Consumer medicine information

Largactil

Chlorpromazine hydrochloride

BRAND INFORMATION

Brand name

Largactil

Active ingredient

Chlorpromazine hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Largactil.

What is in this leaflet

This leaflet answers some common questions about Largactil.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor or pharmacist has weighed the risks of you taking Largactil against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with this medicine. You may need to read it again.

What Largactil is used for

The active ingredient of Largactil is chlorpromazine hydrochloride, one of a group of medicines called phenothiazines.

Largactil is used to treat a number of conditions and may be used either for a short time or for a long time. Largactil is used to treat various problems such as severe depression or behavioural disturbances. Largactil can also be used to treat nausea, vomiting, severe pain and unstoppable hiccups. Your doctor may have prescribed Largactil for another reason.

Ask your doctor if you have any questions about why Largactil has been prescribed for you.

Largactil is available only with a doctor's prescription.

Before you take it

When you must not take it

Do not take Largactil if you have an allergy or any other reaction to Largactil or any of the ingredients listed at the end of this leaflet.

Do not take Largactil if you have taken any other 'phenothiazine' medicine before, which caused your face, lips, tongue, throat, hands or feet to swell up, or made it hard for you to breathe. If you have had an allergic reaction to a phenothiazine before, you may be allergic to Largactil.

Do not take Largactil if you have any of the following:

  • circulatory, blood or bone marrow problems
  • high blood pressure
  • phaeochromocytoma - a rare tumour of the adrenal gland which sits near the kidneys
  • liver problems
  • CNS depression, e.g. coma or drug intoxication

Do not take Largactil after the expiry date (EXP) printed on the pack. If you take this medicine after the expiry date has passed, it may not work as well.

Do not take Largactil if the packaging is torn or shows signs of tampering or if the tablet, syrup or ampoule doesn't look quite right.

If you are not sure whether you should start taking Largactil, contact your doctor or pharmacist.

Before you start to take it

Tell your doctor or pharmacist if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes

Tell your doctor or pharmacist if you are pregnant or intend to become pregnant. Your doctor or pharmacist will discuss the possible risks and benefits of using Largactil during pregnancy.

Tell your doctor or pharmacist if you are breast-feeding or plan to breast-feed. Your doctor or pharmacist will discuss the possible risks and benefits of using Largactil during breastfeeding.

Tell your doctor or pharmacist if you have or have had any medical conditions, especially the following:

  • asthma
  • chronic respiratory disorders
  • kidney or liver disease
  • heart disease
  • blood clots
  • decreased parathyroid activity
  • low blood calcium levels
  • Parkinson's disease
  • prostate problems
  • epilepsy - fits and seizures
  • glaucoma - high pressure in the eye
  • muscle weakness (myasthenia gravis)
  • diabetes
  • dementia

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking Largactil.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Largactil may interfere with each other. These include:

  • benztropine and levodopa - drugs used to treat Parkinson's disease
  • antacid - used to treat stomach upsets
  • lithium - used to treat mood disorders
  • barbiturates - a group of drugs used as sedatives
  • tricyclic antidepressants
  • benzodiazepines - a group of drugs used to treat anxiety and muscle spasms
  • other antipsychotics
  • medicines that are CYP1A2 inhibitors e.g. ciprofloxacin, fluvoxamine, oral contraceptives, vemurafenib
  • medicines used to treat a fast or irregular heart beat e.g. amiodarone, quinidine, disopyramide
  • medicines that can slow your heart beat e.g. diltiazem, verapamil, propranolol
  • medicines that can reduce potassium levels in the blood e.g. diuretics, laxatives
  • other medicines that can affect your heart rate e.g. methadone, pentamidine
  • anaesthetics
  • opioids - a group of pain killing drugs
  • antidiabetic agents - a group of drugs used to treat diabetes
  • amphetamines
  • anticoagulants
  • anticholinergics
  • guanethidine
  • clonidine
  • thiazides - diuretics (fluid tablets)
  • MAOI - a group of drugs used to treat depression
  • adrenaline
  • suxamethonium, atropine and organophosphorous insecticides
  • anticonvulsants - a group of drugs used to treat epilepsy e.g. phenytoin, valproic acid
  • prochlorperazine - a drug used to treat nausea and vomiting
  • desferrioxamine - a drug used to treat iron poisoning

These medicines may be affected by Largactil, or they may affect how well it works. You may need different amounts of your medicine, or you may need to use different medicines. Your doctor or pharmacist will advise you.

Your doctor and pharmacist may have more information on medicines to be careful with or to avoid while taking Largactil.

How to take it

How much to take

Your doctor or pharmacist will tell you how many tablets or how much syrup you will need to take each day. This depends on your condition and whether or not you are taking any other medicines.

Follow all directions given to you by your doctor and pharmacist carefully.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How to take it

Swallow the prescribed dose of Largactil tablets whole with a full glass of water. Do not chew the tablets.

Swallow the prescribed dose of Largactil syrup and follow with a glass of water.

Largactil may be given as an injection into a muscle or as a slow injection into a vein. Largactil injections should only be given by a doctor, nurse or other trained person.

