United States - English - NLM (National Library of Medicine)
PENICILLAMINE- penicillamine capsule
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.
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
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.
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.
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
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
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.
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
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.
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’
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.
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).
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.
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
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
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
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.
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
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.
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.
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.
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.
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
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
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
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 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
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.
(see WARNINGS, Pregnancy)
The efficacy of Penicillamine Capsules in juvenile rheumatoid arthritis have not been established.
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
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).
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
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
Gastrointestinal side effects are usually reversible following cessation of therapy.
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.
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.
Myasthenia gravis (see WARNINGS); dystonia.
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).
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