Consumer medicine information

Quinbisul

Quinine bisulfate heptahydrate

BRAND INFORMATION

Brand name

Quinbisul

Active ingredient

Quinine bisulfate heptahydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Quinbisul.

SUMMARY CMI

QUINBISUL Tablets

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using QUINBISUL?

QUINBISUL contains the active ingredient quinine bisulfate heptahydrate.

QUINBISUL is used treat malaria, together with other medicines.

For more information, see Section 1. Why am I using QUINBISUL? in the full CMI.

2. What should I know before I use QUINBISUL?

Do not use if you have ever had an allergic reaction to QUINBISUL, medicines containing quinine, tonic water or bitter lemon drinks which contain quinine or any of the ingredients listed at the end of the CMI.

For more information, see Section 2. What should I know before I use QUINBISUL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with QUINBISUL and affect how it works. Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use QUINBISUL?

  • QUINBISUL is taken together with other anti-malarial medicines.
  • The dose varies from person to person.
  • More instructions can be found in Section 4. How do I use QUINBISUL? in the full CMI.

5. What should I know while using QUINBISUL?

Things you should do
  • Tell your doctor if you are pregnant or plan to become pregnant.
  • Tell your doctor if you have any medical conditions, including irregular heart beat.
  • Tell your doctor if you need to have any tests on your urine or require surgery.
Things you should not do
  • Do not take more than the prescribed dose.
  • Do not give this medicine to anyone else, even if their symptoms are similar to yours.
  • Avoid drinking large amounts of tonic water and bitter lemon drinks while you are taking QUINBISUL.
Driving or using machines
  • Be careful driving or operating machinery until you know how QUINBISUL affects you. QUINBISUL may cause dizziness and affect vision in some people.
Looking after your medicine
  • Keep QUINBISUL tablets in a cool dry place where the temperature is below 25°C.

For more information, see Section 5. What should I know while using QUINBISUL? in the full CMI.

6. Are there any side effects?

There are a number of side effects associated with this medicine. It is important to be aware of them so that you can identify any symptoms if they occur (see the full CMI for more details). The serious side effects are: signs of allergy; sweating; bruising or bleeding more easily than normal; decreased or no urine production, signs of frequent infections such as fever, chills, sore throat or mouth ulcers; chest pain, irregular heart beats, symptoms of liver disease with yellowing of the eyes or skin (jaundice) and dark urine, loss of consciousness, coma, death.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

QUINBISUL Tablets

Active ingredient(s): Quinine bisulfate heptahydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using QUINBISUL tablets. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist. All medicines have risks and benefits. Your doctor has weighed the risks of you taking QUINBISUL against the benefits this medicine is expected to have for you.

You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using QUINBISUL.

Keep this leaflet with your medicine. You may need to read it again.

Where to find information in this leaflet:

1. Why am I using QUINBISUL?
2. What should I know before I use QUINBISUL?
3. What if I am taking other medicines?
4. How do I use QUINBISUL?
5. What should I know while using QUINBISUL?
6. Are there any side effects?
7. Product details

1. Why am I using QUINBISUL?

QUINBISUL is used to treat malaria, together with other medicines. It works by interfering with the growth of the parasite that causes malaria.

Ask your doctor if you have any questions about why QUINBISUL has been prescribed for you.

Your doctor, may have prescribed it for another purpose.

QUINBISUL is only available with a doctor's prescription.

There is no evidence that it is addictive.

2. What should I know before I use QUINBISUL?

Warnings

Do not take QUINBISUL if you are allergic to:

  • medicines containing quinine (e.g. Quinate)
  • tonic water or bitter lemon drinks which contain quinine
  • any of the ingredients at the end of this leaflet.

Some of the symptoms of an allergic reaction may include skin rash, itching, flushing of the skin, swelling of the face, fever, shortness of breath, ringing in the ears and changes in vision.

Do not take QUINBISUL if you have or have ever had:

  • a severe side effect caused by quinine (such as unusual bruising or bleeding or kidney problems)
  • myasthenia gravis - a condition causing muscle weakness
  • tinnitus - ringing in the ears
  • optic neuritis - a disease of the nerves of the eye, causing blindness
  • glucose-6-phosphate dehydrogenase (G-6-PD) deficiency - an inherited condition
  • blackwater fever.
  • haemoglobinuria - presence of excess haemoglobin in the urine.

