QUININE SULPHATE TABLETS 300MG
Active substance: QUININE SULPHATE
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SUMMARY OF PRODUCT CHARACTERISTICS
1
NAME OF THE MEDICINAL PRODUCT
Quinine Sulphate Tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION 300mg Quinine Sulphate BP
3.
PHARMACEUTICAL FORM Sugar-coated tablets
4
4.1
CLINICAL PARTICULARS
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
Treatment of uncomplicated malaria: Adult dosage: Equivalent of 496mg of quinine base every eight hours for 7 days, given by mouth. Followed by (or with) an appropriate dose of sulphadoxine/ pyrimethamine combination. Children: Equivalent of 8.26mg/kg quinine base every eight hours for 7 days, given by mouth. Followed by (or with) an appropriate dose of sulphadoxine/pyrimethamine combination.
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.
4.3
Contraindications
Known hypersensitivity to quinine or any of the excipients in the tablet. 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 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 nonpharmacological measures have not worked. Quinine sulphate should not be used for this indication during pregnancy (see Section 4.6). Hypersensitivity to quinine should be tested for in each patient Glucose-6-phosphate dehydrogenase deficient patients with malaria may be at increased risk of haemolysis during quinine therapy. Quinine may aggravate the symptoms of myasthenia gravis. Quinine may precipitate Blackwater fever. 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. Hypersensitivity to quinine may also occur with symptoms of cinchonism together with urticaria, flushing, pruritus, rash, fever, angioedema, dyspnoea and asthma. 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.
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. 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, i.e. Warfarin. Clearance of quinine was reduced and half-life increased in patients pretreated with cimetidine. 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
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 benefit out weigh the risks. Treatment of chloroquine-resistant stains of falciparum 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 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 risk.
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 Blood and disorders lymphatic Adverse Reaction
system 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 Nervous system disorders Eye disorders Agitation, confusion Headache, vertigo Blurred vision, defective colour perception, visual field constriction Tinnitus, impaired hearing Atrioventricular conduction disturbances, hypotension, prolongation of the QT interval, widening of the QRS complex and T wave flattening and Bronchospasm
Ear and labyrinth disorders Cardiac disorders
Respiratory, thoracic mediastinal disorders Gastrointestinal disorders
Nausea, vomiting, diarrhoea, abdominal pain Skin and subcutaneous tissue Flushing, rash, urticaria, disorders eczematous dermatitis, oedema, erythema, lichen planus, pruritis, photosensitivity Musculoskeletal and connective Muscle weakness, aggravation of tissue disorders myasthenia gravis Renal and urinary disorders Renal insufficiency, acute renal failure
4.9 Overdose
Symptoms: Quinine over dosage may lead to serious and irreversible side effects and can be fatal. In acute over dosage, symptoms of cinchonism may occur, including convulsions, nausea, vomiting, tinnitus, deafness, headache, vasodilatation, disturbed vision, QT prolongation and renal failure. The visual disorders may be severe and there may be impairment of consciousness, coma, respiratory depression, arrhythmia and cardiogenic shock. 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; 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. Each 300 mg tablet is equivalent to 248 mg quinine base.
5.1.
Pharmacodynamic Properties 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 the 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 arc altered significantly by malarial infection, with reduction in volume of distribution and clearance.
5.3.
Preclinical Safety Data N/A
6
PHARMACEUTICAL PARTICULARS
6.1.
List of excipients Maize Starch Lactose Magnesium Stearate Stearic Acid Talc Sodium Croscarmellose Opaglos Sucrose Titanium Dioxide 30.0mg 22.5mg 3.0mg 6.0mg 6.0mg 7.5mg 15.0mg 171.0mg 1.5mg
6.2.
Incompatibilities None known.
6.3 6.4.
Shelf life 5 years Special precautions for storage Protect from light and moisture. Store below 25C.
6.5.
Nature and contents of container Plastic securitainers with tamper evident polypropylene lids. (Materials comply to EEC directives for plastics in contact with drugs and foodstuffs). Packed in pack sizes: 25, 28, 50, 56, 100, 250, 500 and 1000. Blister packs of 0.25mm PVC and 20 microns Aluminium foil.
6.6.
Instruction for use and handling None.
7.
MARKETING AUTHORISATION HOLDER Pharmvit Limited 177 Bilton Road Perivale, Greenford, Middlesex UB6 7HQ
8.
