Forane 99.9% w/w, inhalation vapour liquid

  • Name:

    Forane 99.9% w/w, inhalation vapour liquid

  • Company:
    info
  • Active Ingredients:

    Isoflurane

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 19/01/16

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Summary of Product Characteristics last updated on medicines.ie: 6/2/2019

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AbbVie Limited

AbbVie Limited

Company Products

Medicine NameActive Ingredients
Medicine Name Chirocaine 1.25mg/ml solution for infusion Active Ingredients levobupivacaine hydrochloride
Medicine Name Chirocaine 2.5 mg/ml solution for injection/concentrate for solution for infusion Active Ingredients levobupivacaine hydrochloride
Medicine Name Chirocaine 5 mg/ml solution for injection/concentrate for solution for infusion Active Ingredients levobupivacaine hydrochloride
Medicine Name Chirocaine 7.5 mg/ml solution for injection/concentrate for solution for infusion Active Ingredients levobupivacaine hydrochloride
Medicine Name Duodopa intestinal gel Active Ingredients Carbidopa Monohydrate, Levodopa
Medicine Name Forane 99.9% w/w, inhalation vapour liquid Active Ingredients Isoflurane
Medicine Name Moderiba 200mg Film-coated Tablets Active Ingredients Ribavirin
Medicine Name Moderiba 400mg Film-coated Tablets Active Ingredients Ribavirin
Medicine Name Moderiba 600mg Film-coated Tablets Active Ingredients Ribavirin
Medicine Name Sevorane Active Ingredients Sevoflurane
Medicine Name Zemplar 5 microgram/ml Solution for Injection Active Ingredients Paricalcitol
Medicine Name Zemplar capsules, soft Active Ingredients Paricalcitol
1 - 0 of 12 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 6 February 2019 SmPC

Reasons for updating

  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.3 - Preclinical safety data

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.5- Interaction with other medicinal products and other forms of interaction

Inducers of CYP2EI: Medicinal products and compounds that increase the activity of cytochrome P450 isoenzyme CYP2E1, such as isoniazid and alcohol, may increase the metabolism of isoflurane and lead to significant increases in plasma fluoride concentrations.

 

Amended to:

Medicinal products and compounds that increase the activity of cytochrome P450 isoenzyme CYP2E1, such as isoniazid and alcohol, may increase the metabolism of isoflurane and lead to significant increases in plasma fluoride concentrations.

 

 

 

Section 4.6 - Fertility, pregnancy and lactation

 

 

The following statement added under “Pregnancy”:

Studies in animals have shown reproductive toxicity (see section 5.3).

 

Section 5.3 – Preclinical safety data

 

The following section has been added:

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

 

Updated on 15 August 2018 SmPC

Reasons for updating

  • File format updated to PDF

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 20 January 2016 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 20 January 2016 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 7:  Change to address of MAH,


from

AbbVie Limited

Block B

Liffey Valley Office Campus

Quarryvale

Co. Dublin

 

to

 

AbbVie Limited

Citywest Business Park

Dublin 24

Ireland

Updated on 19 January 2016 PIL

Reasons for updating

  • New PIL for new product

Updated on 19 January 2016 PIL

Reasons for updating

  • Change to MA holder contact details

Updated on 16 September 2015 PIL

Reasons for updating

  • Change to side-effects
  • Change to dosage and administration

Updated on 16 September 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text
  • Addition of Minimum Alveolar Concentration (MAC) values for preterm neonates < 32 weeks gestational age and preterm neonates 32 -37 weeks gestational age.
  • Addition of information relating to the induction of anaesthesia in children.
  • Subsection e (Other special populations), Addition of the following statement underneath “Neuromuscular disease”, “Early and aggressive intervention to treat the hyperkalaemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease. “

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.2, Posology and method of administration

  • Addition of Minimum Alveolar Concentration (MAC) values for preterm neonates < 32 weeks gestational age and preterm neonates 32 -37 weeks gestational age.
  • Addition of information relating to the induction of anaesthesia in children.

Section 4.8, Undesirable effects

  • Subsection e (Other special populations), Addition of the following statement underneath “Neuromuscular disease”, “Early and aggressive intervention to treat the hyperkalaemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.

Updated on 2 March 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.2:
The subheadings, "Posology" and "Method of administration" have been added
The subheading "Elderly" has been changed to "Older patients".


