- proguanil hydrochloride
- chloroquine phosphate
This information is intended for use by health professionals
|Paludrine (at the same time each day)||Avloclor (on the same day each week)|
|1 to 4 years||Half of a tablet||Half of a tablet|
|5 to 8 years||One tablet||One tablet|
|9 to 14 years||One and a half tablets||One and a half tablets|
|Creatinine clearance (ml/min/1.73 m2)||Dosage|
|≥ 60||200 mg once daily (standard dose)|
|20 to 59||100 mg once daily|
|10 to 19||50 mg every second day|
|< 10||50 mg once weekly|
|Creatinine clearance (ml/min/1.73 m2)||Approx* serum creatinine (micromol/l)||Renal Impairment Grade (arbitrarily divided for dosage purposes)|
|20 to 59||150 to 300||Mild|
|10 to 19||300 to 700||Moderate|
|< 10||> 700||Severe|
PaludrineRenal Impairment: Haematological changes in patients with severe renal impairment have been reported. (see section 4.8)Paludrine should be used with caution in patients with severe renal impairment. (See also Section 4.2).
AvloclorCaution is necessary when giving Avloclor to patients with renal disease.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 intervalChloroquine 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 (see section 4.5) 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. Therefore, the recommended dose should not be exceeded (see also sections 4.8 and 4.9).If signs of cardiac arrhythmia occur during treatment with chloroquine, treatment should be stopped and an ECG should be performed.
CardiomyopathyIn patients receiving chloroquine therapy cases of cardiomyopathy have been reported, leading to heart failure, sometimes with fatal outcome (see sections 4.8 and 4.9). If signs and symptoms of cardiomyopathy occur during treatment with chloroquine, treatment should be stopped.Caution is necessary when giving Avloclor to patients with impaired hepatic function, particularly when associated with cirrhosis.Caution is also necessary in patients with porphyria. Avloclor 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.Avloclor should be used with care in patients with a history of epilepsy. Potential risks and benefits should be carefully evaluated before use in subjects taking anti-convulsant therapy or with a history of epilepsy as, rarely, cases of convulsions have been reported in association with chloroquine (see section 4.5).The use of Avloclor 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 (see section 4.8) have been reported during treatment with chloroquine, usually disappearing on discontinuation of treatment and / or on symptomatic treatment.
Prolonged or high dose Avloclor therapy:Considerable caution is needed in the use of Avloclor 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 be monitored for cardiomyopathy (see section 4.8).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 36 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.
Drugs known to prolong QT interval / with potential to induce cardiac arrhythmiaChloroquine should be used with caution in patients receiving drugs known to prolong the QT interval e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, antipsychotics, some anti-infectives due to increased risk of ventricular arrhythmia (see sections 4.4 and 4.9). Halofantrine should not be administered with chloroquine. In particular, amiodarone should not be used and its use is contraindicated.Antacids (aluminium, calcium and magnesium salts) and adsorbents (e.g. kaolin) may reduce the absorption of proguanil and chloroquine, so antacids should be taken well separated from Paludrine and Avloclor (at least four hours apart).If the patient is taking ciclosporin then chloroquine may cause an increase in ciclosporin levels.Pre-exposure intradermal human diploid-cell rabies vaccine should not be administered to patients taking chloroquine as this may suppress antibody response. When vaccinated against rabies, that vaccine should precede the start of antimalarial dosing, otherwise the effectiveness of the vaccine might be reduced.Chloroquine significantly reduces levels of praziquantel. Caution is therefore advised during co-administration. Prescribers may consider increasing the dose of praziquantel if the patient does not respond to the initial dose.
|Anticoagulants:||proguanil can potentiate the anticoagulant effect of warfarin and related anticoagulants through a possible interference with their metabolic pathways. Caution is advised when initiating or withdrawing malaria prophylaxis with Paludrine in patients on continuous treatment with anticoagulants.|
|Other antimalarials:||increased risk of convulsion with mefloquine.|
|Cardiac glycosides:||hydroxychloroquine and possibly chloroquine increase plasma concentration of digoxin.|
|Parasympathomimetics:||chloroquine and hydroxychloroquine have potential to increase symptoms of myasthenia gravis and thus diminish effect of neostigmine and pyridostigmine.|
|Ulcer healing drugs:||cimetidine inhibits metabolism of chloroquine (increased plasma concentration).|
PregnancyAvloclor and Paludrine should not be used during pregnancy unless, in the judgement of the physician, potential benefit outweighs the risk.Short-term malaria prophylaxis: There are limited data available from the use of proguanil in pregnant women.Malaria in pregnant women increases the risk of maternal death, miscarriage, still-birth and low birth weight with the associated risk of neonatal death. Travel to malarious areas should be avoided during pregnancy but, if this is not possible, women should receive effective prophylaxis.Proguanil is a dihydrofolate reductase inhibitor (see section 5.1) and adequate folate supplements should be given to pregnant women taking proguanil.Long-term high dose Avloclor therapy:There is evidence to suggest that Avloclor given to women in high doses throughout pregnancy can give rise to foetal abnormalities including visual loss, ototoxicity and cochlear-vestibular dysfunction.
