Adult Dosing

Wilson's disease

• Start 250 mg PO qd; gradually increase to the requisite amount
• Usual dose: In absence of drug reaction, 750-1500 mg/day PO divided tid-qid x 3 months to result in 24 hr cupriuresis of over 2 mg
• Max: 2 g/day
• Note:Determine optimal dosage by measurement of urinary copper excretion and determination of free copper in the serum

Cystinuria

• Start 250 mg PO qd, then gradually increase to requisite amount to reduce the incidence of adverse reactions
• Usual dose: 2 g/day PO divided qid
• Range: 1-4 g/day PO divided qid
• Note: Individualize dosage to limit cystine excretion to 100-200 mg/day in patients with no history of stones, and <100 mg/day in patients with history of stones. Use along with conventional therapy

Rheumatoid arthritis

Initial therapy

• Start 125 mg- 250 mg PO qd; then increase q1-3 months by 125 mg or 250 mg/day, as patient response and tolerance indicate
• If remission occurs, continue same dose
• If no improvement and no signs of serious toxicity after 2-3 months of treatment with doses of 500-750 mg/day, increase dose by 250 mg/day q2-3 months. Continue until a satisfactory remission occurs
• Discontinue therapy if no discernible improvement even after 3-4 months of treatment with 1000-1500 mg of penicillamine/day

Note:

• First evidence of a clinical response may take 2-3 months

Maintenance therapy

• Usual range: 500-750 mg/day PO in divided doses; may need to increase dose by 125 mg or 250 mg/day q3 months in patients who do respond, but exhibit incomplete suppression of their disease after the first 6-9 months of treatment
• Max: 1500 mg/day

Note:

• Manage exacerbations by adding NSAIDs. Consider an increase in the maintenance dose only if patient has demonstrated a true "escape" phenomenon
• If the symptoms are on remission for 6 mo or more, gradually decrease dosage in decrements of 125 mg or 250 mg/day q3 months

Note:

• Administer at least 1 hr before meals or 2 hrs after meals and at least 1 hr apart from any other drug, food, or milk
• Patients may require supplemental pyridoxine
• Avoid concomitant use with gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone, phenylbutazone
• Salicylates, other NSAIDs drugs, or systemic corticosteroids, may be continued when penicillamine is initiated; slowly discontinue analgesic, anti-inflammatory drugs and steroids as symptoms permit
• Administer dosages up to 500 mg/day as a single daily dose and dosages in excess of 500 mg/day in divided doses

Pediatric Dosing

Cystinuria

• 30 mg/kg/day PO div qid; if four equal doses are not feasible, administer larger portion at hs. Consider dose reduction on occurrence of adverse reaction. Important to retain hs dose

[Outline]

• Adult Dosing
• Pediatric Dosing

• Treatment of Wilson's disease in symptomatic and asymptomatic patients
• For minimization of dietary intake of copper
• For promotion of excretion and complex formation (i.e., detoxification) of excess tissue copper

• Cystinuria
• For treatment of rheumatoid arthritis restricted to patients having severe, active disease and who have failed to respond to an adequate trial of conventional therapy

• Hypersensitivity to any of the ingredients of the product
• Pregnancy (except patients with Wilson's disease or cystinuria)
• Breastfeeding
• History of penicillamine-related aplastic anemia
• History of penicillamine-related agranulocytosis
• Use of cytotoxic drug
• Use of antimalarial drug
• History or evidence of renal insufficiency (Rheumatoid arthritis patients)
• Use of gold salt

• Physicians should thoroughly familiarize themselves about toxicity, special dosage considerations and therapeutic benefits of penicillamine before considering its use. Avoid using casually. Constantly supervise the patient. Warn patients to promptly report any symptoms suggesting toxicity

Renal Dose Adjustment

• RA patients with renal impairment: Contraindicated
• Other patients if CrCl < 50 mL/min: Avoid use

Hepatic Dose Adjustment

• Hepatic impairment: Dose adjustments not defined

See Supplemental Patient Information

• Fatalities due to aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture's syndrome, and myasthenia gravis have occurred in patients taking penicillamine
• Once treatment is started it should be preferably continued on a daily basis as interruptions for even a few days have been followed by sensitivity reactions
• On reduction of WBC below 3500/mm³ discontinue therapy
• Leukopenia and thrombocytopenia have occurred in patients during penicillamine therapy
• Even in the absence of clinical bleeding if platelet count <100,000/mm³ temporary cease therapy
• Temporarily cease therapy if values for platelet count/WBC are still within the normal range but progressively decreasing in three successive determinations
• Proteinuria and/or hematuria progressing to a nephrotic syndrome have occurred. Physician must ascertain whether it is a sign of drug-induced glomerulopathy or is unrelated to penicillamine. Closely monitor patients. Some patients may require cessation of therapy on persistent proteinuria and/or hematuria
• Proteinuria exceeding 1 g/24 hours, or progressively increasing proteinuria requires either discontinuance of the drug or a reduction in the dosage
• Discontinue dosage if RA patients develop gross hematuria/persistent microscopic hematuria
• Weigh potential benefit/risk in patients with Wilson's disease or cystinuria due to manifestations of potentially serious urinary abnormalities
• Perform an annual x-ray for renal stones in patients with cystinuria
• On occurrence of abnormal urinary findings associated with hemoptysis and pulmonary infiltrates on x-ray, immediate cessation of therapy is required
• Rare occasions of obliterative bronchiolitis have occurred
• Myasthenic syndrome sometimes progressing to myasthenia gravis, pemphigus vulgaris and pemphigus foliaceus has occurred. Discontinue therapy on occurrence of pemphigus
• Avoid interruptions for even a few days as sensitivity reactions after reinstitution of therapy have occurred
• Monitor RA patients who develop moderate degrees of proteinuria; continue dosage cautiously and obtain quantitative 24-hour urinary protein levels q1-2 wks. Do not up titrate under these circumstances
• Monitor creatinine clearance at baseline; CBC w/ differential count, Platelets, urinalysis, temperature, skin/lymph node monitoring twice weekly x 1 month, then q2 wks x 5 months, then qmo thereafter
• Monitor LFTs q6 months or if Wilson's disease q3 months for 1 yr, then q6 months
• Patients may experience drug fever in the second to third week following initiation of therapy accompanied by a macular eruption; temporarily discontinue drug and later reinstitute in small doses
• Iron deficiency may develop especially in pediatric patients and in menstruating women
• In Wilson's disease, penicillamine causes an increase in the amount of soluble collagen causing increased skin friability. Consider a dose reduction to 250 mg/day when surgery is contemplated; full therapy delayed until wound healing is complete

