Features
Chloroquine is highly toxic in overdose and children are particularly susceptible. The chief symptoms of overdosage include circulatory collapse due to a potent cardiotoxic effect, respiratory arrest and coma. Symptoms may progress rapidly and include:
- General features include nausea and vomiting. Hypokalaemia is common in severe poisoning and metabolic acidosis may also develop. Rarely hepatotoxicity, nephritis, gastric haemorrhage, haematological abnormalities and psychiatric features may occur.
- Neurological features include headache, dizziness, drowsiness, blurred vision, diplopia and, rarely, blindness, may precede restlessness, increased excitability and convulsions. Coma is less common.
- Cardiac features often appear at an early stage. Cardiac arrest may be a presenting feature. Hypotension is very common and may progress to cardiogenic shock and pulmonary oedema.
With serious intoxication, width-increased QRS complex, bradyarrhythmias, nodal rhythm, QT prolongation, atrioventricular block, ventricular tachycardia, torsades de pointes, ventricular fibrillation may occur.
Intraventricular conduction defects with a wide QRS, and prolongation of the QT interval are more common than A-V (atrioventricular) conduction defects. Ventricular tachycardia and fibrillation tend to occur early while torsade de pointes develops after about 8 hours.
Management
Acute overdose with chloroquine can be rapidly lethal and intensive supportive treatment should be started immediately.
Death may result from circulatory or respiratory failure or cardiac arrhythmia but is usually due to cardiac arrest related to the direct effects on the myocardium. If there is no demonstrable cardiac output due to arrhythmias, asystole or electromechanical dissociation, external chest compression should be persisted with for as long as necessary, or until adrenaline and diazepam can be given (see below).
Firstly, maintain a clear airway and ensure adequate ventilation. The benefit of gastric decontamination is uncertain, but activated charcoal can be considered for adults and children aged over 5 years, within 1 hour of ingestion of more than 10 mg/kg of chloroquine base as a single dose or for any amount in a child aged 5 years and under, as it may reduce absorption of any remaining chloroquine from the gut. Activated charcoal should also be considered within 1 hour of ingestion of a weekly dose taken on 2 or more consecutive days. Alternatively, gastric lavage may be considered in adults within 1 hour of a potentially life threatening overdose. There is a risk of cardiac arrest following aspiration of gastric contents in more serious cases.
Monitor circulatory status (with central venous pressure measurement), cardiac rhythm, respiration, conscious level and urinary output. Check urea & electrolytes, liver function and full blood count in symptomatic patients. Consider arterial blood gas analysis in patients who have a reduced level of consciousness or have reduced oxygen saturation on pulse oximetry.
It is not clear if correction of hypokalaemia is essential but it may have a protective effect and should not be corrected in the early stages of poisoning. The degree of hypokalaemia may be correlated with the severity of chloroquine intoxication. If it persists beyond 8 hours, cautious correction should be undertaken with frequent biochemical monitoring of progress. Rebound hyperkalaemia is a risk during recovery.
In case of persistent metabolic acidosis consider intravenous sodium bicarbonate. Rapid correction is particularly important if there is prolongation of the QRS interval. DC (direct current) shock is indicated for ventricular tachycardia and ventricular fibrillation.
Cardiac arrhythmias should be treated with caution. The use of anti-arrhythmic drugs (such as those with quinidine-like effects) is best avoided since they may depress the myocardium further and exacerbate hypotension.
Early administration of the following has been shown to improve survival in cases of serious poisoning:
1. Adrenaline infusion until adequate systolic blood pressure (more than 100mg/Hg) is restored; adrenaline reduces the effects of chloroquine on the heart through its inotropic and vasoconstrictor effects.
2. Diazepam infusion; diazepam may decrease the cardiotoxicity of chloroquine.
Acidification of the urine, haemodialysis, peritoneal dialysis or exchange transfusion have not been shown to be of value in treating chloroquine poisoning. Chloroquine is excreted very slowly, therefore cases of overdosage require observation for several days.
Known hypersensitivity to chloroquine or any other ingredients of the formulation.
Concomitant use with amiodarone.
None have been reported or are known.
The adverse reactions which may occur at doses used in the prophylaxis or treatment of malaria are generally not of a serious nature. Where prolonged high dosage is required, i.e. in the treatment of rheumatoid arthritis, adverse reactions can be of a more serious nature.
Undesirable effects are listed by MedDRA System Organ Classes.
