Penicillamine is indicated for:

• Treatment of Wilson’s disease
• Chronic lead poisoning
• Cystinuria
• Severe, active rheumatoid arthritis in patients who have not responded to adequate conventional therapy

Available evidence suggests that Penicillamine is not effective in ankylosing spondylitis. Due to its significant toxicity, Penicillamine should never be used casually and must be prescribed with caution.

Penicillamine acts as a chelating agent that binds and facilitates the removal of heavy metals such as copper and lead from the body. In copper chelation, in vitro data suggest that one atom of copper binds with two molecules of penicillamine; however, only a small fraction of the theoretical amount is actually excreted in urine. The exact mechanism of lead chelation is not fully understood but is believed to be similar to copper binding. In cystinuria, penicillamine reduces cystine excretion by promoting disulfide exchange between penicillamine and cystine, forming penicillamine-cysteine disulfide, which is more soluble and easily excreted.

Penicillamine also interferes with collagen cross-link formation and can break newly formed cross-links. Its mechanism in rheumatoid arthritis is not fully understood, but it appears to suppress disease activity. Unlike cytotoxic immunosuppressants, it significantly reduces IgM rheumatoid factor without markedly lowering total immunoglobulin levels. It also inhibits T-cell activity in vitro but has little effect on B-cell activity.

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

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.

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 3 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, 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 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 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, 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.

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.

Rheumatoid Arthritis: The principal rule of treatment with Penicillamine 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.

When treatment with Penicillamine 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 1- to 3-month intervals, by 125 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. If there is no improvement and there are no signs of potentially serious toxicity after 2 to 3 months of treatment with doses of 500 to 750 mg/day, increases of 250 mg/day at 2- to 3-month intervals may be continued until a satisfactory remission occurs. 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 should be discontinued.

Penicillamine should not be used in patients receiving gold therapy, antimalarial drugs, cytotoxic drugs, oxyphenbutazone, or phenylbutazone, as these agents may also cause similar serious hematologic and renal toxicities. Other medications such as salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), or systemic corticosteroids may be continued when Penicillamine therapy is initiated. As clinical improvement occurs, analgesic and anti-inflammatory drugs may be gradually discontinued. Steroid withdrawal must be done slowly, and several months of Penicillamine therapy may be required before corticosteroids can be completely stopped.

Penicillamine is contraindicated in:

Patients with hypersensitivity to the drug or any of its components

Pregnancy, except in specific cases such as Wilson’s disease or certain cases of cystinuria

Breastfeeding mothers (due to potential risk to the infant)

Patients with a history of penicillamine-induced aplastic anemia or agranulocytosis

Rheumatoid arthritis patients with renal insufficiency or evidence of kidney damage

Patients with chronic lead poisoning when radiographic evidence shows lead-containing substances in the gastrointestinal tract until clearance is confirmed

Patients currently receiving gold therapy, antimalarials, cytotoxic drugs, oxyphenbutazone, or phenylbutazone

Penicillamine is associated with a high incidence of adverse reactions, some of which may be serious or life-threatening. Continuous close medical monitoring is essential throughout therapy.

Penicillamine has shown teratogenic effects in animal studies, including skeletal abnormalities, cleft palate, and fetal toxicity at high doses. Human case reports have described congenital abnormalities such as growth retardation and connective tissue defects in infants exposed in utero. Although some normal outcomes have been reported, congenital cutis laxa and other birth defects have also been observed. Penicillamine should be used in pregnancy only if the potential benefit clearly outweighs the risk. Women of childbearing potential should be informed of possible risks and closely monitored for early detection of pregnancy.

The use of Penicillamine has been associated with serious and sometimes fatal conditions, including aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture’s syndrome, and myasthenia gravis. Because severe hematologic and renal adverse reactions may occur at any time, regular monitoring is essential. Urinalysis, white blood cell (WBC) count with differential, hemoglobin level, and platelet count should be performed every 2 weeks for the first 6 months of therapy, and monthly thereafter. Patients should be advised to immediately report symptoms such as fever, sore throat, chills, bruising, or bleeding, which may indicate blood disorders. In such cases, laboratory tests must be repeated promptly.

Leukopenia and thrombocytopenia may occur in up to 5% of patients. A confirmed WBC count below 3500 requires immediate discontinuation of Penicillamine. Thrombocytopenia may occur due to marrow suppression or immune mechanisms. A platelet count below 100,000, even without bleeding, requires at least temporary discontinuation. A consistent decline in WBC or platelet count over three consecutive tests, even if still within normal range, also requires temporary stopping of therapy.

Store below 30°C, in a dry place protected from light and moisture. Keep out of reach of children.