Cisplatin "ebewe"

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CISPLATIN “EBEWE” (CISPLATIN “EBEWE”)

Composition:

Active substance: cisplatin;

1 ml of concentrate for infusion solution contains 0.5 mg or 1 mg of cisplatin;

Excipients: sodium chloride, diluted hydrochloric acid, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physico-chemical properties: clear, colorless or almost colorless solution.

Pharmacotherapeutic group. Antineoplastic agents. Platinum compounds.

ATC code L01XA01.

Pharmacological properties.

Pharmacodynamics.

Cisplatin (cis-diamminedichloroplatinum-II) is an inorganic compound containing the heavy metal platinum. Cisplatin binds to all DNA bases, particularly the N-7 atoms of guanine and adenine, and inhibits DNA synthesis by forming intra- and inter-strand cross-links (cross-links) within and between DNA strands. Synthesis of protein and RNA is also suppressed, but to a lesser extent.

Although the antineoplastic activity of cisplatin is primarily associated with inhibition of DNA synthesis, other mechanisms of its antineoplastic action exist. In particular, cisplatin enhances tumor immunogenicity. The oncolytic activity of cisplatin is comparable to that of alkylating agents. Cisplatin also possesses immunosuppressive and antibacterial properties and increases radiosensitivity.

The action of cisplatin on cells is independent of the cell cycle phase.

Pharmacokinetics.

After intravenous administration at doses of 20–120 mg/m² of body surface area, cisplatin rapidly distributes into all tissues. The highest concentrations of platinum are observed in the liver, prostate gland, and kidneys; somewhat lower levels are found in the urinary bladder, muscles, testes, pancreas, and spleen; and the lowest concentrations occur in the intestine, adrenal glands, heart, lungs, brain, including the cerebellum. Within 2 hours after administration, over 90% of the total cisplatin in plasma becomes protein-bound. This binding is likely irreversible. Protein-bound cisplatin lacks antitumor activity. The pharmacokinetics of cisplatin are nonlinear. Without enzymatic involvement, it is transformed into one or more metabolites. After intravenous bolus administration at a dose of 50–100 mg/m² of body surface area, the elimination of cisplatin from plasma exhibits a biphasic pattern. The half-life during the first (distribution) phase lasts 10–60 minutes, while during the second (terminal) phase it ranges from 2 to 5 days. The plasma half-life of cisplatin is prolonged in patients with impaired renal function. Theoretically, it may also be prolonged in patients with ascites due to extensive protein binding of cisplatin.

Due to significant binding of platinum to plasma proteins, prolonged or incomplete elimination of cisplatin from the body is observed. Within 84–120 hours, 27–45% of the administered dose is excreted in urine. With prolonged infusions, a greater amount of cisplatin is excreted in urine. Fecal excretion is minimal, with only small amounts of platinum detected in the gallbladder and large intestine.

Clinical characteristics.

Indications.

• Advanced or metastatic testicular cancer;
• advanced or metastatic ovarian cancer;
• advanced or metastatic bladder cancer;
• advanced or metastatic squamous cell carcinoma of the head and neck;
• advanced or metastatic non-small cell lung cancer;
• advanced or metastatic small cell lung cancer;
• cervical tumors when used in combination with radiotherapy.

Cisplatin may be used as monotherapy or in combination therapy.

The medicinal product is indicated for the treatment of adults and children.

Contraindications.

• Hypersensitivity to cisplatin or to other platinum-containing medicinal products or to any component of the medicinal product in the medical history.
• Impaired renal function (creatinine clearance < 60 mL/min).
• Dehydration (pre- and post-hydration is required to prevent the development of severe renal impairment).
• Bone marrow suppression.
• Hearing impairment.
• Neuropathy caused by cisplatin therapy.
• Pregnancy and breastfeeding period.
• Concomitant use with yellow fever vaccine and prophylactic therapy with phenytoin.

Special safety precautions.

