DESFLURANE 100% INHALATION VAPOUR LIQUID - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Desflurane 100% Inhalation vapour, liquid

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Desflurane 100% (v/v)

3 PHARMACEUTICAL FORM

Inhalation vapour liquid.

Clear, colourless, liquid.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Desflurane is indicated as an inhalation agent for maintenance of anesthesia for inpatient and outpatient surgery in intubated adults, infants and children.

4.2 Posology and method of administration

Desflurane should be administered by persons trained in the administration of general anaesthesia using a vaporizer specifically designed and calibrated for use with desflurane.

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

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 his clinical status.

MAC-values (minimum alveolar concentration at which 50% of patients show no response to a standardized surgical incision) for desflurane decrease with increasing patient age. The dose of desflurane should be adjusted accordingly.

The percentage concentration of desflurane corresponding to 1 MAC has been determined within carrier gas as listed in Table 1 below.___________­____________

Table 1

Percentage concentration of desflurane corresponding to 1 MAC according to patient age and inhalation mixture (Mean ± SD)

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

Maintenance of Anaesthesia in adults

Desflurane is indicated for maintenance of anaesthesia in intubated adults. Surgical levels of anaesthesia may be sustained with 2–6% concentration of desflurane when nitrous oxide is used concomitantly. 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 when nitrous oxide is used concomitantly.

Premedication

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

Concomitant Therapy

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 nitrous oxide (N2O).

If added relaxation is required, supplemental doses of muscle relaxants may be used.

Use in Dental Surgery

The administration of Desflurane for dental use must be limited only to hospitals and ambulatory surgery (see section 4.3., „Contraindica­tions“).

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.

Paediatric population

Maintenance of Anaesthesia in children

Desflurane is indicated for maintenance of anaesthesia in intubated 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.

Method of administration

Desflurane is administered by inhalation.

Blood Pressure and Heart Rate during maintenance

Blood pressure and heart rate should be monitored carefully during maintenance as part of the evaluation of depth of anaesthesia. (See section 4.4)

4.3 Contraindications

– Desflurane should not be used for patients in whom general anesthesia is contraindicated.

– In patients with hypersensitivity to halogenated anesthetics.

– In patients with known or suspected propensity to malignant hyperthermia (MH) or with a corresponding hereditary disposition to MH.

– Desflurane should not be used for maintenance of anaesthesia in nonintubated adults, children and infants due to an increased incidence of respiratory adverse reactions.

– Desflurane should not be used in patients in whom liver dysfunction, unexplained fever or leukocytosis has occurred after a previous halogenated anesthetic administration.

– Desflurane is contraindicated in patients undergoing dental procedures outside a hospital or day care unit.

4.4 Special warnings and precautions for use

Malignant Hyperthermia (MH)

In susceptible individuals (history of malignant hyperthermia, myopathies such as muscular dystrophies, king syndrome, myotinic 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 nonspecific 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.

Perioperative Hyperkalemia

Use of inhaled anaesthetics, has been associated with very rare increases in serum potassium levels that have resulted in cardiac arrhythmias, and death in children during the postoperative period. The condition has been described in patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy. Use of suxamethonium 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.

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.

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 (hypocapnia) until cerebral decompression. Appropriate attention must be paid to maintain cerebral perfusion pressure.

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.

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 adsorbent is normally hydrated. Comply strictly with the instructions of use of CO2 adsorbents given by the manufacturer. When a clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the administration of desflurane.

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.

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

The effects of desflurane in patients with hypovolemia, 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.

Desflurane has coronary dilating effect. In patients with coronary heart disease, it is important to maintain an unobstructed hemodynamics to prevent myocardial ischemia. Desflurane should not be used as the sole means of anesthesia in patients at risk of a coronary heart disease, increased heart rate or increased blood pressure.

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

Maintenance of Anaesthesia in Children

Desflurane should NOT be used for maintenance anaesthesia with LMA or face mask.