Section 4.4:
The following text has been deleted:
An increase in overall metabolism may be reflected in an elevated temperature (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of the CO2 absorption system (hot canister).

The following statement has been added:

There have been postmarketing reports of malignant hyperthermia. Some of these reports have been fatal.

Section 4.5:

The following statements have been added:

Under Combinations advised against:
Concomitant use of succinylcholine with inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in
paediatric patients during the post-operative period.

Under Combinations requiring precautions in using:

Inducers of CYP2EI: Medicinal products and compounds that increase the activity of cytochrome P450 isoenzyme CYP2E1, such as isoniazid and alcohol, may increase the metabolism of isoflurane and lead to significant increases in plasma fluoride concentrations.
Use of isoflurane and isoniazid can increase the risk of potentiation of the hepatotoxic effects.

Section 4.6
The subheading "Nursing Mothers" has been changed to "Breast-feeding".

Section 4.8:
The following statement has been added:

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie













 




Updated on 27 February 2015 PIL

Reasons for updating

  • Change to drug interactions
  • Change to information about drinking alcohol
  • Change to date of revision
  • Change to improve clarity and readability
  • Addition of information on reporting a side effect.

Updated on 20 November 2013 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.4          Special Warnings and Precautions for Use

 

 

·         The sentence

“Isoflurane relaxes the uterus muscle, and the lowest possible concentration of Forane should be used in obstetrical operations (Please refer to section 4.6).”

has been deleted  and replaced with the following:

“Isoflurane, like other inhalational agents, has relaxant effects on the uterus with the potential risk for uterine bleeding.  Clinical judgment should be exercised when using isoflurane during obstetric anaesthesia. Consideration should be taken to use the lowest possible concentration of isoflurane in obstetrical operations. (see section 4.6).”


·         The following statements have been added:

Reports of QT prolongation, associated with torsade de pointes (in exceptional cases, fatal), have been received. Caution should be exercised when administering isoflurane to patients at risk for QT prolongation. (Please refer to section 4.8).

Caution should be exercised in administering general anaesthesia, including isoflurane, to patients with mitochondrial disorders.


·         The sentence “Reports demonstrate that isoflurane can produce hepatic injury ranging from mild transient increases in liver enzymes to fatal hepatic necrosis in rare instances.”  has been changed to  “Reports demonstrate that isoflurane can produce hepatic injury ranging from mild transient increases in liver enzymes to fatal hepatic necrosis in very rare instances.”


·         The sentence “The action of non-depolarising relaxants is markedly potentiated with isoflurane.” has been amended to “All commonly used muscle relaxants are markedly potentiated by  isoflurane, the effect being most profound with non-depolarising agents.”

 

·         Sub-heading Perioperative Hyperkalemia included at the start of paragraph “Use of inhaled anaesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in paediatric patients during the postoperative period.------“

·         The sentence “Isolated cases of increased carboxyhemoglobin have been reported with the use of halogenated inhalation agents with a -CF2H moiety (i.e. desflurane, enflurane and isoflurane)” has been amended to  “ Isolated cases of increased carboxyhemoglobin have been reported with the use of fluorinated  inhalation agents (i.e. desflurane, enflurane and isoflurane).

 

 

Section 4.5          Interaction With Other Medicinal products and Other Forms of Interaction

 

·         The sentence “Muscle relaxants are markedly potentiated by isoflurane.” Has been amended to  “All commonly used  muscle relaxants are markedly potentiated by isoflurane, the effect being most profound with non-depolarising agents.”

 

 

Section 4.6          Fertility, Pregnancy and Lactation

 

·         The sentence  “Isoflurane relaxes the uterus muscle, and the lowest possible concentration of isoflurane should be used in obstetrical operations.” has been amended to “ Isoflurane, like other inhalational agents, has relaxant effects on the uterus with the potential risk for uterine bleeding. Clinical judgment should be exercised when using isoflurane during obstetric anaesthesia. Consideration should be taken to use the lowest possible concentration of isoflurane in obstetrical operations.”

 

Section 4.7          Effects on Ability to Drive and Use Machines

·         The sentence “The patient should not drive or use machines for at least 24 hours after anaesthesia with isoflurane.” has been amended to “The patient should not drive or use machines for 2-4 days following anaesthesia with isoflurane.”