As with all other cytotoxic medicinal products, safety precautions must be observed when handling Cisplatin "Ebewe": protective clothing (disposable gloves, masks, goggles, gowns, caps) must be used, and work should be performed under a fume hood whenever possible.

Contact of cisplatin solutions with skin and/or mucous membranes must be avoided. If such contact occurs, the affected area should be thoroughly rinsed with large amounts of water and moisturizing cream applied in case of irritation (skin reactions may occur in some individuals sensitive to platinum).

Pregnant healthcare workers must not handle cisplatin.

Unused solutions, instruments, and materials used during manipulations with cisplatin must be disposed of according to established procedures.

Dosage (dose calculation) of cisplatin must be performed with particular caution.

Interaction with other medicinal products and other forms of interaction.

The myelosuppressive effect of cisplatin is enhanced when used concomitantly with other agents that suppress bone marrow function or with radiotherapy.

The nephrotoxic effect of cisplatin may be enhanced by concomitant treatment with antihypertensive agents containing furosemide, hydralazine, diazoxide, and propranolol.

Dosages of allopurinol, colchicine, probenecid, or sulfinpyrazone may need to be adjusted when used concomitantly, as cisplatin increases serum uric acid concentration.

Except for patients receiving cisplatin doses exceeding 60 mg/m² body surface area and whose urine output is less than 1000 mL in 24 hours, forced diuresis using tubular diuretics should not be performed in patients, as this may lead to renal damage and increased ototoxicity.

Symptoms of cisplatin ototoxicity (e.g., dizziness, tinnitus) may be masked by concomitant use of thiamine preparations, buclizine, cyclizine, loxapine, meclizine, phenothiazines, thioxanthenes, or trimethobenzamides.

Nephrotoxic agents (e.g., cephalosporins, aminoglycosides) and ototoxic medicinal products (e.g., aminoglycosides) potentiate the toxic effects of cisplatin on the respective organs. Medicinal products primarily excreted by the kidneys (e.g., bleomycin and methotrexate) should be administered cautiously during or after cisplatin therapy, as cisplatin may reduce renal elimination.

When ifosfamide and cisplatin are used in combination, increased protein excretion and enhanced nephrotoxicity have been observed. Ifosfamide also potentiates the ototoxic effect of cisplatin, although ifosfamide itself is not ototoxic.

In one randomized clinical trial, the response to cisplatin therapy in patients with progressive ovarian cancer was poorer when pyridoxine and hexamethylmelamine were used concomitantly.

It has been established that administration of paclitaxel after cisplatin may reduce paclitaxel clearance by 33%, thereby increasing neurotoxicity.

During combined therapy with cisplatin, bleomycin, and etoposide, decreased serum lithium concentrations have been observed in several cases. Therefore, lithium levels should be monitored during treatment.

In patients with metastatic or advanced tumors, docetaxel in combination with cisplatin caused more severe neurotoxic effects (dose-dependent and sensory) than either active substance used as monotherapy at similar doses.

When cisplatin and cyclosporine are used concomitantly, excessive immunosuppression with risk of lymphoproliferative disorders should be considered.

Cisplatin may reduce the absorption of phenytoin and thus reduce the effectiveness of antiepileptic therapy.

Chelating agents, particularly penicillamine, may reduce the efficacy of cisplatin treatment.

Vaccination with live vaccines should not be performed during and for three months after completion of cisplatin therapy. Vaccination with yellow fever vaccine is strictly contraindicated due to the risk of developing fatal systemic disease. Due to the risk of systemic illness, inactivated vaccines are recommended.

When oral anticoagulants are used concomitantly, regular monitoring of the international normalized ratio (INR) is recommended.

In patients receiving cisplatin and anticonvulsant drugs concomitantly, serum concentrations of the latter may decrease to subtherapeutic levels.

Special precautions.

Cisplatin therapy must be administered under the supervision of a qualified oncologist.

