Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Generics [UK] Limited t/a Mylan, Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Agranulocytosis, aplastic anaemia or severe thrombocytopenia due to penicillamine.
Lupus erythematosus.
Moderate or severe renal impairment.
Full blood and platelet counts should be performed 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). 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.
During the first eight weeks of therapy full blood counts should be carried out weekly or fortnightly and also in the week after any increase in dose, otherwise monthly thereafter. In cystinuria or Wilson’s disease, longer intervals may be adequate.
If platelets fall below 120,000 per mm³ or white blood cells below 2,500 per mm³, or if three consecutive falls are noted within the normal range, withdrawal of treatment should be considered. When counts return to normal, treatment may be restarted at a reduced dosage, but should be permanently withdrawn on recurrence of leucopenia or thrombocytopenia. Penicillamine may potentiate the bone marrow suppression caused by clozapine.
Care should be taken and dosage modified, if needed, in patients with renal impairment (see section 4.2).
Especially careful monitoring is necessary in older people 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).
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).
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).
Antihistamines, steroid cover, or temporary reduction of dose will control urticarial reactions (see section 4.8).
Reversible loss of taste may occur. Mineral supplements to overcome this are not recommended (see section 4.8).
Haematuria is rare, but if it occurs in the absence of renal stones or other known causes, treatment should be stopped immediately (see section 4.8).
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).
Breast enlargement has been reported as a rare complication of penicillamine therapy in both women and men (see section 4.8). 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).
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).
Pyridoxine daily may be given to patients on long term therapy, especially if they are on a restricted diet, since penicillamine increases the requirement of this vitamin (see section 4.5).
These tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Concomitant use of iron or antacids: oral absorption of penicillamine may be reduced by concomitant administration of iron or antacid (see section 4.4).
Concomitant use of digoxin: oral absorption of digoxin may be reduced by concomitant administration of penicillamine (see section 4.4).
Concomitant use of NSAIDs and other nephrotoxic drugs may increase the risk of renal damage (see section 4.4).
Concomitant use of gold: concomitant use is not recommended (see section 4.4).
Concomitant use of clozapine: penicillamine may potentiate the blood dyscrasias seen with clozapine (see section 4.4).
Concomitant use of zinc: oral absorption of penicillamine may be reduced by concomitant administration of zinc; absorption of zinc may also be reduced by penicillamine.
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).
The safety of penicillamine for use during pregnancy has not been established (see section 5.3).
There have been several cases of reversible cutis laxa in infants born to mothers taking penicillamine throughout pregnancy. Although there have been no controlled studies on the use of penicillamine during pregnancy, two retrospective studies have reported the successful delivery of 43 normal infants to 28 women receiving between 500 mg and 2000 mg of penicillamine daily. There are also anecdotal reports both of congenital abnormalities and of successful outcomes in patients who have remained on penicillamine during pregnancy. If treatment with penicillamine is to be continued following a risk-benefit analysis, consideration should be given to reducing the dose of penicillamine to the lowest effective dose.
Whilst normal infants have been delivered, there is one report of a severe connective tissue abnormality in the infant of a mother who received 2000 mg penicillamine daily throughout pregnancy. Whenever possible, penicillamine should be withheld during pregnancy, but if stones continue to form, the benefit of resuming treatment must be weighed against the possible risk to the foetus.
Penicillamine should not be administered to patients who are pregnant, and therapy should be stopped when pregnancy is diagnosed or suspected, unless considered to be absolutely essential by the physician.
Due to the lack of data on the use in breast-feeding patients and the possibility that penicillamine may be transmitted to newborns through breast milk, penicillamine should only be used in breast-feeding patients when it is considered absolutely essential by the physician.
None known.
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.
Proteinuria occurs in up to 30% of patients and is partially dose-related (see section 4.4).
Adverse reactions are ranked under the heading of frequency, the most frequent first, using the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000) and not known (frequency cannot be estimated from the available data).
The incidence and severity of some of the adverse reactions, noted below, varies according to the dosage and nature of the disease under treatment.
Common: Thrombocytopenia.
Not known: Neutropenia8, agranulocytosis1, aplastic anaemia1, haemolytic anaemia, leucopenia.
Rare: Allergic reactions including hypersensitivity.
Not known: Anorexia2.
Not known: Loss of taste4.
Not known: Pulmonary haemorrhage.
Not known: Inflammatory conditions of the respiratory tract such as bronchiolitis, pneumonitis, yellow nail syndrome.
Rare: Mouth ulceration, stomatitis.
Not known: Pancreatitis, nausea2, vomiting.
Not known: Cholestatic jaundice.
Rare: Alopecia, pseudoxanthoma elasticum, elastosis perforans, skin laxity.
Not known: Rashes2, urticarial reactions3, dermatomyositis, pemphigus, Stevens-Johnson syndrome, acquired epidermolysis bullosa6, penicillamine dermopathy6.
Not known: Drug induced lupus erythematosus, myasthenia gravis, polymyositis, rheumatoid arthritis.
Very common: Proteinuria.
Rare: Haematuria5.
Not known: Nephrotic syndrome, glomerulonephritis, Goodpasture’s syndrome.
Rare: Breast enlargement7.
Not known: Fever2
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).
4 Reversible loss of taste may occur. Mineral supplements to overcome this are not recommended (see section 4.4).
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).
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).
7 Breast enlargement has been reported as a rare complication of penicillamine therapy in both women and men (see section 4.4).
8 The reaction may occur at any time during treatment and are usually reversible (see section 4.4).
The development of septic arthritis in patients with rheumatoid arthritis has been linked to the use of DMARDs, including penicillamine (see section 4.4).
Deterioration of the neurological symptoms of Wilson’s disease (dystonia, rigidity, tremor, dysarthria) have been reported following the introduction of penicillamine in patients treated for this condition (see section 4.4).
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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Not applicable.
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