Ketamine

The use of ketamine with other central nervous system (CNS) depressants (e.g. ethanol, phenothiazines, sedating H₁–blockers or skeletal muscle relaxants) can potentiate CNS depression and/or increase risk of developing respiratory depression. Reduced doses of ketamine may be required with concurrent administration of other anxiolytics, sedatives and hypnotics.

Sympathomimetics (directly or indirectly acting) and vasopressin may enhance the sympathomimetic effects of ketamine.

Prolonged recovery time may occur if barbiturates and/or narcotics are used concurrently with ketamine.

Ketamine is chemically incompatible with barbiturates and diazepam because of precipitate formation. Therefore, these should not be mixed in the same syringe or infusion fluid.

Drugs that induce CYP3A4 enzyme activity generally increase hepatic clearance, resulting in decreased plasma concentration of CYP3A4 substrate medications, such as ketamine. Coadministration of ketamine with drugs that induce CYP3A4 enzyme may require an increase in ketamine dosage to achieve the desired clinical outcome.

Drugs that inhibit CYP3A4 enzyme activity generally decrease hepatic clearance, resulting in increased plasma concentration of CYP3A4 substrate medications, such as ketamine. Coadministration of ketamine with drugs that inhibit CYP3A4 enzyme may require a decrease in ketamine dosage to achieve the desired clinical outcome.

Ketamine dose reductions should be considered in patients with cirrhosis or other types of liver impairment.

Ketamine is metabolised in the liver and hepatic clearance is required for termination of clinical effects. A prolonged duration of action may occur in patients with cirrhosis or other types of liver impairment. Dose reductions should be considered in these patients. Abnormal liver function tests associated with ketamine use have been reported, particularly with extended use (>3 days) or drug abuse.

Concomitant use of antihypertensive agents and ketamine increases the risk of developing hypotension.

Patients taking thyroid hormones have an increased risk of developing hypertension and tachycardia when given ketamine.

The use of halogenated anaesthetics concomitantly with ketamine can lengthen the elimination half-life of ketamine and delay recovery from anaesthesia. Concurrent use of ketamine (especially in high doses or when rapidly administered) with halogenated anaesthetics can increase the risk of developing bradycardia, hypotension or decreased cardiac output.

Ketamine may potentiate the neuromuscular blocking effects of atracurium and tubocurarine including respiratory depression with apnoea.

Diazepam is known to increase the half-life of ketamine and prolongs its pharmacodynamic effects. Dose adjustments may therefore be needed.

Concomitant use og ketamine with ergometrine may lead to an increase in blood pressure.

When ketamine and theophylline or aminophylline are given concurrently, a clinically significant reduction in the seizure threshold may be observed. Unpredictable extensor-type seizures have been reported with concurrent administration of these agents.

Ketamine has been reported to antagonise the hypnotic effect of thiopental.

Since an increase in cerebrospinal fluid (CSF) pressure has been reported during ketamine anaesthesia, ketamine should be used with special caution in patients with pre-anaesthetic elevated cerebrospinal fluid pressure.

Use with caution in patients with globe injuries and increased intraocular pressure (e.g. glaucoma) because the pressure may increase significantly after a single dose of ketamine.

Ketamine use in caution in patients with acute intermittent porphyria.

Ketamine use in caution in patients with intracranial mass lesions, a presence of head injury, or hydrocephalus.

Ketamine use in caution in patients with hyperthyroidism or patients receiving thyroid replacement (increased risk of hypertension and tachycardia).

Ketamine should be used with caution in patients with mild-to-moderate hypertension and tachyarrhythmias. Cardiac function should be continually monitored during the procedure in patients found to have hypertension or cardiac decompensation.

Cases of cystitis including haemorrhagic cystitis have been reported in patients being given ketamine on a long-term basis. This adverse reaction develops in patients receiving long term ketamine treatment after a time ranging from 1 month to several years. Ketamine is not indicated nor recommended for long term use.

Ketamine use in caution in patients with pulmonary or upper respiratory infection (ketamine sensitises the gag reflex, potentially causing laryngospasm).

Use of ketamine with caution in patients with neurotic traits or psychiatric illness (e.g. schizophrenia and acute psychosis).

Ketamine use in caution in patients with seizures.

Ketamine crosses the placenta. This should be borne in mind during operative obstetric procedures in pregnancy. No controlled clinical studies in pregnancy have been conducted. The use in pregnancy has not been established, and such use is not recommended, with the exception of administration during surgery for abdominal delivery or vaginal delivery.

Some neonates exposed to ketamine at maternal intravenous doses ≥1.5 mg/kg during delivery have experienced respiratory depression and low Apgar scores requiring newborn resuscitation.

Marked increases in maternal blood pressure and uterine tone have been observed at intravenous doses greater than 2 mg/kg.

Data are lacking for intramuscular injection and maintenance infusion of ketamine in the parturient population, and recommendations cannot be made.

The safe use of ketamine during lactation has not been established, and such use is not recommended.

Fertility

Studies in animals have shown reproductive toxicity.

Patients should be cautioned that driving a car, operating hazardous machinery or engaging in hazardous activities should not be undertaken for 24 hours or more after anaesthesia.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called ‘statutory defence’) if:
  • The medicine has been prescribed to treat a medical or dental problem and
  • You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
  • It was not affecting your ability to drive safely

The following Adverse Events have been reported: Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Not known (frequency cannot be estimated from the available data)

Immune system disorders

Rare: Anaphylactic reaction*

Metabolism and nutrition disorders

Uncommon: Anorexia

Psychiatric disorders

Common: Hallucination, Abnormal dreams, Nightmare, Confusion, Agitation, Abnormal behaviour

Uncommon: Anxiety

Rare: Delirium* Flashback*, Dysphoria*, Insomnia, Disorientation*

Nervous system disorders

Common: Nystagmus, Hypertonia, Tonic clonic movements

Eye disorders

Common: Diplopia

Not Known: Intraocular pressure increased

Cardiac disorders

Common: Blood pressure increased, Heart rate increased

Uncommon: Bradycardia, Arrhythmia

Vascular disorders

Uncommon: Hypotension

Respiratory, thoracic and mediastinal disorders

Common: Respiratory rate increased

Uncommon: Respiratory depression, Laryngospasm

Rare: Obstructive airway disorder*, Apnoea*

Gastrointestinal disorders

Common: Nausea, Vomiting

Rare: Salivary hypersecretion*

Hepatobiliary disorders

Not known: Liver function test abnormal, Drug-induced liver injury**

Skin and subcutaneous tissue disorders

Common: Erythema, Rash morbilliform

Renal and urinary disorders

Rare: Cystitis*, Haemorrhagic cystitis*

General disorders and administration site conditions

Uncommon: Injection site pain, Injection site rash

* AE frequency estimated from post-marketing safety database
** Extended period use (>3 days) or drug abuse