Isoflurane

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ISOFLURANE (ISOFLURANE)

Composition:

Active substance: isoflurane;

1 vial (100 ml or 250 ml) contains isoflurane 100%.

Pharmaceutical form. Inhalation vapour, liquid 100%.

Main physicochemical properties: clear, colorless, mobile, non-flammable, dense liquid.

Pharmacotherapeutic group.
Agents for general anesthesia. Halogenated hydrocarbons. ATC code N01AB06.

Pharmacological properties.

Pharmacodynamics.

Isoflurane is a general inhalation anesthetic that provides rapid induction of anesthesia as well as rapid recovery.

Like all inhalation anesthetics, isoflurane causes dose-dependent depression of central nervous system activity and cerebral metabolism, while cerebrospinal fluid pressure may increase due to cerebral vasodilation. Isoflurane causes dose-dependent respiratory depression and reduced ventilatory response to carbon dioxide. The decrease in arterial pressure occurring during isoflurane anesthesia is primarily due to peripheral arterial and venous dilation, whereas heart rate and cardiac output are well maintained up to a maintenance concentration of 2.5%.

Pharmacokinetics.

Isoflurane has very low solubility in blood and body tissues. These low solubility values result in a rapid rise of alveolar partial pressure sufficient for anesthesia.

Biotransformation of isoflurane is extremely low, with only about 0.2% of administered isoflurane excreted as metabolites. Isoflurane is metabolized to trifluoroacetic acid and difluoromethanol, which is hydrolyzed to formic acid and fluoride ion. The half-life of elimination in urine for fluoride and organic fluorine is 36 and 41 hours, respectively.

Although the peak concentration of inorganic fluoride produced by the breakdown of isoflurane is generally much lower than that associated with nephrotoxicity, there is insufficient data regarding use in patients with impaired renal function. Therefore, the drug should be used with particular caution in such patients or in those receiving concomitant nephrotoxic agents.

Clinical characteristics.

Indications.

Induction and maintenance of general inhalational anesthesia.

Contraindications.

Hypersensitivity to isoflurane or to other halogenated anesthetics. Confirmed or suspected genetic predisposition to malignant hyperthermia (e.g., patients with a history of malignant hyperthermia, myopathies such as muscular dystrophy, King's syndrome, myotonia, central core disease).

Isoflurane must not be used in patients who have developed jaundice and/or fever of unknown origin, or in patients with hepatic dysfunction or eosinophilia following administration of isoflurane or another halogenated anesthetic.

Interaction with other medicinal products and other forms of interaction.

Neuromuscular blockers

Isoflurane produces sufficient muscle relaxation for certain intra-abdominal surgeries. Isoflurane is compatible with all commonly used neuromuscular blocking agents, whose effects it significantly potentiates. This effect is most pronounced with non-depolarizing agents; therefore, lower doses should be used in the presence of isoflurane. The effect of non-depolarizing neuromuscular blockers can be reversed by administration of neostigmine, which has no effect on the muscle-relaxing properties of isoflurane.

Adrenaline

The use of adrenaline (epinephrine) by any route during isoflurane anesthesia may lead to supraventricular or ventricular arrhythmias. When adrenaline is used, the dose should be limited to a maximum of 3 mcg/kg body weight in patients with normal cardiac function, and even less in patients with cardiac rhythm disturbances.

Concomitant use of other β-sympathomimetics, such as amphetamines, may lead to arrhythmias. If possible, administration of adrenaline or other β-sympathomimetics should be discontinued several days before surgery.

Calcium antagonists (and other vasodilators)

Isoflurane may cause marked arterial hypotension in patients receiving concomitant therapy with calcium antagonists, particularly those of the dihydropyridine class. In patients chronically taking other vasodilators such as angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, enalapril, lisinopril) or α1-adrenergic blockers (e.g., prazosin), unpredictable hypotension may occur with any form of anesthesia.

Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase inhibitors enhance the effects of general anesthetics. If possible, patients should discontinue MAO inhibitors at least 14 days prior to scheduled surgery.

