Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Largactil injection is a phenothiazine neuroleptic. It is indicated in the following conditions:

- Schizophrenia and other psychoses (especially paranoid) mania and hypomania.

- Anxiety, psychomotor agitation, excitement, violent or dangerously impulsive behaviour. Largactil is used as an adjunct in the short-term treatment of these conditions.

- Intractable hiccup.

- Nausea and vomiting of terminal illness (where other drugs have failed or are not available).

- Induction of hypothermia is facilitated by Largactil which prevents shivering and causes vasodilation.

- Childhood schizophrenia and autism.

Adult Dosage

Route of administration: Deep intramuscular injection.

Oral route administration should be used wherever possible.

Parenteral formulations may be used in emergencies. They may only be administered by deep intramuscular injection. Largactil is too irritant to give subcutaneously. Repeated injections should be avoided if possible.

ADULTS: A single deep intramuscular injection of 25-50mg followed by oral therapy will suffice in many cases, but the intramuscular dose may be repeated if required at 6 to 8 hour intervals. As soon as possible oral administration should be substituted.

ELDERLY: Should be started on half or even quarter of the adult dosage.

Dosage of chlopromazine in schizophrenia, other psychoses, anxiety and agitation, childhood schizophrenias and autism:

Hiccup, induction of hypothermia to prevent shivering:

Nausea and vomiting of terminal illness:

Child Dosage

Contra Indications

Liver or renal dysfunction, cardiac failure, epilepsy, parkinsonism, hypothyroidism, prostatic hypertrophy, narrow angle glaucoma, elderly, phaeochromocytoma, myasthenia gravis.

Special Precautions

Largactil should be avoided in patients with liver or renal dysfunction, Parkinson's disease, hypothyroidism, cardiac failure, phaeochromocytoma, myasthenia gravis and prostate hypertrophy. It should be avoided in patients known to be hypersensitive to phenothiazines or with a history of narrow angle glaucoma or agranulocytosis. It should be used with caution in the elderly, particularly during very hot or cold weather (risk of hyper-, hypothermia). The elderly are particularly susceptible to postural hypotension.

Postural hypotension with tachycardia as well as local pain or nodule formation may occur after intramuscular administration. The patient should be kept supine and blood pressure monitored when receiving parenteral chlorpromazine. The elderly are particularly susceptible to postural hypotension.

Close monitoring is required in patients with epilepsy or a history of seizures, as phenothiazines may lower the seizure threshold.

As agranulocytosis has been reported, regular monitoring of the complete blood count is recommended. The occurrence of unexplained infections or fever may be evidence of blood dyscrasia, and requires immediate haematological investigation.

It is imperative that treatment be discontinued in the event of unexplained fever, as this may be a sign of neuroleptic malignant syndrome (pallor, hyperthermia, autonomic dysfunction, altered consciousness, muscle rigidity). Signs of autonomic dysfunction, such as sweating and arterial instability, may precede the onset of hyperthermia and serve as early warning signs. Although neuroleptic malignant syndrome may be idiosyncratic in origin, dehydration and organic brain disease are predisposing factors.

Acute withdrawal symptoms, including nausea, vomiting and insomnia, have very rarely been reported following the abrupt cessation of high doses of neuroleptics. Relapse may also occur, and the emergence of extrapyramidal reactions has been reported. Therefore, gradual withdrawal is advisable.

In schizophrenia, the response to neuroleptic treatment may be delayed. If treatment is withdrawn, the recurrence of symptoms may not become apparent for some time.

Neuroleptic phenothiazines may potentiate QT interval prolongation which increases the risk of onset of serious ventricular arrhythmias of the torsade de pointes type, which is potentially fatal (sudden death). QT prolongation is exacerbated, in particular, in the presence of bradycardia, hypokalaemia, and congenital or acquired (i.e. drug induced) QT prolongation. The risk-benefit should be fully assessed before Largactil treatment is commenced. If the clinical situation permits, medical and laboratory evaluations (e.g. biochemical status and ECG) should be performed to rule out possible risk factors (e.g. cardiac disease; family history of QT prolongation: metabolic abnormalities such as hypokalaemia, hypocalcaemia or hypomagnesaemia; starvation; alcohol abuse; concomitant therapy with other drugs known to prolong the QT interval) before initiating treatment with Largactil and during the initial phase of treatment, or as deemed necessary during the treatment.

Avoid concomitant treatment with other neuroleptics.

Stroke: In randomised clinical trials versus placebo performed in a population of elderly patients with dementia and treated with certain atypical antipsychotic drugs, a 3-fold increase of the risk of cerebrovascular events has been observed. The mechanism of such risk increase is not known. An increase in the risk with other antipsychotic drugs or other populations of patients cannot be excluded. Largactil should be used with caution in patients with stroke risk factors.

As with all antipsychotic drugs, Largactil should not be used alone where depression is predominant. However, it may be combined with antidepressant therapy to treat those conditions in which depression and psychosis coexist.

Because of the risk of photosensitisation, patients should be advised to avoid exposure to direct sunlight.

In those frequently handling preparations of phenothiazines, the greatest care must be taken to avoid contact of the drug with the skin.

Interactions

Adrenaline must not be used in patients overdosed with Largactil.

The CNS depressant actions of Largactil and other neuroleptic agents may be intensified (additively) by alcohol, barbiturates and other sedatives. Respiratory depression may occur.

Anticholinergic drugs may reduce the antipsychotic effect of Largactil and the mild anticholinergic effect of Largactil may be enhanced by other anticholinergic drugs possibly leading to constipation, heat stroke, etc.