Cisplatin is characterized by cumulative ototoxic, nephrotoxic, and neurotoxic effects. Its toxicity may be enhanced when used concomitantly with other agents that exert toxic effects on these organs and systems.

Nephrotoxicity. Cisplatin causes severe cumulative nephrotoxic effects. To reduce nephrotoxicity, adequate hydration of patients is required before, during, and after intravenous administration of cisplatin. A urine output of 100 mL/hour or more should minimize the nephrotoxic effect of cisplatin. Adequate diuresis can be achieved by pre-hydration with intravenous infusion of 2 L of an appropriate solution, or by similar hydration after cisplatin administration (administration of a solution at a volume of 2500 mL/m² over 24 hours is recommended). If aggressive hydration is insufficient to maintain adequate diuresis, osmotic diuretics (e.g., mannitol) may be administered.

Neuropathy. Cases of severe neuropathy have been reported. These complications may be irreversible and may manifest as paresthesia, areflexia, loss of proprioceptive sensation, and vibratory sensation. Cases of motor function loss have also been reported. Neurological examinations of patients should be performed on a regular basis.

Ototoxicity. Symptoms of ototoxicity may include tinnitus and/or hearing loss in the high-frequency range (4000 to 8000 Hz). In some cases, hearing loss may occur within the normal hearing range. Hearing loss may be unilateral or bilateral and occurs more frequently and severely with repeated administration of the drug; however, in isolated cases, deafness has been reported after the first dose of cisplatin. Prior or concurrent radiotherapy to the head region increases the risk of ototoxic complications, which may be related to peak plasma concentration of cisplatin. It is not established whether cisplatin-induced ototoxicity is reversible. Audiograms must be performed before initiation of cisplatin therapy and prior to each subsequent treatment cycle.

Before, during, and after cisplatin therapy, the following should be monitored:

• renal function;
• liver function;
• hematopoietic system function (erythrocyte, leukocyte, and platelet counts);
• serum electrolyte levels (calcium, sodium, potassium, magnesium concentrations).

Tests should be repeated weekly throughout the entire period of cisplatin treatment.

The next treatment cycle must not be initiated until the following key parameters have normalized (in adults):

• serum creatinine: ≤ 130 µmol/L (1.5 mg/dL);
• blood urea nitrogen: < 25 mg/dL;
• leukocyte count: > 4.0 × 10⁹/L;
• platelet count: > 100 × 10⁹/L;
• audiogram: results within normal limits.

Special caution is required when treating patients with pre-existing peripheral neuropathy not caused by cisplatin, as well as patients with acute bacterial and viral infections.

In case of extravasation, the following steps are necessary:

• immediately discontinue cisplatin infusion;
• without removing the needle, aspirate the extravasated material from the tissues and irrigate them with 0.9% sodium chloride solution (especially if an infusion solution with a cisplatin concentration higher than recommended has been used).

Nausea, vomiting, and diarrhea are commonly observed after cisplatin administration. Prophylactic use of antiemetics may help prevent or reduce the severity of nausea and vomiting. Fluid loss due to vomiting or diarrhea must be adequately replaced.

Cumulative and dose-dependent renal insufficiency is the main toxicity factor limiting the dose of cisplatin. The most common finding is a decline in glomerular filtration rate, manifested by elevated serum creatinine levels and reduced effective renal plasma flow. Hyperuricemia and hyperalbuminemia may contribute to the development of nephrotoxicity. Normalization of renal function must be confirmed before administering the next dose.

Patients on a sodium-controlled diet should exercise caution, as this medicinal product contains:

• 10 mg/20 mL vial – 3 mmol (69 mg) per dose of sodium
• 25 mg/50 mL vial – 7.7 mmol (177 mg) per dose of sodium
• 50 mg/100 mL vial – 15.4 mmol (354 mg) per dose of sodium
• 100 mg/100 mL vial – 15.4 mmol (354 mg) per dose of sodium

Use during pregnancy or breastfeeding.