β-blockers

The use of β-blockers in the perioperative period reduces the ability of isoflurane to increase heart rate. Thus, β-blockers generally exert a cardioprotective effect. If an increase in heart rate or vasoconstriction is required, appropriate sympathomimetic agents should be used. A complete medication history should always be available to the anesthesiologist.

Isoniazid

Isoniazid increases enzyme activity. Patients receiving isoniazid may be more susceptible to hepatotoxic effects of inhaled anesthetics. If possible, isoniazid administration should be discontinued one week prior to surgery.

Opioid analgesics

Opioid analgesics potentiate the respiratory depressant effect of isoflurane.

Special precautions for use.

Isoflurane is a potent respiratory depressant, and this effect is enhanced by the use of narcotic premedication or concomitant administration of other respiratory depressants.

Isoflurane causes increased cerebral blood flow at deep levels of anesthesia (1.5%), which may lead to an increase in cerebrospinal fluid pressure. If necessary, this effect can be avoided or counteracted by hyperventilation of the patient before or during anesthesia. As with other halogenated anesthetics, isoflurane should be used with caution in patients with elevated intracranial pressure. In such cases, hyperventilation may be required.

As with all halogenated anesthetics, repeated anesthesias within a short period of time should be approached with caution, as the risk of hepatotoxicity has not been fully characterized. Experience with repeated anesthesia is limited.

Interactions between isoflurane and desiccated CO₂ absorbents have been reported during closed-circuit anesthesia, resulting in the formation of carbon monoxide. Inhalation of carbon monoxide may lead to significant levels of carboxyhemoglobin in patients. Carboxyhemoglobin exerts toxic effects even at low concentrations and is not easily detected by standard anesthesia monitors such as pulse oximeters. Direct measurement of carboxyhemoglobin should be performed when a patient undergoing closed-circuit anesthesia with a concomitant agent develops oxygen desaturation unresponsive to usual therapeutic interventions. All possible measures should be taken to prevent drying of CO₂ absorbents.

The drug should be used with caution in patients with known hepatic dysfunction.

Isoflurane is a potent systemic dilator of coronary arteries. The effect on systemic arterial pressure is easily controlled in healthy patients, and the drug is used, in particular, as an agent for inducing hypotension. However, the phenomenon of "coronary steal" implies that isoflurane should be used with caution in patients with coronary artery disease. In particular, patients with subendocardial ischemia are expected to be more susceptible to anesthesia.

Use of the drug in children may stimulate salivation and tracheobronchial secretion, although pharyngeal and laryngeal reflexes diminish rapidly.

Since anesthesia levels can be easily and rapidly altered with isoflurane, only vaporizers producing predictable concentrations with high accuracy should be used. The degree of arterial hypotension and respiratory depression may provide some indication of the depth of anesthesia. The depth of anesthesia with isoflurane can be quickly changed. Heart rate remains stable during administration of the drug, but spontaneous respiration should be carefully supported if necessary.

Isoflurane should be administered only by an anesthesiologist or under the supervision of an anesthesiologist and with appropriate anesthesia and resuscitation equipment available.

In the event of symptoms of malignant hyperthermia, administration of isoflurane should be immediately discontinued, intravenous dantrolene should be administered, and supportive therapy initiated.

The use of inhaled anesthetics has been associated with rare cases of elevated plasma potassium levels, which may manifest as arrhythmias; fatal cases in the postoperative period have been reported in children. Particularly susceptible are patients with latent or overt neuromuscular disorders, especially Duchenne muscular dystrophy.

In most of these cases, succinylcholine was administered concomitantly. These patients also showed marked increases in plasma creatine phosphokinase levels, and in some cases, myoglobinuria. Although these manifestations resemble malignant hyperthermia, none of the patients exhibited muscle rigidity or hypermetabolic state. Early and intensive correction of hyperkalemia and treatment of arrhythmias are recommended, followed by evaluation for latent neuromuscular disorders.

Use during pregnancy or breastfeeding.

