Consumer medicine information

Plaquenil Tablets

Hydroxychloroquine sulfate

BRAND INFORMATION

Brand name

Plaquenil

Active ingredient

Hydroxychloroquine sulfate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Plaquenil Tablets.

What is in this leaflet

This leaflet answers some common questions about Plaquenil 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 benefits and risks. In deciding to give you Plaquenil, your doctor has weighed the risks of taking Plaquenil against the benefits it will have for you.

Keep this information with the tablets. You may wish to read it again later.

What is Plaquenil used for

Plaquenil may be used for any of the following conditions:

Rheumatoid arthritis

Rheumatoid arthritis is a form of arthritis with inflammation of the joints, characterised by stiffness, swelling and pain. Plaquenil may be used for short or long-term rheumatoid arthritis treatment.

In treating rheumatoid arthritis, Plaquenil may slow down the process of joint damage and relieve the symptoms of the disease.

Systemic Lupus Erythematous (SLE)

SLE is a disease in which a person's normal immunity is upset. The body produces an excess of blood proteins called antibodies and these antibodies may cause problems in any organ of the body.

These antibodies may end up, for example, in the skin causing a variety of skin rashes or deposit in the kidney, brain, lung and joints causing injury.

Discoid Lupus Erythematous (DLE)

DLE is similar to SLE except it only affects the skin and is characterised by a scaling, red rash.

Malaria (treatment and control of symptoms)

Malaria is an infectious disease caused by the presence of parasites in red blood cells.

The disease is characterised by chills, fever and sweats.

In malaria, Plaquenil destroys the harmful parasite which causes the illness.

Your doctor may have prescribed this medicine for another reason. Ask your doctor if you have any questions about why Plaquenil has been prescribed for you.

Plaquenil is not addictive. This medicine is available only with a doctor's prescription.

Before you take Plaquenil

When you must not take Plaquenil

Do not take Plaquenil if you have ever had an allergic reaction to hydroxychloroquine, chloroquine, or related products or any of the ingredients listed under "Product Description".

If you are uncertain whether you have had an allergic reaction to a related product ask your doctor or pharmacist.

The symptoms of an allergic reaction may include an asthma attack, facial swelling, skin rash or hay fever.

Ask your doctor about the risks and benefits of taking Plaquenil while you are pregnant. When Plaquenil is taken for long periods of time, there is an increased risk to the unborn child. It may cause problems with brain function, hearing, balance and vision.

Ask your doctor about the risks and benefits of taking Plaquenil while you are breastfeeding.

Do not take Plaquenil if you have previously experienced changes in your eyesight when taking medicines for rheumatoid arthritis or malaria.

Plaquenil should not be used in children under 6 years.

Plaquenil should not be used in children over 6 years for long periods.

Do not take Plaquenil after the expiry date printed on the bottle. It may have no effect at all, or worse, an entirely unexpected effect if you take it after the expiry date.

Do not take Plaquenil if the bottle is damaged or shows signs of tampering.

Do not take Plaquenil to treat any other complaint unless your doctor says it is safe. Do not give this medicine to anyone else.

Before you start to take Plaquenil

You must tell your doctor if:

  • You are taking any other medicines for any medical condition
  • You are allergic to quinine.
  • You have allergies to any ingredients listed under "Product Description" at the end of this leaflet.
  • You have any pre-existing eye disorders.
  • You have experienced low blood sugar levels (hypoglycaemia - a "hypo"). Plaquenil may increase the risk of you having a hypo.
  • You have or have had any of these medical conditions:
    - Chloroquine-resistant malaria
    - Liver or kidney problems
    - Diabetes
    - Stomach, brain or blood disorders
    - Disease of the heart muscle
    - Skin diseases, in particular psoriasis which is a kind of itchy rash.
    - Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency which is a lack of a chemical substance which causes the breakdown of sugar in the body.
    - Porphyria, which is a rare disease of blood pigments.

If you have not told your doctor about any of these things, tell him/her before you take any Plaquenil.

Taking Plaquenil with other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines may interfere with Plaquenil. These include:

  • Any medicine to treat depression, including the herbal product St John's wort
  • Digoxin - a medicine used to treat heart disease
  • Medicines to treat diabetes
  • Medicines used to suppress the immune system such as ciclosporin
  • Antiarrythmic drugs such as amiodarone and moxifloxacin
  • Other antimalarial drugs
  • Medicines to treat epilepsy, such as carbamazepine and phenobarbital
  • Tamoxifen (a medicine used to treat breast cancer)
  • Anti-infective medicines
  • Medicines that may affect your blood
  • Medicines that may affect your eyes
  • Antacids containing magnesium or kaolin or cimetidine, used to neutralise stomach acid
  • Itraconazole, an antifungal medication
  • Clarithromycin and rifampicin (antibiotics)
  • Grapefruit juice
  • Anticoagulant drugs such as dabigatran and clopidogrel
  • Medicines to treat high cholesterol, such as gemfibrozil
  • Ritonavir (a medicine used to treat HIV)

These medicines may be affected by Plaquenil or affect the way Plaquenil works.

