SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

QUININE SULPHATE TABLETS BP 200 mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 200 mg Quinine Sulphate.

3 PHARMACEUTICAL FORM

Film-coated tablet.

White, circular, biconvex film-coated tablets with the identifying letters “QC” embossed on one face.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

1)    Treatment of falciparum (malignant tertian) malaria.

2)    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

Posology

For the treatment of falciparum (malignant tertian) malaria:

Adults (including elderly) and children aged 12 years and over: 600mg every eight hours for 7 days. The dose may depend upon the size of the patient, severity of infection, and evidence of renal or liver disease (when the intervals should be increased), due to a prolonged half-life of the drug.

If quinine resistance is known or suspected on completion of the course additional treatment may be given. This may be one of the following:

1.    doxycycline 200mg daily (as a single dose or in 2 divided doses) for at least 7 days.

2.    clindamycin 300mg four times daily for 5 days.

Children aged 11 years and under: 10mg/kg every eight hours for 7 days.

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 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 assess the need for continuation of treatment with quinine.

Method of Administration For oral administration.

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

Cinochonism

•    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.

Cardiac disorders

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

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 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 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.

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

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 flecanide, 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, thioridzine 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 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.

Blood and the lymphatic system disorders: thrombocytopenia, intravascular coagulation, hypoprothrombinaemia, haemoglobinuria, oliguria, haemolytic-uremic syndrome, pancytopenia, haemolysis agranulocytosis and thrombocytopenic purpura have all been reported.

Immune system disorders: reports have been received of eczematous dermatitis, oedema, erythema and lichen planus. Hypersensitivity reactions such as asthma, angioneurotic oedema, photosensitivity, hot and flushed skin, fever, pruritis, thrombocytopenic purpura and urticaria have also been reported.

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, viual 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, connective tissue and bone disorders: muscle weakness may occur, aggrevation 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 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; 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. 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

Childen (<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.

Each 300mg Quinine sulphate tablet is equivalent to 248mg 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. Multiple dose activated charcoal will enhance elimination.

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

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

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 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 Pfalciparum. 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 appears in the bile and saliva.

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

5.3 Preclinical safety data

Not applicable.

6.1    List of excipients

The tablets also contain:

Sodium lauryl sulphate Povidone

Microcrystalline cellulose (E460) Croscarmellose sodium Magnesium stearate Hydrogenated vegetable oil

The coating contains:

Hypromellose Hydroxypropyl Cellulose Medium Chain Triglycerides Macrogol 3350 Titanium Dioxide (E171)

6.2    Incompatibilities

None known.

6.3 Shelf Life

Shelf-life

A three year shelf life is claimed and our marketed products includes a three year expiry date.

Shelf-life after dilution/reconstitution Not applicable.

Shelf-life after first opening Not applicable.

Special Precautions for Storage

Store below 25 °C in a dry place.

6.5 Nature and Contents of Container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene tablet containers with polyfoam wad or polyethylene ullage filler and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass bottles with screw caps and polyfoam wad or cotton wool.

The product may also be supplied in blister packs in cartons:

a)    Carton: Printed carton manufactured from white folding box board.

b)    Blister pack: (i) 250pm white rigid PVC. (ii) Surface printed 20pm hard temper aluminium foil with 5-7g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28s, 30s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s, 250s, 500s, 1000s.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 25,000.

6.6 Instruction for Use, Handling and Disposal

Not applicable.

7. MARKETING AUTHORISATION HOLDER

'Actavis UK Limited'

(trading as Actavis)

Whiddon Valley BARNSTAPLE N Devon EX32 8NS

PL 00142/5073R

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23.12.82

(Renewed: 23.12.87; 01.04.93; 05.10.98)

10 DATE OF REVISION OF THE TEXT

02/07/2015