Quinine

Quinine Bisulphate 300mg Tablets

Each tablet contains 300mg of quinine bisulphate

For the full list of excipients, see section 6.1.

Quinine Bisulphate 300mg Tablets are plain white, film-coated tablets for oral administration.

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 4.4)

Posology

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 the elderly:

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.

Method of administration - Oral

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

- Use in patients with Haemoglobinuria or Haemolysis

- Optic neuritis

- Tinnitus

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

- As quinine has been implicated in precipitating blackwater fever, it is generally contraindicated in patients who have already suffered an attack.

Cinochonism

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 has dose-dependent QT-prolonging effects. Caution is recommended in patients with conditions which predispose to QT prolongation and in patients with atrioventricular block. Quinine should be used with caution in patients with atrial fibrillation heart block, other cardiac conduction defects, or other serious heart disease.

Quinine may cause hypoprothrombinaemia and enhance the effects of anticoagulants..

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

Quinine has been implicated in precipitating blackwater fever when given for prolonged periods, although in some cases, glucose-6-phosphate dehydrogenase deficiency may have been involved. Patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency may be at increased risk of haemolysis during quinine therapy and may develop acute haemolytic anaemia.

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.

Before use for nocturnal leg cramps, the risks, which include significant adverse effects and interactions (see section 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 and frequent, when other treatable causes of cramps have been ruled out, and when non-pharmacological 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.

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

Effects of other drugs on quinine:

Quinine is metabolised via hepatic oxidative cytochrome P450, 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.

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.

Effects of quinine on other drugs.

The plasma concentration of flecanide, digoxin and mefloquine may be increased.

Amantadine: Quinine can reduce the renal clearance of amantadine with risk of amantadine toxicity (including headache, nausea, dizziness).

Analgesics: increased risk of ventricular arrhythmias with levacetylmethadol (avoid concomitant use).

Ciclosporin: Quinine can decrease 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

There is an increased risk of ventricular arrhythmias with other drugs, which prolong the QT interval, including amiodarone, moxifloxacin, pimozide, thioridazine and halofantrine.

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

Anticoagulants: Quinine may cause hypoprothrombinaemia and enhance the effects of anticoagulants. Caution is advised when administering quinine with drugs which could prolong the QT interval.

Antihistamines: Concomitant use of astemizole and terfenadine should be avoided due to the increased risk of ventricular arrhythmias..

Antimalarials: There may be an increased risk of side effects if quinine is used with other antimalarials, for example, chloroquine, halofantrine and mefloquine (increased risk of convulsions), although this should not prevent their use in severe cases. Quinine may increase the plasma concentration of mefloquine. Chloroquine and quinine appear to be antagonistic when given together for P falciparum malaria. There is an increased risk of ventricular arrhythmias with halofantrine.

Antipsychotics: There is an increased risk of ventricular arrhythmias and concomitant use should be avoided with pimozide or thioridazine.

Hypoglycaemics: There is an increased risk of hypoglycaemia when taken concurrently.

Suxamethonium: Quinine enhances the neuromuscular effects of suxamethonium.

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

Pregnancy

Large doses of quinine can induce abortion. 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 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.

Prophylaxis of nocturnal leg-cramps:

Quinine bisulphate should not be used during pregnancy to treat cramps.

Breast-feeding:

Quinine bisulphate is excreted in breast milk, but no problems in humans have been reported. Infants at risk for glucose-6-phosphate dehydrogenase deficiency should not be breast-fed until this disease can be ruled out. However, quinine bisulphate should not be given to nursing mothers unless the benefits outweigh the risks.

Quinine may cause visual disturbances and vertigo, hence patients should be advised that if affected they should not drive or operate machinery.

Adverse drug reactions are ranked by frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

* May occur after long term administration of quinine.

** Toxic doses of quinine may induce abortion, but it is unwise to withhold the drug if less toxic antimalarials are not available.

*** 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 (blurred vision, defective colour perception, visual field constriction and total blindness).

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; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Acute intoxication can be seen after ingestion of doses of 4-12g, but a dose of 8g can prove lethal. The average fatal dose for an adult is about 8g although deaths have been reported from as little as 1.5g in an adult and 900mg in a child.

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 disturbances.

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 quinine base has been taken.

Each 300mg 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.

Pharmacotherpeutic 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.

Pharmacodynamic effect

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.

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.

Quinine is mainly used orally for the treatment of uncomplicated attacks of the chloroquine or multidrug resistant strains of Plasmodium falciparum. In addition, quinine bisulphate 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.

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.

Not applicable

Silicon Dioxide

Guar Gum

Magnesium Stearate

Microcrystalline cellulose

Hydroxypropylmethylcellulose

Polyethylene Glycol

Ethylcellulose

Titanium Dioxide

Beeswax

Purified Water

Digoxin Therapy

Physostigmine Therapy

Four years

Store below 25°C in a dry place. Protect from light

Polypropylene securitainer with appropriate bellows or polyurethane foam wads containing 28 and 500 tablets.

PVC blister with aluminium lidding foil containing 28 tablets.

No special instructions

Kent Pharma UK Limited, The Bower, 4 Roundwood Avenue, Stockley Park, Heathrow, United Kingdom, UB11 1AF.

PL 51463/0061

02/06/1983 / 10/04/2002

30^th December 2021