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DRUG LETTER

THE TECHNIQUE OF PENICILLAMINE ADMINISTRATION IN RHEUMATOID ARTHRITIS ISRAELI A. JAFFE As of the time of this writing, rheumatoid arthritis is not an approved indication for the use of penicillamine in the United States. Although the first reports of the apparent effectiveness of the drug in the treatment of RA were based upon clinical investigation performed in this country (1,2), it was only after the completion of a controlled, multicenter trial in the United Kingdom that these observations were given statistical validity (3). T h e results of a more recent trial demonstrated that penicillamine was at least as efficacious as gold salts when given to patients with less advanced disease (4). Because penicillamine is available in the United States (for the treatment of Wilson's disease and cystinuria), an increasing number of rlieumatologists are initiating limited studies of this drug in selected patients with sustained rheumatoid disease. It is the purpose of this communication to present the dosage regimen currently being employed, as well as to re-emphasize some of the potential toxicities and safety monitoring procedures that should be followed when using this agent in the treatment of patients with RA. T h e graduated dosage regimen as first introFrom the Sew York Medical College, 1249 Fifth Avetiue, Sew York, S e w York 10029. Israeli A. ,affe, M,D,: Profcsso, of Medicine. New York Medical College. Address reprint requests to I h . Jaffe. Submitted for publication February 13, 1975; accepted February 14, 1975.

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Arthritis and Rheumatism, Vol. 18, No. 5 (September-October1975)

duced greatly diminished the incidence of allergic side effects, particularly during the initiation of penicillamine therapy (5). With this regimen, the drug was started in a single daily dose of 250 mg which was increased by 250 mg/day at 2-week intervals to a maintenance level of 1.5 g/day. This regimen has now been further modified, based upon the report of Day et al (6); the newer regimen appears to offer comparable therapeutic efficacy at lower dosage with a consequent further reduction in side effects. T h e patient is first given a single daily dose of 250 mg of penicillamine for 4 weeks; this dose is then increased to 250 mg twice daily for the next 4-week period. If there are no signs of improvement, a third increment to 250 mg 3 times/day is made and is maintained for the next 8 weeks. Most patients who are penicillamine-responsivewill begin to improve during the first 16 weeks of treatment. T h e maintenance dose is defined as the least amount of penicillamine per day that has been required to initiate the clinical response. Although this dose will usually suffice for the majority oE patients, some will subsequently require a higher daily dose in order to achieve maximal disease suppression, particularly in the event of secondary failure (escape). ln sucll is increased by 250 mg/ day at 8-week intervals, because the effect of these increments in dosage " cannot lie assessed in a shorter time period. It is still necessary to perform a complete blood

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count, a platelet count, or an estimation of the adequacy of platelets on peripheral smear every 2 weeks during the first 4 months a n d whenever the niaintenance close is increased. After the dosage has been stabilized at a given level, these tests are required only at monthly intervals. If the white blood cell count falls below 3,70O/mm:’ or the platelet count decreases to the range of 80,000 to lO0,000/mm”, the drug must be cliscontinued, at least temporarily. Pruritus antl minor skin rashes can often be successfully managed by the concomitant administration of an antihistamine. T h e most effective antihistamine has been found to be cyproheptarline (Periactin). Patients who experience drug fever cannot continue with penicillamine therapy antl should not be rechallenged with the drug. A urinalysis must be performed according to the same schedule as the hematologic studies. I n those patients in whom proteinuria develops, the maintenance dose must not be raised, and quantitative protein determinations on 24-hour urine specimens should be done monthly. A progressive increase in protein excretion or the appearance of microscopic or chemical liematuria mandates the termination of penicillamine treatment. This “go slow-go low” regimen results in a reduction in the incidence of generalized cutaneous reactions, liypoguesia (taste impairment), and hematologic toxicity. I t has not yet been possible to determine whether the incidence of proteinuria will also

be decreased because nephropathy may occur relatively late in the course of treatment. Published data, however, indicate that this too may be anticipated (6). Kheumatologists who are planning to study penicillamine in patients with KA are urged to follow the newer regimen as outlined above. By this means, sufficient data will be obtained to determine whether the therapeutic ratio of the drug has indeed been favorably altered.

REFERENCES 1. Jaffe I A : Rheumatoid arthritis with arteritis. Report of a case treated with peiricillamine. A I I I IIntern Sled 61:556563, 1964 2. Jaffe 1’4: The effect of penicillamine on the laboratory parameters in rheumatoid arthritis. Arthritis Rheum 8: 1064-1079, I965 3. Multicenter trial group: Con trolled trial of D(-)penicillamirie i r r severe rheumatoid arthritis. Lancet 1 :275-280, 1973 4. Huskisson EC, Gibson TJ, Balme HW, et al: Trial comparing D-penicillamine and gold in rheumatoid arthritis. Preliminary report. Anii Kheum Dis 33:532-535, 1974 5. Jaffe I A : T h e treatment of rheumatoid arthritis and necrotizing vasculitis with penicillamine. Arthritis Rheum 13:436-443, 1970 6. Day A T , Golding JR, Lee PN, et al: Penicillamine in rheumatoid disease: a long term study. Br bred J 1:180183, 1974