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

How to take Plaquenil

Swallow tablets whole with a little water or other liquid.

It is best to take Plaquenil at meal times.

The dosage will depend on why you are being treated with Plaquenil.

The usual doses are:

Rheumatoid arthritis

Adults
2-3 tablets daily. Your doctor may later reduce this to 1-2 tablets daily.

SLE and DLE

Adults
2-4 tablets daily. Your doctor may later reduce this to 1-2 tablets daily.

Control of Malaria Symptoms

Adults
2 tablets once a week. The tablets should be taken on exactly the same day of each week.

For example, if your first dose is taken on a Monday, then each weekly dose should be taken on a Monday.

Treatment of malaria

Adults
The starting dose is 4 tablets. Take another 2 tablets six to eight hours later and two further tablets on each of the next 2 days.

Always follow the instructions given to you by your doctor.

Dosages for children are calculated according to the child's body weight.

Your doctor will work out the correct dose for you.

Plaquenil should not be used in children for long periods.

Your doctor may ask you to take a different dose. You should follow the instructions on the label.

If you are unsure what dose to take ask your pharmacist or doctor.

If you forget to take Plaquenil

If you are being given Plaquenil for rheumatoid arthritis, SLE or DLE, do not take a double dose to make up for the dose missed. Just continue with the appropriate dose on the next day.

If you are being given Plaquenil for suppression or treatment of malaria, you should take your tablets as soon as you remember, and go back to taking it as you would normally.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much Plaquenil (Overdose)

Immediately telephone your doctor, or the Poisons Information Centre (in Australia telephone 13 11 26 and in New Zealand telephone 0800 POISON or 0800 764766), or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much Plaquenil.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too many tablets you may experience headaches, drowsiness, visual disturbances or fits.

These symptoms may occur within 30 minutes of overdose.

While you are taking Plaquenil

If you are about to start taking any new medicines, tell your doctor and pharmacist that you are taking Plaquenil.

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

Tell your doctor if you experience any of the following symptoms including; weakness, trembling or shaking, sweating, light-headedness, headache, dizziness, lack of concentration, tearfulness or crying, irritability, hunger and numbness around the lips and fingers.

These symptoms may be associated with hypoglycaemia.

If you experience any of the symptoms of hypoglycaemia, you need to raise your blood glucose urgently. You can do this by taking one of the following:

  • 5-7 jelly beans
  • 3 teaspoons of sugar or honey
  • 1/2 can of ordinary (non-diet) soft drink
  • 2-3 concentrated glucose tablets
  • unless you are within 10 to 15 minutes of your next meal or snack, follow up with extra carbohydrates e.g. plain biscuits, fruit or milk - when over the initial symptoms. Taking this extra carbohydrate will prevent a second drop in your blood glucose level.

Make sure you, your friends, family and work colleagues can recognise the symptoms of hypoglycaemia and know how to treat them.

Your doctor will need to perform the following tests during treatment with Plaquenil:

Eye Tests

Your doctor will need to perform some eye tests every few months to check that your eyesight is not changing.

In extremely rare cases, Plaquenil has been associated with blindness. This can be avoided by having regular eye tests.

It is recommended you wear sunglasses when out in the sun.

Blood Tests

Your doctor will need to perform occasional blood tests to check for any blood reactions.

Your doctor may monitor your blood sugar levels if you have experienced hypoglycaemia while taking Plaquenil.

Driving/Operating Machinery

Be careful driving or operating machinery until you know how Plaquenil affects you. Plaquenil may cause problems with the eyesight of some people. Make sure you know how you react to Plaquenil before you drive a car, operate machinery, or do anything else that could be dangerous with blurred vision.

Side Effects

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

Plaquenil helps most people with rheumatoid arthritis, SLE, DLE, treatment of malaria and the control of malaria symptoms, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions.

Tell your doctor if you notice any of the following and they worry you:

Less serious side effects

Stomach problems such as:

  • Nausea
  • Vomiting
  • Diarrhoea
  • Abdominal cramps

Other problems such as:

  • Loss of appetite
  • Muscle weakness
  • Dizziness
  • Ringing in the ears
  • Headache
  • Nervousness
  • Skin rash and itching
  • Hair loss

If you already have psoriasis, you are more likely to experience skin reactions than other people when taking Plaquenil.

