Desflurane 100% (v/v) Inhalation Vapour, liquid – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Desflurane 100% (v/v) Inhalation Vapour, liquid

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Desflurane 100% (v/v)

3 PHARMACEUTICAL FORM

Clear, colourless, Inhalation vapour liquid

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Desflurane is indicated as an inhalation agent for induction and/or maintenance of general anaesthesia for inpatient and outpatient surgery in adults and for themaintenance of anaesthesia in infants and children.

4.2 Posology and method of administration

Desflurane should be administered only by healthcare professionals trained inthe administration of general anaesthesia using a vaporizer specifically designed and calibrated for use with desflurane.

Equipment for maintenance of a patent airway, artificial ventilation, oxygenenrichment and circulatory resuscitation must be immediately available.

Parameters such as ECG, blood pressure, oxygen saturation, andpCO2 upon exhaling must be monitored during anaesthesia (see section 4.4). Posology

The administration of general anaesthesia must be individualized based on the patient’s response. It is determined depending on the desired effect, taking into consideration of the patient’s age and clinicalstatus.

MAC (minimum alveolar concentration at which 50% of patients show no response to a standardized surgical incision) values for desflurane decreases with increasing patient age. The dose of desflurane should be adjusted accordingly. The percentage concentration of desflurane corresponding to 1 MAC hasbeen determined within carrier gas as listed in Table 1 below.

N* = number of crossover pairs (using up-and-down method of quantal response)

Premedication

Premedication should be decided after considering the individual requirements of each patient. The use of anticholinergic medicinal products isa matter of choice for the anaesthetist.

Desflurane can be combined with other substances commonly used in anaesthesia, preferably intravenous opioids benzodiazepines and hypnotics. Opioids or benzodiazepines decrease the amount of desflurane required to produce anaesthesia.

The need of Desflurane also decreases with the concomitant use of nitrousoxide (N2O).

Desflurane reduces the recommended dose of neuromuscular inhibitors.(Please refer also to section 4.5) If increased relaxation is required, additional doses of muscle relaxants may be given.

Induction of Anaesthesia in Adults

Taking into account the poor tolerability of breathing desflurane in awake patient, the benefit risk ratio of such a procedure must be analysed on case bycase basis.

In adults, a starting concentration of 3% is recommended, increased in 0.5- 1.0% increments every 2 to 3 breaths. Inspired concentrations of 4- 11% of desflurane usually produce surgical anaesthesia in 2-4 minutes.

Higher concentrations up to 15% may be used. Such concentrations of desflurane will proportionately dilute the concentration of oxygen and commencing administration of oxygen should be 30% or above.

During induction in adults, the overall incidence of oxyhemoglobindesaturation (SpO2 < 90%) was 6%. High concentrations of desflurane may induce upper airway adverse events.After induction in adults with an intravenous medicinal product such as thiopental or propofol, desflurane can be started at approximately 3.0% (0.5 MAC) - 6.0% (1 MAC), whether the carrier gas is O2 or N2O/O2.

Continuous, short-lived excitement may appear during the induction of anaesthesia with desflurane.

Induction of Anaesthesia in Children

Desflurane should not be used for the induction of general anaesthesia in children because of the high frequency occurrence of coughing, breath holding, apnoea, laryngospasm and increased salivation (see section 4.3 and4.4).

Maintenance of Anaesthesia in adults

Desflurane at 2.5-8.5 % may be required when administered using oxygen or oxygen enriched air. In adults, surgical levels of anaesthesia may be sustained at a reduced concentration of desflurane (2 -6%) when nitrous oxide is used concomitantly.

If high concentrations are used with nitrous oxide, it is important to ensure that the inhaled gaseous mixture contains a minimum of 25% oxygen.

Lower doses of desflurane are needed when using opioids,benzodiazepines or other sedatives (see section 4.5).

