SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Quinine Sulfate 300mg Coated Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Quinine Sulfate BP 300mg For list of excipients see 6.1

3    PHARMACEUTICAL FORM

Coated tablet for oral use.

4    CLINICAL PARTICULARS

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 the treatment of falciparum malaria

Adults: 600mg (two tablets) every eight hours for seven days.

Children: 10mg/kg bodyweight every eight hours for seven 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.

Children under ten years: Not recommended

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

Quinine is contraindicated in patients with a history of hypersensitivity to quinine or any of the excipients in the tablet, in tinnitus or optic neuritis, in myasthenia gravis and in the presence of haemolysis or haemoglobinuria. As quinine has been implicated in precipitating blackwater fever, it is generally contraindicated in patients who have already suffered an attack.

4.4 Special warnings and precautions for use

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 non-pharmacological measures have not worked. Quinine sulfate 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, heart block, other cardiac conduction defects, or other serious heart disease. Quinine may cause hypoprothrombinaemia and enhance the effects of anticoagulants.

Quinine has been implicated in precipitating blackwater fever when given for prolonged periods, although in some cases, glucose-6-phosphate dehydrogenase deficiency may have been involved. Patients with glucose-6-phosphate dehydrogenase deficiency may be at increased risk of haemolysis during quinine therapy and may develop acute haemolytic anaemia.

Owing to the presence of lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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, pruritis, rash, fever, angioedema and asthma.

This medicine contains methyl hydroxyl benzoate (E218) which may cause allergic reactions (possibly delayed).

This medicine contains tartrazine (E102) which may cause allergic reactions.

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.

Other drug interactions

Amantadine: reduced renal clearance of amantadine with risk of amantadine toxicity (including headache, nausea, dizziness).

Analgesics: increased risk of ventricular arrhythmias with levacetylmethadol (avoid concomitant use).

Anti-arrhythmics: plasma concentration of flecainide increased. Increased risk of ventricular arrhythmias with other drugs which prolong the QT interval, including amiodarone (avoid concomitant use). Concomitant use of quinidine may increase the possibility of cinchonism.

Antibacterials: increased elimination of quinine reported with rifampicin. There is an increased risk of ventricular arrhythmias with moxifloxacin.

Anticoagulants: quinine may cause hypoprothrombinaemia and enhance effects of anticoagulants.

Anti-histamines: increased risk of ventricular arrhythmias with astemizole and terfenadine.

Other antimalarials: There may be an increased risk of side effects if quinine is used with other antimalarials, for example, chloroquine, halofantrine and mefloquine (increased risk of convulsions), although this should not prevent their use in severe cases. Quinine may increase the plasma concentration of mefloquine. Chloroquine and quinine appear to be antagonistic when given together for P falciparum malaria. There is an increased risk of ventricular arrhythmias with halofantrine.

Antipsychotics: increased risk of ventricular arrhythmias with pimozide or thioridazine (avoid concomitant use).

Cardiac glycosides: Quinine may increase the plasma concentration of digoxin and it has been recommended that the maintenance dose of digoxin should be halved during concurrent therapy.

Ulcer healing drugs: cimetidine inhibits metabolism (increased plasma quinine concentration).

Quinine can decrease plasma concentrations of ciclosporin.

Concurrent use with oral hypoglycaemics may increase the risk of hypoglycaemia . Quinine enhances the neuromuscular effects of suxamethonium.

4.6 Pregnancy and lactation

Large doses of quinine can induce abortion. Congenital malformations of the optic and auditory nerves have been reported after quinine has failed to induce abortion. Quinine sulfate should not be used during pregnancy unless the benefits outweigh the risks. However, pregnancy in a patient with malaria is not generally regarded as a contraindication to the use of quinine and it should not be withheld from pregnant women with life threatening malaria if other agents are inappropriate. Quinine sulfate should not be used during pregnancy to treat cramps.

Quinine sulfate is excreted in breast milk, but no problems in humans have been reported. Infants at risk for glucose-6-phosphate dehydrogenase deficiency should not be breast-fed until this disease can be ruled out. However, quinine sulfate should not be given to nursing mothers unless the benefits outweigh the risks.

