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QUININE SULPHATE TABLETS BP 200 MG

Active substance(s): QUININE SULPHATE / QUININE SULPHATE / QUININE SULPHATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Quinine Sulphate Tablets BP 200mg.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains quinine sulphate BP 200mg.

3

PHARMACEUTICAL FORM
Coated tablet.

4
4.1

CLINICAL PARTICULARS
Therapeutic indications For the treatment of chloroquine-resistant strains of falciparium 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 Treatment of chloroquine-resistant strains of falciparium malaria: Adults: 600mg every 8 hours for 7 days, followed by (or with) an appropriate dose of a sulphadoxine/pyrimethamine combination, such as Fansidar. Elderly: There is no evidence that the dosage should differ in the elderly. Children: Not recommended. For the treatment and prevention of nocturnal leg cramps: Adults (including elderly): The recommended dose is 200mg at bedtime. The maximum dose is 300mg. A reduction in frequency of leg cramp may take up to 4 weeks to become apparent. Patient 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 Haemoglobinuria Known hypersensitivity to quinine or any of the excipients in the tablet Optic neuritis Tinnitus Myasthenia gravis

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) Before use for nocturnal leg cramps, the risks, which include significant adverse effects and interactions ( see 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 nonpharmacological 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. Quinine should be used with caution in patients with atrial fibrillation or other serious heart disease. It may cause hypoprothrombinaemia. Patients with glucose 6-phophate dehydrogenase (G6PD) deficiency may develop acute haemolytic anaemia. Hypersensitivity to quinine may also occur with symptoms of cinchonism together with urticaria, flushing, puritus, rash, fever, angioedema, dyspnoea and asthma. 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 with quinine should be monitored in case signs of resistance develop.

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. 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 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: Concurrent use with oral hypoglycaemics may increase the risk of hypoglycaemia . Suxamethonium: Quinine enhances the neuromuscular effects of suxamethonium. Ulcer-healing drugs: Cimetidine inhibits quinine metabolism leading to increased plasma-quinine concentrations.

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 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 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 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

4.8

Undesirable effects
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. Its 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. MedDRA system organ class Blood and lymphatic system disorders Adverse Reaction Thrombocytopenia, intravascular coagulation, hypoprothrombinaemia, haemoglobinuria, oliguria, haemolytic-uremic syndrome, pancytopenia, haemolysis, agranulocytosis, thrombocytopenic purpura Reports have been received of eczematous dermatitis, oedema, erythema and lichen planus. Hypersensitivity reactions such as asthma,

Immune system disorders

Metabolism and nutrition disorders

Psychiatric disorders Nervous system disorders Eye disorders Ear and labyrinth disorders Cardiac disorders

Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders Skin and subcutaneous tissue disorders

angioneurotic oedema, photosensitivity, hot and flushed skin, fever, pruritis, thrombocytopenic purpura and urticaria have also been reported Hypoglycaemia may occur after oral administration although it is more common after parenteral administration Agitation, confusion Headache, vertigo, excitement, loss of consciousness, coma and death have been reveived. Blurred vision, defective colour perception, visual field constriction Tinnitus, impaired hearing Atrioventricular conduction disturbances, hypotension coupled with a feeble pulse, prolongation of the QT interval, widening of the QRS complex and T wave flattening Bronchospasm, dyspnoea may occur Nausea, vomiting, diarrhoea, abdominal pain may occur after long term administration of quinine Flushing, rash, urticaria, eczematous dermatitis, oedema, erythema, lichen planus, pruritis, photosensitivity Muscle weakness, aggravation of myasthenia gravis Renal insufficiency and acute renal failure may be due to an immune mechanism or to circulatory failure. Toxic doses of quinine may induce abortion, but it is unwise to withhold the drug if less toxic antimalarials are not available

Musculoskeletal and connective tissue disorders Renal and urinary disorders

Reproductive system and breast disorders

4.9

Overdose
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 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 tetrogenic 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 30 mg/kg of quinine base has been taken. Each that each 200 mg tablet is equivalent to 165 mg quinine base/each 300 mg tablet is equivalent to 248 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 symptomatic to maintain blood pressure, respiration, renal function and to treat arrhythmia, convulsions, hypoglycaemia and acidosis.

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5.1

PHARMACOLOGICAL PROPERTIES
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 faciparum, 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 required.

6
6.1

PHARMACEUTICAL PARTICULARS
List of excipients Lactose, maize starch, magnesium stearate, stearic acid, talc, sodium croscarmellose, opaglos, sucrose and titanium dioxide (E171).

6.2

Incompatibilities Not applicable.

6.3

Shelf life 36 months.

6.4

Special precautions for storage Store in a cool dry place and protect from light.

6.5

Nature and contents of container Securitainers and opaque screw-capped plastic containers. Pack sizes: 25, 50, 100 and 500. Lever-lid tins (polybag lined). Pack size: 1,000.

Ward packs. Pack size: 100.

6.6

Special precautions for disposal Not applicable.

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MARKETING AUTHORISATION HOLDER
Ennogen Pharma Limited Unit G4, Riverside Industrial Estate, Riverside Way, Dartford DA1 5BS UK

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MARKETING AUTHORISATION NUMBER(S)
PL 40147/0070

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
9 April 1992

10

DATE OF REVISION OF THE TEXT
08/01/2013

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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