Cisplatin — ebewe: detailed information

Package leaflet: Information for the patient

Cisplatin-Ebewe
1 mg/ml, concentrate for solution for infusion
Cisplatinum
Please read all of this leaflet carefully before using this medicine because it contains
important information for you.

Keep this leaflet, as you may need to read it again.
If you have any further questions, ask your doctor, pharmacist or nurse.
This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm them even if their symptoms are the same.
If you experience any adverse reactions, including any possible adverse reactions not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Leaflet contents:

What Cisplatin-Ebewe is and what it is used for
Important information before using Cisplatin-Ebewe
How to use Cisplatin-Ebewe
Possible side effects
How to store Cisplatin-Ebewe
Contents of the pack and other information

1. What Cisplatin-Ebewe is and what it is used for

Cisplatin-Ebewe is used in the treatment of cancer. It may be administered alone
(monotherapy) or in combination with other medicines as part of chemotherapy.
Cisplatin-Ebewe is used to treat:

Malignant testicular and ovarian tumours,
Malignant cervical and bladder tumours, head and neck squamous cell carcinoma, lung cancer.

2. Important information before using Cisplatin-Ebewe

When not to use Cisplatin-Ebewe
if the patient has previously experienced an allergic reaction (hypersensitivity) to cisplatin, to other drugs containing platinum, or to any of the other ingredients of this medicine (listed in section 6).
if the patient has impaired kidney function.
if the patient is dehydrated (has lost a significant amount of fluids, e.g. due to diarrhoea or vomiting).
if the patient's bone marrow is not producing blood cells.
if the patient has hearing disorders.
if the patient has nerve damage caused by cisplatin (called neuropathy).
in breastfeeding women.
if the patient is scheduled to receive the yellow fever vaccine.

if the patient is taking phenytoin (used in the treatment of epilepsy).

Warnings and precautions
Before starting treatment with Cisplatin-Ebewe, discuss this with your doctor, pharmacist, or nurse.

Cisplatin-Ebewe may have harmful effects on the nervous system (causing neuropathy), which may manifest as tingling sensations, reduced reflexes, disturbances in deep sensation, and tremors.

Motor disturbances may also occur. The patient will be systematically subjected to neurological examinations.

Cisplatin-Ebewe may cause hearing damage. Symptoms may include tinnitus and/or impaired hearing of high-frequency sounds. Occasionally, impaired speech hearing may occur. The harmful effect on the auditory organ may be more pronounced in children. Hearing loss may be unilateral or bilateral; it occurs more frequently and severely after repeated administration of the drug. Before starting treatment and before each subsequent treatment cycle, the doctor will order a hearing test (so-called audiometry).
Cisplatin-Ebewe may cause kidney damage. To prevent this, the patient will receive large amounts of fluids intravenously before and after drug administration.
Before starting treatment with cisplatin, and during and after completion of treatment, the doctor will order blood tests as well as tests of kidney and liver function. These tests should be repeated weekly throughout the treatment period.
During treatment with Cisplatin-Ebewe, hypersensitivity reactions may occur, sometimes life-threatening.
If a woman or man plans to have children, genetic counselling is recommended after completion of treatment (cisplatin may cause genetic changes).
Cisplatin-Ebewe may cause irreversible infertility in men; therefore, before starting treatment, advice should be sought regarding the possibility of sperm cryopreservation.
Patients must use effective contraception to prevent pregnancy during treatment with cisplatin and for a certain time after treatment ends (see section "Pregnancy, breastfeeding and fertility").
Some medicines taken concurrently with cisplatin may enhance its harmful effects on the auditory organ, kidneys, and nervous system (see section "Cisplatin-Ebewe and other medicines").
After administration of Cisplatin-Ebewe, nausea, vomiting, and diarrhoea may occur. In most patients, these symptoms resolve within 24 hours, while milder nausea and loss of appetite may persist for up to a week after drug administration.
If nausea and vomiting occur after administration of Cisplatin-Ebewe, the doctor will prescribe antiemetic medications. These may also be taken preventively. It is necessary to replenish fluids lost during vomiting and diarrhoea.

Before using Cisplatin-Ebewe, the patient should inform the doctor if they have:

peripheral nerve damage (so-called peripheral neuropathy) not caused by cisplatin,
acute infection caused by bacteria or viruses.

Re-administration of Cisplatin-Ebewe to the patient is possible only after normal results of blood tests, kidney and liver function tests, and hearing tests have been obtained.

Cisplatin-Ebewe and other medicines
Tell your doctor, pharmacist, or nurse about all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take, including those available without a prescription.

