Cisplatin accord

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CISPATINA ACCORD (CISPLATINA ACCORD)

Composition:

Active substance: cisplatin;

1 vial contains 10 mg, or 25 mg, or 50 mg, or 100 mg of cisplatin (1 mg/ml);

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

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless or almost colorless solution.

Pharmacotherapeutic group. Antineoplastic agents. Platinum compounds.

ATC code L01XA01.

Pharmacological Properties.

Pharmacodynamics.

Cisplatin is an antineoplastic agent containing platinum. Cisplatin has biochemical properties similar to bifunctional alkylating agents. It 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 antineoplastic effect of cisplatin is primarily associated with inhibition of DNA synthesis, other mechanisms, including increased tumor immunogenicity, may contribute to its antineoplastic activity. Cisplatin also has immunosuppressive and antimicrobial properties and enhances sensitivity to radiation.

The action of cisplatin on cells is independent of the cell cycle phase. In addition to tumor cells, target tissues are primarily those characterized by rapid cellular proliferation, such as bone marrow, gastrointestinal mucosa, and gonads.

Pharmacokinetics.

Absorption

Cisplatin is usually administered intravenously, predominantly via intravenous infusion over 6–8 hours. During standard intravenous infusions, total plasma platinum levels rise gradually and reach a peak at the end of the infusion.

Distribution

Cisplatin is well distributed into the kidneys, liver, prostate, and intestine. More than 90% of the platinum compound is distributed in the blood through binding (possibly irreversible) to plasma proteins.

The extent of penetration into cerebrospinal fluid (CSF) is low, although a significant amount of cisplatin may be found in intracerebral tumors.

Elimination of total platinum from plasma is rapid during the first four hours after intravenous administration, but then proceeds more slowly due to covalent binding to serum proteins. Levels of free platinum decline with a half-life ranging from 20 minutes to 1 hour, depending on the infusion rate.

After repeated treatment cycles, platinum may accumulate in body tissues and has been detected in certain tissues up to 6 months after the last dose.

Biotransformation

The metabolic pathway of cisplatin is not fully elucidated. Biotransformation occurs via rapid non-enzymatic conversion into inactive metabolites, which have not been precisely identified.

Excretion

Excretion of the free drug and various platinum-containing biotransformation products occurs via urine. Approximately 15–25% of the administered platinum is rapidly eliminated from the body within the first 2–4 hours after cisplatin administration. This early excretion primarily involves free cisplatin. Within the first 24 hours after cisplatin administration, 20–80% is excreted, while the remainder consists of substances bound to tissues or plasma proteins.

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;

Treatment of cervical tumors in combination with other chemotherapy and with radiotherapy.

Cisplatin may be used as monotherapy as well as in combination therapy.

Contraindications.

• Hypersensitivity to cisplatin or to any component of the medicinal product or to other platinum-containing agents.
• Cisplatin causes nephrotoxicity, which is cumulative; therefore, it is contraindicated in patients with a history of renal impairment.
• Cisplatin has also been shown to exhibit cumulative neurotoxicity (including ototoxicity), and should not be administered to patients with a history of hearing disorders.
• Cisplatin is also contraindicated in patients with myelosuppression and dehydration.
• Breastfeeding period (see section "Use during pregnancy or breastfeeding").
• Concomitant use with yellow fever vaccine.

Special precautions.

Preparation and handling of the medicinal product

As with any other cytotoxic agents, caution should be exercised when handling Cisplatin Accord concentrate. The concentrate must be diluted before administration. Dilution should be performed by trained personnel in a designated area under aseptic conditions. Protective gloves should be used. Precautions must be taken to avoid contact of the medicinal product with skin and mucous membranes. If contact with skin occurs, the skin should be immediately washed with soap and water. Skin contact may result in sensations of stinging, burning, and redness. Mucous membranes should be thoroughly rinsed with water if contact occurs. Inhalation may cause dyspnea, chest pain, throat irritation, and nausea.

