Isoflurane


Concise Prescribing Info
Indications/Uses
Induction and maintenance of general anaesthesia.
Dosage/Direction for Use
Adult : Inhalation Individualise dosing according to the desired effect, patient’s age and clinical status. Induction: Initial: 0.5% v/v with oxygen or oxygen-nitrous oxide mixture, increased to 1.5-3% v/v depending on response. Maintenance: 1-2.5% v/v in an oxygen-nitrous oxide mixture; an additional 0.5-1% v/v or 1.5-3.5% v/v may be necessary when given with oxygen alone. For the maintenance of anaesthesia in caesarean section: 0.5-0.75% v/v in an oxygen-nitrous oxide mixture. All doses are administered via calibrated vaporiser. Selection and use of premedication are based on the patient’s need and the discretion of anaesthetist.
Dosage Details
Inhalation/Respiratory
Induction and maintenance of general anaesthesia
Adult: Individualise dosing according to the desired effect, patient’s age and clinical status. Induction: Initially, 0.5% v/v with oxygen or oxygen-nitrous oxide mixture, increased to 1.5-3% v/v depending on response. Maintenance: 1-2.5% v/v in an oxygen-nitrous oxide mixture; an additional 0.5-1% v/v or 1.5-3.5% v/v may be necessary when given with oxygen alone. For the maintenance of anaesthesia in caesarean section: 0.5-0.75% v/v in an oxygen-nitrous oxide mixture. Doses are administered via calibrated vaporiser. Selection and use of premedication are based on the patient’s need and the discretion of anaesthetist.
Elderly: Dose reduction may be necessary.
Special Patient Group
Hypovolaemic, hypotensive, or debilitated patients: Lower concentrations may be necessary.

Pharmacogenomics:

Isoflurane is identified as a triggering agent of malignant hyperthermia (MH). Individuals with malignant hyperthermia susceptibility (MHS) or those carrying certain genetic variants of ryanodine receptor isoform 1 gene (RYR1) and CACNA1S gene are predisposed to potentially fatal hypermetabolic reactions triggered by potent volatile anaesthetics like isoflurane. The prevalence of MHS genetic trait is estimated to be between 1/2,000 and 1/3,000, and approx 70% of individuals with MHS have the RYR1 pathogenic variants as the primary pharmacogenetic trait, while approx 1% of patients with MHS have the CACNA1S pathogenic variants.

The European Malignant Hyperthermia Group (EMHG) consortium has identified the 50-MH causative variants in RYR1 or CACNA1S genes that are considered as diagnostic mutations. Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends performing genetic testing and considering the personal family history of individuals in relation to MH and their susceptibility prior to treatment initiation.

FDA-approved drug label and HCSC product monograph for isoflurane also stated that individuals with a genetic predisposition to MH are at greater risk of developing the hypermetabolic reaction.

Malignant hyperthermia susceptible (MHS)
Patients who are heterozygous for or carriers of at least 1 of the 50 identified RYR1 or CACNA1S MH-causative variant (refer to the detailed CPIC guideline for the list of causative variants). These individuals have increased risk of developing malignant hyperthermia if administered with isoflurane.

Recommendation:
Isoflurane is relatively contraindicated in these patients, except in instances where the benefits outweigh the risks. CPIC recommends the use of alternative agents such as regional anaesthesia (e.g. neuraxial, peripheral nerve block, or local anaesthesia), or non-triggering agent general anaesthesia.

Uncertain susceptibility
Patients who are negative for RYR1 or CACNA1S MH-causative variant. Negative or inconclusive results do not eliminate the risk of susceptibility to malignant hyperthermia.

