SUMMARY OF PRODUCT CHARACTERISTICS 1    NAME OF THE MEDICINAL PRODUCT

Quinine Bisulfate 300 mg Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 300 mg quinine bisulphate equivalent to 178 mg anhydrous quinine base.

Excipient(s) with known effect:

Sucrose

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Coated tablet.

White, biconvex, sugar-coated tablets, plain or marked APS on one side and coded "300 over "1202" on reverse.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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).

Treatment of chloroquine-resistant malaria.

4.2 Posology and method of administration

Posology

Adults

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 reassess the benefit of treatment.

Treatment of Chloroquine-Resistant 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

Treatment of Chloroquine-Resistant Malaria 10 mg/kg every 8 hours for 7 days.

Method of administration For oral administration.

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, overdose,

but may also occur in normal therapeutic doses. Patients 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.

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 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.

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

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, 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 mefloquine may be increased.

Amantadine: Quinine can reduce the renal clearance of amantadine.

If quinine is administered the maintenance dose of digoxin should be halved.

Ciclosporin: Quinine can decrease serum 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 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.

Chloroquine and quinine appear to be antagonistic when given together for P falciparum malaria.

Concomitant use of artemether and lumefantrine should be avoided.

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 bisulphate should not be used during pregnancy unless the benefits outweigh the risks.

Treatment of choloroquine-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 natural leg-cramps

Quinine bisulphate should not be used during pregnancy to treat cramps. Breast-feeding

Quinine bisulphate is excreted in breast milk, but no problems in humans have been reported. However, quinine bisulphate 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	Adverse Reaction
Blood and lymphatic system disorders	Thrombocytopenia, intravascular coagulation, hypoprothrombinaemia, haemoglobinuria, oliguria, haemolytic-uremic syndrome, pancytopenia, haemolysis, agranulocytosis, thrombocytopenic purpura

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, visual field constriction
Ear and labyrinth disorders	Tinnitus, impaired hearing
Cardiac disorders	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	Nausea, vomiting, diarrhoea, 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, Stevens-Johnson syndrome
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 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 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 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

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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

ATC Code: P01B C01. Quinine alkaloid (antimalarials, methanolquinolines).

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.

Quinine increases the refractory period of muscle so that the tetanic stimulation is diminished. It also affects a number of other body systems including the central nervous system, the cardiovascular system, the gastrointestinal tract and the pancreas. In addition, quinine exhibits local anaesthetic action and a local irritant action. As an antimalarial drug it acts primarily as a schizontocide. It is more toxic and less effective than chloroquine, but is especially useful for treatment of chloroquine-resistant strains of malarial infection.

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 sulfate.

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

Preclinical information has not been included because the safety profile of quinine bisulfate has been established after many years of clinical use. Please refer to Section 4.

6.1 List of excipients

The tablet contains:

Maize starch Gelatin Talc (E553)

Crospovidone Stearic acid Calcium stearate Sucrose

Titanium dioxide (E171)

The tablet polish contains: Shellac (E904)

Carnauba wax (E903) White beeswax (E901)

The printing ink contains: Shellac (E904)

Black iron oxide (E172) Propylene Glycol (E1520)

6.2.    Incompatibilities

Not applicable.

6.3.    Shelf Life

24 months.

6.4.    Special Precautions for Storage

Store in original package. Do not store above 25°C.

6.5.    Nature and Content of Container

HDPE or polypropylene containers with caps or child resistant closures in packs of 100 or 500 tablets, (2 desiccants are included in each pack).

Blister strips in packs of 7, 10, 14, 21, 28, 30, 56, 60, 84, 90, 100, 110, 112, 120, 150, 160 and 168 tablets.

Not all pack sizes may be marketed.

Special precautions for disposal and other handling

Not applicable.

7    MARKETING AUTHORISATION HOLDER

TEVA UK Limited, Eastbourne, BN22 9AG.

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/5245R

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

30/09/2005

10    DATE OF REVISION OF THE TEXT

12/07/2016