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1. Quinine Bisulphate Tablets 300mg
2. Quinine Bisulphate Tablets 300mg

SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Quinine Bisulphate Tablets 300mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Quinine Bisulphate 300.00 mg BP

3    PHARMACEUTICAL FORM

Coated tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The treatment of: - chloroquine-resistant 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

Route of administration: Oral For malaria:

Adults: in the treatment of chloroquine-resistant malaria - 600mg at 8 hourly intervals for 7 days.

Children: 10mg per kg bodyweight at 8 hourly intervals for 7 days 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.

Children: Not recommended

4.3 Contraindications

•    Known hypersensitivity to quinine or any of the excipients in the tablet.

•    Haemoglobinuria

•    Optic neuritis.

•    Tinnitus

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

4.4 Special warnings and precautions for use

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

•    Quinine should be used with caution in patients with atrial fibrillation or other serious heart disease. It may cause hypoprothrombinaemia.

•    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 (G6PD) 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 with quinine should be monitored 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 sulphate 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, dysphagia in patients with myasthenia gravis. Renal impairment which may be due to an immune mechanism may occur. Hypoglycaemia may occur.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other drugs on quinine

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, which include 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.

Cimetidine inhibits metabolism (plasma quinine concentration increases).

Effect of quinine on other drugs

The plasma concentration of Flecainide, digoxin and mefloquine may be increased. Amantadine: 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

There is an increased risk of ventricular arrhythmias with other drugs which prolong the QT interval, including amiodarone, moxifloxacin, pimozide, thioridazine and halofantrine.

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 reduced the serum levels of quinine, therefore reducing its therapeutic effect.

Anticoagulants: Quinine may cause hypoprothrombinaemia and enhance the effects 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: There is an increased risk of hypoglycaemia when taken concurrently.

Suxamethonium: Quinine enhances the neuromuscular effects of suxamethonium.

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

4.6 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 sulphate 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 contra-indication 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 sulphate should not be used during pregnancy to treat cramps. Lactation

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

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.

Metabolism and nutrition disorders	Hypoglycaemia may occur after oral administration although it is more common after parenteral administration.
Psychiatric disorders	Agitation, confusion
Nervous system disorders	Reports of headache, vertigo , excitement, 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	There may be atrioventricular conduction disturbances, a fall in blood pressure coupled with a feeble pulse. Prolongation of the QT interval, widening of the QRS complex and T wave flattening has been noted with therapeutic doses.
Respiratory, thoracic and mediastinal disorders	Bronchospasm , dyspnoea may occur.
Gastrointestinal disorders	Diarrhoea,nausea, vomiting, and abdominal pain may occur after long term administration of quinine.
Skin and subcutaneous tissue disorders	Flushing, rash, urticaria, eczematous dermatitis, oedema, erythema, lichen planus, pruritis, photosensitivity
Musculoskeletal and connective tissue disorders	Muscle weakness may occur, aggravation of myasthenia gravis
Renal and urinary disorders	Renal insufficiency-and acute renal failure may be due to an immune mechanism or to circulatory 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 side effects

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.

United Kingdom

Yellow Card Scheme

Freephone: 0808 100 3352 (available from 10 a.m. to 2 p.m. Mondays to Fridays) Website: 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 disturbed vision.

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

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 30 mg/kg of quinine base has been taken.

Quinine bisulphate 300mg tablet is equivalent to 178 mg quinine base.

Quinine is rapidly absorbed.

Consider activated charcoal (50 g for adults; 1 g/kg for children) if the patient presents within 1 hour of ingestion of more than 30 mg/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 mostly symptomatic to maintain blood pressure, respiration, renal function and-treating 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 in an attempt 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 8g, with death resulting in a few hours or delayed for 1-2 days.

Large doses can induce abortion.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: P01B C01. Quinine alkaloid.

Quinine is a cinchona alkaloid and a 4-methanolquinoline antimalarial agent which is a rapidly-acting blood schizontocide with activity against Plasmodium falciparum, P vivax, P ovale and P malariae. It is active against the gametocytes of P malariae and P vivax, but not against mature gametocytes of P falciparum. Since it has no activity against exoerythrocytic forms, quinine does not produce a radical cure in vivax or ovale malarias.

Quinine has effects on the motor end-plate of skeletal muscle and prolongs the refractory period. Like quinidine, quinine is a sodium channel blocker and, therefore, has local anaesthetic, and both anti- and proarrhythmic activity.

The precise mechanism of action of quinine is unclear but it may interfere with lysosome function or nucleic acid synthesis in the malaria parasite.

5.2 Pharmacokinetic properties

The pharmacokinetics of quinine are altered significantly by malaria infection, the major effects being reductions in both its apparent volume of distribution and its clearance.

Absorption: Quinine is rapidly and almost completely absorbed from the GI tract and peak concentrations in the circulation are attained about 1-3 hours after oral administration of the sulphate.

Distribution: Plasma protein binding is about 70% in healthy subjects and rises to 90% or more in patients with malaria.

Quinine is widely distributed throughout the body. Concentrations attained in the CSF of patients with cerebral malaria have been reported to be about 2-7% of those in the plasma.

Metabolism: Quinine is extensively metabolised in the liver and rapidly excreted mainly in the urine. Estimates of the proportion of unchanged quinine excreted in the urine vary from less than 5% to 20%. The pharmacokinetics of quinine are altered significantly by malaria infection, with reductions in both the apparent volume of distribution and clearance.

Elimination: Excretion is increased in acid urine. The elimination half-life is about 11 hours in healthy subjects but may be prolonged in patients with malaria. Small amounts of quinine also appear in the bile and saliva.

Quinine crosses the placenta and is excreted in the breast milk.

5.3 Preclinical safety data

Not applicable

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Microcrystalline cellulose Fumed silicon dioxide Guar gum

Magnesium stearate

Hydroxypropylmethylcellulose

Ethylcellulose

Titanium dioxide

Diethylphthalate

Beeswax

Methanol

Petroleum spirit

Dichloromethane

6.2 Incompatibilities

None known

6.3 Shelf life

48 months all sizes

6.4 Special precautions for storage

High density polystyrene with polythene lids and/or polypropylene containers with polythene lids and polyurethane or polythene inserts

16, 21, 28, 30, 50, 56, 60, 84, 90, 100 tablets.

6.6 Special precautions for disposal

No special instructions

7    MARKETING AUTHORISATION HOLDER

Mercury Pharmaceuticals Ltd Capital House,

85 King William Street,

London EC4N 7BL, UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 12762/0428

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

9^th January 1998

10 DATE OF REVISION OF THE TEXT

28/03/2014