PENICILLAMINE capsule

United States - English - NLM (National Library of Medicine)

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Active ingredient:
Penicillamine (UNII: GNN1DV99GX) (Penicillamine - UNII:GNN1DV99GX)
Available from:
Oceanside Pharmaceuticals
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Penicillamine Capsules are 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 Penicillamine Capsules are not of value in ankylosing spondylitis. 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 t
Product summary:
Penicillamine Capsules, USP 250 mg, are ivory-colored capsules containing a white or nearly white powder, and are coded CUPRIMINE and ATON 705. They are supplied as follows: NDC 68682-020-10 in bottles of 100 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tightly closed container. 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. *** Scheinberg, I.H.; Sternlieb, I.: N. Engl. J. Med. 293: 1300-1302, Dec. 18, 1975. † Lotz, M.; Potts, J.T. and Bartter, F.C.: Brit. Med. J. 2: 521, Aug. 28, 1965 (in Medical Memoranda).
Authorization status:
New Drug Application Authorized Generic
Authorization number:
68682-020-10

PENICILLAMINE- penicillamine capsule

Oceanside Pharmaceuticals

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PENICILLAMINE

Capsules, USP

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, USP 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:

calculated on a dried basis.

The empirical formula is C H NO S, giving it a molecular weight of 149.21. The structural formula

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

Capsules for oral administration contain 250 mg of penicillamine. Each capsule contains the following

inactive ingredients: D&C Yellow No. 10, gelatin, lactose monohydrate, magnesium stearate, and

titanium dioxide.

CLINICAL PHARMACOLOGY

Penicillamine, USP 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 1 g of penicillamine should be followed by the

excretion of about 200 mg of copper; however, the actual amount excreted is about 1% 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 Penicillamine Capsules may not be seen for

2 or 3 months. In those patients who respond, however, the first evidence of suppression of symptoms

such as pain, tenderness, and swelling is generally apparent within 3 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 Penicillamine Capsules be given on an empty

stomach, at least 1 hour before meals or 2 hours after meals, and at least 1 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

inter-individual variations. Food, antacids, and iron reduce absorption of the drug. The peak plasma

concentration of penicillamine occurs 1 to 3 hours after ingestion; it is approximately 1 to 2 mg/L after

an oral dose of 250 mg. The drug appears in the plasma as free penicillamine, penicillamine disulfide,

and penicillamine-cysteine disulfide. When prolonged treatment is stopped, there is a slow elimination

phase lasting 4 to 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-methyl-D-penicillamine. Excretion is mainly renal, mainly as disulfides.

INDICATIONS

Penicillamine Capsules are 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 Penicillamine Capsules are 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 less than 20 mg/dL and either a quantitative

determination in a liver biopsy specimen shows an abnormally high concentration of copper (greater

than 250 mcg/g dry weight) or Kayser-Fleischer rings are present.

Treatment has two objectives:

The first objective is attained by a daily diet that contains no more than 1 or 2 mg 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/L of copper.

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 1 to 3 months. Occasionally, neurologic symptoms become

worse during initiation of therapy with Penicillamine Capsules. 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 Penicillamine Capsules therapy, several short courses of treatment with 2,3 - dimercaprol (BAL)

while continuing Penicillamine Capsules may be considered.

Treatment of asymptomatic patients has been carried out for over 30 years. Symptoms and signs of the

disease appear to be prevented indefinitely if daily treatment with Penicillamine Capsules is continued.

Cys tinuria

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

to minimize dietary intake of copper;

to promote excretion and complex formation (i.e., detoxification) of excess tissue copper.

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, Penicillamine Capsules may

be used as additional therapy, and when patients refuse to adhere to conventional treatment,

Penicillamine Capsules 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 + PS’

CS’ + CSSP

PSSP + CS’

PS’ + CSSP

CSSC + PSSP’

2CSSP

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 Penicillamine Capsules can cause severe adverse reactions, their 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 Penicillamine Capsules (see PRECAUTIONS).

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 5 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 5% 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 White Blood Cells (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 count 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 1 to 2 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 6 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 6 months for the duration of therapy. In Wilson’s disease, these are recommended

every 3 months, at least during the first year of treatment.

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.

Onset of new neurological symptoms has been reported with Penicillamine Capsules (see ADVERSE

REACTIONS). Occasionally, neurological symptoms become worse during initiation of therapy with

Penicillamine Capsules (see INDICATIONS). 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, Penicillamine Capsules 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.

