Paludrine/Avloclor Anti-malarial Travel Pack.

Chloroquine and Proguanil Anti-malarial Tablets.

Paludrine tablets containing 100 mg proguanil hydrochloride

Avloclor tablets containing 250 mg chloroquine phosphate, which is equivalent to 155 mg chloroquine base.

For a full list of excipients, see section 6.1.

Tablets.

Prophylaxis and suppression of malaria.

Non-immune subjects entering a malarious area are advised to begin daily treatment with Paludrine 1 week before, or if this is not possible, then at least 2 days before entering the malarious area. The daily dose of Paludrine should be continued throughout exposure to risk and for 4 weeks after leaving the area.

A single dose of Avloclor should be taken each week on the same day each week. Start one week before exposure to risk and continue until 4 weeks after leaving the malarious area.

Each dose should be taken with water after food.

Adults and children over 14 years: Take two Paludrine tablets daily as directed above. Take two Avloclor tablets once a week as directed above.

Children: Do not give to children under 1 year. The following single dose of Paludrine should be taken at the same time each day and the following single dose of Avloclor should be taken once a week on the same day each week.

For a young child the dose may be administered crushed and mixed with milk, honey or jam.

Provided the Paludrine tablet fragment gives the minimum amount specified, precise accuracy in children's dosage is not essential since the drug possesses a wide safety margin.

The Avloclor dose given to children should be calculated on their body weight (5 mg chloroquine base/kg/week) and must not exceed the adult dose regardless of weight.

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.

Paludrine and Renal Impairment: Based on a theoretical model derived from a single dose pharmacokinetic study, the following guidance is given for adults with renal impairment. (See also Sections 4.3 and 4.4).

The grade of renal impairment and/or the serum creatinine concentration may be approximately equated to creatinine clearance levels as indicated below.

*Serum creatinine concentration is only an approximate guide to renal function unless corrected for age, weight and sex.

Avloclor and 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.

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

Paludrine should be used with caution in patients with severe renal impairment. (See also Section 4.2). There have been rare reports of haematological changes in such patients. Caution is necessary when giving Avloclor to patients with renal disease.

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.

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.

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.

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.

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.

Antacids (aluminium, calcium and magnesium salts) may reduce the absorption of proguanil and chloroquine, so antacids should be taken well separated from Paludrine and Avloclor (at least two hours before or after).

If the patient is taking cyclosporin then chloroquine may cause an increase in cyclosporin 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.

Pregnancy

Avloclor and Paludrine 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 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. Paludrine has been widely used for over 40 years and a causal connection between its use and any adverse effect on mother or foetus has not been established.

Lactation

Although 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.

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

There is no evidence to suggest that Paludrine causes sedation or is likely to affect concentration.

The adverse reactions which may occur at doses used in the prophylaxis of malaria are generally not of a serious nature. Where prolonged high dosage of chloroquine is required, i.e. in the treatment of rheumatoid arthritis, adverse reactions can be of a more serious nature.

Paludrine

At normal dosage levels the side effect most commonly encountered is mild gastric intolerance, including diarrhoea and constipation. This usually subsides as treatment is continued.

Mouth ulceration and stomatitis have on occasion been reported. Isolated cases of skin reactions and reversible hair loss have been reported in association with the use of proguanil.

Rarely, allergic reactions which manifest as urticaria or angioedema and very rarely vasculitis, have been reported.

Drug fever and cholestasis may very rarely occur in patients receiving Paludrine.

Haematological changes in patients with severe renal impairment have been reported.

Avloclor

Adverse reactions reported after Avloclor use are:

Paludrine

The 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.

Avloclor

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 0.25 micrograms/kg/min initially, with increments of 0.25 micrograms/kg/min 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 (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.

Paludrine

Proguanil 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.

Avloclor

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.

Paludrine

Absorption: 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.

Avloclor

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 54-102 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.

Both Paludrine and Avloclor have been extensively used for many years in clinical practice. All relevant information for the prescriber is provided elsewhere in this document.

None known.

5 years.

Do not store above 30°C. Store in the original package.

PVC/PVDC Aluminium Foil Blister Pack of 112's containing 98 Paludrine and 14 Avloclor tablets.

No special instructions.

AstraZeneca UK Limited,

600 Capability Green,

Luton, LU1 3LU, UK.

PL 17901/0037

18^th June 2000/5^th November 2002

6^th July 2010