Do not use the following medicines concurrently with Cisplatin-Ebewe. Inform your doctor or nurse if the patient is taking:

medicines that suppress bone marrow function,
radiotherapy (radiation therapy),
medicines that lower blood pressure (such as furosemide, hydralazine, diazoxide, and propranolol),
medicines used in the treatment of gout (i.e. allopurinol, probenecid, sulfinpyrazone, colchicine),
medicines that increase urine production (so-called loop diuretics, such as furosemide, torasemide, ethacrynic acid),
antihistamines (i.e. buclizine, cyclizine, loxapine, meclizine, phenothiazines, thioxanthenes, or trimethobenzamides), as they may mask symptoms of hearing damage (dizziness and tinnitus),
medicines used in the treatment of certain cancers (so-called cytostatics, e.g. methotrexate, hexamethylmelamine, paclitaxel, docetaxel, etoposide),
vitamin B_,
anticonvulsant medicines (i.e. phenytoin),
penicillamine (a medicine used, among others, in the treatment of lead or copper poisoning), as it may reduce the effectiveness of Cisplatin-Ebewe,
cyclosporine (an immunosuppressive medicine used to suppress immune system function, used in organ transplant recipients or in atopic dermatitis),
oral anticoagulants (medicines preventing blood clot formation),
vaccines containing live viruses (these should not be administered during treatment or within 3 months after discontinuation of Cisplatin-Ebewe),
yellow fever vaccine.

Medicines that may cause kidney damage:

certain antibiotics, such as cephalosporins, aminoglycoside antibiotics, amphotericin B,
contrast agents used in diagnostic imaging.

Medicines that may cause hearing damage:

aminoglycoside antibiotics (e.g. streptomycin, neomycin, gentamicin),
ifosfamide (a cytostatic agent).

Medicines that may cause nervous system damage:

certain cytostatic agents (e.g. paclitaxel, docetaxel, bleomycin, vinblastine).

Pregnancy, breastfeeding and fertility
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or plans to have a child, she should consult her doctor before using this medicine.

Pregnancy
Cisplatin administered to a pregnant woman may be toxic to the foetus and may cause severe congenital malformations. Cisplatin-Ebewe should not be used during pregnancy unless the physician considers it absolutely necessary. Inform the doctor immediately if the patient is pregnant or suspects she may be pregnant.

Women of childbearing potential should use effective contraception during treatment and for at least 7 months after completion of treatment to prevent pregnancy.

Men undergoing treatment with cisplatin are advised to use effective contraception and not father children during treatment and for at least 4 months after stopping treatment.

If patients (women and men) plan to have children, they must undergo genetic testing after completion of treatment.

Fertility
Cisplatin may cause infertility; therefore, it is recommended that men who plan fatherhood in the future seek advice before starting treatment regarding the possibility of sperm cryopreservation.

Breastfeeding
Cisplatin passes into human milk. The use of Cisplatin-Ebewe in breastfeeding women is contraindicated. Breastfeeding mothers should discontinue breastfeeding during cisplatin treatment.

Driving and operating machinery
Cisplatin-Ebewe may affect the ability to drive and operate machinery; therefore, caution should be exercised when performing these activities. Patients experiencing adverse effects such as drowsiness or vomiting should not drive or operate machinery.

Cisplatin-Ebewe contains sodium
The medicine contains 3.54 mg of sodium (the main component of table salt) in 1 ml of concentrate.
The medicine contains 35.4 mg of sodium (the main component of table salt) in a 10 ml vial. This corresponds to 1.77% of the maximum recommended daily sodium intake in the diet of adults.
The medicine contains 71 mg of sodium (the main component of table salt) in a 20 ml vial. This corresponds to 3.55% of the maximum recommended daily sodium intake in the diet of adults.
The medicine contains 177 mg of sodium (the main component of table salt) in a 50 ml vial. This corresponds to 8.85% of the maximum recommended daily sodium intake in the diet of adults.
The medicine contains 354 mg of sodium (the main component of table salt) in a 100 ml vial. This corresponds to 17.7% of the maximum recommended daily sodium intake in the diet of adults.

The medicine may be diluted in 0.9% NaCl solution. The sodium content originating from the diluent should be taken into account when calculating the total sodium content in the prepared diluted solution. For accurate information regarding the sodium content in the solution used to dilute the medicine, refer to the patient leaflet of the diluent used.

3. How to use Cisplatin - Ebewe

Cisplatin - Ebewe must be administered only under the supervision of an oncologist experienced
in the use of chemotherapy. Cisplatin - Ebewe must not be used without medical supervision.
The dosage and duration of treatment are determined by the physician.