Pregnant healthcare workers should not handle cisplatin.

Physiological waste and vomitus should be disposed of carefully.

If the solution is cloudy or contains an insoluble precipitate, the vial should be discarded.

Damaged vials should be disposed of, taking the same safety precautions as for disposal of contaminated waste. Contaminated waste should be stored in special waste containers (see subsection "Disposal").

Preparation for intravenous administration

Withdraw the required amount of solution from the vial and dilute it in at least 1 liter of one of the following solutions:

• 0.9% sodium chloride solution;
• mixture of 0.9% sodium chloride solution and 5% glucose solution (1:1) (final concentrations: 0.45% sodium chloride, 2.5% glucose);
• 0.9% sodium chloride solution and 1.875% mannitol for injection;
• 0.45% sodium chloride, 2.5% glucose, and 1.875% mannitol for injection.

The solution should always be inspected before administration. If the solution is not clear or if an insoluble precipitate forms, it must not be used. Only clear, particle-free solutions should be used.

Needles and other intravenous administration equipment containing aluminum parts must not be used for the preparation or administration of cisplatin solution.

Undiluted concentrate must not be used.

From a microbiological standpoint, the medicinal product should be used immediately. If not used immediately, the user is responsible for the storage duration and conditions after preparation, which must be carried out under controlled and validated aseptic conditions.

Disposal

All materials used in the preparation and administration, or otherwise in contact with cisplatin, must be destroyed in accordance with local regulations for the disposal of cytotoxic substances.

Medicinal products must not be disposed of via wastewater or household waste.

Interaction with other medicinal products and other forms of interaction.

Cisplatin may be used in combination with other cytostatic agents having complementary mechanisms of action. In such cases, additive toxicity may occur.

The myelosuppressive effect of cisplatin may be additive to pre-existing impairments or to similar toxicity from other agents such as cephaloridine, furosemide, aminoglycosides, etc., when used concomitantly.

Nephrotoxic substances

Nephrotoxic drugs (e.g., cephalosporins, aminoglycosides, amphotericin B, or radiographic contrast agents) may potentiate the nephrotoxic effects of cisplatin. Nephrotoxicity may be induced by aminoglycosides administered concomitantly or within 1–2 weeks after cisplatin treatment. Concomitant use of other potentially nephrotoxic drugs (e.g., amphotericin B) is not recommended during cisplatin therapy.

Substances excreted by the kidneys

Particular attention should be paid during or after cisplatin treatment to substances primarily excreted by the kidneys, such as cytostatic agents like bleomycin and methotrexate, due to potential reduced renal excretion.

When ifosfamide is used in combination with cisplatin or after prior cisplatin treatment, the nephrotoxicity of ifosfamide is enhanced.

In combined therapy with cisplatin, bleomycin, and etoposide, decreased serum lithium concentrations have been observed in several cases. Therefore, monitoring of lithium levels is recommended during treatment.

Ototoxic substances

Concomitant and/or sequential use of ototoxic medicinal products (e.g., aminoglycosides and loop diuretics) may potentiate the ototoxic effects of cisplatin on hearing function, especially in the presence of renal impairment.

Except for patients receiving cisplatin doses exceeding 60 mg/m² body surface area (BSA) 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.

Ifosfamide also potentiates the ototoxic effects of cisplatin.

Live attenuated vaccines

The yellow fever vaccine is strictly contraindicated due to the risk of fatal systemic vaccine disease (see section "Contraindications"). Due to the risk of systemic disease, inactivated vaccines are recommended.

Oral anticoagulants

When oral anticoagulants are used concomitantly, 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.

Pyridoxine + altretamine, combination

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

Paclitaxel

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

Anticonvulsants

In patients receiving cisplatin and anticonvulsants (e.g., phenytoin) concomitantly, serum concentrations of the latter may decrease and potentially become subtherapeutic. This is primarily due to reduced absorption of phenytoin and/or enhanced metabolism. Plasma levels of phenytoin should be monitored and the dose adjusted accordingly.

