Cuprimine

Name: Cuprimine

What Is Penicillamine?

Penicillamine is a chelating agent. It attaches to other chemicals in the body, which aids in their removal.

Penicillamine is used to remove excess copper associated with Wilson's disease. It is also used to reduce cystine in the urine and to treat severe rheumatoid arthritis.

Penicillamine may also be used for purposes other than those listed in this medication guide.

Notify your doctor immediately if you develop fever; chills; a sore throat; unusual bruising or bleeding; blood in your urine, unexplained shortness of breath, coughing, or wheezing; muscle weakness; or double vision. These symptoms could be early signs of dangerous side effects.

You cannot take penicillamine if you have taken it in the past and it has damaged your blood cells.

Before taking penicillamine, tell your doctor if you have kidney disease or any other serious illness. You may not be able to take penicillamine, or you may require a lower dose or special monitoring during therapy.

Penicillamine may cause birth defects in an unborn baby. However, it has also been used during pregnancy with no evidence of defects. Penicillamine should not be used during pregnancy except to treat Wilson's disease and some cases of cystine in the urine. Do not take this medication without first talking to your doctor if you are pregnant.

It is not known whether penicillamine passes into breast milk. Since penicillamine may harm a nursing infant, breast-feeding is not recommended during treatment with this medication.

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:

[α] 25° = -62.5° ± 2° (c = 1, 1N NaOH), D

calculated on a dried basis.

The empirical formula is C5H11NO2S, giving it a molecular weight of 149.21. The structural formula is:

It reacts readily with formaldehyde or acetone to form a thiazolidine-carboxylic acid.

Capsules CUPRIMINE (Penicillamine) for oral administration contain either 125 mg or 250 mg of penicillamine. Each capsule contains the following inactive ingredients: D & C Yellow 10, gelatin, lactose, magnesium stearate, and titanium dioxide. The 125 mg capsule also contains iron oxide.

How supplied

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.

Storage

Keep container tightly closed.

REFERENCES

** 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

Side effects

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 (1270 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 WARNINGS and 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.

Cuprimine Drug Class

Cuprimine is part of the drug class:

  • Penicillamine and similar agents

What is the most important information I should know about Cuprimine (penicillamine)?

You should not use penicillamine if you are breast-feeding, if you have ever had an infection or damaged blood cells caused by penicillamine, or if you have kidney disease and you need penicillamine to treat rheumatoid arthritis.

Every person taking penicillamine should remain under the close supervision of a doctor.

Cuprimine (penicillamine) side effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • sudden fever, skin rash, joint pain, or swollen glands;

  • sudden weakness or ill feeling, chills, sore throat, mouth sores, skin sores, red or swollen gums;

  • easy bruising or bleeding;

  • pale skin, feeling light-headed or short of breath, rapid heart rate;

  • muscle weakness in your arms and legs;

  • muscle weakness in your face, drooping eyelids, double vision, trouble chewing or swallowing;

  • new or worsening cough, fever, trouble breathing;

  • swelling in your hands, legs, and feet; or

  • pain or burning when you urinate, foamy or bloody urine, lower back pain.

Common side effects may include:

  • decreased sense of taste;

  • skin rash or peeling, watery blisters;

  • skin changes such as wrinkling or pimples;

  • stomach pain, nausea, vomiting, diarrhea, loss of appetite;

  • numbness or tingly feeling;

  • ringing in your ears; or

  • a wound that will not heal.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Cuprimine Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

More common
  • Fever
  • joint pain
  • lesions on the face, neck, scalp, and/or trunk
  • skin rash, hives, or itching
  • swollen and/or painful glands
  • ulcers, sores, or white spots on lips or in mouth
Less common
  • Bloody or cloudy urine
  • shortness of breath, troubled breathing, tightness in chest, or wheezing
  • sore throat and fever with or without chills
  • swelling of face, feet, or lower legs
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • weight gain
Rare
  • Abdominal or stomach pain (severe)
  • blisters on skin
  • bloody or black, tarry stools
  • chest pain
  • coughing or hoarseness
  • dark urine
  • difficulty in breathing, chewing, talking, or swallowing
  • eye pain, blurred or double vision, or any change in vision
  • general feeling of discomfort or illness or weakness
  • lower back or side pain
  • muscle weakness
  • painful or difficult urination
  • pale stools
  • pinpoint red spots on skin
  • redness, tenderness, itching, burning, or peeling of skin
  • red or irritated eyes
  • red, thick, or scaly skin
  • ringing or buzzing in the ears
  • spitting blood
  • yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Diarrhea
  • lessening or loss of sense of taste
  • loss of appetite
  • nausea or vomiting
  • stomach pain (mild)

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Cuprimine - 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 Cuprimine 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 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, 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 (40-70%) 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 1-3 hours after ingestion; it is approximately 1-2 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 4-6 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.

