Penicillamine (Vistamine) is an orally available medicine primarily used to treat patients with Wilson's disease. It is also used in patients with kidney stones due to cystinuria and as a chelating agent in the lead and copper poisoning. It is also considered a disease-modifying antirheumatic drug and was previously used to treat patients with active Rheumatoid arthritis.

Indications of Penicillamine:

• It is used to treat patients with Wilson's disease, cystinuria, and lead poisoning.
• It was also used previously in the treatment of patients with active Rheumatoid arthritis.

Penicillamine dose in adults:

Note:

Dose reduction may be required in both adults (up to 250mg/day) and children before surgical procedures and the previous dose can be resumed after complete wound healing. Patients may require a daily supplement of pyridoxine with penicillamine.

Penicillamine (Vistamine) dose in the treatment of Cystinuria:

• 1 to 4 g per oral per day in 4 divided doses;
• The usual dose is 2 g/day;
• Initiate therapy at 250 mg/day with gradual upward titration to prevent unwanted effects.

Note:

Adjust the dose to limit cystine excretion to 100 to 200 mg/day (<100 mg/day with a history of stone formation).

Penicillamine (Vistamine) dose in the treatment of Wilson's disease:

Note:

Doses that result in an initial 24-hour urinary copper excretion >2 mg/day should be continued for ~3 months; The maintenance dose is defined by amount resulting in <10 mcg serum free copper/dL.

• Therapy may be started at 250 to 500 mg/day per oral then titrated upward in 250 mg increments every 4 to 7 days to increase tolerance.
• The usual maintenance dose: 750 to 1,000 mg per oral in 2 divided doses
• The maximum dose is 1,000 to 1,500 mg per oral in 2 to 4 divided doses.

• Manufacturer's labeling:

  • Dosing in the prescribing information may not reflect current clinical practice.
  • 750 to 1,500 mg/day in divided doses.
  • The maximum dose: 2,000 mg/day.
  • Note: The daily dose should be limited to 750 mg/day in pregnancy, limit the dose to 250 mg/day during the last 6 weeks of pregnancy and postoperatively until wound healing is complete in case of a planned C section.

Penicillamine (Vistamine) dose in Childrens

Penicillamine (Vistamine) dose in Wilson's disease:

• Diagnosis (adjunct): Penicillamine Challenge Test:

  • 500 mg/dose per oral for 2 doses, administer first immediately prior to a 24-hour urine collection and repeat 12 hours later.
  • Urinary copper excretion >1,600 mcg copper/24 hour is consistent with Wilson disease.

• Treatment:

  • 20 mg/kg per oral in 2 to 3 divided doses, round off to the nearest 250 mg dose, 25% dose reduction is done when clinically stable.
  • The adult maximum daily dose is 1,500 mg/day.

Penicillamine (Vistamine) dose in the treatment of Cystinuria:

• 20 to 40 mg/kg per oral in 4 divided doses.
• The maximum daily dose in children is 40 mg/kg/day.
• The adult maximum daily dose is 4,000 mg/day.
• The manufacturer recommends the larger portion od dose should be given at bedtime and suggests dose adjustment is required to limit cysteine excretion to <100 to 200 mg/day.
• Studies reveal that gradual initiation of penicillamine effectively decreases urinary cysteine level and minimize the toxicity.
• New stone formation was observed during periods of noncompliance to therapy.

Penicillamine (Vistamine) dose in the treatment of Lead poisoning:

Note:

Chelation treatment is required in children when blood lead levels are >45 mcg/dl. AAP considers penicillamine a 3rd line agent for children when blood lead levels are >45 mcg/dL and <70 mcg/dL. Parenteral agents are required for treating children with blood lead levels >70 mcg/dL or symptomatic lead poisoning.

• 10 mg/kg per oral divided b.i.d daily for 14 days initially.
• Increase the dose to 25 to 40 mg/kg/day.
• Gradually increasing the dose is suggested to improve tolerability.
• A reduced dosage of 15 mg/kg/day in 2 divided doses has been shown to be effective in treating mild to moderate lead poisoning (lead concentration 20-40 mcg/dL) with minimal adverse effects, lower doses (10 to 15 mg/kg/day for 4 to 12 weeks) is suggested for treating lead concentrations of 45 to 69 mcg/dL.