Blood Pressure and Heart Rate during Maintenance

Blood pressure and heart rate must be monitored carefully during maintenance as part of the evaluation of depth of anesthesia (see section 4.4).

Maintenance of Anaesthesia in children

Desflurane is indicated for maintenance of anaesthesia in infants and children. Surgical levels of anaesthesia may be maintained in children with end-tidal concentrations of 5.2 to 10% desflurane with or without the concomitant use of nitrous oxide. Although end-tidal concentrations of up to 18% desflurane have been administered for short periods of time, if high concentrations are used with nitrous oxide it is important to ensure that the inspired mixture contains a minimum of 25% oxygen.

Desflurane should not be used for maintenance of anaesthesia in non- intubated children under the age of 6 years due to an increased incidence of respiratory adverse reactions (see section 4.3 and 4.4).

Use in Dental Surgery

The administration of Desflurane for dental use must be limited only to hospitals and ambulatory/outpatient surgery (see section 4.3).

Special populations

Patients with Renal and Hepatic Impairment

Concentrations of 1-4% desflurane together with nitrous oxide or oxygen have been administered successfully in patients with chronic renal or hepatic impairment and during renal transplantation surgery. Because of low metabolism, dose adjustment in patients with renal and

hepatic impairment is not necessary.

Use in Neurosurgical Patients

Desflurane should be administered at 0.8 MAC or less and in conjunctionwith a barbiturate induction and hyperventilation (hypocapnia) until cerebral decompression in patients with known or suspected increases in cerebrospinal fluid pressure (CSFP). Appropriate attention must be paid to maintain cerebral perfusion pressure. (See section 4.4).

Use of desflurane in hypovolaemic, hypotensive, debilitated and elderly patients As with other potent inhalation anaesthetics, a lower concentration ofdesflurane is recommended for use in these patients.

Method of administration

Desflurane is administered by inhalation.

4.3 Contraindications

Desflurane must not be used:

• In patients for whom general anaesthesia is contraindicated.
• In patients with known hypersensitivity to halogenated anaesthetics, other halogenated hydrocarbon compounds.
• In patients with known or suspected propensity to malignant hyperthermia (MH) or with a corresponding hereditary disposition to MH.
• For induction of anaesthesia in children because of the significant risk of cough, breath holding, apnoea, laryngospasm, and increased salivation.
• For maintenance of anaesthesia in non-intubated children under the age of 6 years due to increased incidence of respiratory adverse reactions.
• As the sole anaesthetic in patients at risk of coronary artery disease or in patients whom increases in heart rate or blood pressure are undesirable.
• In patients with a history of confirmed hepatitis or unexplained moderate to severe liver dysfunction (e.g., jaundice, unexplained fever or leukocytosis/eosinophilia) has occurred after a previous halogenated anaesthetic administration.
• In patients undergoing dental procedures outside a hospital or day care unit.

4.4 Special warnings and precautions for use

Desflurane should be used with caution in patients without intubated airway.

Malignant Hyperthermia (MH)

In susceptible individuals (history of malignant hyperthermia, myopathies such as muscular dystrophies, King syndrome, myotonic dystrophy, central core myopathy), potent inhalation anaesthetics may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. Desflurane was shown to be a potential trigger of malignant hyperthermia. The clinical syndrome is signaled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these non-specific signs may also appear during light anaesthesia: acute hypoxia, hypercapnia, and hypovolemia. Treatment of malignant hyperthermia includes discontinuation of triggering medicinal products, administration of intravenous dantrolene sodium, and application of supportive therapy. Renal failure may appear later, and urine flow should be monitored and sustained if possible.

Desflurane should not be used in subjects known to be susceptible to MH. Cases of MH with a fatal outcome while on desflurane have been reported.

Perioperative Hyperkalemia

Use of inhaled anaesthetics, has been associated with very rare increases in serum potassium levels that have resulted in cardiac arrhythmias in patients, during the post-operative period, sometimes with a fatal outcome. The condition has been described in patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy. Use of suxamethonium (succinylcholine) has been associated with most, but not all, of these cases. These patients showed evidence of muscle damage with increased serum creatinine kinase concentration and myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state.

