Quinine Bisulphate Tablets 300 Mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Quinine Bisulfate Tablets 300mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Quinine Bisulfate 300mg Excipient with known effect: Titanium dioxide (E171)
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
White, sugar coated deep convex tablet
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
The treatment of chloroquine-resistant malaria for the protection of pregnant women, nursing mothers, infants and young children in areas where P.falciparum is resistant to Chloroquine 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
Treatment of acute malaria Adults:
600mg three times daily for 7 to 10 days
Children:
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 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.
Route of administration:
Oral
4.3 Contraindications
Hypersensitivity to the active substance(s) or to any of the excipients listed in section
6.1
Haemoglobinuria 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 of 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 nonpharmacological measures have not worked. Quinine 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 or other serious heart disease. 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.
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 flecainide, digoxin and mefloquine may be increased. Quinine can decrease plasma concentrations 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.
Chloroquine and quinine appear to be antagonistic when given together for P falciparum malaria.
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.
Ulcer-healing drugs: Cimetidine inhibits quinine metabolism leading to increased plasma-quinine concentrations.
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 bisulfate should not be used during pregnancy unless the benefits outweigh the risks.
Treatment of chloroquine-resistant strains of falciparum 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.Care should be taken to monitor blood glucose levels during treatment
Prophylaxis of nocturnal leg-cramps: Quinine should not be used during pregnancy to treat cramps.
Lactation
Quinine is excreted in breast milk, but no problems in humans have been reported. However, quinine 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
|
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, 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 disorders |
Bronchospasm, asthma, dyspnoea |
|
MedDRA system organ class |
Adverse Reaction |
|
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 |
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 (<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 bisulfate tablet is equivalent to 178mg 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.
PHARMACOLOGICAL PROPERTIES
5
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Quinine alkaloid ATC code: P01B C01
Quinine is a rapidly acting blood schizonticide with activity against malaria parasites in the erythrocytes such as Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.
It is active against the gametocytes of P. malariae and P. vivax, but not against P. falciparum gametocytes. Since it has no activity against exoerythrocytic forms, quinine does not produce a radical cure in vivax or ovale malaria
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 s unclear but it may interfere with lysosome function or nucleic acid synthesis in the malaria parasite.
Quinine is mainly used orally for the treatment of uncomplicated attacks of the chloroquine or multidrug resistant strains of Plasmodium falciparum. In addition, quinine bisulfate may be used in the treatment of malignant tertian malaria. Notably, both as a suppressive and therapeutic agent, quinine is more toxic and less effective than chloroquine.
5.2 Pharmacokinetic properties
Quinine 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 proteins in the plasma in healthy subjects rising to about 90% in patients with malaria.
Quinine is widely distributed throughout the body. The concentration of the alkaloid 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 is altered significantly by malarial infection, with reductions in both the apparent volumes of distribution and clearance resulting in relatively higher plasma concentrations.
5.3
Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Pregelatinised starch
Powdered cellulose
Crospovidone
Magnesium stearate
Anhydrous colloidal silica
Shellac
Povidone
Dextrin
Sucrose
Kaolin
Talc
Titanium dioxide (E171)
6.2 Incompatibilities
None known
6.3 Shelf life
Opaque plastic containers: 36 months Blister packs: 24 months
6.4 Special precautions for storage
Protect from heat, light and moisture
6.5 Nature and contents of container
1. Opaque plastic containers with plastic caps in pack sizes of 28, 42, 50, 56, 84, 100, 112,
250, 500 and 1000.
2. Opaque plastic container composed of either high density polypropylene or high density
polyethylene with a tamper evident or child resistant tamper evident closure composed of high density polyethylene for all pack sizes (28, 42, 50, 56, 84, 100, 112, 250, 500 and 1000) packaging inclusion: polyether foam or polyethylene or polypropylene made filler.
3. Blister packs of aluminium/opaque PVC subsequently packed in printed cartons in pack sizes of 28, 42, 56, 84 and 112.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special instructions
7 MARKETING AUTHORISATION HOLDER
Bristol Laboratories Limited Unit 3, Canalside Northbridge Road Berkhamsted Hertfordshire HP4 1EG
8 MARKETING AUTHORISATION NUMBER(S)
PL 17907/0514
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 08/03/2004
10 DATE OF REVISION OF THE TEXT
15/06/2016