Cisplatin fares

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CISPLATIN PHARES (CISPLATIN PHARES)

Composition:

Active substance: cisplatin;

1 ml of concentrate contains 0.5 mg of cisplatin;

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

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical characteristics: 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 DNA strands. Synthesis of protein and RNA is also suppressed, although to a lesser extent.

Although the antitumor 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 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 does not exhibit 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 body surface area, the elimination of cisplatin from plasma follows a biphasic pattern. The half-life during the first phase (distribution phase) ranges from 10 to 60 minutes, while the half-life during the second (terminal) phase lasts 2–5 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 blood 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 higher 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 head and neck squamous cell carcinoma;
• advanced or metastatic non-small cell lung cancer;
• advanced or metastatic small cell lung cancer;
• cervical tumors, used in combination with radiotherapy.

Cisplatin may be administered as monotherapy or in combination therapy.

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

Contraindications.

• Hypersensitivity to cisplatin or to other platinum-containing agents or to any component of the product in medical history;
• impaired renal function (creatinine clearance < 60 mL/min);
• body dehydration (pre- and post-hydration is required to prevent the development of severe renal dysfunction);
• bone marrow suppression;
• hearing impairment;
• neuropathy caused by cisplatin treatment;
• pregnancy and breastfeeding period;
• concomitant use with yellow fever vaccine;
• concomitant use with prophylactic phenytoin therapy.

Special safety measures.

As with all other cytotoxic agents, handling cisplatin must be performed with strict adherence to safety procedures: protective clothing (disposable gloves, masks, goggles, gowns, caps) must be used, and work should be carried out in a fume hood whenever possible.

Contact of cisplatin solutions with skin and/or mucous membranes should be avoided. If contact occurs, the affected area should be thoroughly washed with soap and water and moisturized with cream if irritation develops (skin reactions may occur in some individuals sensitive to platinum).

Pregnant healthcare workers should not handle cisplatin.

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

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

Interaction with other medicinal products and other forms of interaction.

Nephrotoxic/ototoxic agents

Nephrotoxic agents (e.g., cephalosporins, aminoglycosides, amphotericin B, or contrast agents) and ototoxic drugs (e.g., aminoglycosides, loop diuretics) may potentiate cisplatin’s toxic effects on kidneys/hearing. Drugs primarily excreted by the kidneys (such as bleomycin and methotrexate) should be used cautiously during or after cisplatin treatment, as cisplatin may reduce renal elimination.

Combination of ifosfamide and cisplatin increases protein excretion and enhances nephrotoxicity. Ifosfamide also potentiates the ototoxic effect of cisplatin, although ifosfamide itself is not ototoxic.

During combined therapy with cisplatin, bleomycin, and etoposide, several cases of decreased serum lithium concentration have been reported. Therefore, monitoring of lithium levels is recommended during treatment.

Nephrotoxic effects of cisplatin may be intensified when used concomitantly with antihypertensive agents containing furosemide, hydralazine, diazoxide, or propranolol.

Doses of allopurinol, colchicine, probenecid, or sulfinpyrazone may require adjustment when used concomitantly with cisplatin, as cisplatin may increase serum uric acid levels.

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

Live attenuated vaccines

Administration of yellow fever vaccine is strictly contraindicated due to the risk of developing fatal systemic disease. Because of the risk of systemic illness, inactivated vaccines are recommended.
Vaccination with live vaccines should not be performed during and for 3 months after completion of cisplatin treatment.

Oral anticoagulants

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

Phenothiazines, antihistamines, and other agents

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

Anticonvulsants

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

Cisplatin may reduce phenytoin absorption and thereby reduce the efficacy of antiepileptic therapy. Initiation of new antiepileptic therapy with phenytoin is strictly contraindicated during cisplatin treatment.

Pyridoxine + altretamine, combination

In a randomized clinical trial, a poorer response to therapy was observed in patients with progressive ovarian cancer receiving concomitant pyridoxine with altretamine (hexamethylmelamine) and cisplatin.

Paclitaxel

It has been established that when paclitaxel is administered after cisplatin, paclitaxel clearance may decrease by 33%, thereby increasing neurotoxicity.

