This information is intended for use by health professionals
a) Rheumatoid arthritisAdults: A dose of 125-250mg daily for the initial 4 week period. Increase by the same amount every 4 to 12 weeks until remission occurs. The minimum maintenance dose to achieve suppression of symptoms should be used and treatment should be discontinued if no benefit is obtained within 12 months. Improvement may not occur for some months.The usual maintenance dose is 500-750mg daily in divided dosages. A few patients may require up to 1500 mg daily to obtain benefit. When clinical assessment shows that suppression of disease activity has been achieved, the dose should be kept at this maintenance level for six months, thereafter reducing the daily dosage by 125 to 250mg amounts every 12 weeks may be attempted. Relapse may occur following withdrawal or when an inadequate dose level is reached, usually within three months, but most patients respond to further courses of penicillamine.Children: The usual maintenance dose is 15 to 20mg/kg/day. The initial dose should be lower (2.5 to 5mg/kg/day) and increased every four weeks over a period of three to six months. Elderly: Increased toxicity unrelated to renal function occurs in the elderly. Initial dose should not exceed 125mg daily for the first month, increasing by similar increments every four to twelve weeks until the minimum maintenance dose to suppress symptoms is reached. Daily dosage should not exceed 1000mg (See section 4.4, Special Warnings and Precautions for use).Renal Insufficiency: Penicillamine therapy should be initiated at a low dose with intervals between dose increases of at least 12 weeks. Fortnightly monitoring for toxicity is mandatory throughout treatment for rheumatoid arthritis.
(b) Wilson's diseaseD-penicillamine is a copper-chelating agent, and is most effectively used in conjunction with a low-copper diet (below 1mg of copper per day). Patients must be maintained in negative copper balance and the minimum dose of penicillamine required to achieve this should be given.
Dosage:Adults: 1500 to 2000mg daily in divided doses. The optimum dose to achieve a negative copper balance (measured by analysis of 24 hour urinary copper excretion and subsequently by monitoring free copper in the serum) should be chosen. The dose may be reduced to 750-1000mg daily when disease control is achieved as evidenced by urinary copper excretion. A dose of 2000mg daily should not be continued for more than one year.Children: 20mg/kg/day in two or three divided doses, given 1 hour before meals. For older children (>12 years) the usual maintenance dose is 0.75-1g daily. Elderly: Up to 20mg per kg body weight daily in divided doses. The dosage should be adjusted to minimal level necessary achieve disease control.Renal Insufficiency: Extra precautions should be taken to monitor for adverse effects in patients with Wilson's disease and renal insufficiency.
(c) CystinuriaIdeally establish the lowest effective dose by quantitative amino acid chromatography of urinei) Dissolution of cystine stonesAdults: For the treatment of cystinuria or cystine stones, 10003000mg daily in divided doses, adjusted to maintain urinary cystine below 200mg/litre. Maintain adequate fluid intake of 3 litres/day to provide a urine flow of 2ml/min.ii) Prevention of cystine stonesAdults: 500mg to 1000mg on retiring. Fluid intake should not be less than 3 litres per day. Urine cystine levels of not more than 300mg/l should be maintained.Children: 20 to 30mg/kg/day in two or three divided doses, given 1 h prior to meals, adjusted to maintain urinary cystine levels below 200mg/litre.Elderly: The minimum dose which maintains urinary excretion of cystine below 200mg/L.Renal insufficiency: If renal insufficiency is present at the onset of therapy, the starting dose should be lower, but it will be necessary to give sufficient penicillamine to achieve urine cystine levels of not more than 300mg/l. The maintenance dose should be reviewed at intervals of not more than four weeks.
d) Lead poisoningAdults: Daily oral dose of 1000-1500mg in divided doses until urinary lead is stabilised at 0.5 mg/day.Children: Penicillamine should only be used in cases where blood lead levels <45mcg/dL. A total of 15-20mg/kg/day in 2-3 doses should be usedElderly: 20mg per kg body weight daily in divided doses until urinary lead is stabilised at less than 0.5mg/day.