There are insufficient data to assess the teratogenic effects of the drug in humans. Animal studies have shown reproductive toxicity. Isoflurane is not recommended for use during the first trimester of pregnancy.

If possible, the use of all anesthetics should be avoided during pregnancy. Anesthesia with isoflurane should be performed with appropriate caution, considering the benefit/risk ratio.

There are data on the use of isoflurane during pregnancy, obstetric anesthesia, and obstetric surgical procedures such as cesarean section. An adequate level of anesthesia during cesarean section can be maintained with 0.5–0.75% isoflurane in an oxygen/nitrous oxide mixture.

Increased blood loss has been observed compared to other inhaled anesthetics (e.g., halothane) in patients undergoing uterine curettage or other gynecological surgical procedures.

When isoflurane is used during lactation, breastfeeding should be interrupted until the drug is completely eliminated from the body.

Ability to affect reaction speed when operating vehicles or machinery.

As with other general anesthetics, patients should not operate vehicles or machinery for 24 hours after isoflurane anesthesia.

Administration and Dosage.

Isoflurane has a slightly pungent ethereal odor, which may limit the rate of induction of anesthesia; however, despite this, induction and, particularly, recovery occur rapidly.

The route of administration is inhalational. The use of specific vaporizers for isoflurane ensures precise control of the administered anesthetic concentration.

The Minimum Alveolar Concentration (MAC), a standard measure of anesthetic potency, is 1.15% in pure oxygen and decreases to 0.5% when 70% nitrous oxide is administered in patients of average age. There are age-related differences: MAC is significantly higher in children and lower in elderly patients.

Minimum Alveolar Concentration (MAC)

Premedication.

The choice of premedication should be based on the individual needs of the patient. The respiratory depressant effect of isoflurane should be taken into account. Anticholinergic agents (e.g., atropine, glycopyrrolate) may be used at the discretion of the anesthesiologist to reduce oral secretions, but they may potentiate the mild tachycardic effects of isoflurane.

Induction.

Since isoflurane has moderate induction potency, induction is usually preceded by administration of a short-acting barbiturate or another intravenous induction agent to prevent coughing. Salivation and coughing may complicate induction with isoflurane in young children. Additionally, isoflurane can be administered with oxygen or with a mixture of oxygen and nitrous oxide.

Induction with isoflurane is recommended to begin at a concentration of 0.5%. Concentrations of 1.5–3% generally produce surgical anesthesia within 7–10 minutes. Arterial pressure decreases during induction, but this can be compensated by surgical stimulation.

Maintenance.

Stable surgical anesthesia with isoflurane is maintained at concentrations of 1% to 2.5% in a mixture of oxygen/70% nitrous oxide. Additional inhaled concentrations of isoflurane (0.5% to 1%) may be required with lower levels of nitrous oxide or when isoflurane is used alone or with an air-oxygen mixture.

During maintenance of anesthesia, arterial pressure decreases depending on the depth of anesthesia. That is, arterial pressure is inversely related to the concentration of isoflurane. Provided there are no other complicating factors, this decrease is likely due to peripheral vasodilation. Cardiac rhythm remains stable. Excessive reduction in arterial pressure may be related to the depth of anesthesia and can be corrected by reducing the inspired concentration of isoflurane. Arterial hypotension can be induced by artificial ventilation with isoflurane at concentrations of 2.5–4%. Prior administration of clonidine significantly reduces the requirement for isoflurane to maintain induced hypotension.

Recovery.

The concentration of isoflurane may be reduced to 0.5% at the beginning of surgical wound closure and then to 0% at the end of surgery, provided the anesthesiologist has confirmed that the effect of any neuromuscular blocking agent has been reversed and the patient is no longer paralyzed.

After discontinuation of all anesthetic agents, the patient's airways should be ventilated several times with 100% oxygen until full recovery. Recovery from anesthesia is rapid.

Children.

The drug can be used in pediatric practice; however, due to the occurrence of coughing, respiratory depression and desaturation, increased secretions, and laryngospasm, the use of isoflurane in children is not recommended.

