Penicillamine is a medication primarily used in the treatment of Wilson's disease, a genetic disorder that causes copper to accumulate in vital organs like the liver and brain. It is also used to treat cystinuria, a condition characterized by the formation of cystine stones in the kidneys, and rheumatoid arthritis.

Penicillamine works by binding to excess copper or cystine in the body, forming complexes that can be excreted through urine. By reducing the levels of copper or cystine, it helps to prevent damage to organs and alleviate symptoms associated with these conditions.

Despite its therapeutic benefits, penicillamine can cause various side effects, including gastrointestinal disturbances, skin rashes, and bone marrow suppression. It requires careful monitoring and management by healthcare professionals during treatment.

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:

• Penicillamine is a medicine used for conditions like Wilson's disease and rheumatoid arthritis.
• It helps by removing excess copper or cystine from the body.
• But, it can cause side effects like stomach problems and skin rashes.
• Before surgery, the dose might be lowered to 250 mg/day, but after surgery, the regular dose can be resumed once the wound heals.
• Taking penicillamine might mean needing more pyridoxine, so patients might need a daily pyridoxine supplement.

Penicillamine (Vistamine) dose in the treatment of Cystinuria:

• In treating Cystinuria, the typical oral dose of Penicillamine ranges from 1 to 4 grams per day, divided into four doses.
• Normally, patients start with 250 mg per day and then slowly increase the dose to avoid side effects.
• The usual daily dose is around 2 grams.
• The goal is to adjust the dose to keep cystine excretion between 100 to 200 mg per day, especially if there's a history of stone formation, aiming to keep it below 100 mg per day.

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

• In the treatment of Wilson's disease, Penicillamine is typically administered orally.
• Initially, therapy can start at a lower dose of 250 to 500 mg per day to enhance tolerability.
• This dose is then increased gradually by 250 mg every 4 to 7 days until reaching a maintenance dose, usually between 750 to 1,000 mg per day, divided into two doses.
• According to the American Association for the Study of Liver Diseases (AASLD) guidelines, the maximum daily dose ranges from 1,000 to 1,500 mg, given in 2 to 4 divided doses.
• Manufacturer's labeling suggests a maximum dose of 2,000 mg per day, but clinical practice often limits this to 750 to 1,500 mg per day.
• For pregnant women, the daily dose should not exceed 750 mg, and during the last 6 weeks of pregnancy and postoperatively, the dose should be limited to 250 mg per day until wound healing is complete.
• The effectiveness of the therapy is monitored by checking the 24-hour urinary copper excretion, which should be kept above 2 mg/day for about three months initially, followed by maintenance doses that result in less than 10 mcg of serum free copper per deciliter.

Penicillamine (Vistamine) dose in Children

Note:

• When taking Penicillamine, the body's need for pyridoxine (vitamin B6) increases, so patients might need a daily pyridoxine supplement.
• Before surgery, the dose of Penicillamine might be lowered to 250 mg per day in adults.
• After surgery, once the wound heals, patients can resume the normal recommended dose of Penicillamine.

Penicillamine (Vistamine) dose in Wilson's disease:

• In the diagnosis of Wilson disease as an adjunct, a Penicillamine Challenge Test involves giving children aged 2 years and older and adolescents a dose of 500 mg for 2 doses. The first dose is administered just before starting a 24-hour urine collection, and the second dose is given 12 hours later. If the urinary copper excretion is greater than 1,600 mcg copper/24 hours (or >25 µmol/24 hours), it's consistent with Wilson disease.
• For treatment, children and adolescents typically start with an oral dose of 20 mg/kg/day, divided into 2 to 3 doses. The dose is rounded off to the nearest 250 mg. When the patient is clinically stable, the dose may be reduced by 25%. The maximum daily dose for adults is 1,500 mg/day.

Penicillamine (Vistamine) dose in the treatment of Cystinuria:

• In the treatment of Cystinuria in children and adolescents, the typical oral dose of Penicillamine ranges from 20 to 40 mg per kilogram of body weight per day, divided into 4 doses.
• The maximum daily dose should not exceed 40 mg/kg/day.
• If it's not possible to divide the doses equally, a larger portion can be given at bedtime.
• The dose should be adjusted to keep cysteine excretion below 100 to 200 mg/day, especially if there's a history of stone formation or pain.
• A gradual initiation of Penicillamine is recommended, starting at 5 mg/kg/day and increasing weekly by 5 mg/kg/day until reaching a final dose of 20 mg/kg/day; some patients may require further increases up to 40 mg/kg/day.
• This approach has been shown to effectively lower urinary cysteine concentrations and may limit treatment-associated toxicity.
• It's important for patients to adhere to the treatment regimen to prevent acute stone crisis or new stone formation.

