AWN-34828800

SUMMARY OF PRODUCT CHARACTERISTICS

Desflurane 100% (v/v) Inhalation

vapour liquid

Desflurane

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.

CM

00

LO

h

o

CM

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)

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 100% (v/v) Inhalation Vapour, liquid for dental use must be limited only to hospitals and ambulatory surgery (see section 4.3., "Contraindications").

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 preexisting 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 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.

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

9.75” X 17.25” (FRONT SIDE)

Package leaflet: Information for the user

Desflurane 100% (v/v) Inhalation

vapour liquid

Desflurane

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

-    Keep this leaflet. You may need to read it again.

-    If you have any further questions, ask your doctor, pharmacist or nurse.

-    If you get any side effects, talk to your doctor, pharmacist or nurse.

This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1.    What Desflurane is and what it is used for

2.    What you need to know before Desflurane is used

3.    How to use Desflurane

4.    Possible side effects

5.    How to store Desflurane

6.    Contents of the pack and other information

1.    What Desflurane is and what it is used for

Desflurane Inhalation, liquid contains desflurane. Desflurane is a general anaesthetic used in surgery.

It is an inhalation anaesthetic (it is given to you as a vapour for you to breathe in). Breathing in desflurane vapour causes you to fall into a deep sleep. It also maintains a deep sleep (general anaesthesia) during which you can undergo surgery. In adults, Desflurane is used for induction and maintenance of anaesthesia. In infants and children, it is used for maintenance of anaesthesia only.

2.    What you need to know before Desflurane is used Desflurane must not be used:

-    if you have or have ever had medical reasons for not receiving general anaesthetics.

-    if you are allergic to halogenated anesthetics.

-    if you or any member of your family has experienced a rapid and significant rise in body temperature during an operation (a condition called malignant hyperthermia).

-    if you are a child to bring on (induce) anaesthesia because of the significant risk of laryngospasm.

-    if you are a child (under 6 years of age) to maintain anaesthesia unless you are intubated. Intubation is when a tube is placed into the airways to help breathing.

-    if you are at risk of increased in heart rate or blood pressure, desflurane as sole anaesthetic should not be used.

-    if in the past after receiving inhalation anaesthesia, you had problems with liver function, unexplained fever or an increased number of certain white blood cells (leukocytosis).

-    if you are undergoing dental procedures outside a hospital or day care unit.

Before receiving this medicine, tell your doctor or anaesthesiologist if any of the above applies to you.

Warnings and precautions

Talk to your doctor or anaesthesiologist before receiving Desflurane :

-    if you have a risk of increased pressure inside the head.

-    if you have a tendency to suffer from bronchoconstriction (a tightening of the lungs and airways leading to coughing, wheezing or shortness of breath).

-    if you are at a risk for coronary artery disease (when the blood vessels do not transport enough blood and oxygen to the heart muscle).

-    if you are pregnant or breast feeding, or if this medicine is administered during delivery (also see “Pregnancy and breast-feeding").

-    if you suffer from a condition that affects the muscles (a neuromuscular disease such as Duchenne muscular dystrophy). You may be given a muscle relaxant at the same time as Desflurane.

-    if you have previously received general anaesthetics, especially if given multiple doses over a short time period.

-    If you are a child with a recent infection of respiratory tract.

Your doctor may administer less Desflurane:

-    in case of a low blood volume (hypovolemia).

-    in case of a low blood pressure (hypotension).

-    in case of weakness.

Your doctor can decide not to give you Desflurane and will choose another type of anaesthesia:

-    if you have liver disease due to alcohol abuse (cirrhosis).

-    if you have viral hepatitis (a virus-induced liver disease).

-    if you have other types of liver diseases.

After anaesthesia with Desflurane you will wake up again quickly. If pain is anticipated after the operation, your doctor will give you a painkiller. Your doctor can do this either at the end of the operation or during the recovery phase.

Your doctor must proceed with special care if an inhalational anaesthetic medicine was administered previously especially if it was multiple times during a short time interval (repeated use).

Desflurane can cause a rapid and significant rise in body temperature during an operation (malignant hyperthermia).

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

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.