Cisplatin may interact with aluminum (see section "Method of administration and dosage").

Special precautions for use.

Cisplatin therapy must be administered under the supervision of a qualified oncologist only in specialized units equipped to provide appropriate monitoring and care. Appropriate resuscitation equipment must be available to manage anaphylactic reactions.

Cisplatin reacts with aluminum, forming a black platinum precipitate. It is essential to avoid using any aluminum-containing intravenous infusion systems, needles, catheters, or syringes. Prior to administration to the patient, the solution must be inspected visually to ensure clarity and absence of particulate matter.

Cisplatin for infusion must not be mixed with any other medicinal products or excipients.

Adequate monitoring and management of treatment and its complications are possible only with an accurate diagnosis and clearly defined treatment protocols.

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

• Renal function;
• Liver function;
• Hematopoietic system function (erythrocyte, leukocyte, and platelet counts);
• Serum electrolyte levels (calcium, sodium, potassium, magnesium).

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

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

• 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.

Nephrotoxicity.

Cisplatin causes severe cumulative nephrotoxic effects, which may be potentiated by aminoglycosides. Cisplatin should not be administered more frequently than once every 3–4 weeks. To ensure adequate urine output and reduce renal toxicity, cisplatin is recommended to be administered via intravenous infusion over 6–8 hours (see section "Administration and dosage").

Repeated cisplatin courses should not be administered unless plasma creatinine levels are below 1.5 mg/100 mL (130 µmol/L) or blood urea levels are below 55 mg/100 mL (9 mmol/L), and circulating blood levels are acceptable. Since cisplatin-induced nephrotoxicity is cumulative, blood urea nitrogen (BUN), plasma creatinine, glomerular filtration rate (GFR), or creatinine clearance (CrCl) must be measured before initiating therapy and before each subsequent cycle.

Adequate hydration must be ensured before and during therapy to minimize the risk of nephrotoxicity. A diuresis of 100 mL/hour or more minimizes the nephrotoxic effect of cisplatin. Adequate diuresis can be achieved by pre-hydration with 2 L of an appropriate intravenous solution, or by similar hydration after cisplatin administration (administration of 2500 mL/m²/BSA over 24 hours is recommended). If aggressive hydration is insufficient to maintain adequate diuresis, osmotic diuretics (e.g., 10% mannitol solution) may be prescribed.

Particular attention should be paid to patients receiving concomitant therapy with other potentially nephrotoxic agents (see section "Interaction with other medicinal products and other forms of interaction").

Bone marrow function.

Frequent monitoring of blood cell counts is required in patients receiving cisplatin. Although hematotoxicity is usually moderate and reversible, severe thrombocytopenia and leukopenia may occur. In patients who develop thrombocytopenia, special precautions are recommended: caution during invasive procedures; monitoring for signs of bleeding or bruising; testing urine, stool, and vomitus for blood; avoidance of aspirin and other NSAIDs. Patients who develop leukopenia should be carefully examined for signs of infection and may require antibiotic support and blood transfusions (see section "Adverse reactions").

Neuropathies.

Severe neuropathies have been reported. These neuropathies may be irreversible and may manifest as paresthesia, areflexia, loss of proprioceptive sensation, and impaired vibratory sense. Cases of motor function loss have also been reported.

Ototoxicity.

Ototoxicity has been observed in 31% of patients receiving a single dose of cisplatin at 50 mg/m², presenting as tinnitus and/or high-frequency hearing loss (4000–8000 Hz). In some cases, hearing impairment may occur in the speech frequency range. The ototoxic effect may be more pronounced in children receiving cisplatin therapy. Cases of delayed hearing loss have been reported in pediatric patients. Long-term monitoring of this patient group is recommended. Hearing loss may be unilateral or bilateral and occurs more frequently and severely with repeated administration, although 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 peak plasma cisplatin concentration. It is not known whether cisplatin-induced ototoxicity is reversible. Audiometry should be performed before initiating therapy and repeated if auditory symptoms or clinical hearing changes occur. Vestibular toxicity has also been reported (see section "Adverse reactions").

