4.1. Therapeutic indications

For the treatment of falciparum malaria

Treatment and prevention of nocturnal leg cramps in adults and the elderly, when cramps cause regular disruption of sleep (see section 4.2 and Section 4.4)

4.2. Posology and method of administration

For falciparum malaria

Adults: the adult dosage regimen by mouth is 600mg of quinine sulfate given every 8 hours for 7 days.

The elderly: as for adults

Children: the dosage regimen for children by mouth is 10mg of quinine sulfate per kg body weight given every 8 hours for 7 days.

Note

If quinine resistance is known or suspected in the patient, then supplementary treatment with another recommended antimalarial drug is necessary.

If part or all of the dose is vomited within 1 hour of administration, then the same amount must be administered immediately.

For the treatment and prevention of nocturnal leg cramps:

Adults (including elderly):

The recommended dose is 300mg at bedtime.

A reduction in frequency of leg cramps may take up to 4 weeks to become apparent. Patients should be monitored closely during the early stages of treatment for adverse effects. After an initial trial of 4 weeks, treatment should be stopped if there is no benefit. Treatment should be interrupted at approximately three monthly intervals to reassess the benefit of treatment.

4.3. Contraindications

-Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

- Optic neuritis

-Tinnitus

-Myasthenia gravis, quinine may cause severe respiratory distress and dysphagia in these patients

-Haemoglobinuria

4.4. Special warnings and precautions for use

Cinchonism

Administration of quinine may give rise to cinchonism, which is generally more severe in overdose, but may also occur in normal therapeutic doses. Patients should be warned not to exceed the prescribed dose, because of the possibility of serious, irreversible side effects in overdose. Treatment for night cramps should be stopped if symptoms of cinchonism emerge. Such symptoms include tinnitus, impaired hearing, headache, nausea, and disturbed vision (see sections 4.8 and 4.9).

Hypersensitivity

Hypersensitivity to quinine may also occur with symptoms of cinchonism together with urticaria, flushing, pruritus, rash, fever, angioedema, dyspnoea and asthma.

Serious hypersensitivity reactions including Stevens-Johnson syndrome have been reported with quinine.

Cardiac disorders

Quinine should be used with caution in patients with atrial fibrillation, conduction defects and heart block or other serious heart disease. It may cause hypoprothrombinaemia.

Quinine has dose-dependent QT-prolonging effects. Caution is recommended in patients with conditions which predispose to QT-prolongation and in patients with atrioventricular block.

Glucose-6-Phosphate Dehydrogenase (G-6-PD) Deficiency

The administration of quinine to a patient who has previously been suffering from a chronic and inadequately controlled malarial infection may precipitate an attack of blackwater fever. However, in some cases deficiency of glucose-6-phosphate dehydrogenase may have been involved. Glucose-6-phosphate dehydrogenase deficient patients with malaria or taking quinine to treat leg cramps may be at an increased risk of haemolytic anaemia during quinine therapy.

Quinine should not be withheld from pregnant women who have life threatening malaria (see section 4.6).

Treatment should be monitored in all patients in case signs of resistance develop.

Before use for nocturnal leg cramps, the risks, which include significant adverse effects and interactions (see above and sections 4.5 and 4.8), should be carefully considered relative to the potential benefits. These risks are likely to be of particular concern in the elderly. Quinine should only be considered when cramps are very painful or frequent, when other treatable causes of cramp have been ruled out, and when non-pharmacological measures have not worked. Quinine bisulfate should not be used for this indication during pregnancy (see section 4.6).

Quinine may cause unpredictable serious and life-threatening thrombocytopenia, which is thought to be an idiosyncratic hypersensitivity reaction. Quinine should not be prescribed or administered to patients who have previously experienced any adverse reaction to quinine, including that in tonic water or other beverages. Patients should be instructed to stop treatment and consult a physician if signs of thrombocytopenia such as unexplained bruising or bleeding occur.

May cause severe respiratory distress and dysphagia in patients with myasthenia gravis.

Renal impairment which may be due to an immune mechanism may occur. Hypoglycaemia may occur.

Patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency may develop acute haemolytic anaemia.

Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine, as it contains lactose.