Pregnancy

Penicillamine can cause fetal harm when administered to a pregnant woman. Penicillamine has been

shown to be teratogenic in rats when given in doses six times higher than the highest dose

recommended for human use. 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. If this drug

is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be

apprised of the potential hazard to the fetus.

Wilson’s Disease

Reported experience*** shows that continued treatment with penicillamine throughout pregnancy

protects the mother against relapse of Wilson’s disease, and that discontinuation of penicillamine has

deleterious effects on the mother, which may be fatal.

If penicillamine is administered during pregnancy to patients with Wilson’s disease, it is recommended

that the daily dosage be limited to 750 mg. If cesarean section is planned, the daily dose should be

reduced to 250 mg, but not lower, for the last 6 weeks of pregnancy and postoperatively until wound

healing is complete.

Cys tinuria

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 1

g/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.

PRECAUTIONS

Some patients may experience drug fever, a marked febrile response to penicillamine, usually in the

second to third week following initiation of therapy. Drug fever may sometimes be accompanied by a

macular cutaneous eruption. In the case of drug fever in patients with Wilson’s disease or cystinuria,

penicillamine should be temporarily discontinued until the reaction subsides. Then penicillamine should

be reinstituted with a small dose that is gradually increased until the desired dosage is attained.

Systemic steroid therapy may be necessary, and is usually helpful, in such patients in whom drug fever

and rash develop several times.

In the case of drug fever in rheumatoid arthritis patients, because other treatments are available,

penicillamine should be discontinued and another therapeutic alternative tried since experience indicates

that the febrile reaction will recur in a very high percentage of patients upon readministration of

penicillamine.

The skin and mucous membranes should be observed for allergic reactions. Early and late rashes have

occurred. Early rash occurs during the first few months of treatment and is more common. It is usually a

generalized pruritic, erythematous, maculopapular, or morbilliform rash and resembles the allergic rash

seen with other drugs. Early rash usually disappears within days after stopping penicillamine and

seldom recurs when the drug is restarted at a lower dosage. Pruritus and early rash may often be

controlled by the concomitant administration of antihistamines.

Less commonly, a late rash may be seen, usually after 6 months or more of treatment, which requires

discontinuation of penicillamine. It is usually on the trunk, is accompanied by intense pruritus, and is

usually unresponsive to topical corticosteroid therapy. Late rash may take weeks to disappear after

penicillamine is stopped and usually recurs if the drug is restarted.

The appearance of a drug eruption accompanied by fever, arthralgia, lymphadenopathy, or other

allergic manifestations usually requires discontinuation of penicillamine.

Certain patients will develop a positive antinuclear antibody (ANA) test and some of these may show a

lupus erythematosus-like syndrome similar to drug-induced lupus associated with other drugs. The

lupus erythematosus-like syndrome is not associated with hypocomplementemia and may be present

without nephropathy. The development of a positive ANA test does not mandate discontinuance of the

drug; however, the physician should be alerted to the possibility that a lupus erythematosus-like

syndrome may develop in the future.

Some patients may develop oral ulcerations which in some cases have the appearance of aphthous

stomatitis. The stomatitis usually recurs on rechallenge but often clears on a lower dosage. Although

rare, cheilosis, glossitis, and gingivostomatitis have also been reported. These oral lesions are

frequently dose-related and may preclude further increase in penicillamine dosage or require

discontinuation of the drug.

Hypogeusia (a blunting or diminution in taste perception) has occurred in some patients. This may last 2

to 3 months or more and may develop into a total loss of taste; however, it is usually self-limited despite

continued penicillamine treatment. Such taste impairment is rare in patients with Wilson’s disease.

Penicillamine should not be used in patients who are receiving concurrently gold therapy, antimalarial

or cytotoxic drugs, oxyphenbutazone or phenylbutazone because these drugs are also associated with

similar serious hematologic and renal adverse reactions.

Patients who have had gold salt therapy discontinued due to a major toxic reaction may be at greater risk

of serious adverse reactions with penicillamine but not necessarily of the same type.

Patients who are allergic to penicillin may theoretically have cross-sensitivity to penicillamine. The

possibility of reactions from contamination of penicillamine by trace amounts of penicillin has been

eliminated now that penicillamine is being produced synthetically rather than as a degradation product of

penicillin.