Audiometry should be performed before initiating therapy and repeated if auditory symptoms or clinical hearing changes occur.

Allergic reactions.

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

Liver function and blood count.

Blood count and liver function should be monitored regularly.

Potential carcinogenic effect.

In isolated 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 has shown carcinogenic effects in mice and rats.

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. Specific therapy for extravasation reactions is currently unknown.

Gastrointestinal tract effects.

Nausea and vomiting may be severe and require adequate antiemetic treatment.

Warnings.

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

Renal toxicity, which is primarily cumulative, is severe and requires special precautions during administration (see sections "Administration and dosage" and "Adverse reactions").

Nausea and vomiting may be intense and require appropriate antiemetic treatment. Patients should be carefully monitored for ototoxicity, myelosuppression, and anaphylactic reactions (see section "Adverse reactions").

Excipients.

This medicinal product contains 3.5 mg of sodium per mL, equivalent to 0.18% of the maximum recommended daily sodium intake of 2 g for adults according to WHO.

Patients on a sodium-restricted diet should exercise caution when using this medicinal product, as it contains:

• 10 mg/10 mL vial – 1.52 mmol (35 mg) of sodium per dose;
• 25 mg/25 mL vial – 3.80 mmol (87.5 mg) of sodium per dose;
• 50 mg/50 mL vial – 7.60 mmol (175 mg) of sodium per dose;
• 100 mg/100 mL vial – 15.21 mmol (350 mg) of sodium per dose.

Cisplatin may subsequently be prepared for administration using sodium-containing solutions (see section "Special safety precautions"), and this should be considered in conjunction with all sodium sources in the patient.

Use during pregnancy or breastfeeding.

Pregnancy. There is insufficient information on the use of cisplatin in pregnant women, but based on the pharmacological properties of cisplatin, serious congenital malformations can be expected. Animal studies have shown reproductive toxicity. Cisplatin should not be administered during pregnancy unless there are life-threatening indications.

Fertile women/Contraception in men and women. Both male and female patients receiving cisplatin should use effective contraception during treatment and for at least 6 months after completion of therapy.

If a patient wishes to have children after completing therapy, they should consult a genetics specialist prior to attempting conception.

Lactation. Cisplatin passes into breast milk; therefore, breastfeeding during cisplatin therapy is contraindicated (see section "Contraindications").

Fertility. Since cisplatin may cause irreversible infertility, men who wish to father children in the future should be advised to consider sperm cryopreservation before starting therapy.

Ability to drive and use machines.

No studies on the effect on the ability to drive and use machines have been conducted. However, the adverse reaction profile (e.g., nephrotoxicity) may negatively affect the ability to drive and operate machinery.

Method of Administration and Dosage.

Dosage

Adults and Children

Cisplatin doses should be determined based on the underlying pathology, expected response to therapy, and whether cisplatin is to be used as monotherapy or as part of combination chemotherapy. The doses listed below are recommended for both adults and children.

For monotherapy, the following treatment 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 administered over 5 consecutive days, with treatment cycles repeated every 3–4 weeks.

In combination therapy, doses should be lower. Cisplatin is usually administered at a dose of 20 mg/m² body surface area or higher every 3–4 weeks.

For the treatment of cervical tumors, cisplatin should be used in combination with radiotherapy or other chemotherapeutic agents. Cisplatin is typically 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 Warnings and Precautions for Use").

If renal function impairment or bone marrow suppression occurs, the dose of the drug must be appropriately reduced (see section "Contraindications").

Method of Administration

The infusion solution, prepared according to the instructions provided in the section "Special Precautions for Handling", may only be administered by intravenous infusion over 6–8 hours.

Hydration

Adequate hydration must be provided from 2 to 12 hours before and for at least 6 hours after the end 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 mixture of 0.9% sodium chloride solution and 5% glucose solution in a 1:1 ratio.

