Summary of Product Characteristics

1    Name of the medicinal product

Quinine Sulfate 300 mg Tablets

2    Qualitative and quantitative composition

Each tablet contains Quinine Sulfate 300 mg.

For excipients see 6.1

3    PHARMACEUTICAL FORM

Coated tablet.

White biconvex sugar coated tablets.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the treatment of Plasmodium 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 oral administration. Swallow the tablets with a drink of water.

For the treatment of malaria

Adults, the elderly and children over 12 years of age: Two tablets to be taken every 8 hours for a period of 7 days.

Children under 12 years of age: Dosage is dependent on bodyweight as follows - 10 mg/kg to be taken every 8 hours for a period of 7 days.

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.

4.3 Contraindications

Known hypersensitivity to quinine or any of the excipients in the tablet.

Contraindicated in those with myasthenia gravis, optic neuritis, tinnitus or haemoglobinuria.

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

Caution is required if administered to patients with atrial fibrillation or other serious heart disease. It may cause hypoprothrombinaemia.

Quinine may cause severe respiratory distress and dysphagia in patients with myasthenia gravis and should not be used in such patients.

Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may develop acute haemolytic anaemia. Glucose-6-phosphate dehydrogenase deficient patients with malaria are at increased risk of haemolysis during quinine therapy.

Treatment with quinine 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 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 sulfate 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.

Patients with rare hereditary problems of galactose or fructose intolerance, the Lapp lactase    deficiency, glucose-galactose malabsorption    or sucrase-isomaltase

insufficiency should not take this medicine.

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 hypoglycaemias 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.

4.6 Fertility, pregnancy and lactation

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 sulfate 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 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 sulfate should not be used during pregnancy to treat cramps.

Lactation

Quinine sulfate 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 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
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
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	Muscle weakness, aggravation of myasthenia
disorders	gravis
Renal and urinary disorders	Renal insufficiency, acute renal failure

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.

Symptoms include vomiting, tinnitus, deafness, headache 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 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.

Each 300 mg tablet is equivalent to 248 mg quinine base.

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 symptomatic to maintain blood pressure, respiration, renal function and to treat arrhythmia, convulsions, hypoglycaemia and acidosis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

P01BC01 - Methanolquinolines

Quinine is a cinchona alkaloid and a 4-methanol-quinolone 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. malariae and P. vivax but not against mature gametocytes of P. falciparum. The precise mechanism of action of quinine is unclear but it may interfere with lyosome function or nucleic acid synthesis in the malaria parasite. Since it has no activity against exoerythrocytic forms, quinine does not produce a radical cure in vivax or ovale malarias.

The increasing spread of resistance to chloroquine has been responsible for the reemergence of quinine as an important agent in the treatment of falciparum malaria and it is currently the treatment of choice in infections due to chloroquine-resistant or multidrug-resistant strains. Quinine is not generally used for malaria prophylaxis.

5.2 Pharmacokinetic properties

The pharmacokinetics of quinine are altered significantly by malaria infection, the major effects being reduction in both its apparent volume of distribution and its clearance.

Quinine is rapidly and almost completely absorbed from the gastrointestinal tract and peak concentrations in the circulation are attained about 1 to 3 hours after oral administration of the sulfate. 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 to 7% of those in the plasma.

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%. Excretion is increased in acid urine. The elimination halflife 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 breast milk.

5.3 Preclinical safety data

No data of relevance to the prescriber which is additional to that already included in other sections of the SPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose

Colloidal Anhydrous Silica Potato Starch Magnesium Stearate Sodium Starch Glycollate (Type A)

Sodium Laurilsulfate Talc

Gelatin

Sucrose

Titanium Dioxide (E171) Carnauba wax

6.2 Incompatibilities

None known.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Tablet containers: Do not store above 25°C. Store in the original container. Keep the container tightly closed.

Blisters: Do not store above 25°C. Store in the original package. Keep the blister in the outer carton.

6.5 Nature and contents of container

HDPP tablet containers with LDPE caps of 500 tablets.

Al/PVC blisters enclosed in an outer carton, pack sizes of 28 and 56 tablets. Not all pack sizes may be marketed.

Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Dalkeith Laboratories Limited

2 Park Street

Woburn

Bedfordshire

MK17 9PG

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 17496/0023

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

02/03/2011

10 DATE OF REVISION OF THE TEXT

12/08/2015