Recommendation:
CPIC recommends assessing the individual’s clinical findings, family history, and other laboratory data, and perform further genetic testing to guide the use of isoflurane.
Contraindications
Known or suspected genetic susceptibility to malignant hyperthermia (e.g. presence of RYR1 or CACNA1S pathogenic variants); history of confirmed hepatitis due to halogenated inhalational anaesthetic or unexplained moderate to severe hepatic dysfunction (e.g. jaundice associated with fever, leucocytosis, and/or eosinophilia) after previous isoflurane or other halogenated inhalational anaesthetic use.
Special Precautions
Patient with hypovolaemia, hypotension, heart failure, coronary artery disease, subendocardial ischaemia; increased intracranial pressure, mitochondrial disorders, myasthenia gravis, neuromuscular disease (e.g. Duchenne muscular dystrophy); who are haemodynamically compromised; at risk of QT prolongation (e.g. congenital long QT syndrome) or bronchoconstriction. Debilitated patients. Elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Respiratory depression, CV effects (e.g. QT prolongation, cardiac steal, reflex tachycardia), hypotension, hepatic effects (e.g. mildly increased liver enzymes, hepatitis with or without jaundice, sensitivity hepatitis), decreased renal, hepatic and splenic blood flow; markedly increased cerebral blood flow (at deeper levels), increased intracranial pressure, bronchospasm, laryngospasm; hypersensitivity reactions (e.g. anaphylaxis).
Cardiac disorders: Ventricular, nodal or atrial arrhythmia.
Gastrointestinal disorders: Nausea, vomiting, retching.
General disorders and administration site conditions: Chills, ataxia, asthenia, fatigue.
Investigations: Increased WBC count, blood glucose, and serum creatinine; decreased BUN.
Musculoskeletal and connective tissue disorders: Myalgia.
Nervous system disorders: Agitation, dizziness, drowsiness, headache.
Psychiatric disorders: Delirium, mood changes, nightmare, confusional state, nervousness.
Respiratory, thoracic and mediastinal disorders: Breath holding, cough, dyspnoea.
Skin and subcutaneous tissue disorders: Diaphoresis.
Potentially Fatal: Malignant hyperthermia. Rarely, severe postoperative hepatic dysfunction (e.g. hepatic necrosis and failure), torsades de pointes; perioperative hyperkalaemia resulting in cardiac arrhythmias (children).
Inhalation/Respiratory: C
Patient Counseling Information
This drug may impair your mental alertness for some time after administration, if affected, do not drive or operate machinery.
MonitoringParameters
Monitor ECG, heart rate and rhythm, blood pressure, serum K, oxygen saturation, end-tidal CO2 and isoflurane levels prior to and throughout anaesthesia.
Overdosage
Symptoms: Hypotension and respiratory depression. Management: Supportive treatment. Discontinue administration; maintain a clear airway and adequate CV function. Initiate assisted or controlled ventilation with pure oxygen. Monitor blood pressure and respiration closely.
Drug Interactions
May increase the risk of ventricular arrhythmia with β-sympathomimetic agents (e.g. isoprenaline), and α- and β-sympathomimetic agents (e.g. epinephrine, norepinephrine). May cause marked hypotension and additive negative inotropic effect with dihydropyridine Ca antagonists and β-blockers. Isoniazid may increase plasma fluoride concentration and potentiate hepatotoxic effects of isoflurane. Potentiated respiratory depressant effects with narcotics, opioids, benzodiazepines and other sedative agents. May increase the risk of haemodynamic instability during surgery with non-selective MAOIs. Markedly potentiate the action of all commonly used muscle relaxants (most profound with non-depolarising agents). Reduced minimum alveolar concentration (MAC) with nitrous oxide. May increase the risk of perioperative hypertension with indirect-acting sympathomimetics (e.g. amphetamines, psychostimulants, appetite suppressants, ephedrine). May cause carboxyhaemoglobinaemia with desiccated CO2 absorbents in anaesthetic circle breathing systems.
Potentially Fatal: Rarely, increased risk of perioperative hyperkalaemia leading to cardiac arrhythmias with succinylcholine.
Food Interaction
May enhance the CNS depressant effects of alcohol.
Action
Description: Isoflurane is a potent, volatile, halogenated general inhalational anaesthetic that alters the activity of neuronal ion channels, specifically the fast synaptic neurotransmitter receptors (e.g. nicotinic acetylcholine, GABA, glutamate receptors). It may depress myocardial contractility, lower blood pressure by decreasing systemic vascular resistance, and reduce sympathetic nervous activity.
Pharmacokinetics:
Absorption: Absorbed on inhalation. Blood/gas partition coefficient: Low.
Distribution: Crosses the placenta.
Metabolism: Minimally metabolised in the liver (<0.2%) mainly by CYP2E1 to inorganic fluoride.
Excretion: Via exhaled gases; urine (0.17% as metabolites).
Chemical Structure

Chemical Structure Image
Isoflurane

Source: National Center for Biotechnology Information. PubChem Database. Isoflurane, CID=3763, https://pubchem.ncbi.nlm.nih.gov/compound/Isoflurane (accessed on Jan. 21, 2020)

Storage
Store between 15-30°C.
ATC Classification
N01AB06 - isoflurane ; Belongs to the class of halogenated hydrocarbons. Used as general anesthetics.
References
Gonsalves SG, Dirksen RT, Sangkuhl K et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes. CPIC Guideline. 2019 Mar;0(0):1-7. doi: 10.1002/cpt.1319. Accessed 30/06/2020

Annotation of CPIC Guideline for Desflurane, Enflurane, Halothane, Isoflurane, Methoxyflurane, Sevoflurane, Succinylcholine and CACNA1S, RYR1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 30/06/2020.

Annotation of FDA Label for Isoflurane and CACNA1S, RYR1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 30/06/2020.

Annotation of HCSC Label for Isoflurane and CACNA1S, RYR1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 30/06/2020.

Anon. CACNA1S - Isoflurane. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 30/06/2020.

Anon. Isoflurane. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 30/06/2020.

Anon. RYR1 - Isoflurane. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 30/06/2020.

Buckingham R (ed). Isoflurane. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 30/06/2020.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 30/06/2020.

Isoflurane 100% Inhalation Vapour, Liquid (Piramal Critical Care Limited). MHRA. https://products.mhra.gov.uk/. Accessed 30/06/2020.

Isoflurane Liquid (Halocarbon Life Sciences, LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 30/06/2020.

Isorane 100% v/v Liquid Inhalation Anaesthetic (I.E. Medica Inc.). MIMS Philippines. http://www.mims.com/philippines. Accessed 20/08/2020.

Joint Formulary Committee. Isoflurane. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 30/06/2020.

Disclaimer: This information is independently developed by MIMS based on Isoflurane from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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