QUININE BISULPHATE TABLETS 300MG

Active substance: QUININE BISULPHATE

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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






4.4

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.

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).




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.



4.5

Treatment with quinine should be monitored in case signs of resistance develop.

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.

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.

4.8

Undesirable effects
Some patients are hypersensitive to quinine bisulphate and they may experience the
symptoms of cinchonism together with asthma and other allergic manifestations
including angioneurotic oedema and haemolytic anaemia.

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
Adverse Reaction
class
Blood and lymphatic system
disorders

Thrombocytopenia, intravascular
coagulation,
hypoprothrombinaemia, haemoglobinuria,
oliguria,
haemolytic-uremic syndrome, pancytopenia,
haemolysis,
agranulocytosis, thrombocytopenic purpura
have all been reported.

Immune system disorders

Report have been recieved 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

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.

5

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
Store in a well closed container. Store in a dry place below 25°

6.5

Nature and contents of container

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
9th January 1998

10

DATE OF REVISION OF THE TEXT
28/03/2014

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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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