PENICILLAMINE capsule

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

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Active ingredient:
PENICILLAMINE (UNII: GNN1DV99GX) (PENICILLAMINE - UNII:GNN1DV99GX)
Available from:
Granules Pharmaceuticals Inc.
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 — 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 o
Product summary:
Penicillamine capsules USP, 250 mg, are hard gelatin capsules, light cream opaque cap printed with a "GPI 250 mg" and light cream opaque body printed with a "907" contains white to off-white powder. They are supplied as follows: Bottles of 100 NDC 70010-907-01 Storage Store at 20 o to 25 o C (68 o to 77 o F). [see USP Controlled Room Temperature]. Dispense in tight, light-resistant container. Manufactured by: Granules Pharmaceuticals Inc. Chantilly, VA 20151 Rev: 12/2020
Authorization status:
Abbreviated New Drug Application
Authorization number:
70010-907-01

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PENICILLAMINE- penicillamine capsule

Granules Pharmaceuticals Inc.

----------

Penicillamine Capsules, USP

Rx Only

BOXED WARNING

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 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

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, USP for oral administration contain 250 mg of penicillamine. Each capsule contains the

following inactive ingredients: Anhydrous lactose, FD & C Yellow # 6, gelatin, magnesium stearate,

and titanium dioxide. In addition, capsule printing ink contains ammonium hydroxide, black iron oxide,

propylene glycol, and shellac glaze.

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 <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 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 thirty years. Symptoms and signs of

the disease appear to be prevented indefinitely if daily treatment with penicillamine capsules are

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

8.0, 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:

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, 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 penicillamine capsules (see PRECAUTIONS).

** 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

CLINICAL PHARMACOLOGY

Penicillamine 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 one gram of penicillamine should be followed by the

excretion of about 200 milligrams of copper; however, the actual amount excreted is about one percent

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

two or three months. In those patients who respond, however, the first evidence of suppression of

symptoms such as pain, tenderness, and swelling is generally apparent within three 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 one hour before meals or two hours after meals, and at least one 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 to 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 cysteine-penicillamine 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.

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 WARNINGSand 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.

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 penicillamine capsules in juvenile rheumatoid arthritis has 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 (1,270 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

WARNINGSand 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.

To report SUSPECTED ADVERSE REACTIONS, contact Granules Pharmaceutical Inc., at 1-

877-770-3183 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, USP 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, USP.

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 penicillamine

capsules, USP, 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 penicillamine capsules, USP 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 penicillamine capsules, USP 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 penicillamine capsules, USP, 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 penicillamine capsules, USP.

Dosage must be individualized to an amount that limits cystine excretion to 100 to 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 penicillamine capsules, USP 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 penicillamine capsules, USP 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 to 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 WARNINGSand 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 penicillamine capsules, USP should be discontinued.

Maintenance Therapy — The maintenance dosage of penicillamine capsules, USP must be

individualized, and may require adjustment during the course of treatment. Many patients respond

satisfactorily to a dosage within the 500 to 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 penicillamine capsules,

USP 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 penicillamine capsules, USP for up to several weeks will usually determine which of

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