Depen (Penicillamine)


Indications

INDICATIONS – DEPEN 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 DEPEN is not of value in ankylosing spondylitis.

Wilson’s Disease – Wilson’s disease (hepatolenticular degeneration) results from the interaction of an inherited defect and an abnormality in copper metabolism. The metabolic defect, which is the consequence of the autosomal inheritance of one abnormal gene from each parent, manifests itself in a greater positive copper balance than normal. As a result, copper is deposited in several organs and appears eventually to produce pathologic effects most prominently seen in the brain, where degeneration is widespread; in the liver, where fatty infiltration, inflammation, and hepatocellular damage progress to postnecrotic cirrhosis; in the kidney, where tubular and glomerular dysfunction results; and in the eye, where characteristic corneal copper deposits are known as Kayser-Fleischer rings.

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.

Diagnosis, suspected on the basis of family or individual history, physical examination, or a low serum concentration of ceruloplasmin*, is confirmed by the demonstration of Kayser-Fleischer rings or, particularly in the asymptomatic patient, by the quantitative demonstration in a liver biopsy specimen of a concentration of copper in excess of 250 mcg/g dry weight.

Treatment has two objectives:

(1) to minimize dietary intake and absorption of copper.

(2) to promote excretion of copper deposited in tissues.

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 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 Kayser-Fleischer 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 DEPEN. Despite this, the drug should not be discontinued permanently. Although temporary interruption may result in clinical improvement of the neurological symptoms, it carries an increased risk of developing a sensitivity reaction upon resumption of therapy (See WARNINGS).

* 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.

Treatment of asymptomatic patients has been carried out for over ten years. Symptoms and signs of the disease appear to be prevented indefinitely if daily treatment with DEPEN can be 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, DEPEN may be used as additional therapy. When patients refuse to adhere to conventional treatment, DEPEN 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:

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 DEPEN 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 DEPEN (see PRECAUTIONS).

general medication guide

CONTRAINDICATIONS – Except for treatment of Wilson’s disease or certain cases of 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.

general medication guide

ADVERSE REACTIONS – To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Penicillamine is a drug with a high incidence of untoward reactions, some of which are potentially fatal. Therefore, it is mandatory that patients receiving penicillamine therapy remain under close medical supervision throughout the period of drug administration (see WARNINGS and PRECAUTIONS).

Reported incidences (%) for the most commonly occurring adverse reactions in rheumatoid arthritis patients are noted, based on 17 representative clinical trials reported in the literature (1270 patients).

Allergic – Generalized pruritus, early and late rashes (5%), pemphigus (see WARNINGS), and drug eruptions which may be accompanied by fever, arthralgia, or lymphadenopathy have occurred (see WARNINGS and PRECAUTIONS). Some patients may show a lupus erythematosus-like syndrome similar to drug-induced lupus produced by other pharmacological agents (see PRECAUTIONS).

Urticaria and exfoliative dermatitis have occurred.

Thyroiditis has been reported; hypoglycemia in association with anti-insulin antibodies has been reported. These reactions are extremely rare.

Some patients may develop a migratory polyarthralgia, often with objective synovitis (see DOSAGE AND ADMINISTRATION).

Gastrointestinal – Anorexia, epigastric pain, nausea, vomiting, or occasional diarrhea may occur (17%).

Isolated cases of reactivated peptic ulcer have occurred, as have hepatic dysfunction and pancreatitis. Intrahepatic cholestasis and toxic hepatitis have been reported rarely. There have been a few reports of increased serum alkaline phosphatase, lactic dehydrogenase, and positive cephalin flocculation and thymol turbidity tests.

Some patients may report a blunting, diminution, or total loss of taste perception (12%); or may develop oral ulcerations. Although rare, cheilosis, glossitis, and gingivo-stomatitis have been reported (see PRECAUTIONS).

Gastrointestinal side effects are usually reversible following cessation of therapy.