Do not take QUINBISUL if the expiry date (Exp.) printed on the pack has passed.

If you take this medicine after the expiry date, it may not work as well.

Do not take QUINBISUL if the packaging shows signs of tampering or the tablets do not look quite right.

Check with your doctor or pharmacist if you:

  • you are allergic to any other medicines, foods, dyes or preservatives.
  • have any medical conditions, including an irregular heart beat. Your doctor may want to take special care.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking or are given QUINBISUL.

Your doctor will advise you whether or not to take QUINBISUL or if you need to adjust the dose or adapt your treatment.

You should not take more than the prescribed dose as a condition called ‘cinchonism’ may occur, even with normal doses. Symptoms of cinchonism include abdominal pain, diarrhoea, disturbed vision (blurred vision, changes in colour perception or field of vision, total blindness), headache, feeling or being sick, ringing in the ears or impaired hearing, rashes, loss of consciousness, fits, shock due to heart problems, irregular heartbeats, death. Tell your doctor if you experience any of them.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you are pregnant or plan to become pregnant.

Your doctor will discuss the risks and benefits of taking QUINBISUL during pregnancy.

Tell your doctor if you are breastfeeding or wish to breastfeed.

Small amounts of QUINBISUL passes into breast milk. Your doctor will discuss the risks and benefits of taking QUINBISUL when breastfeeding.

3. What if I am taking other medicines?

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may be affected by QUINBISUL or may affect how well it works. These medicines include:

  • warfarin; used to prevent blood clots (e.g. Coumadin, Marevan)
  • digoxin; used for heart conditions (e.g. Lanoxin)
  • flecainide; used to treat irregular heartbeats
  • other medicines for malaria, such as mefloquine (e.g. Lariam) and pyrimethamine (e.g. Daraprim)
  • medicines used to relieve the symptoms of urinary tract disorders and infections (e.g. Ural, Citralite)
  • cimetidine; commonly used to treat reflux and ulcers (e.g. Tagamet, Magicul)
  • antacids containing aluminium, which may reduce the absorption of Quinbisul (e.g. Mylanta, Gaviscon).
  • pimozide or thioridazine (to treat some mental disorders)
  • moxifloxacin, rifampicin or antifungals (to treat infections)
  • barbiturates, carbamazepine or phenytoin (medicines to treat epilepsy)
  • HIV medicines
  • suxamethonium (muscle relaxant)
  • terfenadine; used for allergic reactions
  • medicines to treat diabetes

To make sure there is no problem with absorption, QUINBISUL is best taken at least one hour before or one hour after taking antacids.

Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking QUINBISUL.

4. How do I use QUINBISUL?

Follow all directions given to you by your doctor and pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the bottle, ask your doctor or pharmacist.

How much to take

QUINBISUL is taken together with other anti-malarial medicines.

The dose varies from person to person.

The usual dose of Quinbisul for adults is 2 tablets three times a day after meals, for 7 to 14 days.

Elderly people and children may need smaller doses.

When to take / use QUINBISUL

Take your medicine at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How to take QUINBISUL?

Swallow the tablets whole with a glass of water.

If you forget to use QUINBISUL

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

Do not take a double dose to make up for the dose you missed.

If you are not sure what to do ask your doctor or pharmacist.

If you use too much QUINBISUL

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think you or anyone else may have taken too much QUINBISUL. Do this even if there are no signs of discomfort or poisoning.

If you take too much QUINBISUL, you may experience dizziness, ringing in the ears, stomach cramps, skin rash and impaired vision. You may also vomit, have a headache or fever, feel nervous or confused, or have fits.

5. What should I know while using QUINBISUL?

Things you should do

Before starting any new medicine, tell your doctor or pharmacist that you are taking QUINBISUL.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking QUINBISUL.

Keep taking QUINBISUL for as long as your doctor recommends.

If you become pregnant while taking QUINBISUL, tell your doctor.

If you need to have any tests on your urine, tell your doctor you are taking QUINBISUL.

It may affect the results of some tests.

If you plan to have surgery that requires the use of muscle relaxants (e.g. suxamethonium, pancuronium) tell your doctor, anaesthetist or dentist that you are taking QUINBISUL.

