Adverse reactions : תופעות לוואי

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.

Cardiac arrest has been observed with general inhalation anesthetic drugs including isoflurane.

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 “not known”.

Summary of Most Frequent Adverse Drug Reactions
SOC                  Frequency               Adverse Reactions
Blood and lymphatic system        Not known      Carboxyhaemoglobinaemia2 disorders
Immune system disorders           Not known      Anaphylactic reaction1 Not known      Hypersensitivity1
Metabolism and nutrition          Not known      Hyperkalaemia2
disorders                         Not known      Blood glucose increased Psychiatric disorders             Not known      Agitation
Not known      Delirium
Not known      Mood altered5
Nervous system disorders          Not known      Convulsion
Not known      Mental impairment4
Cardiac disorders                 Not known      Arrythmia
Not known      Bradycardia
Not known      Cardiac arrest
Not known      Electrocardiogram QT prolonged
Not known      Tachycardia
Not known      Torsade de pointes
Vascular disorders                Not known      Hypotension2
Not known      Haemorrhage3
Respiratory, thoracic and         Not known      Bronchospasm2
mediastinal disorders             Not known      Dyspnoea1
Not known      Wheezing1
Not known      Respiratory depression2
Not known      Laryngospasm2
Gastrointestinal disorders        Not known      Ileus
Not known      Vomiting

Not known         Nausea
Hepatobiliary disorders            Not known         Hepatic necrosis2 Not known         Hepatocellular injury2
Not known         Blood bilirubin increased
Skin and subcutaneous tissue       Not known         Swelling face1
disorders                          Not known         Dermatitis contact1 Not known         Rash1
Renal and urinary disorders        Not known         Blood creatinine increased Not known         Blood urea decreased
General disorders and              Not known         Hyperthermia malignant2 administration site conditions     Not known         Chest discomfort1 Not known         Chills
Investigations                     Not known         White blood cell count increased1 Not known         Hepatic enzyme increased2
Not known         Fluoride increased1
Not known         Electroencephalogram abnormal
Not known         Blood cholesterol decreased
Not known         Blood alkaline phosphatase
decreased
Not known         Blood creatine phosphokinase
increased
Musculoskeletal and                Not known         Myoglobinuria
connective tissue disorders        Not known         Rhabdomyolysis

1
See 4.8(c)
2
See 4.4
3
In patients undergoing induced abortion. see 4.4
4
May cause a slight decrease in intellectual function for 2-4 days after anesthesia. See 4.4
5
Small 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 anesthetic agents, including isoflurane. These reactions have been confirmed by clinical testing (e.g., methacholine challenge). The etiology of anaphylactic reactions experienced during inhalational anesthetic 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 anesthesia, 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 anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. (See 4.4)

During the induction of anesthesia, 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 anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Early and aggressive intervention to treat the hyperkalaemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease (See 4.4).

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form
http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffect Medic@moh.gov.il.