When to take it

Take Largactil at about the same time each day. Taking your tablets or syrup at the same time each day will have the best effect. It will also help you remember when to take the tablets or syrup.

If you forget to take it

If you miss a dose, simply continue to take Largactil as advised by your doctor or pharmacist. You do not need to make up for the missed dose.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist. If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

How long to take it

Continue taking Largactil until your doctor or pharmacist tells you to stop. Do not stop using it unless your doctor or pharmacist tells you to, even if you feel better.

If you take too much (overdose)

Immediately telephone your doctor or pharmacist or the Poisons Information Centre (telephone Australia 13 11 26, New Zealand 0800 POISON or 0800 764766), or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have taken too much Largactil. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention. If you take too much Largactil, you may experience:

  • drowsiness
  • confusion
  • restlessness
  • excitement
  • breathing difficulties
  • fast heart rate
  • muscle twitching

While you are using it

Things you must do

Tell your doctor immediately if you notice any worm-like movements of the tongue, or other uncontrolled movements of the tongue, mouth, cheeks or jaw which may progress to the arms and legs.

These are symptoms of a condition called tardive dyskinesia, which may develop in people taking phenothiazine medicines, including Largactil.

This condition is more likely to occur during long term treatment with Largactil, especially in elderly women. In very rare cases, this may be permanent. However, if detected early, these symptoms are usually reversible.

Tell any other doctors, dentists, and pharmacists who are treating you that you are taking Largactil.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking Largactil.

If you become pregnant while taking Largactil, tell your doctor or pharmacist.

You should avoid very cold or very hot environments. Largactil may make it difficult for your body to regulate its temperature.

You should avoid exposure to strong sunlight while you are taking Largactil. Do not use a sunlamp or tanning bed or booth. Largactil may cause your skin to be much more sensitive to sunlight than it is normally. Exposure to sunlight may cause a skin rash, itching, redness or severe sunburn. If your skin does appear to be burning, tell your doctor. If exposure to strong sunlight is unavoidable, suitable clothing, including a hat, should be worn. A sunscreen with a high level of protection should also be used.

Things you must not do

Do not give Largactil to anyone else, even if they have the same condition as you.

Do not take Largactil to treat any other complaints unless your doctor or pharmacist tells you to.

Things to be careful of

Be careful when drinking alcohol while taking Largactil. Combining Largactil and alcohol can make you more sleepy, dizzy or light headed. Your doctor may suggest you avoid alcohol while you are being treated with Largactil.

Be careful driving or operating machinery until you know how Largactil affects you. Largactil may cause drowsiness in some people. Make sure you know how you react to Largactil before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs, do not drive. If you drink alcohol, dizziness or light-headedness may be worse.

If Largactil makes you feel light-headed, dizzy or faint, be careful when getting up from a sitting or lying position. Getting up slowly may help.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Largactil.

Largactil helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

If you are over 65 years of age, you may have an increased chance of getting side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • dizziness or light headedness
  • skin problems or discolouration
  • agitation
  • drowsiness or tiredness
  • headache
  • constipation
  • nausea
  • dry mouth
  • nasal congestion
  • difficulty in urinating
  • blurred vision
  • impotence
  • weight gain

These are the more common side effects of Largactil. Mostly these are mild and short-lived.

If any of the following happen, stop taking Largactil and tell your doctor or pharmacist immediately or go to casualty at your nearest hospital:

  • sore throat, fever or any sign of infection
  • breathing difficulty
  • seizures or fits
  • unwanted muscle movements of the mouth, tongue, jaw, cheeks or arms and legs.
  • hardness or rigidity of the muscles.
  • fast heartbeat
  • uncontrolled bleeding or bruising more easily than usual

These are very serious side effects. You may need urgent medical attention or hospitalisation.

Other side effects not listed above may occur in some patients. Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Storage

Largactil ampoules for injection will be stored in the pharmacy or on the ward. The injection is kept in a cool dry place, protected from light.

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they will not keep as well.

Keep your tablets or syrup in a cool dry place. Do not store Largactil or any other medicine in the bathroom or near a sink. Do not leave it in the car on hot days or on window sills. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor or pharmacist tells you to stop taking Largactil or the tablets or syrup has passed the expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

Largactil tablets are white film coated tablets with embossing on one side:

10mg tablet: LG / 10
25mg tablet: LG / 25
100mg tablet: LG / 100

Tablets are available in blister packs of 100.

Largactil syrup* is a dark orange syrupy liquid with the odour of spearmint / peppermint, and is slightly fruity. Syrup is available in an amber glass 100mL bottle with a childproof cap.

Largactil for injection is a clear liquid in a 2mL glass ampoule, in a pack of 10 ampoules.