Things you should not do

  • Do not take QUINBISUL to treat any other conditions unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how QUINBISUL affects you.

QUINBISUL may cause dizziness and affect vision in some people. If this occurs, do not drive or operate machinery or do anything else which could be dangerous.

Effects of food

Avoid drinking large amounts of tonic water and bitter lemon drinks while you are taking QUINBISUL.

Tonic water and bitter lemon drinks contain quinine and may increase the risk of side effects of QUINBISUL.

Things to be careful of

Treatment for night cramps should be stopped if symptoms of cinchonism emerge.

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

Quinine should be used with caution in patients with atrial fibrillation, conduction defects and heart blocks, or other serious heart disease. It may cause hypoprothrombinaemia.

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

Looking after your medicine

Keep QUINBISUL tablets in a cool dry place where the temperature is below 25°C.

Do not store QUINBISUL, or any other medicine, in the bathroom or near a sink.

Do not leave medicines in the car or on window sills. Heat and dampness can destroy some medicines.

Keep your medicines where children cannot reach them. A locked cupboard at least one-and-a-half metres (1.5 m) above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking QUINBISUL.

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Less serious side effects

Less serious side effectsWhat to do
  • ringing in the ears, loss of hearing
  • dizziness, fainting
  • headache
  • confusion, nervousness
  • nausea, vomiting, stomach cramps
  • disturbed vision.
  • diarrhoea
Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • skin rash or redness, itching
  • wheezing or difficulty breathing, swelling of the face
  • sweating
  • bruising or bleeding more easily than normal
  • decreased or no urine production
  • signs of frequent infections such as fever, chills, sore throat or mouth ulcers
  • chest pain, irregular heart beats
  • symptoms of liver disease with yellowing of the eyes or skin (jaundice) and dark urine.
  • loss of consciousness, coma, death.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is available with a doctor's prescription.

What QUINBISUL contains

Active ingredient
(main ingredient)		quinine bisulfate heptahydrate
Other ingredients
(inactive ingredients)

QUINBISUL tablets contain:

  • lactose monohydrate
  • microcrystalline cellulose
  • povidone
  • purified talc
  • sodium starch glycollate
  • pregelatinised maize starch
  • colloidal anhydrous silica
  • magnesium stearate
  • carnauba wax
  • opadry white OY-LS-28908.
Potential allergensContains sugars as lactose.

QUINBISUL does not contain sucrose, gluten, tartrazine or any other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

What QUINBISUL looks like

QUINBISUL is a round, plain, white film coated, unscored, convex tablet. Each bottle contains 50 tablets. (Aust R 116545).

Who distributes QUINBISUL

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was prepared in April 2024

Published by MIMS July 2024

BRAND INFORMATION

Brand name

Quinbisul

Active ingredient

Quinine bisulfate heptahydrate

Schedule

S4

 

1 Name of Medicine

Quinine bisulfate heptahydrate.

2 Qualitative and Quantitative Composition

Each Quinbisul tablet contains 300 mg of quinine bisulphate heptahydrate.

List of excipients of known effect.

Sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Quinbisul tablets are plain, white film coated, unscored, convex tablet.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of malaria due to strains of P. falciparum resistant to chloroquine and the related 4-aminoquinolines.

4.2 Dose and Method of Administration

Adults.

The typical oral dose of quinine in the treatment of chloroquine-resistant P. falciparum malaria is 600 mg three times daily after meals for 7 to 14 days, plus 75 mg pyrimethamine/1,500 mg sulfadoxine as a single dose on the second day of treatment.
In certain emergencies such as cerebral malaria, quinine should be given by intravenous injection or infusion. The dihydrochloride is employed and the injection should be made very slowly, preferably by IV infusion. The optimal daily dose is 10 to 20 mg/kg, usually given as two separate infusions over four hours each. Quinine bisulfate heptahydrate is unsuitable for use in injections since its solution decomposes on heating.

Therapeutic range of serum levels.

2 to 5 microgram/mL.

Paediatric.

For the treatment of chloroquine resistant malaria in children, administer 10 mg/kg quinine three times daily for 7 to 10 days, in combination with an appropriate single dose of pyrimethamine/ sulfadoxine.

Geriatric.