Pregnancy Risk Factor D

• Penicillamine can cause birth defects like congenital cutix laca.
• To prevent relapse, it is permissible to continue taking penicillamine while pregnant for Wilson's Disease.
• It is not recommended to be used during pregnancy for cystinuria.
• It is not recommended to be used during pregnancy in the treatment of rheumatoidarthritis.
• Maximum daily intake should not exceed 750 mg
• Reduce dose to 250 mg/day during the last six weeks of pregnancy. Continue this until wound healing is complete in the case of a C-section.

Penicillamine use during breastfeeding:

• Breast milk does not secrete penicillamine.
• The manufacturer warns against breastfeeding.

Penicillamine (Vistamine) Dose adjustment in renal disease:

• Manufacturer's labeling:

  • There are no dosage adjustments provided in the manufacturer’s labeling; however, the manufacturer labeling suggests a cautious approach for dosing is needed as it is excreted by kidneys.

• Alternate recommendations:

  • Creatinine clearance<50 mL/minute:

    • Avoid use.

  • Hemodialysis:

    • Dialyzable; Administer 33% of usual dose.
    • The dose reduction from 250 mg/day to 250 mg 3 times/week after dialysis is needed in the treatment of rheumatoid arthritis.

Penicillamine (Vistamine) Dose adjustment in liver disease:

There are no dosage adjustments provided in the manufacturer's labeling; however, only a small fraction is metabolized in liver.

Common Side Effects of Penicillamine (Vistamine):

• Gastrointestinal:

  • Diarrhea
  • Dysgeusia

Rare Side Effects of Penicillamine (Vistamine):

• Dermatologic:

  • Skin rash

• Genitourinary:

  • Proteinuria

• Hematologic & oncologic:

  • Thrombocytopenia
  • Leukopenia

Frequency of side effects Not Defined.

• Cardiovascular:

  • Local Thrombophlebitis
  • Vasculitis (Including Renal Vasculitis)

• Central Nervous System:

  • Anxiety
  • Agitation
  • Dystonia
  • Guillain-Barre Syndrome
  • Hyperpyrexia
  • Myasthenia (Including Extraocular Muscles)
  • Myasthenia Gravis
  • Neurological Deterioration
  • Neuropathy
  • Psychiatric Disturbance

• Dermatologic:

  • Alopecia
  • Cheilosis
  • Exfoliative Dermatitis
  • Fragile Skin (Friability Increased)
  • Lichen Planus
  • Papule (White Papules At Venipuncture And Surgical Sites)
  • Pemphigus
  • Pruritus
  • Skin Atrophy (Anetoderma)
  • Toxic Epidermal Necrolysis
  • Urticaria
  • Wrinkling Of Skin (Excessive)
  • Yellow Nail Syndrome

• Endocrine & Metabolic:

  • Hypoglycemia
  • Increased Lactate Dehydrogenase
  • Thyroiditis

• Gastrointestinal:

  • Anorexia
  • Epigastric Pain
  • Glossitis
  • Nausea
  • Oral Mucosa Ulcer
  • Pancreatitis
  • Peptic Ulcer (Reactivation)
  • Stomatitis (Gingivostomatitis)
  • Vomiting

• Genitourinary:

  • Breast Disease (Mammary Hyperplasia)
  • Goodpasture's Syndrome
  • Hematuria
  • Nephrotic Syndrome

• Hematologic & Oncologic:

  • Agranulocytosis
  • Aplastic Anemia
  • Change In Platelet Count (Increase)
  • Eosinophilia
  • Hemolytic Anemia
  • Increased Monocytes
  • Leukocytosis
  • Lymphadenopathy
  • Positive ANA Titer
  • Pure Red Cell Aplasia
  • Sideroblastic Anemia
  • Thrombotic Thrombocytopenic Purpura

• Hepatic:

  • Increased Serum Alkaline Phosphatase
  • Hepatic Failure
  • Intrahepatic Cholestasis
  • Toxic Hepatitis

• Neuromuscular & Skeletal:

