Penicillamine

Public Assessment Report 

for paediatric studies submitted in accordance 

with Article 45 of Regulation (EC) No1901/2006, as 

amended 

PENICILLAMINE 

UK/W/033/pdWS/001 

Rapporteur: 

UK 

Finalisation procedure (day 120): 10 August 2012 

Date of finalisation of PAR 17 September 2012 

Penicillamine 

UK/W/033/pdWS/001 

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ADMINISTRATIVE INFORMATION 

Invented name of the medicinal 

product: 

INN (or common name) of the active 

substance(s): 

MAH: 

See section VI 


See section VI 

Pharmaco-therapeutic group 

(ATC Code): 

Drugs that suppress the rheumatic disease 

process 

Drugs used in metabolic disorders 

Pharmaceutical form(s) and 

strength(s): 

125mg and 250 mg film-coated tablets 


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INDEX 

Executive summary and recommendation 

I. Introduction 

II. Scientific discussion 

II.1 Information on the pharmaceutical formulation used in the clinical 

studies 

II.2 Non-clinical aspects 

1. Introduction 

2. Discussion of non clinical aspects 

II.3 Clinical aspects 


2. Clinical efficacy 

3. Discussion of clinical efficacy 

4. Paediatric safety reports 

5. Discussion of clinical safety 

III. Rapporteur’s overall conclusion and recommendation at Day 89 

IV. MAH response to the preliminary Day 89 PdAR 

V. Member States overall conclusion and recommendation 

VI. List of medicinal products and MAHs involved 


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EXECUTIVE SUMMARY 

Penicillamine is a thiol-group containing chelating agent. The pharmaceutical form is D- 

penicillamine, as L-penicillamine is toxic (it inhibits the action of pyridoxine). It is a metabolite of 

penicillin, although it has no antibiotic properties. 

Penicillamine is indicated in the following conditions: 

- Severe active rheumatoid arthritis, including juvenile forms 

- Wilson's disease (hepatolenticular degeneration) 

- Cystinuria – dissolution and prevention of cystine stones 

- Lead poisoning 

- Chronic active hepatitis 

The currently approved SmPC contains paediatric dosing information for juvenile rheumatoid 

arthritis, Wilson’s disease, cystinuria and lead poisoning but penicillamine is not indicated for use 

in children with chronic active hepatitis. Penicillamine is available in the UK as tablets containing 

125 mg and 250 mg D-Penicillamine. No paediatric oral liquid formulation is available in any 

European country. 

The data package submitted by one MAH under article 45 of the Paediatric Regulation 

contained 14 published articles of clinical trials conducted in the paediatric population and 2 

PSUR reports covering the period 1st October 2004 – 30th April 2009.The MAH in the provided 

clinical overview states that Penicillamine is a well established product and many of the 

submitted studies investigating its efficacy are very old. The MAH concludes that on the basis of 

the data presented under this European work-sharing procedure “no changes are proposed to 

the wording of the current SmPCs in relation the paediatric use except for reducing the dose for 

Penicillamine in the treatment of lead poisoning to l5mg/kg/day from 2Omg/kg/day”. Similarly 

based on the information submitted from the company’s post-marketing experience, the MAH 

concludes that no significant concerns have been identified in regards to the use of penicillamine 

in the paediatric population. 

Based on the review of the presented paediatric data on penicillamine, the rapporteur 

considered that the data presented by the MAH did not reveal any new information on the safety 

and efficacy for the use of penicillamine for the paediatric population. The rapporteur however 

noticed that the dosing information included in section 4.2 regarding Wilson’s disease and 

cystinuria is not very clear. The MAH was requested to review the evidence available and 

propose appropriate dosing recommendations for these conditions based on current clinical 

practice. Regarding the dosing recommendations for the treatment of lead poisoning the 

rapporteur was of the view that penicillamine should be used only in mild cases as demonstrated 

by the evidence provided in the literature (blood lead levels

indications 

• The proposed posology and particularly the stratification of the dosing regime for 

children younger and older that 12 years of age” 

The MAH responded on 13/06/2012 that all available scientific information regarding the 

proposed posology for the paediatric population has been already submitted. It was therefore 

concluded that “in the absence of further data the MAH will accept the rapporteur’s proposal for 

the SmPC”. 

 

No change 

Change 

New study data: 

New safety information: Section 4.9 

Paediatric information clarified: section 4.4 

New indication: sections 4.1 and 4.2 

RECOMMENDATION 

Based on the review of the presented paediatric data the rapporteur considers that for all 

products containing Penicillamine across the EU, it is recommended that SmPCs contain the 

following wordings: 

SmPC wording 

Section 4.1 Therapeutic indications 

1. Severe active rheumatoid arthritis in including juvenile forms 

2. Wilson's disease (hepatolenticular degeneration) in adults and children (0 to 18 years) 

3. Cystinuria – dissolution and prevention of cystine stones in adults and children (0 to 18 

years) 

4. Lead poisoning in adults and children (0 to 18 years) 

5. Chronic active hepatitis in adults 

Section 4.2 Posology and method of administration 

As the smallest available tablet is 125mg, this might not be suitable for very young children 

Rheumatoid arthritis 

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. 

Wilson’s disease 

Children: 20 mg/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. 

Cystinuria 

Children: 20 to 30mg/kg/day in two or three divided doses, given 1 h prior to meals, adjusted to 


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maintain urinary cystine levels below 200mg/litre. 

Lead poisoning 

Children: Penicillamine should only be used in cases where blood lead levels

I. INTRODUCTION 

On 16 February 2011, the MAH submitted the following documents for Penicillamine, in 

accordance with Article 45 of the Regulation (EC) No 1901/2006, as amended on medicinal 

products for paediatric use: 

• An overview documentation of Penicillamine use in paediatric patients 

• Two paediatric safety update reports for the period 1 st October 2004 – 30 th April 2009. 

• 14 published articles of clinical trials conducted in the paediatric population 

• The SmPCs for MAH’s currently authorised Penicillamine preparations in UK, Ireland and 

Malta (tablets 125mg and 250mg) 

The MAH notes that the assessment was conducted on data from the published literature for the 

indications licensed for paediatric use and therefore adult information or data from off licence 

paediatric use has not been included. The MAH emphasizes that Penicillamine is a well 

established product and many of the submitted studies investigating its efficacy date back to the 

1960s and 1970s. In conclusion the MAH recommends that on the basis of the data presented 

under this European work-sharing procedure “no changes are proposed to the wording of the 

current SmPCs in relation the paediatric use except for reducing the dose for Penicillamine in 

the treatment of lead poisoning to l5mg/kg/day from 2Omg/kg/day”. 

II. 

II.1 

SCIENTIFIC DISCUSSION 

Information on the pharmaceutical formulation used in the clinical studies 

Penicillamine is a pharmaceutical of the chelator class. The pharmaceutical form is D- 

penicillamine, as L-penicillamine is toxic (it inhibits the action of pyridoxine). It is a metabolite of 

penicillin, although it has no antibiotic properties. Penicillamine first received authorization in 

Italy on 28th February 1974. The product was first licensed in the UK and Ireland in October 

1974 and February 1975 respectively. The UK and Irish product licenses were transferred to the 

MAH via a Change of Ownership procedure in September 2001. Penicillamine is available in the 

UK and Ireland as tablets containing 125 mg and 250 mg D-Penicillamine. The MAH gained 

approval for 250mg in Malta on 27 October 2008. The MAH notes that “the SmPCs for X 125mg 

and 250mg tablets for Ireland are the subject of safety variations (unrelated to this procedure) 

currently being assessed by the IMB. Essentially these changes will bring the Irish licenses in 

line with the UK.” 

Penicillamine is indicated in the following conditions: 

- Severe active rheumatoid arthritis, including juvenile forms 

- Wilson's disease (hepatolenticular degeneration) 

- Cystinuria – dissolution and prevention of cystine stones 

- Lead poisoning 

- Chronic active hepatitis 

Penicillamine is indicated for use in children in all but the chronic active hepatitis indication. The 

recommended posology for children in the SmPCs is as follows: 

Rheumatoid arthritis: 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. Please note that as the smallest available tablet is 125mg, this may not be suitable for 

children under eight years (or less than 26kg in weight). 

Wilson's disease: Up to 20mg/kg/day in divided doses. Minimum dose 500mg/day. 


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Cystinuria: No dose range established, but urinary cystine levels must be kept below 200mg/l. 

The minimum dose of penicillamine required to achieve this should be given. 

Lead poisoning: 20mg/kg/day. 

Assessor’s Comment 

It is noted that penicillamine is only available in tablets and the lowest dose available is the 

125mg tablet. In all the studies included in this article 45 work-sharing procedure, tablets were 

used for dosing paediatric patients even at the lowest age groups; the daily dose was calculated 

in most instances to the nearest 25mg (as presented for example in Kvien et al 1985). In some 

other cases (example Prieur et al 1985) in order to facilitate dosing, patients were grouped 

according to weight by increments of 5kg. 

The British National Formulary for children (BNF-c) contains the following dosing information for 

Wilson’s disease and cystinuria. It is noted that there is not dosing information for treatment of 

lead poisoning in the BNF-c. 


Child 1month-12 years: 2.5mg/kg twice daily before food, increased at 1-2 weeks intervals to 

10mg/kg twice daily. 

