Quinine Bisulfate Tablets BP 300mg – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Quinine Bisulfate Tablets BP 300mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains quinine bisulfate 300mg

Lactose

Sodium less than 1 mmol sodium (23 mg) per tablet.

For excipients, see 6.1

3 PHARMACEUTICAL FORM

Film-coated tablet

A white, biconvex film-coated tablet

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the treatment of falciparum 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

For falciparum malaria

Adults: the adult dosage regimen by mouth is 600mg of quinine sulfate given every 8 hours for 7 days.

The elderly: as for adults

Children: the dosage regimen for children by mouth is 10mg of quinine sulfate per kg body weight given every 8 hours for 7 days.

Note

If quinine resistance is known or suspected in the patient, then supplementary treatment with another recommended antimalarial drug is necessary.

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 to reassess the benefit of treatment.

4.3 Contraindications

-Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

-Optic neuritis

-Tinnitus

-Myasthenia gravis, quinine may cause severe respiratory distress and dysphagia in these patients

-Haemoglobinuria

4.4 Special warnings and precautions for use

Cinchonism

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

Hypersensitivity to quinine may also occur with symptoms of cinchonism together with urticaria, flushing, pruritus, rash, fever, angioedema, dyspnoea and asthma.

Serious hypersensitivity reactions including Stevens-Johnson syndrome have been reported with quinine.

Cardiac disorders

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 has dose-dependent QT-prolonging effects. Caution is recommended in patients with conditions which predispose to QT-prolongation and in patients with atrioventricular block.

Glucose-6-Phosphate Dehydrogenase (G-6-PD) Deficiency

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 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).

Treatment should be monitored in all patients in case signs of resistance develop.

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 bisulfate 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.

May cause severe respiratory distress and dysphagia in patients with myasthenia gravis.

Renal impairment which may be due to an immune mechanism may occur. Hypoglycaemia may occur.

Patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency may develop acute haemolytic anaemia.

Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine, as it contains lactose.

Reduce the dosage (or increase intervals between doses) in renal or hepatic disease.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. is essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other drugs on quinine

CYP3A4 substrate

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 such as 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.

Amantidine: 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

Drug caused QT prolongation

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

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 reduce the serum levels of quinine, therefore reducing its therapeutic effect.

Anticoagulants: Quinine may cause hypoprothrombinaemia and thereby enhance the effect 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: Concurrent use with oral hypoglycaemics may increase the risk of hypoglycaemia.

Suxamethonium: Quinine enhances the neuromuscular effects of suxamethonium. Concomitant use of quinidine may increase the possibility of cinchonism.

Ulcer healing drugs: Cimetidine inhibits quinine metabolism leading to increased plasma quinine concentrations.

Caution is advised when administering quinine with drugs which could prolong the QT interval.

Quinine may increase the levels of phenobarbital and of carbamazepine.

Patients should be monitored closely during concomitant use of quinine with these agents.

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 falciparium 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 bisulfate should not be used during pregnancy to treat cramps.

Breast-feeding:

Quinine bisulfate is excreted in breast milk, but no problems in humans have been reported. However, quinine bisulfate should not be given to nursing mothers unless the benefits outweigh the risks.

Fertility:

No data available

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 bisulfate 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. In 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.

The following adverse reactions are classified by system organ class and ranked under heading of frequency using the following convention:

Not known (frequency cannot be estimated from the available data)

Reporting of suspected adverse reactions

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 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 visual disturbance.

Features of a significant overdose include convulsions, impairment of consciousness, coma, respiratory depression, QT prolongation, ventricular arrhythmia, cardiogenic shock and renal failure. Fatalities have been reported in adults after doses of 2-8g. 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 30mg/kg of quinine base has been taken.

Note: Each quinine bisulfate 300mg tablet is equivalent to 178mg of quinine base

Quinine is rapidly absorbed. 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 doses 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.

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 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 8 g, 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

Pharmacotherapeutic group: Quinine alkaloid

ATC Code: P01BC01.

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. malariar and P. vivax but not against mature gametocytes P. falciparum. Since it has no activity against exoerythrocyctic forms, quinine does not produce a radical cure in vivax or ovale malarias.

Mechanism of action

The precise mechanism of action of quinine is unclear but it may interfere with lysosome function or nucleic acid synthesis in the malaria parasite.

Pharmacodynamic effects

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.

Quinine increases the refractory period of muscle so that the tetanic stimulation is diminished. It also affects a number of other body systems including the central nervous system, the cardiovascular system, the gastrointestinal tract and the pancreas. In addition, quinine exhibits local anaesthetic action and a local irritant action. As an antimalarial drug it acts primarily as a schizontocide. It is more toxic and less effective than chloroquine, but is especially useful for treatment of chloroquine-resistant strains of malarial infection.

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 sulfate.

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

Preclinical information has not been included because the safety profile of quinine bisulfate has been established after many years of clinical use. Please refer to Section

4.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose

Microcrystalline cellulose

Povidone K30

Ethanol

Sodium starch glycollate

Talc

Colloidal anhydrous silica

Magnesium stearate

Pregelatinised maize starch

Coating Components/Tablet

Purified Water

Isopropyl Alcohol

Hydroxypropylmethylcellulose

Diethyl phthalate

Opadry Y-1-7000 (containing hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol 400)

Carnauba wax

6.2 Incompatibilities

Not Applicable

6.3 Shelf life

AL/PVC Blister packs: 48 months

Polypropylene tablet containers: 36 months

6.4 Special precautions for storage

Store in a dry place below 25°C.

6.5 Nature and contents of container

Polypropylene tablet containers with polyethylene caps and optional use of fillers

PVC (250µm)/aluminium (25µm) foil blisters

Pack sizes: 5, 7, 10, 14, 15, 20, 21, 25, 28, 30, 56, 60, 84, 90, 100, 112, 120, 168, 180, 250 and 500

Not all pack sizes may be marketed

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Strides Pharma UK Ltd

Unit 4 Metro Centre

Tolpits Lane

Watford

Hertfordshire WD18 9SS

8 MARKETING AUTHORISATION NUMBER(S)

PL 13606/0058

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

18/02/1998 / 11/10/2004

10 DATE OF REVISION OF THE TEXT

27/01/2026