Children

In children younger than 6 years of age, Desflurane can be given for maintenance of anaesthesia only if a breathing tube is placed into the airway to help breathing (intubation)

Other medicines and Desflurane

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines, including medicines obtained without a prescription.

Special care is required if any of the following medicines are being taken:

-    Muscle relaxants (such as Suxamethonium, Pancuronium, Atracurium, Vecuronium). These medicines help to relax the muscles. The anaesthesiologist might possibly adjust the dosage.

-    Opioids (such as Fentanyl, Morphine, Remifentanil). These medicines are strong painkillers and frequently used during full anaesthesia.

-    Benzodiazepines (such as Midazolam, Diazepam, Nitrazepam). These are

-    Nitrous oxide (laughing gas). This medicine can be used during full anaesthesia so that the patient sleeps and eases pain.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, tell your doctor or pharmacist before being given this medicine.

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

Driving and using machines

Desflurane can affect your alertness and ability to respond for some time after receiving the medicine. Therefore, do not drive or operate machinery for 24 hours after your operation.

3.    How to use Desflurane

Desflurane will always be administered to you by an anaesthesiologist. The anaesthesiologist will decide on the dose you will receive depending on your age, body weight and the type of operation you are having. During anaesthesia, the anaesthesiologist will check your blood pressure and heart rate. If required, the anaesthesiologist will adjust your dose.

Most commonly Desflurane is administered through a tube which is placed into the airways after you have been given an injection of another anaesthetic that induces sleep;

• Only in rare cases you may be asked to breathe in the Desflurane vapours through a mask to induce sleep.

Waking-up after anaesthesia

After the operation, the anaesthesiologist stop giving you Desflurane. You will wake up within a few minutes.

If you receive more Desflurane than you should

If you receive more Desflurane than you should, administration is stopped. Pure oxygen will be provided. Your blood pressure and heart function will be carefully checked while you wake up.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4.    Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Most side effects are mild to moderate in severity and last a short time. However, some side effects can also be serious.

Desflurane can cause a slight increase in the level of the blood sugar during anaesthesia.

Possible side effects include:

Very common (may affect more than 1 in 10 people)

•    Nausea

•    Vomiting

Common (may affect up to 1 in 10 people)

•    Inflammation of the back of the throat (pharyngitis)

•    Temporary breath holding

•    Headache

•    Inflammation of the outer layer of the eye and inner surface of the eyelids (conjunctivitis)

•    Irregular heartbeat or abnormal heart rhythm

•    Slower heartbeat (bradycardia)

•    Faster heartbeat (tachycardia)

•    High blood pressure (hypertension)

•    Temporary stopping breathing (apnoea), cough and excessive saliva production

•    Sudden spasm of the vocal cords that affects breathing and speaking (laryngospasm)

•    Increased blood counts of certain enzymes called creatine phosphokinase

•    Abnormal recording of the heartbeat (abnormal ECG).

•    Prolongation of QTc interval (abnormal ECG)

Uncommon (may affect up to 1 in 100 people)

•    Agitation

•    Dizziness

•    Heart attack (myocardial infarction)

•    Reduced blood flow to the heart muscle (myocardial ischemia)

•    Irregular heartbeat (arrhythmia)

•    Enlarged blood vessels (vasodilatation)

•    Reduced oxygen supply (hypoxia)

•    Muscle pain (myalgia)

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

•    Blood clotting disorder (coagulopathy)

•    Increased or decreased levels of potassium in the blood (hyperkalemia / hypokalemia)

•    Too much acid in the body fluids (metabolic acidosis)

•    Seizures (convulsions)

•    Yellowing of the eyeball (ocular icterus)

•    Heart failure (when the heart is having difficulty beating) or cardiac arrest(when the heart stops beating)

•    Life threatening irregular heart beat (torsades-de-pointes)

•    Ventricular malfunction (when two of your heart's chambers do not work so well or they stop working)

•    Reduced heart muscle contraction (ventricular hypokinesia)

•    Very high blood pressure (malignant hypertension)

•    Bleeding (haemorrhage)

•    Low blood pressure (hypotension)

•    When your body tissues do not get enough blood (shock)