Prompt and vigorous treatment for hyperkalaemia and arrhythmias is recommended. Subsequent evaluation for latent neuromuscular disease is indicated. Likewise the possible presence of latent neuromuscular disease is subsequently clarified.

Obstetrics

Due to the limited number of patients studied, the safety of desflurane has not been established for use in obstetric procedures. Desflurane is a uterine relaxant and reduces the utero-placental blood flow. (See section 4.6)

Glucose elevation

Desflurane has been associated with some elevation of glucose intra-operatively.

Effects on Liver

With the use of halogenated anaesthetics, disruption of hepatic function, icterus and fatal liver necrosis have been reported: such reactions appear to indicate hypersensitivity. Desflurane may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anaesthetics. Cirrhosis, viral hepatitis or other pre-existing hepatic disease may be a reason to select an anaesthetic, other than a halogenated anaesthetic.

Increased Cerebrospinal Fluid Pressure (CSFP)

Desflurane may produce a dose-dependent increase in cerebrospinal fluid pressure (CSFP) when administered to patients with space occupying lesions. In such patients, desflurane should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation until cerebral decompression. Appropriate attention must be paid to maintain cerebral perfusion pressure.

In cases of threatening intracranial hypertension, the use of desflurane is not recommended.

Cardiovascular Disease

In patients with coronary heart disease, it is important to maintain haemodynamic stability to prevent myocardial ischemia. After a quick increase of the desflurane concentration, marked increase of pulse rate, mean arterial pressure, and adrenaline and noradrenaline levels have been seen. Desflurane should not be used as the sole means of anaesthesia in patients at risk of a coronary heart disease, or to patients where an increased heart rate or increased blood pressure is not desirable. It can be used with other medications, preferably intravenous opioids and hypnotics.

During maintenance of anaesthesia, increases in heart rate and blood pressure occurring after rapid incremental increases in end-tidal concentration of desflurane may not represent inadequate anaesthesia. The changes due to sympathetic activation resolve in approximately 4 minutes. Increases in heart rate and blood pressure occurring before or in the absence of a rapid increase in desflurane concentration may be interpreted as light anaesthesia.

Hypotension and respiratory depression increase as anaesthesia is deepened.

Arrhythmias were observed in association with the use of desflurane. All patients anaesthetized with desflurane should be monitored constantly. Parameters such as ECG, blood pressure, oxygen saturation, and pCO₂ upon exhaling must be monitored in an environment where a complete set of resuscitation equipment is available and the staff is trained in resuscitation techniques.

Desiccated CO₂ absorbents

Desflurane can react with desiccated carbon dioxide (CO₂) absorbents to produce carbon monoxide that may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO₂ canister at high flow rates over many hours or days. The formation of CO is not clinically significant when the absorbent is normally hydrated. Comply strictly with the instructions of use of CO₂ absorbents given by the manufacturer. When a clinician suspects that CO₂ absorbent may be desiccated, it should be replaced before the administration of desflurane.

Post-anaesthetic pain

Rapid emergence with desflurane should be taken into account in cases where post- anaesthesia pain is anticipated. Care should be taken that appropriate analgesia has been administered to the patient at the end of the procedure or early in the post- anaesthesia care unit stay.

General Precautions

Repeated anaesthesia within a short period of time should be approached with caution.

The effects of desflurane in patients with hypovolaemia, hypotension or poor general condition have not been widely investigated. In these patients, it is advisable to reduce the concentrations.

Desflurane should not be given to patients that are prone to bronchoconstriction, due to the risk of bronchospasms.

A continuous excitation of short duration may occur during induction of anaesthesia

. Middle ear surgeries

Desflurane, as well as other volatile anaesthetics increase middle ear pressure especially in children, and hence it is recommended that middle ear pressure be monitored during anaesthesia with desflurane.

