Overdose
No information provided.
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.
Undesirable effects
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 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%) 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.
Neuromuscular
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.
Therapeutic 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 Kayser-Fleischer rings are present.
Treatment has two objectives:
- to minimize dietary intake of copper;
- to promote excretion and complex formation (i.e.,
detoxification) of excess tissue copper.
The first objective is attained by a daily diet that
contains no more than one or two milligrams of copper. Such a diet should
exclude, most importantly, chocolate, nuts, shellfish, mushrooms, liver,
molasses, broccoli, and cereals and dietary supplements enriched with copper, and
be composed to as great an extent as possible of foods with a low copper
content. Distilled or demineralized water should be used if the patient's
drinking water contains more than 0.1 mg of copper per liter.
For the second objective, a copper chelating agent is
used.
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 CUPRIMINE. Despite this, the drug should not be withdrawn.
Temporary interruption carries an increased risk of developing a sensitivity
reaction upon resumption of therapy, although it may result in clinical
improvement of neurological symptoms (see WARNINGS). If the neurological
symptoms and signs continue to worsen for a month after the initiation of
CUPRIMINE 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 penicillamine-cysteine mixed disulfide
as:
CSSC = cystine
CS' = deprotonated cysteine
PSSP = penicillamine disulfide
PS' = deprotonated penicillamine sulfhydryl
CSSP = penicillamine-cysteine mixed disulfide
In this process, it is assumed that the deprotonated form
of penicillamine, PS', is the active factor in bringing about the disulfide
interchange.
Rheumatoid Arthritis
Because CUPRIMINE 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).
Date of revision of the text
March 2010
Name of the medicinal product
Cuprimine
Fertility, pregnancy and lactation
Pregnancy Category D
(see WARNINGS, Pregnancy)
Qualitative and quantitative composition
Capsules CUPRIMINE, 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 25010-705-15 in bottles of 100.
Storage
Keep container tightly closed.
REFERENCES
** For quantitative test for serum ceruloplasmin see: Morell, A.G.; Windsor, J.; Sternlieb, I. ; Scheinberg, I.H.: Measurement of the concentration of ceruloplasmin in serum by determination of its oxidase activity, in “Laboratory Diagnosis of Liver Disease”, F.W. Sunderman; F.W. Sunderman, Jr. (eds.), St. Louis, Warren H. Green, Inc., 1968, pp. 193-195.
† Lotz, M.; Potts, J.T. and Bartter, F.C.: Brit. Med. J.
2: 521, Aug. 28, 1965 (in Medical Memoranda).
Distributed by: Aton Pharma, Lawrenceville, NJ 08648, USA. Manufactured
by: Pharmaceutics International, Inc., 10819 Gilroy Road, Hunt Valley, MD 21031
USA. Revised: March 2010
Special warnings and precautions for use
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.
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. In Wilson's disease, these are recommended every three
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
CUPRIMINE (see ADVERSE REACTIONS). Occasionally, neurological symptoms
become worse during initiation of therapy with CUPRIMINE (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, CUPRIMINE 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 Category D
Penicillamine can cause fetal harm when administered to a
pregnant woman. Penicillamine has been shown to be teratogenic in rats when
given in doses 6 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
the 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 six weeks of pregnancy and postoperatively
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.
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 six months or more of treatment, and 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 two to three 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 two 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 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
Pregnancy Category D
(see WARNINGS, Pregnancy)
Nursing Mothers
See CONTRAINDICATIONS.
Pediatric Use
The efficacy of CUPRIMINE in juvenile rheumatoid
arthritis has not been established.
Geriatric Use
Clinical studies of CUPRIMINE 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.
REFERENCES
*** Scheinberg, I.H.; Sternlieb, I.: N. Engl. J. Med.
293: 1300-1302, Dec. 18, 1975. 8838-00
Dosage (Posology) and method of 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,
or milk. Because penicillamine increases the requirement for pyridoxine, patients
may require a daily supplement of pyridoxine (see PRECAUTIONS).
Wilson's Disease
Optimal dosage can be determined by measurement of
urinary copper excretion and the determination of free copper in the serum. The
urine must be collected in copper-free glassware, and should be quantitatively
analyzed for copper before and soon after initiation of therapy with CUPRIMINE.
Determination of 24-hour urinary copper excretion is of
greatest value in the first week of therapy with penicillamine. In the absence
of any drug reaction, a dose between 0.75 and 1.5 g that results in an initial
24-hour cupriuresis of over 2 mg should be continued for about three months, by
which time the most reliable method of monitoring maintenance treatment is the determination
of free copper in the serum. This equals the difference between quantitatively
determined total copper and ceruloplasmin-copper. Adequately treated patients
will usually have less than 10 mcg free copper/dL of serum. It is seldom
necessary to exceed a dosage of 2 g/day. If the patient is intolerant to
therapy with CUPRIMINE, alternative treatment is trientine hydrochloride.
In patients who cannot tolerate as much as 1 g/day
initially, initiating dosage with 250 mg/day, and increasing gradually to the
requisite amount, gives closer control of the effects of the drug and may help
to reduce the incidence of adverse reactions.
Cystinuria
It is recommended that CUPRIMINE be used along with
conventional therapy. By reducing urinary cystine, it decreases crystalluria
and stone formation. In some instances, it has been reported to decrease the
size of, and even to dissolve, stones already formed.
The usual dosage of CUPRIMINE in the treatment of
cystinuria is 2 g/day for adults, with a range of 1 to 4 g/day. For pediatric
patients, dosage can be based on 30 mg/kg/day. The total daily amount should be
divided into four doses. If four equal doses are not feasible, give the larger portion
at bedtime. If adverse reactions necessitate a reduction in dosage, it is
important to retain the bedtime dose.