More serious side effects

Tell your doctor if you notice any of the following:

  • Visual disturbances
  • Any hearing loss
  • Suicidal behaviour
  • Frequent fevers, severe chills, bruising, sore throat or mouth ulcers (these may be signs of blood reactions)
  • Changes in the way your heart beats
  • More severe symptoms of hypoglycaemia, including:
    - disorientation
    - seizures, fits or convulsions
    - loss of consciousness

These are serious side effects. You may need urgent medical attention.

Serious side effects are rare.

Tell your doctor if you notice anything else that is making you feel unwell. Some people may get other side effects while taking Plaquenil.

After taking Plaquenil

Storage

Keep your tablets in the bottle until it is time to take them. If you take the tablets out of the bottle they will not keep well.

Keep it in a cool dry place where the temperature stays below 25°C. Heat and dampness can destroy some medicines. Do not leave Plaquenil in the car on hot days.

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

Keep Plaquenil where young children cannot reach it.

Children are particularly sensitive to the unwanted effects of Plaquenil.

A locked cupboard at least one and a half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking the tablets, ask your pharmacist what to do with any tablets that are left over.

Product Description

What Plaquenil looks like

Plaquenil comes as white to off-white peanut shaped tablets marked "PLAQUENIL" with black ink. A bottle contains 100 tablets.

Ingredients

Active Ingredient
Each Plaquenil tablet contains 200mg hydroxychloroquine sulfate.

Other ingredients

  • Calcium Hydrogen Phosphate Dihydrate
  • Starch-Maize
  • Magnesium Stearate
  • Water-Purified
  • hypromellose
  • Macrogol 400
  • Titanium dioxide
  • Polysorbate 80
  • Carnauba Wax
  • Black Ink

Australian Registration Number

AUST R 50055

Supplier

Plaquenil is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Tel: 1800 818 806

Plaquenil is supplied in New Zealand by:

sanofi-aventis new zealand limited
56 Cawley St
Ellerslie, Auckland, New Zealand
Phone: (09) 580 1810

This leaflet was prepared in April 2020.

plaquenil-ccdsv13-cmiv9-29apr20

Published by MIMS June 2020

BRAND INFORMATION

Brand name

Plaquenil

Active ingredient

Hydroxychloroquine sulfate

Schedule

S4

 

1 Name of Medicine

Hydroxychloroquine sulfate.

6.7 Physicochemical Properties

Chemical structure.

Hydroxychloroquine sulfate is designated chemically as 2 {N (4-(7-Chloro-4-quinolylamino)pentyl)-N-ethylamino}ethanol sulfate and has the following chemical structure:
C18H26ClN3O, H2SO4. Molecular Weight: 433.96.

CAS number.

747-36-4 (hydroxychloroquine sulfate).
118-42-3 (hydroxychloroquine).

2 Qualitative and Quantitative Composition

Film coated tablets containing hydroxychloroquine sulfate 200 mg (equivalent to 155 mg base).
For full list of excipients, see Section 6.1.

3 Pharmaceutical Form

White to off-white peanut shaped tablets, marked "Plaquenil" in black ink on one face of the tablet.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antimalarials, ATC code: P01BA02.

Mechanism of action.

Anti-malarial. Plaquenil also exerts a beneficial effect in mild systemic and discoid lupus erythematosus and rheumatoid arthritis. The precise mechanism of action is not known.

Malaria.

Like chloroquine phosphate, Plaquenil is highly active against the erythrocytic forms of P. vivax and P. malariae and most strains of P. falciparum (but not the gametocytes of P. falciparum).
Plaquenil does not prevent relapses in patients with vivax or malariae malaria because it is not effective against exo-erythrocytic forms of the parasite, nor will it prevent vivax or malariae infection when administered as a prophylactic. It is highly effective as a suppressive agent in patients with vivax or malariae malaria, in terminating acute attacks, and significantly lengthening the interval between treatment and relapse. In patients with falciparum malaria, it abolishes the acute attack and effects complete cure of the infection, unless due to a resistant strain of P. falciparum.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

No data available.

5.3 Preclinical Safety Data

Genotoxicity.

There are limited data on hydroxychloroquine genotoxicity. Chloroquine is reported in the literature to elicit both gene mutations and chromosomal/DNA breaks in some in vitro systems but not others and in in vivo studies using rodents when dosed via the intraperitoneal route. Chromosomal effects were not observed in vivo when chloroquine was administered orally.

Carcinogenicity.

No carcinogenicity studies are available on hydroxychloroquine. A dietary carcinogenicity study in rats with the parent drug chloroquine was negative. No other carcinogenicity study was conducted in mice or other species. In the absence of sufficient human and animal data an increased risk of cancer in patients receiving long term treatment cannot be ruled out.

4 Clinical Particulars

4.1 Therapeutic Indications

Rheumatoid arthritis; mild systemic and discoid lupus erythematosus; the suppression and treatment of malaria.