Others

Myelosuppressive effects of cisplatin are enhanced when used concomitantly with other myelosuppressive agents or radiotherapy.

Use of cisplatin in combination with bleomycin and vinblastine may lead to Raynaud’s phenomenon.

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

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

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

Special precautions for use.

Cisplatin reacts with aluminum, forming a black precipitate of platinum, therefore the use of aluminum-containing instruments (including intravenous infusion sets, needles, catheters, syringes) should be avoided. For further details, see section "Incompatibilities".

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

Before treatment, during therapy, and after treatment with cisplatin, the following parameters must be monitored:

• Renal function;
• Liver function;
• Hematopoietic system function (number of erythrocytes, leukocytes, and platelets);
• Serum electrolyte levels (calcium, sodium, potassium, magnesium concentrations).

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

The next treatment cycle should not be initiated until the main parameters have normalized, namely (in adults):

• Serum creatinine ≤ 130 µmol/L (1.5 mg/dL);
• Blood urea < 25 mg/dL;
• Leukocyte count > 4.0 × 10⁹/L;
• Platelet count > 100 × 10⁹/L;
• Audiogram – results within normal limits.

Cisplatin exhibits 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 before, during, and after intravenous administration of cisplatin is essential. A diuresis of 100 mL/hour or more should minimize the nephrotoxic effect of cisplatin. Adequate diuresis can be achieved by pre-hydration with intravenous administration 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 active hydration is insufficient to maintain adequate diuresis, osmotic diuretics (e.g., mannitol) may be prescribed.

Neuropathy

Cases of severe neuropathy have been reported. These complications may be irreversible and may manifest as paresthesia, areflexia, loss of proprioceptive sensation, and vibration sense. Cases of motor function loss have also been reported. Neurological examinations of patients should be performed regularly.

Neurotoxicity is cumulative.

Before the start of each treatment cycle, the absence of symptoms of peripheral neuropathy should be confirmed.

Ototoxicity

Ototoxicity has been observed in 31% of patients receiving a single dose of cisplatin at 50 mg/m², manifesting as tinnitus and/or hearing loss in the high-frequency range (4000–8000 Hz). In some cases, hearing loss in the speech frequency range may occur. Hearing loss may be unilateral or bilateral and occurs more frequently and severely with repeated administration of the drug; however, isolated cases of deafness after the first dose of cisplatin have been reported. Prior or concurrent radiotherapy to the head region increases the risk of ototoxic complications, possibly related to the peak plasma concentration of cisplatin. It is not known whether cisplatin-induced ototoxicity is reversible. Audiograms must be performed before initiation of cisplatin therapy and before each subsequent treatment cycle. Vestibular toxicity has also been reported (see section "Adverse reactions").

Allergic reactions

As with other platinum-containing medicinal products, hypersensitivity reactions may occur, mostly during infusion. These require immediate discontinuation of the infusion and appropriate symptomatic treatment. Cross-reactions, sometimes fatal, have been reported with all platinum compounds (see sections "Contraindications" and "Adverse reactions").

Anaphylactic reactions have been observed with the use of cisplatin. These reactions can be managed with antihistamines, epinephrine, and/or glucocorticoids.

Liver function and blood count

Blood count and liver function should be monitored regularly.

Potential carcinogenic effects

In rare cases, acute leukemia in humans has been temporally associated with cisplatin use; these cases were usually associated with the use of other leukemogenic agents.

Cisplatin is a bacterial mutagen and causes chromosomal aberrations in animal cell cultures. Carcinogenicity is possible but has not yet been demonstrated. Cisplatin exerts teratogenic and embryotoxic effects in mice.

Reactions at the site of administration

Reactions at the site of administration may occur during cisplatin infusion. Due to the risk of extravasation, the infusion site should be carefully monitored for possible infiltration during administration. Specific therapy for extravasation reactions is currently unknown.

In case of paravenous administration, the following steps are required:

• Immediately stop the cisplatin infusion;
• Without removing the needle, aspirate the extravasate from the tissues and flush them with 0.9% sodium chloride solution (especially if using an infusion solution with a cisplatin concentration higher than recommended).