Hematological – Penicillamine can cause bone marrow depression (see WARNINGS). Leukopenia (2%) and thrombocytopenia (4%) have occurred. Fatalities have been reported as a result of thrombocytopenia, agranulocytosis, aplastic anemia, and sideroblastic anemia.

Thrombotic thrombocytopenic purpura, hemolytic anemia, red cell aplasia, monocytosis, leukocytosis, eosinophilia, and thrombocytosis have also been reported.

Renal – Patients on penicillamine therapy may develop proteinuria (6%) and/or hematuria which, in some, may progress to the development of the nephrotic syndrome as a result of an immune complex membranous glomerulopathy (see WARNINGS).

Central Nervous System – Tinnitus, optic neuritis, and peripheral sensory and motor neuropathies (including polyradiculoneuropathy, i.e., Guillain-Barre Syndrome) have been reported. Muscular weakness may or may not occur with the peripheral neuropathies.

Neuromuscular – Myasthenia gravis (see WARNINGS).

Other – Adverse reactions that have been reported rarely include thrombophlebitis; hyperpyrexia (see PRECAUTIONS); falling hair or alopecia; lichen planus; polymyositis; dermatomyositis; mammary hyperplasia; elastosis perforans serpiginosa; toxic epidermal necrolysis; anetoderma (cutaneous macular atrophy); and Goodpasture’s syndrome, a severe and ultimately fatal glomerulonephritis associated with intra-alveolar hemorrhage (see WARNINGS). Fatal renal vasculitis has also been reported. Allergic alveolitis, obliterative bronchiolitis, interstitial pneumonitis, and pulmonary fibrosis have been reported in patients with severe rheumatoid arthritis, some of whom were receiving penicillamine. Bronchial asthma also has been reported.

Increased skin friability, excessive wrinkling of skin, and development of small, white papules at venipuncture and surgical sites have been reported (see PRECAUTIONS).

The chelating action of the drug may cause increased excretion of other heavy metals such as zinc, mercury, and lead.

There have been reports associating penicillamine with leukemia. However, circumstances involved in these reports are such that a cause and effect relationship to the drug has not been established.

general medication guide

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 every two weeks for at least the first six months of penicillamine therapy 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 per cubic mL 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 per cubic mL, 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.

Proteinuria and/or hematuria may develop during therapy and may be warning signs of membranous glomerulopathy which can progress to a nephrotic syndrome. Close observation of these patients is essential. In some patients the proteinuria disappears with continued therapy; in others penicillamine must be discontinued. When a patient develops proteinuria or hematuria the physician must ascertain whether it is a sign of drug-induced glomerulopathy or is unrelated to penicillamine.

Rheumatoid arthritis patients who develop moderate degrees of proteinuria may be continued cautiously on penicillamine therapy, provided that quantitative 24-hour urinary protein determinations are obtained at intervals of one to two weeks. Penicillamine dosage should not be increased under these circumstances. Proteinuria which exceeds 1 g/24 hours, or proteinuria which is progressively increasing requires either discontinuance of the drug or a reduction in the dosage. In some patients, proteinuria has been reported to clear following reduction in dosage.

In rheumatoid arthritis patients, penicillamine should be discontinued if unexplained gross hematuria or persistent microscopic hematuria develops.

In patients with Wilson’s disease or cystinuria the risks of continued penicillamine therapy in patients manifesting potentially serious urinary abnormalities must be weighed against the expected therapeutic benefits.

When penicillamine is used in cystinuria, an annual x-ray for renal stones is advised. Cystine stones form rapidly, sometimes in six months.

Up to one year or more may be required for any urinary abnormalities to disappear after penicillamine has been discontinued.

Because of rare reports of intrahepatic cholestasis and toxic hepatitis, liver function tests are recommended every six months for the duration of therapy.

Goodpasture’s syndrome has occurred rarely. The development of abnormal urinary findings associated with hemoptysis and pulmonary infiltrates on x-ray requires immediate cessation of penicillamine.

