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Nursing Mothers

Due to insufficient information regarding the excretion of isoflurane in human milk, the potential risks and benefits for each specific patient should be carefully considered before isoflurane is administered to nursing women.

Pediatric Use

During the induction of anesthesia, saliva flow and tracheobronchial secretion can increase and can be the cause of larynogospasm, particularly in children.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Isoflurane, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data. (see WARNINGS /Pediatric Neurotoxicity, PRECAUTIONS/ Pregnancy, and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY).

Effects on Ability to Drive and Use Machines

Patients should be advised that performance of activities requiring mental alertness, such as driving a vehicle or operating machinery, may be impaired for some time after general anesthesia. Therefore, patients should not undertake hazardous tasks, such as driving, for at least 24 hours following administration of a general anesthetic.

ADVERSE REACTIONS

The following adverse reactions were identified from controlled clinical studies of adult and pediatric subjects exposed to isoflurane. The studies were conducted using a variety of pre-medications, other anesthetics, and surgical procedures of varying lengths.

The most serious reported adverse reactions in alphabetical order are agitation, arrhythmia, breath holding, elevated liver enzyme, hypotension and laryngospasm.

The most frequent adverse reactions (incidence ≥ 5%) described in Table 1 are agitation, breath holding, chills/shivering, cough, delirium, laryngospasm, nausea, and vomiting.

Adverse reactions with and incidence between 1% and 5% are provided in Table 2. Adverse reactions with an incidence less than 1% are provided in Table 3.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 1: Adverse Reactions ≥ 5%

System Organ Class (SOC)

Adverse Reaction

Frequency

PSYCHIATRIC DISORDERS

Delirium

6.2% (N=2830)

NERVOUS SYSTEM DISORDERS

Agitation

(Excitement)

Induction

51.8%

(N=515) 1

RESPIRATORY, THORACIC,

AND MEDIASTINAL DISORDERS

Breath holding

Induction

23.9%

(N=515) 1

Cough

Induction

28.2%

(N=515) 1

Laryngospasm

Induction

8.0%

(N=515) 1

GASTROINTESTINAL DISORDERS

Nausea

Recovery

15.4 %

(N=2830)

Vomiting

Recovery

9.5%

(N=2830)

GENERAL DISORDERS AND

ADMINISTRATIVE SITE CONDITIONS

Chills/shivering

14.0%

(N=1691) 2

1 Represents patients not receiving intravenous agents or muscle relaxants for intubation (i.e., patients receiving inhalation induction).

2 Reflects the number of patients with recorded body temperature measurements.

Table 2: Adverse Reactions between 1% and 5%

System Organ Class (SOC)

Adverse Reaction

Frequency

NERVOUS SYSTEM

DISORDERS

Movement

Maintenance

1.8% (N=2830)

CARDIAC DISORDERS

Ventricular arrhythmia

(Intraoperative)

Induction

2.1% (N=2161)

Maintenance

2.7% (N=2253)

Nodal arrhythmia

(Intraoperative)

Induction

4.0% (N=2161)

Maintenance

1.7% (N=2253)

Atrial arrhythmia

(Intraoperative)

Induction

1.6% (N=2161)

Maintenance

2.2% (N=2253)

Arrhythmia (Postoperative)

1.1% (N=2830)

RESPIRATORY, THORACIC,

AND MEDIASTINAL DISORDERS

Breath holding

Maintenance

1.1%

(N=359) 1

Cough

Maintenance

4.2 %

(N=359) 1

1 Represents patients not receiving intravenous agents or muscle relaxants for intubation (i.e., patients receiving inhalation induction).