Use of a higher than recommended dose of Cisplatin - Ebewe
Receiving an excessive amount of Cisplatin - Ebewe is unlikely, but if the patient suspects
that too much medication has been administered, they should immediately contact their doctor or
nurse.

Acute overdose of cisplatin may cause kidney failure, liver failure, hearing loss, ocular toxicity (including retinal detachment), severe bone marrow suppression, nausea, vomiting, and/or peripheral neuropathy. Overdose may result in death.

Overdose (>200 mg/m² BSA) may directly affect the respiratory center due to cisplatin crossing the blood-brain barrier, potentially leading to respiratory disturbances resulting in death, as well as acid-base imbalances.

In case of overdose, the physician will prescribe administration of large amounts of intravenous fluids and medications that increase urine production.

Missed dose of Cisplatin - Ebewe
Do not administer a double dose to make up for a missed dose.

If you have any further questions regarding the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
Adverse reactions following cisplatin administration depend on the dose used and may intensify with subsequent doses. Severe nausea and vomiting occur in most patients during cisplatin treatment. Nausea may persist for up to 7 days after administration of the medicine.

Severe adverse reactions
Seek immediate medical attention if the patient experiences:

severe pain or swelling in the legs, chest pain, or difficulty breathing (which may indicate dangerous blood clots in veins) (common: may occur in 1 out of 10 patients).

Very common adverse reactions (may affect more than 1 in 10 people):

bone marrow suppression and reduced white blood cell count (increased susceptibility to infections), reduced platelet count (increased tendency to bruising), and reduced red blood cell count (may cause anaemia);
decreased sodium levels in blood;
fever.

Common adverse reactions (may affect up to 1 in 10 people):

infections, including sepsis (characterised by rapidly rising fever, chills, rapid breathing, and fast heartbeat);
heart rhythm disorders, including very slow heartbeat (bradycardia), very fast heartbeat (tachycardia), and other electrocardiogram (ECG) changes.

Uncommon adverse reactions (may affect up to 1 in 100 people):

allergic reactions, including severe ones (facial swelling, wheezing, bronchospasm, increased heart rate, hypotension, as well as rash, urticaria, skin redness, and itching);
decreased magnesium levels in blood;
hearing damage;
metallic deposits on gums;
disturbances in sperm production and maturation;
ovulation disorders;
breast enlargement in men (gynaecomastia).

Rare adverse reactions (may affect up to 1 in 1,000 people):

risk of developing secondary acute leukaemia;
weakened immune defences (suppression of immune system function);
increased blood cholesterol levels (hypercholesterolaemia);
nervous system disorders (seizures, peripheral neuropathy, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome, loss of vital brain functions, including severe cerebrovascular complications, cerebral artery inflammation, carotid artery occlusion, encephalopathy);
myocardial infarction, hypertension (may occur even several years after completion of chemotherapy);
inflammation of the oral mucosa.

Very rare adverse reactions (may affect up to 1 in 10,000 people):

increased iron levels in blood;
cardiac arrest (particularly when treated in combination with other cytotoxic medicines).

Adverse reactions with unknown frequency (frequency cannot be estimated from available data):

infection (may be life-threatening);
anaemia due to destruction of red blood cells (haemolytic anaemia);
positive Coombs test;
increased blood amylase activity;
inappropriate antidiuretic hormone secretion;
dehydration;
decreased calcium levels in blood (hypocalcaemia), tetany;
decreased phosphate levels in blood (hypophosphataemia);
decreased potassium levels in blood (hypokalaemia);
increased uric acid levels in blood (hyperuricaemia);
cerebrovascular incident, haemorrhagic stroke, ischaemic stroke, cerebral arteritis;
Lhermitte’s sign (a sensation of an electric shock running down the spine when bending the head forward);
loss of taste sensation;
myelopathy;
autonomic neuropathy (nerve damage);
blurred vision, colour vision disturbances, eye movement disorders, cortical blindness, optic neuritis, optic disc swelling, retinal pigmentation;
tinnitus, deafness, vestibular disturbances with dizziness;
thrombotic microangiopathy (e.g. thrombotic changes in small vessels of various organs with haemolytic-uraemic syndrome), Raynaud’s disease;
vomiting, nausea, anorexia, hiccups, diarrhoea, stomach pain;
increased liver enzyme activity, increased blood bilirubin levels, decreased albumin levels, increased blood urea nitrogen, creatinine, uric acid, and (or) decreased creatinine clearance;
pulmonary embolism;
rash, hair loss;
muscle cramps;
kidney failure (including acute), tubular disorders;
weakness, malaise;
heart disorders;
extravasation at the injection site (with local soft tissue damage, including phlebitis, fibrosis, necrosis, pain, swelling, and redness).