Assessment of undesirable effects is based on the following frequency groupings:
Very common: >1/10
Common: >1/100 to <1/10
Uncommon: >1/1,000 to <1/100
Rare: >1/10,000 to <1/1,000
Very rare: <1/10,000
Not known: cannot be estimated from the available data
| System Organ Class | Undesirable Effect and Frequency |
| Blood and lymphatic system disorders | Not known Bone marrow failure Aplastic anaemia Agranulocytosis Thrombocytopenia Neutropenia Pancytopenia |
| Immune system disorders | Not known Hypersensitivity and anaphylactic reactions, including urticaria, angioedema and vasculitis. |
| Metabolism and nutrition disorders | Not known Hypoglycaemia. |
| Psychiatric Disorders | Rare Hallucinations Not known Psychotic disorder including anxiety, personality change Insomnia Confusion Depression |
| Nervous system disorders | Not known Convulsion Visual field defects Headache Neuromyopathy Acute extrapyramidal disorders (such as dystonia, dyskinesia, tongue protrusion, torticollis) |
| Eye disorders | Not known Retinal degeneration Macular defects of colour vision Pigmentation Optic atrophy scotomas Blindness Corneal opacity and pigmented deposits Vision blurred Accommodation disorder Diplopia |
| Ear and labyrinth disorders | Not known Tinnitus Hypoacusis Deafness neurosensory |
| Cardiac disorders | Rare Cardiomyopathy Not known Atrioventricular block , QT-prolongation |
| Vascular Disorders | Not known Hypotension |
| Respiratory, thoracic and mediastinal | Not known Diffuse parenchymal lung disease |
| Gastrointestinal disorders: | Not known Gastrointestinal disorder Nausea Vomiting Diarrhoea Abdominal pain |
| Hepatobiliary disorders | Rare Changes in liver function, including hepatitis and abnormal liver function tests |
| Skin and subcutaneous tissue disorders | Not known Macular, urticarial and purpuric skin eruptions Alopecia Erythema multiforme Drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) Stevens-Johnson syndrome (SJS) Toxic epidermal necrolysis (TEN) Precipitation of psoriasis Pruritus Photosensitivity reaction Lichenoid keratosis Pigmentation disorder * Exfoliative dermatitis Acute generlised exanthematous pustulosis (AGEP) |
| Musculoskeletal and connective tissue disorders | Not known Myopathy |
| Investigations | Not known Electrocardiogram change** |
* Long term use
**At high doses
Reporting of suspected adverse reactions
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 the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.
Arechin has been widely used for many years in clinical practice. There is no animal data which adds significant information relevant to the prescriber, to that covered elsewhere in this document.
a) Treatment of malaria.
b) Prophylaxis and suppression of malaria.
c) Treatment of amoebic hepatitis and abscess.
d) Treatment of discoid and systemic lupus erythematosus.
e) Treatment of rheumatoid arthritis.
Pharmacotherapeutic group: Antiprotozoals, Antimalarials
ATC code: P01BA01
The mode of action of chloroquine on plasmodia has not been fully elucidated. Chloroquine binds to and alters the properties of DNA. Chloroquine also binds to ferriprotoporphyrin IX and this leads to lysis of the plasmodial membrane.
In suppressive treatment, chloroquine inhibits the erythrocytic stage of development of plasmodia. In acute attacks of malaria, it interrupts erythrocytic schizogony of the parasite. Its ability to concentrate in parasitised erythrocytes may account for the selective toxicity against the erythrocytic stages of plasmodial infection.
Studies in volunteers using single doses of chloroquine phosphate equivalent to 300mg base have found peak plasma levels to be achieved within one to six hours. These levels are in the region of 54 - 102microgram/litre, the concentration in whole blood being some 4 to 10 times higher. Following a single dose, chloroquine may be detected in plasma for more than four weeks. Mean bioavailability from tablets of chloroquine phosphate is 89%. Chloroquine is widely distributed in body tissues such as the eyes, kidneys, liver, and lungs where retention is prolonged. The elimination of chloroquine is slow, with a multi exponential decline in plasma concentration. The initial distribution phase has a half-life of 2-6 days while the terminal elimination phase is 10-60 days. Approximately 50-70% of chloroquine in plasma is bound to the plasma proteins.
The principal metabolite is monodesethylchloroquine, which reaches a peak concentration of 10-20 microgram/litre within a few hours. Mean urinary recovery, within 3-13 weeks, is approximately 50% of the administered dose, most being unchanged drug and the remainder as metabolite. Chloroquine may be detected in urine for several months.
When used as malaria prophylaxis official guidelines and local information on prevalence of resistance to anti-malarial drugs should be taken into consideration.
Chloroquine has been shown to cause severe hypoglycaemia including loss of consciousness that could be life threatening in patients treated with and without antidiabetic medications. Patients treated with chloroquine should be warned about the risk of hypoglycaemia and the associated clinical signs and symptoms. Patients presenting with clinical symptoms suggestive of hypoglycaemia during treatment with chloroquine should have their blood glucose level checked and treatment reviewed as necessary.
Prolongation of QTc interval
Chloroquine has been shown to prolong the QTc interval in some patients.
Chloroquine should be used with caution in patients with congenital or documented acquired QT prolongation and/or known risk factors for prolongation of the QT interval such as:
- cardiac disease e.g. heart failure, myocardial infarction,
- proarrhythmic conditions e.g bradycardia (< 50 bpm)
- a history of ventricular dysrhythmias
- uncorrected hypokalemia and/or hypomagnesemia
- and during concomitant administration with QT interval prolonging agents
as this may lead to an increased risk for ventricular arrhythmias, sometimes with fatal outcome.
The magnitude of QT prolongation may increase with increasing concentrations of the drug.9).
