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«78732XX CAPSULES CUPRIMINE® (PENICILLAMINE) Physicians planning to use penicillamine should thoroughly familiarize themselves with its toxicity, ...»

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78732XX

CAPSULES

CUPRIMINE®

(PENICILLAMINE)

Physicians planning to use penicillamine should thoroughly familiarize themselves with its toxicity, special

dosage considerations, and therapeutic benefits. Penicillamine should never be used casually. Each patient

should remain constantly under the close supervision of the physician. Patients should be warned to report

promptly any symptoms suggesting toxicity.

DESCRIPTION

Penicillamine is a chelating agent used in the treatment of Wilson's disease. It is also used to reduce cystine excretion in cystinuria and to treat patients with severe, active rheumatoid arthritis unresponsive to conventional therapy (see INDICATIONS). It is 3-mercapto-D-valine. It is a white or practically white, crystalline powder, freely soluble in water, slightly soluble in alcohol, and insoluble in ether, acetone, benzene, and carbon

tetrachloride. Although its configuration is D, it is levorotatory as usually measured:

25° [α] = -62.5° ± 2° (c = 1, 1N NaOH), D calculated on a dried basis.

The empirical formula is C5H11NO2S, giving it a molecular weight of 149.21. The structural formula is:

It reacts readily with formaldehyde or acetone to form a thiazolidine-carboxylic acid.

Capsules CUPRIMINE* (Penicillamine) for oral administration contain either 125 mg or 250 mg of penicillamine. Each capsule contains the following inactive ingredients: D & C Yellow 10, gelatin, lactose, magnesium stearate, and titanium dioxide. The 125 mg capsule also contains iron oxide.

CLINICAL PHARMACOLOGY

Penicillamine is a chelating agent recommended for the removal of excess copper in patients with Wilson's disease. From in vitro studies which indicate that one atom of copper combines with two molecules of penicillamine, it would appear that one gram of penicillamine should be followed by the excretion of about 200 milligrams of copper; however, the actual amount excreted is about one percent of this.

Penicillamine also reduces excess cystine excretion in cystinuria. This is done, at least in part, by disulfide interchange between penicillamine and cystine, resulting in formation of penicillamine-cysteine disulfide, a substance that is much more soluble than cystine and is excreted readily.

Penicillamine interferes with the formation of cross-links between tropocollagen molecules and cleaves them when newly formed.

The mechanism of action of penicillamine in rheumatoid arthritis is unknown although it appears to suppress disease activity. Unlike cytotoxic immunosuppressants, penicillamine markedly lowers IgM rheumatoid factor but produces no significant depression in absolute levels of serum immunoglobulins. Also unlike cytotoxic immunosuppressants which act on both, penicillamine in vitro depresses T-cell activity but not B-cell activity.

In vitro, penicillamine dissociates macroglobulins (rheumatoid factor) although the relationship of the activity to its effect in rheumatoid arthritis is not known.

–  –  –

In rheumatoid arthritis, the onset of therapeutic response to CUPRIMINE may not be seen for two or three months. In those patients who respond, however, the first evidence of suppression of symptoms such as pain, tenderness, and swelling is generally apparent within three months. The optimum duration of therapy has not been determined. If remissions occur, they may last from months to years, but usually require continued treatment (see DOSAGE AND ADMINISTRATION).

In all patients receiving penicillamine, it is important that CUPRIMINE 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, milk, antacid, zinc or iron-containing preparation. This permits maximum absorption and reduces the likelihood of inactivation by metal binding in the gastrointestinal tract.

Pharmacokinetics Penicillamine is absorbed rapidly but incompletely (40-70%) from the gastrointestinal tract, with wide interindividual variations. Food, antacids, and iron reduce absorption of the drug. The peak plasma concentration of penicillamine occurs 1-3 hours after ingestion; it is approximately 1-2 mg/L after an oral dose of 250 mg. The drug appears in the plasma as free penicillamine, penicillamine disulfide, and cysteine-penicillamine disulfide.

When prolonged treatment is stopped, there is a slow elimination phase lasting 4-6 days.

More than 80% of plasma penicillamine is bound to proteins, especially albumin and ceruloplasmin. The drug also binds to erythrocytes and macrophages. A small fraction of the dose is metabolized in the liver to S-methylD-penicillamine. Excretion is mainly renal, mainly as disulfides.

INDICATIONS

CUPRIMINE 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 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 KayserFleischer rings are present.

Treatment has two objectives:

(1) to minimize dietary intake of copper;

(2) 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.

In symptomatic patients this treatment usually produces marked neurologic improvement, fading of KayserFleischer rings, and gradual amelioration of hepatic dysfunction and psychic disturbances.

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. Despite this, the drug should not be withdrawn. Temporary ** 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.

CUPRIMINE® (Penicillamine) 78732XX XXXXXXX 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 therapy, several short courses of treatment with 2,3 - dimercaprol (BAL) while continuing CUPRIMINE 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 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 may be used as additional therapy, and when patients refuse to adhere to conventional treatment, CUPRIMINE 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 penicillaminecysteine mixed disulfide as:

–  –  –

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 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).

CUPRIMINE® (Penicillamine) 78732XX XXXXXXX

CONTRAINDICATIONS

Except for the treatment of Wilson's disease or certain patients with cystinuria, use of penicillamine during pregnancy is contraindicated (see WARNINGS).

Although breast milk studies have not been reported in animals or humans, mothers on therapy with penicillamine should not nurse their infants.

Patients with a history of penicillamine-related aplastic anemia or agranulocytosis should not be restarted on penicillamine (see WARNINGS and ADVERSE REACTIONS).

Because of its potential for causing renal damage, penicillamine should not be administered to rheumatoid arthritis patients with a history or other evidence of renal insufficiency.

WARNINGS The use of penicillamine has been associated with fatalities due to certain diseases such as aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture's syndrome, and myasthenia gravis.

Because of the potential for serious hematological and renal adverse reactions to occur at any time, routine urinalysis, white and differential blood cell count, hemoglobin determination, and direct platelet count must be done twice weekly, together with monitoring of the patient's skin, lymph nodes and body temperature, during the first month of therapy, every two weeks for the next five months, and monthly thereafter. Patients should be instructed to report promptly the development of signs and symptoms of granulocytopenia and/or thrombocytopenia such as fever, sore throat, chills, bruising or bleeding. The above laboratory studies should then be promptly repeated.

Leukopenia and thrombocytopenia have been reported to occur in up to five percent of patients during penicillamine therapy. Leukopenia is of the granulocytic series and may or may not be associated with an increase in eosinophils. A confirmed reduction in WBC below 3500/mm3 mandates discontinuance of penicillamine therapy. Thrombocytopenia may be on an idiosyncratic basis, with decreased or absent megakaryocytes in the marrow, when it is part of an aplastic anemia. In other cases the thrombocytopenia is presumably on an immune basis since the number of megakaryocytes in the marrow has been reported to be normal or sometimes increased. The development of a platelet count below 100,000/mm3, even in the absence of clinical bleeding, requires at least temporary cessation of penicillamine therapy. A progressive fall in either platelet count or WBC in three successive determinations, even though values are still within the normal range, likewise requires at least temporary cessation.



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