Pre-cisplatin hydration: Intravenous infusion of one of the specified solutions at a rate of 100–200 mL/hour over 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 specified 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, the patient should receive an intravenous infusion of 37.5 g of mannitol (375 mL of 10% solution) or diuretics (provided renal function is normal).

Mannitol or diuretics should also be administered when the cisplatin dose exceeds 60 mg/m² BSA.

Patients should drink large amounts of fluids for 24 hours after cisplatin administration to ensure adequate urine output.

The sterile concentrate of Cisplatin Accord 1 mg/mL must be diluted prior to administration. Instructions for dilution before use are provided in the section "Special Precautions for Handling".

Although cisplatin is administered intravenously, the drug may also be administered via intraperitoneal instillation in patients with intraperitoneal malignant tumors (e.g., ovarian tumors). High concentration gradients between intraperitoneal and plasma drug levels can be achieved through intraperitoneal administration.

During administration, avoid using any devices containing aluminum that may come into contact with cisplatin (intravenous infusion sets, needles, catheters, syringes).

Children.

In children, key parameters (serum creatinine, urea, leukocytes, platelets, audiogram) must return to age-appropriate normal values before initiating the next treatment cycle.

Overdose.

Caution must be exercised to prevent accidental overdose.

Acute cisplatin overdose may lead to an exacerbation of its expected toxicities, such as renal failure, hepatic failure, severe neurosensory toxicity (e.g., deafness), oculotoxicity (including retinal detachment), profound bone marrow suppression, intractable nausea and vomiting, and/or neuritis. Overdose may be fatal.

Renal function, cardiovascular status, and blood counts should be monitored daily to assess potential toxicity to these systems. Serum magnesium and calcium levels, as well as symptoms and signs of involuntary muscle irritability, must be closely monitored. If symptomatic tetany develops, electrolyte supplementation should be administered. After acute overdose, liver enzymes in serum and serum uric acid should be monitored daily.

There is no specific antidote for cisplatin overdose. Hemodialysis is effective, even partially, only if performed within the first 3 hours after cisplatin administration. If hemodialysis is performed more than 4 hours after overdose, the effect on cisplatin elimination from the body will be minimal due to the rapid and extensive binding of platinum to blood proteins.

In case of overdose, general supportive measures are indicated.

If fever develops during prolonged myelosuppression, appropriate empirical antibiotic therapy should be initiated after culture sampling.

Side effects.

The most frequently reported adverse reactions associated with cisplatin use are: hematological (leukopenia, thrombocytopenia, and anemia), gastrointestinal (anorexia, nausea, vomiting, and diarrhea), hearing disorders (hearing impairment), renal disorders (renal failure, nephrotoxicity, hyperuricemia), and fever.

Severe ototoxicity, nephrotoxicity, and bone marrow suppression have been reported in nearly 1/3 of patients receiving cisplatin as monotherapy. These effects are generally dose-dependent and cumulative. Ototoxicity may be more severe in children.

The following frequency criteria were used in assessing adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (≤1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations.

Common – sepsis; frequency not known – infectiona.

Blood and lymphatic system disorders.

Very common – bone marrow suppression, thrombocytopenia, leukopenia, anemia; frequency not known – Coombs-positive hemolytic anemia, thrombotic microangiopathy (hemolytic uremic syndrome), neutropenia.

Benign, malignant, and unspecified neoplasms (including cysts and polyps).

Rare – acute leukemia.

Immune system disorders.

Uncommon – anaphylactoid reactionsb.

Endocrine system disorders.

Frequency not known – increased serum amylase levels, syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders.

Very common – hyponatremia; uncommon – hypomagnesemia; frequency not known – dehydration, hypokalemia, hypophosphatemia, hyperuricemia, hypocalcemia, tetany.

Nervous system disorders.

Rare – seizures, peripheral neuropathy, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome; frequency not known – cerebrovascular complications, hemorrhagic stroke, ischemic stroke, taste loss, cerebral arteritis, Lhermitte's sign, myelopathy, autonomic neuropathy.

