Hydroxychloroquine Sulphate 200 mg Film – Coated Tablets

Quinoric 200mg Film-Coated Tablets

Each film-coated tablet contains 200 mg Hydroxychloroquine Sulphate B.P.

For a full list of excipients, see section 6.1

Film coated tablet

White, circular, biconvex film coated tablets embossed with 'BL' on one face and '200' on the other.

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

Adults (including the elderly)

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

In patients able to receive 400mg daily:

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

Children

The minimum effective dose should be employed and should not exceed 6.5 mg/kg/day based on ideal body weight. The 200 mg 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.

- known hypersensitivity to 4-aminoquinoline compounds

- pre-existing maculopathy of the eye

- pregnancy (see section 4.6 Pregnancy and lactation).

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. Thereafter, ophthalmological examinations must be repeated at least every 12 months.

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

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

- 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.

- renal insufficiency

- visual acuity below 6/8

- age above 65 years

- cumulative dose more than 200 g.

Hydroxychloroquine 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.

Hydroxychloroquine 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:

• 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.

• patients with severe gastrointestinal, neurological or blood disorders.

Although the risk of bone marrow depression is low, periodic blood counts are advisable and Hydroxychloroquine should be discontinued if abnormalities develop.

Caution is also advised in patients with 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.

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

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

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

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 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.

Hydroxychloroquine has a major influence on the 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.

Adverse events observed with Hydroxychloroquine, from spontaneous reports, are classified in body systems however are not listed according to the MedDRA frequency convention, as the frequencies are unknown:

* Frequency not known.

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

The symptoms of overdosage may include headache, visual disturbances, cardiovascular collapse and convulsions 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 gastric lavage. Finely powdered 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 reverse chloroquine cardiotoxicity.

Respiratory support may be needed and the need for incubation or tracheotomy considered. Shock should be treated by administration of fluid (with plasma expanders if necessary) with central venous pressure monitoring. In severe cases, the administration of dopamine should be considered.

A patient who survives the acute phase and is asymptomatic should be closely observed for at least 6 hours.

ATC Code : P01BA02 , 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 sulphadryl groups, interference with enzyme activity (including phospholipase, NADH- cytochrome C reductase, cholinestrase, proteases and hydrolases) , DNA binding , stabilisation of lysosomal membranes, inhibition of prostagalandin formation, inhibition of polymorphonuclear cell chemotaxis and phagocytosis, possible interference with interleukin 1 production from monocytes and inhibition of neutrophil superoxide release.

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 229 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.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Maize starch

Calcium Hydrogen Phosphate dihydrate

Colloidal anhydrous silica

Polysorbate 80

Purified Talc

Magnesium stearate

Hypromellose

Titanium dioxide

Macrogol 6000

Not Applicable.

3 years.

Blisters : No special storage precautions. Store in the original package.

Containers : No special storage precautions. Store in the original container, tightly closed.

Al/PVC blister, pack sizes of 60 tablet.

HDPE tablet containers , pack sizes of 100 ,500 , 1000 tablets

Not all pack sizes may be marketed.

No special requirements.

Bristol Laboratories Ltd.

Unit 3, Canalside, Northbridge Road,

Berkhamsted, Herts, HP4 1EG,

United Kingdom.

PL 17907/0017

15/02/2007

July 2008