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

• In the treatment of lead poisoning in children and adolescents, the optimal dose of Penicillamine is not firmly established.
• However, several dosing regimens have been suggested.
• Initially, a dose of 10 mg per kilogram of body weight per day, divided into two doses, is commonly used for two weeks.
• After this initial period, the dose is typically increased to a range of 25 to 40 mg per kilogram of body weight per day.
• Gradually increasing the dose over a few weeks may improve tolerability.
• Alternatively, a reduced dosage of 15 mg per kilogram of body weight per day, given in two divided doses, has also shown effectiveness in treating mild to moderate lead poisoning (blood lead concentration 20 to 40 mcg/dL) with fewer adverse effects.
• Lower doses ranging from 10 to 15 mg per kilogram of body weight per day for 4 to 12 weeks have been suggested for treating lead concentrations of 45 to 69 mcg/dL.
• However, it's important to note that Penicillamine is considered a third-line agent for children with blood lead levels greater than 45 mcg/dL and less than 70 mcg/dL according to the American Academy of Pediatrics (AAP); children with higher levels or symptomatic lead poisoning should be treated with parenteral agents.

Pregnancy Risk Factor D

• Penicillamine is risky during pregnancy, with a risk factor of D.
• Babies exposed to penicillamine during pregnancy have had birth defects, like congenital cutix laxa and other issues.
• It's not safe to use it for rheumatoid arthritis during pregnancy.
• For cystinuria treatment, doctors weigh the benefits against the risks.
• But, continuing treatment for Wilson's disease during pregnancy helps prevent relapse, though the dosage should be limited to 750 mg per day.
• If a cesarean section is planned, the dose should be reduced to 250 mg per day for the last 6 weeks of pregnancy and continued until the wound heals.

Penicillamine use during breastfeeding:

• It's uncertain if penicillamine passes into breast milk.
• The manufacturer advises against using it while breastfeeding.

Penicillamine (Vistamine) Dose adjustment in renal disease:

Manufacturer's Labeling:

• No dosage adjustments provided.
• Cautious dosing recommended due to mainly renal elimination.

Alternate Recommendations:

• Creatinine Clearance (CrCl) <50 mL/minute: Avoid use (Aronoff, 2007).
• Hemodialysis: Penicillamine is dialyzable; Administer 33% of usual dose (Aronoff, 2007). Consider reducing dosage to 250 mg 3 times per week after dialysis, especially for rheumatoid arthritis treatment (Swarup, 2004).

Penicillamine (Vistamine) Dose adjustment in liver disease:

• No dosage adjustments provided.
• Small fraction metabolized hepatically.

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):

Renal Insufficiency (in patients with rheumatoid arthritis):

• Avoid use in patients with renal insufficiency, especially those with rheumatoid arthritis.

Previous Penicillamine-related Aplastic Anemia or Agranulocytosis:

• Avoid if there's a history of penicillamine-related aplastic anemia or agranulocytosis.

Breastfeeding:

• Contraindicated during breastfeeding due to uncertain excretion into breast milk.

Pregnancy (in patients with rheumatoid arthritis):

• Avoid use during pregnancy, especially in patients with rheumatoid arthritis.

Additional Canadian Labeling Contraindications (not in US labeling):

• Hypersensitivity to Penicillamine: Avoid use in patients allergic to penicillamine or any component of the formulation.
• Chronic Lead Poisoning with Radiographic Evidence of Lead-containing Substances in GI Tract: Contraindicated in patients with chronic lead poisoning who have radiographic evidence of lead-containing substances in the gastrointestinal tract.
• Pregnancy (in Patients with Chronic Lead Poisoning): Avoid use during pregnancy in patients with chronic lead poisoning.
• Concomitant Use with Certain Medications: Avoid concomitant use with gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone, or phenylbutazone.

Warnings and precautions

Allergy reactions:

• About 33% of patients may experience allergic reactions with penicillamine. Rash can happen early or late in therapy.
• Early rashes typically go away when the drug is stopped and usually don't come back when restarting at a lower dose. Late-onset rashes, occurring after 6 months, should prompt discontinuation without rechallenge.

Bronchiolitis obliterans

• Rarely, penicillamine can cause bronchiolitis obliterans, a lung condition. Patients should report any unexplained breathing problems, like wheezing or coughing.

Dermatologic:

• Penicillamine can increase skin collagen, making it more fragile, especially in areas like knees and elbows. Bruising or bleeding may occur.
• Macular cutaneous eruptions with drug fever may happen 2-3 weeks after starting therapy.

Drug fever:

• Drug fever can occur, typically 2-3 weeks after starting treatment. It's especially common in rheumatoid arthritis patients. Discontinue for marked febrile response.

Gastrointestinal:

• Taste changes and oral ulcers may occur. Dose reduction may be needed for severe cases.

Goodpasture's Syndrome:

• Penicillamine has been linked to Goodpasture's syndrome, a severe condition affecting the kidneys and lungs. If unusual urinary findings accompany hemoptysis and lung infiltrates, stop treatment immediately.

Hematologic toxicities

• Fatalities from blood cell issues like agranulocytosis and aplastic anemia have been reported. Monitor blood counts regularly and discontinue if levels drop too low.

Hepatotoxicity:

• Liver function tests should be done periodically, especially in the first year of therapy.

Lupus erythematosus-like syndrome:

• Some patients may develop lupus-like symptoms, even with positive ANA tests. This doesn't always mean stopping treatment, but it should raise caution.