Reduce the dosage (or increase intervals between doses) in renal or hepatic disease.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. is essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other drugs on quinine

CYP3A4 substrate

Quinine is metabolised via hepatic oxidative cytochrome P450 pathways, predominantly by CYP3A4. There is the potential for increased quinine toxicity with concurrent use of potent CYP3A4 inhibitors, which include azole antifungal drugs and HIV protease inhibitors.

Sub-optimal quinine serum levels may result from concomitant use of CYP3A4 inducers such as rifampicin, barbiturates, carbamazepine and phenytoin.

Care should be taken when quinine is used in combination with other CYP3A4 substrates, especially those causing prolongation of the QT interval.

Effect of quinine on other drugs

The plasma concentration of flecainide, digoxin and mefloquine may be increased.

Amantidine: Quinine can reduce the renal clearance of amantadine

Ciclosporin: Quinine can decrease serum plasma concentrations of ciclosporin

Cardiac glycosides: Quinine increases plasma concentrations of cardiac glycosides and reduced dosage of concomitant cardiac glycosides such as digoxin to half the maintenance dose may be necessary.

Other drug interactions

Drug caused QT prolongation

There is an increased risk of ventricular arrhythmias with other drugs which prolong the QT interval, including amiodarone, moxifloxacin, pimozide, thioridazine and halofantrine, and therefore concomitant use with these products should be avoided

Antiarrhythmics: Concomitant use of amiodarone should be avoided due to the increased risk of ventricular arrhythmias. The plasma concentration of flecainide is increased by quinine. Concomitant use of quinidine may increase the possibility of cinchonism.

Antibacterials; There is an increased risk of ventricular arrhythmias when moxifloxacin is given with quinine. Rifampicin can reduce the serum levels of quinine, therefore reducing its therapeutic effect.

Anticoagulants: Quinine may cause hypoprothrombinaemia and thereby enhance the effect of anticoagulants.

Antihistamines: Concomitant use of terfenadine should be avoided due to the increased risk of ventricular arrhythmias.

Antimalarials: According to the manufacturer of artemether with lumefantrine concomitant use should be avoided. There is an increased risk of convulsions when given with mefloquine. Chloroquine and quinine appear to be antagonistic when given together for P falciparum malaria. There is a decrease in plasma concentrations of primaquine.

Antipsychotics: There is an increased risk of ventricular arrhythmias and concomitant use should be avoided with pimozide or thioridazine.

Hypoglycaemics: Concurrent use with oral hypoglycaemics may increase the risk of hypoglycaemia.

Suxamethonium: Quinine enhances the neuromuscular effects of suxamethonium. Concomitant use of quinidine may increase the possibility of cinchonism.

Ulcer healing drugs: Cimetidine inhibits quinine metabolism leading to increased plasma quinine concentrations.

Caution is advised when administering quinine with drugs which could prolong the QT interval.

Quinine may increase the levels of phenobarbital and of carbamazepine.

Patients should be monitored closely during concomitant use of quinine with these agents.

4.6. Fertility, pregnancy and lactation

Pregnancy:

Quinine may cause congenital abnormalities of the CNS and extremities. Following administration of large doses during pregnancy, phototoxicity and deafness have been reported in neonates. Quinine bisulfate should not be used during pregnancy unless the benefits outweigh the risks.

Treatment of chloroquine-resistant strains of falciparium malaria: Pregnancy in a patient with malaria is not generally regarded as a contraindication to the use of quinine. As malaria infection is potentially serious during pregnancy and poses a threat to the mother and foetus, there appears to be little justification in withholding treatment in the absence of a suitable alternative.

Prophylaxis of nocturnal leg-cramps: Quinine bisulfate should not be used during pregnancy to treat cramps.

Breast-feeding:

Quinine bisulfate is excreted in breast milk, but no problems in humans have been reported. However, quinine bisulfate should not be given to nursing mothers unless the benefits outweigh the risks.

Fertility:

No data available

4.7. Effects on ability to drive and use machines

Quinine may cause visual disturbances and vertigo, hence patients should be advised that if affected they should not drive or operate machinery

4.8. Undesirable effects

Some patients are hypersensitive to quinine bisulfate and they may experience the symptoms of cinchonism together with asthma and other allergic manifestations including angioneurotic oedema and haemolytic anaemia.