Child 12-18 years: 0.75-1g twice daily before food, max 2g daily for 1 year; usual maintenance 

dose 0.75-1g daily. 

Cystinuria 

Child 1month-12 years: 5-10mg/kg twice daily before food, adjusted to maintain urinary cystine 

below 200mg/litre. 

Child 12-18 years: 0.5-1.5g twice daily before food, adjusted to maintain urinary cystine below 

200mg/litre. 

The MAH is strongly encouraged to consider developing age appropriate paediatric formulations 

to fulfil this clearly unmet therapeutic need in order to minimize the risk of dosing errors, 

particularly in very young patients or when the exact dose needs careful titration due to side 

effects. 

II.2 

Non-clinical aspects 


Non-clinical studies have not been provided or summarized by the MAH on Penicillamine. It is 

noted that in the literature review conducted by the MAH no preclinical studies relevant to either 

the adult or the paediatric use of the drug were identified. The currently approved SmPCs in 

section 5.3 contains the information that Penicillamine has been shown to be teratogenic in rats 

in doses several times higher than those recommended for human use. 

2. Discussion of non clinical aspects 

Penicillamine is a thiol-group containing chelating agent, variably absorbed from the 

gastrointestinal tract. The drug undergoes a rapid distribution phase, followed by a slower 

elimination phase. Penicillamine is strongly plasma-protein bound. Most penicillamine is bound 

to albumin but some is bound to α-globulins or ceruloplasmin. Penicillamine is not extensively 

metabolized in man. Information regarding the PK properties of Penicillamine in the paediatric 

population has not been proved as apart of this paediatric work-sharing procedure. Regarding its 

mode of action, penicillamine is a chelating agent which aids the elimination from the body of 

certain heavy metal ions, including copper, lead and mercury, by forming stable soluble 

complexes with them that are readily excreted by the kidney. This mechanism of action is not 

expected to be different in paediatric population. 


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There are concerns that patients at extremes of age might be more at particular risk as the 

current approved SmPC contains the following wording in section 4.4: “Especially careful 

monitoring is necessary in the elderly since increased toxicity has been observed in this patient 

population regardless of renal function”. These clinical considerations don’t appear to have been 

reviewed in very young children or in paediatric patients with moderate or severe renal 

impairment. This could be considered a major barrier for a more broadly expanded penicillamine 

use, particularly in very young children. 

The literature suggests that D-penicillamine can be potentially teratogenic, since it crosses the 

placental barrier. Indeed there are cases of infants born with severe connective-tissue defects 

after prenatal exposure to penicillamine. Also there has been a published case report of two 

siblings born to a mother with Wilson's disease on D-penicillamine, who both developed 

transient goitrous hypothyroidism (Hanukoglu et al 2008); the authors concluded that it is 

possible that D-penicillamine probably inhibited thyroperoxidase activity in utero as documented 

also in healthy infants and during childhood in patients with Wilson's disease. 

II.3 

Clinical aspects 


The MAH has conducted a literature search and provided a comprehensive overview of the 

available information regarding the use of penicillamine in paediatric patients with the conditions 

for which the medicine is licensed in children. Fourteen published paediatric articles have been 

provided, 6 in juvenile rheumatoid arthritis(JRA), 4 in Wilson’s disease, 2 in cystinuria and 2 

articles in lead poisoning. 

The paediatric studies are listed below: 

1. Giannini EH, Cassidy JT, et al. Comparative efficacy and safety of advanced drug 

therapy in children with juvenile rheumatoid arthritis. Semin Arthritis Rheum.1993; 23: 

34-46 

2. Brewer EJ, Giannini EH, Kuzmina N, Alekseev L. Penicillamine and hydroxychloroquine 

in the treatment of severe juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. 

double-blind placebo-controlled trial. N.Engl.J Med 1986;314:1269-76. 

3. Kvien TK, Hoyeraal HM, Sandstad B. Slow acting antirheumatic drugs in patients with 

juvenile rheumatoid arthritis--evaluated in a randomized, parallel 50-week clinical trial. 

J Rheumatol 1985;12: 533-39. 

4. Kerckhove CV, Giannini EH, Lovell DJ. Temporal patterns of response to d- 

penicillamine, hydroxychloroquine, and placebo in juvenile rheumatoid arthritis 

patients. Arthritis & Rheumatism 1988; 31: 1252-58. 

5. Ansell BM, Hall MA. Penicillamine in chronic arthritis of childhood. J Rheumatol Suppl. 

1981 Jan-Feb;7:112-5. 

6. Prieur AM, Piussan C, Manigne P, Bordigoni P, Griscelli C. Evaluation of d-penicillamine 

in juvenile chronic arthritis. A double-blind, multicenter study. Arthritis & Rheumatism 

1985; 28: 376–382. 

7. Iorio R, D'Ambrosi M et al. Serum transaminases in children with Wilson's disease. J 

Pediatr.Gastroenterol.Nutr 2004;39:331-336 

8. Li M, Zhang YH, Qin J. Treatment of Wilson's disease with penicillamine and zinc salts: 

a follow-up study. Zhonghua Er.Ke Za Zhi 2003;41:119-122. 

9. Fukuoka−Noriyasu, Morita−Shushi, et al. Appropriate administration schedule of 

D−penicillamine for pediatric Wilson's disease patients based on urinary copper 

excretion. Yakugaku Zasshi, August 2002, vol. 122, no. 8, p. 585−588 

10. Van Caillie−Bertrand M, Degenhart HJ, Luijendijk I, Bouquet J, Sinaasappel M. Wilson's 

disease: Assessment of D−penicillamine treatment. Archives of Disease in Childhood, 

1985;60(7): 652−55 


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11. Strologo, D., L., Laurenzi, C., Legato, A., and Pastore, A. Cystinuria in children and young 

adults: success of monitoring free-cystine urine levels. Pediatr.Nephrol. 2007;22:1869- 

1873 

12. DeBerardinis RJ, Coughlin CRII, Kaplan P. Penicillamine Therapy for Pediatric 

Cystinuria: Experience from a cohort of American children. Journal of Urology, 

2008;180(6): 2620-23 

13. Shannon MW, Townsend MK. Adverse effects of reduced-dose d-penicillamine in 

children with mild-to-moderate lead poisoning. Ann Pharmacother. 2000;34:15-18 

14. Lifshitz M, Levy J. Efficacy of D−penicillamine in reducing lead concentration in 

children: A prospective, uncontrolled study. Journal of Pharmacy Technology, 

2000;16(3):98−101 

It appears that no paediatric clinical trials have been performed or sponsored by the MAH. 

Further information from 2 paediatric safety reports (PSURs) for the period 1 st October 2004 – 

30 th April 2009 have been included as an overview of the drug’s safety profile. 

2. Clinical Efficacy 

The MAH has summarized the available data from the published literature regarding the 

paediatric aspects of penicillamine use in the licensed indications. It is noted that the rapporteur 

conducted an additional literature review which revealed a number of publications on other 

paediatric conditions such as juvenile scleroderma, copper-metabolism disorders and prevention 

of retinopathy of prematurity. For the majority of these conditions the evidence of a clear 

therapeutic benefit was inconclusive and therefore these publications are not presented in this 

report. However it would be interesting for the MAH to review the use of penicillamine in chronic 

active hepatitis which is a listed adult indication to identify any paediatric off-label use. 

a. Juvenile rheumatoid arthritis 

Comparative efficacy and safety of advanced drug therapy in children with juvenile 

rheumatoid arthritis. 

Giannini EH, Cassidy JT, et al. Semin Arthritis Rheum.1993; 23: 34-46 

Results from three randomised placebo-controlled trials were combined in a meta-analysis to 

compare the clinical utility of four advanced drug therapy agents used to treat JRA: D- 

penicillamine, hydroxychloroquine (study 1), oral gold (study 2), and two different low doses of 

oral methotrexate (study 3). The studies were supervised by the Pediatric Rheumatology 

Collaborative Study Group (PRCSG) which is a multinational consortium of 35 medical centres 

aiming to study systematically available therapies for rheumatic diseases of childhood. The 

authors noted that they only selected those 3 studies as they were based on standardised 

guidelines from the PRCSG, were conducted by the same investigators and therefore had high 

degree of homogeneity with regard to patient eligibility criteria, protocol specifications, data 

collection, and methods of analysis. 

A total of 520 children aged 18 months to 17 years with JRA were enrolled into these trials (162 

in study 1,231 in study 2, and 127 in study 3). All three studies were multicentre, prospective, 

parallel, placebo-controlled, double-blind, and randomized. Disease activity not adequately 

controlled by NSAIDs and a minimum of three joints with active arthritis had to be present for 

entry. Inadequate response to at least one advanced drug therapy before entry was 

recommended but not required. Study 1 continued for 1 year (data after the 6-month visit were 

not used in this analysis); studies 2 and 3 ended after 6 months. Clinical and laboratory 

evaluations were done monthly for studies 2 and 3 and once every 2 months for study 1. The 

doses used were D-penicillamine (10 mg/kg/d), hydroxychloroquine (6 mg/kg/d), auranofin (oral 

gold, 0.15 to 0.20 mg/kg/d), and two low dose levels of methotrexate [5MTX, 5 mg/m 2 /wk; 


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10MTX, 10 mg/m 2 /wk]. Advanced drug therapy had to have been discontinued least 3 months 

before the first dose of the blinded medication. Prednisone was not allowed in study 1 and had 

to have been discontinued at least 1 month before entry. Subjects in studies 2 and 3 were 

permitted to continue low-dose prednisone not exceeding 0.5 mg/kg/d (10 mg/d maximum). The 

dose of prednisone had to be constant for at least 1 month before entry and to remain unaltered 

throughout the duration of the trial. The articular severity score (the summation of severity 

ratings for swelling, pain on motion, tenderness, and limitation of motion), the physician's global 

assessment of patient response, and a composite index were considered the primary indicators 

of drug effectiveness. To be classified as a responder by composite index, a child had to be 

judged as improved by the physician's and the parent's global assessment and had to have a 

decrease from baseline of at least 25% in articular severity score. Other indices of articular 

disease and laboratory parameters were considered secondary measures of outcome. 