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

Warnings

This cytostatic agent has greater toxicity than conventional antineoplastic chemotherapy agents.

Renal toxicity, which is primarily cumulative, is severe and requires special precautions during administration (see sections "Method of administration and dosage" and "Adverse reactions"). Nausea, vomiting, and diarrhea are commonly observed after cisplatin administration (see section "Adverse reactions"). In most patients, these symptoms resolve within 24 hours. Milder nausea and anorexia may persist for up to 7 days after treatment.

Nausea and vomiting may be intense and require appropriate antiemetic treatment. Prophylactic use of antiemetics may help prevent or reduce the severity of nausea and vomiting. Fluid loss due to vomiting or diarrhea must be compensated.

Patients should be carefully monitored for ototoxicity, myelosuppression, and anaphylactic reactions (see section "Adverse reactions").

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

• 10 mg/20 mL vial – 3.08 mmol (70.74 mg) of sodium per dose;
• 25 mg/50 mL vial – 7.70 mmol (176.85 mg) of sodium per dose;
• 50 mg/100 mL vial – 15.40 mmol (353.70 mg) of sodium per dose.

Fertility

Cisplatin has demonstrated mutagenic effects. This agent may also adversely affect fertility. Since other antineoplastic agents are known to have carcinogenic potential, this possibility should be considered with long-term cisplatin use.

Both men and women of reproductive age must use effective contraception during treatment and for at least 6 months after therapy. Patients who wish to have children after completion of therapy should consult a genetics specialist beforehand. Since cisplatin treatment may cause irreversible infertility, men who wish to father children in the future should consider sperm cryopreservation prior to starting therapy.

Use during pregnancy or breastfeeding.

Data on the use of cisplatin in pregnant women are insufficient. However, cisplatin is considered to cause severe fetal developmental abnormalities when used during pregnancy. Therefore, cisplatin should not be used in pregnant women.

Cisplatin is excreted 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 vehicles or operate machinery have not been conducted. However, adverse reactions (e.g., nephrotoxicity, effects on the central nervous system and sensory organs) may negatively affect the ability to drive or operate machinery. Patients experiencing such adverse reactions (e.g., somnolence, confusion, or vision loss) should not drive or operate machinery.

Method of Administration and Dosage

Preparation of the Infusion Solution

Cisplatin must be diluted under aseptic conditions prior to administration. Instruments containing aluminum must not be used during preparation or administration of the infusion solution if they may come into contact with the drug (this includes intravenous infusion sets, needles, catheters, and syringes).

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

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

Only clear, colorless solutions free from visible particulate matter should be used. If the solution is not clear or contains a precipitate, it must not be used. The infusion solution should be administered immediately after preparation.

Dosage for Adults and Children

Cisplatin dosage depends on the specific pathology, expected response to therapy, and whether cisplatin is used as monotherapy or as part of combination chemotherapy. The dosage recommendations below apply to both adults and children.

Recommended regimens for monotherapy:

• 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.

Dosages should be lower when cisplatin is used in combination chemotherapy. Typically, cisplatin is administered at a dose of 20 mg/m² body surface area or higher every 3–4 weeks.

For the treatment of cervical cancers, cisplatin must be used in combination with radiotherapy. Cisplatin is usually administered at a dose of 40 mg/m² body surface area weekly for 6 weeks.

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

Dosage adjustments are required in case of renal impairment or bone marrow suppression (see section "Contraindications").

The infusion solution must be administered exclusively by intravenous infusion.

The infusion solution should be administered over 6–8 hours. Adequate hydration must be provided 2–12 hours before and for at least 6 hours after completion of cisplatin infusion. Hydration is necessary to maintain sufficient diuresis during and after cisplatin administration. In adults, hydration is achieved by intravenous infusion of 0.9% sodium chloride solution or a 1:1 mixture of 0.9% sodium chloride and 5% glucose solution.

Pre-hydration: Intravenous infusion of one of the above solutions at a rate of 100–200 mL/hour for 6–12 hours.

Post-hydration: Intravenous infusion of an additional 2 L of one of the above solutions at a rate of 100–200 mL/hour for 6–12 hours.