Cinchonism is more common in overdose, but may occur even after normal doses of quinine. In its mild form symptoms include tinnitus, impaired hearing, rashes, headache, nausea and disturbed vision. In more severe manifestations, symptoms may include gastrointestinal symptoms, oculotoxicity, CNS disturbances, cardiotoxicity and death (see section 4.9). Visual disorders may include blurred vision, defective colour perception, visual field constriction and total blindness.

The following adverse reactions are classified by system organ class and ranked under heading of frequency using the following convention:

Not known (frequency cannot be estimated from the available data)

MedDRA system organ class

Adverse Reaction

Blood and lymphatic system disorders

Thrombocytopenia, intravascular coagulation, hypoprothrombinaemia, Haemoglobinuria, oliguria, haemolytic uraemic syndrome, pancytopenia, haemolysis, agranulocytosis, thrombocytopenic purpura

Immune system disorders

Generalised hypersensitivity reactions including angioneurotic oedema and fever.

Metabolism and nutritional disorders

Hypoglycaemia

Psychiatric disorders

Agitation, confusion

Nervous system disorders

Headache, Vertigoexcitement, loss of consciousness, coma and death have been received.

Eye disorders

Blurred vision, defective colour perception, visual field constriction,

Ear and labyrinth disorders

Tinnitus, impaired hearing

Cardiac disorders

Atrioventricular conduction disturbances, hypotension, prolongation of the QT interval, widening of the QRS complex and T wave flattening

Respiratory, thoracic and mediastinal disorders

Bronchospasmdyspnoea may occur

Gastrointestinal Disorders

Nausea, vomiting, diarrhoea, abdominal pain

Skin and subcutaneous tissue disorders

Flushing, rash, urticaria, eczematous dermatitis, oedema, erythema, lichen planus, pruritus, photosensitivityStevens-Johnson syndrome

Musculoskeletal and connective tissue disorders

Muscle weakness, aggravation of myasthenia gravis

Renal and urinary disorders

Renal insufficiency, and acute renal failure

Reproductive system and breast disorders

Toxic doses of quinine may induce abortion, but it is unwise to withhold the drug if less toxic antimalarials are not available.

Reporting of suspected adverse reactions

Reporting 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 at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Symptoms

Quinine overdosage may lead to serious side effects including irreversible visual loss and can be fatal. In acute overdosage, symptoms of cinchonism may occur, including convulsions, nausea, vomiting, tinnitus, deafness, headache, vasodilation and visual disturbance.

Features of a significant overdose include convulsions, impairment of consciousness, coma, respiratory depression, QT prolongation, ventricular arrhythmia, cardiogenic shock and renal failure. Fatalities have been reported in adults after doses of 2-8g. High doses of quinine are teratogenic and may cause miscarriage. Hypokalaemia and hypoglycaemia may also occur.

Treatment:

Children (< 5 years) who have ingested any amount should be referred to hospital.

Older children and adults should be referred to hospital if more than 30mg/kg of quinine base has been taken.

Note: Each quinine bisulfate 300mg tablet is equivalent to 178mg of quinine base

Quinine is rapidly absorbed. Consider activated charcoal (50g for adults; 1g/kg for children) if the patient presents within 1 hour of ingestion of more than 30mg/kg quinine base or any amount in a child under 5 years. Multiple dose activated charcoal will enhance quinine elimination.

Observe patients for at least 12 hours after ingestion. Monitor cardiac conduction and rhythm, serum electrolytes, blood glucose and visual acuity.

Other treatment is symptomatic to maintain blood pressure, respiration, renal function and to treat arrhythmia, convulsions, hypoglycaemia and acidosis.

Elimination from the body may be assisted by the acidification of the urine with ammonium chloride. Haemodialysis and haemoperfusion should be instituted but this has limited value because quinine is extensively metabolised in the liver and only a small proportion is excreted unchanged in the urine. Signs of haemolytic anaemia may be indicative of a need to treat acute renal failure. Respiratory failure may be combatted by assisted respiration. Cardiac rhythm should be monitored. Vasodilators such as nicotinic acid and amylnitrite may be given to reverse visual impairment. Beneficial effects have been achieved with stellate ganglion block. The average fatal dose in adults has been reported to be with 8 g, with death resulting in a few hours or delayed for 1-2 days.

Large doses can induce abortion.