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Agranulocytosis, aplastic anaemia or severe thrombocytopenia due to penicillamine.
4.4 The following red text has been added:
Monitoring of blood and platelet counts should be carried out at appropriate intervals, together with urinalysis for detection of haematuria and proteinuria (see Section 4.8 “Undesirable effects”). Urinalysis should be carried out weekly at first, and following each increase in dose, then monthly, although longer intervals may be adequate for cystinuria and Wilson’s disease. Increasing or persistent proteinuria may necessitate withdrawal of therapy.
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”).
Penicillamine should be used with caution in patients who have had adverse reactions to gold.
Concomitant or previous treatment with gold may increase the risk of side effects with penicillamine treatment. Therefore penicillamine should be used with caution in patients who have previously had adverse reactions to gold and concomitant treatment with gold should be avoided (see Section 4.5, “Interaction with other medicinal products and other forms of interaction”).
If concomitant oral iron, digoxin or antacid therapy is indicated, this should not be given within two hours of taking penicillamine (see Section 4.5, “Interaction with other medicinal products and other forms of interaction”).
Antihistamines, steroid cover, or temporary reduction of dose will control urticarial reactions (see Section 4.8 “Undesirable effects).
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. This may necessitate a reduction in dosage (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.
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”).
Pyridoxine daily may be given to patients on long term therapy, especially if they are on a restricted diet, since penicillamine increases the requirement for this vitamin (see Section 4.5. Interactions with Other Medicinal Products and Other forms of Interaction).
4.5 The following red text has been added:
Pyridoxine daily may be given to patients on long term therapy, especially if they are on a restricted diet, since penicillamine increases the requirement for this vitamin (see Section 4.4 Special warnings and Precautions for Use).
4.8 The following red text has been added:
The most common of all side-effects are thrombocytopenia and proteinuria.
Thrombocytopenia occurs commonly. The reaction may occur at any time during treatment and is usually reversible (see Section 4.4 “Special Warnings and Precautions for Use”).
Proteinuria occurs in up to 30% of patients and is partially dose-related (see Section 4.4 “Special Warnings and Precautions for Use”).
Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (greater than or equal to 1 in 10); common (less than or equal to 1 in 100, less than 1 in 10); uncommon (greater than or equal to 1 in 1,000, less than 1 in 100); rare (greater than or less than 1 in 10,000, less than 1 in 1,000) very rare (less than 1 in 10,000), not known (where no valid estimate of the incidence has been derived).
NB: The incidence and severity of some of the adverse reactions, noted below, varies according to the dosage and nature of the disease under treatment.
Table 1
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Blood and Lymphatic system disorders
Common: Thrombocytopenia
Not known: Neutropenia8., agranulocytosis1., aplastic anaemia1., haemolytic anaemia, leucopenia
Gastrointestinal disorders:
Rare: Mouth ulceration, stomatitis
Not known: Pancreatitis, Nausea2., vomiting
General disorders and administration site conditions
Not known: Fever2.
Hepatobiliary disorders
Not known: Cholestatic jaundice
Immune system disorders
Rare: Allergic reactions including hypersensitivity
Metabolism and nutrition disorders
Not known: Anorexia2.
Musculoskeletal and connective tissue disorders
Not known: Drug induced lupus erythamatosus, myasthenia gravis, polymyositis, rheumatoid arthritis
Nervous system disorders
Not known: Loss of taste4.
Renal and urinary disorders
Very common: Proteinuria
Rare: Haematuria5.
Not known: Nephrotic syndrome, glomerulonephritis, Goodpasture’s syndrome
Reproductive system and breast disorders
Rare: Breast enlargement7.
Respiratory, thoracic and mediastinal disorders
Not known: Inflammatory conditions of the respiratory tract such as bronchiolitis, pneumonitis
Skin and subcutaneous tissue disorders
Rare: Alopecia, pseudoxanthoma elasticum, elastosis perforans, skin laxity
Not known: Rash2., urticarial reactions3., dermatomyositis, pemphigus, Stevens-Johnson syndrome, acquired epidermolysis bullosa6., penicillamine dermopathy6..
Vascular disorders
Not known: Pulmonary haemorrhage
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1. Deaths from agranulocytosis and aplastic anaemia have occurred.
2. Nausea, anorexia, fever and rash may occur early in therapy, especially when full doses are given from the start.
3. Antihistamines, steroid cover, or temporary reduction of dose will control urticarial reactions (see Section 4.4 “Special Warnings and Precautions for Use”).
4. Reversible loss of taste may occur Mineral supplements to overcome this are not recommended (see Section 4.4 “Special Warnings and Precautions for Use”).
5. Haematuria is rare, but if it occurs in the absence of renal stones or other known cause, treatment should be stopped immediately (see Section 4.4 “Special Warnings and Precautions for Use”).
6. A late rash, described as acquired epidermolysis bullosa and penicillamine dermopathy, may occur after several months or years of therapy (see Section 4.4 “Special Warnings and Precautions for Use”).
7. Breast 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. The reaction may occur at any time during treatment and are usually reversible (see Section 4.4 “Special Warnings and Precautions for Use”).
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 (see Section 4.4 “Special Warnings and Precautions for Use”).
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