4.3 Contraindications

Plaquenil is contraindicated in:
patients with pre-existing maculopathy of the eye;
patients with known hypersensitivity to 4-aminoquinoline compounds; and
long-term therapy in children;
children under 6 years of age.

4.4 Special Warnings and Precautions for Use

Plaquenil is not effective against chloroquine resistant strains of P. falciparum.
Patients should be warned to keep Plaquenil out of the reach of children, as small children are particularly sensitive to the 4-aminoquinolines.
Plaquenil should be used with caution or not at all in patients with severe gastrointestinal, neurological or blood disorders. If such severe disorders occur during therapy, the drug should be stopped. Periodic blood counts are advised.
When used in patients with porphyria or psoriasis, these conditions may be exacerbated. Plaquenil should not be used in these conditions unless, in the judgement of the physician, the benefit to the patient outweighs the possible risk.

Chronic cardiac toxicity.

Cases of cardiomyopathy resulting in cardiac failure, in some cases with fatal outcome, have been reported in patients treated with Plaquenil. Clinical monitoring for signs and symptoms of cardiomyopathy is advised and Plaquenil should be discontinued if cardiomyopathy develops. Chronic toxicity should be considered when conduction disorders (bundle branch block/ atrio-ventricular heart block) as well as biventricular hypertrophy are diagnosed.

Hypoglycaemia.

Hydroxychloroquine has been shown to cause severe hypoglycaemia including loss of consciousness that could be life threatening in patients treated with and without anti-diabetic medications. Patients treated with hydroxychloroquine should be warned about the risk of hypoglycaemia and the associated clinical signs and symptoms. Patients presenting with clinical symptoms suggestive of hypoglycaemia during treatment with hydroxychloroquine should have their blood glucose level checked and treatment reviewed as necessary.

QT interval prolongation.

Hydroxychloroquine prolongs the QTc interval and should not be used in patients receiving drugs known to prolong the QT interval, e.g. class IA and III antiarrhythmics, tricyclic antidepressants, antipsychotics, some anti-infectives due to increased risk of ventricular arrhythmia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.9 Overdose).
Hydroxychloroquine should be used with caution in patients with congenital or documented acquired QT prolongation and/or known risk factors for prolongation of the QT interval such as:
cardiac disease, e.g. heart failure, myocardial infarction;
proarrhythmic conditions, e.g. bradycardia (< 50 bpm);
a history of ventricular dysrhythmias;
uncorrected hypokalaemia and/or hypomagnesaemia.
The magnitude of QT prolongation may increase with increasing concentrations of the drug. Therefore, the recommended dose should not be exceeded (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects)).

Ophthalmological.

Irreversible retinal damage has been observed in some patients who had received long-term or high dosage 4-aminoquinolone therapy for discoid and systemic lupus erythematosus, or rheumatoid arthritis. Retinopathy has been reported to be dose related. Exceeding the recommended daily dose sharply increases the risk of retinal toxicity.
If there is any indication of abnormality in the visual field, or retinal macular areas (such as pigmentary changes, loss of foveal reflex), or any visual symptoms (such as light flashes and streaks) which are not fully explainable by difficulties of accommodation or corneal opacities, the drug should be discontinued immediately and the patient closely observed for possible progression. Retinal changes (and visual disturbances) may progress after cessation of therapy. (See Section 4.8 Adverse Effects (Undesirable Effects).)
Concomitant use of hydroxychloroquine with drugs known to induce retinal toxicity, such as tamoxifen, is not recommended.
Before starting treatment with hydroxychloroquine, all patients should have a careful complete examination of both eyes which includes slit lamp microscopy for corneal changes, fundoscopy, visual acuity, central visual field and colour vision. A complete eye examination before treatment will determine the presence of any visual abnormalities, either coincidental or due to the disease and establish a baseline for further assessment of the patient's vision.
Ophthalmological testing should be conducted at 6 monthly intervals in patients receiving hydroxychloroquine at a dose of not more than 6 mg per kg body weight per day.
Ophthalmological testing should be conducted at 3-4 monthly intervals in the following circumstances:
dose exceeds 6 mg per kg ideal (lean) body weight per day. Absolute body weight used as a guide to dosage could result in an overdosage in the obese;
significant renal impairment;
significant hepatic impairment;
elderly;
complaints of visual disturbances;
duration of treatment exceeds 8 years.
Corneal changes often subside on reducing the dose or on interrupting therapy for a short period of time, but any suggestion of retinal change or restriction in the visual field is an indication for complete withdrawal of the drug.
The use of sunglasses in patients exposed to strong sunlight is recommended, as this may be an amplifying factor in retinopathy.

Skin reactions.

Pleomorphic skin eruptions (morbilliform, lichenoid, purpuric), itching, dryness and increased pigmentation sometimes appear after a few months of therapy. The rash is usually mild and transient. If a rash appears, Plaquenil should be withdrawn and only started again at a lower dose.
Patients with psoriasis appear to be more susceptible to severe skin reactions than other patients.

Other monitoring on long-term treatments.

Patients on long-term therapy should have periodic full blood counts. If evidence of abnormalities such as, agranulocytosis, aplastic anaemia, thrombocytopenia or leukopenia becomes apparent, and cannot be attributed to the disease being treated, Plaquenil should be discontinued.
All patients on long-term therapy with this preparation should be questioned and examined periodically, including the testing of knee and ankle reflexes, to detect any evidence of muscular weakness. If weakness occurs discontinue the drug.

Miscellaneous.

Gastrointestinal disturbances such as nausea, anorexia, abdominal cramps or rarely vomiting, occur in some patients. The symptoms usually stop on reducing the dose or temporarily stopping the drug.
Muscle weakness, vertigo, tinnitus, nerve deafness, headache and nervousness have been reported less frequently.
In the treatment of rheumatoid arthritis, if objective improvement (such as reduced joint swelling, increased mobility) does not occur within six months, the drug should be discontinued. Safe use of the drug in the treatment of juvenile rheumatoid arthritis has not been established.
Suicidal behaviour has been reported in very rare cases in patients treated with hydroxychloroquine.
Extrapyramidal disorders may occur with hydroxychloroquine.
Also observe caution in patients with gastrointestinal, neurological, or blood disorders, in those with a sensitivity to quinine, and in glucose-6-phosphate dehydrogenase deficiency.

Use in hepatic impairment.

Observed caution in patients with hepatic disease, as well as in those taking medicines known to affect the organ. A reduction in dosage may be necessary.

Use in renal impairment.

Observed caution in patients with renal disease, as well as in those taking medicines known to affect the organ. A reduction in dosage may be necessary.

Use in the elderly.

See Section 4.4 Special Warnings and Precautions for Use, Ophthalmological.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacodynamic interactions.

Drugs known to prolong QT interval/with potential to induce cardiac arrhythmia.

Hydroxychloroquine should not be used in patients receiving drugs known to prolong the QT interval, e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, antipsychotics, some anti-infectives due to increased risk of ventricular arrhythmia (see Section 4.4 Special Warnings and Precautions for Use; Section 4.9 Overdose). Halofantrine should not be administered with hydroxychloroquine.

Antidiabetic drugs.

As hydroxychloroquine may enhance the effects of a hypoglycaemic treatment, a decrease in doses of insulin or antidiabetic drugs may be required.

Antimalarials.

Hydroxychloroquine can lower the convulsive threshold. Co-administration of hydroxychloroquine with other antimalarials known to lower the convulsion threshold (e.g. mefloquine) may increase the risk of convulsions.

Antiepileptic drugs.

The activity of antiepileptic drugs might be impaired if co-administered with hydroxychloroquine.

Others.

There is a theoretical risk of inhibition of intra-cellular α-galactosidase activity when hydroxychloroquine is co-administered with agalsidase.
Concurrent use with drugs with oculotoxic or haemotoxic potential should be avoided if possible.
It has been suggested that 4-aminoquinolines are pharmacologically incompatible with monoamine oxidase inhibitors.
Hydroxychloroquine sulphate may also be subject to several of the known interactions of chloroquine even though specific reports have not appeared. These include: potentiation of its direct blocking action at the neuromuscular junction by aminoglycoside antibiotics; inhibition of its metabolism by cimetidine which may increase plasma concentration of the antimalarial; antagonism of effect of neostigmine and pyridostigmine; reduction of the antibody response to primary immunisation with intradermal human diploid-cell rabies vaccine.

Effects of other medicinal products on hydroxychloroquine.

Antacids.

Concomitant administration with magnesium-containing antacids or kaolin may result in reduced absorption of chloroquine. Per extrapolation, hydroxychloroquine should therefore be administered at least two hours apart from antacids or kaolin.

CYP inhibitors or inducers.

Concomitant use of cimetidine, a moderate CYP2C8 and CYP3A4 inhibitor, resulted in a 2- fold increase of chloroquine exposure. Per extrapolation, due to the similarities in structure and metabolic elimination pathways between hydroxychloroquine and chloroquine, a similar interaction could be observed for hydroxychloroquine. Caution is advised (e.g. monitoring for adverse reactions) when CYP2C8 and CYP3A4 strong or moderate inhibitors (such as gemfibrozil, clopidogrel, ritonavir, itraconazole, clarithromycin, grapefruit juice) are concomitantly administered.
Lack of efficacy of hydroxychloroquine was reported when rifampicin, a CYP2C8 and CYP3A4 strong inducer, was concomitantly administered. Caution is advised (e.g. monitoring for efficacy) when CYP2C8 and CYP3A4 strong inducers (such as rifampicin, St John's Wort, carbamazepine, phenobarbital) are concomitantly administered.

Effects of hydroxychloroquine on other medicinal products.

P-gp substrates.

The inhibitory potential of hydroxychloroquine on P-gp substrates has not been evaluated. In vitro observations show that all other aminoquinolines tested inhibit P-gp. Therefore, there is a potential for increased concentrations of P-gp substrates when hydroxychloroquine is concomitantly administered.
Increased plasma cyclosporin levels have been reported when cyclosporin and hydroxychloroquine are co-administered.
Increased digoxin serum levels were reported when digoxin and hydroxychloroquine were coadministered. Caution is advised (e.g. monitoring for adverse reactions or for plasma concentrations as appropriate) when P-gp substrates with narrow therapeutic index (such as digoxin, ciclosporin, dabigatran) are concomitantly administered.

Praziquantel.

In a single-dose interaction study, chloroquine has been reported to reduce the bioavailability of praziquantel. It is not known if there is a similar effect when hydroxychloroquine and praziquantel are co-administered. Per extrapolation, due to the similarities in structure and pharmacokinetic parameters between hydroxychloroquine and chloroquine, a similar effect may be expected for hydroxychloroquine.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no animal data on hydroxychloroquine action on fertility. A study in male rats showed a decrease in testosterone levels, weight of testes, epididymis, seminal vesicles and prostate after 30 days of oral treatment with chloroquine at 5 mg/day. In another rat study with chloroquine the male fertility rate was decreased after 14 days of intraperitoneal treatment at 10 mg/kg/day.
There are no data in humans.
(Category D)
Hydroxychloroquine crosses the placenta. Data are limited regarding the use of hydroxychloroquine during pregnancy. It should be noted that 4-aminoquinolines in therapeutic doses have been associated with central nervous system damage, including ototoxicity (auditory and vestibular toxicity, congenital deafness), retinal haemorrhages and abnormal retinal pigmentation. Hydroxychloroquine should be avoided in pregnancy except when, in the judgement of the physician, the potential benefits outweigh the potential hazards.
The use of this drug in the treatment of malaria or suppression of malaria in high risk situations may be justified if the treating physician considers the risk to the foetus is outweighed by the benefits to the mother and foetus.
Hydroxychloroquine is excreted in breast milk and it is known that infants are extremely sensitive to the toxic effects of 4-amonioquinones. In one study, the daily HCQ exposures to infant from breast milk were estimated to be less than 2% of the maternal dose (after bodyweight correction).
Although hydroxychloroquine is excreted in breast milk, the amount is insufficient to confer any protection against malaria to the infant. Separate chemoprophylaxis for the infant is required.
There are very limited data on the safety in the breastfed infant during long-term hydroxychloroquine treatment; the prescriber should assess the potential risks and benefits of use during breastfeeding, according to indication and duration of treatment.

4.8 Adverse Effects (Undesirable Effects)

Note.

Very common: ≥ 1/10 (≥ 10%); common: ≥ 1/100 and < 1/10 (≥ 1% and < 10%); uncommon: ≥ 1/1000 and < 1/100 (≥ 0.1% and < 1.0%); rare: ≥ 1/10,000 and < 1/1000 (≥ 0.01% and < 0.1%); very rare: < 1/10,000 (< 0.01%); not known: frequency cannot be estimated from available data.

Blood and lymphatic system disorders.

Rare: bone marrow depression, anaemia, aplastic anaemia, leucopenia, thrombocytopenia.
Very rare: agranulocytosis.

Immune system disorders.

Not known: urticaria, angioedema, bronchospasm.

Metabolism and nutrition disorders.

Common: anorexia.
Not known: hypoglycaemia.
Hydroxychloroquine may exacerbate porphyria.

Psychiatric disorders.

Common: affect lability.
Very rare: psychosis, suicidal behaviour, nightmares.

Nervous system disorders.

Common: headache.
Uncommon: dizziness, nerve deafness, nervousness.
Rare: convulsions, neuromyopathy.
Very rare: nystagmus, ataxia.
Not known: extrapyramidal disorders such as dystonia, dyskinesia, tremor.

Eye disorders.

Common: blurring of vision.
Uncommon: corneal changes, retinal changes, retinopathy with changes in pigmentation and visual field defects. In its early form, it appears reversible on discontinuation of Plaquenil. If allowed to develop, there may be a risk of progression even after treatment withdrawal.
Patients with retinal changes may be asymptomatic initially, or may even have scotomatous vision with paracentral, pericentral ring types, temporal scotomas and abnormal colour visions.
Corneal changes including oedema and opacities have occurred from three weeks (infrequently) to some years after the beginning of therapy. They are either symptomless or may cause disturbances such as halos, blurring of vision, or photophobia. They may be transient or are reversible on stopping treatment. Should these types of corneal changes occur with Plaquenil, it should be either stopped or temporarily withdrawn.
Not known: Cases of maculopathies and macular degeneration have been reported and may be irreversible.
Reversible extra-ocular muscle palsies and temporary blurring of vision due to interference with accommodation have also been noted.
Retinal changes such as abnormal macular pigmentation and depigmentation (sometimes described as a "bull's eye"), pallor of the optic disc, optic atrophy and narrowing of the retinal arterioles have been reported.
Originally, the condition was thought to be progressive and irreversible but more recent evidence suggests that routine ophthalmological examinations may detect retinal changes, especially pigmentation, at an early and reversible stage when there is no apparent visual disturbance.
Much evidence suggests that there is a threshold of dosage above which retinopathy appears. These results seem to correlate more with daily dosage than with a cumulative dose, although the risk increases with increased duration of treatment.
Before starting treatment with hydroxychloroquine, all patients should have a careful complete examination of both eyes which includes slit lamp microscopy for corneal changes, fundoscopy, visual acuity, central visual field and colour vision, repeated at six month intervals during therapy (see Section 4.4 Special Warnings and Precautions for Use, Ophthalmological).
Any adverse changes in the ocular findings or the appearance of scotoma, night blindness or other retinal changes require immediate discontinuation of Plaquenil; these patients should not subsequently receive any pharmacologically similar drugs.

Ear and labyrinth disorders.

Uncommon: vertigo, tinnitus.
Not known: hearing loss.

Cardiac disorders.

Rare: cardiomyopathy which may result in cardiac failure, and in some cases a fatal outcome (see Section 4.4 Special Warnings and Precautions for Use).
Chronic toxicity should be considered when conduction disorders (bundle branch block / atrio-ventricular heart block) as well as biventricular hypertrophy are diagnosed.
Not known: QT interval prolongation in patients with specific risk factors, which may lead to arrhythmia (torsade de pointes, ventricular tachycardia) (See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Gastrointestinal disorders.

Very common: abdominal pain, nausea.
Common: diarrhoea, vomiting.

Hepatobiliary disorders.

Uncommon: abnormal liver function tests.
Very rare: fulminant hepatitis.

Skin and subcutaneous tissue disorders.

Common: skin rashes, alopecia, pruritus.
Uncommon: pigmentary changes, bleaching of hair.
Very rare: bullous eruptions such as acute generalised exanthematous pustulosis (AGEP), exfoliative dermatitis and erythema multiforme, Stevens-Johnson syndrome, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome), toxic epidermal necrolysis, photosensitivity.

Musculoskeletal and connective tissue disorders.

Uncommon: sensorimotor disorders.
Not known: absent or hypoactive deep tendon reflexes, muscle weakness or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups (muscle weakness may be reversible after drug discontinuation, but recovery may take many months). Depression of tendon reflexes and abnormal nerve conduction studies.
Very rare: extraocular muscle palsies.

Miscellaneous.

Rare: exacerbation or precipitation of porphyria and attacks of psoriasis.
Very rare: weight loss, lassitude.

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 (Australia).

4.2 Dose and Method of Administration

Rheumatoid arthritis.

Plaquenil is cumulative in action and will require several weeks to exert its beneficial therapeutic effects, whereas minor side effects may occur relatively early. Several months of therapy may be required before maximum effects can be obtained.

Initial dosage.

In adults, a suitable initial dosage is from 400 to 600 mg daily, preferably taken at meal times. In a few patients the side effects may require temporary reduction of the initial dosage. Generally, after five to ten days the dose may be gradually increased to the optimum response level, frequently without return of side effects.

Maintenance dosage.

When a good response is obtained (usually in four to twelve weeks) the dose can be reduced to 200 to 400 mg daily (but should not exceed 6 mg/kg per day) and can be continued as maintenance treatment. The minimum effective maintenance dose should be employed. The incidence of retinopathy has been reported to be higher when the maintenance dose is exceeded.
If objective improvement (such as reduced joint swelling or increased mobility) does not occur within six months the drug should be discontinued.
If a relapse occurs after medication is withdrawn, therapy may be resumed or continued on an intermittent schedule if there are no ocular contraindications.
Safe use of Plaquenil for the treatment of juvenile rheumatoid arthritis has not been established.

Use in combination therapy.

Plaquenil may be used safely and effectively in combination with corticosteroids, salicylates, NSAIDs, and methotrexate and other second line therapeutic agents. Corticosteroids and salicylates can generally be decreased gradually in dosage or eliminated after the drug has been used for several weeks. When gradual reduction of steroid dosage is suggested, it may be done by reducing every four to five days, the dose of cortisone by no more than 5 to 15 mg; of methylprednisolone from 1 to 2 mg and dexamethasone from 0.25 to 0.5 mg. Treatment regimens using agents other than corticosteroids and NSAIDs are under development. No definitive dose combinations have been established.

Lupus erythematosus.

In mild systemic and discoid cases, the antimalarials are the drugs of choice.
The dosage of Plaquenil depends on the severity of the disease and the patient's response to treatment. For adults an initial dose of 400-800 mg daily is recommended. This level can be maintained for several weeks and then reduced to a maintenance dose of 200-400 mg daily.

Malaria.

Plaquenil is active against the erythrocytic forms of P. vivax and P. malariae and most strains of P. falciparum (but not the gametocytes of P. falciparum).
Plaquenil does not prevent relapses in patients with vivax or malariae malaria because it is not effective against exo-erythrocytic forms, nor will it prevent vivax or malariae infection when administered as a prophylactic.
It is effective as a suppressive agent in patients with vivax or malariae malaria, in terminating acute attacks and significantly lengthening the interval between treatment and relapse. In patients with falciparum malaria it abolishes the acute attack and effects complete cure of the infection, unless due to a resistant strain of P. falciparum.

Malaria suppression.

Adults.

400 mg (310 mg base) on exactly the same day of each week.

Children.

The weekly suppressive dose is 5 mg (base) per kg bodyweight but should not exceed the adult dose regardless of weight.
Suppressive therapy should begin two weeks prior to exposure. Failing this, in adults an initial loading dose of 800 mg (620 mg base), or in children 10 mg base per kg, may be taken in two divided doses, six hours apart. The suppressive therapy should be continued for eight weeks after leaving the endemic area.

Treatment of the acute attack.

Adults.

An initial dose of 800 mg followed by 400 mg in six to eight hours and 400 mg on each of two consecutive days. (Total dose of 2 g or 1.55 g base.) A single dose of 800 mg (620 mg base) has also proved effective.

Children.

The dosage is calculated on the basis of bodyweight (total dose of 25 mg base per kg).

First dose.

10 mg base per kg (not exceeding a single dose of 620 mg base).

Second dose.

5 mg base per kg (not exceeding 310 mg base), six hours after first dose.

Third dose.

5 mg base per kg eighteen hours after second dose.

Fourth dose.

5 mg base per kg twenty-four hours after third dose.
For radical cure of vivax and malariae malaria, concomitant therapy with an 8-aminoquinoline is necessary.

4.7 Effects on Ability to Drive and Use Machines

Patients should be warned about driving and operating machinery since hydroxychloroquine can impair visual accommodation and cause blurring of vision. If the condition is not self-limiting, the dosage may need to be temporarily reduced.

4.9 Overdose

Symptoms.

Overdosage with the 4-aminoquinolines is dangerous. Children are particularly sensitive to these compounds and a number of fatalities have been reported following the accidental ingestion of chloroquine, sometimes in relatively small doses (0.75 or 1 gram in one 3 year old child).
The 4-aminoquinolines are very rapidly and completely absorbed after ingestion and toxic symptoms following overdosage may occur within 30 minutes. Toxic symptoms consist of headache, drowsiness, visual disturbances, hypokalaemia, cardiovascular collapse and convulsions.
The ECG may reveal rhythm and conduction disorders including, QT prolongation, torsade de pointe, ventricular tachycardia, ventricular fibrillation, width-increased QRS complex, bradyarrhythmias (including bradycardia), nodal rhythm, atrioventricular block, followed by sudden potentially fatal respiratory and cardiac arrest. Immediate medical attention is required as these effects may appear shortly after the overdose.

Treatment.

Treatment is symptomatic and must be prompt. Emesis is not recommended because of the potential for CNS depression, convulsions and cardiovascular instability. Activated charcoal should be administered. The dose of activated charcoal should be at least five times the estimated amount of hydroxychloroquine ingested.
Consideration should be given to using diazepam parenterally as there have been reports that it may decrease cardiotoxicity.
Respiratory support and management of shock should be instituted as necessary.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets contain the inactive ingredients calcium hydrogen phosphate dihydrate, maize starch, purified water, and magnesium stearate. The film coating contains small amounts of hypromellose, macrogol 400, titanium dioxide, polysorbate 80, carnauba wax, black ink (Tekprint SB-9014SD), and purified water.

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

Plaquenil tablets should be stored below 25°C.

6.5 Nature and Contents of Container

Plaquenil is supplied as 100 tablets in an HDPE bottle.

6.6 Special Precautions for Disposal

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

Summary Table of Changes