4.1. Therapeutic indications

Cocaine Hydrochloride Solution is indicated to provide local anaesthesia and vasoconstriction of accessible mucous membranes prior to surgery especially in the oral, laryngeal, and nasal cavities. Vasoconstriction prevents excessive blood loss and reduces obstruction/restriction of the operative field.

4.2. Posology and method of administration

For topical use only. Not for injection or to be taken.

The maximum total dose recommended for application to the mucosa in fit adults is 1.5mg/Kg.

It should be used only by those skilled in the precautions needed to minimise absorption and the consequent risk of arrhythmias.(see section on Precautions)

Method of Administration

Adults

Prime the pump dispenser by activating the pump 3 times.

The concentration of the cocaine hydrochloride solution is 100mg/ml. The dispenser contains only 2.5ml of solution.

One spray delivers 130µl of solution (containing 13mg of Cocaine). Therefore, a maximal dose of 1.5mg/Kg of cocaine (approx. 1ml of 10% solution), is equivalent to approximately 8-9 sprays for a 70Kg adult, and this dose must not be exceeded.

Any remaining solution should be returned to the pharmacy.

Children

Cocaine hydrochloride solution should not be administered to children .

Elderly

Cocaine hydrochloride solution should not be administered to the elderly .

Indications from some studies of medicinal cocaine show that death can ensue from 0.8-1.0g (8-10ml of a 10% w/v solution of cocaine).

Some persons have a cocaine idiosyncrasy and death may occur quite suddenly after doses of only 20mg.

The patient must be monitored for any signs or symptoms of toxicity during and after administration of cocaine. The appropriate treatment must be available and medical equipment must be ready for use at all times.

4.3. Contraindications

Cocaine hydrochloride is largely (90%) metabolised by cholinesterase, thus those patients taking cholinesterase inhibitors such as Ecothiopate eye drops for the treatment of glaucoma, or neostigmine for the treatment of Myasthenia Gravis, or those patients with hereditary Pseudocholinesterase deficiency, should not be administered cocaine hydrochloride. If these patients are given cocaine hydrochloride, higher blood levels result, with a greater risk of drug toxicity.

Adrenaline is believed to enhance the toxic effects of cocaine by further increasing the level of circulating catecholamines, and thus should not be used in association. Other sympathomimetic drugs are thus also contra-indicated. Cocaine hydrochloride's use is also contra-indicated in patients receiving α-modifying drugs such as guanethidine sulphate, reserpine and tricyclic anti-depressants; as these drugs also increase the activity of the sympathetic nervous system.

Cocaine is contra-indicated in patients with epilepsy because it lowers the seizure threshold.

Cocaine should be avoided in Porphyria, as it has been shown to be porphyrinogenic in animals or in vitro systems, thus exacerbating the disorder.

4.4. Special warnings and precautions for use

Indications from some studies of medicinal cocaine show that death can ensue from 0.8-1.0g (8-10ml of a 10% w/v solution of cocaine).

Some persons have a cocaine idiosyncrasy and death may occur quite suddenly after doses of only 20mg.

Cocaine should not be applied to damaged mucosa or open wounds because of the risk of systemic toxicity from enhanced absorption.

Cocaine should be used with caution in patients with hypertension, cardiovascular disease or thyrotoxicosis because the vasoconstriction and tachycardia may reduce cardiac oxygenation while increasing oxygen demand It should also be used with caution in patients with diabetes because cocaine sensitises the person to adrenaline which mobilises glucose and causes blood glucose levels to go out of control.

At high doses cocaine depresses the respiratory centres and thus should be cautiously employed in combination with other respiratory depressants (e.g. opiates, barbiturates, alcohol).

The use of cocaine in the elderly is not recommended because of the risk of vasoconstriction and tachycardia. Cocaine is also not recommended in children, or in pregnancy or lactation.

Overall, the patient's condition, the appropriate dose and method of administration must all be considered prior to the application of cocaine. The initial signs and symptoms of cocaine toxicity and the appropriate treatment required to combat toxicity must be known to the surgeon or anaesthetist.

