Cuprimine

Dosage for Penicillamine is highly individualized and depends strictly on the condition being treated and the patient's response to therapy. Healthcare providers typically use a "start low and go slow" approach, particularly in rheumatoid arthritis.

• Wilson's Disease: The standard adult dose is 750 mg to 1.5 grams per day, usually divided into four doses. Doses may be adjusted based on 24-hour urinary copper excretion levels. Some patients may require up to 2 grams per day.
• Cystinuria: The typical dose is 2 grams per day (range: 1 to 4 grams), divided into four doses. The goal is to keep urinary cystine excretion below 100-200 mg per day.
• Rheumatoid Arthritis: The initial dose is 125 mg or 250 mg once daily. If the patient tolerates this and does not show improvement within 2 to 3 months, the dose may be increased by 125 mg to 250 mg per day at 2- to 3-month intervals. Most patients respond to 500 mg to 750 mg per day.

Penicillamine is used in children for Wilson's disease and cystinuria, but its use in juvenile rheumatoid arthritis is less common and requires extreme caution.

• Wilson's Disease (Pediatric): Usually 20 mg/kg/day divided into two or three doses. The dose should be rounded to the nearest 250 mg increment.
• Cystinuria (Pediatric): Usually 30 mg/kg/day divided into three or four doses.

Renal Impairment

Penicillamine is primarily excreted by the kidneys. In patients with moderate to severe renal impairment, the drug can accumulate, leading to increased toxicity. Healthcare providers may reduce the dose or avoid use entirely in patients with significant kidney disease, especially when treating rheumatoid arthritis.

Hepatic Impairment

While Penicillamine is used to treat liver-related Wilson's disease, patients with pre-existing non-Wilson's hepatic impairment should be monitored closely for signs of drug-induced liver injury.

Elderly Patients

Clinical studies suggest that elderly patients may be more prone to skin rashes and renal toxicity. Dosing should be conservative, starting at the lowest end of the range, reflecting the higher frequency of decreased hepatic, renal, or cardiac function.

For maximum effectiveness, Penicillamine must be taken correctly:

• Timing: Take the medication on an empty stomach, at least 1 hour before or 2 hours after meals.
• Consistency: Take it at the same time(s) each day to maintain steady blood levels.
• Administration: Swallow capsules or tablets whole. Do not crush or chew them unless specifically instructed by your doctor.
• Vitamin B6: Because Penicillamine increases the body's requirement for pyridoxine (Vitamin B6), many doctors prescribe a daily 25 mg supplement of Vitamin B6 to prevent deficiency.
• Storage: Store at room temperature (20°C to 25°C / 68°F to 77°F) in a dry place, away from direct sunlight.

If you miss a dose, take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and return to your regular schedule. Do not double the dose to catch up, as this increases the risk of acute toxicity.

There is limited data on acute Penicillamine overdose. Symptoms may include severe nausea, vomiting, and acute allergic reactions. In the event of a suspected overdose, contact a poison control center immediately or seek emergency medical attention. Treatment is generally supportive.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop the medication without medical guidance, as stopping suddenly can cause a flare-up of Wilson's disease symptoms.

Penicillamine is associated with a high incidence of adverse reactions, which often lead to discontinuation of the drug. Common side effects include:

• Gastrointestinal Distress: Nausea, vomiting, epigastric pain, and diarrhea are frequent, especially during the first few weeks of therapy.
• Taste Alterations (Hypogeusia): A blunting or total loss of taste is common. This usually resolves spontaneously even with continued therapy, but it can take 2 to 3 months.
• Skin Rashes: An early rash (occurring within the first few months) is often generalized and itchy. It typically disappears within days of stopping the drug.

• Proteinuria: The presence of protein in the urine, which can be a sign of kidney irritation.
• Thrombocytopenia: A decrease in blood platelets, which may lead to easier bruising or bleeding.
• Leukopenia: A decrease in white blood cells, increasing the risk of infection.
• Stomatitis: Mouth sores or ulcers.

• Aplastic Anemia: A life-threatening condition where the bone marrow stops producing enough new blood cells.
• Goodpasture's Syndrome: A rare autoimmune disease that can cause bleeding in the lungs and kidney failure.
• Myasthenia Gravis: A condition causing muscle weakness, which Penicillamine can sometimes induce.
• Pemphigus: A group of rare autoimmune diseases that cause blistering of the skin and mucous membranes.

