Quinine Bisulphate Tablets Bp 300mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Quinine Bisulphate Tablets BP 300mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 300mg Quinine Bisulphate BP
Also contains sucrose. For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
White, round, biconvex, sugar-coated tablets
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
a) Treatment of uncomplicated attacks of falciparum malaria due to chloroquine or
multi-drug resistant strains.
b) 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 treatment of chloroquine resistant malaria
Adult (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: Equivalent of 10mg/kg every eight hours for 7 days.
If part or all of the dose is vomited within 1 hour of administration, then the same amount must be administered immediately.
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 toreassess the benefit of treatment.
Method of Administration
For oral administration.
4.3 Contra-indications:
• Known hypersensitivity to quinine or any of the excipients in the tablet.
• Acute haemoglobinuria
• Optic neuritis
• Tinnitus
• Myasthenia gravis, quinine may cause severe respiratory distress and dysphagia in these patients.
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 of night cramps should be stopped if symptoms of cinchonism emerge. Such symptoms include tinnitus, impaired hearing; headache, nausea, and disturbed vision (see section 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).
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-phophate dehydrogenase deficient patients with malaria or taking quinine to treat leg cramps may be at increased risk of haemolysis during quinine therapy.
Patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency may develop acute haemolytic anaemia. Quinine may precipitate Black water fever. Quinine may aggravate the symptoms of myasthenia gravis.
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, conduction defects and heart block or other serious heart disease. It may cause hypoprothrombinaemia.
Quinine can affect the results of certain urine tests for alkaloids and steroids.
It may also interfere with tests for plasma catecholamines as well as slowing the erythrocyte sedimentation rate.
Hypersensitivity to quinine may also occur with symptoms of cinchonism together with urticaria, flushing, pruritus, rash, fever, angioedema, dyspnoea and asthma.
Excessive amounts of beverages containing quinine should not be consumed while taking quinine, as this may increase the risk of adverse reactions and toxicity.
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.
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
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.
Amantadine: Quinine can reduce the renal clearance of amantadine.
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, and therefore concomitant use with these products should be avoided. Co-administration of other drugs known to alter cardiac conduction (e.g. antiarrhythmic or B-adrenergic blocking agents, calcium channel blockers, some antihistamines or Hl-blocking agents, tricyclic antidepressants and antipsychotics) might also contribute to a prolongation of the QT interval.
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.
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.
Concurrent use with oral hypoglycaemics may increase the risk of hypoglycaemia.
Quinine may cause hypoprothrombinaemia and enhance the effects of anticoagulants, i.e. warfarin.
Concomitant use of terfenadine should be avoided due to the increased risk of ventricular arrhythmias.
Quinine can reduce the renal clearance of amantadine
Cimetidine, which inhibits metabolism, may cause increased plasma quinine concentrations. Quinine enhances the neuromuscular effects of suxamethonium.
Concomitant use of artemether and lumefantrine should be avoided due to increased risk of ventricular arrhythmias.
Concomitant administration of mefloquine and quinine may produce electrocardiogram abnormalities and increase the risk of convulsions. Chloroquine and quinine appear to be antagonistic when given together for P falciparum malaria.
There is a decrease in plasma concentrations of primaquine.
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 chloroquine-resistant strains of falciparium malaria.
Pregnancy in patients with malaria is not generally regards 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 Bisulphate should not be used during pregnancy to treat cramps. Lactation
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-uraemic 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, pruritus, thrombocytopenic purpura and urticaria have also been reported. |
|
Metabolism and nutrition disorders |
Hypoglycaemia |
|
Psychiatric disorders |
Agitation, confusion |
|
Nervous system disorders |
Headache, vertigo, excitement, loss of consciousness, coma and death |
|
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, dyspnoea |
|
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, pruritus, 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: |
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.
4.9 Overdose:
Symptoms:
Quinine over dosage may lead to serious side effects including irreversible visual loss and can be fatal. In acute over dosage, symptoms of cinchonism may occur, including convulsions, nausea, vomiting, tinnitus, deafness, headache, vasodilatation and disturbed vision. Features of a significant overdose include 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 - 8 g.
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.
Consider activated charcoal (50 g for adults; 4g/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 5Years. 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.
Note: each 300 mg tablet is equivalent to 178 mg quinine base.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code: P01B C01. Quinine alkaloid (antimalarials, methanolquinolines).
Quinine is a rapidly acting blood schizontide 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 it has no activity against exoerythrocytic forms quinine does not produce a radical cure in vivax or ovale malarias. Quinine supresses the asexual cycle of development of the malarial parasite in the erythrocytes through interference with its DNA
On skeletal muscle quinine has dual action; it acts directly on muscle fibre and also effects muscular transmission by increasing the threshold of excitability of the motor end-plate.
5.2. Pharmacokinetic Properties
Quinine is rapidly and almost completely absorbed from the gastro-intestinal tract. Peak concentrations in the circulation are attained about 1 to 3 hours after ingestion. About 70% is bound to proteins in plasma in healthy subjects rising to 90% in patients with malaria. Quinine is widely distributed throughout the body. Concentrations in CFS are 2 to 7% of those in the plasma. Quinine is extensively metabolized in the liver and excreted in urine. Unchanged quinine in urine vary from less than 5 to 20%. Excretion is increased in acid urine.
Elimination half-life is about 11 hours in healthy subjects but may be prolonged in patients with malaria. Pharmacokinetics are altered significantly by malarial infection, with reduction in volume of distribution and clearance.
5.3. Preclinical Safety Data
None stated.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
|
Starch |
60.0 mg |
|
Polyvinylpyrrolidone |
3.0 mg |
|
Talc |
6.0 mg |
|
Stearic Acid |
3.0 mg |
|
Sodium Starch Glycollate |
3.0 mg |
|
Opaglos |
5.0 mg |
|
Sucrose |
78.0 mg |
|
Titanium dioxide |
2.0 mg |
6.2. Incompatibilities
None known
6.3 Shelf life
5 years
6.4. Special precautions for storage
Stored in a cool dry place, below 25°C. Protected from bright light.
6.5 Nature and contents of container
Plastic securitainer with tamper evident polypropylene lids. (Materials comply to EEC directives for plastics in contact with drugs and foodstuffs).Packed in pack Sizes: 28, 30, 50, 56,100,250, 500 and 1000.
Not all pack sizes may be marketed.
Blister packs of 0.25mm PVC and 0.25mm microns Aluminium foil.
6.6 Special instructions for disposal:
None
7. MARKETING AUTHORISATION HOLDER
Pharmvit Limited
Unit 13, Metropolitan Centre,
Derby Road, Greenford,
Middlesex UB6 8UJ
8. MARKETING AUTHORISATION NUMBER
PL 04556/0030
9. DATE OF FIRST AUTHORIZATION / RENEWAL OF THE AUTHORIZATION:
Date of first authorisation: 07 July 1995 Date of latest renewal: 09 March 2009
10 DATE OF REVISION OF THE TEXT
15/01/2015