Chlorpromazine

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

Morphine derivatives (analgesics, antitussives and substitution treatments), barbiturates, benzodiazepines, anxiolytics other than benzodiazepines, antihypertensive agents increased central depression. Respiratory depression may occur. Changes in alertness can make it dangerous to drive or operate machinery.

Administration of chlorpromazine with CYP1A2 inhibitors, in particular strong or moderate inhibitors may lead to an increase of chlorpromazine plasma concentrations. Therefore patients may experience a chlorpromazine dose-dependent adverse drug reaction.

Imipramine antidepressants, histamine H₁-receptor antagonists, anticholinergic, antiparkinsonism agents, atropinic antispasmodics, disopyramide: build up of atropine-associated adverse effects such as urinary retention, constipation and dry mouth.

Alcohol potentiates the sedative effect of neuroleptics. Changes in alertness can make it dangerous to drive or operate machinery. Alcoholic beverages and medication containing alcohol should be avoided

Decreased GI absorption of phenothiazine neuroleptics. Do not administer phenothiazine neuroleptics simultaneously with topical GI agents (administer more than 2 hours apart if possible).

Concomitant administration of high chlorpromazine doses (100 mg/day), and antidiabetic agents can lead to an increase in blood sugar levels (decreased insulin release). Forewarn the patient and advise increased self-monitoring of blood and urine levels. If necessary, adjust the antidiabetic dosage during and after discontinuing neuroleptic treatment.

Potentiation of the antihypertensive effect and risk of orthostatic hypotension (additive effects). Phenothiazines enhance the hypotensive effect of anaesthetics and calcium channel blockers. Severe postural hypotension may occur with concomitant administration of chlorpromazine and ACE inhibitors.

Dopaminergic antiparkinsonism agents (amantadine, bromocriptine, cabergoline, levodopa, lisuride, pergolide, piribedil, ropinirole) are not recommended: reciprocal antagonism of the antiparkinsonism agent and neuroleptic. Neuroleptic-induced extrapyramidal syndrome should be treated with an anticholinergic rather than a dopaminergic antiparkinsonism agent (dopaminergic receptors blocked by neuroleptics).

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

A decrease in fertility was observed in female animals treated with chlorpromazine. In male animals data are insufficient to assess fertility.

In humans, because of the interaction with dopamine receptors, chlorpromazine may cause hyperprolactinaemia which can be associated with impaired fertility in women. In men, data on consequences of hyperprolactinaemia are insufficient with regard to fertility.

Simultaneous administration of deferoxamine 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 chlorpromazine since it shares many of the pharmacological properties of prochlorperazine.

Reciprocal antagonism of levodopa and the neuroleptic. In Parkinson’s patients, it is recommended to use the minimal doses of each drug.

Concomitant use can cause confusional syndrome, hypertonia and hyperreflexivity, occasionally with a rapid increase in serum concentrations of lithium.

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. If the clinical situation permits, medical and laboratory evaluations should be performed to rule out possible risk factors before initiating treatment with a neuroleptic agent and as deemed necessary during treatment.

Where clinically possible, the absence of any factors favouring the onset of ventricular arrhythmias should be ensured before administration:

• bradycardia less than 55 beats per minute;
• hypokalaemia;
• congenital long QT interval;
• ongoing treatment with any drug which could induce marked bradycardia (<55 beats per minute), hypokalaemia, intracardiac conduction depression or QT prolongation.

With the exception of emergencies, it is recommended that the initial work up of patients receiving a neuroleptic should include an ECG.

Treatment must be interrupted in the event of unexplained hyperpyrexia since this can be one of the signs of neuroleptic malignant syndrome (pallor, hyperthermia, disorders of autonomic function). Signs of autonomic instability, such as hyperhydrosis and irregular blood pressure, can precede the onset of hyperthermia and as such constitute premonitory signs of the syndrome. While this neuroleptic-related effect can be of idiosyncratic origin, certain risk factors such as dehydration and brain damage would seem to indicate a predisposition.