> Warning: Stop taking Penicillamine and call your doctor immediately if you experience any of the following:

• Hematologic Signs: Unusual bleeding, easy bruising, sore throat, or fever (may indicate bone marrow suppression).
• Renal Signs: Swelling in the face, feet, or ankles; cloudy or smoky urine (may indicate nephrotic syndrome).
• Pulmonary Signs: Shortness of breath, coughing up blood, or unexplained wheezing.
• Autoimmune Signs: Severe muscle weakness, drooping eyelids, or double vision.
• Severe Skin Reactions: Blistering, peeling, or painful rashes that cover large areas of the body.

Prolonged use of Penicillamine can lead to connective tissue changes. This includes Penicillamine-induced elastosis perforans serpiginosa (a skin condition) and increased skin friability. Some patients may develop a condition similar to systemic lupus erythematosus (SLE), characterized by joint pain and skin rashes. These symptoms usually resolve after the medication is discontinued.

According to the FDA, Penicillamine carries significant warnings regarding its toxicity. It should only be prescribed by physicians who are experienced in its use and who can provide the necessary close clinical and laboratory monitoring. The drug can cause severe blood disorders, including agranulocytosis and aplastic anemia, which have been fatal in some cases. Furthermore, it can cause significant kidney damage (nephrotic syndrome) and various autoimmune-like conditions.

Report any unusual symptoms to your healthcare provider immediately. Regular blood and urine tests are not optional; they are a critical safety requirement for anyone taking Penicillamine.

Penicillamine is a high-alert medication. Patients must be fully informed of the potential risks and the necessity of frequent laboratory monitoring. It is not a simple "painkiller" or "supplement"; it is a potent chemical modifier of the body's metabolism and immune system.

No FDA black box warnings for Penicillamine are currently listed in the same format as newer drugs, but the "Warnings" section of the official label functions as a boxed warning. It states: "Penicillamine should be used only by physicians who can monitor the patient for serious toxicity. Patients should be warned to report promptly any symptoms of granulocytopenia and/or thrombocytopenia, such as fever, sore throat, chills, bruising, or bleeding."

• Allergic Reactions: Patients with a history of penicillin allergy may theoretically be at higher risk for reacting to Penicillamine, although cross-reactivity is considered rare. However, severe allergic reactions, including anaphylaxis, have been reported.
• Nephrotoxicity: Penicillamine can cause significant damage to the renal glomeruli (the filtering units of the kidney). This often manifests as proteinuria. If protein levels in the urine exceed 1 gram per 24 hours, the drug may need to be stopped.
• Hepatotoxicity: While rare, Penicillamine can cause intrahepatic cholestasis (blocked bile flow) and toxic hepatitis. Patients should watch for yellowing of the skin or eyes (jaundice).
• Bone Marrow Suppression: This is the most dangerous side effect. It can occur at any time during therapy and may be sudden. Weekly blood counts are often required during the first few months of treatment.

To ensure safety, your healthcare provider will require the following tests:

• Complete Blood Count (CBC) with Differential: Weekly for the first month, then every two weeks for the next five months, and monthly thereafter.
• Urinalysis: To check for protein and blood in the urine, following the same schedule as the CBC.
• Liver Function Tests: Periodically to ensure the liver is processing the drug safely.
• Physical Exams: To check for skin changes, lymph node swelling, and signs of muscle weakness.

Penicillamine generally does not cause drowsiness or impairment of motor skills. However, if you experience rare side effects like myasthenia gravis (muscle weakness) or vision changes, you should avoid driving and consult your doctor immediately.

There is no direct chemical interaction between Penicillamine and alcohol. However, because both can stress the liver and kidneys, and because Wilson's disease patients already have compromised liver function, alcohol consumption should be strictly limited or avoided as per your specialist's advice.

In Wilson's disease, Penicillamine is usually a lifelong therapy. Stopping it can lead to a rapid and potentially fatal accumulation of copper. In rheumatoid arthritis, if the drug is stopped, it should be done under medical supervision to monitor for a flare-up of joint inflammation.

> Important: Discuss all your medical conditions with your healthcare provider before starting Penicillamine, especially any history of kidney disease or blood disorders.

Certain medications should never be combined with Penicillamine due to the risk of severe, additive toxicity:

• Gold Therapy (Auranofin, Aurothioglucose): Both Penicillamine and gold can cause severe kidney and blood marrow damage. Using them together significantly increases the risk of life-threatening toxicity.
• Antimalarials (Chloroquine, Hydroxychloroquine): When used for RA, these can increase the risk of skin and blood side effects.
• Phenylbutazone: This older NSAID is known for bone marrow suppression; combining it with Penicillamine is extremely dangerous.
• Cytotoxic Drugs (Cyclophosphamide, Azathioprine): Combining these with Penicillamine can lead to profound immune suppression and bone marrow failure.

• Digoxin: Penicillamine may decrease the blood levels of digoxin, potentially making it less effective for heart conditions. Digoxin levels should be monitored closely.
• Immunosuppressants: Drugs like corticosteroids may be used with Penicillamine, but the combination requires careful monitoring for increased infection risk.

• Antacids: Aluminum and magnesium-containing antacids can bind to Penicillamine in the gut, preventing its absorption. If an antacid is necessary, it should be taken at least 2 hours apart from Penicillamine.
• Iron Supplements: Ferrous sulfate and other iron products chelate with Penicillamine, reducing the effectiveness of both. Space these doses by at least 2 to 3 hours.

• Dairy Products: Calcium in milk and cheese can interfere with Penicillamine absorption. Always take the drug on an empty stomach.
• High-Protein Meals: Amino acids from protein can compete with Penicillamine for absorption in the small intestine. This is why the "1 hour before or 2 hours after meals" rule is critical.

• Zinc Supplements: Like iron and copper, zinc binds to Penicillamine. While zinc is sometimes used as a maintenance therapy for Wilson's disease, it should not be taken at the same time as Penicillamine.
• Magnesium Supplements: These can reduce Penicillamine absorption significantly.
• Vitamin B6 (Pyridoxine): This is a positive interaction. Penicillamine depletes B6, so supplementation is usually recommended by healthcare providers.

Penicillamine may interfere with certain laboratory tests:

• Urine Ketone Tests: It may cause a false-positive result for ketones in the urine when using nitroprusside-based reagents.
• Amino Acid Screening: It can alter the results of chromatography tests used to identify amino acids in the blood or urine.

For each major interaction, the mechanism is usually either chelation (the drug binds to the metal/mineral in the stomach) or additive toxicity (two drugs causing the same type of organ damage). Management always involves careful timing of doses or choosing alternative medications.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter vitamins.

There are several scenarios where Penicillamine must NEVER be used because the risks far outweigh any potential benefits:

1. 1History of Penicillamine-Induced Agranulocytosis or Aplastic Anemia: If a patient has previously experienced a severe drop in white blood cells or a total failure of the bone marrow due to this drug, they must never take it again. Re-exposure can be fatal.
2. 2Renal Insufficiency in Rheumatoid Arthritis: While Penicillamine is used for Wilson's disease patients with some kidney issues, it is strictly contraindicated in RA patients who have significant pre-existing renal impairment due to the high risk of nephrotic syndrome.
3. 3Breastfeeding: Penicillamine is excreted in human milk and poses a significant risk of toxicity to the nursing infant. Breastfeeding is generally contraindicated while on this medication.

These are conditions where the drug should only be used if the benefit is deemed essential and no other options exist:

• Pregnancy (Except Wilson's/Cystinuria): Penicillamine is known to cause birth defects. However, in Wilson's disease, the risk of the mother dying from copper toxicity if she stops the drug is often higher than the risk to the fetus. In RA, it is usually avoided during pregnancy.
• Mild to Moderate Renal Impairment: Requires extreme caution and frequent monitoring of urine protein levels.
• Active Infection: Because the drug can lower white blood cell counts, it may worsen the course of an infection.

• Penicillin Allergy: While Penicillamine is a derivative of penicillin, many patients with penicillin allergies tolerate it well. However, healthcare providers remain cautious, as severe cross-allergic reactions have been documented in rare instances. If you have a history of anaphylaxis to penicillin, ensure your doctor is aware.

> Important: Your healthcare provider will evaluate your complete medical history, including any past reactions to medications, before prescribing Penicillamine.