Ingredients

Largactil tablets contain:

  • chlorpromazine hydrochloride 10mg, 25mg, or 100mg (active ingredient)
  • lactose monohydrate
  • maize starch
  • colloidal anhydrous silica
  • magnesium stearate
  • hypromellose
  • macrogol 200
  • titanium dioxide

Largactil syrup* contains:

  • chlorpromazine hydrochloride 25mg/5mL (active ingredient)
  • sucrose
  • caramel
  • citric acid
  • polysorbate 20
  • peppermint oil
  • spearmint oil
  • sodium citrate dihydrate
  • ascorbic acid
  • sodium sulphite
  • sodium metabisulphite
  • sodium benzoate
  • fruit cup essence
  • purified water

Largactil ampoules contain:

  • chlorpromazine hydrochloride 50mg/2mL (active ingredient)
  • sodium sulfite
  • sodium metabisulphite
  • sodium chloride
  • sodium citrate dihydrate
  • water for injections

Sponsor

  • sanofi-aventis australia pty ltd
    12-24 Talavera Road
    Macquarie Park NSW 2113
    Toll Free Number (medical information): 1800 818 806
    Email: [email protected]
  • sanofi-aventis new zealand limited
    Level 8, 56 Cawley Street Ellerslie
    Auckland, New Zealand
    Toll Free Number (medical information): 0800 283 684
    Email: [email protected]

Largactil® is a registered trademark.

Australian Registration Numbers:

10mg tablet AUST R 51620
25mg tablet AUST R 51618
100mg tablet AUST R 51619
25mg/5mL syrup AUST R 118128
50mg/2mL ampoule AUST R 27511

This leaflet was prepared in December 2019.

* Largactil Syrup not available in New Zealand

largactil-ccdsv4-cmiv8-17dec19

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Largactil

Active ingredient

Chlorpromazine hydrochloride

Schedule

S4

 

1 Name of Medicine

Chlorpromazine hydrochloride.

6.7 Physicochemical Properties

Chlorpromazine is 10-(3-dimethyl-aminopropyl)-2-chlorophenothiazine, a dimethylamine derivative of phenothiazine. Chlorpromazine 100 mg is approximately equivalent to 111 mg of chlorpromazine hydrochloride. MW = 355.3.
Chlorpromazine hydrochloride is an odourless white powder, which decomposes and changes colour on exposure to light. Chlorpromazine hydrochloride is soluble in water, alcohol and chloroform but practically insoluble in ether. The pH of a 10% aqueous solution of the hydrochloride is 4 to 5.

Chemical structure.

Chemical structure of chlorpromazine hydrochloride:

CAS number.

69-09-0.

2 Qualitative and Quantitative Composition

Tablets: Each tablet contains 10 mg, 25 mg or 100 mg of chlorpromazine hydrochloride.
Syrup: Each 1 mL of syrup contains 5 mg of chlorpromazine hydrochloride.
Injection: The injection solution contains 50 mg/2 mL of chlorpromazine hydrochloride.

Excipients with known effect.

Tablets: Lactose monohydrate.
Syrup: Sucrose, sodium sulfite, sodium metabisulfite, sodium benzoate.
Injection: Sodium sulfite, sodium metabisulfite.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets, Syrup, Injection Solution.

Tablets.

10 mg: white to off-white, circular biconvex, film-coated tablets one face impressed LG10 with the reverse side plain film coated tablet.
25 mg: white to off-white, circular biconvex, film-coated tablets one face impressed LG25 with the reverse side plain film coated.
100 mg: white to off-white, circular biconvex, film-coated tablets one face impressed LG100 with the reverse side plain film coated.

Syrup.

The syrup is a clear bright, golden brown, syrupy liquid.

Injection.

The injection solution is a clear, bright, very pale yellow liquid.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Chlorpromazine is a major tranquilliser. It is a phenothiazine which has antipsychotic actions, the exact basis for which are not fully understood.
Its clinical properties include alleviating anxiety, tension and agitation, potentiating CNS depressants including analgesics, narcotics and sedatives; an antiemetic action.
Chlorpromazine is a dopamine inhibitor. It inhibits prolactin release inhibitory factor, considered to be dopamine, thereby stimulating the release of prolactin. The turnover of dopamine in the brain is also increased. The antagonism of central dopaminergic function may be related to the therapeutic effect in psychotic conditions.
Chlorpromazine can produce alpha-adrenergic blockade which may produce hypotension. Chlorpromazine also has a tendency to produce elevated serum glucose and cholesterol levels.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Chlorpromazine is readily absorbed from the gastrointestinal tract but is subject to considerable first-pass metabolism in the gut and the liver. Following oral administration, peak plasma levels are reached in 1-4 hours; following intramuscular injection, peak plasma levels usually occur in 15-30 minutes. Oral absorption is erratic and incomplete with 10-80% of the oral dose reaching the systemic circulation. There is wide intersubject variation.

Distribution.

Chlorpromazine is widely distributed to the body tissue. It crosses the blood-brain barrier and achieves higher concentrations in the brain than in the plasma. The average volume of distribution of chlorpromazine is quite large, ranging from 10-35 L/kg (mean 22 L/kg). It is highly protein bound (90-99%). Chlorpromazine has been detected in urine for up to one year after discontinuation of chronic administration.

Metabolism.

