4.1. Therapeutic indications

Intravenous anaesthesia.

Induction of general anaesthesia and also as an adjunct to provide hypnosis during balanced anaesthesia with other anaesthetic agents, including analgesics and muscle relaxants.

As an adjunct for control of refractory convulsive disorders of various aetiology, including those caused by local anaesthetics.

Reducing the intracranial pressure in patients with increased intracranial pressure, if controlled ventilation is provided.

4.2. Posology and method of administration

Posology

Using of thiopental is reserved only for health care personnel trained in anaesthesiology. A person qualified in the use of anaesthetics should be constantly available during the administration of the medicinal product.

After continuous administration of thiopental the effect duration is prolonged, personnel qualified in the use of anaesthetics should be constantly available during the administration of the medicinal product.

A normal adult dose for induction of anaesthesia is 4-6 mg/kg body weight, but the individual response to the drug is so varied that there can be no fixed dosage. The drug should be titrated against patient requirements as governed by age, sex, body weight and the patient's general condition. The dose should usually be reduced and carefully titrated in patients with a poor general condition. Younger patients require relatively larger doses than middle-aged and elderly persons; the latter metabolize the drug more slowly. Pre-puberty requirements are the same for both sexes, but adult females require less than adult males. Dose is usually proportional to body weight and obese patients require a larger dose than relatively lean persons of the same weight.

Test dose

It is advisable to inject a small intravenous ''test'' dose of 25 to 75 mg (1 to 3 ml of a 2,5% solution) to assess tolerance or unusual sensitivity to thiopental and pausing to observe patient reaction for at least 60 seconds. If unexpectedly deep anaesthesia develops or if respiratory depression occurs, consider these possibilities:

1. The patient may be unusually sensitive to thiopental.

2. The solution may be more concentrated than had been assumed.

3. The patient may have received too much premedication.

If the test dose results in local or regional pain, extravasal or intraarterial administration should be suspected (see section 4.4).

Use in anaesthesia

Moderately slow induction can usually be accomplished in a healthy female or male adult weighing 60-80 kg by injection of 50 to 75 mg of thiopental at intervals of 20 to 40 seconds, depending on the reaction of the patient. Once anaesthesia is established, additional injections of 25 to 50 mg can be given whenever the patient moves. Slow injection is recommended to minimize respiratory depression and the possibility of overdosage.

The smallest dose consistent with attaining the surgical objective is the desired goal. Momentary apnea following each injection is typical, and progressive decrease in the amplitude of respiration appears with increasing dosage. Pulse remains normal or increases slightly and returns to normal.

Muscles usually relax about 30 seconds after unconsciousness is attained, but this may be masked if a skeletal muscle relaxant is used.

The tone of jaw muscles is a fairly reliable index. The pupils may dilate but later contract.

Sensitivity to light is not usually lost until a level of anaesthesia deep enough to permit surgery is attained. Nystagmus and divergent strabismus are characteristic during early stages, but at the level of surgical anaesthesia, the eyes are central and fixed. Corneal and conjunctival reflexes disappear during surgical anaesthesia.

When thiopental is used as the sole anaesthetic agent, the desired level of anesthesia can be maintained by injection of small repeated doses as needed or by using a continuous intravenous infusion with a 0.2% or 0.4% concentration (see section 6.6).

With continuous infusion, the depth of anaesthesia is controlled by adjusting the rate of infusion.

Paediatric population

The doses are recommended for healthy paediatric population, and doses may have to be adjusted depending on for example concomitant illness, preanaesthesia.

Newborns

IV 3 to 4 mg/kg then 1 mg/kg as needed

Infants

IV 5 to 8 mg/kg then 1 mg/kg as needed.

Children

IV 5 to 6 mg/kg then 1 mg/kg as needed.

The suggested paediatric dosage categories are only indicative of required doses. Actual dosing must be individualized and titrated to effect based on age, maturity and the general condition of the paediatric patient.

Use in convulsive states

75 mg to 125 mg (3mls to 5mls of a 2.5% w/v solution) should be given as soon as possible after the convulsion begins. Further doses may be required to control convulsions following the use of a local anaesthetic. Other regimens, such as the use of intravenous or rectal diazepam, may be used to control convulsive states.