Table 3: Adverse Reactions less than 1%

System Organ Class (SOC)

Adverse Reaction

Frequency

PSYCHIATRIC DISORDERS

Mood changes

0.3%

(N=2830)

Nightmare

0.4%

(N=2175) 1

NERVOUS SYSTEM DISORDERS

Convulsive pattern on

electroencephalogram

0.5%

(N=200) 2

Seizure

0.04%

(N=2830)

VASCULAR DISORDERS

Hypotension

Postoperative

0.3%

(N=2830)

Hypertension

Postoperative

0.1%

(N=2830)

RESPIRATORY, THORACIC,

AND MEDIASTINAL DISORDERS

Laryngospasm

Maintenance

0.8%

(N=359) 3

Secretions

Induction

0.2%

(N=515) 3

Maintenance

0.0%

(N=359) 3

GASTROINTESTINAL DISORDERS

Vomiting

Induction

0.8%

(N=515) 3

Retching

Induction

1.0%

(N=515) 3

Maintenance

0.8%

(N=359) 3

SKIN AND SUBCUTANEOUS

TISSUE DISORDERS

Diaphoresis

Induction

0.2%

(N=515) 3

Maintenance

0.0%

(N=359) 3

1 Reflects the number of patients interviewed by a physician in the recovery period.

2 Reflects the number of recorded electroencephalograms.

3 Represents patients not receiving intravenous agents or muscle relaxants for intubation (i.e., patients receiving inhalation induction).

The following adverse reactions were observed, but due to limited data, frequency could not be determined.

Blood and Lymphatic System Disorders:

White blood cell count increased

Metabolism and Nutrition Disorders:

Blood glucose increased

Psychiatric Disorders:

Confused state, Nervousness

Nervous System Disorders:

Ataxia; Dizziness; Drowsiness; Intellectual function decrease

Vascular Disorders:

Hypotension (Intraoperative); Hypertension (Intraoperative)

Hepatobiliary Disorders:

Blood bilirubin increased; Bromsulphthalein clearance

decreased; Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood alkaline phosphatase increased; Blood lactate dehydrogenase increased

Musculoskeletal, Connective Tissue and

Bone Disorders:

Myalgia

General Disorders and Administrative

Site Conditions:

Asthenia; Fatigue

Post-Marketing Adverse Reactions:

The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC), then by preferred term in order of decreasing severity.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

BLOOD AND LYMPHATIC SYSTEM DISORDERS: Carboxyhemoglobin increased

IMMUNE SYSTEM DISORDERS: Anaphylactic reaction

METABOLISM AND NUTRITION DISORDERS: Hyperkalemia in patients with underlying myopathies

PSYCHIATRIC DISORDERS: Withdrawal syndrome (following multi-day exposure; symptoms include seizure, hallucination, ataxia, agitation, confusion)

NERVOUS SYSTEM DISORDERS: Brain edema, Intracranial pressure increased, Migraine, Myoclonus, Nystagmus, Pupils unequal, Headache

CARDIAC DISORDERS: Cardiac arrest, Ventricular fibrillation, Torsade de pointes, Myocardial infarction, Myocardial ischemia, Atrioventricular block complete, Atrioventricular block second degree, Atrial fibrillation, Electrocardiogram QT prolonged, Atrioventricular block first degree, Ventricular tachycardia, Ventricular extrasystoles, Tachycardia, Bradycardia, Cardiac output decreased

VASCULAR DISORDERS: Flushing

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Apnea, Hypoxia, Bronchospasm, Airway obstruction, Respiratory depression, Hypercapnia, Stridor, Hiccough

GASTROINTESTINAL DISORDERS: Pancreatitis

HEPATOBILIARY DISORDERS: Hepatic necrosis, Hepatic failure, Hepatitis fulminant, Cholestatic hepatitis, Hepatitis, Hepatic steatosis, Jaundice, Gamma- glutamyltransferase increased

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Rash

MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS: Rhabdomyolysis

RENAL AND URINARY DISORDERS: Acute renal failure**, Oliguria**

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Malignant hyperthermia, hypothermia

INJURY, POISONING, AND PROCEDURAL COMPLICATIONS*: Unwanted awareness during anesthesia; Dyspnea, Bronchospasm, Stridor, Cough, Dizziness, Paresthesia, Hepatic reactions, Flushing, Rash, Contact dermatitis, Erythema, Periorbital edema, Eye irritation, Conjunctival hyperemia, Headache

*All reactions categorized within this SOC, with the exception of, Unwanted awareness during anesthesia, were from occupational exposure in non-patients.

**Cases of acute renal failure and oliguria have been reported after isoflurane anesthesia. These events may be secondary to hypotension or other effects of isoflurane.

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