Pemphigus

• Pemphigus, a skin disorder, may occur during or after treatment. High-dose steroids or immunosuppressants may be needed.

Penicillin cross-sensitivity

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

Proteinuria/hematuria:

• Protein or blood in urine may develop. Monitor for kidney issues, and reduce dose if needed.

Myasthenia gravis:

• Penicillamine has been associated with myasthenia gravis. Symptoms usually go away after stopping the drug.

Toxicity symptoms: [US Boxed Warn]

• Patients should report symptoms of toxicity like fever, sore throat, or bleeding promptly.

Cystinuria:

• Continuation of daily treatment is crucial to avoid hypersensitivity. Pyridoxine supplementation is recommended.

Lead poisoning:

• Identify and remove lead sources before starting treatment.
• Penicillamine is a third-line option and should only be used when other therapies aren't tolerated.

Rheumatoid arthritis:

• Patients with poor nutrition should take pyridoxine supplements.

Wilson's disease

• Daily treatment should be continued without interruption. Pyridoxine supplements are recommended.

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

Risk Factor C (Monitor therapy)
Digoxin	PenicillAMINE may decrease the serum concentration of Digoxin.
Risk Factor D (Consider therapy modification)
Polyvalent Cation Containing Products	May decrease the serum concentration of PenicillAMINE. Management: Separate the administration of penicillamine and oral polyvalent cation containing products by at least 1 hour.
Risk Factor X (Avoid combination)
Gold Sodium Thiomalate	May enhance the adverse/toxic effect of PenicillAMINE. Specifically, this combination may increase the risk for serious hematologic and/or renal adverse reactions.

Monitoring parameters:

General Monitoring:

• Urinalysis, CBC with differential, platelet count, skin assessment, lymph nodes examination, and body temperature should be done twice weekly during the first month of therapy, then every 2 weeks for 5 months, followed by monthly checks.
• Liver function tests (LFTs) should be done every 6 months.

Hypersensitivity Signs/Symptoms:

• Keep an eye out for signs of hypersensitivity reactions.

Cystinuria:

• Monitor urinary cystine levels.
• Consider annual X-rays for renal stones.

Lead Poisoning:

• Check serum lead concentration at baseline and 7-21 days after completing chelation therapy.
• Monitor hemoglobin or hematocrit, iron status, and free erythrocyte protoporphyrin or zinc protoporphyrin.
• Look out for neurodevelopmental changes.

Wilson's Disease:

• Measure serum non-ceruloplasmin bound copper, 24-hour urinary copper excretion, and LFTs every 3 months during the first year of treatment.
• Consider periodic ophthalmic exams.

Proteinuria and Hematuria Monitoring:

• Monitor urine for protein and blood.
• If proteinuria develops, consider doing a quantitative 24-hour urine protein test at 1- to 2-week intervals initially (first 2-3 months).

How to administer Penicillamine (Vistamine)?

• Oral doses up to 500 mg can be given as a single dose. Doses exceeding 500 mg should be divided into multiple doses.
• For patients with difficulty swallowing capsules, the contents can be mixed with 15 to 30 mL of chilled puréed fruit or fruit juice and administered within 5 minutes.
• Take on an empty stomach, either 1 hour before or 2 hours after meals, and at least 1 hour apart from other medications, milk, antacids, and zinc-containing products. If taking iron-containing products, wait at least 2 hours.

Cystinuria:

• If giving unequal doses, administer the larger dose at bedtime.
• Ensure patients drink about one pint of fluid at bedtime and another pint during the night.

Mechanism of action of Penicillamine:

• Penicillamine works by chelating with heavy metals like lead, copper, and mercury, forming stable and soluble complexes that are then excreted in urine.
• Additionally, it can lower levels of circulating IgM rheumatoid factor and suppress T-cell activity, while sparing B-cell function.
• In the case of cystinuria, penicillamine combines with cystine to create a compound that is more soluble, helping to prevent the formation of cystine stones.

Onset of Action:

• Rheumatoid arthritis: Typically takes 2 to 3 months.
• Wilson disease: Onset usually occurs within 1 to 3 months.

Absorption:

• Rapid but incomplete, ranging from 40% to 70%.
• Absorption is reduced by food, antacids, and iron.

Protein Binding:

• More than 80% of penicillamine binds to albumin and ceruloplasmin.

Metabolism:

• Mostly metabolized in the liver, with small amounts converted to S-methyl-D-penicillamine.

Half-Life Elimination:

• Ranges from 1.7 to 7 hours, with significant variability.
• After prolonged treatment, a slow elimination phase lasting 4 to 6 days may occur upon stopping the medication.

Time to Peak Plasma Concentration:

• Typically peaks in the plasma between 1 to 3 hours after administration.

Excretion:

• Primarily excreted in urine, mostly 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:

Penicillamine Suspension 250 mg/5ml
Penisol- Vk Ds	Lisko Pakistan (Pvt) Ltd

 

Penicillamine 250 mg Tablets
Vistamin	Wilsons Pharmaceuticals

 

Penicillamine 500 mg Tablets
Penisol- Vk Ds	Lisko Pakistan (Pvt) Ltd