Cuprenil^® (Tablets) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Teva Operations Poland, Sp. z o.o. (Poland)

ATC Code

M01CC01 (Penicillamine)

Active Substance

Penicillamine (Rec.INN registered by WHO)

Dosage Form

Cuprenil®

Film-coated tablets, 250 mg: 30 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets purple-pink in color, round, biconvex, with a smooth surface without spots or chips.

Excipients: potato starch – 43.75 mg, lactose monohydrate – 166.25 mg, povidone K25 – 25 mg, talc – 10 mg, magnesium stearate – 5 mg.

Shell composition hypromellose – 10.51 mg, macrogol 4000 – 0.8 mg, titanium dioxide (E171) – 2.51 mg, azorubine colorant (E122) – 1.18 mg.

15 pcs. – blisters (2) – cardboard packs with first opening control.
100 pcs. – polyethylene bottles (1) – cardboard packs^×.

^× protective stickers may be additionally applied.

Clinical-Pharmacological Group

Chelating agent

Pharmacotherapeutic Group

Anti-inflammatory agent

Pharmacological Action

Cuprenil^® has high complex-forming activity towards metals, mainly copper, mercury, arsenic, lead, iron, and calcium.

The drug reduces the resorption of copper from food and eliminates its excess from tissues.

It affects various parts of the immune system (suppression of T-helper function of lymphocytes, inhibition of neutrophil chemotaxis and release of enzymes from the lysosomes of these cells, enhancement of macrophage function).

It has the ability to disrupt collagen synthesis by breaking the cross-links between newly synthesized tropocollagen molecules.

Penicillamine is a pyridoxine antagonist; it has an anti-inflammatory effect.

Pharmacokinetics

The drug forms chelates with heavy metal ions – stable complex compounds, soluble in water and excreted in the urine.

It is easily absorbed from the digestive tract, reaching C_max in the blood within 1-3 hours. Up to 50% of penicillamine is absorbed in the gastrointestinal tract.

The drug is metabolized in the liver.

Elimination of the drug occurs in 2 phases: T_1/2 for the first is 1 hour, for the second – reaches 90 hours. About 70-80% of the absorbed drug is excreted as metabolites (cysteine-Penicillamine, disulfide) in the urine.

Indications

• Wilson’s disease;
• Poisoning with copper, inorganic mercury compounds, lead (provided further lead ingestion through the gastrointestinal tract is excluded), gold, zinc, iron;
• Cystine nephrolithiasis;
• Systemic scleroderma;
• Rheumatoid arthritis.

ICD codes

Dosage Regimen

The drug should be taken orally at least 30 minutes before meals, with water, or 2 hours after meals or other medications.

Wilson’s disease

Adults 1.5 – 2 g/day in divided doses. After achieving disease remission, the dose can be reduced to 0.75 g or 1 g/day. In patients with a negative copper balance, the minimum effective dose of penicillamine should be used.

The dose of 2 g/day should be used for no more than 1 year.

Elderly patients 20 mg/kg body weight/day in divided doses. The dose should be adjusted to achieve disease remission and maintain a negative copper balance.

Children usually 20 mg/kg body weight/day in divided doses. Minimum dose – 500 mg/day

Cystinuria

It is best to establish the minimum effective dose after quantitative determination of the concentration of amino acids in the urine by chromatographic method.

Dissolution of cystine stones

Adults 1-3 g/day in divided doses. The concentration of cystine in the urine should be kept below 200 mg/l.

Prevention of cystine lithiasis.

Adults 0.5-1 g/day until the concentration of cystine in the urine is below 300 mg/l.

Elderly patients are prescribed the minimum dose until the concentration of cystine in the urine is below 200 mg/l.

Children The minimum dose is prescribed, which allows achieving a concentration of cystine in the urine below 200 mg/l.

Attention: during treatment, it is recommended to drink plenty of fluids – at least 3 liters per day. The patient should drink 500 ml of water before going to bed and then 500 ml at night when the urine is more concentrated and more acidic than during the day. Usually, the more fluid the patient drinks, the lower their need for penicillamine.

A diet low in methionine is also recommended to keep cystine synthesis as low as possible. Due to the low protein content, such a diet is not recommended for children during growth and pregnant women.

Lead poisoning

Adults 1-1.5 g/day in divided doses until urinary lead excretion reaches 0.5 mg/day.

Elderly patients 20 mg/kg body weight/day in divided doses until urinary lead excretion reaches 0.5 mg/day.

Children 20 mg/kg body weight/day.

Rheumatoid arthritis

Adults 250 mg/day during the first month of using the drug. Then the dose is increased every 4-12 weeks by 250 mg until disease remission is achieved. After that, the minimum effective dose is used, which allows suppressing the symptoms of the disease. If the therapeutic effect is not achieved within 6 months of using the drug, treatment should be discontinued.

The maintenance dose is usually 500-750 mg/day. The dose of 1.5 g of the drug per day should not be exceeded. After achieving disease remission lasting 6 months, it is recommended to gradually reduce the dose of the drug by 250 mg every 12 weeks.

