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Changes / Addition highlighted below: 4.3 Contraindications
Hypersensitivity to penicillamine or any of the excipients (see Section 6.1), except in a life-threatening situation, when desensitisation should be attempted (see Section 5.1, “Pharmacodynamic properties”).
Agranulocytosis, aplastic anaemia or severe thrombocytopenia due to penicillamine.
Lupus erythematosus.
Persistent proteinuria.
Moderate or severe renal impairment.
4.4 Special warnings and special precautions for use
Full blood counts including platelets, and renal function should be assessed prior to treatment with penicillamine.
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”).
Full blood counts should be carried out weekly or fortnightly during the first eight weeks of therapy, in the week after any increase in dose, and otherwise monthly thereafter. In cystinuria or Wilson's disease, longer intervals may be adequate.
Withdrawal of treatment should be considered if platelets fall below 120,000 or white blood cells below 2,500/mm3, or if three successive falls are noted within the normal range. Treatment may be restarted at a reduced dose when counts return to normal, but should be permanently withdrawn on recurrence of neutropenia or thrombocytopenia. Penicillamine may potentiate the bone marrow suppression caused by clozapine
In patients with normal renal function, urine should be tested weekly at first, and following each increase in dose, then monthly, although longer intervals may be adequate for cystinuria and Wilson’s disease. Increasing proteinuria may necessitate withdrawal of therapy.
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.
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”). In some patients breast enlargement was considerable and/or prolonged with poor resolution and others required surgery. 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”).
Pyroxidine 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 Interaction with other medicinal products and other forms of interaction
Concomitant use of iron or antacids: oral absorption of penicillamine may be reduced by concomitant administration of iron or antacids (see Section 4.4 “Special Warnings and Precautions for Use”).
Concomitant use of digoxin: oral absorption of digoxin may be reduced by concomitant administration of penicillamine (see Section 4.4 “Special Warnings and Precautions for Use”).
Concomitant use of NSAIDs and other nephrotoxic drugs may increase the risk of renal damage (see Section 4.4 “Special Warnings and Precautions for Use”).
Concomitant use of gold: concomitant use not recommended (see Section 4.4 “Special Warnings and Precautions for Use”).
Concomitant use of clozapine: penicillamine may potentiate the blood dyscrasias seen with clozapine (see Section 4.4 “Special Warnings and Precautions for Use”).
Concomitant use of zinc: oral absorption of penicillamine may be reduced by concomitant administration of zinc; absorption of zinc may also reduced by penicillamine.
Pyroxidine 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).
4.6 Pregnancy and lactation
Usage in pregnancy: The safety of penicillamine for use during pregnancy has not been established. It has been shown to be teratogenic in rats when given in doses several times higher than those recommended for human use.
Lactation: Due to the lack of data on use in breast feeding patients and the possibility that penicillamine may be transmitted to newborns through breast milk, Distamine should only be used in breast feeding patients when it is considered absolutely essential by the physician.
Section 4.3 - Now includes the following red text
Section 4.4 - Now includes the following red text
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”). Full blood counts should be carried out weekly or fortnightly during the first eight weeks of therapy, in the week after any increase in dose, and otherwise monthly thereafter. In cystinuria or Wilson's disease, longer intervals may be adequate. Withdrawal of treatment should be considered if platelets fall below 120,000 or white blood cells below 2,500/mm3, or if three successive falls are noted within the normal range. Treatment may be restarted at a reduced dose when counts return to normal, but should be permanently withdrawn on recurrence of neutropenia or thrombocytopenia. In patients with normal renal function, urine should be tested weekly at first, and following each increase in dose, then monthly, although longer intervals may be adequate for cystinuria and Wilson’s disease. Increasing proteinuria may necessitate withdrawal of therapy. 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”). In some patients breast enlargement was considerable and/or prolonged with poor resolution and others required surgery. 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”). Section 4.6 - Now includes the following red text Lactation: penicillamine is contraindicated in breast-feeding (see Section 4.3 “Contra-indications). Section 4.8 - Now includes the following red text The most common of all side-effects are thrombocytopenia and proteinuria. Thrombocytopenia occurs commonly. The reaction may occur at any time during treatment and are 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). Blood and Lymphatic system disorders Common: Thrombocytopenia Not known: Neutropenia8., agranulocytosis1., aplastic anaemia1., haemolytic anaemia Gastrointestinal disorders: Rare: Mouth ulceration, stomatitis Not known: Pancreatitis, Nausea2., vomiting General disorders and administration site conditions Not known: Fever2. Hepatobiliary disorders Not known: 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 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”).
Withdrawal of treatment should be considered if platelets fall below 120,000 or white blood cells below 2,500/mm3, or if three successive falls are noted within the normal range. Treatment may be restarted at a reduced dose when counts return to normal, but should be permanently withdrawn on recurrence of neutropenia or thrombocytopenia.
Section 4.6 - Now includes the following red text
Lactation: penicillamine is contraindicated in breast-feeding (see Section 4.3 “Contra-indications).
Section 4.8 - Now includes the following red text The most common of all side-effects are thrombocytopenia and proteinuria. Thrombocytopenia occurs commonly. The reaction may occur at any time during treatment and are 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). Blood and Lymphatic system disorders Common: Thrombocytopenia Not known: Neutropenia8., agranulocytosis1., aplastic anaemia1., haemolytic anaemia Gastrointestinal disorders: Rare: Mouth ulceration, stomatitis Not known: Pancreatitis, Nausea2., vomiting General disorders and administration site conditions Not known: Fever2. Hepatobiliary disorders Not known: 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 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”).
Thrombocytopenia occurs commonly. The reaction may occur at any time during treatment and are 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).
Blood and Lymphatic system disorders
Common: Thrombocytopenia
Not known: Neutropenia8., agranulocytosis1., aplastic anaemia1., haemolytic anaemia
Gastrointestinal disorders:
Rare: Mouth ulceration, stomatitis
Not known: Pancreatitis, Nausea2., vomiting
General disorders and administration site conditions
Not known: Fever2.
Hepatobiliary disorders
Not known: 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
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”).
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”).
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”).