Avloclor 250 mg Tablets

Tablets containing 250 mg chloroquine phosphate Ph. Eur. which is equivalent to 155 mg chloroquine base.

For a full list of excipients, see section 6.1.

Tablets.

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.

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.

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 Avloclor 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 - 15 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 Avloclor 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 Avloclor 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 Avloclor 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 Avloclor to patients with renal disease or hepatic disease.

Known hypersensitivity to chloroquine or any other ingredients of the formulation.

Concomitant use with amiodarone. (See section 4.5)

When used as malaria prophylaxis official guidelines and local information on prevalence of resistance to anti-malarial drugs should be taken into consideration.

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.

Caution is necessary when giving Avloclor to patients with renal disease.

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 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 Avloclor for long-term high dosage therapy and such use should only be considered when no other drug is available. Patients on longterm 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 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.

If the patient is taking amiodarone then chloroquine and hydroxychloroquine may increase the risk of cardiac arrhythmias including ventricular arrhythmias, bradycardias and cardiac conduction defect. Concurrent use is contraindicated.

Antacids (aluminium, calcium and magnesium salts) and adsorbents (e.g. kaolin) may reduce the absorption of chloroquine, so should be taken well separated from 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 the antibody response. When vaccinated against rabies, that vaccine should precede the start of the 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.

Pregnancy

Avloclor should not be used during pregnancy unless, in the judgement of the physician, potential benefit outweighs the risk.

Short-term malaria prophylaxis:

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.

Long-term high dose:

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.

Lactation

Although Avloclor is 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 are used for rheumatoid disease, breast feeding is not recommended.

Defects in visual accommodation may occur on first taking Avloclor and patients should be warned regarding driving or operating machinery.

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.

Cardiovascular: hypotension and ECG changes (at high doses) cardiomyopathy.

Central nervous system: convulsions and psychotic reactions including hallucinations (rare), anxiety, personality changes.

Eye disorders: retinal degeneration, macular defects of colour vision, pigmentation, optic atrophy scotomas, field defects, blindness, corneal opacities and pigmented deposits, blurring of vision, difficulty in accommodation, diplopia.

Gastro-intestinal: gastro-intestinal disturbances, nausea, vomiting, diarrhoea, abdominal cramps.

General: headache.

Haematological: bone marrow depression, aplastic anaemia, agranulocytosis, thrombocytopenia, neutropenia.

Hepatic: Changes in liver function, including hepatitis and abnormal liver function tests, have been reported rarely.

Hypersensitivity: allergic and anaphylactic reactions, including urticaria, angioedema and vasculitis.

Hearing disorders: tinnitus, reduced hearing, nerve deafness.

Muscular: neuromyopathy and myopathy.

Respiratory: diffuse parenchymal lung disease.

Skin: macular, urticarial and purpuric skin eruptions, occasional depigmentation or loss of hair, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, precipitation of psoriasis, pruritus, photosensitivity, lichen-planus type reaction, pigmentation of the skin and mucous membranes (long term use).

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 after initial nausea and vomiting. Cardiac complications may occur without progressively deepening coma.

Death may result from circulatory or respiratory failure or cardiac arrhythmia. 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).

Gastric lavage should be carried out urgently, first protecting the airway and instituting artificial ventilation where necessary. There is a risk of cardiac arrest following aspiration of gastric contents in more serious cases. Activated charcoal left in the stomach may reduce absorption of any remaining chloroquine from the gut. Circulatory status (with central venous pressure measurement), respiration, plasma electrolytes and blood gases should be monitored, with correction of hypokalaemia and acidosis if indicated. Cardiac arrhythmias should not be treated unless life threatening; drugs with quinidine-like effects should be avoided. Intravenous sodium bicarbonate 1-2mmol/kg over 15 minutes may be effective in conduction disturbances, and DC shock is indicated for ventricular tachycardia and ventricular fibrillation.

Early administration of the following has been shown to improve survival in cases of serious poisoning:

1. Adrenaline infusion 0.25micrograms/kg/min initially, with increments of 0.25micrograms/kg/min 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 (2mg/kg over 30 minutes as a loading dose, followed by 1-2mg/kg/day for up to 2-4 days). Diazepam may minimise cardiotoxicity.

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.

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.

Avloclor 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.

Magnesium stearate Ph. Eur.

Maize starch Ph. Eur.

None have been reported or are known.

5 years.

Do not store above 30°C. Protect from light and moisture.

HDPE bottle of 100's and PVC/Aluminium Foil Blister Pack of 20's

No special instructions.

AstraZeneca UK Limited

600 Capability Green,

Luton, LU1 3LU, UK

PL 17901/0003

18^th June 2000/4^th June 2005

6^th July 2010