Some drugs interfere with absorption of neuroleptic agents: antacids, anti-Parkinson drugs and lithium.

Documented adverse clinically significant interactions occur with alcohol, guanethidine and hypoglycaemic agents.

Where treatment for neuroleptic-induced extrapyramidal symptoms is required, anticholinergic antiparkinsonian agents should be used in preference to levodopa, since neuroleptics antagonise the antiparkinsonian action of dopaminergics.

High doses of Largactil reduce the response to hypoglycaemic agents the dosage of which might have to be raised.

The hypotensive effect of most antihypertensive drugs especially alpha adrenoceptor blocking agents may be exaggerated by Largactil.

The action of some drugs may be opposed by Largactil; these include amphetamine, levodopa, clonidine, guanethidine and adrenaline.

Increases or decreases in the plasma concentrations of a number of drugs, e.g. propranolol Phenobarbital have been observed but were not of clinical significance.

Simultaneous administration of desferrioxamine and prochlorperazine has been observed to induce a transient metabolic encephalopathy characterised by loss of consciousness for 48-72 hours. It is possible this may occur with Largactil since it shares many of the pharmacological properties of prochlorperazine.

There is an increased risk of arrhythmias when neuroleptics are used with concomitant QT prolonging drugs (including certain antiarrhythmics, antidepressants and other antipsychotics) and drugs causing electrolyte imbalance.

There is an increased risk of agranulocytosis when neuroleptics are used concurrently with drugs with myelosuppressive potential, such as carbamazepine or certain antibiotics and cytotoxics.

In patients treated concurrently with neuroleptics and lithium, there have been rare reports of neurotoxicity.

Adverse Reactions

Generally, adverse reactions occur at low frequency; the most common reported adverse reactions are nervous system disorders.

Blood and lymphatic system disorders: A mild leucopaenia occurs in up to 30% of patients on prolonged high dosage. Agranulocytosis may occur rarely; it is not dose related.

Immune system disorders: Allergic phenomena such as angiodema, bronchospasm, and urticaria have occurred with phenothiazines but anaphylactic reactions have been exceedingly rare. In very rare cases, treatment with chlorpromazine may be associated with systemic lupus erythematosus.

Endocrine: Hyperprolactinaemia which may result in galactorrhoea, gynaecomastia, amenorrhoea and impotence.

Nervous system disorders: Acute dystonias or dyskenias, usually transitory are more common in children and young adults and usually occur within the first 4 days of treatment or after dosage increases.

Akathisia characteristically occurs after large initial doses.

Parkinsonism is more common in adults and the elderly. It usually develops after weeks or months of treatment. One or more of the following may be seen: tremor, rigidity, akinesia or other features of Parkinsonism. Commonly just tremor.

Tardive Dyskinesia: If this occurs it is usually, but not necessarily, after prolonged high dosage. It can even occur after treatment has been stopped. Dosage should therefore be kept low whenever possible.

Insomnia and agitation may occur.

Eye disorders: Ocular changes and the development of a metallic greyish-mauve coloration of exposed skin have been noted in some individuals, mainly females, who have received chlorpromazine continuously for long periods (four to eight years).

Cardiac disorders: ECG changes include QT prolongation (as with other neuroleptics), ST depression, U-Wave and T-Wave changes. Cardiac arrhythmias, including ventricular arrhythmias and atrial arrhythmias, a-v block, ventricular tachycardia, which may result in ventricular fibrillation or cardiac arrest have been reported during neuroleptic phenothiazine therapy, possibly related to dosage. Pre-existing cardiac disease, old age, hypokalaemia and concurrent tricyclic antidepressants may predispose.

There have been isolated reports of sudden death, with possible causes of cardiac origin, as well as cases of unexplained sudden death, in patients receiving neuroleptic phenothiazines.

There have been isolated reports of sudden death, with possible causes of cardiac origin, as well as cases of unexplained sudden death, in patients receiving neuroleptic phenothiazines.

Vascular disorders: Hypotension, usually postural, commonly occurs. Elderly or volume depleted subjects are particularly susceptible: it is more likely to occur after intramuscular administration.

Gastrointestinal disorders: dry mouth may occur.

Respiratory, thoracic and mediastinal disorders: Respiratory depression is possible in susceptible patients. Nasal stuffiness may occur.

Hepato-biliary disorders: Jaundice, usually transient, occurs in a very small percentage of patients taking chlorpromazine. A premonitory sign may be a sudden onset of fever after one to three weeks of treatment followed by the development of jaundice. Chlorpromazine jaundice has the biochemical and other characteristics of obstructive (cholestatic) jaundice and is associated with obstructions of the canaliculi by bile thrombi; the frequent presence of an accompanying eosinophilia indicates the allergic nature of this phenomenon. Liver injury, sometimes fatal, has been reported rarely in patients treated with chlorpromazine. Treatment should be withheld on the development of jaundice.

Skin and subcutaneous tissue disorders: Contact skin sensitisation may occur rarely in those frequently handling preparations of chlorpromazine. Skin rashes of various kinds may also be seen in patients treated with the drug. Patients on high dosage may develop photosensitivity in sunny weather and should avoid exposure to direct sunlight.

Reproductive system and breast disorders: Priapism has been very rarely reported in patients treated with chlorpromazine.

General disorders and administration site conditions: Neuroleptic malignant syndrome (hyperthermia, rigidity, autonomic dysfunction and altered consciousness) may occur.

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