Chlorpromazine metabolism is complex. There is extensive first-pass metabolism after oral administration, accounting for a low oral bioavailability of unchanged drug, especially at low oral doses. Over 150 metabolites have been postulated, of which about half have been detected in blood and urine. Major metabolic pathways are hepatic and include demethylation, N-oxidation, sulphoxidation, deamination and conjugation. The metabolites of clinical importance appear to be 7-hydroxychlorpromazine, 3-hydroxychlorpromazine, desmethylchlorpromazine and chlorpromazine N-oxide, all of which are biologically active, and chlorpromazine sulphoxide, which is not biologically active. Chlorpromazine is almost completely metabolised with less than 1% excreted in the urine as unchanged drug. Serum levels of unchanged drug and clinical effect do not correlate well. A therapeutic serum level is usually between 100-300 nanogram/mL and toxic effects appear by 750 nanogram/mL but routine serum level monitoring is not necessary. Serum levels in chronic dosing may be lower than those reached after acute dosing.

Excretion.

Chlorpromazine and its metabolites are removed from the body significantly in the urine, in small amounts in faeces and in lesser amounts in sweat and hair. Average urinary excretion in 24 hours ranges from 43-65% of the daily dose. There is a wide variation in the elimination half-lives proposed by various groups and also wide interpatient variation.
There may be several elimination phases, consisting of an early phase of 2-3 hours, an intermediate phase of 15 hours and a late phase of up to 60 days.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of acute functional psychosis (e.g. schizophrenia, mania or psychotic depression).
Long-term treatment of schizophrenia.
Short-term treatment of agitation and severe depression.
Severe behavioural disturbances, as can be found in some children with mental retardation or autism, including the treatment of self injurious and aggressive behaviour or overactivity. Use of chlorpromazine should be in conjunction with an appropriate nonpharmacological management program and long-term use should only be carried out under the supervision of a physician experienced in the management of psychotic disorders in children.
In the management of terminal illness to enhance the effect of analgesics and to control nausea and vomiting.
Control of intractable hiccough.

4.3 Contraindications

Chlorpromazine should never be used in the following circumstances:
Circulatory collapse.
CNS depression, e.g. coma or drug intoxication.
Previous history of a hypersensitivity reaction (e.g. jaundice or blood dyscrasia) to phenothiazines, especially chlorpromazine itself, or to any of the excipients contained in the tablets, syrup or injection.
Bone marrow depression.
Phaeochromocytoma.
Hepatic failure or active hepatic disease.
Largactil syrup contains sodium metabisulfite, sodium sulfite and sodium benzoate and Largactil injection contains sodium metabisulfite and sodium sulfite and may cause allergic type reactions including anaphylactic symptoms and asthmatic episodes in susceptible people.

4.4 Special Warnings and Precautions for Use

Chlorpromazine generally should not be used in epilepsy, Parkinson's disease, hypoparathyroidism, myasthenia gravis and prostatic hypertrophy.

Epilepsy.

Chlorpromazine should be avoided in patients with epilepsy as treatment with neuroleptics can result in a lowered seizure threshold. Chlorpromazine may be used in conjunction with anticonvulsant drugs.

Parkinson's disease.

Chlorpromazine should be avoided in parkinsonism as phenothiazines may block postsynaptic dopamine receptors in the striatum. There is also a possible antagonistic effect of chlorpromazine with dopaminergic agonists used in the treatment of parkinsonism.

Hypoparathyroidism.

Use of chlorpromazine should be avoided in hypoparathyroidism as a severe dystonic reaction has been reported in patients with untreated hypoparathyroidism.

Myasthenia gravis.

As the underlying defect in myasthenia gravis is a decrease in the number of available acetylcholine receptors at neuromuscular junctions, chlorpromazine should be avoided in myasthenia gravis due to its strong antimuscarinic effects.

Prostate hypertrophy.

Chlorpromazine should be avoided in patients with prostate hypertrophy due to the anticholinergic effects of phenothiazines.

Antiemetic effects.

The antiemetic effects of chlorpromazine may mask signs of overdosage of toxic drugs or obscure the diagnosis of conditions such as intestinal obstruction and brain tumour.

Temperature regulation.

Phenothiazines depress the mechanism for regulation of temperature. Severe hypothermia may occur during swimming in cold water or in patients receiving antipyretic therapy, and heat stroke may occur in hot weather. Patients who develop pyrexia along with clouding of consciousness and rigidity should cease medication and undergo immediate investigation, as these are the early symptoms of the neuroleptic malignant syndrome, a potentially lethal adverse effect of major tranquillisers (see Section 4.8 Adverse Effects (Undesirable Effects)).

Prolonged usage.

As with all phenothiazines, long-term usage of chlorpromazine can cause the development of tardive dyskinesia which may be irreversible (see Section 4.8 Adverse Effects (Undesirable Effects)).

Agranulocytosis.

Agranulocytosis has been reported at an incidence of between 1:1,300 and 1:500,000. Most reported cases have occurred between the fourth and tenth week of treatment.
Warn patients to report the sudden appearance of sore throat, fever or other signs of infection. If white blood cell and differential counts indicate cellular depression, stop treatment and start antibiotic and other suitable therapy, subject to the expert guidance of a haematologist.

Retinopathy.

Periodic ophthalmological examinations should be performed during prolonged therapy.

Respiratory disease.

Chlorpromazine should be used with caution in patients with chronic respiratory disorders. Chlorpromazine can suppress the cough reflex, hence aspiration of vomitus is possible.

Reye's syndrome.