Patients with Wilson’s disease or cystinuria should be given 25 mg/day of pyridoxine during therapy,

since penicillamine increases the requirement for this vitamin. Patients also may receive benefit from a

multivitamin preparation, although there is no evidence that deficiency of any vitamin other than

pyridoxine is associated with penicillamine. In Wilson’s disease, multivitamin preparations must be

copper-free.

Rheumatoid arthritis patients whose nutrition is impaired should also be given a daily supplement of

pyridoxine. Mineral supplements should not be given, since they may block the response to

penicillamine. Iron deficiency may develop, especially in pediatric patients and in menstruating women.

In Wilson’s disease, this may be a result of adding the effects of the low copper diet, which is probably

also low in iron, and the penicillamine to the effects of blood loss or growth. In cystinuria, a low

methionine diet may contribute to iron deficiency, since it is necessarily low in protein. If necessary,

iron may be given in short courses, but a period of 2 hours should elapse between administration of

penicillamine and iron, since orally administered iron has been shown to reduce the effects of

penicillamine.

Penicillamine causes an increase in the amount of soluble collagen. In the rat, this results in inhibition of

normal healing and also a decrease in tensile strength of intact skin. In man, this may be the cause of

increased skin friability at sites especially subject to pressure or trauma, such as shoulders, elbows,

knees, toes, and buttocks. Extravasations of blood may occur and may appear as purpuric areas, with

external bleeding if the skin is broken, or as vesicles containing dark blood. Neither type is

progressive. There is no apparent association with bleeding elsewhere in the body and no associated

coagulation defect has been found. Therapy with penicillamine may be continued in the presence of

these lesions. They may not recur if dosage is reduced. Other reported effects probably due to the

action of penicillamine on collagen are excessive wrinkling of the skin and development of small, white

papules at venipuncture and surgical sites.

The effects of penicillamine on collagen and elastin make it advisable to consider a reduction in dosage

to 250 mg/day, when surgery is contemplated. Reinstitution of full therapy should be delayed until

wound healing is complete.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal carcinogenicity studies have not been done with penicillamine. There is a report that

five of ten autoimmune disease-prone New Zealand black (NZB) hybrid mice developed lymphocytic

leukemia after 6 months’ intraperitoneal treatment with a dose of 400 mg/kg penicillamine 5 days per

week.

Penicillamine is directly mutagenic to S. typhimurium strain TA92 in the Ames test; mutagenicity is

enhanced by kidney postmitochondrial subcellular fraction 9. Penicillamine does not induce gene

mutations in Chinese hamster V79 cells.

Penicillamine induces sister-chromatid exchanges and chromosome aberrations in cultivated mammalian

cells. No studies on the effect of penicillamine on fertility are available.

Pregnancy

(see WARNINGS, Pregnancy)

Nursing Mothers

See CONTRAINDICATIONS.

Pediatric Use

The efficacy of Penicillamine Capsules in juvenile rheumatoid arthritis have not been established.

Geriatric Use

Clinical studies of Penicillamine Capsules are limited in subjects aged 65 and over; they did not include

sufficient numbers of elderly subjects aged 65 and over to adequately determine whether they respond

differently from younger subjects. Review of reported clinical trials with penicillamine in the elderly

suggest greater risk than in younger patients for overall skin rash and abnormality of taste. In general,

dose selection for an elderly patient should be cautious, starting at the low end of the dosing range,

reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant

disease or other drugs.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug

may be greater in patients with impaired renal function. Because elderly patients are more likely to have

decreased renal function, care should be taken in dose selection and careful monitoring of renal function

is recommended.

ADVERSE REACTIONS

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).

Gas trointes tinal

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

Isolated cases of reactivated peptic ulcer have occurred, as have hepatic dysfunction including hepatic

failure 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 gingivostomatitis 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%) also 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). Renal failure has been reported.

Central Nervous System

Tinnitus, optic neuritis, and peripheral sensory and motor neuropathies (including

polyradiculoneuropathy, i.e., Guillain-Barré syndrome) have been reported. Muscular weakness may or

may not occur with the peripheral neuropathies. Visual and psychic disturbances; mental disorders; and

agitation and anxiety have been reported.

Neuromus cular

Myasthenia gravis (see WARNINGS); dystonia.

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). Vasculitis, including 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); yellow nail syndrome.

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.

To report SUSPECTED ADVERSE REACTIONS, contact Oceanside Pharmaceuticals at 1-800-

321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DOSAGE AND ADMINISTRATION

In all patients receiving penicillamine, it is important that Penicillamine Capsules 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 Penicillamine

Capsules.

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