 

 

Section 4.8           Undesirable Effects

 

·         The following undesirable effects have been added to sub-section a (Summary of safety Profile). : , hyperkalemia, elevated serum creatine kinase and myoglobinuria, agitation, delirium, Cardiac arrest, bradycardia, and tachycardia.

·         The following adverse reactions have been added to sub-section b (Tabulated summary of adverse reactions):
Cardiac arrest, Bradycardia, Tachycardia, Electrocardiogram QT prolonged, Torsade de pointes, Myoglobinuria, Rhabdomyolysis

·         Subsction c (Description of selected adverse reactions):  The sentence “Transient elevations in white blood count have been observed even in the absence of surgical stress.” has been amended to  “Transient increases in blood bilirubin, blood glucose and serum creatinine with decrease in BUN, serum cholesterol and alkaline phosphatase have been observed.  As with all other general anaesthetics, transient elevations in white blood count have been observed even in the absence of surgical stress.”

  • The following information has also been added to this sub-section:

Bronchospasm and laryngospasm due to airway irritation have been reported with volatile anaesthetics during inhalation.

Reports of QT prolongation, associated with torsade de pointes (in exceptional cases, fatal), have been received.

 

Section 5.1          Pharmacodynamic properties

 

·         The sentence “Although slight pungency may limit the rate of induction, excessive salivation and tracheobronchial secretions are not stimulated.” has been amended to “Although slight pungency may limit the rate of induction, excessive salivation and tracheobronchial secretions do not appear to be stimulated.”

·         The sentence “Forane appears to sensitise the myocardium to adrenaline to an even lesser extent than enflurane.” has been amended to “Forane appears to sensitise the myocardium to adrenaline.”




 

 

 

Updated on 20 November 2013 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to drug interactions

Updated on 15 March 2013 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 7:

Marketing Authorisation holder has changed to:

AbbVie Limited

Block B

Liffey Valley Office Campus

Quarryvale

Co. Dublin



Section 8:
Marketing Authorisation number has changed to:

PA 1824/1/1

Updated on 14 March 2013 PIL

Reasons for updating

  • Change to marketing authorisation holder

Updated on 21 December 2012 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.4     Special Warnings and Precautions for Use


Vaporisers specially calibrated for Forane should be used so that the concentration of anaesthetic delivered can be accurately controlled. Hypotension and respiratory depression increase as anaesthesia is deepened.

Increased blood losses comparable with those found following anaesthesia with other inhalation agents have been recorded with isoflurane in patients undergoing induced abortion
uterine curettage.

 

Isoflurane relaxes the uterus muscle, and the lowest possible concentration of Forane should be used in obstetrical operations (Please refer to section 4.6).

 

General

As with any potent general anaesthetic, Forane should only be administered in an adequately equipped anaesthetising environment by those who are familiar with the pharmacology of the drug and qualified by training and experience to manage the anaesthetised patient.


Since levels of anaesthesia may be altered quickly and easily with Forane, only vaporisers which deliver a predictable output with reasonable accuracy, or techniques during which inspired or expired concentrations can be monitored, should be used.  The degree of hypotension and respiratory depression may provide some indication of anaesthetic depth.

Reports demonstrate that isoflurane can produce hepatic injury ranging from mild transient increases in liver enzymes to fatal hepatic necrosis in rare instances. 

 

It has been reported that previous exposure to halogenated hydrocarbon anaesthetics, especially if the interval is less than 3 months, may increase the potential for hepatic injury. Cirrhosis, viral hepatitis or other preexisting liver disease can be a reason to select an anaesthetic other than a halogenated anaesthetic.

 

 

All patients anaesthetised with Forane should be constantly monitored, including ECG, BP, oxygen saturation and end tidal CO2 in a setting where full resuscitative equipment is available and with staff fully trained in resuscitative techniques. The presence of additional risk factors should be taken into consideration (see section 4.8).

 

Forane is a profound respiratory depressant, which effect is accentuated by narcotic premedication or concurrent use of other respiratory depressants. Respiration should be closely monitored and assisted or controlled ventilation employed where necessary.  Measurement of tidal volume may provide an indication of depth of anaesthesia in the spontaneously breathing patient.

 

 

Hypotension and myocardial depression are related to the depth of anaesthesia. The concomitant use of nitrous oxide and surgical stimulation may limit the extent of the hypotension. Excessive fall in blood pressure, unless due to hypovolaemia, should be corrected by lightening the depth of anaesthesia.