Paediatric population

Intravenously 2 mg/kg initially and then individually titrated until satisfactorily clinical effect has been established. A maximum dose of 5 mg/kg/h should not be exceeded.

Use in neurological patients with raised intracranial pressure

Intermittent bolus injections of 1.5 to 3mg/kg of bodyweight may be given to reduce elevations of intracranial pressure if controlled ventilation is provided.

Paediatric population

The safety of thiopental in paediatric populations to treat raised intracranial pressure has not yet been established.

Hepatic impairment

Reduced dose should be used in patients with hepatic impairment (see section 4.4).

Renal impairment

Thiopental should be used with caution in patients with renal impairment (see section 4.4).

Method of administration

Thiopental Injection must only be administered by the intravenous route. Care should be taken to ensure intravenous administration (see section 4.4). For instructions on dilution of the medicinal product before administration, see section 6.6. Infusion should only be given through a central venous catheter.

4.3. Contraindications

Hypersensitivity to the active substance, other barbiturates or to any of the excipients listed in section 6.1.

Thiopental is contra-indicated in respiratory obstruction, acute asthma, severe shock and dystrophia myotonica. Administration of any barbiturate is contra-indicated in porphyria.

4.4. Special warnings and precautions for use

Thiopental may cause addiction.

Keep endotracheal intubation equipment, oxygen and resuscitative equipment readily available.

Caution must be taken in patients with increased intracranial pressure or asthma.

If used under these conditions reduce dosage and administer slowly.

Use in neurological patients with raised intracranial pressure

Thiopental has been associated with reports of severe or refractory hypokalaemia during infusion; severe rebound hyperkalaemia may occur after cessation of thiopental infusion. The potential for rebound hyperkalaemia should be taken into account when stopping thiopental therapy.

Caution must be taken in patients with potential airway compromise, such as conditions involving inflammation in the mouth, jaw and throat.

Cardiorespiratory depression

Thiopental sodium causes respiratory depression and a reduction in cardiac output and may precipitate acute circulatory failure in patients with cardiovascular disease, particularly constrictive pericarditis. Care should also be exercised with severe cardiovascular diseases, severe respiratory diseases and hypertension of various aetiology.

When particular caution is required

Special care is needed in administering thiopental sodium to patients with the following conditions:- hypovolaemia, severe haemorrhage, burns, cardiovascular disease, myasthenia gravis, adrenocortical insufficiency (even when controlled by cortisone), cachexia, raised intracranial pressure and raised blood urea.

Dose reduction required

Reduced doses are recommended in shock, dehydration, severe anaemia, hyperkalaemia, toxaemia, metabolic disorders e.g. thyrotoxicosis, myxoedema and diabetes.

Increased doses

Increased doses may be necessary in patients who have either a habituation or addiction to alcohol or drugs of abuse. Under these circumstances it is recommended that supplementary analgesic agents are used.

Hepatic impairment

Thiopental sodium is metabolised primarily by the liver so doses should be reduced in patients with hepatic impairment.

Renal impairment

Barbiturate anaesthetics should be used with caution in severe renal disease. Reduced doses are also indicated in the elderly and in patients who have been premedicated with narcotic analgesics.

Use in underlying disease

Patients taking long-term medications such as acetylsalicylic acid, oral anticoagulants, oestrogens, MAOIs and lithium may need to adjust the dose or stop therapy prior to elective surgery. Patients with diabetes or hypertension may need to adjust their therapy before anaesthesia (see section 4.5).

Thiopental concentrations less than 2.0 % can cause hemolysis.

Extravascular infiltration:

Extravascular injection should be avoided. Care should be taken to ensure that the needle is within the lumen of the vein before intravenous injection of Thiopental. Extravascular injection may cause chemical irritation of the tissues varying from slight tenderness to venospasm, extensive necrosis, severe pain and sloughing. This is due primarily to the high alkaline pH (10 to 11) of clinical concentrations of the drug. If extravasation occurs, the local irritant effects can be reduced by injection of 1% lidocaine locally to relieve pain and enhance vasodilatation. Local application of heat also may help to increase local circulation and removal of the infiltrate (see section 4.8).

