(1995; 152 pages) [French] [Spanish]
Group: antimalarial agent
Tablet 200 mg, 300 mg base (as sulfate)
Injection 150 mg, 300 mg base (as dihydrochloride) per ml in 2-ml ampoule [quinine anhydrous base 100 mg is equivalent to 122 mg of quinine hydrochloride dihydrate or quinine dihydrochloride or 121 mg of quinine sulfate dihydrate]
Quinine, an alkaloid derived from the bark of the cinchona tree, is a blood schizontocidal agent that is more toxic than chloroquine. Its use has become reestablished because of the widespread emergence of chloroquine-resistant - and, more recently, multiple-drug-resistant - strains of malarial parasites.
Quinine is rapidly absorbed when taken orally and peak plasma concentrations are attained after 1-3 hours. It is highly protein-bound but it readily crosses the placental barrier and small amounts penetrate into the cerebrospinal fluid. It is metabolized in the liver, has a plasma half-life of 10 hours and is subsequently excreted in the urine, mainly as hydroxylated metabolites.
Quinine is used in the treatment of falciparum malaria in areas of multiple-drug-resistant P. falciparum.
It is administered parenterally to patients with severe or complicated malaria who cannot take drugs by mouth because of coma, convulsions or vomiting.
It is administered orally to less seriously ill patients with infections likely to be resistant to chloroquine or mefloquine, sometimes in combination with pyrimethamine/sulfadoxine or a tetracycline.
Dosage and administration
Unless otherwise stated, all dosages are described in terms of the base. However, most dose-finding studies for parenteral administration have been carried out with the salt quinine dihydrochloride.
Adults and children: an initial dose of 16.4 mg (equivalent to 20 mg of dihydrochloride)/kg is infused over 4 hours followed by 8.2 mg (equivalent to 10 mg of dihydrochloride)/kg every 8 hours in adults and every 12 hours in children. However, the initial dose should be halved if the patient has received quinine, quinidine or mefloquine during the previous 12-24 hours. The maintenance doses should be reduced threefold in patients with impaired renal function. Pulse and blood pressure should be closely monitored during administration and the rate of infusion reduced if dysrhythmias occur.
The required dose, diluted preferably in 5% (w/v) glucose solution to counteract hypoglycaemia, is given in a total volume of 5-10 ml/kg by infusion into a large vein. In the absence of glucose, physiological saline may be used. This method of administration minimizes the danger of severe hypotension and subsequent respiratory collapse.
Where facilities for intravenous infusion do not exist, quinine can be administered intramuscularly in the same dosage. The required dose should be divided equally between two sites, one in each anterior thigh. However, in some cases, muscle necrosis and sterile abscesses have been reported.
Parenteral treatment should be discontinued as soon as the patient is able to take quinine orally. A radical cure should then be effected using pyrimethamine/sulfadoxine, mefloquine or oral quinine combined with tetracycline (except in pregnant women and children under 8 years), according to the susceptibility of the parasite.
When quinine is not available, quinidine may be administered. An initial loading dose of 15 mg/kg in physiological saline is given over 4 hours. This is followed by a maintenance dose of 7.5 mg/kg infused every 8 hours until the patient is able to take quinidine by mouth. Pulse, blood pressure and electrocardiographic monitoring must be undertaken.
Quinine should be given orally for the treatment of uncomplicated multi-drug-resistant falciparum malaria and to complete the treatment of patients with severe or complicated malaria, who are initially treated parenterally. If part or all of a dose is vomited within 1 hour, the same amount must be readministered immediately.
Adults: 500 mg (equivalent to quinine sulfate dihydrate 600 mg) every 8 hours for 3, 7 or 10 days.
Children: 8.2 mg (equivalent to quinine sulfate dihydrate 10 mg)/kg every 8 hours for 3, 7 or 10 days.
The duration of treatment depends on the local susceptibility of P. falciparum to quinine and on whether treatment is combined with pyrimethamine/sulfadoxine or tetracycline.
• Known hypersensitivity.
Whenever possible, blood glucose should be monitored throughout treatment. Both the disease itself and the administration of quinine may promote insulin secretion and induce hypoglycaemia. This may require correction by infusion of a 20% or 50% glucose solution. In patients who are seriously ill, treatment should always be accompanied by continuous infusion of carbohydrates.
Haemolysis can occasionally be severe enough to warrant discontinuation of quinine treatment if an alternative is available.
Use in pregnancy
Quinine should not be withheld during pregnancy, despite its alleged abortifacient properties at high dosage, since it safeguards the life of the mother.
Attention should be given to the considerable risk of hypoglycaemia in pregnant women with severe malaria.
Serious reactions are infrequent provided the plasma concentration is not allowed to rise above 15 mg/l.
Signs of mild to moderate cinchonism (tinnitus, headache, blurred vision, altered auditory acuity, nausea and diarrhoea) often supervene after the third day of treatment. These rarely, if ever, constitute grounds for withdrawal. However, if, as a result of non-compliance, quinine has to be withdrawn prematurely, tetracycline must be administered for a further 7 days.
Idiosyncratic reactions can also occur, but they are uncommon. They include pruritic, urticarial or erythematous rashes, subcutaneous or submucous haemorrhage, and oedema of the eyelids, mucous membranes and lungs. Haemoglobinuria and asthma are rare.
Hypoglycaemia should be treated promptly with supplementary glucose.
Renal damage, culminating in acute renal failure and anuria, is a frequent terminal event in malaria. Rarely, anuria is a consequence of blackwater fever, a syndrome comprising massive haemolysis, haemoglobinaemia and haemoglobinuria. Although this has been ascribed in the past to inadequate quinine therapy, the supporting evidence is insecure. Blackwater fever certainly occurs in patients who have not received treatment with quinine.
Dose-related adverse effects are largely limited to the cardiovascular, gastrointestinal and central nervous systems. They usually arise from excessive infusion, but quinine accumulation can result from oral administration.
The most frequently encountered signs of overdosage are:
• Tinnitus, decreased auditory acuity and vertigo. Permanent deafness has resulted from exposure to toxic doses.
• Amblyopia, constricted visual fields, diplopia and night blindness. Recovery is slow but usually complete.
• Quinidine-like effects resulting in hypotension, conduction disturbances, anginal symptoms and ventricular tachycardia.
• A local irritant effect on the gastrointestinal tract resulting in nausea, vomiting, abdominal pain and diarrhoea.
A single oral dose greater than 3 g is capable of causing serious and potentially fatal intoxication in adults, preceded by depression of the central nervous system and seizures. Much smaller doses can be lethal in children.
Dysrhythmias, hypotension and cardiac arrest can result from the cardiotoxic action and ocular toxicity can lead to blindness.
Emesis should be induced and gastric lavage undertaken as rapidly as possible. Activated charcoal should then be administered.
Supportive measures, to be employed as necessary, include ventilation, and symptomatic treatment of dysrhythmias, cardiac failure and convulsions. No specific measures of proven efficacy exist to reduce the toxicity or to promote the excretion of quinine.
Tablets should be stored in tightly closed containers, protected from light. Quinine injection should also be stored protected from light.