  • Arthralgia
  • Connective Tissue Disease (Elastosis Perforans Serpiginosa)
  • Dermatomyositis
  • Lupus-Like Syndrome
  • Polyarthralgia (Migratory
  • Often With Objective Synovitis)
  • Polymyositis

• Ophthalmic:

  • Blepharoptosis
  • Diplopia
  • Optic Neuritis
  • Visual Disturbance

• Otic:

  • Tinnitus

• Renal:

  • Renal Failure

• Respiratory:

  • Asthma
  • Bronchiolitis Obliterans
  • Hypersensitivity Pneumonitis
  • Interstitial Pneumonitis
  • Pulmonary Fibrosis

• Miscellaneous:

  • Fever

Contraindications to Penicillamine (Vistamine):

• Pregnancy (in rheumatoidarthritis)
• Breastfeeding
• Penicillamine-related aplastic anemia and agranulocytosis
• In rheumatoidarthritis, renal insufficiency.
• Hypersensitivity to any component of the formulation or penicillamine
• Pregnancy (with chronic lead poisoning).
• Combination of antimalarial, and cytotoxic drugs with gold therapy, or oxyphenbutazone, or phenylbutazone
• Radiological evidence of chronic lead poisoning in the GI tract.

Warnings and precautions

• Allergy reactions:

  • About 33% of patients will experience allergic reactions.
  • Initial therapy is effective in reducing rash. It usually disappears after a few days.It is best to not re-challenge rash that has developed late (e.g. after 6 months).
  • The therapy should be stopped if there are any allergic reactions such as fever, lymphadenopathy, arthralgia or other reactions.

• Bronchiolitis obliterans

  • Patients with undiagnosed cough or wheezing, exertional dyspnea, or other symptoms should have pulmonary function tests done.

• Dermatologic:

  • Penicillamine can cause skin to become more friable, particularly at pressure points such as elbows and shoulders. This can lead to bleeding.
  • This condition is not likely to recur and therapy may continue.
  • In 1-2 weeks, macular cutaneous eruptions may occur.
  • Before surgery, dose reduction is necessary. Once wound healing has completed, the previous dose can be resumed.

• Drug fever:

  • Drug fever may occur during the first 2-3 weeks of treatment. Treatment should be stopped immediately if the patient is febrile due to rheumatoid, Wilson's, or cystinuria.
  • In Wilson's disease and cystinuria, dose reduction should be done after the fever has subsided. Rheumatoid arthritis sufferers may need to use alternate agents due to the higher chance of recurrence.

• Gastrointestinal:

  • It is possible to experience taste alteration or stomatitis. This can be resolved by reducing the dose.
  • Glossitis and gingivostomatitis can be severe and require that therapy is stopped.

• Goodpasture's Syndrome:

  • A case of hemoptysis or pulmonary infiltrates in the chest x-ray should be considered. This can lead to life-threatening Goodpasture syndrome.

• Hematologic toxicities

  • Penicillamine can lead to thrombocytopenia, anemia, and agranulocytosis.
  • For platelet counts below 100,000/mm3, or WBC below 3500/mm3, withhold therapy
  • It is important to monitor for the signs and symptoms of leukopenia or thrombocytopenia.

• Hepatotoxicity:

  • It is rare to see intrahepatic cholestasis (or toxic hepatitis) with drug therapy. Regular monitoring of hepatic function tests for Wilson's disease and Wilson's disease is necessary.

• Lupus erythematosus-like syndrome:

  • Patients with positive antinuclear antibodies (ANA) should be closely monitored as this can lead to lupus-like syndrome.

• Pemphigus

  • In cases of pemphigus, therapy should be stopped immediately and treated with high-dose immunosuppressants and corticosteroids for the long-term.

• Penicillin cross-sensitivity

  • Penicillin allergy patients may have cross-sensitivity to penicillin. However, penicillin is not in penicillamine.

• Proteinuria/hematuria:

  • Nephrotic syndrome can present with proteinuria and hematuria.
  • Rheumatoid Arthritis with persistent hematuria should be treated immediately. Dosage reductions for proteinuria greater than 1 g/day, or gradually increasing, should also be considered.
  • Proteinuria may be resolved by reducing the dose.

• Myasthenia gravis:

  • Penicillamine may cause tp myasthenic Syndrome, which can lead to myasthenia gravis.