Initiating dosage with 250 mg/day, and increasing
gradually to the requisite amount, gives closer control of the effects of the
drug and may help to reduce the incidence of adverse reactions.
In addition to taking CUPRIMINE, patients should drink
copiously. It is especially important to drink about a pint of fluid at bedtime
and another pint once during the night when urine is more concentrated and more
acid than during the day. The greater the fluid intake, the lower the required
dosage of CUPRIMINE.
Dosage must be individualized to an amount that limits
cystine excretion to 100-200 mg/day in those with no history of stones, and
below 100 mg/day in those who have had stone formation and/or pain. Thus, in
determining dosage, the inherent tubular defect, the patient's size, age, and
rate of growth, and his diet and water intake all must be taken into
consideration.
The standard nitroprusside cyanide test has been reported
useful as a qualitative measure of the effective dose:† Add 2 mL of freshly
prepared 5 percent sodium cyanide to 5 mL of a 24-hour aliquot of protein-free
urine and let stand ten minutes. Add 5 drops of freshly prepared 5 percent sodium
nitroprusside and mix. Cystine will turn the mixture magenta. If the result is
negative, it can be assumed that cystine excretion is less than 100 mg/g
creatinine.
Although penicillamine is rarely excreted unchanged, it
also will turn the mixture magenta. If there is any question as to which
substance is causing the reaction, a ferric chloride test can be done to
eliminate doubt: Add 3 percent ferric chloride dropwise to the urine. Penicillamine
will turn the urine an immediate and quickly fading blue. Cystine will not
produce any change in appearance.
Rheumatoid Arthritis
The principal rule of treatment with CUPRIMINE in
rheumatoid arthritis is patience. The onset of therapeutic response is
typically delayed. Two or three months may be required before the first
evidence of a clinical response is noted (see CLINICAL PHARMACOLOGY).
When treatment with CUPRIMINE has been interrupted
because of adverse reactions or other reasons, the drug should be reintroduced
cautiously by starting with a lower dosage and increasing slowly.
Initial Therapy
The currently recommended dosage regimen in rheumatoid
arthritis begins with a single daily dose of 125 mg or 250 mg, which is
thereafter increased at one to three month intervals, by 125 mg or 250 mg/day,
as patient response and tolerance indicate. If a satisfactory remission of
symptoms is achieved, the dose associated with the remission should be
continued (see Maintenance Therapy). If there is no improvement and
there are no signs of potentially serious toxicity after two to three months of
treatment with doses of 500-750 mg/day, increases of 250 mg/day at two to three
month intervals may be continued until a satisfactory remission occurs (see Maintenance
Therapy) or signs of toxicity develop (see WARNINGS AND PRECAUTIONS).
If there is no discernible improvement after three to four months of treatment
with 1000 to 1500 mg of penicillamine/day, it may be assumed the patient will
not respond and CUPRIMINE should be discontinued.
Maintenance Therapy
The maintenance dosage of CUPRIMINE must be
individualized, and may require adjustment during the course of treatment. Many
patients respond satisfactorily to a dosage within the 500-750 mg/day range.
Some need less.
Changes in maintenance dosage levels may not be reflected
clinically or in the erythrocyte sedimentation rate for two to three months
after each dosage adjustment.
Some patients will subsequently require an increase in
the maintenance dosage to achieve maximal disease suppression. In those
patients who do respond, but who evidence incomplete suppression of their
disease after the first six to nine months of treatment, the daily dosage of CUPRIMINE
may be increased by 125 mg or 250 mg/day at three-month intervals. It is
unusual in current practice to employ a dosage in excess of 1 g/day, but up to
1.5 g/day has sometimes been required.
Management Of Exacerbations
During the course of treatment some patients may
experience an exacerbation of disease activity following an initial good
response. These may be self-limited and can subside within twelve weeks. They
are usually controlled by the addition of non-steroidal anti-inflammatory
drugs, and only if the patient has demonstrated a true “escape” phenomenon
(as evidenced by failure of the flare to subside within this time period)
should an increase in the maintenance dose ordinarily be considered.
In the rheumatoid patient, migratory polyarthralgia due
to penicillamine is extremely difficult to differentiate from an exacerbation
of the rheumatoid arthritis. Discontinuance or a substantial reduction in
dosage of CUPRIMINE for up to several weeks will usually determine which of
these processes is responsible for the arthralgia.
Duration Of Therapy
The optimum duration of therapy with CUPRIMINE in
rheumatoid arthritis has not been determined. If the patient has been in
remission for six months or more, a gradual, stepwise dosage reduction in
decrements of 125 mg or 250 mg/day at approximately three month intervals may
be attempted.
Concomitant Drug Therapy
CUPRIMINE should not be used in patients who are
receiving gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone, or
phenylbutazone (see PRECAUTIONS). Other measures, such as salicylates,
other non-steroidal anti-inflammatory drugs, or systemic corticosteroids, may
be continued when penicillamine is initiated. After improvement commences,
analgesic and anti-inflammatory drugs may be slowly discontinued as symptoms
permit. Steroid withdrawal must be done gradually, and many months of treatment
with CUPRIMINE may be required before steroids can be completely eliminated.
Dosage Frequency
Based on clinical experience, dosages up to 500 mg/day
can be given as a single daily dose. Dosages in excess of 500 mg/day should be
administered in divided doses.
Interaction with other medicinal products and other forms of interaction
SIDE EFFECTS
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 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%) 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.
Neuromuscular
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.
DRUG INTERACTIONS
No information provided.