Hearing disorders manifest as tinnitus and (or) impaired hearing of high-frequency sounds (4000–8000 Hz). These are dose-dependent, may be irreversible, and sometimes affect only one ear.
Hearing impairment caused by cisplatin may be particularly severe in children.
Cranial irradiation before or during cisplatin administration increases the risk of hearing loss.
Anorexia, nausea, vomiting, stomach pain, and diarrhoea often occur between 1 and 4 hours after cisplatin administration and resolve within 24 hours in most patients. Milder nausea and anorexia may persist for up to 7 days after treatment.
Following intravenous administration, local swelling, pain, redness, skin ulceration, and phlebitis may occur at the injection site.
Approximately 14 days after cisplatin administration, a significant decrease in white blood cell count is commonly observed (<1.5 x 10⁹/L in 5% of patients). Platelet count reduction becomes noticeable after about 3 weeks (<50 x 10⁹/L in <10% of patients). The recovery period to normal values is approximately 39 days. Anaemia occurs with similar frequency but usually develops later than leucopenia and thrombocytopenia.
If neurological symptoms occur, cisplatin treatment should be discontinued immediately. Neurotoxic effects caused by cisplatin may be reversible, but in 30–50% of patients, changes are irreversible even after treatment ends. Neurotoxicity may occur after the first dose of cisplatin or after a prolonged treatment period. Severe neurotoxicity may occur in patients who have received cisplatin at high concentrations or over a long duration.

Reporting of adverse reactions
If any adverse reactions occur, including those not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring of Adverse Drug Reactions, 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
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Cisplatin - Ebewe

Keep this medicine out of the sight and reach of children.
Store below 25°C. Keep in the original packaging to protect from light.
Do not store in the refrigerator or freeze.
Do not use this medicine after the expiry date stated on the carton after EXP. The expiry date refers to the last day of the specified month.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the package and other information

What Cisplatin - Ebewe contains
The active substance is cisplatin. 1 ml of concentrate contains 1 mg of cisplatin.
The other ingredients are: sodium chloride, hydrochloric acid (diluted) and water for injections.

What Cisplatin - Ebewe looks like and contents of the pack
The concentrate is a clear, colourless solution.
The medicine is available in vials containing 10 mg/10 ml, 20 mg/20 ml, 50 mg/50 ml or 100 mg/100 ml.
Vials may be placed in transparent containers made of plastic (e.g. ONKO-Safe or Sleeving).

Marketing Authorisation Holder and Manufacturer
EBEWE Pharma Ges.m.b.H. Nfg. KG
Mondseestrasse 11
4866 Unterach, Austria

Manufacturer
Fareva Unterach GmbH
Mondseestraße 11
4866 Unterach, Austria

For more detailed information, please contact:
Sandoz Polska Sp. z o.o.
ul. Domaniewska 50 C
02-672 Warsaw
tel. 22 209 70 00

Information intended exclusively for medical professionals

Dosage
Cisplatin dosage depends on the underlying disease, expected response, and whether cisplatin is used as monotherapy or as part of combination chemotherapy.
For monotherapy, the following two dosage regimens are recommended:

Single dose of 80–100 mg/m² administered every 3 to 4 weeks,
20 mg/m²/day for 5 consecutive days every 3 to 4 weeks.

If cisplatin is used in combination chemotherapy, the dose should be reduced.
The dose typically ranges from at least 20 mg/m², administered every 3–4 weeks.
Dosage should be appropriately reduced in patients with impaired renal function or suppressed bone marrow function.

The cisplatin solution, prepared according to instructions, should be administered as an intravenous infusion over 6 to 8 hours.

Adequate hydration of the patient is essential, starting 2 to 12 hours before administration and continuing for at least 6 hours after cisplatin infusion. Hydration is necessary to ensure sufficient urine output (diuresis) during and after cisplatin administration. This can be achieved by intravenous infusion of one of the following solutions:

0.9% sodium chloride solution,
0.9% sodium chloride solution with 5% glucose solution (1:1).

Pre-infusion hydration:
Intravenous infusion at 100 to 200 ml/hour for 6 to 12 hours.
Post-infusion hydration:
Intravenous infusion of an additional 2 liters at 100 to 200 ml/hour over 6 to 12 hours.