Women of childbearing potential / contraception in men and women. Due to the genotoxic potential of cisplatin, women of childbearing potential are advised to use effective contraception and avoid pregnancy during cisplatin therapy and for at least 7 months after its discontinuation. Men are advised to use effective contraception and avoid fathering children during cisplatin therapy and for at least 4 months after its discontinuation.

Fertility. Cisplatin may cause temporary or permanent infertility. Therefore, men who wish to father children in the future should be advised to undergo sperm cryopreservation prior to starting therapy.

Pregnancy. There is insufficient data on the use of cisplatin in pregnant women. Cisplatin may have toxic effects on the fetus and, based on its pharmacological properties, may cause serious fetal malformations. Animal studies have demonstrated reproductive toxicity and transplacental carcinogenicity. Therefore, cisplatin should not be used during pregnancy unless there are life-threatening indications.

Both men and women of reproductive age receiving cisplatin should use contraceptive methods to prevent conception during treatment and for at least 6 months after therapy. Patients who wish to have children after completing therapy should consult a genetics specialist prior to attempting conception.

Breastfeeding. Cisplatin has been detected in breast milk; therefore, breastfeeding during cisplatin therapy is contraindicated.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of cisplatin on the ability to drive or operate machinery have not been conducted. However, adverse reactions (e.g., nephrotoxicity) may negatively affect the ability to drive or operate machinery. Patients experiencing such adverse reactions (e.g., somnolence or vomiting) should not drive or operate machinery.

Method of Administration and Dosage

Cisplatin "Ebewe", concentrate for solution for infusion, must be diluted before use.

Preparation of the Infusion Solution

Cisplatin "Ebewe" must be diluted under aseptic conditions prior to administration. Medical devices containing aluminum in parts that may come into contact with the drug (including intravenous infusion sets, needles, catheters, syringes) must not be used during the preparation and administration of the infusion solution.

The required amount of concentrate, calculated according to the recommendations below, should be diluted in 1–2 L of 0.9% sodium chloride solution or a mixture of 0.9% sodium chloride solution and 5% glucose solution in a 1:1 ratio (in such a solution, the concentration of sodium chloride is 0.45% and glucose is 2.5%).

If pre-infusion hydration is not feasible, the concentrate may also be diluted with a mixture of 0.9% sodium chloride solution and 5% mannitol solution in a 1:1 ratio (in such a solution, the concentration of sodium chloride is 0.45% and mannitol is 2.5%).

Infusion solutions containing cisplatin at a concentration of 0.1 mg/mL, prepared by diluting Cisplatin "Ebewe" with 0.9% sodium chloride solution or a 1:1 mixture of 0.9% sodium chloride and 5% glucose solution, are physically and chemically stable for 28 days. Solutions diluted with a 1:1 mixture of 0.9% sodium chloride and 5% mannitol are stable for 3 days when stored protected from light at 2–8°C. From a microbiological standpoint, the infusion solution should be administered immediately after preparation. If not used immediately, the duration and conditions of storage are the responsibility of the medical staff or physician. Generally, storage should not exceed 24 hours at 2–8°C, unless the solution was prepared under controlled and validated aseptic conditions.

Only clear, colorless solutions free from visible particulate matter should be used. The infusion solution is intended for single use only.

The diluted solution must be administered only by intravenous infusion.

Dosage for Adults and Children

Cisplatin dosage is determined based on the underlying disease, expected patient response to therapy, and whether cisplatin is used as monotherapy or as part of combination chemotherapy. The recommended dosages below apply to both adults and children.

For monotherapy, the following regimens are recommended:

• Single dose of 50–120 mg/m² body surface area every 3–4 weeks;
• Daily doses of 15–20 mg/m² body surface area for 5 consecutive days, repeated every 3–4 weeks.

For combination chemotherapy, lower doses are required. The standard dose is 20 mg/m² or more, administered once every 3–4 weeks.

The next treatment cycle should be initiated only after a comprehensive assessment of the patient's condition (see section "Special Instructions").

Patients with Impaired Renal Function or Bone Marrow Suppression

Dosage must be appropriately reduced in case of renal dysfunction or bone marrow suppression.

Method of Administration

For Intravenous Infusion

The infusion solution must be administered only by intravenous infusion over 6–8 hours. Adequate hydration must be provided 2–12 hours before and for at least 6 hours after the completion of cisplatin infusion to ensure sufficient diuresis during and after administration. Hydration is achieved by intravenous infusion of one of the following solutions: 0.9% sodium chloride solution or a 1:1 mixture of 0.9% sodium chloride and 5% glucose solution.

Pre-treatment Hydration with Cisplatin: Intravenous infusion of one of the above solutions at a rate of 100–200 mL/hour for 6–12 hours, with a total volume of at least 1 L.

Post-infusion Hydration: Intravenous infusion of an additional 2 L of one of the above solutions at a rate of 100–200 mL/hour over 6–12 hours. If urine output remains below 100–200 mL/hour after hydration, forced diuresis may be required. In such cases, administer 37.5 mg of mannitol as a 10% solution (375 mL of 10% mannitol solution) intravenously, or use diuretics, provided renal function is normal. Mannitol or diuretics should also be administered when the cisplatin dose exceeds 60 mg/m² body surface area. Patients should be encouraged to drink large amounts of fluids for 24 hours after cisplatin infusion to ensure adequate urine output.

Children

In children, key parameters (serum creatinine, blood urea, leukocytes, platelets, audiogram) should be checked before initiating the next treatment cycle to ensure they have returned to age-appropriate normal values.

Overdose

Acute cisplatin overdose may lead to renal failure, hepatic failure, deafness, ophthalmotoxicity (including retinal detachment), severe bone marrow suppression, intractable nausea and vomiting, and/or neuropathy. Overdose can be fatal. Prompt and adequate hydration and osmotic diuresis immediately after overdose may reduce the toxic effects of cisplatin.

In cases of significant overdose (≥ 200 mg/m² body surface area), cisplatin may cross the blood-brain barrier, resulting in direct effects on the respiratory center, potentially causing life-threatening respiratory disturbances and acid-base imbalances.

There is no specific antidote for cisplatin overdose. Hemodialysis performed within 4 hours after overdose has minimal effect on removing cisplatin from the body, as cisplatin rapidly and strongly binds to proteins.

In case of overdose, general supportive measures are indicated.

Side effects.

Adverse reactions depend on the dose of cisplatin and may be cumulative in nature.

Reported adverse effects include: hematological disorders (leukopenia, thrombocytopenia, and anemia), gastrointestinal disturbances (anorexia, nausea, vomiting, and diarrhea), ototoxicity (hearing disorders), renal disorders (renal failure, nephrotoxicity, hyperuricemia), and fever.

In patients receiving cisplatin as monotherapy, serious ototoxicity, nephrotoxicity, bone marrow suppression, and auditory organ toxicity have been reported; these effects are generally dose-dependent and cumulative. Ototoxicity may be more severe in children.

Infections and infestations. Sepsis and infections have been observed, with infection complications leading to fatal outcomes in some patients.

Renal and urinary system disorders. Mild, reversible renal function impairment may occur after a single administration of cisplatin at medium doses (20–50 mg/m² body surface area). When cisplatin is administered at high doses (50–120 mg/m² body surface area) or daily, renal failure with tubular necrosis may develop, manifesting as uremia or anuria. Renal failure may be irreversible.