Eye disorders.

Frequency not known – blurred vision, color vision disturbances, cortical blindness, retrobulbar neuritis, optic disc edema, retinal pigmentation.

Ear and labyrinth disorders.

Uncommon – ototoxicity; frequency not known – tinnitus, deafness.

Cardiac disorders.

Common – arrhythmia, bradycardia, tachycardia; rare – myocardial infarction; very rare – cardiac arrest; frequency not known – cardiac dysfunction.

Vascular disorders.

Common – venous thromboembolism; frequency not known – Raynaud’s phenomenon.

Gastrointestinal disorders.

Rare – stomatitis; frequency not known – vomiting, nausea, anorexia, hiccups, diarrhea.

Hepatobiliary disorders.

Frequency not known – increased liver enzymes, increased blood bilirubin levels.

Respiratory, thoracic and mediastinal disorders.

Frequency not known – pulmonary embolism.

Skin and subcutaneous tissue disorders.

Frequency not known – rash, alopecia.

Musculoskeletal and connective tissue disorders.

Frequency not known – muscle spasms.

Renal and urinary disorders.

Frequency not known – acute renal failure, renal failurec, tubular dysfunction.

Reproductive system and breast disorders.

Uncommon – impaired spermatogenesis.

General disorders and administration site reactions.

Frequency not known – pyrexia (very common), asthenia, malaise, extravasation at injection sited.

a – infectious complications were fatal in some patients;

b – symptoms include: facial swelling, wheezing, bronchospasm, tachycardia, and arterial hypotension – these will be included in parentheses for anaphylactoid reaction in the frequency list of adverse reactions specified above;

c – elevated blood urea nitrogen, creatinine, serum uric acid levels and/or decreased creatinine clearance are indicative of renal failure;

d – local soft tissue toxicity, including cellulitis, fibrosis, and necrosis (common), pain (common), swelling (common), and erythema (common), results from extravasation.

e – usually when used concomitantly with potentially leukemogenic agents.

Renal and urinary disorders

Renal toxicity has been observed in 28–38% of patients receiving a single dose of cisplatin at 50 mg/m². Renal toxicity becomes more prolonged and severe with repeated treatment cycles.

Gastrointestinal disorders

Nausea and vomiting occur in most patients, usually beginning within 1 hour after treatment and lasting up to 24 hours or longer. Anorexia, nausea, and intermittent vomiting may persist for up to a week.

Eye disorders

Optic neuritis, papilledema, and cortical blindness have been reported after cisplatin treatment. Improvement and/or complete recovery usually occurs after immediate discontinuation of treatment. Blurred vision and altered color perception have been reported after treatment regimens using higher doses of cisplatin or more frequent administration than recommended.

Hearing and labyrinth disorders

Ototoxicity has been observed in 31% of patients receiving a single dose of cisplatin at 50 mg/m² BSA. Hearing system damage appears to be dose-dependent and cumulative, and is more frequently reported in very young and elderly patients. Unilateral or bilateral tinnitus, usually reversible, and/or high-frequency hearing loss may occur.

The overall incidence of audiogram abnormalities is 24%, with considerable variation. These abnormalities typically appear within 4 days after drug administration and are characterized by a decrease in pure-tone threshold of at least 15 decibels. The damage is cumulative and irreversible. Audiogram abnormalities are most commonly observed in the 4000–8000 Hz frequency range.

Cases of delayed-onset hearing loss have been reported in pediatric patients (see section "Special precautions"). Delayed onset of symptoms months or years after treatment has also been reported.

