Document: spc-doc_PL 29595-0006 change

• spc-doc_PL 00116-0327
• spc-doc_PL 29595-0006

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SUMMARY OF PRODUCT CHARACTERISTICS

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

Inhalation vapour liquid Clear, colourless, liquid

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Desflurane is indicated as an inhalation agent for induction and maintenance of general anesthesia for inpatient and outpatient surgery in adults and for the maintenance of anaesthesia in 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)
Age	N*	100 % Oxygen	N*	60% Nitrous Oxide/ 40% Oxygen
2 weeks	6	9.2 ± 0.0	-	-
10 weeks	5	9.4 ± 0.4	-	-
9 months	4	10.0 ± 0.7	5	7.5 ± 0.8
2 years	3	9.1 ± 0.6	-	-
3 years	-	-	5	6.4 ± 0.4
4 years	4	8.6 ± 0.6	-	-
7 years	5	8.1 ± 0.6	-	-
25 years	4	7.3 ± 0.0	4	4.0 ± 0.3
45 years	4	6.0 ± 0.3	6	2.8 ± 0.6
70 years	6	5.2 ± 0.6	6	1.7 ± 0.4

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

Induction of Anaesthesia in Adults

Taking into account the poor tolerability of breathing of the desflurane in an awake patient, the benefit ration/risk of such a procedure must be analyzed case by case 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. 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.

During induction in adults, the overall incidence of oxyhemoglobin desaturation (SpO2 < 90%) was 6%. High concentrations of desflurane may induce upper airway adverse events. See section 4.8.

Maintenance of Anaesthesia in 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.

Induction in Neurosurgical Patients

Desflurane should be administered at 0.8 MAC or less and in conjunction with 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).

Paediatric population

Desflurane should not be used for the induction of general anesthesia in children because of the high frequency occurrence of laryngospasm (see section 4.3 and 4.4).

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).

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.

Method of administration

Desflurane is administered by inhalation.

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.

-    For induction of anaesthesia in children because of the significant risk of laryngospasm. 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.

-    Desflurane should not be used as the sole anaesthetic in patients in whom increases in heart rate or blood pressure are undesirable.

-    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

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, 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 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.

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 postanaesthesia 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 postanaesthesia 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.

A continuous excitation of short duration may occur during induction of anesthesia.

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

Caution should be exercised when desflurane is used for maintenance anaesthesia with laryngeal mask airway (LMA) or face mask in children 6 years old or younger because of the increased potential for adverse respiratory events, e.g. coughing and laryngospasm, especially with removal of the LMA under deep anaesthesia (see section 4.2)

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.

MAC Desflurane	Pancuronium	Atracurium	Suxamethonium	Vecuronium
0.65. MAC/ 60% N2O/O2	0.026	0.123	* ND	* ND
1.25. MAC / 60% N2O/O2	0.018	0.091	* ND	* ND
1.25. MAC / 100% O2	0.022	0.120	0,362	0.019

* ND = not determined

Pre-anaesthetic medication

No clinically significant of adverse interactions related to the widespread use of preanesthetic 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

	Concentration* (%) of desflurane in O2	% Reduction in Concentration
No Fentanyl	6.33- 6.35	-
Fentanyl (3 pg / kg)	3.12-3.46	46-51
Fentanyl (6 pg / kg)	2.25 -2.97	53-64
No midazolam	5.85- 6.86	-
Midazolam (25pg/kg)	4.93	15.7

Midazolam (50 pg / kg) 4.88

* Patients aged 18-65 years

4.6 Fertility, pregnancy and lactation

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.

There are no adequate data from the use of desflurane in pregnant or lactating women, therefore desflurane is not indicated for use during pregnancy and lactation.

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 (> 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.

Table 4 Adverse Drug Reactions
System Organ Class	Side Effect	Frequency
Infections and infestations	Pharyngitis	Common
Blood and lymphatic system	Coagulopathy	Not known
disorders
Metabolism and nutrition	Hyperkalemia	Not known
disorders	Hypokalemia	Not known
	Metabolic acidosis	Not known
Psychiatric disorders	Breath Holding	Common
	Agitation	Uncommon
Nervous system disorders	Headache	Common
	Drowsiness	Uncommon
	Convulsions	Not known
Eye disorders	Conjuctivitis	Common
	Ocular Icterus	Not known
Cardiac disorders	Nodal arrhythmia	Common
	Bradycardia	Common
	Tachycardia	Common
	Hypertension	Common
	Myocardial infarction	Uncommon
	Myocardial ischaemia	Uncommon
	Arrhythmia	Uncommon
	Cardiac arrest Torsades de	Not known
	Pointes	Not known
	Ventricular failure	Not known
	Ventricular hypokinesia	Not known
	Atrial fibrillation	Not known
Vascular disorders	Vasodilation	Uncommon
	Malignant hypertension	Not known
	Hemorrhage	Not known
	Hypotension	Not known
	Shock	Not known
Respiratory, thoracic and	Apnea1	Common
mediastinal disorders	Cough1	Common
	Laryngospasm2	Common

	Hypoxia1 Respiratory failure Difficulty in breathing Bronchospasm Hemoptysis	Uncommon Not known Not known Not known Not known
Gastrointestinal disorders	Vomiting1	very common
	Nausea1	very common
	Excessive saliva secretion1	Common
	Acute pancreatitis	Not known
	Abdominal pain	Not known
Hepatobiliary disorders	Liver failure Liver cell necrosis Cytolytic hepatitis Cholestasis Jaundice Impaired liver function, liver disease	Not known
Skin and subcutaneous tissue	Urticaria	Not known
disorders	Erythema
Musculoskeletal and connective	Myalgia	Uncommon
tissue disorders	Rhabdomyolysis	Not known
General disorders and	Malignant Hyperthermia	Not known
administration site conditions	Asthenia Discomfort
Investigations	Increasing creatinine	Common
	Phosphokinase	Common
	Abnormal ECG	Common
	Prolongation of QTc interval	Not known
	Changes in the ST-T-track	Not known
	Inversion of the T wave in the ECG Alanine aminotransferase inc	Not known Not known
	reased	Not known
	Aspartate aminotransferase i	Not known
	ncreased Abnormal coagulation value s Elevated ammonia levels Bilirubin increased	Not known

¹    Reported during induction and maintenance of anesthesia

²    Reported during induction of anesthesia

³    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: 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.

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

Acute and sub chronic 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.

Reproductive toxicity

Embryotoxicity studies in which rats and rabbits were administered 1 MAC desflurane during the phase of organogenesis showed embryo toxic effects after an exposure period of 4 MAC-hours a day. In rats effects on cycle, fertility, gestation, birth, lactation and the peri-postnatal development of offspring were examined. At an exposure of the dams with 4 MAC hours, lower birth weight of newborns and reduced weight gain during the suckling period were observed. The fertility of male and female rats was reduced at this dose. The reproductive toxicity effects were limited to those dose-groups, in which other toxic effects also occurred in the parents.

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

2 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 / EPDM closure and an aluminium crimp.

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.

MARKETING AUTHORISATION HOLDER

Piramal Healthcare UK Limited Whalton Road, Morpeth, Northumberland,

NE 613YA,

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 29595/0006

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/05/2015

10    DATE OF REVISION OF THE TEXT

14/05/2015