SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Hydroxychloroquine sulfate 200mg film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Hydroxychloroquine Sulfate 200mg

3    PHARMACEUTICAL FORM

Film Coated Tablet

CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults

Treatment of rheumatoid arthritis, discoid and systemic lupus erythematosus, and dermatological conditions caused or aggravated by sunlight. Paediatric Population

Treatment of juvenile idiopathic arthritis (in combination with other therapies), discoid and systemic lupus erythematosus.

4.2 Posology and method of administration

Adults (including the elderly)

The minimum effective dose should be employed. This dose should not exceed 6.5mg/kg/day (calculated from ideal body weight and not actual body weight) and will be either 200mg or 400mg per day.

In patients able to receive 400mg daily:

Initially 400mg daily in divided doses. The dose can be reduced to 200mg when no further improvement is evident. The maintenance dose should be increased to 400mg daily if the response lessens.

Paediatric Population

The minimum effective dose should be employed and should not exceed 6.5mg/kg/day based on ideal body weight. The 200mg tablet is therefore not suitable for use in children with an ideal body weight of less than 31kg.

Each dose should be taken with a meal or glass of milk.

Hydroxychloroquine is cumulative in action and will require several weeks to exert its beneficial effects, whereas minor side effects may occur relatively early. For rheumatic disease treatment should be discontinued if there is no improvement by 6 months. In light-sensitive diseases, treatment should only be given during periods of maximum exposure to light.

The tablets are for oral administration.

4.3 Contraindications

-    hypersensitivity to hydroxychloroquine or to any of the excipients

-    known hypersensitivity to 4-aminoquinoline compounds

-    pre-existing maculopathy of the eye

-    pregnancy (see section 4.6 Pregnancy and lactation)

4.4 Special warnings and precautions for use

General

•    The occurrence of retinopathy is very uncommon if the recommended daily dose is not exceeded. The administration of doses in excess of the recommended maximum is likely to increase the risk of retinopathy, and accelerate its onset.

•    All patients should have an ophthalmological examination before initiating treatment with Hydroxychloroquine sulfate. Thereafter, ophthalmological examinations must be repeated at least every 12 months.

The examination should include testing visual acuity, careful ophthalmoscopy, fundoscopy, central visual field testing with a red target, and colour vision.

This examination should be more frequent and adapted to the patient in the following situations:

o daily dosage exceeds 6.5mg/kg lean body weight. Absolute body weight used as a guide to dosage could result in an overdosage in the obese o renal insufficiency o visual acuity below 6/8 o age above 65 years o cumulative dose more than 200g.

•    Hydroxychloroquine sulfate should be discontinued immediately in any patient who develops a pigmentary abnormality, visual field defect, or any other abnormality not explainable by difficulty in accommodation or presence of corneal opacities. Patients should continue to be observed for possible progression of the changes.

•    Patients should be advised to stop taking the drug immediately and seek the advice of their prescribing doctor if any disturbances of vision are noted, including abnormal colour vision.

•    Hydroxychloroquine sulfate should be used with caution in patients taking medicines which may cause adverse ocular or skin reactions. Caution should also be applied when it is used in the following:

o patients with hepatic or renal disease, and in those taking drugs known to affect those organs. Estimation of plasma hydroxychloroquine levels should be undertaken in patients with severely compromised renal or hepatic function and dosage adjusted accordingly.

o Although the risk of bone marrow depression is low, periodic blood counts are advisable as anaemia, aplastic anaemia, agranulocytosis, a decrease in white blood cells, and thrombocytopenia have been reported. Hydroxychloroquine sulfate should be discontinued if abnormalities develop.

o caution is also advised in patients with a sensitivity to quinine, those with glucose-6-phosphate dehydrogenase deficiency, those with porphyria cutanea tarda which can be exacerbated by hydroxychloroquine and in patients with psoriasis since it appears to increase the risk of skin reactions.

o patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

•    Small children are particularly sensitive to the toxic effects of 4-aminoquinolines; therefore patients should be warned to keep Hydroxychloroquine sulfate out of the reach of children.

•    All patients on long-term therapy should undergo periodic examination of skeletal muscle function and tendon reflexes. If weakness occurs, the drug should be withdrawn.

4.5 Interaction with other medicinal products and other forms of interaction

Hydroxychloroquine sulfate has been reported to increase plasma digoxin levels: serum digoxin levels should be closely monitored in patients receiving combined therapy.

Hydroxychloroquine sulfate 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.

As with chloroquine, antacids may reduce absorption of hydroxychloroquine so it is advised that a 4 hour interval be observed between Hydroxychloroquine sulfate and antacid dosaging.

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

4.6 Use during pregnancy and lactation

Pregnancy:

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 hemorrhages and abnormal retinal pigmentation. Therefore Hydroxychloroquine sulfate should not be used in pregnancy.

Lactation:

Careful consideration should be given to using hydroxychloroquine during lactation, since it has been shown to be excreted in small amounts in human breast milk, and it is known that infants are extremely sensitive to the toxic effects of 4-aminoquinolines.

4.7 Effects on ability to drive and use machines

Impaired visual accommodation soon after the start of treatment has been reported and patients should be warned regarding driving or operating machinery. If the condition is not self-limiting, it will resolve on reducing the dose or stopping treatment.

4.8 Undesirable effects ♦Ocular effects:

Retinopathy with changes in pigmentation and visual field defects can occur, but appears to be uncommon if the recommended daily dose is not exceeded. In its early form it appears reversible on discontinuation of Hydroxychloroquine sulfate. 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 have scotomatous vision with paracentral, pericentral ring types, temporal scotomas and abnormal colour vision.

Corneal changes including oedema and opacities have been reported. They are either symptomless or may cause disturbances such as haloes, blurring of vision or photophobia. They may be transient and are reversible on stopping treatment.

Blurring of vision due to a disturbance of accommodation which is dose dependent and reversible may also occur.

Dermatologic effects:

Skin rashes sometimes occur; pruritus, pigmentary changes in skin and mucous membranes, bleaching of hair and alopecia have also been reported. These usually resolve readily on stopping treatment.

Bullous eruptions including very rare cases of erythema multiforme and Stevens-Johnson syndrome, photosensitivity and isolated cases of exfoliative dermatitis have been reported. Very rare cases of acute generalised exanthematous pustulosis (AGEP) has to be distinguished from psoriasis, although hydroxychloroquine may precipitate attacks of psoriasis. It may be associated with fever and hyperleukocytosis. Outcome is usually favourable after drug withdrawal.

♦Gastrointestinal effects:

Gastrointestinal disturbances such as nausea, diarrhoea, anorexia, abdominal pain and, rarely, vomiting may occur. These symptoms usually resolve immediately on reducing the dose or on stopping treatment.

♦CNS effects:

Less frequently, dizziness, vertigo, tinnitus, hearing loss, headache, nervousness, emotional lability, toxic psychosis and convulsions have been reported with this class of drugs.

'Neuromuscular effects:

Skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups have been noted. Myopathy may be reversible after drug discontinuation, but recovery may take many months.

Associated mild sensory changes, depression of tendon reflexes and abnormal nerve conduction may be observed.

♦Cardio-vascular effects:

Cardiomyopathy has been rarely reported.

Chronic toxicity should be suspected when conduction disorders (bundle branch block/atrioventricular heart block) as well as biventricular hypertrophy are found. Drug withdrawal may lead to recovery.

♦Hematologic effects:

Rarely, there have been reports of bone-marrow depression. Blood disorders such as anaemia, aplastic anaemia, agranulocytosis, a decrease in white blood cells and thrombocytopenia have been reported.

Hydroxychloroquine may precipitate or exacerbate porphyria.

♦Liver effects:

Isolated cases of abnormal liver function tests have been reported; rare cases of fulminant hepatic failure have also been reported.

Urticaria, angioedema and bronchospasm have been reported.

• Metabolisim and nutrition disorders

Hypoglycaemia (see section 4.4) frequency unknown

4.9 Overdose

Overdosage with the 4-aminoquinolines is dangerous particularly in infants, as little as 1-2g having proved fatal.

The symptoms of overdosage may include headache, visual disturbances, cardiovascular collapse, convulsions, hypokalaemia, and rhythm and conduction disorders, followed by sudden and early respiratory and cardiac arrest. Since these effects may appear soon after taking a massive dose, treatment should be prompt and symptomatic. The stomach should be immediately evacuated, either by emesis or by gastric lavage. Activated charcoal in a dose at least five times of the overdose may inhibit further absorption if introduced into the stomach by tube following lavage and within 30 minutes of ingestion of the overdose.

Consideration should be given to administration of parenteral diazepam in cases of overdosage; it has been shown to be beneficial in reversing chloroquine cardiotoxicity.

Respiratory support and shock management should be instituted as necessary.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties ATC Code: P01BA02

Pharmacotherapeutic group: Anti rheumatic

Antimalarial agents like chloroquine and hydroxychloroquine have several pharmacological actions which may be involved in their therapeutic effect in the treatment of rheumatic disease, but the role of each is not known. These include interaction with sulphydryl groups, interference with enzyme activity (including phospholipase, NADH - cytochrome C reductase, cholinesterase, proteases and hydrolases), DNA binding, stabilisation of lysosomal membranes, inhibition of prostaglandin formation, inhibition of polymorphonuclear cell chemotaxis and phagocytosis, possible interference with interleukin 1 production from monocytes and inhibition of neutrophil superoxide release.

5.2 Pharmacokinetic properties

Hydroxychloroquine has actions, pharmacokinetics and metabolism similar to those of chloroquine. Following oral administration, hydroxychloroquine is rapidly and almost completely absorbed. In one study, mean peak plasma hydroxychloroquine concentrations following a

single dose of 400mg in healthy subjects ranged from 53-208ng/ml with a mean of 105ng/ml. The mean time to peak plasma concentration was 1.83 hours. The mean plasma elimination half-life varied, depending on the post-administration period, as follows: 5.9 hours at C_max-10 hours), 26.1 hours (at 10-48 hours) and 299 hours (at 48-504 hours). The parent compound and metabolites are widely distributed in the body and elimination is mainly via the urine, where 3% of the administered dose was recovered over 24 hours in one study.

5.3 Preclinical safety data

There are no preclinical safety data of relevance to the prescriber, which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose Monohydrate Maize Starch Hypromellose Croscarmellose Sodium

Magnesium Stearate

Talc

Titanium Dioxide Macrogol 6000 Iron Oxide Yellow El72 Polysorbate 80

6.2    Incompatibilities

No incompatibilities are known.

6.3    Shelf life

3 years

6.4    Special precautions    for storage

Do not store above 25°C.

6.5 Nature and contents of container

250pm clear PVC/20pm aluminium foil blister pack containing 10 tablets.

The blister packs are packed in a outer cardboard carton containing 28, 30 or 60 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

None

7. MARKETING AUTHORISATION HOLDER

Abbey Place

24-28 Easton Street High Wycombe HP 11 1NT UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 33271/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

15/09/2011

10 DATE OF REVISION OF THE TEXT

21/04/2015