The extrapyramidal symptoms which can occur secondary to chlorpromazine may be confused with the central nervous system signs of an undiagnosed primary disease responsible for the vomiting, e.g. Reye's syndrome or other encephalopathy. The use of chlorpromazine and other hepatotoxins should be avoided in children and adolescents whose signs and symptoms suggest Reye's syndrome.

Glaucoma.

As with all drugs which exert an anticholinergic effect, and/or cause mydriasis, chlorpromazine should be used with caution in patients with glaucoma. As the clinical features of neuroleptic malignant syndrome include autonomic dysfunction, care should be taken when giving chlorpromazine to patients with a history of neuroleptic malignant syndrome and glaucoma. Patients should be monitored for symptoms and signs of neuroleptic malignant syndrome (see Section 4.8 Adverse Effects (Undesirable Effects)).

Photosensitivity.

Patients on high doses should be warned that they may develop photosensitivity in sunny weather and should avoid exposure to strong sunlight, e.g. at the beach or snow. If exposure is unavoidable, patients should be encouraged to wear suitable clothing including a hat and to apply an SPF 15+ sunscreen. The tendency to this adverse effect may be increased with chronic dosing. Periodic examinations for lens opacities and abnormal pigmentation are required.

Hypotension.

Chlorpromazine should be used with extreme caution in patients with cardiovascular disease, phaeochromocytoma, or other conditions in which a sudden drop in blood pressure would be undesirable; if it is used in conjunction with other drugs likely to cause postural hypotension, an adjustment of dosage may be necessary. Avoid adrenaline in the treatment of phenothiazine induced hypotension, as the action of adrenaline may be reversed causing a further fall in blood pressure.

QT intervals.

Very rare cases of QT interval prolongation have been reported with chlorpromazine.
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, hypokalemia, 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 Adverse Effects (Undesirable Effects)).

Cerebrovascular events.

An increased risk of cerebrovascular events has been reported in elderly patients with dementia treated with atypical antipsychotic drugs. An increase in the risk of cerebrovascular events with other antipsychotic drugs or other populations of patients cannot be excluded.
Chlorpromazine should therefore be used with caution in patients with stroke risk factors.

Venous thromboembolism.

Cases of venous thromboembolism, sometimes fatal, have been reported with antipsychotic drugs. Therefore, chlorpromazine should be used with caution in patients with risk factors for thromboembolism (see Section 4.8 Adverse Effects (Undesirable Effects)).

Hyperglycaemia.

Hyperglycaemia or intolerance to glucose has been reported in patients treated with chlorpromazine. 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 (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in hepatic impairment.

If bilirubinaemia, bilirubinuria or icterus occur, the drug should be discontinued and liver function tests performed. Routine tests are advisable during prolonged therapy. Due to the extensive hepatic metabolism and clearance of chlorpromazine, caution should be taken when treating patients with hepatic impairment. Dose reduction may be necessary in such patients.
Treatment should be discontinued immediately and another antipsychotic drug should be considered as an alternative in the following situations.

Severe liver toxicity.

Severe liver toxicity, sometimes resulting in death, has been reported with chlorpromazine use. Patients or caregivers should be instructed to report immediately signs and symptoms such as asthenia, anorexia, nausea, vomiting, abdominal pain or icterus to a physician. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately (see Section 4.8 Adverse Effects (Undesirable Effects)).

Eosinophilia.

The presence of eosinophilia may indicate an allergic reaction to chlorpromazine. A thorough clinical examination and a repeat complete blood count (CBC) with differential count to confirm the presence of eosinophilia should be performed.

Use in renal impairment.

Chlorpromazine should be given cautiously to patients with renal disease.

Use in the elderly.

The elderly are relatively more susceptible to the adverse effects of chlorpromazine. The starting dose should be about half the usual adult dose and dosage increments should be gradual and reviewed regularly.

Elderly patients with dementia.

Elderly patients with dementia related psychosis treated with antipsychotic drugs are at an increased risk of death. Although the causes 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 patients is not clear.

Paediatric use.

Children need to be monitored for hypothermia and hypotension (see Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

The presence of phenothiazines may produce false positive phenylketonuria (PKU) test results.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions resulting in decreased chlorpromazine levels.

Food, alcohol and benztropine can reduce the absorption of chlorpromazine. Antacids can slow the absorption of chlorpromazine. Lithium and chronic administration of barbiturates can lead to increased clearance of chlorpromazine.

Interactions resulting in increased chlorpromazine levels.

Tricyclic antidepressants decrease the clearance of chlorpromazine and may lead to increased serum levels.
Administration of chlorpromazine with CYP1A2 inhibitors, in particular strong (such as ciprofloxacin and fluvoxamine) or moderate (such as oral contraceptives, thiabendazole and vemurafenib) inhibitors, leads to an increase in chlorpromazine plasma concentrations.
Therefore, patients may experience any chlorpromazine dose dependent adverse drug reaction.

Interactions in which other drugs are affected by chlorpromazine.

