Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Aventis Pharma Ltd, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PT, UK Trading as: Sanofi, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PT, UK
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.
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 (see Section 4.8) and requires immediate haematological investigation.
Neuroleptic malignant syndrome: treatment must be interrupted in the event of unexplained hyperpyrexia since this can be one of the signs of neuroleptic malignant syndrome (pallor, hyperthermia, autonomic dysfunction, altered consciousness, muscle rigidity). Signs of autonomic instability, such as hyperhydrosis and irregular blood pressure, can precede the onset of hyperthermia and as such constitute premonitory signs of this 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.
Largactil should be avoided in patients with, hypothyroidism, 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.
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 If treatment is withdrawn, the recurrence of symptoms may not become apparent for some time.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. 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 (see Section 4.8).
Where clinically possible, the absence of any factors favouring the onset of ventricular arrhythmias should be ensured before administration:
With the exception of emergencies, it is recommended that the initial work up of patients receiving a neuroleptic should include an ECG.
Except under exceptional circumstances, this drug must not be administered to patients with Parkinson’s disease.
The concomitant use of chlorpromazine with lithium, other QT prolonging agents, and dopaminergic antiparkinsonium agents is not recommended (see Section 4.5).
The onset of paralytic ileus, potentially indicated by abdominal bloating and pain, must be treated as an emergency (see Section 4.8).
Cases of venous thromboembolism (VTE), sometimes fatal have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Largactil and preventative measures undertaken.
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.
Elderly Patients with Dementia: Elderly patients with dementia-related psychosis treated with antipsychotics 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 2.6% in the placebo group. Although the causes of death in clinical trials with atypical antipsychotics were varied, most of the deaths appeared to be either cardiovascular (eg. heart failure, sudden death) or infectious (eg. 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 patients is not clear.
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.
Largactil is not licensed for the treatment of dementia-related behavioural disturbances.
Because of the risk of photosensitisation, patients should be advised to avoid exposure to direct sunlight (see Section 4.8).
In those frequently handling preparations of phenothiazines, the greatest care must be taken to avoid contact of the drug with the skin.
Hyperglycaemia or intolerance to glucose has been reported in patients treated with Largactil. Patients with established diagnosis of diabetes mellitus or with risk factors for the development of diabetes who are started on Largactil, should get appropriate glycaemic monitoring during treatment (see section 4.8).
The following populations must be closely monitored after administration of chlorpromazine:
Adrenaline must not be used in patients overdosed with Largactil.
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.
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 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 Largactil since it shares many of the pharmacological properties of prochlorperazine.
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.
Dopaminergics (quinaglide, cabergoline), not including dopaminergic antiparkinsonism agents, are contraindicated (see Section 4.3); reciprocal antagonism of the dopaminergic agent and neuroleptic.
Citalopram and escitalopram are contraindicated.
Dopaminergic antiparkinsonium agents (amantadine, bromocriptine, cabergoline, levodopa, lisuride, pergolide, piribedil, ropinirole) are not recommended: reciprocal antagonism of the antiparkinsonism agent and neuroleptic (see Section 4.4). Neuroleptic-induced extrapyramidal syndrome should be treated with an anticholinergic rather than a dopaminergic antiparkinsonism agent (dopaminergic receptors blocked by neuroleptics).
Levodopa: reciprocal antagonism of levodopa and the neuroleptic. In Parkinson’s patients, it is recommended to use the minimal doses of each drug.
QT prolonging drugs: There is an increased risk of arrhythmias when neuroleptics are used with concomitant QT prolonging drugs (including certain antiarrhythmics, antidepressants and other antipsychotics including sultopride) and drugs causing electrolyte imbalance (see Section 4.4).
Alcohol: 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 (see section 4.4).
Lithium (high doses of neuroleptics): concomitant use can cause confusional syndrome, hypertonia and hyper-reflexivity, occasionally with a rapid increase in serum concentrations of lithium (see Section 4.4). There have been rare cases of neurotoxicity Lithium can interfere with the absorption of neuroleptic agents.
Anti-diabetic agents: concomitant administration of high chlorpromazine doses (100mg/day) and anti-diabetic 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 anti-diabetic dosage during and after discontinuing neuroleptic treatment.
Topical gastrointestinal agents (magnesium, aluminium and calcium salts, oxides and hydroxides): decreased GI absorption of phenothiazine neuroleptics. Do not administer phenothiazine neuroleptics simultaneously with topical GI agents (administer more than 2 hours apart if possible).
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.
There is a possible pharmacokinetic interaction between inhibitors of CYP2D6, such as phenothiazines, and CYP2D6 substrates.
Antihypertensive agents: potentiation of the antihypertensive effect and risk of orthostatic hypotension (additive effects). Guanethidine has adverse clinically significant interactions documented.
Atropine and other atropine derivatives: imipramine, antidepressants, histamine H1-receptor antagonists, anticholinergic antiparkinsonism agents, atropinic antispasmodics, dispyramide: build-up of atropine-associated adverse effects such as urinary retention, constipation and dry mouth, heat stroke etc.