A study of the pharmacokinetics of quinine in elderly (older than 65 years) and young (20 to 40 years) subjects indicated that a significantly higher peak plasma concentration was achieved in the elderly subjects following a standard oral dose of quinine sulfate. This is probably influenced by the decrease in plasma clearance observed in the elderly patients. In view of this it may be necessary to reduce the normal adult dosage.

4.3 Contraindications

Quinbisul should not be used in patients hypersensitive to quinine, in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or in patients with a history of blackwater fever.
Since thrombocytopenia, which may be fatal, and haemolytic uraemic syndrome with acute renal failure may follow the administration of quinine in highly sensitive patients, a history of this occurrence associated with previous quinine ingestion contraindicates its further use. Recovery usually occurs following withdrawal of the medication and appropriate therapy.
Myasthenia gravis (see Section 4.8 Adverse Effects (Undesirable Effects)); tinnitus; optic neuritis; 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. Patient 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. Symptoms of cinchonism include tinnitus, impaired hearing, headache, nausea and disturbed vision (see Section 4.8 Adverse Effects (Undesirable Effects)).

Hypersensitivity.

Hypersensitivity reactions, including cutaneous flushing, pruritus, rash (urticarial, papular, scarlatinal), fever, facial oedema, angioedema, gastrointestinal distress, dyspnoea, tinnitus and impairment of vision and hearing have been reported with quinine. Extreme flushing of the skin with intense, generalised pruritus is the most frequently reported hypersensitivity reaction to the drug. Haemoglobinuria and asthma have also been reported rarely. If evidence of hypersensitivity occurs during quinine therapy, the drug should be discontinued.
Serious hypersensitivity reactions including Stevens-Johnson syndrome have been reported with quinine.

Haemolysis.

Haemolysis, with the potential for haemolytic anaemia, has been reported when quinine was administered to patients with G-6-PD deficiency. Quinine should be stopped immediately if haemolysis occurs and supportive measures instituted.

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.

Resistance.

Treatment with quinine should be monitored in case signs of resistance develop.

Thrombocytopenia.

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 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.

Prothrombin formation.

Quinine is capable of causing hypoprothrombinaemia (i.e. depresses the formation of prothrombin) and may enhance the effects of anticoagulants. The simultaneous administration of vitamin K counteracts the prolongation of the prothrombin time.

Atrial fibrillation.

Patients with atrial fibrillation should be digitalised before receiving quinine, because quinine may otherwise cause an increase in the ventricular rate.

Myasthenia gravis.

Quinine may cause severe respiratory distress and dysphagia in patient with myasthenia gravis. Renal impairment which may be due to an immune mechanism may occur. Hypoglycaemia may occur.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

Quinine may produce an elevated value for urinary 17-ketogenic steroids when the Zimmerman method is used.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of other drugs on quinine.

CYP3A4 inhibitors.

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 includes azole antifungal drugs and HIV protease inhibitors.

CYP3A4 inducers.

Sub-optimal quinine serum levels may result from concomitant use of CYP3A4 inducers, which include rifampicin, barbiturates, carbamazepine and phenytoin.

CYP3A4 substrate.

Care should be taken when quinine is used in combination with other CYP3A4 substrate, especially those causing prolongation of the QT interval.

Antacids.

Concurrent use of aluminium-containing antacids may delay or decrease absorption of quinine.

Effect of quinine on other drugs.

The plasma concentration of flecainide, digoxin and mefloquine may be increased. Quinine can decrease serum plasma concentrations of ciclosporin.

Quinine-containing beverages.

Excessive quantities of quinine-containing beverages should not be consumed while taking quinine as this may increase the risk of adverse reactions and toxicity.

Pyrimethamine.

Pyrimethamine may displace quinine from plasma protein binding sites resulting in excessive free quinine, and perhaps quinine toxicity.

Cardiac glycosides.

Increased plasma levels of digoxin have been demonstrated in individuals after concomitant quinine administration. Increased plasma levels of digitoxin have been demonstrated in individuals after concomitant quinidine administration. It is therefore recommended that plasma levels of digoxin or digitoxin be determined periodically for those individuals taking either of these glycosides and quinine concomitantly.

Antacids.