Chlorpromazine can increase the depressant action of central nervous system depressants such as benzodiazepines, anaesthetic drugs, opioids, barbiturates and lithium. Chlorpromazine may reduce serum phenytoin levels, may reduce propranolol clearance and may antagonise antidiabetic agents and levodopa, increase valproic acid levels, antagonise the effects of amphetamines, diminish the effect of oral anticoagulants and interact with anticholinergic drugs such as orphenadrine to produce hypoglycaemia.
Phenothiazines such as chlorpromazine are potent inhibitors of CYP2D6. Coadministration of chlorpromazine with amitriptyline, a CYP2D6 substrate, may lead to an increase in the plasma levels of amitriptyline. Monitor patient for dose dependent adverse reactions associated with amitriptyline.
Chlorpromazine can oppose the effects of adrenaline to produce a paradoxical fall in blood pressure (see Section 4.9 Overdose). It can also oppose the effects of guanethidine and clonidine.
Thiazide diuretics may accentuate the orthostatic hypotension that may occur with phenothiazines. Interaction with quinidine may lead to additive myocardial depression. Interaction with MAOIs may lead to additive hypotensive effects. Interactions with suxamethonium, organophosphorus insecticides and atrophine or related drugs are also a possibility.
Chlorpromazine may lower the convulsive threshold; dosage adjustments of anticonvulsants may be necessary (see Section 4.4 Special Warnings and Precautions for Use).
Simultaneous administration of desferrioxamine and prochlorperazine can induce a transient metabolic encephalopathy. Interaction of desferrioxamine and chlorpromazine is a possibility.
Caution is required with the use of the following medicines due to the risk of QT prolongation (see Section 4.4 Special Warnings and Precautions for Use):
Class Ia antiarrhythmic agents such as quinidine and disopyramide.
Class III antiarrhythmic agents such as amiodarone and sotalol.
Other medications such as bepridil, cisapride, sultopride, thioridazine, methadone, intravenous erythromycin, intravenous vincamine, halofantrine, pentamidine, sparfloxacin.
Medicines which induce bradycardia, such as bradycardia inducing calcium channel blockers (diltiazem, verapamil), beta-blockers, clonidine, guanfacine, digitalis.
Medicines which can cause hypokalaemia, such as diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactides.
Other antipsychotics.

4.6 Fertility, Pregnancy and Lactation

Effects on 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.
(Category D)
Studies in animals by oral route have shown reproductive toxicity (dose related embryo foetotoxicity: increased resorptions and dead foetuses). Increased incidence of malformations was observed in mice but only at doses inducing maternal mortality. There is inadequate animal data regarding reproductive toxicity with chlorpromazine by parenteral route.
Data from available epidemiological studies in children exposed in utero to chlorpromazine cannot exclude the risk of congenital malformations and neurodevelopmental disorders.
Neonates exposed to antipsychotic drugs (including chlorpromazine) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been postmarket reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self limited, in other cases neonates have required additional medical treatment or monitoring.
The following effects have also been reported (in postmarketing surveillance) in neonates exposed to phenothiazines during the third trimester of pregnancy:
various degrees of respiratory disorders ranging from tachypnoea to respiratory distress, bradycardia, most often when other drugs such as psychotropic or antimuscarinic drugs were coadministered;
signs related to the atropinic properties of phenothiazines such as meconium ileus, delayed meconium passage, initial feeding difficulties, abdominal bloating, tachycardia.
Appropriate monitoring and treatment of neonate born to mother receiving chlorpromazine are recommended.
Therefore, the use of Largactil is not recommended during pregnancy and in women of childbearing potential not using contraception unless the potential benefits outweigh the potential risks. The administered dose and duration of treatment should be as low and short as possible.
Chlorpromazine has been found to be excreted in breast milk in variable amounts, therefore it is not recommended for nursing mothers unless the expected benefits outweigh any potential risk.

4.8 Adverse Effects (Undesirable Effects)

The following adverse effects have been reported for chlorpromazine or phenothiazines in general.

More common adverse effects.

Cardiovascular.

Postural hypotension, ECG changes.

Dermatological.

Contact dermatitis, photosensitivity, urticarial, maculopapular, petechial or oedematous reactions.

Endocrine.

Elevated prolactin levels, impaired thermoregulation, hyperglycaemia, other hypothalamic effects.

Gastrointestinal.

Dry mouth, constipation.

Immunological.

Raised ANA titre, positive SLE cells.

Genitourinary.

Urinary retention.

Blood and lymphatic system disorders.

Leucopenia, agranulocytosis, eosinophilia, hemolytic anaemia, aplastic anaemia, thrombocytopenic purpura and pancytopenia have been reported.

Nervous system.

Autonomic: dry mouth, mental confusion, postural hypotension, nasal congestion, nausea, obstipation, constipation, adynamic ileus, urinary retention, priapism, miosis and mydriasis, atonic colon, ejaculatory disorders/impotence.
Central: convulsions, extrapyramidal reactions (parkinsonism, akathisia) tardive dyskinesia, nonextrapyramidal effects including lowering of seizure threshold and paradoxical effects, e.g. agitation, excitement and aggravation of schizophrenic symptoms; drowsiness, dystonias, motor restlessness.

Ocular.

Blurred vision, photophobia, miosis, mydriasis, corneal deposits.

Respiratory.

Stuffy nose, respiratory depression.

Local reactions (injection).

Pain at injection site, injection abscess.

General.

