DOSAGE AND ADMINISTRATION
In all patients receiving penicillamine, it is important
that CUPRIMINE be given on an empty stomach, at least one hour before meals or
two hours after meals, and at least one hour apart from any other drug, food,
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 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.
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
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
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.
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.
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.
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
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.
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.
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.
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.
† 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