Obliterative bronchiolitis has been reported rarely. The patient should be cautioned to report immediately pulmonary symptoms such as exertional dyspnea, unexplained cough, or wheezing. Pulmonary function studies should be considered at that time.

Myasthenic syndrome sometimes progressing to myasthenia gravis has been reported. Ptosis and diplopia, with weakness of the extraocular muscles, are often early signs of myasthenia. In the majority of cases, symptoms of myasthenia have receded after withdrawal of penicillamine.

Most of the various forms of pemphigus have occurred during treatment with penicillamine. Pemphigus vulgaris and pemphigus foliaceus are reported most frequently, usually as a late complication of therapy. The seborrhea-like characteristics of pemphigus foliaceus may obscure an early diagnosis. When pemphigus is suspected, DEPEN should be discontinued. Treatment has consisted of high doses of corticosteroids alone or, in some cases, concomitantly with an immunosuppressant. Treatment may be required for only a few weeks or months, but may need to be continued for more than a year.

Once instituted for Wilson’s disease or cystinuria, treatment with penicillamine should, as a rule, be continued on a daily basis. Interruptions for even a few days have been followed by sensitivity reactions after reinstitution of therapy.

Use In Pregnancy – Penicillamine has been shown to be teratogenic in rats when given in doses 6 times higher than the highest dose recommended for human use (based on a standard weight of 50 kg). Skeletal defects, cleft palates, and fetal toxicity (resorptions) have been reported.

There are no controlled studies on the use of penicillamine in pregnant women. Although normal outcomes have been reported, characteristic congenital cutis laxa and associated birth defects have been reported in infants born of mothers who received therapy with penicillamine during pregnancy. Penicillamine should be used in women of childbearing potential only when the expected benefits outweigh the possible hazards. Women on therapy with penicillamine who are of childbearing potential should be apprised of this risk, advised to report promptly any missed menstrual periods or other indications of possible pregnancy, and followed closely for early recognition of pregnancy.

Wilson’s Disease – Reported experience* shows that continued treatment with penicillamine throughout pregnancy protects the mother against relapse of the Wilson’s disease, and that discontinuation of penicillamine has deleterious effects on the mother.

If penicillamine is administered during pregnancy to patients with Wilson’s disease, it is recommended that the daily dosage be limited to 1 g. If cesarean section is planned, the daily dosage should be limited to 250 mg during the last six weeks of pregnancy and post-operatively until wound healing is complete.

Cystinuria – If possible, penicillamine should not be given during pregnancy to women with cystinuria (see CONTRAINDICATIONS). There are reports of women with cystinuria on therapy with penicillamine who gave birth to infants with generalized connective tissue defects who died following abdominal surgery. If stones continue to form in these patients, the benefits of therapy to the mother must be evaluated against the risk to the fetus.

Rheumatoid Arthritis – Penicillamine should not be administered to rheumatoid arthritis patients who are pregnant (see CONTRAINDICATIONS) and should be discontinued promptly in patients in whom pregnancy is suspected or diagnosed.

There is a report that a woman with rheumatoid arthritis treated with less than one gram a day of penicillamine during pregnancy gave birth (cesarean delivery) to an infant with growth retardation, flattened face with broad nasal bridge, low set ears, short neck with loose skin folds, and unusually lax body skin.

general medication guide

DESCRIPTION – Penicillamine is 3-mercapto-D-valine, a disease modifying antirheumatic drug. 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:

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.

Depen® (penicillamine tablets, USP) Titratable Tablets for oral administration contain 250 mg of penicillamine.

Other ingredients (inactive): edetate disodium, hypromellose, lactose, magnesium stearate, magnesium trisilicate, polyethylene glycol, povidone, simethicone emulsion, starch, and stearic acid.

Depen Package Photos

About the Author

Truman Lewis
Truman has been a bureau chief and correspondent in D.C., Los Angeles, Phoenix and elsewhere, reporting for radio, television, print and news services, for more than 30 years. Most recently, he has reported extensively on health and consumer issues for ConsumerAffairs.com and FairfaxNews.com.