 

Regardless of the anaesthetics employed, maintenance of normal hemodynamics is important  forimportant for the avoidance of myocardial ischemia in patients with coronary artery disease.

 

As with other halogenated agents, Forane must be used with caution in patients with increased intracranial pressure. Forane may cause a rise in cerebrospinal fluid pressure and cerebral blood flow, which may be reversible by hyperventilation. This should be borne in mind when considering use in neurosurgery.

Isoflurane markedly increases cerebral blood flow at deeper levels of anaesthesia. There may be a transient rise in cerebral spinal fluid pressure which is fully reversible with hyperventilation. 

Isoflurane must be used with caution in patients with increased intracranial pressure. In such cases hyperventilation may be necessary.  This should be borne in mind when considering use in neurosurgery.

 

Use of isoflurane in hypovolemic, hypotensive and debilitated patients has not been extensively investigated.  A lower concentration of isoflurane is recommended for use in these patients.

The action of non-depolarising relaxants is markedly potentiated with isoflurane.


Isoflurane may cause a slight decrease in intellectual function for 2-4 days following anaesthesia. Small changes in moods and symptoms may persist for up to 6 days after administration. This must be taken into account when patients resume normal daily activities, including driving or operating heavy machinery (please refer to section 4.7).


A potentiation of neuromuscular fatigue can be seen in patients with neuromuscular diseases, such as myasthenia gravis. Forane should be used with caution in these patients. 

 

Forane should be administered with caution to patients who can develop bronchoconstriction since bronchospasm can occur (see section 4.8).

Isoflurane may cause respiratory depression which may be augmented by narcotic premedication or other agents causing respiratory depression. Respiration should be supervised and if necessary, assisted (see section 4.8).

Measurement of tidal volume may provide an indication of depth of anaesthesia in the spontaneously breathing patient.

 

During the induction of anaesthesia, saliva flow and thracheobronchial secretion can increase and can be the cause of laryngospasm, particularly in children (see section 4.8). 

Children Under Two Years of Age: Caution should be exercised when Forane is used in small children due to limited experience with this patient-group.

Reports demonstrate that isoflurane can produce hepatic injury ranging from mild transient increases in liver enzymes to fatal hepatic necrosis in rare instances.  Repeated exposure to halogenated hydrocarbon anaesthetics may increase the risk of hepatic injury, especially if the interval is less than 3 months.

 

Caution should be exercised when administering Forane to patients with pre-existing liver disease.

 

Malignant hyperthermia:   In susceptible individuals, Forane (isoflurane) anaesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia.  The syndrome includes non-specific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressures. (It should also be noted that many of these non-specific signs may appear with light anaesthesia, acute hypoxia, etc.)  An increase in overall metabolism may be reflected in an elevated temperature (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of the CO2 absorption system (hot canister).  PaO2 and pH may decrease and hyperkalemia and a base deficit may appear.

 

Treatment includes discontinuance of triggering agents (e.g. Forane).  Intravenous administration of dantrolene sodium, and application of supportive therapy.  Such therapy includes vigorous efforts to restore body temperature to normal, respiratory  and  circulatory  support  as  indicated,  and management of electrolyte-fluid-acid-base derangements.  (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management).  Renal failure may appear later and urine flow should be sustained if possible.

 

Use of inhaled anaesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in paediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all of these cases. These patients also experienced significant elevations in serum creatine kinase levels and in some cases changes in urine consistant with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity of hypermetabolic state. Early and aggressive intervention to treat the hyperkalaemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.

 

Although peak inorganic fluoride concentrations which result from the breakdown of isoflurane are generally much lower than those considered nephrotoxic, no information is available on levels in patients with compromised renal function.  The drug should therefore be used with extreme caution in these patients, or in those receiving nephrotoxic drugs concomitantly.

 

This agent should be administered cautiously to those on anti hypertensives or any drug which may influence the response of the sympathetic nervous system.

 

Some halogenated inhalation agents with a CH-F2 moiety, i.e. desflurane, isoflurane and enflurane have been reported to interact with dry CO2 absorbents to form carbon monoxide.  In order to minimise the risk of formation of carbon monoxide in closed and re-breathing circuits, and the possibility of increased carboxyhaemoglobin levels in exposed patients, CO2 absorbents should not be allowed to dry out.

