Wilpen Capsule

Wilpen is indicated for:

• treatment of Wilson's disease
• chronic lead poisoning
• 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 Wilpen is not of value in ankylosing spondylitis.
Because of the severe toxicity of this agent, Wilpen should never be used casually.

As a chelating agent, penicillamine removes copper and lead from the body. In copper chelation, 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. The manner in which lead is chelated is not known. It may be bound in the same way as copper. 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 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 satisfactoryremission 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.

Wilpen should not be used in patients who are receiving gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone, or phenylbutazone. Other measures, such as salicylates, other non-steroidal anti-inflammatory drugs, or systemic corticosteroids, may be continued when Wilpen 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 Wilpen may be required before steroids can be completely eliminated.

Patients who are hypersensitive to this drug or to any ingredient in the formulation. 

Pregnancy. Exceptions to this contraindication include the treatment of Wilson's disease or certain cases of cystinuria.

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.

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.

Penicillamine should not be given with chronic lead poisoning when there is x-ray evidence of lead-containing substances in the gastrointestinal tract. Treatment with the drug may be instituted after the gastrointestinal tract has been cleared of these substances. Studies in animals suggest that Penicillamine may be ineffective, and possibly hazardous, if excessive oral ingestion of lead continues during administration of the drug.

Penicillamine should not be used in patients who are receiving gold therapy,w 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.

Wilpen is a drug with a high incidence of untoward reactions, some of which are potentially fatal. Therefore, it is mandatory that patients receiving Wilpen therapy remain under close medical supervision throughout the period of drug administration.

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 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. 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 and followed closely for early recognition of pregnancy.

The use of Wilpen 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 every two weeks for at least the first six months of Wilpen therapy 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 Wilpen 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 mandates discontinuance of Wilpen 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, even in the absence of clinical bleeding, requires at least temporary cessation of Wilpen 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.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.