Use with caution in patients with mixed drug overdoses; toxic effects of other drugs taken may emerge once benzodiazepine effects are reversed.

Pregnancy & Lactation

Pregnancy

FDA category C Teratogenic

Teratogenic effects were not seen in animal reproduction studies. Embryocidal effects were seen at large doses. Use during labor and delivery is not recommended. In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).

Lactation

It is not known if flumazenil is excreted in breast milk. The manufacturer recommends that caution be used if administering to breast-feeding women.

Monitoring

Clinical pearl	Monitor for return of sedation, respiratory depression, benzodiazepine withdrawal, and other residual effects of benzodiazepines for at least 2 hours and until the patient is stable and resedation is unlikely.

Chemistry & Properties

Formula	C15H14FN3O3
Molecular weight	303.29 g/mol
IUPAC name	ethyl 8-fluoro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate
CAS	78755-81-4
PubChem CID	3373
InChIKey	`OFBIFZUFASYYRE-UHFFFAOYSA-N`
logP	1.77 (XLogP 1.0)
Polar surface area	64.43 Å²
H-bond acceptors / donors	5 / 0
Drug-likeness (QED)	0.79
Lipinski violations	0

SMILES

CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes (logBB -0.3)

Receptor binding (top 5)

Target	Action	Affinity
GABAA receptor α5 subunit (GABRA5)	Allosteric modulator	pKi 9.2
GABAA receptor α1 subunit (GABRA1)	Allosteric modulator	pKi 9.1
GABAA receptor α2 subunit (GABRA2)	Allosteric modulator	pKi 9.1
GABAA receptor α3 subunit (GABRA3)	Allosteric modulator	pKi 9.0
GABAA receptor α6 subunit (GABRA6)	Allosteric modulator	pKi 6.8

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (29, DDInter)

Interacting drug	Severity	Management
Amitriptyline	major
Amoxapine	major
Clomipramine	major
Desipramine	major
Doxepin	major
Doxepin (topical)	major
Imipramine	major
Maprotiline	major
Nortriptyline	major
Protriptyline	major
Trimipramine	major
Alprazolam	moderate
Chlordiazepoxide	moderate
Clobazam	moderate
Clonazepam	moderate
Clorazepic acid	moderate
Diazepam	moderate
Estazolam	moderate
Flurazepam	moderate
Halazepam	moderate
Lorazepam	moderate
Midazolam	moderate
Oxazepam	moderate
Quazepam	moderate
Temazepam	moderate
Triazolam	moderate
Baclofen	minor
Nalmefene	minor
Zolpidem	minor

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Exitine 0.5mg/5ml Solution For Inj	Injection 0.1 mg/ml	5 vial	MS PHARMA/JORDAN	—
Flunexate IV Amp	Ampoule 0.5 mg/5 ml	5 amp	Hikma Pharmaceuticals Co.Ltd/Jordan	—