Paediatric population

Desflurane is not indicated for the induction of inhaled anaesthesia in children and infants, due to the frequent occurrence of a cough, breath holding, apnoea, laryngospasms and increased secretions.

Caution should be exercised when desflurane is used for maintenance of anaesthesia with laryngeal mask airway (LMA) or face mask in children aged 6 years or younger because of the increased potential for adverse respiratory events, e.g. cough and laryngospasm, especially with removal of the LMA after deep anaesthesia.

Desflurane is not indicated for maintenance of anaesthesia in non-intubated children

Desflurane should be used with caution in children with history of asthma or a recent infection of the upper airways since there might be a risk of bronchoconstriction and an increased airway resistance.

When children recover after anaesthesia, a short period of agitation can occur that prevents cooperation.

QT interval prolongation

There have been reports of QT interval prolongation cases, associated very rarely with Torsade de Pointes (see section 4.8). Caution should be exercised when administering desflurane to sensitive patients.

4.5 Interaction with other medicinal products and other forms of interaction

Nitrous oxide used concomitantly decreases the MAC of desflurane

(ReferTable 1).

Depolarizing and non-depolarizing Myorelaxants

Commonly used muscle relaxants are potentiated by desflurane.

Anesthetic concentrations of desflurane at equilibrium reduce the ED95 of suxamethonium by approximately 30% and that of atracurium and pancuronium by approximately 50% compared to N2O /opioid anesthesia.

Table 2 shows the doses of pancuronium,

atracurium,suxamethonium and vecuronium required to obtain a 95% depression (ED95) of neuromuscular transmission according to different concentrations of desflurane (these doses are identical to those required for isoflurane). The ED95 of vecuronium is lower than 14%, with desflurane than isoflurane. In addition, recovery from neuromuscular blockade is longer with desflurane than isoflurane.

Table 2. - Dose of myorelaxant (mg/kg) inducing 95% depression of neuromuscular transmission.

* ND = notdetermined

The hypotensive effect may be potentiated when desflurane is administered concomitantly with ACEIs, tricyclic antidepressants, MAOIs, antihypertensive drugs, antipsychotic drugs or beta blockers.

Relaxometry is recommended for the exact dosing.

Pre-anaesthetic medication

No clinically significant of adverse interactions related to the widespread use of pre-anaesthetic medicinal products or medicinal products used during anaesthesia (intravenous anaesthetics and local anaesthetics) have been reported during clinical trials. The effect of desflurane on the availability of other medicinal products has not been determined.

Awakening is affected by concomitant anesthetics with sedative-hypnotic effect such as benzodiazepines, opioids, etc.

Opiates and benzodiazepines

Patients anaesthetized with different concentrations of desflurane and receiving increasing doses of fentanyl or midazolam showed a reduction in anaesthetic requirements or MAC. (Refer Table 3). It is anticipated that there will be a similar influence on MAC with other opioid and sedative medicinal products.

Table 3. Effect of Fentanyl or Midazolam on Desflurane MAC

* Patients aged 18-65 years

Contraindications for concomitant use

• Should be avoided or used with extreme caution in patients undergoing anaesthesia in view of the risk of inducing ventricular fibrillation

4.6 Fertility, Pregnancy and lactation

Pregnancy:

Due to the limited number of patients studied, the safety of desflurane has not been established for use in obstetric procedures. Desflurane is a uterine relaxant and reduces the utero-placental blood flow. Animal studies have shown reproductive toxicity (see section 5.3). Desflurane should only be used in pregnant women when absolutely necessary.

Breastfeeding:

There is insufficient information on the excretion of desflurane/metabolites in human milk. A risk to newborns/ infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from <Invented name> therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Breastfeeding should be avoided after anaesthesia until desflurane has been eliminated (around 24 hours).

Fertility

Data concerning potential effects of desflurane on human fertility are not available. In rats, effects on fertility were observed (see section 5.3).