Baseline characteristics appear to be largely similar between the trials. It is noted that Study 3 

contained a higher proportion of children with systemic course of illness than did the other two 

groups (p < 0.001), although all of these children also had polyarthritis. Also subjects in study 3 

were younger at the time of onset (p< 0.001) and have had the disease significantly longer than 

children in studies 1 and 2 (p< 0.001). Only one intra-trial significant difference was detected; 

subjects in the 5MTX group had a statistically lower articular severity score at baseline than 

those in the 10MTX group (Newman-Keuls, p

Figure 2: Percentages of children showing various degrees of improvement from baseline in 

articular severity score and percentage of children classified as improved using the composite 

index. 

Table 1 summarizes the numbers of children in each treatment group that did not complete the 

trials. The percentage of dropouts was similar for gold, 5MTX, and 10MTX. Those in the D- 

penicillamine and hydroxychloroquine groups had a lower frequency of early discontinuation 

after 6 months of study. 

Table 1: Frequency of and Reasons for Early Discontinuation From Trial 

Although many adverse clinical reactions and abnormal laboratory values were recorded in all 

groups, only a small number were judged to be clinically significant or attributed to the study 

medication by the examining physician. For the penicillamine treated group, gastrointestinal 

complaints were by far the most common. Other AEs were headache/dizziness, ophthalmologic 

complains and anorexia/weight loss. All physical side effects resolved either spontaneously or 

after discontinuation of the medication, and no child suffered permanent residual from any 

adverse event. 


This is a rather old study investigating the use of disease-modifying antirheumatic drugs which 

were utilised in the early 80s in severe cases of RA that didn’t respond to NSAIDs. As the 

authors acknowledged, their use in children was based in positive results observed in adults 

12 


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so the 3 placebo-controlled paediatric studies presented here were aiming to confirm their 

effects in JRA. However this meta-analysis fails to demonstrate a positive effect of D- 

penicilamine as well as hydroxychloroquine and oral gold. Based on current knowledge, only 

MTX still remains the first line of treatment for severe cases of JRA and more advance therapies 

have been authorised and are now widely used in paediatric rheumatology. 

Penicillamine and hydroxychloroquine in the treatment of severe juvenile rheumatoid 

arthritis. Results of the U.S.A.-U.S.S.R. double-blind placebo-controlled trial. 

Brewer EJ, Giannini EH, Kuzmina N and Alekseev L. N.Engl.J Med 1986;314:1269-1276. 

The purpose of this study was to compare the efficacy and safety of penicillamine and 

hydroxychloroquine to placebo in patients with JRA who were considered to be candidates for 

therapy with slower-acting antirheumatic drugs; it was a joint effort of centres from the United 

States and the Soviet Union. The study had a randomized double-blind placebo-control 12 

month design and a total of 162 children with severe JRA aged 18 months to less than 17 years 

participated. The majority of the patients included had a diagnosis of polyarticular disease 

(n=142). The overall mean age at disease onset was 6.5 years and age and duration of disease 

at study entry averaged 9.7 and 3.2 years respectively. One group of subjects received 10 mg of 

penicillamine per kilogram of body weight per day; another group received 6 mg of 

hydroxychloroquine per kilogram daily, and a third group received placebo. All three groups 

were allowed a single concurrent non-steroidal anti-inflammatory drug, but no other antirheumatic 

medications, including corticosteroids. Four clinical indexes of articular inflammation 

were assessed: joint swelling, pain upon movement, joint tenderness and limitation of 

movement. Sum of all the severity ratings was calculated at each visit (at 2,4,6,9 and 12 

months) and the total number of joints involved was recorded. A difference of 30% in response 

rate between the active drug and placebo groups was considered statistically significant. 

One hundred forty-three patients (88.3%) completed at least 6 months of therapy; 123 (76%) 

completed 12 months of treatment. No statistical differences at the physician’s global 

assessments of response to therapy between the active drug and placebo groups were detected 

at 6 or 12 months. Although the parents’ global assessments of their child’s response tend to 

favour the active agents over placebo, the differences were not significant either. Table 2 shows 

the clinical changes in selected indexes of articular disease during follow-up. After 6 months of 

therapy, the rate of response in the active drug groups was not significantly higher than in the 

placebo group. After one year of therapy the findings were the same except that more patients in 

the hydroxychloroquine group had less pain in movement than did those in the placebo group. 


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Table 2 : Assessment of changes in indexes of articular disease 

The authors of the study argue that the cut-off point used in this study to indicate clinical 

important improvement might be too low and therefore too easily reached regardless of 

treatment. To investigate this further, they reanalyzed the data using 50% improvement as the 

cut-off point but still no significant differences with placebo were found. They also evaluated a 

subset of patients with more severe disease and again they didn’t detect significant differences 

in the rate of response. 

Regarding the safety findings in this study, haemoglobin and/or haematocrit were markedly 

reduced in 10 patients (6 on penicillamine) and leukopenia was reported in total 10 patients (4 

on penicillamine). Haematuria, proteinuria and pyuria occurred frequently. In one patient from 

the penicillamine group who had proteinuria, nephritic syndrome developed after 9 months of 

treatment with 10mg of penicillamine and 2mg of tolmetin. The syndrome rapidly resolved after 

the discontinuation of both drugs. The other most frequent abnormal change in clinical chemistry 

values was the elevation of liver enzymes. Abdominal disorders were frequently reported but 

could be associated with aspirin consumption. Clinical important rash was reported in 10 

patients (4 on penicillamine) but resolved without sequelae. Ocular toxicity was very rare in this 

study, with one patient reporting conjunctivitis due to penicillamine and one patient having 

deposits of hydroxychloroquine in corneal epithelium. 


This is the study comparing penicillamine and hydroxychloroquine with placebo which was 

included in the metanalysis paper summarized previously. The investigators were unable to 

demonstrate that either penicillamine or hydroxychloroquine are superior to placebo in the 


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treatment of children with juvenile rheumatoid arthritis, regardless of the severity of the disease 

or the efficacy cut-off endpoint selected. As the authors acknowledged, this study demonstrated 

a high response rate in the placebo treated group who received NSAIDs, a fact that corresponds 

with the current knowledge that children with JRA have substantial control of the disease after 1 

year of basic treatment. However a significant number of patients, particularly in the younger age 

group with polyarticular type of the disease have recurrence of the symptomatology but this 

study did not have adequate follow-up period to demonstrate such a reduction of the placebo 

effect. 

Slow acting antirheumatic drugs in patients with juvenile rheumatoid arthritis--evaluated 

in a randomized, parallel 50-week clinical trial 

Kvien TK, Hoyeraal HM and Sandstad B. J Rheumatol. 1985;12:533-539. 

This was a randomized parallel 50-week open controlled study aiming to compare the efficacy 

and safety of hydroxychloroquine, gold sodium thiomalate (GSTM) and D-penicillamine in 

patients with pauciarticular and polyarticular JRA. Seventy-two patients were enrolled in this 

study with medial age of 129 months (range 43 months to 15.9 years) and medial disease 

duration of 16 months (range 3 to 164 months). Hydroxychloroquine was given at 5mg/kg BID. 

The patients received the drug for 9 months, followed by a withdrawal period of 3 months to 

prevent ocular adverse reactions. GSTM was given at a weekly dose of 0.7mg/kg IM. 

Penicillamine daily dose was increased during the first 1 weeks of the trial: 2.5mg/kg was given 

at week 1-4, 5mg/kg week 5-8, 7.5mg/kg week9-12 and 10mg/kg after week 12. The daily dose 

was given BID between meals. Concomitant therapy with NSAID was kept constant at least 1 

week prior to the study ad preferably during the study. 

The comparison of changes in values of disease activity measurements indicated no apparent 

difference in efficacy between the treatment regimes. Improvement was observed throughout the 

duration of the study in all treatment groups. 

Adverse reactions were noted in 2 patients treated with hydroxychloroquine (dermatitis and GI 

upset), 5 patients treated with GSTM (dermatititis, stomatitis, proteinuria, eosinophilia) and 12 

patients (p

espond to any of the drugs used in this trial. The lack of placebo group does not allow further 

conclusions about the effect of the study medications; however these results appear to be in line 

with those reported in the previous JRA studies. The literature suggests that treatment with 

penicillamine is generally well-tolerated; noticeably in this study adverse reactions appear to be 

somewhat more frequent than previously reported. 

Temporal patterns of response to d-penicillamine, hydroxychloroquine, and placebo in 

juvenile rheumatoid arthritis patients. 

Kerckhove CV, Giannini EH and Lovell DJ. Arthritis & Rheumatism1988, 31: 1252–1258. 