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

4.5 Interaction with other medicinal products and other forms of interaction

Desflurane potentiates the action of myorelaxants commonly used. Nitrous oxide used simultaneously decreases the MAC of desflurane (see Table 1).

Depolarizing and nondepolarizing Myorelaxants

Commonly used muscle relaxants are potentiated by desflurane. Anaesthetic 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 anaesthesia

Table 2 shows the doses of pancuronium, atracurium and suxamethonium 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 – Determination (mg / kg) of myorelaxant inducing a 95% depression of neuromuscular transmission.

* ND = not determined

Pre-anaesthetic medication

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

Opiates and benzodiazepines

Patients anesthetized with different concentrations of desflurane and receiving increasing doses of fentanyl showed a significant reduction in anesthetic requirements or MAC. The administration of increasing doses of midazolam intravenously shows a small decrease in MAC (see 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 concentration corresponding to 0.6–0.8 MAC/O2

* Patients aged 18–65 years

Beta Sympathomimetics (isoprenaline) and alpha and beta-agonists (epinephrine or adrenalin; norepinephrine or noradrenaline)

Risk of severe ventricular arrhythmia as a result of an increased heart rate.

Cautious use is recommended.

Adrenaline (epinephrine) used for local haemostatic action, by subcutaneous or gingival injections

Risk of severe ventricular arrhythmia as a result of an increase in heart rate, even though the myocardial sensitivity with respect to adrenalin (epinephrine) is lower than in the use of desflurane when the use of the other halogenated anesthetics. Therefore, the dosage in adults should be limited to, for example, 0.1 mg of epinephrine within 10 minutes or 0.3 mg within 1 hour.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Desflurane is a uterine relaxant and reduces the uterine-placental blood flow. Limited animal data do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, Desflurane should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

It is unknown whether desflurane is excreted in human milk. The potential risk for the nursing infant is unknown. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Desflurane therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There is no clinical data on the effect of desflurane on fertility, Studies in rats and rabbits have revealed no evidence of impaired fertility at therapeutic exposures (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 and general 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 Common Uncommon Rare

Very rare

(> 1 / 10)

(> 1 / 100 to < 1 / 10)

(> 1 / 1000 to < 1 / 100)

(> 1/ 10 000 to < 1 / 1000)

(<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.

Table 4 Adverse Drug Reactions

1 Reported during induction and maintenance of anesthesia 2

2 Reported by non-patients after accidental exposure

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product 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 at Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Human experience

There is no experience with overdose in human.

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; anesthetics; 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.

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 anesthetics (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 anesthesia, with similar cardiovascular profile. EEG monitoring did not detect epileptogenic or other central nervous system undesirable effects during the desflurane-anesthesia, and concomitant use of adjuvant medicinal products produced no unanticipated or toxic EEG responses.

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

Pharmacological effect of desflurane correlates with end-tidal desflurane concentration.

Characteristics in patients

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

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.

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

Non-clinical data do not have relevant information to the existing clinical experience. This is based on results from conventional studies on acute and subchronic toxicity and genotoxicity.

Carcinogenicity studies have not been conducted.

Studies on reproduction toxicity in rats and rabbits have not shown an increased risk of congenital anomalies. Fertility was not affected after 1 MAC-Hour per day exposure (cumulative 63 and 14 MAC-Hours for males and females, respectively). At higher doses, parental toxicity (mortalities and reduced weight gain) was observed which could affect fertility. These effects are not relevant at clinical exposures.

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

2 years.

Chemical and physical in-use stability has been demonstrated for 7 days at 25°C.

6.4 Special precautions for storage

No special storage conditions.

Store in an upright position with cap firmly in place. Replace cap after each use.

6.5 Nature and contents of container

250-mL amber-colored plastic coated glass bottles containing 240mL of desflurane, sealed with a semi-transparent valve assembly and aluminum ferrule, and secured with PET sealing film.

Packaged product is supplied in boxes of 6.

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

Cadiasun Pharma GmbH

Lendersweg 27, 47877 Willich Germany

8 MARKETING AUTHORISATION NUMBER(S)

PL 42069/0004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

29/07/2021