Agranulocytosis has been reported rarely, most commonly in the first three months of treatment, but occasionally later. Other blood dyscrasias including thrombocytopenia and haemolytic anaemia have occurred very rarely. All patients must be advised that, if they experience fever, sore throat or any other infection, they should inform their physician immediately and undergo a complete blood count. Treatment will be discontinued if any marked changes (hyperleucocytosis, granulocytopenia) are observed in the latter.

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 patient cannot be excluded. Chlorpromazine should be used with caution in patients with stroke risk factors.

Chlorpromazine impairs body temperature regulation and cases of severe hypothermia or hyperpyrexia have been reported, usually in association with moderate or high dosage. The elderly or hypothyroid patient may be particularly susceptible to hypothermia. The hazard of hyperthermia may be increased by especially hot or humid weather or by drugs, such as anti-Parkinson agents, which impair sweating. It has also been reported after intramuscular injections of chlorpromazine.

Chlorpromazine commonly causes increased susceptibility to sunburn and patients should be warned to avoid excessive exposure. Phototoxic or photoallergic reactions may occur. Various skin rashes and reactions, including exfoliative dermatitis and erythema multiforme have been reported. Contact skin sensitivity may be produced by contact with chlorpromazine. The occurrence of antinuclear antibodies has been reported. SLE has very rarely occurred.

Cases of venous thromboembolism (VTE) sometimes fatal, have been reported with antipsychotic drugs. Therefore chlorpromazine should be used with caution in patients with risk factors for thromboembolism.

Hyperglycaemia or intolerance to glucose has been reported in patients treated with hlorpromazine. Patients with an established diagnosis of diabetes mellitus or with risk factors for the development of diabetes who are started on chlorpromazine should get appropriate glycaemic monitoring during treatment.

Faecal impaction, severe paralytic ileus or megacolon have been reported. The signs of intestinal obstruction may be obscured by the anti-emetic action of chlorpromazine. The onset of paralytic ileus, potentially indicated by abdominal bloating and pain must be treated as an emergency.

With long-term usage, chlorpromazine can cause increased melanin pigmentation of the skin, which eventually may develop a bluish-grey colouration. Pigment deposits also occur in the eye and other tissues. Permanent deposits, leading to impairment of vision, may develop in the lens. Epithelial keratopathy has been reported. Toxic pigmentary retinopathy, which may cause progressive loss of vision has occurred very rarely, with excessively high doses.

Except under exceptional circumstances, this drug must not be administered to patients with Parkinson’s disease.

Chlorpromazine can rarely cause obstructive jaundice associated with stasis in biliary canaliculi. It has been thought to be a hypersensitivity reaction and some cases have shown premonitory fever and associated eosinophilia. It has normally been reversible on stopping the drug, but extremely rare cases of progressive liver disease have been reported. In most cases the jaundice has appeared between one to four weeks after the start of the treatment. Chlorpromazine treatment should be withdrawn and not given again.

Transient abnormalities of liver function tests may occur in the absence of jaundice.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared to a rate of about 2.65 in the placebo group. Although the cause of death in clinical trials with atypical antipsychotics were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patient is not clear.

A large amount of exposure to chlorpromazine during pregnancy did not reveal any teratogenic effect. However, there is evidence of harmful effects in animals, so like other drugs, it should be avoided in pregnancy unless the physician considers it essential. It may occasionally prolong labour and at such a time should be withheld until the cervix is dilated 3-4cm.

It is advised to keep an adequate maternal psychic balance during pregnancy in order to avoid decompensation. If a treatment is necessary to ensure this balance, the treatment should be started or continued at effective dose all through the pregnancy.

Neonates exposed to antipsychotics (including chlorpromazine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

Chlorpromazine being excreted in milk, breast-feeding is not recommended during treatment.

Fertility

A decrease in fertility was observed in female animals treated with chlorpromazine. In male animals data are insufficient to assess fertility.

In humans, because of the interaction with dopamine receptors, chlorpromazine may cause hyperprolactinaemia which can be associated with impaired fertility in women. In men, data on consequences of hyperprolactinaemia are insufficient with regard to fertility.

The attention of patients, particularly drivers and machine operators, should be drawn to the risk of drowsiness with this medication especially at the start of treatment.