Data generated by the previously described double-blind placebo controlled multicentre 

prospective 12 month parallel clinical trial (Brewer et al 1986) in 162 patients were analysed. 

The aim was to define the time course and clinical response pattern in patients with active JRA 

taking an NSAID and either D-penicillamine, hydroxychloroquine or placebo, and to determine 

the probability of an eventual response after various treatment intervals. 

The cumulative response curves for the 3 treatment groups at the 25% and 50% improvement 

levels are shown below. 

Figure 3: Cumulative response curves of 162 JRA patients at the 25% and 50% improvement levels 

by drug treatment 

Overall 79 patients (49%) were classified as 25% responders by the end of the trial and 36 

patients (22%0) responded at the 50% improvement level after a year. There was no statistically 

significant difference in the 25% or the 50% response rate for either drug versus placebo. 

Table 4: number (%) of patients with JRA who showed 25% or 50% improvement after 12 months 

of treatment with D-penicillamine (DP), hydroxychloroquine (HCQ) or placebo 

The time required for therapeutic benefit to become apparent following initiation of treatment or 

placebo (each administered concomitantly with a non-steroidal anti-inflammatory drug) was 

calculated. The average time until the 25% response was attained was 105±57 days for the 


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penicillamine group, 129±86 days for the hydroxychloroquine group, and 140±106 days for the 

placebo group. No statistically significant differences in mean respond time were observed 

between the treatment and control groups at either the 255 or the 50% improvement level. All 3 

groups took longer to show 50% clinical improvement than it took to show 25%. However the 

difference in mean time to response between the 25% and 50% improvement level for placebo 

was only 24 days compared with 144 and 82 days for penicillamine and hydroxychloroquine 

respectively. Data from examinations between the initial and final assessments were used to 

determine when the response first occurred. Approximately 50% of all patients who showed 

improvement at 12 months had already done so by 2 months. The authors concluded that a 

favourable response to these anti-rheumatic drugs is unlikely if improvement has not occurred 

within the first 6 months of therapy. 

Table 5: Percentage of patients with JRA who demonstrated 25% or 50% improvement after 1 year 

if that level of improvement was not reached after 2, 4, 6 or 9 months of treatment with D- 

penicillamine (DP), hydroxychloroquine (HCQ) or placebo 


The authors suggest that this study aims to address the clinical dilemma to whether discontinue 

treatment with penicillamine or hydroxychloroquine in a JRA patient who initially fails to show 

improvement or continue therapy and risk adverse effects in the hope of an ultimate response. 

The results of the study indicate that 4 months of treatment with penicillamine is sufficient to 

allow a therapeutic response to take place; after that any chance for a change in the patient’s 

status is unlike. However if there is a 25% improvement after the 4 month treatment period, 

continuation of penicillamine would lead to further improvement only in 40% of the patients by 

the end of 1 year of treatment. In a disease such as JRA which is characterized by frequent 

remissions, it is difficult to differentiate between the natural course of the condition and the 

effects from the drug therapy, particularly as this study demonstrated a 40% response rate to 

placebo. The authors actually suggest that based on the results of this study, continuation of 

treatment with NSAIDs for more than 6 months might not be warranted as a valuable therapeutic 

effect has been demonstrated in the placebo group of this study using stable doses of NSAID 

and possibly intense physiotherapy regime. 

Penicillamine in chronic arthritis of childhood. 

Ansell BM, Hall MA. J Rheumatol Suppl. 1981 Jan-Feb;7:112-5. 

This paper describes the 3 year follow-up of 50 patients treated in a comparative study of 

penicillamine and gold involving patients who had not previously received any long acting drug; 

they could however be on corticosteroids. A total of 24 patients were treated gold and 26 were 

treated with penicillamine. Corticosteroids were administered to 13 patients in the gold group 

and to 12 in the penicillamine group. Improvement was measured by a reduction in the numbers 

of actively involved joints in association with a fall in the ESR, a rise in haemoglobin levels and 

when applicable a reduction in corticosteroids use. The authors reported that in doses of 15 to 

30 mg/kg, penicillamine is of benefit in up to 69% of juvenile polyarthritis patients at the 3 year 

follow-up when used as the first long-acting drug. Side effects accounted for 5 withdrawals in the 

penicillamine group; side effects in this treatment group, particularly proteinuria in the second 

year. Radiologic changes lagged considerably behind clinical improvement. 


UK/W/033/pdWS/001 

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The authors also summarised an open study which was performed on children who failed to 

respond to gold or in one case azathioprine. Twenty-six patients had commenced therapy more 

than 3 years previously. Penicillamine was effective in only 53% of patients. Proteinuria, the 

main side effect, was often due to amyloid in the first 2 years but in the third year, it tended to 

result from penicillamine. One child had a lupus-like reaction. Rash was uncommon, and 

haematologic problems were relatively few; both usually respond to dosage alterations. 


There is very limited information regarding the design of the studies described in this paper to 

allow meaningful assessment of the safety and efficacy of the treatment of penicillamine either 

as 1 st or 2 nd line treatment in children with JRA. The exact age range of the patients included in 

these studies is not provided. The concomitant use of cortosteroids also influences the 

therapeutic effect of penicillamine; furthermore it is noted that treatment with gold had been 

considerably more steroid sparing than penicillamine. 

Evaluation of d-penicillamine in juvenile chronic arthritis. A double-blind, multicenter 

study. 

Prieur AM, Piussan C, Manigne P, Bordigoni P and Griscelli C. Arthritis & Rheumatism 1985, 28: 

376–382. 

A 6-month, multi-centre, comparative double-blind, placebo controlled study of the efficacy of D- 

penicillamine was conducted in 74 children with juvenile chronic arthritis with a mean age of 9 

years (range 3-18 years). Patients with systematic features and involvement of less than 4 joints 

were excluded from the study. Systemic corticosteroid therapy >0.5 mg/kg/day of prednisone or 

the equivalent and use of slow-acting antirheumatic drugs (SAARD) during the previous 3 

months were also exclusion criteria. A minimum dose of penicillamine 5 mg/kg/day during the 

first 2 months and 10 mg/kg/day during the next 4 months was administered. Throughout the 

trial, 10 mg/kg/ day of pyridoxine hydrochloride was given concomitantly. 

The results were analyzed in 70 children, including the 8 who were lost to follow-up. Seven 

patients were withdrawn from the trial because of relapse or side effects (Table 6). Four patients 

in the placebo group exhibited a relapse between the 2 nd and 3 rd months of treatment, and a fifth 

patient had a systemic flare while receiving penicillamine. Two severe side effects led to the 

withdrawal of penicillamine. Fifty-five patients (31 in the DP group and 24 in the placebo group) 

completed the entire study 

Table 6: Reasons for dropout during the study 

Overall functional improvement was observed only in the penicillamine group: 5 of 9 children 

who were in functional class 3-4 at the beginning of the study were in class 1-2 at the end of the 

study. The general symptoms were initially different in the penicillamine and placebo groups and 

could not be compared objectively. The duration of morning stiffness was reduced, though not 

significantly, in the group receiving penicillamine. Significant improvement was observed in the 

total number of stiff joints and the total number of painful joints. The sum of severity of pain was 


UK/W/033/pdWS/001 

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markedly decreased in the treated group. Seven children in the penicillamine group and 4 in the 

placebo group were in remission at the end of the 6-month study. In the penicillamine group, the 

daily consumption of aspirin was significantly reduced. Prednisone dosage was not significantly 

reduced in either group. 

Adverse effects were observed in 19 patients. In 2, both receiving penicillamine, these effects 

were severe enough to necessitate stopping the trial. In 10 patients receiving penicillamine and 

7 receiving placebo, effects were generally mild and disappeared without withdrawal of the drug. 

In 10 patients (6 in the penicillamine group and 4 in the placebo group), vomiting and abdominal 

pain were recorded. In 4 (3 in the penicillamine group and 1 in the placebo group), transient 

rashes were observed. 


Interestingly this study demonstrates a positive effect of penicillamine treatment compared to 

placebo in paediatric patients with polyarthitis. However it is noted that low doses of 

corticosteroids were permitted in this trial. It is also noted that there was no difference in 

remission rates between children on penicillamine and those receiving placebo. Another 

limitation of the study was the short follow-up duration, limited to only 6 months; this fact in 

addition to the finding that significant improvement was noted in the placebo group limits the 

robustness of the evidence generated by this study. 

b. Wilson’s disease 

Serum transaminases in children with Wilson's disease. 

Iorio R, D'Ambrosi M, et al J Pediatr.Gastroenterol.Nutr. 2004;39:331-336 

The aim of this multicenter retrospective study was to evaluate the efficacy of penicillamine and 

zinc therapy in a large number of children with Wilson’s disease. The main parameter of 

treatment efficacy was serum alanine aminotransferase (ALT) activity, which may be the only 

altered laboratory sign in early Wilson’s disease. Patients were included in the study if Wilson’s 

disease was diagnosed based on at least two of the following: low plasma ceruloplasmin (100μg/24h), increased urine copper after penicillamine 

challenge (>1590 μg/24 hr) and increased liver copper (>250μg/g dry weight). Zinc dosage was 

considered adequate if zinc blood levels were higher than 150 mg/dL and zinc 24-hour urine 

levels were higher than 2 mg/day. Penicillamine dosage was considered adequate if after one 

year of therapy, urine copper levels were less than 500 μg/day. Data were analyzed with the χ 2 

test and with Fisher’s exact test and Student’s t-test as appropriate. 

A total of 109 patients (median age at diagnosis 7.2 years; range 1 to 18 years), treated for a 

median of 76 months (range 12 to 271 months) were included in the study. Of them, 96 (88%) 

had at presentation clinical and/or laboratory signs of liver disease and six (6%) had neurologic 

manifestations. In seven (6%) patients, Wilson’s disease was diagnosed during family screening 

with molecular analysis. 103 of the 109 patients had hypertransaminasemia at diagnosis 

(median ALT value, 240 IU/L; range 45 to 640 IU/L); ALT activity was normal in the remaining six 

patients. No patient had haemolytic anaemia or abnormal renal laboratory function test results. 

Only one of the five patients with liver failure required liver transplantation, the others improved 

after treatment with penicillamine. Eighty-seven patients were first treated with penicillamine 

(median dosage 20 mg/kg/day), and 22 were treated with zinc sulfate (median dosage 300 

mg/day divided in 2–3 doses; range 150-600 mg/day). 

Serum ALT level normalized in 56 of 87 (64%) patients treated with penicillamine, within a 

median of 17 months (range 2-96 months). Four of the 56 patients had a relapse of 

hypertransaminasemia; one of these did not comply with therapy. Twelve (41%) of the 29 

patients with persistence of hyper-ALT continued penicillamine therapy and 17 (59%) switched 

to zinc. Only 4 patients normalized ALT level during zinc therapy within 38 months (range 7-48 

IU/L). Five of these 17 patients switched to zinc because of penicillamine-related side effects 


UK/W/033/pdWS/001 

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(tremor, thrombocytopenia and proteinuria) besides persistence of hypertransaminasemia. 

Only 22 (20%) of the 109 patients in the study received zinc as first treatment. Eleven (50%) of 

the 22 patients treated with zinc had normal ALT levels within a median of 6 months (range 1-36 

months). Two of these 11 patients did not comply with therapy and had a relapse of 

hypertransaminasemia. Among the 11 patients with persistent hypertransaminasemia during 

zinc therapy, six continued zinc, whereas the remaining five switched to penicillamine. Within a 

median of 6 months (range 6-9 months), three (60%) of the latter patients normalized ALT levels 

during penicillamine therapy. 

Overall when comparing between the 2 treatment groups, in penicillamine-treated and zinctreated 

patients with persistent hypertransaminasemia, the serum ALT level decreased from a 

basal median of 236 IU/L (range, 54 to 640 IU/L) to a median of 78 IU/L (range 46 to 960 IU/L) 

at the end of follow up (p=0.0245). Liver disease did not worsen in any patient during the 

observation period. Liver function tests improved and ALT level normalized in three patients with 

cirrhosis and liver failure. The authors concluded that they were not able to identify a predictive 

factor of persistent hypertransaminasemia despite correct treatment. 


This study identifies the lack of guidelines for the treatment of children with Wilson’s disease. 

The rapporteur agrees with the authors that since the two treatment groups were significantly 

different in several parameters (including age at treatment onset, ALT basal level, and evidence 

of liver disease) comparison of efficacy of penicillamine versus zinc can not be established. 

Intriguing findings of this study were that 36% of children with Wilson’s disease-related liver 

disease had persistent hypertransaminasemia despite treatment with penicillamine or zinc and 

also the very limited evidence of lack of compliance (only 10% of these cases.) 

Treatment of Wilson's disease with penicillamine and zinc salts: a follow-up study. 

Li M, Zhang YH, and Qin J. Zhonghua Er.Ke Za Zhi 2003;41:119-122. 

In this study, the effect of the therapy with combined penicillamine (10-30 mg/kg/d) and zinc 

(22.5 mg, 3 times per day) was evaluated based on the follow-up observations of 21 patients 

with Wilson's disease. Before treatment, all the 21 patients were suffered from chronic liver 

disorder. Among them, 13 patients (62%) showed to be reactive to the treatment for their liver 

disorder, 5 patients (24%) died, and 3 patients (14%) dropped off the study. Among the 5 

patients who died, 3 died within 40 days after treatment, one had taken penicillamine only 8 

mg/(kg.d), and one died after discontinuation of the treatment by the parents. Of the 12 patients 

having neurological involvement, neurological symptoms disappeared or markedly improved in 

11 patients after treatment. A patient with renal tubular acidosis responded well to the treatment. 

Urine routine analysis was followed up in 6 of the 7 patients with haematuria. Haematuria 

disappeared in one, became less severe in 1, and remained unchanged in 4 patients. 

Hypersensitivity to penicillamine was found in one patient. WBC and platelet were found 

decreased further in 3 patients after treatment. The authors concluded that the combined 

therapy with penicillamine and zinc salts was effective in treatment of patients with Wilson's 

disease 

Appropriate administration schedule of D−penicillamine for pediatric Wilson's disease 

patients based on urinary copper excretion. 

Fukuoka−Noriyasu, Morita−Shushi et al Yakugaku Zasshi, August 2002, vol. 122, no. 8, p. 

585−588 

The purpose of this study was to increase the amount of copper excreted resulting from the 

administration of D-penicillamine in paediatric Wilson's disease patients. By measuring the 

urinary copper excretion after adjusting the administration schedules, the appropriate timing for 

DP administration was investigated. The subjects were three brothers with paediatric Wilson's 


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disease. The initial daily dose of penicillamine was 5 mg/kg/day, and gradually increased to the 

maintenance dose of 20 mg/kg/day. Until the maintenance daily dose was reached, 

penicillamine was administered 2 h after the morning and evening meal. After reaching the 

maintenance daily dose of penicillamine, the appropriate timing for taking DP was investigated in 

both the morning and evening. Three schedules of penicillamine administration were compared: 

2 h after meals; 30 min before meals (with fasting); and 1 h before the morning and 1.5 before 

the evening meal (direction 1). The resulting urinary copper excretion on each dosing schedule 

was compared. Little difference was found in urinary copper excretion on the first two schedules, 

i.e., 2 h after meals and 30 min before meals. When penicillamine was administered 30 min 

before meals, urinary copper excretion was 1173 μg/day in the first brother, 918 μg/day in the 

second, and 875 μg/day in the third. When penicillamine was administered according to direction 

1, however, urinary copper excretion was increased significantly to 1701 μg/day in the first 

brother, 2701μg /day in the second, and 3808 μg/day in the third. It is known that the efficiency 

of urinary copper excretion with penicillamine administration depends on the maintenance of 

chelating ability after absorption from the gastrointestinal tract. These results indicate that the 

excretion was lower when penicillamine was administered 2 h after or 30 min before meals (with 

fasting). Thus to achieve better copper excretion efficiency, the authors suggest that 

administration 1 h before the morning and 1.5 before the evening meal is recommended for 

Wilson's disease patients. 


As both these studies are in Chinese and only brief abstracts are available, no further 

conclusions on the safety and efficacy of penicillamine treatment in paediatric patients with 

Wilson’s disease can be made. However JM Walshe in Lancet 2007 strongly advocates the view 

that penicillamine should always be given before meals, not after. Based on evidence published 

by him in 1967 “when penicillamine is given before the administration of a test dose of 

radiocopper (64-Cu) it mobilises much more of the metal than when given afterwards.” His 

conclusion is that “Presumably the penicillamine, present in the plasma, can chelate the copper 

before it becomes protein-bound. If the drug is given after the copper has been absorbed and 

handled by the liver, it is much less vulnerable to chelation” 

Wilson's disease: Assessment of D−penicillamine treatment. 

Van Caillie−Bertrand M, Degenhart HJ, Luijendijk I, Bouquet J and Sinaasappel M. Archives of 

Disease in Childhood, 1985;60(7) : 652−655 

To assess the efficacy of treatment and avoid possible deficiency, the serum copper and zinc 

concentrations and 24 hour urinary copper and zinc excretion were determined from the 

beginning of treatment with D−penicillamine in four children with Wilson's disease. The four 

children were aged 5, 3, 7 and 10 years when treatment was started and none of them had 

neurological symptoms. Penicillamine was given in 3 divided doses with meals at an initial dose 

of 500ng daily (one patient received 300mg). this dose was maintained during the first 6 months 

for patients 2, 3 and 4, after which a challenge dose was given equal to the maintenance dose + 

250mg. depending upon the results obtained, the maintenance dose was increased or continued 

unchanged. 

The data show a progressive decrease in both serum copper and zinc concentrations in all. 

Urinary copper excretion gradually levelled off to approximately 50% of initial values, but zinc 

excretion increased. Urinary zinc:copper ratios therefore increased with the duration of 

treatment. Copper elimination was considered adequate as soon as challenge with a test dose 

of penicillamine did not result in an increase in copper excretion. Urinary zinc excretion was 

increased further by the test dose. Zinc depletion was suspected clinically in one patient on 

penicillamine maintenance treatment. Lowering the dose alleviated the symptoms, urinary zinc 

loss decreased from 64 to 34 mumol/24 hours, and copper excretion remained largely 

unchanged. The authors concluded that data obtained indicate that penicillamine alters the 


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metabolism of both copper and zinc. The extent of this is not only dose dependent but is also 

related to the efficacy of copper elimination. Both copper and zinc concentrations must by 

monitored to assess the benefits of treatment and the risks of inducing manifest or subclinical 

zinc deficiency. The report does not detail adverse events extensively; it mentions one of the 4 

participants who developed skin lesions after 7 months of penicillamine at a dose of 1g/day, but 

these were alleviated after reducing the dose to 750mg/day. 


It is known that patients should be closely monitored by measurement of copper urinary 

excretion to avoid copper delinquency from excessive treatment. The primary signs of copper 

deficiency in children are a hypochromic microcytic anaemia and depressed white blood cell 

count. However this information is not currently included in the SmPC. 

c. Cystinuria 

Cystinuria in children and young adults: success of monitoring free-cystine urine levels. 

Strologo DL, Laurenzi C, Legato A and Pastore A. Pediatr.Nephrol. 2007;22:1869-1873 

The aim of this study was to evaluate prospectively, in a paediatric population, the efficacy of a 

medical approach for long-term treatment of cystinuria, to prevent the formation of new renal 

stones and to reduce the numbers and dimensions of pre-existing renal stones. Twenty patients 

with proven cystinuria (defined as cystine excretion above 300 μmol/mmol of creatinine in 

patients with a history of at least one cystine renal stone) were included in the study. The 

patients’ mean age at the start of study was 12.6 years (range 1.8–24 years). Mean age at 

diagnosis was 6.3 years (range 0.33–18.42 years). Patients were followed for a mean time of 42 

months (median 36 months range 12–86.4 months). All patients were treated with a combined 

approach. Alkali was administered to raise urine pH to 7-8. All in all, nine patients received 

sodium bicarbonate and ten potassium citrate. Urine pH and proteinuria were measured weekly, 

with dipsticks, and recorded by all patients. Sixteen patients were treated with alphamercaptopropionyl 

glycine and two with D-penicillamine. Cystine-binding drug dosages were 

adjusted in order to keep the urine free-cystine level below 100 μmol/mmol creatinine (target 

level). The two patients treated with penicillamine received a mean dose of 17.8 mg/kg/day and 

16.3 mg/kg/day, respectively. Free and drug-bound urine cystine levels were measured 

separately in morning urine samples every 4–6 months and renal stones were monitored by 

renal ultrasound scan every 4-6 months. 

A total of 18 patients completed the study; two of the 20 patients were excluded from the study 

in the first 2 months due to allergy to penicillamine and mercaptopropionyl glycine (tiopronin), in 

one case, and to the development of severe proteinuria in the other. Stone episodes before the 

start of the study were 0.28 per year and fell to 0.03 per year after the free-cystine target level 

had been reached, with only one patient requiring surgical intervention (percutaneous lithotripsy) 

to remove an obstructive stone. In this case, no relapse was observed 12 months after 

treatment. In several patients there was a reduction in the numbers and dimensions of preexisting 

renal stones, as demonstrated by repeated ultrasound scans. 


This is a very interesting study prospectively collecting data on the effect of treatment on renal 

stone formation in paediatric patients. However there are several limitations in this study. The 

number of patients treated with penicillamine is too small to further generalize the positive 

therapeutic effect in the reduction of new stone episodes. Serious adverse events requiring the 

withdrawal of the treatment occurred in 3 patients out of the initial 20, although data from one of 

them were included in the efficacy analysis. However 14% discontinuation rate is significant as 

treatment in these patients has to be of long duration aiming to avoid long-term sequelae of 

renal impairment. The positive effect of treatment could be therefore influenced by poor 


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compliance and occurrence of adverse events. 

Penicillamine therapy for Paediatric Cystinuria: Experience from a cohort of American 

children. 

DeBerardinis RJ, Coughlin CR II, Kaplan P. Journal of Urology, December 2008, vol. 180, no. 6, 

p. 2620−2623 

The aim of the study was to review the 18 years experience from a biochemical genetic clinic in 

treating paediatric cystinuria with penicillamine by performing a comprehensive, retrospective 

chart review on all children treated. The charts of all 11 children with cystinuria treated at the 

clinic were reviewed. In order to prevent penicillamine side effects the following protocol was 

used to gradually increasing the dose of penicillamine and appropriately follow-up the patients 

during treatment: 

Mean ± SD patient age at diagnosis was 5.8 ± 4.3 years (range 1.2 to 12). Urinary cystine 

concentration was tracked before and after initiation of treatment, penicillamine side effects and 

incidence of new stones during maintenance therapy. During the gradual escalation of 

penicillamine to the target dose none of the 11 patients experienced toxicity and all had 

improved urinary cystine concentration (mean ± SD percent reduction 54% ± 25%, range 5% to 

81%). The investigators followed the patients for a total of 1,203 months (mean ± SD 109 ± 73 

months, range 41 to 221), periodically assessing urinary cystine concentration, urine protein 

content, complete blood count, blood urea nitrogen, creatinine and liver function. During this 

time only 2 patients experienced significant side effects. One female patient (22 years old) 

developed elastosis perforans serpiginosa after 15 years of treatment and one male patient (7 

years old) developed generalized amino aciduria after 3 years treatment and recurred while off 

therapy. Several patients had ultrasound evidence of new stones and/or suffered acute stone 

crises at some point during the period evaluated. However the authors concluded that in every 

case these events coincided with periods of poor compliance, evidenced by history and/or lack 

of penicillamine disulfide in the urine. 


Poor compliance and late adverse reactions to treatment remain major limitations for the 

success of the penicillamine treatment in paediatric cystinuria patients. The variation in the 

frequency and distribution of side effects related to D-penicillamine in patients with cystinuria 

and Wilson's disease from different published studies may be ascribed to dose variation, 

duration of use, the patient's general medical condition, and, possibly, to differences in the 


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antigenicity of the drug in various disease states. The gradual dosing regime of penicillamine 

proposed here appears reasonable but the limited number of patients included in this study does 

allows more broad general application of the proposed algorithm in all cases of cystinuria. 

Furthermore this algorithm does not address the issue of delayed side effects of the 

penicillamine such as haematological effects and proteinuria which often lead to discontinuation 

of treatment. 

d. Lead poisoning 

Adverse effects of reduced-dose d-penicillamine in children with mild-to-moderate lead 

poisoning. 

Shannon MW and Townsend MK. Ann Pharmacother. 2000;34:15-18 

The aim of this study was to investigate the safety and efficacy of penicillamine in children when 

given under a low-dose protocol for the treatment of mild to moderate lead poisoning. The 

reasoning was that previously it has been reported (Shannon et al 1989) that penicillamine is 

associated with a relatively high incidence of adverse effects (33%) when given in the standard 

dose of 25-30 mg/kg/d; furthermore there was some evidence that lower doses of penicillamine 

(15mg/kg/day) may reduce the rate of adverse effects without a significant reduction in the 

drug's efficacy. Retrospective analysis of clinical treatment course of children who received 

penicillamine during 1996 in the Lead and Toxicology Clinic of Children's Hospital, Boston was 

undertaken. The investigators examined the incidence of rash, white blood cell and platelet 

count depression and abnormal urinalysis with penicillamine when given in a dose of 15 mg/kg/d 

to children with blood lead concentrations

children (2−16 y old; mean 8.7) have been treated with penicillamine 30mg/kg/day in 3 divided 

doses. 

Mean ± SD blood lead concentrations prior to therapy were 60.3 ± 12.9 μg/dL (range 47.8−83) 

Mean blood zinc protoporphyrin (ZPP) was 337.86 ± 58.55 μmol Hb (range 247−394). After 90 

days of treatment with D−penicillamine the mean blood lead concentration dropped by 31.7% to 

a mean of 40.7 ± 8.6 μg/dL (range 30−53) and lowered mean ZPP blood concentrations by 40% 

(t=4.89; p=0.0004). Three patients with blood lead concentrations > 45 μg/mL at the end of 

treatment were subsequently treated successfully with succimer, an alternative oral chelator. No 

adverse effects during penicillamine treatment were noted. 


The authors of this article concluded that although the reduction of the lead levels after 90 days 

of treatment with penicillamine was significant (31.7%), the lead concentrations remained to 

unacceptable levels in the paediatric patients treated. Based on these findings, the effectiveness 

of penicillamine treatment in symptomatic children with high blood lead concentrations remains 

questionable. The rapporteur is of the view that there is evidence to support the use of oral 

penicillamine in lead induced encephalopathy or when blood lead levels are > 70 mcg/dL. 

3. Discussion on clinical efficacy 

In the submitted published articles, a number of serious conditions relevant to the paediatric 

population are reviewed. Data from the submitted studies have demonstrated the expected 

effect of penicillamine based on its mechanism of action. However the overall quality of the 

evidence provided is very limited as the number of patients was overall very small and the 

conclusions are based on borderline clinical improvement in limited cases. Furthermore no 

paediatric appropriate formulations appear to be available across Europe with an increased risk 

of adverse reactions and dosing errors, particularly in very young patients. It is noted that in the 

majority of the submitted studies the calculation of the dosing regime for the study participants 

was round up according to groups of weight in order to fit the administration of divided tablets as 

needed. 

Juvenile rheumatoid arthritis 

The MAH reviewed the evidence submitted under this work-sharing procedure for the use of 

penicillamine in JRA and concluded that “In 2 of the 5 studies in Juvenile Rheumatoid Arthritis, 

efficacy of penicillamine seems limited when compared to placebo”. Currently newer agents 

have been widely used in paediatric rheumatoid arthritis patients as disease modifying agents 

such as Methotrexate, Enbrel or Humira. The rapporteur is of the view that penicllamine use in 

this condition is more historical than actually reflecting current clinical practice. 

Wilson’s Disease 

Wilson’s disease affects approximately 0.6 in 10,000 people in the European Union; this is 

below the threshold for orphan designation, which is 5 people in 10,000. The review of the 

literature reveals that there is no consensus available on the optimal treatment in Wilson 

disease. The studies submitted by the MAH and those identified by the rapporteur are quite 

heterogeneous and generally of low validity. Nevertheless, it is suggested by the currently 

available data that patients with hepatic presentation of Wilson disease are probably most 

effectively treated by D-penicillamine. Zinc seems to be preferred above penicillamine for 

treatment of presymptomatic and neurological patients, as in these subgroups, the tolerability 

profile is in favour of zinc, while no obvious differences in clinical efficacy could be observed. 

The current approved SmPC of penicillamine continues a warning regarding the possible 

deterioration of the neurological symptoms at the initiation of the penicillamine treatment in these 

patients. The rapporteur agrees with the MAH that the therapeutic effect of penicillamine in 

children has only been studied in very few small trials. As patients face lifelong need for 

medication with increased risk of adverse reactions, the long term benefit on disease 


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progression from early initiation of penicillamine therapy has not been investigated. It is noted 

that apart from Zinc and penicillamine, Trientine is also used for this condition but it is only 

recommended in older patients (>2 years) whom have been proven to be intolerant of 

penicillamine. 

Cystinuria 

Literature suggests that early recognition and treatment of urinary metabolic abnormalities will 

reduce the number of invasive procedures and renal damage in children with urolithiasis; most 

patients with cystinuria require multiple urological procedures during their lifetime. Therefore 

urine dilution, alkalization and chelating therapy have remained the cornerstones of the 

therapeutic approach. Penicillamine has been widely used for the treatment of cystinuria but 

poor compliance due to adverse reactions limits the effectiveness in reducing the morbidity and 

surgical procedures in these patients. Other agents are also use but there are concerns with 

long term treatment in children with them as well. Recent publication presents a case where 9 

months after introduction of tiopronin, a 3 years old boy manifested generalized oedema, 

oliguria, and biochemical indices of nephrotic syndrome. 


Lead is a developmental neurotoxin. Children are extremely vulnerable if exposed. Lead 

exposure has been associated with many cognitive and motor deficits, as well as distractibility 

and other characteristics of attention deficit hyperactivity disorder. Children's blood lead levels 

have declined considerably over the past 3 decades with removal of lead from gasoline and 

paint; nevertheless children can still be exposed to lead from lead paint in older homes, old 

water pipes, battery, toys and other sources. Children with lead poisoning can be treated with 

penicillamine, but larger doses do appear to have significant adverse events. The retrospective 

study by Shannon et al suggests that a lower dose of 15mg/kg/day is more appropriate than the 

current 20mg/kg/day as stated in the current SmPC. The review of the available literature on the 

treatment of paediatric lead reveals that the proposed dosing regimes are large empiric and 

penicillamine appear effective only in mild cases. As an orally available product, penicillamine 

may have a role in reducing moderate lead poisoning (blood lead levels

exposed to penicillamine for this reporting period. Similarly during the period between March 

2008 and April 2009 it is estimated that approximately 1,700 patients were exposed. It is noted 

however that the doses for cystinuria and Wilson’s disease are significantly higher although 

patients with these conditions are more rare. 

a. PSUR 1 st October 2004 – 29 th February 2008 

During this review period there were 11 reports (22 events) received by the MAH. There were no 

fatalities reported to the MAH or recorded in the clinical literature during the period covered by 

this review. One non-serious case was received directly from a reporting healthcare professional 

and 3 were forwarded by regulating authorities. The remaining cases were identified from a 

search of the published literature. During the reporting period, no clinical studies were performed 

by or sponsored by the MAH. 

A literature report described 2 cases of elastosis perforans associated with pseudopsuedoxanthamoa 

elasticum in 2 female patients on chronic penicillamine treatment for Wilson’s 

disease (Becuwe C et al 2005). A further literature report described a case of elastosis perforans 

serpiginosa secondary to cutis laxa in a female patient on chronic penicillamine for cystinuria. 

The patients had been on penicillamine for approximately 25 years and cutis laxa had developed 

a few years after the initiation of treatment. Elastosis perforans was diagnosed after the patient 

presented with dysphagia and pulmonary fibrosis (Rosen LB et al 2005). 

A case report of penicillamine-induced ANCA-associated crescentic glomerulonephritis in a 

patient with Wilson’s disease was identified in the literature (Bienaime F et al 2007). The 19 

years old female patient presented with acute renal failure after 2 years of penicillamine therapy. 

A causal link was suggested between the penicillamine treatment and the Antineutrophil 

cytoplasmic antibody (ANCA) induced vasculitis and the treatment was stopped. The patient’s 

condition resolved over a period of 2 years and copper chelation therapy with zinc acetate was 

prescribed. 

A case report of chronic myeloid leukaemia in a patient with scleroderma also identified in the 

literature (Kasifoglu T et al 2006). The 50 year old patient she was on penicillamine chronic 

therapy for 7 years. three explanations for the cause of the myeloid leukaemia were proposed by 

the reporters: coincidence, common pathogenic mechanism or penicillamine provocation. They 

report that cases exist in the literature of haematological malignancies associated with 

scleroderma but there is also a further 2 reports of lymphoblastic and lymphocytic leukaemia 

following penicillamine therapy in the literature. 

A retrospective case control study (Edwards CJ et al 2007) has examined the link between 

development of septic arthritis in patients with RA and the use of DMARD therapies. The UK 

GPRD was used to identify RA patients and a marching control cohort. The incidence rate of 

septic arthritis was 12.9 times higher in patients than in controls. In addition the use of DMARDs 

was associated with an increased risk of developing septic arthritis particularly prednisolone 

(Incidence rate ratio IRR 2.94), penicillamine (IRR 2.54) and sulfasalazine (IRR 1.74). Although 

patients under this treatment usually have more aggressive articular disease, it is possible that 

the septic arthritis is the consequence of the immuno-suppression induced by these drugs. 


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Table 7: Summary Tabulation of the case reports 

Regarding exposure during pregnancy or lactation, there was one regulatory report of in utero 

exposure during the period of this review although a number of other concurrent medicines were 

also identified in this case. No further information is provided. 

The conclusion of this PSUR report was that the benefit:risk of penicillamine treatment remained 

acceptable; however changes to the labelling were proposed : 

Section 4.4 Special warnings and special precautions 

The following wording was added: 

In section 4.8 Undesirable effects pseudoxanthoma elasticum, elastosis perforans and skin laxity 

have been listed as rare skin and subcutaneous disorders. 


It is noted that following the submission of this PSUR, important changes have been made to 

address a number of safety concerns identified, including the risk of septic arthritis and the rare 

skin complications. 

b. PSUR 1 st March 2008 – 30 th April 2009 

Seven case reports (10 events) have been received during the period of this review. Six case 

were considered to be serious. There were no fatalities reported to the MAH or recorded in the 

clinical literature during the period covered by this review. One non-serious case was received 

28 


UK/W/033/pdWS/001

directly from a reporting healthcare professional. 

Table 8: Summary tabulation of the case reports 

A French literature report describes a case of papules erythematosus in a 23 year old male 

patient on long term penicillamine treatment for Wilson’s disease. Another literature report 

described a case of penicillamine induced elastosis of the mucosal lip in a 45 years old male 

patient with Wilson disease after he was treated for approximately 20 years. The literature also 

described an event of penicillamine induced bulllous pemphigoid in a 47 year old male treated 

for Wilson’s disease. Citations for these papers were not provided. 

A 78 year old polymedicated female treated with penicillamine for 2 years developed 

glomerulonephritis, nephritic syndrome, proteinuria and oedema. There is no clear information of 

her medical history however the events were reported as recovered after the discontinuation of 

treatment. 

A spontaneous report from a pharmacist was received regarding a male patient treated with 

penicillamine for 6 years and subsequently developed thrombocytopenia. A regulatory report 

described a case of a 15 years old male with a history of asthma and abnormal liver function 

who received 500mg of penicillamine and developed an anaphylactic reaction on the day of the 

treatment. The reaction was reported as recovered after the discontinuation of the treatment. 

A non-serious report was received by a pharmacist reporting a patient treated for 10 years with 

penicillamine for Wilson’s disease who developed glomerulonephritis. 

The PSUR conclusion was that the benefit:risk ratio of penicillamine treatment remained 

unchanged. Changes to the labelling were proposed to align the information published in the 

BNF as follows (noted in bold type): 


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29


After the review of the safety data included in this PSUR, the MAH proposed further changes to 

update the warnings and interactions sections of the SmPC. The rapporteur agrees that these 

changes were necessary as they reflect common clinical scenarios with potential patient safety 

implications. 

5. Discussion on clinical safety 

The MAH concluded that after review of the adverse event information provided in the PSURs 

“no paediatric signals have been identified”. Therefore no change in the safety information 

included in the SmPC is proposed under this Article 45 procedure. 

The adverse reactions and drug interactions mentioned here are well known side effects of the 

long term penicillamine treatment and have been currently included in the relevant sections of 

the SmPCs of penicillamine containing products. Regarding the paediatric use, the rapporteur 

agrees that no specific paediatric issue has been identified through the safety information 

included in these PSURs. It is evident that as in Wilson’s disease and cystinuria the treatment 

must be started immediately after the diagnosis and continued for life, the patients must be 

informed that long term use of penicillamine increases the risk of developing often serious 

complications. 

III. 

RAPPORTEUR’S CONCLUSION AND RECOMMENDATION AT 

DAY 89 

The use of penicillamine in the paediatric population is very limited in patients with juvenile 

rheumatoid arthritis as newer agents have been used successfully in recent years. Penicillamine 

is however used extensively in patients with Wilson’s disease, cystinuria and in mild cases of 

lead poisoning; nevertheless there are some concerns on the safety of its long term use which 

are adequately reflected in the current approved SmPC. The data presented by the MAH do not 

reveal any new information on the safety and efficacy for the use of penicillamine for the 

paediatric population. 


UK/W/033/pdWS/001 

30

The rapporteur however notices that the dosing information included in section 4.2 regarding 

Wilson’s disease and cystinuria is not very clear. For Wilson’s disease international guidelines 

suggest 5 to 20mg/kgr/day divided in 2-3 doses given 1 hour before meals. Similarly for 

cystinuria, the current SmPC contains the wording that “No dose range established”. However 

doses 10-30mg/kg/day divided in 2-3 doses have been suggested. The MAH is requested to 

review the evidence available and propose appropriate dosing recommendations for these 

conditions based on current clinical practice. 

Regarding the dosing recommendations for the treatment of lead poisoning the rapporteur is of 

the view that penicillamine should be used only in mild cases as demonstrated by the evidence 

provided in the literature (blood lead levels


It is noted that, the MAH did not provide any wording regarding the treatment of the juvenile 

forms for rheumatoid arthritis. 

The current approve SmPC contains the following information in section 4.2: “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”. 

In the studies assessed under this European paediatric work-sharing procedure, treatment with 

penicillamine did not result in significant therapeutic benefit when compared with placebo or 

other NSAIDs or DMARDs. However it is noted that in the majority of the studies assessed (4 

out of 5 papers) the dose used was up to 10mg/kg/day (staring at 2.5 or 5mg/kg in 2 studies) 

which is significantly lower than the dose currently recommended in the SmPC. A recent 

Cochrane Review in adult patients (Suarez-Almazor et al 2000) concluded “D-penicillamine 

appears to have a clinically and statistically significant benefit on the disease activity of patients 

with rheumatoid arthritis. Its efficacy appears to be similar to that of other disease modifying antirheumatic 

drugs (DMARDs), but with a significantly higher toxicity. Its effects on long-term 

functional status and radiological progression are not clear from this review”. It is noted that it is 

still included in the latest textbook of Paediatric Rheumatology by Cassidy, Petty, Laxer, Lindsley 

as a potential therapeutic option with some clinical tips such as dosing and with warnings of a 

lupus like syndrome in some patients as a potential SAE. The rapporteur acknowledges that 

particularly in severe active cases, not responding to NSAIDs and/or DMARDs, recently licensed 

biologicals such as anti-TNFs are now considered the standard care in paediatric JIA patients, 

further limiting the role of penicillamine. Based on the evidence reviewed, the efficacy of 

penicillamine in juvenile rheumatoid arthritis has not been established; however it is not the 

scope of this procedure to remove currently licensed indications and therefore the rapporteur is 

of the view that the currently approved posology for juvenile forms of rheumatoid arthritis should 

be maintained. 



The MAH provided as proposed wording for section 4.2 of the SmPC the dosing information as 

available in the BNF-c. Scientific justification for the proposed dose has not been provided. The 

rapporteur notices that particularly for children over the age of 12 years the dosing regime 

proposed by the MAH is confusing as a dose of 0.75 to 1g twice daily is proposed (i.e. 1.5 to 2 g 

per day) but then it is said that “the usual maintenance dose is 0.75-1g daily”. The proposed 

posology for children > 12 years is equal to the proposed adult maintenance doses. In the 

studies included in this procedure under Article 45 the dose used was 20mg/kg/day (Iorio et al 

2004 and Fukuoka-Noriyasu et al 2002) without proposing different dose ranges for younger or 

older age groups. In the recently published guidelines by European Association for the Study of 

the liver (EASL 2012) it is recommended that “dosing children is 20 mg/kg/day rounded off to the 

nearest 250 mg and given in two or three divided doses”. In the same guideline it is 

recommended that “D-Penicillamine is best administered 1 h prior to meals, because food 

inhibits its absorption”. In conclusion, based on the evidence assessed in the work-sharing 

procedure, the rapporteur does not find the proposed paediatric posology for the treatment of 

Wilson disease acceptable unless the MAH provides robust scientific justification. 


UK/W/033/pdWS/001 

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Cystinuria 


The MAH provided as proposed wording for section 4.2 of the SmPC the dosing information as 

available in the BNF-c. Scientific justification for the proposed dose has not been provided. The 

previous approved SmPC contained the following dosing information for paediatric patients: 

“Children: No dose range established, but urinary cystine levels must be kept below 200mg/l. 

The minimum dose of penicillamine required to achieve this should be given”. 

In the studies submitted, the dose used was 20mg/kg/day (DeBerardinis et al 2008). A review of 

the literature by the rapporteur identified that “the effect of the drug is dose-dependent. A 250- 

mg/d increase in dose decreases the urinary cystine level by 75-100 mg/d. Doses of 1-2 g/d are 

effective in reducing the urinary cystine level to 200 mg/g of creatinine.” The USA label of 

penicillamine contains the following posology: ”For pediatric patients, dosage can be based on 

30 mg/kg/day. The total daily amount should be divided into four doses”. The rapporteur notices 

that no evidence have been identified supporting separate dosing regimes for children younger 

and older than 12 years of age as proposed by the MAH. It is also noted that the proposed 

posology for children older than 12 years is similar to the dosing recommendation for adults. The 

MAH should provide scientific evidence to support the proposed dosing regimes. 



Based on the evidence reviewed the rapporteur agrees with the MAH’s proposed wording for the 

treatment of children with mild lead poisoning. 

Chronic active hepatitis 

The MAH based on the request of the rapporteur conducted a literature search to investigate the 

use of penicillamine in children with chronic active hepatitis. It was concluded that there were a 

number of articles which discuss the use of penicillamine where the cause of the chronic 

hepatitis is Wilson's disease. These articles have been included in the MAH’s original 

submission. The MAH did not identify any publications for the use of penicillamine in chronic 

active hepatitis outside of Wilson's disease. The MAH therefore concluded that the following 

wording is used in section 4.2 under chronic active hepatitis: 


The rapporteur agrees with the MAH’s conclusion that there is no evidence supporting the use of 

penicillamine in children with chronic active hepatitis. It is therefore concluded that its use is not 


UK/W/033/pdWS/001 

33

ecommended in paediatric patients with chronic active hepatitis. However the proposed wording 

is not acceptable. Based on the current SmPC guideline (2009) the rapporteur proposes the 

following wording: 

“The safety and efficacy of penicillamine in children less than 18 years with chronic active 

hepatitis have not been established. No data are available” 

After a request from the rapporteur, the MAH provided an updated version for the PILs of 

penicillamine containing medicines. Following the assessment of the initial SmPC proposals, the 

rapporteur requested the following clarifications before finalizing this work-sharing procedure: 

“The MAH is requested to provide additional scientific information regarding: 

• The proposed age limit of 1 month for the use of penicillamine in all paediatric 

indications 

• The proposed posology and particularly the stratification of the dosing regime for 

children younger and older that 12 years of age” 

The MAH responded on 13/06/2012 that all available scientific information regarding the 

proposed posology for the paediatric population has been already submitted. It was therefore 

concluded that “in the absence of further data the MAH will accept the rapporteur’s proposal for 

the SmPC”. 

V. MEMBER STATES OVERALL CONCLUSION AND 

RECOMMENDATION 

Based on the review of the presented paediatric data the rapporteur considers that for all 

products containing Penicillamine across the EU, it is recommended that SmPCs and PILs 

contain the following wordings: 

SmPC wording 

Section 4.1 Therapeutic indications 

1. Severe active rheumatoid arthritis in including juvenile forms 

2. Wilson's disease (hepatolenticular degeneration) in adults and children (0 to 18 

years) 

3. Cystinuria – dissolution and prevention of cystine stones in adults and children (0 

to 18 years) 

4. Lead poisoning in adults and children (0 to 18 years) 

5. Chronic active hepatitis in adults 

Section 4.2 Posology and method of administration 

As the smallest available tablet is 125mg, this might not be suitable for very young children 

Rheumatoid arthritis 

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. 


Children: 20 mg/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. 

Cystinuria 

Children: 20 to 30mg/kg/day in two or three divided doses, given 1 h prior to meals, adjusted to 


UK/W/033/pdWS/001 

34

maintain urinary cystine levels below 200mg/litre. 


Children: Penicillamine should only be used in cases where blood lead levels

eport 

VI. 

LIST OF MEDICINAL PRODUCTS AND MARKETING 

AUTHORISATION HOLDERS INVOLVED 

Marketing Authorisation Holder 

Alliance Pharmaceuticals Limited 

Alliance Pharmaceuticals Limited 

Product name 

Distamine 125mg Film-coated Tablets 

Distamine 250mg Film-coated Tablets 


UK/W/033/pdWS/001 

36

Penicillamine

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