• Toxicity symptoms: [US Boxed Warn]

  • You should look out for symptoms such as fever, sore throat or bleeding.

• Cystinuria:

  • Cysticinuria can be treated with additional pyridoxine (25 mg/day).

• Lead poisoning:

  • Before starting treatment, it is important to identify and remove any sources of lead exposure.
  • The patient should stay away from contaminated environments until lead abatement is complete.
  • Penicillamine should not be used if succimer and edetate CALCIUM didium have caused severe reactions.
  • Before recommending chelation drug therapy, primary care providers should consult specialists in the treatment of lead poisoning.

• Rheumatoid arthritis:

  • Patients with rheumatoid arthritis will need to take additional pyridoxine (25 mg/day).

• Wilson's disease

  • Additional pyridoxine can be added to the therapy.
  • Patients with persistently worsening symptoms should not stop taking dimercaprol.
  • However, it is recommended to continue using dimercaprol for short-term use in those who experience worsening symptoms.

Penicillamine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• CBC
• LFTS every 6 monthly
• Urine routine exam:
  • Proteinuria and hematuria.
  • A quantitative 24-hour urine protein at 1- to 2week intervals initially (first 2-3 months) is recommended if proteinuria develops.
• Look for skin or lymph nodes
• Body temperature twice weekly during the first month of therapy, then every 2 weeks for 5 months, then monthly.
• Signs/symptoms of hypersensitivity.
• Urinary cystine, annual X-ray for renal stones ( in patients with cystinuria)
• Serum lead concentration (baseline and 7-21 days after completing chelation therapy); hematocrit, iron status, free erythrocyte protoporphyrin or zinc protoporphyrin, neurodevelopmental changes (in lead poisoning).
• Serum non-ceruloplasmin bound-copper, 24-hour urinary copper excretion, and periodic ophthalmic exam ( in Wilson disease).

How to administer Penicillamine (Vistamine)?

• Doses 500 mg or less per day can be given orally as a single dose; Doses exceeding 500 mg per day should be administered in divided doses.
• It should be taken on an empty stomach (1 hour before or 2 hours after meals) and at least 1 hour apart from other drugs, milk, antacids, and zinc-containing products or at least 2 hours apart from iron-containing products.
• The contents of the capsules may be administered in 15 to 30 mL of chilled puréed fruit or fruit juice within 5 minutes of preparation for patients with swallowing difficulty.

Cystinuria:

• If administering 4 equal doses is not feasible, administer the larger dose at bedtime.
• Patients should drink about one pint of fluid at bedtime and another pint during the night.

Mechanism of action of Penicillamine:

• By chelating penicillamine with lead, copper and mercury, it forms stable soluble compounds (excreted into urine).
• Combining it with cystine creates a more liquid compound that prevents the formation cystine calculi. 
• It also depresses the circulating IgM-rheumatoid factors and T-cell activity.

The onset of action:

• Rheumatoid arthritis: 2 to 3 months
• Wilson disease: 1 to 3 months

Absorption:

• Rapid but incomplete (40% to 70%) and reduced by food, antacids, and iron

Protein binding:

• >80% to albumin and ceruloplasmin

Metabolism:

• Occurs in the liver (small amounts metabolized to s-methyl-d-penicillamine)

Half-life elimination:

• 1.7 to 7 hours (Roberts 2008); large variations exist and a slow elimination phase lasting 4 to 6 days may occur after stopping long term therapy.

Time to peak plasma concentration is 1 to 3 hours

Excretion:

• Urine (primarily as disulfides)

International Brands of Penicillamine:

• Cuprimine
• D-Penamine
• Depen Titratabs
• Adalken
• Artamin
• Atamir
• Byanodine
• Cilamin
• Cuprenil
• Cuprimine
• Cuprimune
• Cupripen
• D-Penamine
• D-Penil
• Distamine
• Kelatin
• Kelatine
• Mercaptyl
• Metalcaptase
• Metalcaptase[inj.]
• Pemine
• Penamine
• Penicilamin
• Penicillamin
• Retadel
• Reumacillin
• Trisorcin
• Trolovol
• Vistamin

Penicillamine Brands in Pakistan: