Cuprenil

Package Leaflet: Information for the User

CUPRENIL, 250 mg, coated tablets

(Penicillamine)

Read the package leaflet carefully before taking the medicine, as it contains important information for the patient.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including any not listed in this leaflet, please inform your doctor or pharmacist.

Table of Contents of the Leaflet

• 1. What is Cuprenil and what is it used for
• 2. Important information before taking Cuprenil
• 3. How to take Cuprenil
• 4. Possible side effects
• 5. How to store Cuprenil
• 6. Contents of the pack and other information

1. What is Cuprenil and what is it used for

Cuprenil is a medicine with high metal complexing activity. The action of the medicine involves binding to metals, mainly copper, mercury, lead, iron, and other heavy metals, forming stable, soluble complexes that are excreted in the urine.
It is a drug of choice in Wilson's disease (lenticular degeneration) - a disease characterized by abnormal copper metabolism in the body, which accumulates in various organs: kidneys, brain, liver, and eyes.
Cuprenil is also used in the treatment of rheumatoid arthritis. The mechanism of action of the medicine has not been precisely understood, but it probably reduces the titer of rheumatoid factor and the concentration of immunoglobulin complexes in serum and synovial fluid.
Cuprenil is used in the treatment and prevention of cystinuria, in which penicillamine forms a penicillamine-cysteine disulfide with cystine. It is more soluble than cystine and is easily excreted in the urine.
Cuprenil is also used in the treatment of lead poisoning and chronic active hepatitis.

2. Important information before taking Cuprenil

When not to take Cuprenil

• If you are allergic to the active substance (penicillamine) or any of the other ingredients of this medicine (listed in section 6).
• If you have systemic lupus erythematosus.
• If you have previously been treated with penicillamine and have experienced aplastic anemia or agranulocytosis.
• Due to the potential for harmful effects on the kidneys, penicillamine should not be used in patients with rheumatoid arthritis with concurrent kidney function disorders, currently or in the past.
• If you have chronic lead poisoning and an X-ray examination of the gastrointestinal tract reveals the presence of a lead-releasing object. Treatment with the medicine can be started after the removal of lead-containing substances from the gastrointestinal tract.
• If you are being treated with gold preparations, antimalarial drugs, cytostatics, oxyphenbutazone, or phenylbutazone.

Warnings and precautions

In some patients taking penicillamine, the following disorders have been observed:
aplastic anemia (bone marrow failure), agranulocytosis (deficiency of one type of white blood cell - neutrophils), thrombocytopenia (deficiency of platelets), Goodpasture's syndrome, and myasthenia gravis (a disease characterized by muscle weakness).
During treatment, every 2 weeks for the first 6 months of treatment, and then every month, the following should be performed: urinalysis, blood morphology with a smear, and platelet count.
During treatment, the following symptoms may occur: fever, sore throat, chills, petechiae, and bleeding. These symptoms indicate blood morphology disorders such as granulocytopenia and/or thrombocytopenia.
If the above symptoms occur, you should immediately inform your doctor and repeat the above tests.
During treatment, proteinuria (presence of protein in the urine) and/or hematuria (presence of red blood cells in the urine) may occur, which can be a warning sign of impending kidney damage. This disorder can lead to nephrotic syndrome associated with excessive protein loss in the urine. You should inform your doctor about these symptoms.
In some patients, the symptom of kidney damage (proteinuria) may disappear during treatment, while in others, proteinuria may persist, and penicillamine treatment should be discontinued. When proteinuria and hematuria occur, the doctor must ensure that the symptoms of kidney damage are related to treatment.
In patients with Wilson's disease or cystinuria treated with penicillamine, who have developed changes in urine, the doctor should consider discontinuing the medicine.
During penicillamine treatment in patients with cystinuria, it is recommended to perform an X-ray examination of the urinary system once a year to detect kidney stones as soon as possible. Cystine stones can form very quickly, sometimes within 6 months.
Although there is limited data on liver disorders, such as intrahepatic cholestasis and toxic hepatitis, the doctor should recommend performing liver function tests every 6 months during Cuprenil treatment.

You should immediately inform your doctor if you experience any of the following symptoms:

exertional dyspnea, unexplained cough, or wheezing.The doctor should consider performing pulmonary function tests.
Myasthenic syndrome has been reported, sometimes leading to the development of myasthenia gravis. Ptosis, diplopia, and weakness of the extraocular muscles are often early symptoms of myasthenia gravis. In most cases, myasthenia gravis symptoms disappear after discontinuation of penicillamine.
If you experience pemphigus (blistering of the skin), you should immediately discontinue penicillamine treatment.
Patients who have discontinued gold therapy due to serious side effects may be at increased risk of side effects during penicillamine treatment.
If treatment is discontinued for any reason, re-treatment should be started with small doses, gradually increasing them to achieve an effective therapeutic dose.
Precautions
Usually, within the second or third week of starting treatment, some patients may experience fever as a response to penicillamine. Fever is often accompanied by a rash.
An early allergic reaction in the form of a rash usually resolves within a few days of discontinuing the medicine and rarely occurs after re-administration of small doses of the medicine.
If you experience itching and a rash, your doctor may prescribe antihistamines. Re-administration of the medicine should be started with small doses.
Much less often, usually after 6 months or later, a late allergic reaction in the form of a rash is observed, which necessitates discontinuation of the medicine.
The occurrence of a drug rash with fever, joint pain, lymphadenopathy, and other allergic symptoms usually necessitates discontinuation of the medicine.
Patients allergic to penicillin may be cross-sensitive to penicillamine. The likelihood of side effects caused by contamination of penicillamine with trace amounts of penicillin during production has been eliminated, as penicillamine is now produced synthetically, not by degradation of penicillin.
Before planned surgery, due to the effect of penicillamine on collagen and elastin, your doctor should reduce the daily dose of the medicine to 250 mg. Treatment with a higher dose can be resumed only after complete healing of postoperative wounds.

Children and adolescents

Due to the availability of tablets only in a dose of 250 mg, the product is not suitable for use in younger children under 12 years of age.

Other medicines and Cuprenil

Inform your doctor about all medicines you have taken recently, including those available without a prescription.
Cuprenil increases the body's need for vitamin B6. A deficiency of vitamin B6 may contribute to the development of anemia or peripheral neuropathy.
The medicine binds to metals, so when taking iron-containing medicines, a 2-hour interval should be maintained between taking these medicines and Cuprenil.
The medicine should not be used concurrently with medicines that suppress bone marrow function, such as gold-containing medicines, antimalarial medicines, cytostatics, or those containing oxyphenbutazone or phenylbutazone.
The information in this leaflet may also apply to medicines used in the past or those that will be used in the future.

Taking Cuprenil with food and drink

The medicine should be taken on an empty stomach, at least 30 minutes before a meal (1 hour before a meal in children with Wilson's disease or cystinuria), with water.

Pregnancy and breastfeeding

Pregnancy

If you are pregnant or breastfeeding, or think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
The safety of using the medicine in pregnant women has not been established. Animal studies have shown that after administration of doses six times higher than the maximum recommended doses in humans, penicillamine causes congenital defects in the skeletal system and cleft palate in fetuses.
The use of Cuprenil in pregnant women depends on the indications:

• rheumatoid arthritis - the medicine should not be used
• cystinuria - the use of the medicine is not recommended
• Wilson's disease - it is recommended to reduce the daily dose to 1000 mg. Before a planned cesarean section, it is recommended to reduce the daily dose of the medicine to 250 mg for the last 6 weeks of pregnancy and until complete healing of postoperative wounds.

Breastfeeding

Ask your doctor or pharmacist for advice before taking any medicine.
There is no data on the penetration of the medicine into breast milk, so it is not recommended to use Cuprenil during breastfeeding.

Driving and using machines

The medicine is considered safe and does not cause disorders of psychophysical fitness to drive vehicles and operate machinery.
Cuprenil contains lactose monohydrate and azorubine lake (E 122). For this reason, if you have previously been diagnosed with intolerance to some sugars, you should contact your doctor before taking the medicine. Due to the presence of azorubine lake (E 122), Cuprenil may cause allergic reactions.

3. How to take Cuprenil

Cuprenil should always be taken according to your doctor's instructions. If you are unsure, ask your doctor or pharmacist.
The dose depends on the indication. In children, the dose may depend on body weight. Due to the dose, the medicine may not be suitable for very young children.
Rheumatoid arthritis, including juvenile rheumatoid arthritis

• Adults: 125 to 250 mg per day in the first month of treatment. Then, the dose should be increased every 4 to 12 weeks by 125 to 250 mg until the symptoms of the disease disappear. Then, the doctor will recommend taking the smallest effective dose that will prevent the symptoms of the disease from returning. If there is no improvement after 12 months of treatment, the doctor may recommend discontinuing the medicine. Usually, the maintenance dose is 500 to 750 mg per day. Do not take more than 1500 mg of the medicine per day. After 6 months from the disappearance of the disease symptoms, the doctor will recommend gradually reducing the dose of the medicine by 125 to 250 mg every 12 weeks.
• Patients in advanced age: Do not take a higher initial dose than 125 mg per day in the first month of treatment. Then, the doctor may recommend increasing the dose every 4 to 12 weeks by 125 mg until the symptoms of the disease disappear. Do not take more than 1000 mg of the medicine per day.
• Children: Usually, a dose of 15 to 20 mg/kg body weight per day is used. The initial dose should be smaller (2.5 to 5.0 mg/kg body weight per day) and can be gradually increased every 4 weeks for 3 to 6 months.

Wilson's disease

• Adults: 1500 mg to 2000 mg per day in divided doses. After the symptoms of the disease disappear, the doctor may recommend reducing the dose of the medicine to 750 mg or 1000 mg per day. Patients with adequate copper levels (negative copper balance) should take the smallest effective dose of the medicine. Doses of 2000 mg per day should not be used for more than 1 year.
• Patients in advanced age: Usually, a dose of 20 mg/kg body weight per day is used, in divided doses. The dose should be adjusted to achieve disappearance of the disease symptoms and maintain a negative copper balance.
• Children: Usually, a dose of 20 mg/kg body weight per day is used, in two or three divided doses, taken 1 hour before meals. For older children (over 12 years), the usual dose is 0.75 g to 1 g per day.

Cystinuria
The doctor will determine the smallest effective dose based on the results of the amino acid concentration in the urine.
Dissolving cystine stones

• Adults: 1000 to 3000 mg per day in divided doses. The cystine concentration in the urine should be maintained below 200 mg/l.

Preventing cystine stones

• Adults: The usual dose is 500 to 1000 mg per day, until the cystine concentration in the urine is less than 300 mg/l.
• Patients in advanced age: The doctor will recommend taking the smallest dose to achieve a cystine concentration in the urine of less than 200 mg/l.

Children: 20 to 30 mg/kg body weight per day in two or three divided doses, taken 1 hour before meals, adjusted to achieve a cystine concentration in the urine of less than 200 mg/l.
Note
During treatment, it is recommended to drink a large amount of fluids, at least 3 liters per day.
The patient should drink 500 ml of water before bedtime and another 500 ml at night, when the urine is more concentrated and acidic than during the day. Usually, the more fluids the patient drinks, the less they need Cuprenil.
The doctor should also recommend a diet low in the amino acid methionine to minimize cystine production. Such a diet is not recommended for children during growth or for pregnant women due to low protein content.
Lead poisoning

• Adults: The usual dose is 1000 to 1500 mg per day, in divided doses, until the lead excretion in the urine is within the range of 0.5 mg per day.
• Patients in advanced age: The usual dose is 20 mg/kg body weight per day, in divided doses, until the lead excretion in the urine is within the range of 0.5 mg per day.
• Children: The medicine should only be used when the blood lead level is less than 45 µg/dL. The total dose should be 15 to 20 mg/kg body weight per day in 2-3 divided doses.

Chronic active hepatitis

• Adults: The initial dose is 500 mg per day, in divided doses. Then, the dose can be gradually increased every 3 months, up to 1250 mg per day. During Cuprenil treatment, corticosteroids should not be used. The doctor will recommend periodic liver function tests to assess liver function.
• Children: The safety and efficacy of the medicine in children under 18 years of age with chronic active hepatitis have not been established. There are no available data.

If you feel that the effect of the medicine is too strong or too weak, ask your doctor.

Using a higher dose of Cuprenil than recommended

In case of overdose, inform your doctor, who will recommend appropriate treatment.
If you have taken a higher dose of the medicine than you should, or if someone else has taken it, immediately inform your doctor or pharmacist.

Missing a dose of Cuprenil

If you miss a dose of Cuprenil, take the next dose at the usual time. Do not take a double dose to make up for the missed dose.
In case of doubts about the use of the medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, Cuprenil can cause side effects, although not everybody gets them.
Frequency of side effects:

• very common - more than 1 in 10 patients
• common - more than 1 in 100 patients, but less than 1 in 10 patients
• uncommon - more than 1 in 1000 patients, but less than 1 in 100 patients
• rare - more than 1 in 10,000 patients, but less than 1 in 1000 patients
• very rare - less than 1 in 10,000 patients, not known (frequency cannot be estimated from the available data)

Common:
Allergic reactions, thrombocytopenia, lymphadenopathy, fever, joint pain, kidney damage, urinary tract infection, urticaria, rash, itching, oral mucositis.
Uncommon:
Agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia.
Rare:
Myasthenia gravis, lupus-like syndrome, Goodpasture's syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, cholestatic jaundice, optic neuritis, tinnitus, chronic bronchitis, pancreatitis, gastric ulcer recurrence.

Reporting side effects

If you experience any side effects, including any not listed in this leaflet, please inform your doctor or pharmacist. Side effects can be reported directly to the Department of Drug Safety Monitoring, Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products, Al. Jerozolimskie 181 C 02-222 Warsaw, Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl
Side effects can also be reported to the marketing authorization holder. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Cuprenil

Store in a temperature below 25°C.
Keep the medicine out of the sight and reach of children.
Do not use the medicine after the expiry date stated on the packaging. The expiry date refers to the last day of the month.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

What Cuprenil contains

The active substance of the medicine is penicillamine.

• 1 tablet contains 250 mg of penicillamine
• Other ingredients are: potato starch, lactose monohydrate, povidone, talc, magnesium stearate. The coating contains: hypromellose, macrogol 4000, titanium dioxide (E 171), azorubine lake (E 122).

What Cuprenil looks like and contents of the pack

Purple-pink, round, biconvex tablets with a uniform surface, without spots and damage.
2 blisters of 15 tablets (30 units) in a cardboard box.
1 bottle of 100 tablets.

Marketing authorization holder

Teva Pharmaceuticals Polska Sp. z o.o.
ul. Emilii Plater 53
00-113 Warsaw
Poland
tel.: (22) 345 93 00

Manufacturer

Teva Operations Poland Sp. z o.o.
ul. Mogilska 80
31-546 Kraków
Date of last revision of the leaflet:April 2022