DESFLURANE Inhalation vapour liquid Ref.[9256] Active ingredients: Desflurane

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 (hypocapnia) 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.

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.

Nitrous oxide used concomitantly decreases the MAC of desflurane (Refer Table 1).

Depolarizing and non-depolarizing Myorelaxants

Commonly used muscle relaxants are potentiated by desflurane.

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 = not determined

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.

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

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).

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.

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:

Infections and infestations

Common: Pharyngitis

Blood and lymphatic system disorders

Not known: Coagulopathy

Metabolism and nutrition disorders

Not known: Hyperkalaemia, Hypokalaemia, Metabolic

Psychiatric disorders

Common: Breath

Uncommon: Holding

Nervous system disorders

Common: Headache

Uncommon: Somnolence

Not known: Seizure, Dizziness³, Migraine³, Encephalopathy³

Eye disorders

Common: Conjunctivitis

Not known: Ulcerative keratitis³, Ocular hyperaemia³, Visual acuity reduced³, Eye irritation³, Eye pain³

Cardiac disorders

Common: Nodal arrhythmia, Bradycardia, Tachycardia

Uncommon: Myocardial infarction, Myocardial ischaemia, Arrhythmia

Not known: Cardiac arrest, Torsade de Pointes, Ventricular failure, Ventricular hypokinesia, Atrial

Vascular disorders

Common: Hypertension

Uncommon: Vasodilation

Not known: Malignant hypertension, Haemorrhage, Hypotension

Respiratory, thoracic and mediastinal disorders

Common: Apnoea¹, Cough¹, Laryngospasm²

Uncommon: Hypoxia¹

Not known: Respiratory failure, Dyspnoea, Bronchospasm, Haemoptysis

Gastrointestinal disorders

Very common: Vomiting¹, Nausea¹

Common: Salivary hypersecretion¹, Pancreatitis acute

Hepatobiliary disorders

Not known: Hepatic failure, Hepatic necrosis, Hepatitis, Cholestasis, Jaundice, Hepatic function abnormal, Liver disorder, Ocular icterus³

Skin and subcutaneous tissue disorders

Not known: Urticaria, Erythema

Musculoskeletal and connective tissue disorders

Uncommon: Myalgia

Not known: Rhabdomyolys

General disorders and administration site conditions

Not known: Malignant, Hyperthermia, Asthenia, Discomfort

Investigations

Common: Blood creatine phosphokinase increased, Electrocardiogram abnormal, Electrocardiogram Prolongation of QTc interval

Not known: Electrocardiogram ST-T change, Electrocardiogram T wave inversion, Alanine aminotransferase increased, Aspartate aminotransferase increased, Coagulation test abnormal, Ammonia increased

Injury, poisoning and procedural complications³

Not known: Agitation postoperative

Ear and Labyrinth disorders

Not known: Vertigo

¹ Reported during induction and maintenance of anaesthesia
² Reported during induction of anaesthesia
³ Reported by non-patients after accidental exposure

Paediatric population

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

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, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.