MARKETING AUTHORISATION NUMBER PL 04556/0032
9. DATE OF AUTHORISATION 9th April 1992
FIRST
AUTHORISATION/RENEWAL
OF
THE
10
DATE OF REVISION OF THE TEXT
15/06/2010
1
NAME OF THE MEDICINAL PRODUCT
Quinine Sulphate Tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION 300mg Quinine Sulphate BP
3.
PHARMACEUTICAL FORM Sugar-coated tablets
4
4.1
CLINICAL PARTICULARS
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
Treatment of uncomplicated malaria: Adult dosage: Equivalent of 496mg of quinine base every eight hours for 7 days, given by mouth. Followed by (or with) an appropriate dose of sulphadoxine/ pyrimethamine combination. Children: Equivalent of 8.26mg/kg quinine base every eight hours for 7 days, given by mouth. Followed by (or with) an appropriate dose of sulphadoxine/pyrimethamine combination.
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.
4.3
Contraindications
Known hypersensitivity to quinine or any of the excipients in the tablet. 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 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 nonpharmacological measures have not worked. Quinine sulphate should not be used for this indication during pregnancy (see Section 4.6). Hypersensitivity to quinine should be tested for in each patient Glucose-6-phosphate dehydrogenase deficient patients with malaria may be at increased risk of haemolysis during quinine therapy. Quinine may aggravate the symptoms of myasthenia gravis. Quinine may precipitate Blackwater fever. 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. Hypersensitivity to quinine may also occur with symptoms of cinchonism together with urticaria, flushing, pruritus, rash, fever, angioedema, dyspnoea and asthma. 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.
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. 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, i.e. Warfarin. Clearance of quinine was reduced and half-life increased in patients pretreated with cimetidine. 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
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 benefit out weigh the risks. Treatment of chloroquine-resistant stains of falciparum 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 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 risk.
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 Blood and disorders lymphatic Adverse Reaction
system 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 Nervous system disorders Eye disorders Agitation, confusion Headache, vertigo Blurred vision, defective colour perception, visual field constriction Tinnitus, impaired hearing Atrioventricular conduction disturbances, hypotension, prolongation of the QT interval, widening of the QRS complex and T wave flattening and Bronchospasm
Ear and labyrinth disorders Cardiac disorders
Respiratory, thoracic mediastinal disorders Gastrointestinal disorders
Nausea, vomiting, diarrhoea, abdominal pain Skin and subcutaneous tissue Flushing, rash, urticaria, disorders eczematous dermatitis, oedema, erythema, lichen planus, pruritis, photosensitivity Musculoskeletal and connective Muscle weakness, aggravation of tissue disorders myasthenia gravis Renal and urinary disorders Renal insufficiency, acute renal failure
4.9 Overdose
Symptoms: Quinine over dosage may lead to serious and irreversible side effects and can be fatal. In acute over dosage, symptoms of cinchonism may occur, including convulsions, nausea, vomiting, tinnitus, deafness, headache, vasodilatation, disturbed vision, QT prolongation and renal failure. The visual disorders may be severe and there may be impairment of consciousness, coma, respiratory depression, arrhythmia and cardiogenic shock. 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; 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. Each 300 mg tablet is equivalent to 248 mg quinine base.
5.1.
Pharmacodynamic Properties 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 the 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 arc altered significantly by malarial infection, with reduction in volume of distribution and clearance.
5.3.
Preclinical Safety Data N/A
6
PHARMACEUTICAL PARTICULARS
6.1.
List of excipients Maize Starch Lactose Magnesium Stearate Stearic Acid Talc Sodium Croscarmellose Opaglos Sucrose Titanium Dioxide 30.0mg 22.5mg 3.0mg 6.0mg 6.0mg 7.5mg 15.0mg 171.0mg 1.5mg
6.2.
Incompatibilities None known.
6.3 6.4.
Shelf life 5 years Special precautions for storage Protect from light and moisture. Store below 25C.
6.5.
Nature and contents of container Plastic securitainers with tamper evident polypropylene lids. (Materials comply to EEC directives for plastics in contact with drugs and foodstuffs). Packed in pack sizes: 25, 28, 50, 56, 100, 250, 500 and 1000. Blister packs of 0.25mm PVC and 20 microns Aluminium foil.
6.6.
Instruction for use and handling None.
7.
MARKETING AUTHORISATION HOLDER Pharmvit Limited 177 Bilton Road Perivale, Greenford, Middlesex UB6 7HQ
8.
MARKETING AUTHORISATION NUMBER PL 04556/0032
9. DATE OF AUTHORISATION 9th April 1992
FIRST
AUTHORISATION/RENEWAL
OF
THE
10
DATE OF REVISION OF THE TEXT
15/06/2010
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 drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.