Cautions: Use cautiously in

• Renal impairment
• Myelosuppression
• Neurological disorder
• Iron deficiency
• Surgery
• Pregnancy (in Wilson's disease, limit daily intake to < 1 g, if cesarean planned, decrease daily dose to 250 mg for last 6 wks of pregnancy and until incision is healed)
• Geriatric population

Supplemental Patient Information

• Instruct patients to report promptly the development of signs and symptoms of granulocytopenia and/or thrombocytopenia such as fever, sore throat, chills, bruising or bleeding
• Caution patients to report immediately pulmonary symptoms such as exertional dyspnea, unexplained cough or wheezing
• Advise patients to intake a pint of fluid at qhs drink and another pint once during the night when urine is more concentrated and more acidic than during the day

Pregnancy Category:D

Breastfeeding: Unsafe; Breastmilk transfer to the infant is likely to be low because of high protein binding (80%) and short half-life. Some data suggest that use of penicillamine is unacceptable during lactation. In infants who breastfeed infrequently, take the drug right after nursing and wait for 4-6 hrs before nursing to minimize the amount in breastmilk. Implications for infants due to reduced levels of copper and zinc levels in breastmilk are not known. This information is based on LactMed database (available at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT last accessed 15 December 2010). Contraindicated according to the manufacturer.

• HEMA: Agranulocytosis, aplastic anemia, anemia, eosinophilia, leukopenia, thrombocytopenia, thrombocytosis
• DERM: Exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, lupus erythematosus, pruritus, rash
• IMMU: Myasthenia gravis
• GI: Gingivostomatitis, hepatic failure, intrahepatic cholestasis, hepatitis, pancreatitis, anorexia, epigastric pain, nausea, vomiting, diarrhea, taste changes, oral ulcerations
• GU: Goodpasture syndrome, nephrotic syndrome, renal failure, proteinuria
• RESP: Bronchiolitis obliterans
• CNS: Optic neuritis, peripheral sensory and motor neuropathies, muscular weakness
• MISC: hypersensitivity reaction, allergic reaction

• Cystine-depleting agent; precise mechanism of action of penicillamine in rheumatoid arthritis is unknown; appears to suppress disease activity. Lowers IgM rheumatoid factor producing no significant depression in absolute levels of serum immunoglobulins, depresses T-cell activity. Also removes excess copper in patients and reduces excess cystine excretion in cystinuria
• Rapid but incomplete absorption (40-70%) from the gastrointestinal tract
• Metabolized by liver; CYP450: Unknown
• Excreted in urine
• Half-life: 1-3 hrs; 4-6 days on prolonged use

US Trade Name(s)

• Cuprimine
• Depen

US Availability

Cuprimine

• CAPS: 250 mg

Depen

• TABS: 250 mg

Canadian Trade Name(s)

• Cuprimine

Canadian Availability

Cuprimine

• CAPS: 250 mg

UK Trade Name(s)

• Distamine

UK Availability

Distamine

• TABS: 125, 250 mg

Australian Trade Name(s)

• D-Penamine

Australian Availability

D-Penamine

• TABS: 125, 250 mg

[Outline]

Rheumatologic

Antirheumatic Agents

Emergency/Critical Care

Antidotes

Chelating Agents

Pricing data from www.DrugStore.com in U.S.A.

• Depen Titratabs 250 MG TABS [Bottle] (MEDA PHARMACEUTICALS)
  30 mg = $146.99
  90 mg = $419.97
• Cuprimine 250 MG CAPS [Bottle] (VALEANT)
  30 mg = $220
  90 mg = $635.95

Warning: This pricing information is subject to change at the sole discretion of DS Pharmacy. For the most current and up-to-date pricing information, please visit drugstore.com.

• Cuprimine 125 MG Oral Capsule (Merck & Co., Inc.)
• Cuprimine 250 MG Oral Capsule (Aton Pharma, Inc.)
• Cuprimine 250 MG Oral Capsule (Merck & Co., Inc.)
• Depen 250 MG Oral Tablet (Meda Pharmaceuticals Inc.)