Intra-arterial injection:

Intra-arterial injection can occur inadvertently, especially if an aberrant superficial artery is present at the medial aspect of the antecubital fossa. The area selected for intravenous injection of the drug should be palpated for detection of an underlying pulsating vessel. Accidental intra-arterial injection may cause arteriospasm and severe pain along the course of the artery with blanching of the arm and fingers. Appropriate corrective measures should be instituted promptly to avoid possible development of gangrene. Methods suggested for dealing with this complication vary with the severity of symptoms (see section 4.8).

The following have been suggested (controlling investigations are missing):

1. Dilute the injected Thiopental by removing the tourniquet and any restrictive garments.

2. Leave the intravenous cannula in place, if possible.

3. Inject the artery with a dilute solution of papaverine, or lidocaine, to inhibit smooth muscle spasm.

4. If necessary, perform sympathetic block of the brachial plexus and/or stellate ganglion to relieve pain and assist in opening collateral circulation. Papaverine can be injected into the subclavian artery,if desired.

5. Unless otherwise contraindicated, treat with heparin to prevent thrombus formation.

6. Consider local infiltration of an alpha-adrenergic blocking agent such as phentolamine into the vasospastic area.

7. Provide additional symptomatic treatment as required.

Thiopental Injection contains sodium:

This medicinal product contains 51-56 mg (or 2.2-2.4 mmol) sodium per dose of 0.5 g vial and 102-112 mg (or 4.4-4.9 mmol) sodium per dose of 1 g vial, equivalent to 2.8 % (0.5 g vial) and 5.6 % (1 g vial) of the WHO recommended maximum daily intake of 2g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Thiopental sodium has been shown to interact with sulphafurazole. Reduced initial doses may be required to achieve adequate anaesthesia, but repeat doses may also be necessary to maintain anaesthesia.

Gastrointestinal drugs: Metoclopramide and droperidol reduce the dose of thiopental sodium required to induce anaesthesia.

The use of anaesthetics with other CNS depressant drugs such as those used for premedication may produce synergistic effects on the CNS and, in some cases, a smaller dose of general anaesthetic should be used. Bradycardia occurring during anaesthetic induction with thiopental has been reported in patients also receiving fentanyl.

Benzodiazepines: Midazolam potentiates the anaesthetic effects of thiopental sodium.

Probenecid: Pretreatment with probenecid has been shown to potentiate thiopental sodium anaesthesia.

Angiotensin-II receptor antagonists: Enhanced hypotensive effect when general anaesthetics given with angiotensin-II receptor antagonists.

Antibacterials: General anaesthetics possibly potentiate hepatotoxicity of isoniazid; effects of thiopental sodium enhanced by sulphonamides; hypersensitivity-like reactions can occur when general anaesthetics given with intravenous vancomycin.

Antidepressants: Increased risk of arrhythmias and hypotension when general anaesthetics given with tricyclic antidepressants. Hypotension and hypertension have been seen with MAOIs.

Antipsychotics: Patients being treated with phenothiazine antipsychotics may experience increased hypotension. Some phenothiazines, especially promethazine, may also increase the incidence of excitatory phenomena produced by barbiturate anaesthetics; cyclizine may possibly have a similar effect. The sedative properties may be also potentiated by thiopental sodium.

Diazoxide: Enhanced hypotensive effect when general anaesthetics given with diazoxide.

Diuretics: Enhanced hypotensive effect when general anaesthetics given with diuretics.

Methyldopa: Enhanced hypotensive effect when general anaesthetics given with methyldopa.

Moxonidine: Enhanced hypotensive effect when general anaesthetics given with moxonidine.

Nitrates: Enhanced hypotensive effect when general anaesthetics given with nitrates.Vasodilator antihypertensives: Enhanced hypotensive effect when general anaesthetics given with hydralazine, minoxidil or nitroprusside.

It should be noted that thiopental will interact with beta-blockers and calcium antagonists causing a fall in blood pressure.

ACE inhibitors: Enhanced hypotensive effect when general anaesthetics given with ACE inhibitors.

Adrenergic neuron blockers: Enhanced hypotensive effect when general anaesthetics given with adrenergic neurone blockers.

Alpha-blockers: Enhanced hypotensive effect when general anaesthetics given with alpha-blockers.

Herbal medicines: Animal data suggest valerian and St John's Wort may prolong the effect of thiopental sodium.

Analgesics: Pretreatment with aspirin has been shown to potentiate thiopental sodium anaesthesia. Opioid analgesics can potentiate the respiratory depressant effect of barbiturate anaesthetics and the dose of anaesthetic may need to be reduced. The analgesic effect of pethidine can be reduced by thiopental sodium.

Opioids potentiate the respiratory depressive effect. The effect is enhanced by alcohol, hypnotics, central acting muscle relaxants, anxiolytics, antipsychotics and antihistamines.

Thiopental interacts with opioid analgesics (decreased sensibility to pain) and sufentanile (decrease dose dependently the need of barbiturates at induction of anaesthesia). Increased doses may be necessary in patients with alcohol- or narcotics misuse.

Pharmacokinetic interactions

Concomitant use of barbiturates and quetiapine may result in a reduced serum concentration of quetiapine.

Barbiturates increase by enzyme induction the elimination of androgens, some antiepileptics, felodipin, glucocorticoids, metronidazol, peroral anticoagulants and oestrogens and thereby decrease the plasmaconcentration of these substances.

Barbiturates inhibit the hypoglycaemic effect of peroral antidiabetics (sulfonyl-urine substances).

Barbiturates inhibit the effect of bronchodilators (aminophylline).

4.6. Fertility, pregnancy and lactation

Pregnancy

It has been shown that thiopental can be used without adverse effects during pregnancy. However, when considering use of thiopental the clinician should only use the drug when the expected benefits outweigh any potential risks.

Breast-feeding

Thiopental readily crosses the placental barrier and appears in breast milk. Therefore, breast-feeding should be temporarily suspended (for at least 12 hours) or breast milk expressed before the induction of anaesthesia.

Fertility

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

4.7. Effects on ability to drive and use machines

Thiopental has major influence on the ability to drive and use machines. Even though the recovery after use of Thiopental is rapid; post-operative vertigo, disorientation and sedation may be prolonged and out-patients given thiopental should therefore be advised not to drive or use machinery especially within the first 24 to 36 hours.

4.8. Undesirable effects

The frequencies of adverse events are ranked according to the following:

Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100, rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

System Organ Class

Common (≥1/100 to <1/10)

Rare (≥1/10,000 to <1/1,000)

Not known (cannot be estimated from the available data)

Immune system disorders

Allergic reactions

Anaphylactic reaction

Skin reactions

Hypersensitivity

Metabolism and nutrition disorders

Hypokalaemia

Hyperkalaemia

Anorexia

Nervous system disorders

Somnolence

Delayed wakening

Headache

Dizziness

Cardiac disorders

Heart arrythmia

Myocardial depression

Hypotension

Respiratory, thoracic and mediastinal disorders

Respiratory depression

Bronchospasm

Laryngospasm

Coughing

Snoring

General disorders and administration site conditions

Shivering

Anaphylactoid reactions (urticaria, bronchospasm, fall in blood pressure and angioedema)

Malaise

Fatigue

Immune hemolytic anemia with renal failure and paralysis of nervus radialis have been reported in rare cases. Reactions which may be caused by the diluent, preparation - or solving technique or by administration of prepared solutions with thiopenthal sodium include fever, venous thrombosis or phlebitis at the injection site, and events after extravasal injection.

Laryngeal spasm may occur, together with coughing or sneezing, during the induction procedure. For this reason it is not advised to use thiopental sodium alone for peroral endoscopy.

Excessive doses are associated with hypothermia and profound cerebral impairment.

Postoperative vomiting is infrequent, but shivering may occur and there may be persistent drowsiness, confusion and amnesia.

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 website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

Overdosage may occur from too rapid or repeated injections. Too rapid injection may be followed by an alarming fall in blood pressure and shock. Apnea may occur in connection with too excessive or too rapid injections. Also laryngospasm, coughing and other respiratory difficulties may occur, but may also be a sign of subdosing (reflex induced).

Management

In the event of suspected or apparent overdosage, the drug should be discontinued. A patent airway should be secured. Oxygenation and ventilation should be monitored and supported as needed. The circulation should be monitored and supported as needed.