If urine output remains below 100–200 mL/hour after hydration, forced diuresis may be required. In such cases, 37.5 g of mannitol (375 mL of 10% solution) is administered intravenously or diuretics are used (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 consume large amounts of fluids for 24 hours after cisplatin administration to ensure adequate urine output.

After Dilution

From a microbiological standpoint, the diluted solution should be administered immediately. If immediate administration is not possible, responsibility for storage duration and conditions of the ready-to-use solution lies with the user (healthcare personnel). As a general rule, the solution should be stored for no longer than 24 hours at 2–8°C, unless dilution was performed under controlled, strictly aseptic conditions.

Children

In children, before initiating the next treatment cycle with Cisplatin PharEks, key laboratory parameters (serum creatinine, urea, leukocytes, thrombocytes, audiogram) should return 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, vomiting, and/or neuropathy. Overdose can be fatal. 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, potentially causing direct effects on the respiratory center, resulting in life-threatening respiratory disorders and acid-base imbalances.

There is no specific antidote for cisplatin overdose. Hemodialysis performed within 4 hours after overdose has minimal effect, as cisplatin binds rapidly and tightly to proteins.

In cases of overdose, general supportive measures are indicated.

Anticonvulsant medications should be used to control seizures. Daily monitoring of renal and cardiovascular function and blood analysis is necessary to assess potential toxic effects on these organ systems. Serum magnesium and calcium levels should be closely monitored for signs and symptoms of skeletal muscle irritation. Electrolytes should be administered if tetany develops. Daily monitoring of serum liver enzymes and uric acid levels is required after acute overdose.

Adverse Reactions

Adverse effects depend on cisplatin doses and may be cumulative.

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

In patients receiving cisplatin as monotherapy, serious ototoxicity, nephrotoxicity, bone marrow suppression, and auditory organ damage 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 (infection complications led 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, acute 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. Hydration before and after cisplatin administration and maintaining a diuresis of 100 mL/hour or more reduce the risk of nephrotoxic injury. Nephrotoxic symptoms have been observed after a single dose of cisplatin 50 mg/m² body surface area without adequate hydration. Hyperuricemia (asymptomatic or with gout symptoms) 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 therapy discontinuation) have been reported. Hemolysis possibly caused by cisplatin has 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, white blood cell counts may significantly decrease (to 1.5 × 10⁹/L or lower). The lowest platelet count is observed around day 21 (in some patients, it may decrease to 50 × 10⁹/L or lower). Parameters 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), and hiccups are commonly observed. These symptoms usually resolve within 24 hours in most patients. Milder nausea and anorexia may persist for up to 7 days after drug administration. In isolated cases, mucosal inflammation of the oral cavity (stomatitis) 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 impairment may be irreversible and sometimes affects only one ear. Tinnitus and/or high-frequency hearing loss (4000–8000 Hz) are commonly observed. Hearing impairment has also been reported in the conventional hearing range (250–2000 Hz). Deafness and vestibular dysfunction combined with systemic vertigo may also occur. Cranial irradiation before or concurrently with cisplatin therapy increases the risk of hearing loss. However, only in isolated cases do patients lose the ability to communicate normally after cisplatin treatment. Complications may be more severe in children.

Visual disorders. Visual loss has been observed in isolated cases after combination chemotherapy with cisplatin and other agents. Cases of optic disc edema with visual disturbances, cortical blindness, color vision disturbances, blurred vision, and retinal pigmentation have been reported; however, these effects are reversible, and vision usually recovers after treatment discontinuation. Only one case of unilateral retrobulbar neuritis with loss of visual acuity has been documented after polychemotherapy followed by cisplatin treatment.

Nervous system disorders. Cisplatin therapy may cause peripheral neuropathy (usually bilateral and sensory), in some cases loss of taste or tactile sensation, retrobulbar neuritis with visual loss, and cerebral function disturbances (confusion, slurred speech, in isolated cases cortical blindness, memory loss, paralysis), leukoencephalopathy, reversible posterior leukoencephalopathy syndrome. Cases of Lhermitte’s sign, autonomic neuropathy, and spinal myelopathy have been reported. Severe brain damage has been reported (including one case of acute cerebrovascular complications, cerebral arteritis, carotid artery occlusion, encephalopathy). Seizures may also occur. If a patient develops any of the above-mentioned cerebral symptoms, cisplatin therapy must be discontinued immediately. Cisplatin neurotoxicity may be reversible, but in some patients, impaired functions do not recover even after therapy discontinuation. Neurotoxic effects may occur after prolonged therapy or even after the first dose. Unknown: hemorrhagic stroke, ischemic stroke.

Metabolism and nutrition disorders. In isolated cases, hypomagnesemia, hypocalcemia, hyponatremia, hyperuricemia, tetany, hypophosphatemia, and hypokalemia with muscle spasms and/or ECG changes may develop due to cisplatin-induced kidney damage (with reduced tubular reabsorption of these cations). Dehydration may occur.

Allergic reactions. In isolated cases, anaphylactic reactions (with symptoms such as rash, urticaria, erythema, itching) may occur. Isolated reports of arterial hypotension, tachycardia, dyspnea, bronchospasm, facial swelling, and fever have been documented. In such cases, treatment with antihistamines, epinephrine (adrenaline), and corticosteroids may be required. Angioneurotic edema may occur.

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

Cardiac disorders. In isolated cases, cardiac rhythm disturbances such as bradycardia, tachycardia, and other arrhythmias may occur. ECG changes have occasionally been observed. Cardiac arrest has been reported during cisplatin therapy in combination with other cytostatics, although this is extremely rare. Severe ischemic heart disease, cardiac dysfunction, myocardial infarction, and cardiac arrest are possible.

Vascular disorders. In isolated cases, vascular disorders (cerebral or myocardial ischemia, peripheral circulation disturbances similar to Raynaud’s syndrome) have been reported. Thrombotic microangiopathy (hemolytic uremic syndrome), leukoencephalopathy, pulmonary artery embolism, and venous thromboembolism are possible.

Immune system disorders. Immunosuppression and wheezing are possible.

Endocrine disorders. Increased serum amylase levels are possible. In isolated cases, inappropriate antidiuretic hormone secretion has been observed.

Other adverse effects. After intravenous administration, local swelling and pain, erythema, fever, asthenia, malaise, skin ulcers, and phlebitis at the injection site may occur. Due to the risk of extravasation (local soft tissue toxicity, including cellulitis, fibrosis, necrosis, pain, swelling, erythema), careful monitoring of the infusion site for possible infiltration during drug administration is recommended.

Metallic deposits on the gums, hiccups, and muscle spasms have been observed.

Alopecia, impaired spermatogenesis and ovulation, and painful gynecomastia are possible.

Cases of pneumonia and respiratory failure have been reported.

A possible association between cisplatin use and the development of 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 disturbances similar to Raynaud’s syndrome).

Cisplatin is theoretically carcinogenic (due to its mechanism of action), but there is no practical evidence of this. In isolated cases, acute leukemia has been observed during cisplatin therapy, which is generally associated with other leukemogenic agents.

During cisplatin therapy, hypercholesterolemia, inappropriate antidiuretic hormone secretion, increased serum amylase levels, and thrombotic microangiopathy combined with hemolytic uremic syndrome have been observed in isolated cases.

Increased serum iron concentration is occasionally observed.

Shelf life.

3 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 (including intravenous infusion sets, needles, catheters, syringes, etc.) must not be used during the preparation and administration of the infusion solution if they may come into contact with the drug.

Cisplatin must not be mixed with any medicinal products except those specified in the section "Administration and dosage." Cisplatin must not be diluted with 5% glucose solution or 5% mannitol solution, but only with their mixtures with 0.9% sodium chloride solution (see section "Administration and dosage").

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

The drug must not be mixed with any other medicinal products in the same container.

Packaging.

20 mL, 50 mL, or 100 mL concentrate in a vial. 1 vial per box.

Prescription status. Prescription only.

Manufacturer.

Timoorgan Pharma GmbH.

Manufacturer's address and place of business.

Schiffgrabben 23, Goslar, Niedersachsen, 38690, Germany.