Elderly patients the initial dose should not exceed 250 mg/day during the first month of using the drug. Then the dose can be increased every 4-12 weeks by 250 mg until disease remission is achieved. The dose of 1 g of the drug per day should not be exceeded.

Children usually 15-20 mg/kg body weight/day. The initial dose is 2.5-5.0 mg/day, it can be gradually increased every 4 weeks for 3-6 months to the minimum effective dose, but not more than 500 mg.

Systemic scleroderma

250 mg/day during the first month of using the drug. Then the dose is increased every 4-12 weeks by 250 mg to 1 g/day with a subsequent reduction to 250-500 mg/day. The effect is evaluated after 6-12 months of using the drug.

Adverse Reactions

Anorexia, nausea, vomiting, diarrhea, aphthous stomatitis, glossitis; intrahepatic cholestasis, pancreatitis; skin rash; epidermal necrolysis; complete loss or distortion of taste sensations, reversible polyneuritis (associated with pyridoxine deficiency); nephritis, hematuria; eosinophilia, thrombocytopenia, leukopenia; anemia (aplastic or hemolytic), agranulocytosis; allergic alveolitis, interstitial pneumonitis, diffuse fibrosing alveolitis, Goodpasture’s syndrome; myasthenia, polymyositis, dermatomyositis, polyneuritis; fever; lupus-like reactions (arthralgia, myalgia, erythematous rash, appearance of antinuclear antibodies and antibodies to DNA); breast enlargement with the development of galactorrhea (in women); alopecia.

Contraindications

• Agranulocytosis;
• Renal failure;
• Hematopoiesis disorders;
• Pregnancy and breastfeeding period (except for Wilson’s disease in a dose up to 1 g/day);
• Children under 3 years of age (for this dosage form);
• Hypersensitivity to penicillamine and other components of the drug.

Should not be used in combination with gold preparations, aminoquinoline and cytostatic drugs, phenylbutazone.

With caution: during surgical interventions, anemia, proteinuria.

Use in Pregnancy and Lactation

Contraindication: pregnancy and breastfeeding period (except for Wilson’s disease in a dose up to 1 g/day).

Use in Renal Impairment

Contraindication: renal failure.

Pediatric Use

Contraindication: children under 3 years of age (for this dosage form).

Geriatric Use

Dose adjustment is required (see Dosage Regimen).

Special Precautions

When using Cuprenil^®, constant medical supervision is required: complete blood test (including platelet count) and urine test every 3 days, then every week; monitoring of kidney function; general and neurological examinations every month. In case of side effects, which the patient is obliged to inform the doctor about, the drug should be immediately discontinued, and after they cease, it can be reused at the doctor’s discretion, starting from the lowest dose.

Precautions should be taken when using Cuprenil^® and anti-inflammatory or other agents that may cause bone marrow function disorders simultaneously.

In case of discontinuation of gold preparations due to lack of effect, Cuprenil^® can be used after 6 months.

Patients with impaired renal function should appropriately reduce the dose of the drug and use it with caution.

If the patient is recommended treatment with iron preparations, a two-hour interval should be observed when using Cuprenil^®.

Due to the effect of penicillamine on collagen and elastin, any surgical interventions (including dental) during the use of the drug should be performed with caution.

During treatment, urine analysis and clinical blood test should be monitored once every 2 weeks for the first 6 months of treatment, then monthly; kidney and liver function should be monitored once every 6 months. In Wilson’s disease or cystinuria, pyridoxine is prescribed for continuous use simultaneously with penicillamine (due to dietary restrictions used to treat these diseases); during long-term treatment, these patients should regularly undergo X-ray or ultrasound examination of the kidneys and urinary tract. When using Cuprenil^®, it is necessary to compensate for the deficiency of vitamin B₆. If signs of pyridoxine deficiency develop in patients with rheumatoid arthritis, and if these signs do not resolve on their own, 25 mg of pyridoxine per day is additionally prescribed. If fever, increasing proteinuria, hematuria, lung or liver damage, severe hematological or neurological disorders, myasthenia, hematuria, lupus-like reactions or other severe adverse reactions develop during treatment, the drug is discontinued and glucocorticosteroids are prescribed if necessary. In case of isolated proteinuria, if it does not increase and does not exceed 1 g/day, treatment with penicillamine is continued, in other cases – discontinued.

Effect on the ability to drive vehicles and mechanisms

The drug does not cause impairment of psychophysical functions, the ability to drive vehicles and operate moving mechanical devices.

Overdose

No cases of overdose have been reported. Antidote is unknown. Treatment is symptomatic.

Drug Interactions

Cuprenil^® is a vitamin B₆ antagonist.

The drug should not be used with drugs that can cause bone marrow function disorders.

The drug forms stable complex compounds with heavy metals.

Antimalarial drugs, levamisole and phenylbutazone increase the risk of side effects.

Antacids reduce the absorption of the drug.

Storage Conditions

Store at a temperature from 15°C (59°F) to 25°C (77°F), in a place inaccessible to children.

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.