Penicillamine is classified as FDA Pregnancy Category D. This means there is clear evidence of human fetal risk based on adverse reaction data from investigational or marketing experience. Specifically, Penicillamine use during pregnancy has been associated with cutis laxa (a connective tissue disorder) in newborns.

However, for patients with Wilson's Disease, the American Association for the Study of Liver Diseases (AASLD) notes that therapy must continue during pregnancy, as stopping it can lead to hepatic failure. In such cases, the dose is often reduced to the lowest effective amount (usually 750 mg or less) to minimize fetal risk. For RA patients, Penicillamine should generally be discontinued before conception.

There is limited data on the exact concentration of Penicillamine in breast milk, but because of its low molecular weight, it is expected to pass to the infant. Due to the potential for serious adverse reactions in the nursing infant (such as blood disorders and skin issues), the manufacturer recommends that women taking Penicillamine do not breastfeed.

Penicillamine is approved for use in children for Wilson's disease and cystinuria. It is critical to monitor growth and development in these children, as the drug's effect on collagen and connective tissue could theoretically affect bone growth. Dosing is strictly weight-based (mg/kg). Its use in juvenile idiopathic arthritis is generally reserved for refractory cases and is managed by pediatric rheumatologists.

Elderly patients (over age 65) may be at increased risk for toxicity. Clinical experience suggests that the elderly have a higher incidence of skin rashes and a greater likelihood of developing proteinuria. Because renal function naturally declines with age, and Penicillamine is cleared renally, lower starting doses and more frequent monitoring are mandatory in this population.

In patients with kidney disease, the half-life of Penicillamine is prolonged. For Wilson's disease, the drug may still be used with extreme caution, but for RA, even mild renal impairment is often a reason to choose a different medication. Dose adjustments are based on the Glomerular Filtration Rate (GFR) and the presence of protein in the urine.

In Wilson's disease, the liver is the target organ for treatment. However, if a patient develops drug-induced hepatitis (evidenced by elevated liver enzymes not related to Wilson's), the drug must be stopped. There are no specific Child-Pugh based adjustments, but clinical monitoring for jaundice and liver tenderness is essential.

> Important: Special populations require individualized medical assessment and often more frequent laboratory testing.

Penicillamine is a thiol-containing compound (D-3-mercaptovaline). Its primary molecular mechanism involves the formation of stable, water-soluble complexes with heavy metals, particularly copper, mercury, lead, and iron. This process is known as chelation. The sulfhydryl group (-SH) on the penicillamine molecule binds to the metal ion, creating a ring structure that the body can then filter through the kidneys and excrete in the urine.

In cystinuria, Penicillamine reacts with the disulfide bond of cystine to form a penicillamine-cysteine mixed disulfide. This mixed disulfide is 50 times more soluble in urine than cystine, which prevents the crystallization of stones. In rheumatoid arthritis, the drug is thought to interfere with the formation of cross-links in collagen and may alter the immune response by inhibiting the activity of T-cells and decreasing the concentration of immune complexes.

• Dose-Response: The amount of copper excreted in the urine is directly proportional to the dose of Penicillamine administered, up to a plateau.
• Onset of Effect: In Wilson's disease, chelation begins immediately, but clinical improvement in neurological or hepatic symptoms may take months. In RA, the onset is slow, usually taking 2 to 3 months before any reduction in joint swelling or pain is noticed.
• Duration: The effect lasts as long as the drug is maintained at therapeutic levels in the blood.

| Parameter | Value |

|---|---|

| Bioavailability | 40% - 70% (Highly food-dependent) |

| Protein Binding | ~80% (Primarily to Albumin) |

| Half-life | 1 - 7 hours (Initial); Terminal is much longer |

| Tmax | 1 - 3 hours |

| Metabolism | Hepatic (to inactive disulfides) |

| Excretion | Renal (>80% as metabolites) |

• Molecular Formula: C5H11NO2S
• Molecular Weight: 149.21 g/mol
• Solubility: Freely soluble in water, slightly soluble in alcohol, and insoluble in ether.
• Structure: It is a white or off-white crystalline powder with a characteristic odor. It is the D-isomer of the amino acid valine with a thiol group substitution.

Penicillamine belongs to the class of Chelating Agents and Disease-Modifying Antirheumatic Drugs (DMARDs). While it is chemically related to penicillin, it has no antibiotic properties and should not be used to treat infections.