Isolated cases of increased carboxyhemoglobin have been reported with the use of halogenated inhalation agents with a -CF2H moiety (i.e. desflurane, enflurane and isoflurane). No clinically significant concentrations of carbon monoxide are produced in the presence of normally hydrated absorbents. Care should be taken to follow manufacturers' instructions for CO2 absorbents.

 

Standard anaesthesia monitors such as pulse oximeters are not a reliable method for detecting carboxyhaemoglobin.

 

Direct measurement of carboxyhaemoglobin should be carried out in the event that a patient on closed circuit anaesthesia with an implicated agent develops oxygen desaturation which does not respond to the usual therapeutic measures.

 

Rare cases of extreme heat, smoke and/or spontaneous fire in the anaesthesia machine have been reported during the administration of general anaesthesia with drugs in this class when used in conjunction with desiccated CO2 absorbents, specifically those containing potassium hydroxide (e.g. Baralyme). When a clinician suspects that the CO2 absorbent may be desiccated, it should be replaced before administration of isoflurane. The colour indicator of most CO2 absorbents does not necessarily change as a result of desiccation.

Therefore, the lack of significant colour change should not be taken as an assurance of adequate hydration. CO2 absorbents should be replaced routinely regardless of the state of the colour indicator.

 

The action of non-depolarising relaxants is markedly potentiated with isoflurane. Isoflurane, as well as other general anaesthetics, may cause a slight decrease in intellectual function for two or three days following anaesthesia. As with other anaesthetics, small changes in moods and symptoms may persist for up to 6 days after administration.

 

4.5     Interaction With Other Medicinal products and Other Forms of Interaction


Combinations advised against:

 

Beta- sympathomimetic agents like isoprenaline and alpha- and beta- sympathomimetic agents like adrenaline and noradrenaline should be used with caution during isoflurane narcosis, due to a potential risk of ventricular arrhythmia. 

 

Non-selective MAO-inhibitors:  Risk of crisis during the operation.  Treatment should be stopped 15 days prior to surgery.

 

Combinations requiring precautions in using:

 

Indirect-acting sympathomimetics (amphetamines and their derivatives, psychostimulants, appetite suppressants, ephedrine and its derivatives): Risk of perioperative hypertension. In patients undergoing elective surgery, treatment should ideally be discontinued several days before surgery.

 

Adrenaline, by subcutaneous or gingival injections:  risk of serious ventricular arrhythmia as a consequence of increased heart rate, although the myocardial sensitivity with respect to adrenaline is lower with the use of isoflurane than in the case of halothane.

 

Cardiovascular compensation reactions may be impaired by beta-blockers.

 

Use of isoflurane and isoniazide can increase the risk of potentiation of the hepatotoxic effects.

 

Calcium antagonists, in particular dihydropyridine derivates: isoflurane may lead to marked hypotension in patients treated with calcium antagonists.

 

Caution should be exercised when calcium antagonists are used concomitantly with inhalation anaesthetics due to the risk of additive negative inotropic effect.

 

Opioids, benzodiazepines and other sedative agents are associated with respiratory depression, and caution should be exercised when concomitantly administered with isoflurane.

 

Isoflurane markedly potentiates the effects of all commonly used muscle relaxants, especially the non-depolarising agents, and these agents should be used in reduced dosage. Muscle relaxants are markedly potentiated by isoflurane. Neostigmine has an effect on the nondepolarising relaxants, but has no effect on the relaxing action of isoflurane itself. Care should also be exercised when using antibiotics of the aminoglycoside group e.g. neomycin, concurrently with isoflurane.  Neostigmine does not antagonise the direct muscle relaxant effect of isoflurane.



Isoflurane does not sensitise the myocardium to the effects of catecholamines in dogs. Limited data suggests that subcutaneous infiltration of 0.25 mg (50 ml of 1:200,000 solution) adrenaline of 3.4 mcg/kg in a 70 kg adult, does not produce an increase in ventricular arrhythmias, provided there is no concomitant myocardial hypoxia. The utmost care must be used to prevent overdosage or unduly rapid adrenaline absorption.



Isoflurane should be administered with caution to patients on beta adrenergic blockers.  Limited animal data suggests that isoflurane may be used safely in the presence of therapeutic levels of propranolol.

 

The MAC of isoflurane is decreased by the use of nitrous oxide (see section 4.2).