Other CNS depressants: morphine derivatives (analgesics, antitussives and substitution treatments), barbiturates, benzodiazepines, anxiolytics other than benzodiazepines, hypnotics, sedative antidepressants, histamine H1 receptor antagonists, central antihypertensive agents increased central depression. Changes in alertness can make it dangerous to drive or operate machinery.
There is inadequate evidence of the safety of Largactil in human pregnancy. There is evidence of harmful effects in animals. 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 3-4 cm. Possible adverse effects on the foetus include lethargy or paradoxical hyperexcitability, tremor and low Apgar score.
A large amount of exposure to chlorpromazine during pregnancy did not reveal any teratogenic effect.
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 pregnancy.
Neonates exposed to antipsychotics (including Largactil) 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, bradycardia, tachycardia, feeding disorder, meconium ileus, delayed meconium passage, abdominal bloating. Consequently, newborns should be monitored carefully in order to plan appropriate treatment.
Largactil may be excreted in milk, therefore breastfeeding should be suspended during treatment.
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 (see Section 4.8). In men, data on consequences of hyperprolactinaemia are insufficient with regard to fertility.
Patients should be warned about drowsiness during the early days of treatment and advised not to drive or operate machinery.
Very common (≥1/10)
Common (≥1/100 to <1/10)
Not known (cannot be estimated from available data)
Not known: Agranulocytosis, Leucopenia
Not known: Systemic lupus erythematosus, Antinuclear antibody positive1, Bronchospasm, Anaphylactic reactions
Common: Hyperprolactinaemia, Amenorrhoea
Not known: Galactorrhoea, Gynaecomastia, Erectile dysfunction, Impotence, Female sexual arousal disorder
Very common: Weight increased
Common: Glucose tolerance impaired (see section 4.4)
Not known: Hyperglycaemia (see section 4.4), Hypertriglyceridaemia, Hyponatraemia, Inappropriate antidiuretic hormone secretion
Common: Anxiety
Not known: Lethargy, Mood altered
Very common: Sedation2, Somnolence2, Dyskinesia (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.), Tardive dyskinesia3, Extrapyramidal disorder, Akathisia-often after large initial dose
Common: Hypertonia, Convulsion
Not known: Tortcolis, Oculogyric crisis, Trismus, Akinesia, Hyperkinesia, Neuroleptic malignant syndrome (hyperthermia, rigidity, autonomic dysfunction and altered consciousness) (see section 4.4), Parkinsonism (more common in adults and the elderly. It usually develops after weeks or months of treatment) to include tremor, rigidity or other features of Parkinsonism
Not known: Accommodation disorder4, Deposit eye5, Ocular changes7
Common: ECG changes include Electrocadiogram QT prolonged (as with other neuroleptics) (see section 4.4), ST depression, U-Wave and T-Wave changes.
Not known: Cardiac arrhythmias, including Ventricular arrhythmia and atrial arrhythmias, a-v block, Ventricular fibrillation, Ventricular tachycardia, Torsade de pointes, 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, Sudden death/Sudden cardiac death (with possible causes of cardiac origin as well as cases of unexplained sudden death, in patients receiving neurleptic phenothiazines) (see section 4.4)
Very common: Orthostatic hypotension (Elderly or volume depleted subjects are particularly susceptible: it is more likely to occur after intramuscular administration.)
Not known: Embolism venous, Pulmonary embolism (sometimes fatal), Deep vein thrombosis (see section 4.4)
Not known: Respiratory depression, Nasal stuffiness
Very common: Dry mouth, Constipation (see section 4.4)
Not known: Colitis ischaemic, Ileus paralytic (see section 4.4), Intestinal perforation (sometimes fatal), Gastrointestinal necrosis (sometimes fatal), Necrotising colitis (sometimes fatal), Intestinal obstruction
Not known: Jaundice cholestatic6, Hepatocellular Liver Injury6, Cholestatic liver injury6, Mixed liver injury
Not known: Dermatitis allergic, Angioedema, Contact skin sensitisation may occur rarely in those frequently handling preparations of chlorpromazine (see section 4.4), Skin rashes, Urticaria, Photosensitivity reaction
Not known: Urinary retention4, Pregnancy, puerperium and perinatal conditions, Drug withdrawal syndrome neonatal (see section 4.6)
Not known: Priapism
Not known: Temperature regulation disorder, Insomnia, Agitation
1 may be seen without evidence of clinical disease
2 particularly at the start of treatment
3 particularly during long term treatment; may occur after the neuroleptic is withdrawn and resolve after reintroduction of treatment or if the dose is increased.
4 linked to anticholinergic effects
5 in the anterior segment of the eye caused by accumulation of the drug but generally without any impact on sight
6 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 (see section 4.4).
7 The development of a metallic greyish-mauve coloration of exposed skin has been noted in some individuals, mainly females, who have received chlorpromazine continuously for long periods (four to eight years).
Risk of allergic reactions including anaphylactic reactions and bronchospasm owing to the presence of sodium sulfite and disulfite in the formulation.
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Largactil injection solutions have a pH of 5.0-6.5; they are incompatible with benzylpenicillin potassium, pentobarbital sodium and phenobarbital sodium.
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