Concurrent use of aluminium-containing antacids may delay or decrease absorption of quinine.
There is an increased risk of ventricular arrythmias with other drugs which prolong the QT interval, including amiodarone, moxifloxacin, pimozide, thioridazine and halofantrine. Caution is advised when administering quinine with drugs which could prolong the QT interval.

Antiarrhythmics.

Concomitant use of amiodarone should be avoided due to the increased risk of ventricular arrythmias, the plasma concentration of flecainide is increased by quinine. Concomitant use of quinine may increase the possibility of cinchonism.

Antibacterials.

There is an increase level of ventricular arrhythmias when moxifloxacin is given with quinine. Rifampicin can reduce the serum levels of quinine, therefore reducing its therapeutic effect.

Anticoagulants.

Cinchona alkaloids, including quinine, have the potential to depress the hepatic enzyme system that synthesises the vitamin K-dependent factors. The resulting hypoprothrombinaemic effect may enhance the action of warfarin and other oral 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 concentration of primaquine.

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.

Neuromuscular blocking agents.

The effects of neuromuscular blocking agents (particularly pancuronium, succinylcholine and tubocurarine) may be potentiated with quinine, and result in respiratory difficulties.

Acidifiers and alkalinisers.

Ammonium chloride and other drugs which may lower the pH of the urine (urinary acidifiers) considerably increases the renal excretion of quinine. Conversely, urinary alkalinisers (such as acetazolamide and sodium bicarbonate) may increase quinine blood levels with potential for toxicity.
Quinine may increase the levels of phenobarbital and carbamazepine. Patients should be monitored closely during concomitant use of quinine with these agents.

Mefloquine.

Because adverse cardiac effects may be additive, mefloquine should not be used concomitantly with quinine. Concomitant use of mefloquine and quinine may result in ECG abnormalities or cardiac arrest and may increase the risk of seizures.

Cimetidine.

Cimetidine has been reported to reduce the clearance and prolong the elimination half-life of quinine following concomitant oral administration of the drugs in healthy adults. The clinical significance of this interaction is not known.

Potential interaction.

Skeletal muscle relaxants.

In view of the known effect of quinine in patients with myasthenia gravis (see Section 4.8 Adverse Effects (Undesirable Effects)), it may potentiate the effect of both depolarising and nondepolarising muscle relaxants.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D)
The use of antimalarials in the treatment of malaria is accepted because the small risk to the foetus is outweighed by the benefits to the mother and foetus. Prophylaxis in high risk situations is also justified.
In toxic doses, quinine causes foetal damage in the form of deafness, phototoxicity development disturbances and malformations of the CNS extremities and cranium in both animals and humans. Its ability to induce uterine contractions also constitutes a risk of abortion.
 Caution should be exercised when quinine is given to nursing mothers because quinine is excreted in small amounts in breast milk.

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 Adverse Effects (Undesirable Effects)

When quinine is given repeatedly in full doses, a typical group of symptoms occurs to which the term cinchonism has been applied. Cinchonism has certain features in common with salicylate poisoning. Mildest forms consist of tinnitus, impaired hearing, headache, nausea, and slightly disturbed vision. If the medication is continued or in overdose, symptoms also involve the gastrointestinal tract, the central nervous and cardiovascular systems, and the skin. In some individuals, small doses of quinine cause toxic manifestations and death. Visual disorders may include blurred vision, defective colour perception, visual field constriction and total blindness.
The following adverse reactions have been reported with quinine in therapeutic or excessive dosage (individual or multiple symptoms may represent cinchonism or hypersensitivity).

Blood and lymphatic system disorders.

Thrombocytopenia, intravascular coagulation, hypoprothrombinaemia, haemoglobinuria, oliguria, haemolytic-uremic syndrome, pancytopenia, haemolysis, agranulocytosis, thrombocytopenic purpura.

Immune system disorders.

Report 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 may occur after oral administration although it is more common after parenteral administration.

Psychiatric disorders.

Agitation, apprehension, restlessness, confusion.

Nervous system disorders.

Headache, vertigo, excitement, loss of consciousness, come death.

Eye disorders.

Visual disturbances including blurred vision with scotomata, photophobia, diplopia, mydriasis, constricted visual fields, night blindness and disturbed colour perception. Visual disturbances are generally reversible following discontinuation of the drug, but in severe cases, optic atrophy may result.