Nephrotoxicity is cumulative. It may appear 2–3 days or up to 2 weeks after the first dose of cisplatin. Serum creatinine and urea concentrations may increase. Adequate hydration before and after cisplatin administration, along with a diuresis rate of 100 mL/h or higher, reduces the risk of nephrotoxic injury. Nephrotoxic symptoms have been observed after a single 50 mg/m² dose of cisplatin without sufficient hydration. Hyperuricemia (asymptomatic or symptomatic gout) may occur. Hyperuricemia in combination with nephrotoxic injury has been reported in 25–30% of patients.

Blood and lymphatic system disorders. Cisplatin causes dose-dependent, predominantly reversible leukopenia, thrombocytopenia, and anemia. Myelosuppression is cumulative. Isolated cases of Coombs-positive hemolytic anemia (reversible after discontinuation of therapy) have been reported. Hemolysis possibly induced by cisplatin has also been reported. Severe bone marrow suppression (including agranulocytosis and/or aplastic anemia) may occur after high-dose cisplatin administration. Approximately 14 days after cisplatin administration, leukocyte counts may significantly decrease (to 1.5 × 10⁹/L or lower). The lowest platelet count is typically observed around day 21 (in some patients, it may drop to 50 × 10⁹/L or lower). Counts usually normalize by approximately day 39.

Benign, malignant, and unspecified neoplasms. Cases of acute leukemia have been observed.

Gastrointestinal disorders. Anorexia, nausea, vomiting, abdominal pain, and diarrhea (usually within 1–4 hours after cisplatin administration), as well as hiccups, have been reported. These symptoms typically resolve within 24 hours in most patients. Milder nausea and anorexia may persist for up to 7 days after drug administration. In rare cases, mucositis may develop.

Auditory and vestibular disorders. Hearing impairment has been observed in some patients receiving cisplatin at a dose of 50 mg/m² body surface area. Cisplatin ototoxicity is cumulative. Hearing loss may be irreversible, and sometimes only one ear is affected. Tinnitus and/or high-frequency hearing loss (4000–8000 Hz) are commonly observed. Hearing impairment may also occur in the normal hearing range (250–2000 Hz). Complete deafness and vestibular dysfunction with systemic vertigo may also occur. Cranial irradiation before or during cisplatin therapy increases the risk of hearing loss. However, only in rare cases do patients lose the ability to communicate normally after cisplatin treatment. Complications may be more severe in children.

Eye disorders. In rare cases, vision loss has been observed after combination chemotherapy with cisplatin and other agents. Cases of optic disc edema with visual disturbances, color vision defects, blurred vision, and retinal pigmentation have been reported; these effects are generally reversible after discontinuation of therapy. Only one case of unilateral retrobulbar neuritis with visual acuity loss has been documented after polychemotherapy followed by cisplatin treatment.

Nervous system disorders. Cisplatin therapy may cause peripheral neuropathy (usually bilateral and sensory), and in some cases, loss of taste or tactile sensation, retrobulbar neuritis with vision loss, and cerebral function disturbances (confusion, dysarthria, cortical blindness, memory loss, or paralysis in isolated cases). Cases of Lhermitte’s sign, autonomic neuropathy, and spinal myelopathy have been reported. Severe central nervous system toxicity has been reported, including one case of acute cerebrovascular complications, cerebral arteritis, carotid artery occlusion, and encephalopathy. Seizures may also occur. If any of the above cerebral symptoms occur, cisplatin therapy must be discontinued immediately. Neurotoxic effects of cisplatin may be reversible, but in some patients, neurological dysfunction persists even after treatment ends. Neurotoxic symptoms may appear after prolonged therapy or even after the first dose. Unknown frequency: hemorrhagic stroke, ischemic stroke.

Metabolism and nutrition disorders. Hypomagnesemia, hypocalcemia, hyponatremia, hypophosphatemia, and hypokalemia may develop in rare cases, leading to muscle spasms and/or ECG changes due to cisplatin-induced renal damage (with reduced tubular reabsorption of these cations). Dehydration may also occur.

Hypersensitivity reactions. Anaphylactic reactions (rash, urticaria, erythema, pruritus) have been reported in rare cases. Isolated reports include arterial hypotension, tachycardia, dyspnea, bronchospasm, facial swelling, and angioedema. In such cases, treatment with antihistamines, epinephrine (adrenaline), and corticosteroids may be required. Angioedema may occur.

Hepatobiliary disorders. Liver function disturbances with elevated serum transaminases have been reported in rare cases, though these changes are reversible. Decreased albumin levels have occasionally been observed, possibly related to cisplatin therapy. Increased levels of liver enzymes and bilirubin may also occur.

Cardiac disorders. Arrhythmias, including bradycardia, tachycardia, and other arrhythmias, have been reported in rare cases. ECG changes have occasionally been observed. Cardiac arrest has been reported during cisplatin therapy in combination with other cytostatics, though this is extremely rare. Severe ischemic heart disease, cardiac dysfunction, and myocardial infarction may occur.

Vascular disorders. Vascular complications (cerebral or myocardial ischemia, peripheral circulation disorders resembling Raynaud’s syndrome) have been reported in rare cases. Thrombotic microangiopathy (hemolytic uremic syndrome), leukoencephalopathy, and pulmonary embolism are possible. Venous thromboembolism may frequently occur.

Immune system disorders. Immunosuppression and hoarseness may occur.

Endocrine disorders. Increased serum amylase levels may occur. In rare cases, inappropriate antidiuretic hormone secretion has been observed.

Other adverse effects. Local swelling, pain, erythema, skin ulceration, and phlebitis at the injection site may occur after intravenous administration. Due to the risk of extravasation, careful monitoring of the infusion site for possible infiltration is recommended during drug administration.

Metallic deposits on the gums and hiccups have been observed.

Alopecia, impaired spermatogenesis and ovulation, and painful gynecomastia may occur.

Cases of pneumonia and respiratory failure have been reported.

A possible association between cisplatin use and secondary non-lymphoblastic leukemia has been reported.

According to data from several independent sources, a possible link exists between combination chemotherapy with cisplatin and other agents and the development of vascular disorders (cerebral or coronary ischemia, peripheral circulation disorders resembling Raynaud’s syndrome).

Cisplatin is theoretically carcinogenic (due to its mechanism of action), although there is no practical evidence of this. Cases of acute leukemia have been observed during cisplatin therapy, generally associated with other leukemogenic agents.

During cisplatin therapy, hypercholesterolemia, inappropriate antidiuretic hormone secretion, elevated serum amylase, and thrombotic microangiopathy combined with hemolytic uremic syndrome have been reported in rare cases.

Increased serum iron concentration has been observed occasionally.

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

Concentrate for infusion solution 0.5 mg/mL – 3 years.
Concentrate for infusion solution 1 mg/mL – 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Do not refrigerate or freeze. Keep out of reach of children.

Incompatibilities.

Cisplatin reacts with aluminum, forming a black platinum precipitate. Therefore, instruments containing aluminum parts (including intravenous infusion sets, needles, catheters, syringes, etc.) that may come into contact with the drug must not be used during the preparation and administration of the infusion solution.

Cisplatin "Ebewe" must not be mixed with any medicinal products except those specified in the section "Dosage and administration." Cisplatin "Ebewe" must not be diluted with 5% glucose solution or 5% mannitol solution, but only with mixtures of these solutions with 0.9% sodium chloride solution.

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

Packaging.

20 mL (10 mg), 50 mL (25 mg), 100 mL (50 mg), or 100 mL (100 mg) in a vial.

Brown glass vials stoppered with gray rubber closures and sealed with aluminum crimp caps; 1 vial per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Fareva Unterach GmbH
or
Ebewe Pharma Ges.m.b.H. Nfg. KG

Manufacturer's address and place of business.

Mondseestrasse 11, 4866 Unterach am Attersee, Austria.
Mondseestrasse 11, 4866 Unterach am Attersee, Austria.