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

Cholinesterase Inhibitors.

e.g. Ecothiopate eye drops for the treatment of Glaucoma, and neostigmine for the treatment of Myasthenia Gravis.

If these drugs are administered to patients receiving cocaine, higher blood levels result, with a greater risk of drug toxicity. (See Contra-indications)

Adrenaline and other sympathomimetics.

Adrenaline is believed to enhance the toxic effects of cocaine by further increasing the level of circulating catecholamines. (See Contra-indications)

Ephedrine is used in the treatment of reversible airways obstruction and is present in some cough linctus preparations. Amphetamines (CNS stimulants) have some similar actions to sympathomimetics..

Monoamine-Oxidase Inhibitors.

Cocaine potentiates the effects and toxicity of MAO inhibitors, e.g. phenelzine or isocarboxazid.

α-Modifying Drugs.

e.g. guanethidine sulphate and reserpine, both used in the treatment of hypertension; and tricyclic anti-depressants such as imipramine and amitriptyline. These drugs also increase the activity of the Sympathetic Nervous System, which is also increased by administration of cocaine.

Halothane.

Maintenance of anaesthesia with halothane, a volatile anaesthetic agent, may augment any interaction between cocaine and catecholamines by sensitising the myocardium. However, deeper levels of general anaesthesia inhibit adrenal release of catecholamines and may conversely decrease the potential arrhythmogenic effects.

Cholinesterase Inhibitors.

4.6. Pregnancy and lactation

Cocaine is not recommended for use during pregnancy and lactation.

Cocaine exposure early in pregnancy is reflected by cocaine and metabolite burden in the meconium, which is initially formed at the end of the first trimester, due to cocaine crossing the placenta.

Animal and autopsy studies indicate that the cocaine metabolite benzoylecgonine preferentially accumulates in foetal tissue. Recent human and animal studies suggest that the slowly eliminated metabolites of cocaine have significant physiological and behavioural properties. There is also an increased risk of spontaneous abortion and other birth complications due to vasoconstriction by cocaine increasing maternal blood pressure and reducing placental blood flow.

The following signs and symptoms are typical of babies born following cocaine use by the mother during pregnancy : irritability, inconsolability, hypertoxicity, tremulousness, hyperactive moro reflex, sneezing or yawning, lethargy, suck reflex, high pitched cry, poor feeding, poor weight gain, fever, diarrhoea, spitting or vomiting, tachypnoea, tachycardia, skin abrasions and respiratory distress. Cocaine is also excreted in breast milk.

4.7. Effects on ability to drive and use machines

Due to the pharmacological actions of cocaine, it is recommended that patients who have been administered cocaine do not drive or operate machinery.

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:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

4.8. Undesirable effects

Cocaine may cause restlessness, excitement, euphoria, garrulousness and increased motor activity. With high doses or repeated use, confusion, paranoia, hallucinations, altered tactile sensations and psychosis have been reported. Seizures can occur, perhaps due to lowering of the seizure threshold, or hyperpyrexia, or due to life threatening cardiac arrhythmias.

Cocaine directly causes a rise in body temperature by increasing heat production through stimulated muscle activity, and indirectly by causing vasoconstriction that decreases heat loss. A direct pyrogenic effect may be caused by cocaine's direct effect on thermoregulatory centres in the hypothalamic area.

Low doses of cocaine in humans do not change respiratory rate or depth, but at higher doses a CNS mediated increase in respiratory rate and decrease in tidal volume is described.

A migraine-like headache may be the result of cocaine induced vascular changes. Adrenergic stimulation may cause intensive hypertension, due to tachycardia and peripheral vasoconstriction. Cocaine increases cardiac activity, which raises oxygen demand within myocardial tissue. Other signs of adrenergic excess seen with cocaine include mydriasis, diaphoresis, tremor, hyperactive bowel sounds and hyperreflexia. Vasoconstriction due to cocaine may also produce ischaemia in the fingers, toes, spinal cord, kidneys, spleen, and intestines.

Cocaine suppresses Rapid Eye Movement (REM) sleep and total sleep. In low doses cocaine has an anorexic effect.

4.9. Overdose

The signs and symptoms of overdose must be known to the otolaryngologist or anaesthetist administering cocaine topically.