If signs of cardiac arrhythmia occur during treatment with chloroquine, treatment should be stopped and an ECG should be performed.
Cardiomyopathy
In patients receiving chloroquine therapy cases of cardiomyopathy have been reported, leading to heart failure, sometimes with fatal outcome. If signs and symptoms of cardiomyopathy occur during treatment with chloroquine, treatment should be stopped.
Caution is necessary when giving Arechin to patients with impaired hepatic function, particularly when associated with cirrhosis.
Caution is also necessary in patients with porphyria. Arechin may precipitate severe constitutional symptoms and an increase in the amount of porphyrins excreted in the urine. This reaction is especially apparent in patients with high alcohol intake.
A small number of cases of diffuse parenchymal lung disease have been identified in patients taking chloroquine. A response after therapy with steroids has been observed in some of these cases.
Cases of drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been identified in patients taking chloroquine alone or in combination with proguanil. Recovery after discontinuation of treatment and response after therapy with steroids has been observed.
Caution is necessary when giving Arechin to patients with renal disease.
Arechin should be used with care in patients with a history of epilepsy. Potential risks and benefits should be carefully evaluated before use in subjects on anticonvulsant therapy or with a history of epilepsy as rare cases of convulsions have been reported in association with chloroquine.
Considerable caution is needed in the use of Arechin for long-term high dosage therapy and such use should only be considered when no other drug is available. Patients on long-term therapy should also be monitored for cardiomyopathy.
Irreversible retinal damage and corneal changes may develop during long term therapy and after the drug has been discontinued. Ophthalmic examination prior to and at 3-6 monthly intervals during use is required if patients are receiving chloroquine
- at continuous high doses for longer than 12 months
- as weekly treatment for longer than 3 years
- when total consumption exceeds 1.6 g/kg (cumulative dose 100 g)
Full blood counts should be carried out regularly during extended treatment as bone marrow suppression may occur rarely. Caution is required if drugs known to induce blood disorders are used concurrently.
The use of Arechin in patients with psoriasis may precipitate a severe attack.
Caution is advised in patients with glucose-6-phosphate dehydrogenase deficiency, as there may be a risk of haemolysis.
Acute extrapyramidal disorders have been reported during treatment with chloroquine, usually disappearing on discontinuation of treatment and /or on symptomatic treatment.
Defects in visual accommodation may occur on first taking Arechin and patients should be warned regarding driving or operating machinery.
The dose should be taken after food.
a) Treatment of malaria
i) P. falciparum and P. malariae infections
Adults: A single dose of four tablets, followed by two tablets six hours later and then two tablets a day for two days.
Children: A single dose of 10mg base/kg, followed by 5mg base/kg six hours later and then 5mg base/kg a day for two days.
| Age (years) | Initial dose | Second dose 6 hours after first | Dose on each of the two subsequent days |
| 1 - 4 | 1 Tablet | ½ Tablet | ½Tablet |
| 5 - 8 | 2 Tablets | 1 Tablet | 1 Tablet |
| 9 -14 | 3 Tablets | 1½ Tablets | 1½ Tablets |
ii) P. vivax and P. ovale infections
Adults: A single dose of four tablets, followed by two tablets six hours later and then two tablets a day for two days. Follow with a course of treatment with primaquine if a radical cure is required.
Children: A single dose of 10mg base/kg, followed by 5mg base/kg six hours later and then 5mg base/kg a day for two days. Follow with a course of treatment with primaquine if a radical cure is required.
Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.
Hepatic or Renally Impaired Patients: Caution is necessary when giving Arechin to patients with renal disease or hepatic disease.
b) Prophylaxis and suppression of malaria
Adults: Two tablets taken once a week, on the same day each week. Start one week before exposure to risk and continue until four weeks after leaving the malarious area.
Children: A single dose of 5mg chloroquine base/kg per week on the same day each week. Start one week before exposure to risk and continue until four weeks after leaving the malarious area.
For practical purposes, children aged over 14 years may be treated as adults. The dose given to infants and children should be calculated on their body weight and must not exceed the adult dose regardless of weight.
1 - 4 years ½ tablet
5 - 8 years 1 tablet
9 - 14 years 1½ tablets
Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.
Hepatic or Renally Impaired Patients: Caution is necessary when giving Arechin to patients with renal disease or hepatic disease.
c) Amoebic hepatitis
Adults: Four tablets daily for two days followed by one tablet twice daily for two or three weeks.
Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.
Hepatic or Renally Impaired Patients: Caution is necessary when giving Arechin to patients with renal disease or hepatic disease.
d) Lupus erythematosus
Adults: One tablet twice daily for one to two weeks followed by a maintenance dosage of one tablet daily.
Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.
Hepatic or Renally Impaired Patients: Caution is necessary when giving Arechin to patients with renal disease or hepatic disease.
e) Rheumatoid arthritis
Adults: The usual dosage is one tablet daily.
Elderly Patients: There are no special dosage recommendations for the elderly, but it may be advisable to monitor elderly patients so that optimum dosage can be individually determined.
Hepatic or Renally Impaired Patients: Caution is necessary when giving Arechin to patients with renal disease or hepatic disease.
No special instructions.
