SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Paludrine 100 mg tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Proguanil hydrochloride B.P. 100 mg.

3    PHARMACEUTICAL FORM

Tablets for oral administration.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

‘Paludrine’ is an effective antimalarial agent.

It is recommended for the prevention and suppression of malaria.

4.2    Posology and method of administration

Non-immune subjects entering a malarious area are advised to begin 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.

Adults:    Two tablets (200 mg) daily.

Children: Under 1 year:	1/4	tablet	(25	mg)	daily
1 to 4 years:	1/2	tablet	(50	mg)	daily
5 to 8 years:	1	tablet	(100	mg)	daily

9 to 14 years: 1    1/2 tablets (150 mg) daily

Over 14 years: Adult dose daily

The daily dose is best taken with water, after food, at the same time each day.

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

For a young child, the dose may be administered crushed and mixed with milk, honey or jam. The treatment should be started at least two days before entering the malarious area and continued for the whole period of stay and 4 weeks after leaving the area.

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.

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)

Creatinine    Dosage

(clearance ml/mm 1.73 m²)

>60    200 mg once daily (standard dose)

20 to 59    100mg once daily

l0 to 19    50mg every second day

<10    50 mg once weekly

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

Approx*    Renal    Impairment

Serum creatinine    Grade (arbitrarily divided

(micromol/l)    for dosage purposes)

>60

20 to 59 10 to 19 <10

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

4.3 Contraindications

‘Paludrine’ should be used with caution in patients with severe renal impairment. (See also Sections 4.2 and 4.4)

4.4 Special warnings and precautions for use

‘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.

In any locality where drug-resistant malaria is known or suspected, it is essential to take local medical advice on what prophylactic regimen is appropriate. Prophylactic use of Paludrine alone may not be sufficient.

4.5 Interaction with other medicinal products and other forms of interaction

Antacids may reduce the absorption of proguanil, so should be taken at least 23 hours apart.

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.

4.6 Fertility, Pregnancy and lactation

Pregnancy: 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.

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

Malaria in pregnant women increases the risk of maternal death, miscarriage, still-birth and low birth weight with the associated risk of neonatal death. Although travel to malarious areas should be avoided during pregnancy, if this is unavoidable effective prophylaxis is therefore strongly advised in pregnant women.

Lactation: Although Paludrine is excreted in breast milk, the amount is insufficient to confer any benefit on the infant. Separate chemoprophylaxis for the infant is required.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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.

4.9 Overdose

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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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.

5.2 Pharmacokinetic properties

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 cvtochrome P450, GYP 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.

5.3 Preclinical safety data

Proguanil is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Calcium carbonate Gelatin

Magnesium stearate Maize starch

6.2 Incompatibilities

None known.

6.3 Shelf life

5 years.

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