•    Difficulty breathing (respiratory failure) or stopping breathing(respiratory arrest)

•    Sudden tightening of muscles in the airways (bronchospasm)

•    Coughing up blood from the lungs (haemoptysis)

•    Sudden inflammation of the pancreas (acute pancreatitis)

•    Stomach pain (abdominal pain)

•    Death of liver tissue (hepaticnecrosis)

•    Inflammation of the liver (cytolytic Hepatitis)

•    Blocked flow of bile from the liver (cholestasis)

•    Yellowing of the skin or eyeball (jaundice)

•    Disturbances in liver function or liver disease

•    Hives (urticaria)

•    Redness of the skin (erythema)

•    Muscle fibre breakdown (rhabdomyolysis)

•    Rapid and significant rise in body temperature during an operation (malignant hyperthermia).The signs of illness include:

-    Excess carbon dioxide in the blood (hypercapnia)

-    Muscle stiffness (rigidity)

-    Increased heartbeat (tachycardia)

-    Increased breathing (tachypnea)

-    Blue colouration of the skin (cyanosis)

-    Irregular heartbeat or abnormal heart rhythm (arrhythmia)

-    Low or high blood pressure and fever

•    Feeling of weakness (asthenia)

•    General discomfort

•    Changes in the recording of the cardiac activity (changes of the ST-T-measurements or inversion of the T wave in the ECG)

•    Increase in the liver enzymes (increased alanine- or aspartate-aminotransferase values)

•    Blood clotting disorder (abnormal clotting values)

•    Increased ammonia values

•    Elevated levels of bilirubin increased

•    Liver failure

Accidental exposure

The following side effects occurred in patients who were accidentally exposed to Desflurane

•    Dizziness

•    Severe headache (migraine)

•    Irregular, faster heartbeat (tachyarrhythmia)

•    Palpitations

•    Burning sensation in the eyes

•    Temporary blindness

•    Brain disease (encephalopathy)

•    Inflammation or infection of part of the eye (ulcerative keratitis)

•    Bloodshot eyes (ocular hyperemia)

•    Reduced visual sharpness and clarity

•    Eye irritation

•    Eye pain

•    Fatigue

•    Burning sensation of the skin Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse.This includes any possible side effects not listed in this leaflet.You can also report side effects directly via the Yellow Card Scheme at: HYPERLINK "http://www.mhra.gov.uk/yellowcard" www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine.

5.    How to store Desflurane

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label , after 'EXP.'. The expiry date refers to the last day of that month.

Store below 30°C.

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

6.    Contents of the pack and other information What Desflurane contains

-    The active substance is desflurane 100% (v/v).

-    There are no other ingredients.

What Desflurane looks like and contents of the pack

Desflurane is an inhalation vapour liquid.

Desflurane is a clear, colourless liquid.

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.

Marketing Authorisation Holder and Manufacturer

Piramal Healthcare UK Limited Whalton Road, Morpeth, Northumberland,

NE 61 3YA, United Kingdom

This leaflet was last revised in 04/2015.

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.

MAC Desflurane

0.65. MAC/60% N2O/O2

1.25.    MAC /60% N₂O/O₂

1.25.    MAC / 100% O₂ * 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/O,

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

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: HYPERLINK "http://www.mhra.gov.uk/yellowcard" 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

No Fentanyl Fentanyl (3 pg / kg) Fentanyl (6 pg / kg)

No midazolam Midazolam (25pg/kg) Midazolam (50 pg / kg)

* Patients aged 18-65 years

Concentration* (%) of

desflurane in O

6.33- 6.35

3.12-3.46

2.25 -2.97

5.85- 6.86

4.93

4.88

% Reduction in Concentration

46-51

53-64

15.7

16.6

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

¹    Reported during induction and maintenance of anesthesia

²    Reported during induction of anesthesia

³    Reported by non-patients after accidental exposure

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 and other handling

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 Healthcare UK Limited

Whalton Road, Morpeth Northumberland, NE61 3YA United Kingdom

8.    MARKETING AUTHORISATION NUMBER(S)

PL 29595/0006

9.    DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORIZATION

10. DATE OF REVISION OF TEXT

AWN-34828800

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