For Healthcare Professionals

Applies to penicillamine: oral capsule, oral tablet

Nervous system

Very common (10% or more): Blunting, diminution, or total loss of taste (12%)
Frequency not reported: Headache, dizziness, deterioration of neurological symptoms of Wilson's disease (dystonia, rigidity, tremor, dysarthria) following introduction of therapy in patients treated for this condition (this may be a consequence of mobilization and redistribution of copper from the liver to the brain), arthralgia, tinnitus, peripheral sensory and motor neuropathies (including polyradiculoneuropathy, i.e., Guillain-Barre Syndrome)[Ref]

Gastrointestinal

Very common (10% or more): Epigastric pain (17%), nausea (17%), vomiting (17%), diarrhea (17%)
Rare (0.01% to 0.1%): Mouth ulceration, stomatitis, glossitis
Frequency not reported: Pancreatitis, reactivated peptic ulcer[Ref]

Hematologic

Common (1% to 10%): Thrombocytopenia, leukopenia
Frequency not reported: Neutropenia (usually reversible), agranulocytosis (sometimes fatal), aplastic anemia (sometimes fatal), hemolytic anemia, lymphadenopathy, thrombotic thrombocytopenic purpura, red cell aplasia, monocytosis, leukocytosis, eosinophilia, thrombocytosis[Ref]

Renal

Common (1% to 10%): Proteinuria
Rare (less than 0.1%): Hematuria, renal vasculitis
Frequency not reported: Nephrotic syndrome, glomerulonephritis, Goodpasture's syndrome[Ref]

Musculoskeletal

Rare (less than 0.1%): Polymyositis, dermatomyositis
Frequency not reported: Lupus erythematosus, myasthenia gravis, rheumatoid arthritis, septic arthritis (in patients with rheumatoid arthritis), muscular weakness[Ref]

Dermatologic

Common (1% to 10%): Rash (early and/or later in therapy), pruritus
Rare (less than 0.1%): Alopecia, pseudoxanthoma elasticum, elastosis perforans, skin laxity, lichen planus
Frequency not reported: Urticaria, epidermolysis bullosa, exfoliative dermatitis, dermopathy, dermatomyositis, pemphigus, Stevens-Johnson syndrome[Ref]

Respiratory

Rare (less than 0.1%): Bronchial asthma
Frequency not reported: Pulmonary hemorrhage, dyspnea, pleural effusion, alveolitis, pulmonary fibrosis, bronchiolitis, pneumonitis[Ref]

Other

Frequency not reported: Deafness, fever, the chelating action of the drug may cause increased excretion of other heavy metals (in addition to copper) such as zinc, mercury, and lead[Ref]

Genitourinary

Rare (less than 0.1%): Breast enlargement[Ref]

Hepatic

Rare (less than 0.1%): Intrahepatic cholestasis, toxic hepatitis
Frequency not reported: Cholestatic jaundice, hepatic dysfunction, pancreatitis, increased serum alkaline phosphatase, increased lactic dehydrogenase, positive cephalin flocculation test, positive thymol turbidity test[Ref]

Ocular

Frequency not reported: Abnormal vision, optic neuritis[Ref]

Cardiovascular

Rare (less than 0.1%): Thrombophlebitis[Ref]

Endocrine

Very rare (less than 0.01%): Thyroiditis[Ref]

General

Both the frequency and severity of many side effects are dose related and vary according to the disease being treated. Initiating therapy at lower doses and titrating up helps to attenuate some side effects.[Ref]

Hypersensitivity

Rare (less than 0.1%): Allergic reactions including hypersensitivity[Ref]

Psychiatric

Frequency not reported: Confusion[Ref]

Some side effects of Cuprimine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Penicillamine Identification

Substance Name

Penicillamine

CAS Registry Number

52-67-5

Drug Class

Antirheumatic Agents

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