Weight gain.

Less common adverse effects.

Cardiovascular.

Arrhythmias, hypertensive crisis (following abrupt withdrawal), A-V block, ventricular tachycardia, QT interval prolongation and fibrillation.
There have been isolated reports of sudden death, with possible causes of cardiac origin (see Section 4.4 Special Warnings and Precautions for Use), as well as cases of unexplained sudden death, in patients receiving neuroleptic phenothiazines.
Cases of venous thromboembolism, including cases of pulmonary embolism, sometimes fatal, and cases of deep vein thrombosis have been reported with antipsychotic drugs (see Section 4.4 Special Warnings and Precautions for Use).

Dermatological.

Skin pigmentation and rarely purpura, exfoliative dermatitis and toxic epidermal necrolysis.

Endocrine.

Hyperthermia, hypothermia, lactation and moderate breast engorgement in females on large doses, false positive pregnancy tests, amenorrhoea, gynecomastia, hypoglycaemia, glycosuria.

Gastrointestinal.

Paralytic ileus.

General.

Rarely, systemic lupus erythematosus has been reported in patients treated with chlorpromazine. In some cases, positive antinuclear antibodies may be seen without evidence of clinical disease.
Allergic reactions.

Genitourinary.

Inappropriate ADH secretion, water retention, oedema, incontinence.

Blood and lymphatic system disorders.

Coagulation defects.

Hepatic.

Cholestatic jaundice and liver injury, mainly of hepatocellular, cholestatic or mixed type, sometimes resulting in death, has been reported in patients treated with chlorpromazine (see Section 4.4 Special Warnings and Precautions for Use).

Musculoskeletal.

Neuroleptic malignant syndrome, myasthenia gravis.

Nervous system.

Fits, cerebral oedema, nightmares, abnormality of cerebrospinal fluid proteins.

Ocular.

Precipitation/aggravation of narrow angle glaucoma, optic atrophy, pigmentary retinopathy, lens opacities.

Psychiatric.

Dysphoria, catatonic excitement.

Serious or life threatening reactions.

Of the above, the following are potentially life threatening: profound hypotension, cardiac arrhythmia, agranulocytosis, progressive hepatic fibrosis, malignant hyperpyrexia.

Temperature regulation.

Hypothermia or hyperthermia may be life threatening (see Section 4.4 Special Warnings and Precautions for Use). In hot climates, patients are particularly at risk if they are overweight, physically active, and taking high doses of neuroleptics and antiparkinsonian agents. Physically debilitated, aged, alcoholic and organic brain syndrome patients may also be at risk.

Sudden death.

Phenothiazine produced sudden death has been reported and is possibly due to cardiac effects (ventricular fibrillation), asphyxia, convulsions or hyperpyrexia. Fortunately, occurrences are rare. There are also reports of unexplained sudden death in patients receiving neuroleptic phenothiazines.

Tardive dyskinesia.

Tardive dyskinesia may develop in patients on antipsychotic drugs. The disorder consists of repetitive involuntary movements of the tongue, face, mouth or jaw (e.g. protrusion of the tongue, puffing the cheeks, puckering of the mouth, chewing movements). The trunk and limbs are less frequently involved. It has been reported that fine vermicular movements of the tongue may be an early sign of the syndrome.
Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of the drug increases. Less commonly, the syndrome can develop after relatively brief treatment periods at low doses. The risk seems to be greater in elderly patients, especially females.
The syndrome may become clinically recognisable either during treatment, upon dosage reduction or upon withdrawal of treatment. The dosage of antipsychotic drug should be reduced periodically (if clinically possible) and the patient observed for signs of the disorder, since the syndrome may be masked by a higher dose. In patients requiring long-term treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.
There is no known effective treatment for tardive dyskinesia. Antiparkinsonian agents usually do not alleviate symptoms. It is suggested that antipsychotic agents be discontinued if symptoms of tardive dyskinesia appear.

Neuroleptic malignant syndrome.

A potentially fatal syndrome called neuroleptic malignant syndrome has been reported in association with antipsychotic drugs. The syndrome is characterised by muscular rigidity, fever, hyperthermia, altered consciousness and autonomic instability (e.g. tachycardia, labile blood pressure, profuse sweating, dyspnoea).
The management of neuroleptic malignant syndrome should include immediate discontinuation of antipsychotic drugs, intensive monitoring and treatment of symptoms, and treatment of any associated medical problems.

Other adverse effects.

In postmarketing surveillance cases of intolerance to glucose and hyperglycaemia have been reported (see Section 4.4 Special Warnings and Precautions for Use).

Metabolism and nutrition disorders.

Hypertriglyceridaemia, hyponatraemia.

Gastrointestinal disorders.

Colitis ischaemic, intestinal obstruction, gastrointestinal necrosis, necrotising colitis (sometimes fatal), intestinal perforation (sometimes fatal).

Skin and subcutaneous tissue disorders.

Angioedema, urticaria.

Blood and lymphatic system disorders.

Thrombocytopenia.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

4.2 Dose and Method of Administration

Dosage varies with the individual and the purpose for which the drug is used, so that only general guidance can be given on the dosage likely to be effective and well tolerated. Initial dosage should be low with increases at frequent, regular intervals until the desired response has been obtained.