4.7 Effects on ability to drive and use machines

There are no data on the effects of desflurane following anaesthesia on the ability to drive or use machines. However, patients should be advised that the ability to perform such tasks may be impaired after general anaesthesia. It is therefore advisable to avoid such tasks for a period of 24 hours after anaesthesia.

4.8 Undesirable effects

Desflurane may cause dose-dependent cardiac and respiratory depression and a slight intraoperative increase in blood glucose levels. Most undesirable effects are mild to moderate. Nausea and vomiting have been observed in the postoperative period, common sequelae of surgery andgeneral anaesthesia, which may be due to inhalational anaesthetic, other medicinal products administered intraoperatively or post-operatively and to the patient's response to the surgical procedure.

The adverse reactions listed below are categorized using the following frequency convention:

Very common (≥ 1 / 10)

Common (≥ 1 / 100 to <1 / 10)

Uncommon (≥ 1 / 1000 to <1 / 100) Rare

(≥ 1/10 000 to <1/1000) Very rare (<1/10

000)

Not known (frequency cannot be estimated from the available data)

Table 4 lists the adverse drug reactions by system organ class according to MedDRA terminology and frequencies.

¹ Reported during induction and maintenance of anaesthesia ² Reported during induction of anaesthesia

³ Reported by non-patients after accidental exposure

Other adverse reactions reported with similar products include: CARDIAC DISORDERS: Prolonged QT

electrocardiogram

Paediatric population

The frequency, type, and intensity of these adverse reactions are consideredidentical for children and adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinalproduct is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card inthe Google Play or Apple App Store.

4.9 Overdose

Overdose Symptoms and Treatment

The symptoms of overdose of desflurane are anticipated to be similar to those of other volatile agents with a deepening of anaesthesia, cardiac and/or respiratory depression in spontaneous breathing patients, and hypotension in ventilated patients in whom hypercarbia and hypoxia may occur only at a late stage.

In the event of overdose, the following actions should be taken: Desflurane should be stopped, a clear airway should be established and assisted or controlled ventilation with pure oxygen should be initiated. The hemodynamic function must be properly supported and maintained.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Nervous system; anaesthetics; general; Halogenated hydrocarbons; ATC code: N01AB07

Desflurane is one of a family of halogenated methyl ethyl ethers, which are administered by inhalation, producing a dose-related temporary loss of consciousness and of pain sensations, suppression of voluntary motor activity, reduction of autonomic reflexes, and depression of respiration and the cardiovascular system. Desflurane is a colorless, volatile liquid with a boiling point of 22.8º C. It is not flammable or explosive in the mixing ratios used in anaesthesiology

Other members of the series include enflurane and isoflurane which are halogenated with chlorine as well as fluorine. Desflurane is halogenated exclusively with fluorine.

As suggested by its structure, the diffusion coefficient of gas in the blood for desflurane (0.42) is lower than all available volatile anaesthetics (isoflurane has 1.4 blood-gas partition coefficient), and slightly lower than nitrous oxide (0.46). These data indicate that desflurane would meet the need for an agent characterised by rapid recovery.

Animal studies have shown more rapid induction and awakening with desflurane than from isoflurane anaesthesia, with similar cardiovascular profile. EEG monitoring did not detect epileptogenic or other central nervous system undesirable effects during the desflurane-anaesthesia, and concomitant use of adjuvant medicinal products produced no unanticipated or toxic EEG responses.

Clinical studies to date evaluating myocardial ischemia, infarction and death as outcome parameters have not established that the coronary arteriolar property of desflurane is associated with coronary steal or myocardial ischemia in patients with coronary artery disease.

Studies in pigs susceptible to malignant hyperthermia indicated that desflurane is a powerful trigger for malignant hyperthermia.

Pharmacological effect of desflurane is dose-dependent.