Caution should be exercised when administering isoflurane to children under 2 years of age due to limited experience with the drug in this age group.

Overdose.

Overdose of isoflurane leads to significant respiratory depression and marked reduction in arterial pressure, the latter primarily due to peripheral vasodilation rather than direct myocardial depression. If overdose occurs, administration of the drug should be immediately discontinued, airway patency ensured, and ventilation with oxygen or controlled ventilation initiated.

Adverse Reactions

Adverse reactions associated with the use of isoflurane are generally dose-dependent extensions of pharmacophysiological effects and include hypotension, respiratory depression, and arrhythmias. Potential serious adverse reactions include malignant hyperthermia, hyperkalemia, elevated serum creatine kinase levels, myoglobinuria, anaphylactic reactions, and hepatic adverse reactions (see sections "Special Warnings and Precautions" and "Adverse Reactions"). Postoperatively, tremor, nausea, vomiting, intestinal obstruction, agitation, and delirium have been observed.

Cardiac arrest, bradycardia, and tachycardia have been reported during the use of general inhalational anesthetics, including isoflurane.

Prolongation of the QT interval with ventricular tachycardia «torsade de pointes» (in some cases resulting in fatal outcomes) has been reported.

The table below lists adverse reactions reported during clinical trials and the post-marketing period. Based on available data, the frequency of adverse reactions cannot be estimated; therefore, it is listed as "unknown".

1See section "Side effects".

2See section "Special precautions".

3In patients undergoing elective termination of pregnancy.

4May cause a slight decrease in intellectual function for 2–4 days following anesthesia.

5Slight changes in mood and symptoms may persist for up to 6 days.

Description of individual side effects

Transient increases in blood levels of bilirubin, serum glucose, and creatinine, along with decreases in blood urea nitrogen (BUN), serum cholesterol, and alkaline phosphatase have been observed. As with other general anesthetics, transient increases in blood leukocyte count have been observed even in the absence of surgical stress.

Rare cases of hypersensitivity (including contact dermatitis, rash, dyspnea, wheezing, chest discomfort, facial swelling, or anaphylactic reactions) have been reported, particularly in association with prolonged occupational exposure to inhaled anesthetics, including isoflurane. These reactions have been confirmed in clinical studies (e.g., methacholine challenge test). However, the etiology of anaphylactic reactions occurring during exposure to inhaled anesthetics remains unclear due to the influence of multiple concomitant medications, many of which are known to cause such reactions. A minimal increase in serum inorganic fluoride levels occurs during and after isoflurane anesthesia due to the biological degradation of the agent.

The low levels of serum inorganic fluoride (mean value of 4.4 µmol/L in one study) that have been reported are unlikely to cause renal toxicity, as they are significantly below the proposed threshold levels for renal toxicity.

Children

The use of inhaled anesthetics has rarely been associated with increased serum potassium levels leading to cardiac arrhythmias and fatal outcomes in pediatric patients in the postoperative period.

During induction of anesthesia, salivation and tracheobronchial secretions may increase, potentially causing laryngospasm.

Other special patient groups

Neuromuscular disorders

The use of inhaled anesthetics has been associated with rare increases in serum potassium levels leading to cardiac arrhythmias and fatal outcomes in pediatric patients during the postoperative period. Patients with either latent or overt neuromuscular disorders, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Early and aggressive intervention is recommended for the treatment of hyperkalemia and persistent arrhythmias, followed by evaluation for latent neuromuscular disorders.

Elderly patients

Lower concentrations of isoflurane are generally required to maintain surgical anesthesia in elderly patients.

Shelf life. 5 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of the reach of children.

Packaging.

100 ml or 250 ml of the medicinal product in a bottle. 1 bottle per cardboard package.

Prescription status. Prescription only.

Manufacturer.

Piramal Pharma Limited.

Manufacturer's address and location of operations.

S.No. 7-70, 70/1 and 70/2, Digwal Village, Kohir Mandal, Sangareddy, Telangana 502321, India (IN).