LactationAlthough both Paludrine and Avloclor are excreted in breast milk, the amount is too small to be harmful when used for malaria prophylaxis but as a consequence is insufficient to confer any benefit on the infant. Separate chemoprophylaxis for the infant is required. However, when long-term high doses of chloroquine are used for rheumatoid disease, breast feeding is not recommended.
|System Organ Class||Undesirable effect and Frequency|
|Blood and lymphatic system disorders||Not known Haematological changes such as aplastic anaemia, anaemia megaloblastic and pancytopenia (see section 4.4).|
|Immune system disorders||Rare Hypersensitivity, including urticaria, angioedema Very Rare Vasculitis.|
|Gastrointestinal disorders||Not known Gastric disorder, including diarrhoea and constipation* Mouth ulceration Stomatitis|
|Hepatobiliary disorders||Very rare Cholestasis|
|Skin and subcutaneous tissue disorders||Not known Skin reactions such as skin exfoliation, rash, pruritus and alopecia**|
|General disorders and administration site conditions:||Very Rare Pyrexia|
AvloclorAdverse reactions reported after Avloclor use are:
|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 (see section 4.4).|
|Psychiatric Disorders||Rare Hallucinations Not known Psychotic disorder including anxiety, personality change Insomnia Confusion Depression|
|Nervous system disorders||Not known Convulsion (see section 4.4) Visual field defects Headache Neuromyopathy Acute extrapyramidal disorders (such as dystonia, dyskinesia, tongue protrusion, torticollis) (see section 4.4)|
|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 (see section 4.4) Not known Atrioventricular block , QT-prolongation (see sections 4.4 and 4.9)|
|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 (AEGP)|
|Musculoskeletal and connective tissue disorders||Not known Myopathy|
|Investigations||Not known Electrocardiogram change**|
Reporting of suspected adverse reactionsReporting 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.
FeaturesThe following effects have been reported in cases of overdosage: Haematuria, renal irritation, epigastric discomfort and vomiting. There is no specific antidote and symptoms should be treated as they arise.
ManagementConsider activated charcoal in patients who have ingested 30 mg/kg or more within 1 hour. Check urea and electrolytes (U&Es), liver function test (LFTs) and full blood count (FBC) in all patients. Check FBC again 3 days and again one week after the overdose or in case any new symptoms appear.
FeaturesChloroquine 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 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.
ManagementAcute 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 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 even 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 100mm/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.
PaludrineProguanil is an antimalarial drug and dihydrofolate reductase inhibitor. It acts like the other antifolate antimalarials by interfering with the folic-folinic acid systems and thus exerts its effect mainly at the time the nucleus is dividing. Since its activity is dependent on its metabolism, proguanil has a slow schizonticidal effect in the blood. It also has some schizonticidal activity in the tissues.Proguanil is effective against the exoerythrocytic forms of some strains of plasmodium falciparum but it has little or no activity against the exoerythrocytic forms of p. Vivax. It has a marked sporonticidal effect against some strains of p falciparum; it does not kill the gametocytes, but renders them non-infective for the mosquito while the drug is present in the blood. Malaria parasites in the red blood cells are killed more rapidly by chloroquine or quinine than by proguanil, which is therefore not the best drug to use for the treatment of acute malaria.Soon after proguanil was introduced, it was observed that the drug was inactive as an inhibitor of the in vitro growth of p. Gallinaceum and p. Cynomolgi, but that sera from dosed monkeys were active against p. Cynomolgi in vitro. These findings suggested that proguanil was activated in vivo.Since that time it has been accepted by most investigators in this field that cycloguanil is the active metabolite of proguanil and that parent compound is inactive per se.Cycloguanil acts by binding to the enzyme dihydrofolate reductase in the malaria parasite. The effect of this action is to prevent the completion of schizogony. This is seen in the asexual blood stages as an arrest of maturation of the developing schizonts and an accumulation of large, abnormal looking trophozoites.Proguanil is highly active against the primary exoerythocytic forms of p. Falciparum and it has a fleeting inhibiting action on those of p. Vivax. Proguanil is therefore a valuable drug for causal prophylaxis in falciparum malaria.
AvloclorThe 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.
PaludrineAbsorption: Rapid, reaching a peak at 3 to 4 hours. The active metabolite (cycloguanil) peaks somewhat later (4 to 9 hours).Half-life: The half-life of proguanil is 14 to 20 hours, whilst cycloguanil has a half-life of the order of 20 hours. Accumulation during repeated dosing is therefore limited, steady-state being reached within approximately 3 days.Metabolism: Transformation of proguanil into cycloguanil is associated with cytochrome P450, CYP 2C19, activity. A smaller part of the transformation of proguanil into cycloguanil is probably catalysed by CYP 3A4.Elimination: Elimination occurs both in the faeces and, principally, in the urine. In the event of a daily dose being missed, the blood levels fall rapidly but total disappearance of the drug only occurs 3 to 5 days after stopping treatment.
AvloclorStudies 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 54-102 microgram/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.
|Calcium carbonate||Magnesium stearate (E572)|
|Magnesium stearate (E572)|