Quinine Sulphate 300mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT
Quinine Sulphate 300mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 300mg of quinine sulphate For Excipients See Section 6.1
3 Pharmaceutical Form
Tablet
Plain white sugar coated tablet.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Quinine Sulphate 300mg Tablets are indicated for the treatment of malaria from Plasmodium falciparum, including chloroquine-resistant strains, but they are not suitable for the prophylaxis of malaria.
Quinine Sulphate 300mg Tablets are also indicated for the 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
Falciparum malaria
Adults (including the elderly) and children over 12 years:
The usual oral dose is 600mg given every 8 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 prolonged half-life of the drug.
Children under 12 years:
An oral dose of 10mg of quinine sulphate per kg of body weight, given every 8 hours for 7 days is recommended.
For the treatment and prevention of nocturnal leg cramps:
Adults (including the 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.
Kidney and liver impairment
In patients with liver disease and renal impairment the half-life of quinine sulphate may be increased, therefore these patients should be closely monitored and dose adjustments may be necessary.
4.3 Contraindications
Known hypersensitivity to quinine or any of the excipients in the tablet.
Haemolysis 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 in 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 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.
As quinine has been implicated in precipitating blackwater fever, Quinine Sulphate 300mg Tablets are generally contraindicated in patients who have already suffered an attack.
Quinine Sulphate 300mg Tablets should be used with caution in patients with atrial fibrillation or other serious heart diseases. It may cause hypoprothrombinaemia. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may develop acute haemolytic anaemia.
Quinine should not be withheld from pregnant women who have life threatening malaria.
Treatment with quinine should be monitored in case signs of resistance develop.
Hypersensitivity to quinine may also occur with symptoms of cinchonism together with urticaria, flushing, pruritus, rash, fever, angioedema, dyspnoea and asthma.
4.5 Interaction with other medicinal products and other forms of interaction
Effects 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. Quinine can decrease plasma concentration of ciclosporin.
Quinine can reduce the renal clearance of amantadine.
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.
Concurrent use with oral hypoglycaemics may increase the risk of hypoglycaemia.
Quinine may cause hypoprothrombinaemia and enhance the effects of anticoagulants.
Quinine enhances the neuromuscular effects of suxamethonium.
Concomitant use of quinidine may increase the possibility of cinchonism.
Concomitant use of terfenadine should be avoided due to the increased risk of ventricular arrhythmias.
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 with P falciparum malaria.
Ulcer-healing drugs: Cimetidine inhibits quinine metabolism leading to increased plasma-quinine concentrations.
4.6 Pregnancy and lactation
Pregnancy:
Congenital malformations in the human have been reported with the use of quinine sulphate, primarily with large doses (up to 30g) for attempted abortion. In about half of these reports, the malformation was deafness related to auditory nerve hypoplasia. Among the other abnormalities reported were limb anomalies, visceral defects, phototoxicity and mental deficiency. The relationship of these malformations to material quinine therapy remains uncertain. Other reports have not associated use with malformations, but with foetal natal death. In animal tests, teratogenic effects were found in rabbits and guinea pigs and were absent in mice, rats, dogs, and monkeys. Quinine sulphate should not be used during pregnancy unless the benefits outweigh the risks. 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 to treat cramps during pregnancy.
Lactation:
Quinine sulphate is excreted in breast milk in small amounts, 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. Patients should be advised that if affected they should not drive or operate machinery.
4.8
Undesirable effects
Undesirable effects are listed by organ class in the Table below.
|
MedDRA System Organ Class |
Adverse reaction |
|
Blood and lymphatic system disorders |
Thrombocytopenia, intravascular coagulation, hypoprothrombinaemia, haemoglobinuria, oliguria, haemolyticuremic 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, blindness |
|
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 disorder |
Bronchospasm, asthma, dyspnoea |
|
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 |
|
Reproductive system and breast disorders |
Abortion (with toxic doses - however, it is unwise to withhold the drug if less toxic antimalarials are not available) |
4.9 Overdose
Symptoms
Quinine overdosage may lead to serious side effects including irreversible visual loss, and can be fatal. Symptoms include vomiting, Tinnitus, deafness, headache, vasodilation 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 tetrogenic and may cause miscarriage. Hypokalaemia and hypoglycaemia may also occur.
Treatment
Children (<5years) 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 tablet is equivalent to 248mg quinine base.
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 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 sulphate 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 P falciparum gametocytes. Since no activity against exoerythrocytic forms, quinine does not produce a radial cure in vivax or ovale malarias.
In addition quinine sulphate exerts relaxant effects on skeletal muscle. It increases the tension response to a single maximal stimulus delivered to the muscle directly or through the nerve but it increases the refractory period of muscle so that the response to tetanic stimulation is reduced.
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
Quinine sulphate is rapidly and almost completely absorbed form the gastro-intestinal tract, occurring predominately in the upper small intestine. Peak concentrations is the circulation are attained about 1 - 3 hours after ingestion and about 70% is bound to plasma proteins in healthy subjects rising to about 90% in patients with malaria.
Quinine sulphate is widely distributed throughout the body. The concentration in cerebrospinal fluid is only about 2 to 5% of that in the plasma. It is extensively metabolised in the liver with only approximately 10% of a given dose excreted unchanged when the urine is acidified. The elimination half-life is about 11 hours in healthy subjects, but may be prolonged in patients with malaria. The pharmacokinetics of quinine sulphate are altered significantly in patients with malaria, with reductions in both the apparent volume of distribution and clearance, resulting in relatively higher plasma concentrations.
5.3 Preclinical safety data
Not applicable
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Starch
Sucrose
PVP (Povidone)
Primogel (Sodium Starch Glycolate) Talc
Magnesium Stearate Deionised Water HSE Bleached Shellac BPC Titanium Dioxide Beeswax Carnauba Wax Ethanol 96%
6.2 Incompatibilities
None
6.3 Shelf-Life
Polypropylene securitainer 3 years.
PVC blister with aluminium lidding foil 2 years.
6.4 Special precautions for storage
Do not store above 25°C. Store in a dry place. Protect from light.
6.5 Nature and Content of Container
Polypropylene securitainer with appropriate bellows or polyurethane foam wads containing 28 and 500 tablets.
Also available in a PVC blister with aluminium lidding foil containing 28 tablets.
6.6 Instructions for Use, Handling and Disposal
No special instructions
7. MARKETING AUTHORISATION HOLDER
ATHLONE LABORATORIES LIMITED, BALLYMURRAY,
CO. ROSCOMMON,
IRELAND.
8. MARKETING AUTHORISATION NUMBER(S)
PL 06453/0040
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
13/1/1992
10 DATE OF REVISION OF THE TEXT
11/05/2012