PENICILLAMINE- penicillamine capsule

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

PENICILLAMINE (UNII: GNN1DV99GX) (Penicillamine - UNII:GNN1DV99GX)

Available from:

Apotex Corp.

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 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: (1) to minimize dietary intake of copper; (2) 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. 1 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 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 mg 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, 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). 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.

Product summary:

Penicillamine capsules are hard gelatin capsules with ivory, opaque body and ivory, opaque cap. The capsules are imprinted with "APO" and "PEN" over "250" in black ink. White to off-white granular fill. They are supplied as follows:   Bottle of 100, NDC 60505-4696-1   Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Dispense in a tightly closed container with a child-resistant cap. APOTEX INC. Penicillamine Capsules, USP 250 mg Revised: January 2020  Revision: 4

Authorization status:

Abbreviated New Drug Application

Summary of Product characteristics

PENICILLAMINE - PENICILLAMINE CAPSULE
APOTEX CORP.
----------
PENICILLAMINE CAPSULES
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 molecular formula is C H
NO S, giving it a molecular weight of 149.21 g/mol. The
structural formula is:
It reacts readily with formaldehyde or acetone to form a
thiazolidine-carboxylic acid.
Penicillamine capsules for oral administration contain 250 mg of
penicillamine. Each
capsule contains the following inactive ingredients: magnesium
stearate, microcrystalline
cellulose. The capsule shell contains black pharmaceutical ink, D&C
yellow #10, gelatin
and titanium dioxide. The capsule imprinting black ink contains
ammonium hydroxide
28%, iron oxide black, propylene glycol and shellac.
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
5
11
2
penicillamine should be followed by the excretion of about 200
milligrams of copper;
however, the actual amount excreted is about one percent of