If urine output after hydration is less than 100 to 200 ml/hour, forced diuresis may be required. Forced diuresis can be induced by intravenous administration of 37.5 g mannitol (375 ml of 10% mannitol solution) or by administration of a diuretic, provided renal function is normal. Administration of mannitol or a diuretic is also necessary when the administered cisplatin dose exceeds 60 mg/m². To ensure adequate urine output, the patient should drink large amounts of fluids for 24 hours following the end of cisplatin infusion.

Extravasation
In case of extravasation, cisplatin infusion must be stopped immediately. The needle should not be removed. The extravasated cisplatin solution should be aspirated from the tissue and the area flushed with 0.9% sodium chloride solution (if a cisplatin solution with higher concentration than recommended was used).

Storage of the medicinal product
Vials after opening, prior to dilution
The concentrate should be withdrawn from the vial immediately before use.
From a microbiological standpoint, the product should be used immediately. Otherwise, the responsibility for storage conditions and duration of the remaining product in the vial lies with the user. Physical and chemical stability of the product has been demonstrated for up to 28 days at temperatures below 25°C, regardless of light exposure, provided withdrawal was performed under controlled, validated aseptic conditions.

After dilution
From a microbiological standpoint, the product should be used immediately. Otherwise, the responsibility for storage conditions and duration of the prepared solution lies with the user.
The solution may be stored for no longer than 24 hours at 2°C–8°C, protected from light, unless dilution was performed under controlled, validated aseptic conditions.

Physical and chemical stability of a 0.10 mg/ml solution (diluted with 0.9% sodium chloride solution or 0.9% sodium chloride solution with 5% glucose solution) has been demonstrated for up to 28 days at temperatures below 25°C, protected from light. The stability of the cisplatin solution is influenced by chloride ions; therefore, the sodium chloride concentration of the diluent must be no less than 0.45%.

Preparation of the medicinal product for administration
The concentrate of Cisplatin-Ebewe must be diluted before use.
During preparation of the infusion solution, contact between cisplatin and any aluminum-containing devices (infusion sets, needles, catheters, syringes) must be avoided.

Preparation of the infusion solution must be performed under sterile conditions. Reconstitution of the concentrate and further dilution and handling should be carried out under controlled and validated aseptic conditions.

For dilution of the concentrate, one of the following solutions should be used:

0.9% sodium chloride solution,
0.9% sodium chloride solution with 5% glucose solution (1:1) (resulting solution contains 0.45% sodium chloride and 2.5% glucose).

If pre-treatment hydration of the patient is not possible, the concentrate may be diluted with a mixture of 0.9% sodium chloride solution and 5% mannitol solution (1:1) (resulting solution contains 0.45% sodium chloride and 2.5% mannitol).

Preparation of cisplatin solution for infusion
The required amount (dose) of cisplatin concentrate at a concentration of 1 mg/ml should be diluted with 1–2 liters of one of the solutions listed above. The diluted solution should be administered only via intravenous infusion. Only clear, colorless solutions free from visible particles should be administered.

Cytotoxic drugs should be prepared only by appropriately trained personnel who have knowledge of the products used and who work under conditions ensuring proper preparation and administration.

As with other cytotoxic agents, extreme caution must be exercised when handling cisplatin: gloves, face masks, and protective clothing must be worn. Whenever possible, all procedures involving cisplatin should be performed under a safety cabinet. Contact with skin and/or mucous membranes must be avoided. Pregnant women should not handle cisplatin.

Contact of the medicinal product with skin: Wash skin thoroughly with large amounts of water. If a burning sensation occurs, apply ointment (note: skin reactions may occur in some individuals sensitive to platinum).

Spilled solution should be wiped up (after wearing gloves) using a sponge designated exclusively for this purpose. The surface should then be washed twice with water. The solution together with the sponges should be placed in a plastic bag and sealed. In case of spillage, all materials that have come into contact with cisplatin should be stored and disposed of in accordance with local procedures regulating the disposal of cytotoxic agents.

Disposal of medicinal product waste
Any unused product or waste material should be disposed of in accordance with local regulations.

Incompatibilities
Cisplatin reacts with aluminum, resulting in the formation of a black precipitate of platinum. Therefore, it is essential to avoid aluminum-containing devices (intravenous infusion sets, needles, catheters, syringes) that may come into contact with cisplatin.

The 1 mg/ml cisplatin concentrate should not be diluted with 5% glucose solution alone or 5% mannitol solution alone, but only with mixtures additionally containing sodium chloride.

Antioxidants (e.g., pyrosulfite), bicarbonates (sodium bicarbonate), sulfates, fluorouracil, and paclitaxel may inactivate cisplatin in infusion sets.