MAC (minimum alveolar concentration) is reduced by concomitant administration of N20 in adults (see section 4.2).

 

4.6     Fertility, Pregnancy and Lactation

 

Reproduction studies have been carried out on animals after repeated exposures to anaesthetic concentrations of Forane.  Studies with the rat demonstrated no effect on the fertility, pregnancy or delivery or on the viability of the offspring.  No evidence of teratogenicity was revealed. Comparable experiments in rabbits produced similar negative results.  The relevance of these studies to the human is not known.  Safety in pregnancy has not been established.  Adequate data have not been developed to establish the use of Forane in pregnancy or obstetrics other than for caesarian section.

 

It is not known whether isoflurane is excreted in human milk therefore caution should be exercised when isoflurane is administered to a nursing woman.

 

Gynaecological use: Blood losses comparable with those found following anaesthesia with other inhalation agents have been observed with Forane in patients undergoing uterine curettage.

Use in Pregnancy

There are no or limited amount of data from the use of isoflurane in pregnant women. Studies in animals have shown reproductive toxicity. Isoflurane should only be used during pregnancy if the benefit outweighs the potential risk.

 

Isoflurane relaxes the uterus muscle, and the lowest possible concentration of isoflurane should be used in obstetrical operations.

Use in Cesarean Section

Isoflurane, in concentrations up to 0.75%, has been shown to be safe for the maintenance of anaesthesia for cesarean section (please refer to section 4.4).

Nursing Mothers

It is not known whether isoflurane/metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isoflurane is administered to a nursing woman.

 

 

4.7     Effects on Ability to Drive and Use Machines

 

The action of non-depolarizing relaxants is markedly potentiated with isoflurane.

Isoflurane, as well as other general anaesthetics, may cause a slight decrease in intellectual function for two or three days following anaesthesia. As with other anaesthetics, small changes in moods and symptoms may persist for up to 6 days after administration. This must be taken into account when patients resume normal daily activities, including driving or operating heavy machinery.

Isoflurane can have an influence on driving and using machines. The patient should not drive or use machines for at least 24 hours after anaesthesia with isoflurane. Changes in behaviour and intellectual function may persist for up to 6 days after administration. This must be taken into account when patients resume normal daily activities, including driving or operating heavy machinery.

 

4.8      Undesirable Effects

a. Summary of the safety profile

Adverse reactions encountered in the administration of isoflurane are in general dose dependent extensions of pharmacophysiologic effects and include respiratory depression, hypotension and arrhythmias.  Potential serious undesirable effects  include malignant hyperthermia, anaphylactic reactions and liver adverse reactions (please refer to section 4.4 and 4.8). Shivering, nausea, vomiting and ileus have been observed in the postoperative period.

 

b. Tabulated summary of adverse reactions

The following table displays adverse reactions reported in clinical trials and from post-marketing experience.  Frequency cannot be estimated from the available data, therefore it is “unknown”.

 

Summary of Most Frequent Adverse Drug Reactions

SOC

Frequency

Adverse Reactions

Blood and lymphatic system disorders

Unknown

Carboxyhaemoglobinaemia2

Immune system disorders

Unknown

Unknown

Anaphylactic reaction1

Hypersensitivity1

Metabolsim and nutrition disorders

Unknown

Unknown

Hyperkalaemia2

Blood glucose increased

Psychiatric disorders

Unknown

Unknown

Unknown

Agitation

Delirium

Mood altered5

Nervous system disorders

Unknown

Unknown

Convulsion

Mental impairment4

Cardiac disorders

Unknown

Arrhythmia

Vascular disorders

Unknown

Unknown

Hypotension2

Haemorrhage3

Respiratory, thoracic and mediastinal disorders

Unknown

Unknown

Unknown

Unknown

Unknown

Bronchospasm2

Dyspnoea1

Wheezing1

Respiratory depression2

Laryngospasm2

Gastrointestinal disorders

Unknown

Unknown

Unknown

Ileus

Vomiting

Nausea

Hepatobiliary disorders

Unknown

Unknown

Unknown

Hepatic necrosis2

Hepatocellular injury2

Blood bilirubin increased.

Skin and subcutaneous tissue disorders

Unknown

Unknown

Unknown

Swelling face1

Dermatitis contact1

Rash1

Renal and urinary disorders

Unknown

Unknown

Blood creatinine increased

Blood urea decreased

General disorders and administration site conditions

Unknown

Unknown

Unknown

Hyperthermia malignant2

Chest discomfort1

Chills

Investigations

Unknown

 

Unknown

Unknown

Unknown

 

Unknown

Unknown

White blood cell count increased1

Hepatic enzyme increased2

Fluoride increased1

Electroencephalogram abnormal

Blood cholesterol decreased

Blood alkaline phosphatase decreased

1See 4.8(c)

2See 4.4

3In patients undergoing induced abortionuterine curettage. See 4.4.

4May cause a slight decrease in intellectual function for 2-4  days after anaesthesia.  See 4.4.

5Small changes in moods and symptoms may persist for up to 6 days. See 4.4.

 

 

c. Description of selected adverse reactions

 

 Transient elevations in white blood count have been observed even in the absence of surgical stress.

 

Rare reports of hypersensitivity (including dermatitis contact, rash, dyspnoea, wheezing, chest discomfort, swelling face, or anaphylactic reaction) have been received, especially in association with long-term occupational exposure to inhaled anaesthetic agents, including isoflurane.  These reactions have been confirmed by clinical testing (e.g., methacholine challenge). The etiology of anaphylactic reactions experienced during inhalational anaesthetic exposure is, however, unclear because of the exposure to multiple concomitant drugs, many of which are known to cause such reactions.

 

Minimally raised levels of serum inorganic fluoride occur during and after isoflurane anaesthesia, due to biodegradation of the agent.  It is unlikely that the low levels of serum inorganic fluoride observed (mean 4.4 µmol/l in one study) could cause renal toxicity, as these are well below the proposed threshold levels for kidney toxicity.

 

d. Paediatric population

 

Use of inhaled anaesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in paediatric patients during the postoperative period. (See 4.4.)

 

During the induction of anaesthesia, saliva flow and tracheobronchial secretion can increase and can be the cause of laryngospasm. (See 4.4.)

 

e. Other special populations

 

Neuromuscular disease:

Use of inhaled anaesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in paediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable.  (See 4.4.)

 

Elderly:

Lesser concentrations of isoflurane are normally required to maintain surgical anaesthesia in elderly patients. (See 4.2.)




As with other halogenated anaesthetics, hypotension and respiratory depression have been observed. Close monitoring of blood pressure and respiration is recommended. 

 

This agent causes a rise in blood sugar levels during anaesthesia. This should be borne in mind during administration to diabetic subjects.

 

Summary of Most Frequent Adverse Drug Reactions

SOC

Frequency

Adverse Reactions

Immune system disorders

Not known

Anaphylactic reaction*

Hypersensitivity*

Nervous system disorders

Not known

Convulsions

Cardiac disorders

Not known

Arrhythmia

Vascular disorders

Not known

Hypotension

Respiratory, thoracic and mediastinal disorders

Not known

Dyspnoea*

Wheezing*

Respiratory depression

Gastrointestinal disorders

Not known

Vomiting

Nausea

Hepatobiliary disorders

Not known

Hepatic necrosis

Hepatic injury

Skin and subcutaneous tissue disorders

Not known

Swelling face*

Dermatitis contact*

Rash*

General disorders and administration site conditions

Not known

Hyperthermia malignant

Chest discomfort*

Chills

Investigations

Not known

Electroencephalograph abnormal

White blood cell count increased

Hepatic enzyme increased

Fluoride increased

 

*May be associated with hypersensitivity reactions, particularly in association with long-term occupational exposure to inhaled anaesthetic agents.

 

4.9     Overdose

 

Supportive measures may be necessary to correct hypotension and respiratory depression resulting from excessively deep levels of anaesthesia.

Hypotension and respiratory depression have been observed.  Close monitoring of blood pressure and respiration is recommended. Supportive measures may be necessary to correct hypotension and respiratory depression resulting from excessively deep levels of anaesthesia.

 



Updated on 13 December 2012 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to drug interactions

Updated on 8 November 2010 SmPC

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  • Change to section 6.3 - Shelf life

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The following in-uses stability statement has been added to section 6.3:

"In-use stability: Use within 3 months from opening when stored in the original pacakage and below 25C"

Updated on 3 November 2010 PIL

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  • Change to storage instructions
  • Change due to user-testing of patient information

Updated on 5 October 2009 PIL

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  • Improved electronic presentation

Updated on 26 June 2009 SmPC

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  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 4.7 - Effects on ability to drive and use machines

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  • In Section 4.2 (Posology and Method of Administration), the MAC table has been separated to show a clear divide between Paediatric and adult patients.
  • In Section 4.4 (Special Warnings and Special Precautions for Use), the following statements has been added 'regardless of anaesthetics employed, maintenance of normal hemodynamics is important for the avoidance of myocardial ishchemia in patients with coronary heart disease.' Also, to the statement regarding repeat exposure increasing the risk of hepatic injury, the following has been added 'especially if the interval is less than 3 months'. Also, the following statement has been added to this section 'The action of non-depolarising relaxants is markedly potentiated with isoflurane. Isoflurane as well as other general anaesthetics, may cause a slight decrease in intellectual function for two to three days following anaesthesia. As with other anaesthetics, small changes in moods and symptoms may persist for up to 6 days after administration.'
  • In Section 4.5 (Interaction With Other Medicaments and Other Forms of Interaction), The following statement has been added; 'The MAC of isoflurane is decreased by the use of nitrous oxide (see section 4.2)'
  • In Section 4.6 (Pregnancy and Lactation), the following statement has been added; 'It is not known whether isoflurane is excreted in human milk therefore, caution should be exercised when isoflurane is administered to a nursing woman.'
  • In Section 4.7 (Effects on Ability to Drive and Use Machines), The following information has been added; 'The action of non-depolarising relaxants is markedly potentiated with isoflurane. Isoflurane as well as other general anaesthetics, may cause a slight decrease in intellectual function for two to three days following anaesthesia. As with other anaesthetics, small changes in moods and symptoms may persist for up to 6 days after administration. This must be taken into account when patients resume normal daily activities, including driving or operating machinery.'
  • In Section 4.8 (Undesiarble Effects), Whole section has been reformatted to comply with MedDRA system and standardised fequencies. Hypersensitivity and related reactions have been added.
  • In Section 5.1 (Pharmacodynamic properties), The ATC code has been added.

Updated on 23 June 2009 PIL

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  • Change to side-effects
  • Change to information about pregnancy or lactation
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  • Change to date of revision

Updated on 11 March 2009 PIL

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  • Change to name of manufacturer

Updated on 9 December 2008 PIL

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  • Change of trade or active ingredient name
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  • Change to further information section

Updated on 5 December 2008 SmPC

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  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation

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Section 2 (Qualitative and Quanititative Composition) - 'w/w' has been added for clarity
Section 6.3 (Shelf Life) Has been reworded for clarity
Section 6.4 (Special precautions for storage) 'In oder to protect from light' hass been added.
Section 6.6 (Instructions for use/handling) 'Any unsued product or waste material should be disposed of in accordance with local requirements' has been added.
Section 9 (Date of renewal updated)

Updated on 17 November 2008 PIL

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  • Change to name of manufacturer

Updated on 21 August 2007 SmPC

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  • Change to section 6.5 - Nature and contents of container
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6.5     Nature and contents of Container

 

100 ml and 250 ml Type III Ph.Eur  amber glass bottles, closed with an aluminium cap with LDPE liner

Not all pack sizes may be marketed.

Updated on 9 January 2007 SmPC

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  • Correction of spelling/typing errors

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Updated on 6 October 2006 PIL

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  • Change to warnings or special precautions for use

Updated on 5 October 2006 SmPC

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  • Change to section 4.4 - Special warnings and precautions for use

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4.4       Special Warnings and Special Precautions for Use

Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in paediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all of these cases. These patients also experienced significant elevations in serum creatine kinase levels and in some cases changes in urine consistant with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity of hypermetabolic state. Early and aggressive intervention to treat the hyperkalaemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.

Updated on 12 May 2006 SmPC

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  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

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Updated on 30 January 2006 SmPC

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  • Change to section 6.4 - Special precautions for storage
  • Change to section 1 - Name of medicinal product
  • Change to section 3 - Pharmaceutical form
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Updated on 25 January 2006 PIL

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  • Change to storage instructions
  • Change to appearance of the medicine
  • Change to date of revision

Updated on 17 August 2005 PIL

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  • New PIL for medicines.ie

Updated on 18 August 2003 SmPC

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  • Change to section 1 - Name of medicinal product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 18 August 2003 SmPC

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  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 17 June 2003 SmPC

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  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may not be renewed (A)