Ear and labyrinth disorders.

Tinnitus, deafness, vertigo, and impaired hearing.

Skin and subcutaneous tissue disorders.

Rashes (urticarial, the most frequent type of allergic reaction, papular or scarlatinal), urticaria, eczematous dermatitis, oedema, erythema, lichen planus pruritus, flushing of the skin, sweating, photosensitivity.

Respiratory, thoracic and mediastinal disorders.

Asthmatic symptoms. Bronchospasm, dyspnoea may occur.

Cardiac disorders.

There may be disturbances in cardiac rhythm or conduction, fall in blood pressure coupled with feeble pulse, and syncope. Prolongation of the QT interval, widening of the QRS complex and T wave flattening has been noted with therapeutic doses. Hypotension, ventricular tachycardia and anginal symptoms have occurred with prolonged quinine therapy in highly sensitive patients.

Gastrointestinal disorders.

Diarrhoea, nausea and vomiting (may be CNS related), and abdominal pain may occur after long term administration.

Musculoskeletal and connective tissue disorders.

Quinine decreases neuromuscular transmission by increasing the threshold of excitability at the myoneural junction, and depresses the muscle action potential. It may therefore aggravate the symptoms of patients with myasthenia gravis.

Hepatic.

Hepatitis.

Renal.

Anuria, uraemia, haemoglobinuria.

Serious or life-threatening reactions.

Quinine can cause thrombocytopenia which may be fatal. There have been reports of haemolytic uraemic syndrome with acute renal failure following a single 300 mg dose of quinine. Acute haemolytic anaemia is rare and normally disappears on withdrawal of the drug.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

The most common signs and symptoms of overdosage are tinnitus, dizziness, skin rash and gastrointestinal disturbances (intestinal cramping). With higher doses, cardiovascular and CNS effects may occur, including headache, fever, vomiting, apprehension, confusion and convulsions. Other effects are listed in Section 4.8 Adverse Effects (Undesirable Effects).
Fatalities have been reported from a single dose of 2-8 g of quinine and a single fatality reported with a 1.5 g dose (which may reflect an idiosyncratic effect). Several cases of blindness following large overdoses of quinine, with partial recovery of vision in each instance, have been reported. Tinnitus and impaired hearing may occur at plasma quinine concentrations over 10 microgram/mL. This level would not be normally attained with the dose of 1-2 quinine tablets daily, but in hypersensitive patients, as little as 0.3 g of quinine may produce tinnitus.
Treatment of overdose with Quinbisul should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient together with careful monitoring of ECG, respiratory status and central nervous system toxicity. There is no specific antidote for overdose with Quinbisul. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug.
Patients should be warned of possible blindness but reassured that some recovery of sight frequently occurs. Stellate block has also been used effectively for quinine-associated blindness. Residual visual impairment occasionally yields to vasodilators.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Antimalarial action.

Quinine is not a true causal prophylactic agent; it is incapable of preventing sporozoite induced vivax or falciparum malaria in human volunteers. However, it is effective as a suppressive drug and in the control of overt clinical attacks. Its primary action is schizonticidal, and no lethal effect is exerted on sporozoites or pre-erythrocytic tissue forms. In addition, quinine is gametocytocidal for P. vivax and P. malariae but not for P. falciparum. The exact mechanism of quinine's antimalarial action is uncertain. Quinine can form a hydrogen bonded complex with double stranded DNA which inhibits protein synthesis by preventing strand separation and therefore DNA replication and transcription to RNA.

Central nervous system.

Quinine has slight analgesic and antipyretic activity. Quinine has indifferent results on fevers, other than malarial fever, indicating that it is not a potent antipyretic, and it is rarely used for this purpose. Quinine resembles the salicylates in its analgesic properties, especially in joint and muscle pain. It acts centrally, but is ineffective against severe pain.

Cardiovascular system.

The actions of quinine on cardiac muscle are qualitatively similar to those of its isomer quinidine. Therapeutic doses of quinine have little if any effect on the normal cardiovascular system in man.

Smooth muscle.

Quinine has little effect on smooth muscle other than a slight oxytocic action on the gravid uterus, especially during the third trimester of pregnancy. The spleen may contract as a result of the direct action of quinine on the musculature of its capsule, thus producing a lymphocytosis sometimes observed after therapeutic doses of the drug.

