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    PENICILLAMINE




    Dr Alan Worsley Bsc(hons) PhD MRPharmS

    National Poisons Information Service (Newcastle Centre)
    Regional Drug & Therapeutics Centre
    Wolfson Building
    Claremont Place
    Newcastle upon Tyne
    NE1 4LP
    UK


    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom.  The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information
    Service.


    PENICILLAMINE (Distamine)

    Summary

    Type of product

    For the treatment of severe rheumatoid arthritis and cystinuria

    Ingredients/tablet

    Penicillamine 50, 125 and 250mg

    Fatal Dose

    Not Known- A 52 year old male presented at hospital 8 hours after
    ingesting 3.1g. Symptoms included vomiting, dehydaration, abdominal
    pain and tachycardia.

    Features

    Nausea and vomiting, abdominal pain, hyperpyrexia, thrombocytopaenia,
    neutropaenia, proteinuria, haematuria and tachycardia

    Management

    Empty the stomach if >500mg ingested, maintain a good diuresis.
    Monitor renal function and treat failure conventionally. Supportive

    Antidotes

    There are no specific antidotes

    Elimination techniques

    No data available

    REFERENCES

    ABPI Data Sheet Compendium. Datapharm publications Limited 1996-1997

    British National Formulary. Number 32 (September 1996). British
    Medical Associiation and Royal Pharmaceutical Society.

    Dollery C, Therapeutic Drugs. (Pt 2), Churchill Livingstone. 1994

    PENICILLAMINE

    Brand Name

         Distamine

    Generic Name

         Penicillamine

    Chemical Group/family

         Anti-rheumatic
         BNF 10.13

    Reference number

         CAS-52-67-5 (penicillamine)
         CAS-2219-30-9 (hydrochloride)

    Manufacturer/supplier

         Eli Lilly & Co Ltd,
         Dextra Court,
         Chapel Hill,
         Basingstoke, Hants.
         RG21 5SY
         Tel: 01256 315000

    Presentation

         Penicillamine 50mg, 125 mg, 250 mg tablets.

    Physicochemical properties:(Dollery)3

         3,3-Dimethyl-D-cysteine

    Molecular weight
         149.2

    pKa (COOH, NH, SH)
         1.8, 7.9, 10.5

    Solubility
         in alcohol         1 in 530
         in water           1 in 9
         octanol/water partition coefficient   -

    USES

    Indications

    Penicillamine is indicated in Wilson's disease, cystinuria, rheumatoid
    arthritis, juvenile chronic polyarthritis, palindromic rheumatism,
    sero-negative polyarthritis, progressive systemic sclerosis, chronic
    active hepatitis.

    Therapeutic Dosage (BNF)2

    Adults

    Severe active rheumatoid arthritis, 500-750 mg daily maintenance (max
    1.5g daily)
    Wilson's disease, 1.5-2.0g daily in divided doses.
    Cystinuria, 1-3g daily in divided doses (adjusted to maintain urinary
    cysteine below 200mg/litre.
    Chronic active hepatitis.

    Child

    Severe active rheumatoid arthritis15-20mg/kg maintenance.
    Wilson's disease, up to 20mg/kg daily in divided doses.
    Cystinuria, minimum dose to maintain urinary cysteine below
    200mg/litre.

    Contraindications

    hypersensitivity (except in life threatening situations) systemic
    lupus erythematosus.

    Pharmacokinetics  (Dollery)3

         Oral absorption 40%
         presystemic metabolism -
         plasma half life
         mean 1-6h
         volume of distribution 0.8litre/kg
         plasma protein binding up to 85%

    Toxicokinetics

         No specific data available

    Adverse effects (Data Sheet)1

    Nausea, anorexia, fever and rash may occur early in therapy.
    Thrombocytopenia occurs commonly and neutropenia less often.
    Proteinuria occurs in 30% of patients and is dose related. Haematuria
    is rare.
    Haemolytic anaemia, nephrotic syndrome.

    Pregnancy

    Penicillamine crosses the placenta to the fetus and has been
    administered during pregnancy for the treatment of rheumatoid
    arthritis, cystinuria and Wilson's disease4. Conflicting reports
    suggest that penicillamine should either be stopped during
    pregnancy5, or be continued during pregnancy with the treatment of
    Wilson's disease, but discontinued in the treatment of rheumatoid
    arthritis6.

    The use of penicillamine has been observed in approximately 100
    pregnancies. Eight anomalies were observed, of which 5 cases were
    cutis laxa. The later three cases were not thought to be related to
    penicillamine, because they did not conclude connective tissue
    anomalies7.

    Breast Milk

    There are no reports that describe the use of penicillamine during
    lactation or if the drug is excreted in milk have been located.
    Authors of one review recomend avoiding penicillamine during
    lactation5.

    Interactions (BNF)2

    Antacids: reduced absorption of penicillamine
    Iron: reduced absorption of penicillamine
    Zinc:reduced absorption of penicillamine

    EPIDEMIOLOGY OF POISONING

    Limited specific data of penicillamine poisoning are available.

    A 52 year old male presented at hospital 8 hours after ingesting 3.1 g
    penicillamine. Symptoms included, vomiting, dehydration, abdominal
    pain and tachycardia.

    Side effects reported at therapeutic dosage include:

    Initially nausea, anorexia, fever and skin reactions; taste loss
    (mineral supplements not recommended); blood disorders including
    thrombocytopaenia, agranulocytosis and aplastic anaemia; proteinuria,
    rarely haematuria (withdraw immediately); haemolytic anaemia,
    nephrotic syndrome, lupus erythematosus-like syndrome, myasthenia
    Gravis-like syndrome, pemphigus, Goodpasture's syndrome, and
    Stevens-Johnson syndrome also reported; in non-rheumatoid conditions
    rheumatoid arthritis-like syndrome also reported; late rashes (reduce
    dose or withdraw treatment).

    MANAGEMENT

    No specific details available

    Decontamination

    If ingestion is within 2 hours, 50-100grams (adults) or 25-50 grams
    (children) of oral activated charcoal may be administered. Lactulose
    (20ml) should be given to prevent constipation. There is no data to
    indicate whether or not this is effective in penicillamine poisoning.

    Supportive care

    General supportive care should be given

    Monitoring

    As no data are available on penicillamine poisoning vital signs should
    be monitored-pulse, blood pressure, respiration.

    Antidotes

    There are no specific antidotes

    Elimination techniques

    No data available

    Investigations

    No data is available on penicilllamine poisoning, but routine
    investigations including renal function tests, urinalysis and
    electrolytes could be carried out.

    Case Data

    Other Toxicological Data
         No data available

    Ecotoxicological Data
         No data available

    Hazard Warnngs
         No data available

    Waste disposal data
         No data available

    Author

    Dr Alan Worsley Bsc(hons) PhD MRPharmS

    National Poisons Information Service (Newcastle Centre)
    Regional Drug & Therapeutics Centre
    Wolfson Building
    Claremont Place
    Newcastle upon Tyne
    NE1 4LP
    UK

    This monograph was produced by the staff of the Newcastle Centre of
    the National Poisons Information Service in the United Kingdom. The
    work was commissioned and funded by the UK Departments of Health, and
    was designed as a source of detailed information for use by poisons
    information centres.

    Peer review was undertaken by the Directors of the UK National Poisons
    Information Service.

    Last updated January 1997

    REFERENCES

    1. ABPI Data Sheet Compendium. Datapharm Publications Limited. 1996-
    1997

    2. British National Formulary. Number 32 (september 1996). British
    Medical Association and Royal Pharmaceutical Society.

    3. Dollery C. Therapeutic Drugs. (Suppl 2), Churchill Livingstone.
    1994

    4. Crawhall JC et al . BMJ (1967);2:216-8

    5. Ostensen M et Husby G. Scand J Rheumatol. (1985);14:1-7

    6. Miehle W. Z Rhematol (1988);47(suppl 1):20-3

    7. Gal P et Ravenel SD. J Clin Dysmorphol (1984);2:9-12