Adults.

Sedation, hypotension and anticholinergic effects may be prominent, especially in acute administration.

Oral.

A suitable initial dose for ambulant patients is 25 mg three times daily increased, if necessary, by 25 mg two or three times daily up to a total of 600 mg-800 mg per day. The usual maintenance doses range from 25 to 100 mg three times daily, but higher doses are sometimes used in bed patients or in psychotic cases.
Largactil syrup is intended for administration to patients who refuse tablets or have difficulty in swallowing. Crushing the tablets is not recommended, as contact of the active material with the skin should be avoided in order to minimise the risk of dermatitis.

Parenteral.

Chlorpromazine injectable solutions are irritant and should be given by deep intramuscular injection or, after dilution with normal saline, by intravenous infusion. Blood pressure and vital signs should be taken before and monitored closely after injections. The usual single dose for adults is 25 to 50 mg by deep intramuscular injection and this may be repeated as necessary three to four times in 24 hours. Initial dosage of this order may sometimes cause a transient postural hypotension so that the patient should be kept under observation for the first few days of treatment. The intramuscular injection should be given in the upper outer quadrant of the buttock or upper portion of the deltoid muscle. The site should be rotated for repeated injections.

Children.

Over 5 years of age, one-third to one-half of the appropriate adult dosage may be given; for younger children the oral dose may be calculated on the basis of 0.5 mg/kg bodyweight. This gives doses of 5 mg at 1 year, 7.5 mg at 3 years and 10 mg at 6 years. These doses may be repeated three or four times a day as necessary. Children need to be monitored for hypothermia and hypotension.

Hepatic or renal impairment.

The dosage in these patients may need to be reduced (see Section 4.4 Special Warnings and Precautions for Use).

Elderly or debilitated.

The dosage in these patients may need to be reduced (see Section 4.4 Special Warnings and Precautions for Use).

4.7 Effects on Ability to Drive and Use Machines

Chlorpromazine may impair mental and/or physical abilities especially during the first few days of therapy. Therefore, caution patients about activities requiring alertness (e.g. operating machinery or vehicles).

4.9 Overdose

The symptoms of overdosage with chlorpromazine include CNS depression progressing from drowsiness to coma with areflexia; patients with early or mild intoxication may experience restlessness, confusion and excitement. Other symptoms include hypotension, tachycardia, hypothermia, pupillary constriction, tremor, muscle twitching, spasm or rigidity, convulsions, muscular hypotonia, difficulty in swallowing and breathing, cyanosis and respiratory and/or vasomotor collapse, possibly with sudden apnoea. Polyuria has also been noted which may result in dehydration. Deaths in young children have followed ingestion of 350 to 800 mg of chlorpromazine. Acute toxicity has been determined in animals. LD50 values range from 15 mg/kg (intravenous, rabbit) to 75 mg/kg (oral, mouse).
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia) or the National Poisons Information Centre on 0800 POISON or 0800 764 766 (New Zealand).

Treatment.

Symptomatic and supportive treatment should be administered as appropriate. Removal of the drug by inactivation by administering activated charcoal should be considered. Emetics should not be used, not only because the antiemetic action of chlorpromazine prevents the effect of the emetic agent, but also because the sedative and extrapyramidal side effects increase the risk of pulmonary aspiration should vomiting occur.
To counter acute hypotension, the patient should be placed in the head down position and noradrenaline or phenylephrine administered intravenously. Adrenaline is contraindicated as it may produce a further fall in blood pressure (see Section 4.4 Special Warnings and Precautions for Use).
The central nervous depression should generally be allowed to recover naturally, however artificial respiration may be required. Appropriate antibiotic therapy should be instituted for any respiratory infections.
Hypothermia should be allowed to recover naturally unless the temperature approaches levels at which cardiac arrhythmias may be feared (e.g. 29.4°C). Shivering is a sign of the waning effects of the drug.
Severe extrapyramidal reactions should be treated with benztropine or another antiparkinsonian agent (intramuscular dose in adults: 1 to 2 mg, children: 0.2 to 0.25 mg initially with increments if necessary).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablets.

Lactose monohydrate, maize starch, colloidal anhydrous silica, magnesium stearate, hypromellose, macrogol 200, titanium dioxide. All tablets are coated with opaspray white M-1-7111B (PI 1471).

Syrup.

Citric acid, sucrose, caramel, spearmint oil, peppermint oil, essence fruit cup special HC4497 (PI 1747), polysorbate 20, sodium citrate dihydrate, ascorbic acid, sodium sulfite, sodium metabisulfite, sodium benzoate, purified water.

Injection.

Sodium sulfite, sodium metabisulfite, sodium chloride, sodium citrate dihydrate, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Tablets.

Store tablets below 30°C.

Syrup.

Store below 25°C. Protect from light.

Injection.

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Tablets.

10 mg (white, film coated) blister pack: 100s.
25 mg (white, film coated) blister pack: 100s.
100 mg (white, film coated) blister pack: 100s.

Syrup.

100 mL glass type III bottle (25 mg/5 mL).

Injection.

2 mL ampoules (50 mg/2 mL): 10s.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes