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CUPRIMINE (penicillamine) is indicated in the treatment of Wilson's disease, cystinuria, and in patients with severe, active rheumatoid arthritis who have failed to respond to an adequate trial of conventional therapy. Available evidence suggests that CUPRIMINE (penicillamine) is not of value in ankylosing spondylitis.
Wilson's Disease — Wilson's disease (hepatolenticular degeneration) occurs in individuals who have inherited an autosomal recessive defect that leads to an accumulation of copper far in excess of metabolic requirements. The excess copper is deposited in several organs and tissues, and eventually produces pathological effects primarily in the liver, where damage progresses to postnecrotic cirrhosis, and in the brain, where degeneration is widespread. Copper is also deposited as characteristic, asymptomatic, golden-brown Kayser-Fleischer rings in the corneas of all patients with cerebral symptomatology and some patients who are either asymptomatic or manifest only hepatic symptomatology.
Two types of patients require treatment for Wilson's disease: (1) the symptomatic, and (2) the asymptomatic in whom it can be assumed the disease will develop in the future if the patient is not treated.
The diagnosis, if suspected on the basis of family or individual history or physical examination, can be confirmed if the plasma copper-protein ceruloplasmin** is < 20 mg/dL and either a quantitative determination in a liver biopsy specimen shows an abnormally high concentration of copper ( > 250 mcg/g dry weight) or Kayser-Fleischer rings are present.
Treatment has two objectives:
- to minimize dietary intake of copper;
- to promote excretion and complex formation (i.e., detoxification) of excess tissue copper.
The first objective is attained by a daily diet that contains no more than one or two milligrams of copper. Such a diet should exclude, most importantly, chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and cereals and dietary supplements enriched with copper, and be composed to as great an extent as possible of foods with a low copper content. Distilled or demineralized water should be used if the patient's drinking water contains more than 0.1 mg of copper per liter.
For the second objective, a copper chelating agent is used.
Clinical experience to date suggests that life is prolonged with the above regimen.
Noticeable improvement may not occur for one to three months. Occasionally, neurologic symptoms become worse during initiation of therapy with CUPRIMINE (penicillamine) . Despite this, the drug should not be withdrawn. Temporary interruption carries an increased risk of developing a sensitivity reaction upon resumption of therapy, although it may result in clinical improvement of neurological symptoms (see WARNINGS). If the neurological symptoms and signs continue to worsen for a month after the initiation of CUPRIMINE (penicillamine) therapy, several short courses of treatment with 2,3 - dimercaprol (BAL) while continuing CUPRIMINE (penicillamine) may be considered.
Treatment of asymptomatic patients has been carried out for over thirty years. Symptoms and signs of the disease appear to be prevented indefinitely if daily treatment with CUPRIMINE (penicillamine) is continued.
Cystinuria - Cystinuria is characterized by excessive urinary excretion of the dibasic amino acids, arginine, lysine, ornithine, and cystine, and the mixed disulfide of cysteine and homocysteine. The metabolic defect that leads to cystinuria is inherited as an autosomal, recessive trait. Metabolism of the affected amino acids is influenced by at least two abnormal factors: (1) defective gastrointestinal absorption and (2) renal tubular dysfunction.
Arginine, lysine, ornithine, and cysteine are soluble substances, readily excreted. There is no apparent pathology connected with their excretion in excessive quantities.
Cystine, however, is so slightly soluble at the usual range of urinary pH that it is not excreted readily, and so crystallizes and forms stones in the urinary tract. Stone formation is the only known pathology in cystinuria.
Normal daily output of cystine is 40 to 80 mg. In cystinuria, output is greatly increased and may exceed 1 g/day. At 500 to 600 mg/day, stone formation is almost certain. When it is more than 300 mg/day, treatment is indicated.
Conventional treatment is directed at keeping urinary cystine diluted enough to prevent stone formation, keeping the urine alkaline enough to dissolve as much cystine as possible, and minimizing cystine production by a diet low in methionine (the major dietary precursor of cystine). Patients must drink enough fluid to keep urine specific gravity below 1.010, take enough alkali to keep urinary pH at 7.5 to 8, and maintain a diet low in methionine. This diet is not recommended in growing children and probably is contraindicated in pregnancy because of its low protein content (see PRECAUTIONS).
When these measures are inadequate to control recurrent stone formation, CUPRIMINE (penicillamine) may be used as additional therapy, and when patients refuse to adhere to conventional treatment, CUPRIMINE (penicillamine) may be a useful substitute. It is capable of keeping cystine excretion to near normal values, thereby hindering stone formation and the serious consequences of pyelonephritis and impaired renal function that develop in some patients. Bartter and colleagues depict the process by which penicillamine interacts with cystine to form penicillamine-cysteine mixed disulfide as:
CSSC = cystine
CS' = deprotonated
cysteine PSSP = penicillamine disulfide
PS' = deprotonated penicillamine sulfhydryl
CSSP = penicillamine-cysteine mixed disulfide
In this process, it is assumed that the deprotonated form of penicillamine, PS', is the active factor in bringing about the disulfide interchange.
Rheumatoid Arthritis — Because CUPRIMINE (penicillamine) can cause severe adverse reactions, its use in rheumatoid arthritis should be restricted to patients who have severe, active disease and who have failed to respond to an adequate trial of conventional therapy. Even then, benefit-to-risk ratio should be carefully considered. Other measures, such as rest, physiotherapy, salicylates, and corticosteroids should be used, when indicated, in conjunction with CUPRIMINE (see PRECAUTIONS).
DOSAGE AND ADMINISTRATION
In all patients receiving penicillamine, it is important that CUPRIMINE (penicillamine) be given on an empty stomach, at least one hour before meals or two hours after meals, and at least one hour apart from any other drug, food, or milk. Because penicillamine increases the requirement for pyridoxine, patients may require a daily supplement of pyridoxine (see PRECAUTIONS).
Wilson's Disease — Optimal dosage can be determined by measurement of urinary copper excretion and the determination of free copper in the serum. The urine must be collected in copper-free glassware, and should be quantitatively analyzed for copper before and soon after initiation of therapy with CUPRIMINE (penicillamine) .
Determination of 24-hour urinary copper excretion is of greatest value in the first week of therapy with penicillamine. In the absence of any drug reaction, a dose between 0.75 and 1.5 g that results in an initial 24-hour cupriuresis of over 2 mg should be continued for about three months, by which time the most reliable method of monitoring maintenance treatment is the determination of free copper in the serum. This equals the difference between quantitatively determined total copper and ceruloplasmin-copper. Adequately treated patients will usually have less than 10 mcg free copper/dL of serum. It is seldom necessary to exceed a dosage of 2 g/day. If the patient is intolerant to therapy with CUPRIMINE (penicillamine) , alternative treatment is trientine hydrochloride.
In patients who cannot tolerate as much as 1 g/day initially, initiating dosage with 250 mg/day, and increasing gradually to the requisite amount, gives closer control of the effects of the drug and may help to reduce the incidence of adverse reactions.
Cystinuria — It is recommended that CUPRIMINE (penicillamine) be used along with conventional therapy. By reducing urinary cystine, it decreases crystalluria and stone formation. In some instances, it has been reported to decrease the size of, and even to dissolve, stones already formed.
The usual dosage of CUPRIMINE (penicillamine) in the treatment of cystinuria is 2 g/day for adults, with a range of 1 to 4 g/day. For pediatric patients, dosage can be based on 30 mg/kg/day. The total daily amount should be divided into four doses. If four equal doses are not feasible, give the larger portion at bedtime. If adverse reactions necessitate a reduction in dosage, it is important to retain the bedtime dose.
Initiating dosage with 250 mg/day, and increasing gradually to the requisite amount, gives closer control of the effects of the drug and may help to reduce the incidence of adverse reactions. In addition to taking CUPRIMINE (penicillamine) , patients should drink copiously. It is especially important to drink about a pint of fluid at bedtime and another pint once during the night when urine is more concentrated and more acid than during the day. The greater the fluid intake, the lower the required dosage of CUPRIMINE (penicillamine) .
Dosage must be individualized to an amount that limits cystine excretion to 100-200 mg/day in those with no history of stones, and below 100 mg/day in those who have had stone formation and/or pain. Thus, in determining dosage, the inherent tubular defect, the patient's size, age, and rate of growth, and his diet and water intake all must be taken into consideration.
The standard nitroprusside cyanide test has been reported useful as a qualitative measure of the effective dose:†Add 2 mL of freshly prepared 5 percent sodium cyanide to 5 mL of a 24-hour aliquot of protein-free urine and let stand ten minutes. Add 5 drops of freshly prepared 5 percent sodium nitroprusside and mix. Cystine will turn the mixture magenta. If the result is negative, it can be assumed that cystine excretion is less than 100 mg/g creatinine.
Although penicillamine is rarely excreted unchanged, it also will turn the mixture magenta.If there is any question as to which substance is causing the reaction, a ferric chloride test can be done to eliminate doubt: Add 3 percent ferric chloride dropwise to the urine. Penicillamine will turn the urine an immediate and quickly fading blue. Cystine will not produce any change in appearance.
Rheumatoid Arthritis — The principal rule of treatment with CUPRIMINE (penicillamine) in rheumatoid arthritis is patience. The onset of therapeutic response is typically delayed. Two or three months may be required before the first evidence of a clinical response is noted (see CLINICAL PHARMACOLOGY).
When treatment with CUPRIMINE (penicillamine) has been interrupted because of adverse reactions or other reasons, the drug should be reintroduced cautiously by starting with a lower dosage and increasing slowly.
Initial Therapy — The currently recommended dosage regimen in rheumatoid arthritis begins with a single daily dose of 125 mg or 250 mg, which is thereafter increased at one to three month intervals, by 125 mg or 250 mg/day, as patient response and tolerance indicate. If a satisfactory remission of symptoms is achieved, the dose associated with the remission should be continued (see Maintenance Therapy). If there is no improvement and there are no signs of potentially serious toxicity after two to three months of treatment with doses of 500-750 mg/day, increases of 250 mg/day at two to three month intervals may be continued until a satisfactory remission occurs (see Maintenance Therapy) or signs of toxicity develop (see WARNINGS and PRECAUTIONS). If there is no discernible improvement after three to four months of treatment with 1000 to 1500 mg of penicillamine/day, it may be assumed the patient will not respond and CUPRIMINE (penicillamine) should be discontinued.
Maintenance Therapy — The maintenance dosage of CUPRIMINE (penicillamine) must be individualized, and may require adjustment during the course of treatment. Many patients respond satisfactorily to a dosage within the 500-750 mg/day range. Some need less.
Changes in maintenance dosage levels may not be reflected clinically or in the erythrocyte sedimentation rate for two to three months after each dosage adjustment.
Some patients will subsequently require an increase in the maintenance dosage to achieve maximal disease suppression. In those patients who do respond, but who evidence incomplete suppression of their disease after the first six to nine months of treatment, the daily dosage of CUPRIMINE (penicillamine) may be increased by 125 mg or 250 mg/day at three-month intervals. It is unusual in current practice to employ a dosage in excess of 1 g/day, but up to 1.5 g/day has sometimes been required.
Management of Exacerbations — During the course of treatment some patients may experience an exacerbation of disease activity following an initial good response. These may be self-limited and can subside within twelve weeks. They are usually controlled by the addition of non-steroidal antiinflammatory drugs, and only if the patient has demonstrated a true "escape" phenomenon (as evidenced by failure of the flare to subside within this time period) should an increase in the maintenance dose ordinarily be considered.
In the rheumatoid patient, migratory polyarthralgia due to penicillamine is extremely difficult to differentiate from an exacerbation of the rheumatoid arthritis. Discontinuance or a substantial reduction in dosage of CUPRIMINE (penicillamine) for up to several weeks will usually determine which of these processes is responsible for the arthralgia.
Duration of Therapy — The optimum duration of therapy with CUPRIMINE (penicillamine) in rheumatoid arthritis has not been determined. If the patient has been in remission for six months or more, a gradual, stepwise dosage reduction in decrements of 125 mg or 250 mg/day at approximately three month intervals may be attempted.
Concomitant Drug Therapy — CUPRIMINE (penicillamine) should not be used in patients who are receiving gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone, or phenylbutazone (see PRECAUTIONS). Other measures, such as salicylates, other non-steroidal anti-inflammatory drugs, or systemic corticosteroids, may be continued when penicillamine is initiated. After improvement commences, analgesic and anti-inflammatory drugs may be slowly discontinued as symptoms permit. Steroid withdrawal must be done gradually, and many months of treatment with CUPRIMINE (penicillamine) may be required before steroids can be completely eliminated.
Dosage Frequency — Based on clinical experience, dosages up to 500 mg/day can be given as a single daily dose. Dosages in excess of 500 mg/day should be administered in divided doses.
Capsules CUPRIMINE (penicillamine) , 250 mg, are ivory-colored capsules containing a white or nearly white powder, and are coded CUPRIMINE (penicillamine) and MSD 602. They are supplied as follows: NDC 25010-705-15 in bottles of 100.
Keep container tightly closed.
** For quantitative test for serum ceruloplasmin see: Morell, A.G.; Windsor, J.; Sternlieb, I. ; Scheinberg, I.H.: Measurement of the concentration of ceruloplasmin in serum by determination of its oxidase activity, in “Laboratory Diagnosis of Liver Disease”, F.W. Sunderman; F.W. Sunderman, Jr. (eds.), St. Louis, Warren H. Green, Inc., 1968, pp. 193-195.
†Lotz, M.; Potts, J.T. and Bartter, F.C.: Brit. Med. J. 2: 521, Aug. 28, 1965 (in Medical Memoranda).
Distributed by: Aton Pharma, Lawrenceville NJ 08648, USA. Manufactured by: Merck and Co., Inc. West Point, PA 19486, USA. Issued May 2007. FDA revision date: 10/26/2004
Last reviewed on RxList: 12/17/2008
This monograph has been modified to include the generic and brand name in many instances.
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