e) Chronic Active HepatitisAdults: Penicillamine is intended for the maintenance treatment of chronic active hepatitis. The diagnosis should be based on a history of at least three months duration with features of chronic aggressive hepatitis, with or without cirrhosis. Treatment with penicillamine should not be commenced until the disease process has been brought under control, initially by treatment with corticosteroids. Disease control should be evidenced by biochemical analysis of liver function to include evaluation of serum bilirubin and transaminase activity.Penicillamine therapy should be commenced with 500mg daily, in divided doses, increasing gradually over three months to the maintenance dose of 1250mg daily. Concurrently, the dosage of corticosteroids should be reduced and phased out over a three-month period. Throughout therapy, liver function tests should be carried out at suitable intervals for assessment of disease status.Children: The safety and efficacy of penicillamine in children less than 18 years with chronic active hepatitis have not been established. No data are available.Elderly: Not recommended.
In general the elderly are more likely to have adverse effects.Because of the potential for serious haematological and renal adverse reactions to occur at any time full blood count and urinalysis should be performed weekly for at least the first 2 months of therapy, (or after any change in dose) and should be repeated monthly thereafter. In cystinuria or Wilson's disease, longer intervals may be adequate.Patients should be instructed to report promptly the development of signs and symptoms of granulocytopaenia and/or thrombocytopenia such as fever, chills, sore throat, easy bruising or unexplained bleeding, mouth ulcers or rashes. Laboratory tests should be repeated in this case.Consider withdrawing therapy if platelet count falls below 120 000/mm3 or WBC below 2500/mm3, or if either parameter shows 3 successive falls within the reference range. Therapy can be re-introduced at a lower dose, when the count returns to normal, but should be discontinued permanently if neutropaenia or thrombocytopenia recurs.Similarly, proteinuria and/or haematuria may be warning signs of glomerulonephritis. In some patients the proteinuria disappears with continued therapy but close observation is essential and therapy should be discontinued if there is heavy or increasing proteinuria or significant haematuria.Care should be exercised in patients with renal insufficiency; modification of dosage may be necessary (see Section 4.2; Posology and Method of Administration).Especially careful monitoring is necessary in the elderly since increased toxicity has been observed in this patient population regardless of renal function.With the exception of Wilson's disease, patient's platelet and white cell counts must be normal before commencing treatment. A low platelet or white cell count is not a contra-indication to commence treatment of Wilson's disease. Treatment should be discontinued however, if a low initial count falls further and/or excessive bruising or petechial haemorrhages occur. Liver function tests should be carried out at a frequency determined by the clinical setting (e.g. chronic active hepatitis will require more frequent monitoring.Concomitant use of NSAIDs and other nephrotoxic drugs may increase the risk of renal damage (see Section 4.5, Interaction with other medicinal products and other forms of interaction).Antihistamines, corticosteroids, or temporary reduction of dose will control allergic phenomena (see Section 4.8 Undesirable effects) occurring early, unless severe.In the treatment of rheumatoid arthritis, response to penicillamine is often slow and the use of existing analgesics, anti-inflammatories or steroids should be continued and later gradually withdrawn, subject to patient improvement.Pyridoxine 25 mg daily may be given to patients taking penicillamine for long periods, especially if they are on a restricted diet, (e.g. Wilson's disease or cystinuria) since penicillamine increases the requirement for this vitamin (see Section 4.5,Interactions with Other Medicinal Products and Other forms of Interaction).It has been suggested that doses of penicillamine should be reduced to 250 mg daily for 6 weeks prior to elective surgery because of possible effects of penicillamine on collagen and elastin (and thereby on wound healing).Reversible loss of taste may occur. Mineral supplements to overcome this are not recommended (see Section 4.8 Undesirable effects).Haematuria is rare but if it occurs in the absence of renal stones or other known cause, treatment should be stopped immediately (see Section 4.8 Undesirable effects).A late rash, described as "acquired epidermolysis bullosa" and "penicillamine dermopathy" may occur, after several months or years of therapy and may necessitate discontinuation of treatment (see Section 4.8 Undesirable effects).The use of DMARDS, including penicillamine, has been linked to the development of septic arthritis in patients with rheumatoid arthritis, although rheumatoid arthritis is a stronger predictor for the development of septic arthritis than the use of a DMARD (see section 4.8 Undesirable effects).Deterioration of the neurological symptoms of Wilson's disease (dystonia, rigidity, tremor, dysarthria) have been reported following introduction of penicillamine in patients treated for this condition. This may be a consequence of mobilisation and redistribution of copper from the liver to the brain (see section 4.8 Undesirable effects).Breast enlargement has been reported as a rare complication of penicillamine therapy in both women and men (see Section 4.8 Undesirable effects). Danazol has been used successfully to treat breast enlargement which does not regress on drug discontinuation.
Blood and lymphatic system disorders:Common: ThrombocytopeniaNot known: Neutropenia8, agranulocytosis1, aplastic anaemia1, haemolytic anaemia, leucopoenia
Immune system disorders:Rare: Allergic reactions including hypersensitivity
Metabolism and nutrition disorders:Not known: Anorexia2
Psychiatric disorders:Not known: Confusion2
Nervous system disorders:Not known: Loss of taste4, headache2, dizziness2
Eye disorders:Not known: Abnormal vision2
Ear and labyrinth disorders:Rare: Deafness
Vascular disorders:Not known: Pulmonary haemorrhage
Respiratory, thoracic and mediastinal disorders:Not known: Dyspnoea, pleural effusion, alveolitis, pulmonary fibrosis, bronchiolitis, pneumonitis
Gastrointestinal disorders:Rare: Mouth ulceration, stomatitis, glossitisNot known: Pancreatitis, nausea2, vomiting2, diarrhoea2
Hepatobiliary disorders:Not known: Cholestatic jaundice
Skin and subcutaneous tissue disorders:Rare: Alopecia, pseudoxanthoma elasticum, elastosis perforans, skin laxityNot known: Rash2, urticarial reactions3, epidermolysis bullosa6, penicillamine dermopathy6, dermatomyositis, pemphigus, Stevens-Johnson syndrome.
Musculoskeletal, connective tissue and bone disorders:Not known: Drug induced lupus erythamatosus, myasthenia gravis, polymyositis, rheumatoid arthritis
Renal and urinary disorders:Very common: ProteinuriaRare: Haematuria5Not known: Nephrotic syndrome, glomerulonephritis, Goodpasture's syndrome
Reproductive system and breast disorders:Rare: Breast enlargement7
General disorders and administration site conditions:Not known: Fever21Deaths from agranulocytosis and aplastic anaemia have occurred2Nausea, anorexia, fever, rash, vomiting, diarrhoea, headaches, dizziness, abnormal vision and confusion may occur early in therapy especially when full doses are given from the start3Penicillamine may cause allergic reactions such as urticaria and erythema accompanied by hyperpyrexia. Transient rashes and fever may occur early in therapy; if persistent, antihistamines or temporary withdrawal of treatment with or without a short course of steroids may be necessary. Penicillamine may be re-introduced at a lower dosage. If steroids are given, penicillamine should be reintroduced before steroid withdrawal.Urticarial reactions have been reported (see Section 4.4, Special Warnings and Precautions for Use).4Reversible loss of taste may occur (See section 4.4 Special Warnings and Precautions for Use).5Haematuria may occur rarely, (see section 4.4 special warnings and precautions for use).6A late rash, described as "epidermolysis bullosa" and "penicillamine dermopathy" may occur, after several months or years of therapy and may necessitate discontinuation of treatment.7Breast enlargement has been reported as a rare complication of penicillamine therapy in both women and men. (see Section 4.4, Special Warnings and Precautions for Use).8 Neutropenia may occur at any time during treatment and is usually reversibleIron deficiency may occur in menstruating women.The development of septic arthritis in patients with rheumatoid arthritis has been linked to the use of DMARDS, including penicillamine (see section 4.4 Special warnings and Precautions for use)Deterioration of the neurological symptoms of Wilson's disease (dystonia, rigidity, tremor, dysarthria) have been reported following introduction of penicillamine in patients treated for this condition. This may be a consequence of mobilisation and redistribution of copper from the liver to the brain (see Section 4.4 Special warnings and Precautions for use).