Toxicity first occurs as an overstimulated excited state. The toxic reaction may progress to convulsions, loss of consciousness, respiratory and cardiovascular depression or arrest, and death.

Toxicity may arise from any route of cocaine administration. Clinically, otolaryngologists reported a higher percentage of untoward reactions when cocaine was applied to the tracheobronchial tree rather than the nasal mucosa.

Symptoms of acute toxicity include delirium, tremor, massive convulsions and a direct cardiotoxic effect due to its sympathomimetic effect.

Controlled clinical studies have been performed examining the dose-response effects from intranasal (snorting) administration of cocaine. At 10mg no observable subjective or physiological effects were apparent; at 25mg there was an increase in systolic blood pressure and mild euphoria reported as relaxation; at 100mg, heart rate and diastolic blood pressure were increased and a strong feeling of euphoria was present. These effects were short-lasting and lethargy and irritability as an after-effect were reported by a few subjects within one hour after a cocaine administration.

The LD50 (lethal dose that is fatal in 50% of cases) of cocaine in adults is estimated to be 500mg after oral administration.

A fatal dose of cocaine is about 0.8-1g for an adult. This is the amount contained in 8-10ml of a 10% w/v cocaine solution. This must be emphasised in order to appreciate the potency and danger of this cocaine solution.

On an acute basis, cocaine can prolong the time to reach orgasm in men and women.

Cocaine use by pregnant women can interfere with gestation and produce abnormalities, possibly permanent, in their children. (See Pregnancy And Lactation)

At clinical doses, cocaine has little general toxicity, when applied locally and for a short period of time.

Treatment of Overdose :

If a cocaine-impregnated pledget is still in the nose when toxicity occurs, it must be promptly removed. Seizures, and cardiovascular and respiratory collapse in the late stages have been treated with respiratory support, anti-convulsants, and cardiotonic drugs.

The treatment of acute poisoning by cocaine should include the removal of any remaining drug from the mucosal surface by rinsing with tap water or normal saline.

In a medical setting where cocaine is used, positive-pressure breathing equipment should be functional and easily accessible, and intravenous diazepam should be immediately available.

Intravenous pentobarbital is a more stable preparation; it is slower acting but can be used if diazepam is not available.

Steps in the Management of Cocaine Overdose.

Prevent convulsion :

At first sign of excitability (talkative stage), administer:

diazepam injectable 5mg/ml 1-2ml intravenously in patients aged 5 years to adult

Hypertension :

labetalol, phentolamine or sodium nitroprusside (not propranolol since it potentiates cocaine toxicity - see below*)

Psychiatric reactions :

Delusions may respond to neuroleptics (phenothiazine and butyrophenone) but these agents also may increase the chance of seizures; benzodiazepines may be useful in reducing anxiety.

Respiratory support :

After convulsion or if apnoeic or if Cheyne-Stokes respiration:

Positive pressure ventilation - mouth to mouth, bag and mask, endotracheal

Cardiac resuscitation and anti-arrhythmics :

In massive overdosage

* Propranolol has been used to treat cocaine-induced hypertension and arrhythmias but, following a report of paradoxical hypertension presumably due to unopposed α-adrenergic stimulation, a beta-blocker with both α- and β-adrenergic effects such as labetalol is now preferred by some for hypertension; sodium nitroprusside, or phentolamine may also be used.

However, one must be aware that like propranolol, labetalol may worsen hypertension in patients with hyperadrenergic states, because the β-blocking properties of labetalol are much more potent than its α-blocking properties. Like propranolol, labetalol has the potential to cause a state of relatively unopposed α-effect, thereby raising the blood pressure. If such a complication ensues, treatment with a pure α-blocker such as phentolamine, or a vasodilator such as nitroprusside, diazoxide, or possibly nifedipine is indicated. It has been found that esmolol, an ultra short-acting β1 - selective adrenergic blocker with an elimination half-life of about 9 minutes, is an attractive choice for the treatment of a cocaine-induced hyperadrenergic state, because the β1 -selectivity rendered hypertension or coronary artery spasm from unopposed α-adrenergic tone is less of a risk than with non-selective β-blocking drugs.