5.2 Pharmacokinetic properties

General characteristics

As predicted from its physiochemical profile, pharmacokinetic studies in animals as in man indicate that desflurane washes into the body more rapidly than other volatile anaesthetics, and allows faster induction. It also washes out of the body more rapidly allowing quick recovery and flexibility in adjustment of the depth of anaesthesia. Desflurane is eliminated via the lungs, undergoing only minimal metabolism (0.02%), hence low potential for toxicity.

Characteristics in patients

The pharmacological effect is proportional to the inspired concentration of desflurane. The main adverse effects are exacerbations of the pharmacological action.

The MAC (minimum alveolar concentration) decreases with increasing age. A reduction of dose is recommended in hypovolemic, hypotensive and weak patients, as indicated in section 4.4.

5.3 Preclinical safety data

Safety pharmacology, acute and subchronic toxicity

Non-clinical data on acute and subchronic toxicity of desflurane show that it triggers in a concentration- dependent manner a predictable and controllable depression of respiration and circulatory system. There was no development of organ specific toxicity with desflurane in this case.

In swine, desflurane did not sensitize the myocardium to exogenously administered epinephrine. Desflurane appears to produce coronary vasodilation at arteriolar level in selected animal models, in a similar fashion to that of isoflurane. In an animal model simulating coronary artery disease with conscious, chronically instrumented dogs, desflurane does not appear to divert blood from collateral dependent myocardium to normally perfused areas (“coronary steal”).

Reproductive toxicity

Embryotoxicity studies in which rats and rabbits were administered desflurane during the phase of organogenesis showed embryo toxic effects after an exposure period of 4 MAC-hours a day (approximately 40 cumulative MAC hours). No adverse reaction was detected after an exposure period of 10 cumulative MAC hours.

In rats, during gestation and lactation, increased post-implantation loss and reduction in weight-gain of offspring was observed after a maternal exposure period of 4 MAC hours/per day. During this same period, maternal exposure of 1 MAC hour/day did not cause adverse effects. All of the adverse effects observed on the foetus or offspring were limited to groups where maternal toxicity (death and reduced weight gain) occurred, that is, the effects on the offspring may reflect the pharmacological effect of desflurane on the female animal.

The fertility of male and female rats was reduced at an exposure of 4 MAC hours/day. The effects were limited to those dose-groups, in which maternal toxicity was observed.

Published studies in animals (including primates) at doses resulting in light to moderate anaesthesia demonstrate that the use of anaesthetic agents during the period of rapid brain growth or synaptogenesis results in cell loss in the developing brain that can be associated with prolonged cognitive deficiencies. The clinical significance of these nonclinical findings is not known.

Mutagenicity

A detailed investigation by in-vivo and in-vitro studies revealed no evidence of mutagenic properties of desflurane.

Carcinogenicity

Long-term studies on carcinogenicity of desflurane were not carried out.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None

6.2 Incompatibilities

Desflurane may react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide (CO).

In order to prevent the risk of formation of carbon monoxide in re-breathing circuits and the possibility of elevated carboxyhaemoglobin levels, fresh (wet) carbon dioxide-absorbing material should be used.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 30°C.

Store the bottle in an upright position with the cap tightly closed.

6.5 Nature and contents of container

250 mL amber Type III glass bottle, and PVC coating on the outside of the bottle with HDPE / Ethylene Propylene Diene Monomer (EPDM) closure and an aluminium crimp.

Pack sizes of 1 and 6 bottles.

Not all pack sizes may be marketed

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Accidental exposure of health professionals to desflurane can lead to a risk of undesirable effects.

7 MARKETING AUTHORISATION HOLDER

Piramal Critical Care Limited

Suite 4, Ground Floor

Heathrow Boulevard - East Wing,

280 Bath Road,

West Drayton, UB7 0DQ,

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 37071/0024

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorisation:14/05/2015 Date of Renewal: 29 August 2019

10 DATE OF REVISION OF THE TEXT

21/03/2024