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

MedDRA system organ class	Adverse Reaction
Blood and lymphatic system disorders	Thrombocytopenia, intravascular coagulation, hypoprothrombinaemia, haemoglobinuria, oliguria, haemolytic-uremic syndrome, pancytopenia, haemolysis, agranulocytosis, thrombocytopenic purpura
Immune system disorders	Generalised hypersensitivity reactions including angioneurotic oedema and fever
Metabolism and nutrition disorders	Hypoglycaemia
Psychiatric disorders	Agitation, confusion
Nervous system disorders	Headache, vertigo
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	Bronchospasm
Gastrointestinal disorders	Nausea, vomiting, diarrhoea, abdominal pain
Skin and subcutaneous tissue disorders	Flushing, rash, urticaria, eczematous dermatitis, oedema, erythema, lichen planus, pruritis, photosensitivity
Musculoskeletal and connective tissue disorders	Muscle weakness, aggravation of myasthenia gravis
Renal and urinary disorders	Renal insufficiency, acute renal failure

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

Acute intoxication can be seen after ingestion of doses of 4-12g, but a dose of 8g can prove lethal. The average fatal dose for an adult is about 8g although deaths have been reported from as little as 1.5g in an adult and 900mg in a child.

Symptoms: Quinine overdosage may lead to serious side effects including irreversible visual loss, and can be fatal.

Symptoms include vomiting, tinnitus, deafness, headache, and visual disturbance.

Features of a significant overdose include convulsions, impairment of consciousness, respiratory depression, QT prolongation, ventricular arrhythmia, cardiogenic shock and renal failure. 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 30 mg/kg of quinine base has been taken.

Each 200 mg tablet is equivalent to 165 mg quinine base, each 300 mg tablet is equivalent to 248 mg quinine base.

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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Quinine is a highly active blood schizonticide and suppresses the asexual cycle of development of malaria parasites in the erythrocytes. It has no action on the tissue forms of the malaria parasites and therefore will not prevent relapse of Plasmodium vivax, P. ovale or P. malariae infections.

5.2 Pharmacokinetic properties

Quinine is almost completely absorbed from the gastrointestinal tract. Maximal blood concentrations are attained within one to three hours of ingestion. Most of the quinine is bound to plasma proteins. Quinine readily diffuses across the placenta. Quinine is extensively metabolised, mainly in the liver, and only a small proportion is excreted unchanged.

5.3 Preclinical safety data

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose DC Maize starch

Microcrystalline cellulose Sodium starch glycollate Povidone Purified water Magnesium stearate

Sugar Coating

Opaglos (Colorcon Ltd)

Mineral water sugar Calcium carbonate Talc

Titanium dioxide Acacia spray-dried Syrup

White Beeswax Carnauba wax

Printing Ink

Water

Polyvinylpyrrolidone (E1201)

Ammonium hydroxide (E527)

Methylparaben Dimethylpolysiloxane (E900)

Methylated silica Erythrosine (E127)

Brilliant Blue FCF (E133)

Tartrazine (E102)

6.2    Incompatibilities

None stated.

6.3    Shelf life

36 months for polypropylene/polyethylene containers.

24 months for blister packaging.

6.4 Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

Polypropylene or polyethylene containers containing 100 or 500 tablets.

Strips of opaque white or clear PVC film and 20p aluminium foil in multiples of 10 or 14 tablets.

The tablets will be packed in multiple strips of 10 tablets ie 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 tablets

The tablets will be packed in multiple strips of 14 tablets ie 14, 28, 56, 84 and 112 tablets.

6.6 Special precautions for disposal

N/A.

7    MARKETING AUTHORISATION HOLDER

Wockhardt UK Ltd Ash Road North Wrexham Industrial Estate Wrexham LL13 9UF United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 29831/0182

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of First Authorisation    14 June 1982

Date of Last Renewal

DATE OF REVISION OF THE TEXT

20/10/2015