Blood and lymphatic system disorders

Myelosuppression occurs in approximately 30% of patients receiving cisplatin, but is mostly mild or moderate and reversible at standard doses. Leukopenia and thrombocytopenia are dose-dependent and more pronounced with higher doses or in patients previously treated with myelosuppressive therapy. Decreased circulating platelets and leukocytes typically occurs between days 18–23 (range: 7.3 to 45), with most patients recovering by day 39 (range: 13 to 62). Leukopenia and thrombocytopenia are more pronounced at doses exceeding 50 mg/m² BSA. Anemia (hemoglobin decrease >2 g%) occurs at a similar frequency but usually with a later onset than leukopenia and thrombocytopenia. Subsequent cisplatin courses should not be initiated until platelet count exceeds 100,000/mm³ and leukocyte count exceeds 4,000/mm³. A high incidence of severe anemia requiring packed red blood cell transfusions has been observed with cisplatin use.

Immune system disorders

In patients previously treated with cisplatin, rare reactions potentially secondary to cisplatin therapy have been reported. Patients with a history or family history of atopy are at particular risk. Facial swelling, wheezing, tachycardia, arterial hypotension, and nonspecific maculopapular rash may occur within minutes after administration. Severe reactions can be managed with intravenous epinephrine, corticosteroids, or antihistamines.

Nervous system disorders

Neurotoxicity may occur. It is cumulative and may be irreversible.

It is typically characterized by neuropathies, but seizures and taste loss have also occurred. Peripheral neuropathies, including paresthesia in upper and lower extremities, tremor, and taste disturbances, have been observed in some patients, usually after prolonged therapy.

Hypomagnesemia or hypokalemia

Hypomagnesemia occurs quite frequently with cisplatin use, while hypocalcemia is less common. Magnesium loss is likely related to renal tubular damage impairing reabsorption of this cation. Hypomagnesemia and/or hypocalcemia may manifest symptomatically with muscle irritability or spasms, clonus, tremor, carpopedal spasm, and/or tetany. This is not dose-related. Electrolyte monitoring is required.

Electrolyte imbalance disorders

Hyponatremia, hypokalemia, and hypophosphatemia may occur.

Hyperuricemia

Hyperuricemia associated with cisplatin use is more pronounced at doses exceeding 50 mg/m² BSA. Allopurinol effectively reduces uric acid levels.

Cardiac reactions, including tachycardia and arrhythmia, have been reported. Vascular toxic effects associated with cisplatin use in combination with other antineoplastic agents have been reported rarely. These may include myocardial infarction, cerebrovascular accidents, thrombotic microangiopathy (hemolytic-uremic syndrome), or cerebral arteritis.

Other toxic effects

Raynaud’s phenomenon has been reported in patients receiving a combination of bleomycin, vinblastine, with or without cisplatin. Hypomagnesemia induced by cisplatin is considered a possible contributing, though not significant, factor. However, the exact cause of Raynaud’s phenomenon in this context remains unknown.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is of great importance. It allows continuous 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 via the Automated Pharmacovigilance Information System at: http://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

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

Incompatibilities

Avoid contact with aluminum. Cisplatin reacts with aluminum to form a black platinum precipitate; therefore, avoid using any devices containing aluminum (e.g., intravenous infusion sets, needles, catheters, syringes).

Cisplatin degrades in solutions with low chloride content; chloride concentration should be at least equivalent to 0.45% NaCl.

Due to lack of compatibility studies, Cisplatin Accord must not be mixed with any other medicinal products.

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

Cisplatin may only be diluted with solutions specified in the "Special precautions for handling" section.

Packaging

Brown glass vial stoppered with a chlorobutyl rubber closure with fluoropolymer coating and aluminum cap; 1 vial in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Accord Healthcare Polska Sp. z o.o. Skład Importera / Accord Healthcare Polska Sp. z o.o. Magazyn Importera.

Manufacturer's address and place of business

ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing authorization holder

Accord Healthcare Polska Sp. z o.o. / Accord Healthcare Polska Sp. z o.o.

Inquiries regarding defective product quality, safety concerns, improper use, or complaints are accepted 24/7 via phone: +380993100335 or by email: [email protected].

Marketing authorization holder's address

7 Tasmowa St., Warsaw, 02-677, Poland.