Skeletal muscle.

Quinine increases the tension response to a single maximal stimulus delivered to the muscle directly or through the nerve, but it increases the refractory period of muscle so that the response to tetanic stimulus is diminished. Quinine also decreases the excitability of the motor end-plate region so that the responses to repetitive nerve stimulation and to acetylcholine are reduced. Thus it has a curare-like effect on skeletal muscle.

Other actions.

Quinine has strong prostaglandin antagonistic action and weak agonistic activity. The antagonistic effect is clearly demonstrable at concentrations attained therapeutically. Quinine has slight local anaesthetic activity. The anaesthesia may last for many hours or days.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Quinine bisulfate heptahydrate is readily and almost completely absorbed from the gastrointestinal tract, even in patients with marked diarrhoea. Absorption occurs mainly from the upper small intestine and peak plasma concentrations are achieved 1 to 3 hours after ingestion. For example, after single doses of 4 mg/kg in aqueous solution peak plasma concentrations of 1.1 and 2.4 microgram/mL were achieved in young and old adults, respectively. After chronic administration of total daily doses of 1 g of quinine, the average plasma quinine concentration is approximately 7 microgram/mL.

Distribution.

Quinine is widely distributed into body tissues. Only 2 to 5% of the plasma quinine concentration is found in the CSF, probably as a result of the extent of binding to plasma proteins. Quinine readily crosses the placenta and has been found in the tissues of the foetus. The apparent volume of distribution has been found to vary with age and dose. For example, in the case of young and elderly subjects receiving oral doses of 4 mg/kg, the apparent volumes of distribution were 3.2 and 1.7 litres/kg respectively. In another study, the apparent volumes of distribution following doses of 100, 325 and 650 mg three times daily for three days were 38.6, 58.1 and 85.8 litres respectively.

Metabolism.

Metabolism of quinine occurs largely in the liver, with less than 5% of unaltered drug excreted in the urine. Metabolism occurs largely by hydroxylation, principally to a 2-hydroxyquinoline derivative and a 6-hydroxyquinuclidine derivative, both of which show little antimalarial activity. In a study of quinine disposition during malaria and experimentally induced fever it was found that in all subjects, plasma levels of quinine, and the ratio of plasma quinine to plasma metabolites, were increased during malaria, suggesting impaired hepatic metabolism of quinine. A similar observation was noted for changes in quinine metabolism during artificially induced fever.

Excretion.

After termination of therapy, plasma levels fall rapidly and only negligible concentrations of quinine are present after 24 hours. Less than 5% of quinine is excreted in the urine, and renal excretion is twice as rapid in acid urine as in alkaline urine. Renal excretion of quinine is limited by the binding of a large fraction to plasma proteins.

Half-life.

In one study a dose-dependent prolongation of plasma quinine half-life was observed. After doses of 100, 325 and 650 mg three times daily for three days, measurements of plasma half-lives were 8.5, 12.4, and 16.4 hours respectively. In another study 5 subjects were given 540 mg of quinine base every 8 hours until a total of 9 doses had been administered. The average plasma half-life values before malaria and during malaria were found to be 7.3 and 8.3 hours respectively.

Clinical implications of pharmacokinetic data.

Quinine bisulfate heptahydrate is readily absorbed after oral administration. Volume of distribution is dose-dependent. Protein binding is 70%. Clearance is principally by hepatic metabolism. Plasma half-life is about 8 hours, increasing with dosage.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Quinbisul tablet contains the following inactive excipients: lactose monohydrate, microcrystalline cellulose, povidone, purified talc, sodium starch glycollate, pregelatinised maize starch, colloidal anhydrous silica, magnesium stearate, carnauba wax and Opadry white OY-LS-28908 (PI).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

HDPE bottles of 30* and 50 tablets. (*30 tablets currently not available in Australia).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Quinine bisulfate is the heptahydrate of (8S,9R)-6-methoxycinchonan-9-ol hydrogen sulfate.

Chemical structure.


Molecular formula: C20H24N2O2,H2SO4,7H2O.
Molecular weight: 548.6.

CAS number.

549-56-4 (anhydrous).

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes