Hydroxychloroquine Sulfate Actavis

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 Sulfate Actavis 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.

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.

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 Plaquenil. 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:

- daily dosage exceeds 6.5 mg/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.

Plaquenil 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.

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.

Plaquenil 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 Sulfate Actavis 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 as anaemia, aplastic anaemia, agranulocytosis, a decrease in white blood cells, and thrombocytopenia have been reported. Plaquenil should be discontinued if abnormalities develop.

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 Sulfate Actavis and in patients with psoriasis since it appears to increase the risk of skin reactions.

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 Plaquenil 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 Sulfate Actavis has been shown to cause severe hypoglycaemia including loss of consciousness that could be life threatening in patients treated with and without antidiabetic medications. Patients treated with Hydroxychloroquine Sulfate Actavis 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 Sulfate Actavis should have their blood glucose level checked and treatment reviewed as necessary.

Extrapyramidal disorders may occur with Plaquenil.

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 Plaquenil. 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:

- daily dosage exceeds 6.5 mg/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.

Plaquenil 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.

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.

Plaquenil 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 as anaemia, aplastic anaemia, agranulocytosis, a decrease in white blood cells, and thrombocytopenia have been reported. Plaquenil should be discontinued if abnormalities develop.

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.

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 Plaquenil 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 has been shown to cause severe hypoglycaemia including loss of consciousness that could be life threatening in patients treated with and without antidiabetic 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.

Extrapyramidal disorders may occur with Plaquenil.

The following CIOMS frequency rating is used, when applicable:

Very common > 10 %; Common > 1 and <10 %; Uncommon > 0.1 and < 1 %; Rare > 0.01 and <0.1 %; Very rare < 0.01 %; Not known (frequency cannot be estimated from available data).

Blood and Lymphatic system disorders

Not known: Bone-marrow depression, anaemia, aplastic anaemia, agranulocytosis, leucopenia and thrombocytopenia

Immune system disorders

Not known: Urticaria, angioedema, bronchospasm

Metabolism and nutrition disorders

Common: Anorexia

Not known: Hypoglycemia

Hydroxychloroquine Sulfate Actavis may precipitate or exacerbate porphyria.

Psychiatric disorders

Common: Affect lability

Uncommon: Nervousness

Not known: Psychosis

Nervous system disorders

Common: Headache

Uncommon: Dizziness

Eye disorders

Common: Blurring of vision due to a disturbance of accommodation which is dose dependent and reversible

Uncommon: 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 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 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.

Not known: Cases of maculopathies and macular degeneration have been reported (the onset ranging from 3 months to several years of exposure to Hydroxychloroquine Sulfate Actavis) and may be irreversible.

Ear and labyrinth disorders

Uncommon: Vertigo, tinnitus

Not known: Hearing loss

Cardiac disorders

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

Gastrointestinal disorders

Very common: Abdominal pain, nausea

Common: Diarrhoea, vomiting.

These symptoms usually resolve immediately on reducing the dose or on stopping treatment.

Hepatobiliary disorders

Uncommon: Abnormal liver function tests

Not known: Fulminant hepatic failure

Skin and subcutaneous tissue disorders

Common: Skin rash, pruritus

Uncommon: Pigmentation disorders in skin and mucous membranes, bleaching of hair, alopecia

These usually resolve readily on stopping treatment.

Not known: Bullous eruptions including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome) photosensitivity, exfoliative dermatitis, acute generalised exanthematous pustulosis (AGEP).

AGEP has to be distinguished from psoriasis, although Hydroxychloroquine Sulfate Actavis may precipitate attacks of psoriasis. It may be associated with fever and hyperleukocytosis. Outcome is usually favourable after drug withdrawal.

Musculoskeletal and connective tissue disorders

Uncommon: Sensory motor disorders

Not known: Skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups.

Myopathy may be reversible after drug discontinuation, but recovery may take many months.

Depression of tendon reflexes and abnormal nerve conduction studies.

Metabolism and nutrition disorders

Hypoglycaemia. Frequency: unknown.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

The following CIOMS frequency rating is used, when applicable:

Very common > 10 %; Common > 1 and <10 %; Uncommon > 0.1 and < 1 %; Rare > 0.01 and <0.1 %; Very rare < 0.01 %; Not known (frequency cannot be estimated from available data).

Blood and Lymphatic system disorders

Not known: Bone-marrow depression, anaemia, aplastic anaemia, agranulocytosis, leucopenia and thrombocytopenia

Immune system disorders

Not known: Urticaria, angioedema, bronchospasm

Metabolism and nutrition disorders

Common: Anorexia

Not known: Hypoglycemia

Hydroxychloroquine may precipitate or exacerbate porphyria.

Psychiatric disorders

Common: Affect lability

Uncommon: Nervousness

Not known: Psychosis

Nervous system disorders

Common: Headache

Uncommon: Dizziness

Eye disorders

Common: Blurring of vision due to a disturbance of accommodation which is dose dependent and reversible

Uncommon: 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 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 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.

Not known: Cases of maculopathies and macular degeneration have been reported (the onset ranging from 3 months to several years of exposure to hydroxychloroquine) and may be irreversible.

Ear and labyrinth disorders

Uncommon: Vertigo, tinnitus

Not known: Hearing loss

Cardiac disorders

<9)

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

Gastrointestinal disorders

Very common: Abdominal pain, nausea

Common: Diarrhoea, vomiting.

These symptoms usually resolve immediately on reducing the dose or on stopping treatment.

Hepatobiliary disorders

Uncommon: Abnormal liver function tests

Not known: Fulminant hepatic failure

Skin and subcutaneous tissue disorders

Common: Skin rash, pruritus

Uncommon: Pigmentation disorders in skin and mucous membranes, bleaching of hair, alopecia

These usually resolve readily on stopping treatment.

Not known: Bullous eruptions including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome) photosensitivity, exfoliative dermatitis, acute generalised exanthematous pustulosis (AGEP).

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.

Musculoskeletal and connective tissue disorders

Uncommon: Sensory motor disorders

Not known: Skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups.

Myopathy may be reversible after drug discontinuation, but recovery may take many months.

Depression of tendon reflexes and abnormal nerve conduction studies.

Metabolism and nutrition disorders

Hypoglycaemia. Frequency: unknown.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Antimalarial agents like chloroquine and Hydroxychloroquine Sulfate Actavis 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.

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.

Hydroxychloroquine Sulfate Actavis has actions, pharmacokinetics and metabolism similar to those of chloroquine. Following oral administration, Hydroxychloroquine Sulfate Actavis is rapidly and almost completely absorbed. In one study, mean peak plasma Hydroxychloroquine Sulfate Actavis concentrations following a single dose of 400mg in healthy subjects ranged from 53-208 ng/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.

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 53-208 ng/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.