INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CARBOPLATIN «EBEWE»

Composition:

active substance: carboplatin;

1 ml of concentrate contains 10 mg of carboplatin;

excipient: water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

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

Pharmacotherapeutic group. Antineoplastic agents. Platinum compounds.

ATC code L01X A02.

Pharmacological Properties.

Pharmacodynamics.

Carboplatin is an antineoplastic agent that is an inorganic platinum complex. The antitumor activity of carboplatin is comparable to that of cisplatin against a broad spectrum of tumors, regardless of their localization. The mechanism of antitumor action of carboplatin is associated with inhibition of nucleic acid synthesis, leading to cell death. The drug causes regression of primary tumors and metastases.

Studies using DNA alkaline elution method and DNA binding assays have demonstrated qualitative similarities in the mechanisms of action of carboplatin and cisplatin. Like cisplatin, carboplatin induces changes in the superhelical conformation of DNA, associated with the "DNA shortening effect." It also causes the formation of interstrand and intrastrand cross-links in DNA.

Pharmacokinetics.

After intravenous administration of carboplatin, a linear relationship is observed between doses and concentrations of total and free ultrafilterable platinum in blood plasma. The relationship between doses and the area under the pharmacokinetic curve for total platinum is also linear.

When the drug is administered for 4 consecutive days, no accumulation of carboplatin in blood plasma is observed.

The terminal half-life periods of free ultrafilterable platinum and carboplatin in humans are approximately 6 hours and 1.5 hours, respectively. During the initial phase, free ultrafilterable platinum is predominantly present in the form of carboplatin. The terminal half-life of total plasma platinum exceeds 24 hours. Approximately 87% of plasma platinum binds to proteins within 24 hours after administration.

Carboplatin is primarily excreted via the urine (approximately 70% of platinum is excreted within 24 hours). Most of the platinum is excreted within the first 6 hours.

Total and renal clearance of free ultrafilterable platinum correlate with glomerular filtration rate, but not with tubular secretion.

According to reports, creatinine clearance in children varies 3–4 times. Published data in adult patients indicate that renal function may influence changes in carboplatin clearance.

Clinical characteristics.

Indications.

Carboplatin "Ebewe" should be administered to adult patients.

Carboplatin is indicated for the treatment of the following types of cancer:

1. In progressive epithelial ovarian cancer as:
   • first-line therapy;
   • second-line therapy, if other treatments have proven ineffective.
2. In small cell lung cancer.

Contraindications.

Carboplatin is contraindicated in patients:

• with hypersensitivity to the active substance or to other platinum-containing compounds;
• during breastfeeding (see section "Use in pregnancy or breastfeeding");
• with severe myelosuppression;
• with bleeding tumors;
• with bleeding infections and acute infections (e.g., Herpes zoster);
• with prior severe renal dysfunction (creatinine clearance < 30 ml/min), except when, in the opinion of the physician and patient, potential benefits outweigh the risks;
• when administered simultaneously with the yellow fever vaccine;
• with hearing impairment.

Special safety precautions.

This medicinal product is intended exclusively for the preparation of a single dose.

Contact with skin and/or eyes. In case of contact of carboplatin with skin or eyes, the affected area must be thoroughly rinsed with water or physiological saline. Skin irritation may be treated with a mild cream. In case of eye contact, medical advice should be sought.

Disposal. Any unused portions or waste must be destroyed in accordance with current regulations.

Dilution. Prior to infusion, the medicinal product must be diluted with 5% glucose solution to a concentration of 0.5 mg/ml.

Guidelines for safe handling of cytostatic agents:

1. Preparation of carboplatin must be performed only by qualified personnel trained in the safe handling of chemotherapeutic agents.
2. Preparation must be carried out in a specially designated area.
3. Appropriate protective gloves must be worn during preparation.
4. Precautions must be taken to avoid accidental contact of the agent with the eyes. In case of eye contact, eyes must be thoroughly rinsed with water and/or physiological saline.
5. Pregnant personnel must not handle cytotoxic medicinal products.
6. Disposal of materials (syringes, needles, etc.) used in the preparation of cytostatic agents must be carried out with special care and in compliance with safety regulations. Residual agent and solid waste must be placed in a double-bagged, sealed polyethylene bag and incinerated at 1000 °C. Liquid waste may be flushed with large amounts of water.
7. The work surface should be covered with absorbent paper with a plastic backing for single use.
8. Luer-lock fittings must be used for all syringes and infusion systems. To minimize pressure and the risk of aerosol formation, large-diameter needles are recommended. Aerosol formation can also be reduced by using vented needles.

After dilution.

The ready-to-use solution, prepared with 5% glucose solution, is physically and chemically stable at concentrations of 0.4 mg/ml and 4.0 mg/ml for 28 days when stored protected from light at 2–8 °C or 20–25 °C (container material: PE, PVC, glass). The infusion solution should be used immediately after preparation if stored at room temperature without protection from light.

From a microbiological standpoint, the ready-to-use solution should be used immediately. If immediate use is not intended, the user is responsible for ensuring appropriate storage conditions and duration prior to use. Generally, the solution should not be stored for longer than 24 hours at 2–8 °C, unless it has been prepared under controlled and validated aseptic conditions.

Interaction with other medicinal products and other forms of interaction.

Due to the increased risk of thrombosis in cancer patients, anticoagulant therapy is often prescribed. Significant inter-individual variations in coagulation parameters during the disease, as well as possible interactions between oral anticoagulants and chemotherapy agents, necessitate regular monitoring of the International Normalized Ratio (INR).

Concomitant administration with yellow fever vaccine is contraindicated due to the risk of developing fatal generalized infection.

Combination with live attenuated vaccines (except yellow fever vaccine) is not recommended due to the risk of systemic, potentially fatal disease. This risk is increased in immunocompromised patients due to the underlying disease. Inactivated vaccines should be used when available (e.g., polio).

Concomitant use of nephrotoxic and ototoxic agents, such as aminoglycosides, vancomycin, capreomycin, and diuretics, is not recommended. Changes in renal clearance induced by these agents may increase toxicity.

When carboplatin is used concomitantly with loop diuretics, renal and hearing impairments may occur more frequently.

When carboplatin is combined with other agents that suppress bone marrow function, the myelosuppressive effects of carboplatin and/or the co-administered drugs may be enhanced. Concomitant use with other nephrotoxic agents may lead to severe and prolonged myelotoxicity due to reduced renal clearance of carboplatin.

Extreme caution is required when carboplatin is administered with warfarin, as increased INR values have been reported.

Concomitant use with phenytoin or fosphenytoin is not recommended due to the risk of convulsions, as cytotoxic agents reduce gastrointestinal absorption of phenytoin, and due to the risk of increased toxicity or loss of efficacy of cytotoxic agents resulting from increased hepatic metabolism of phenytoin.

Carboplatin should not be administered simultaneously with agents containing chelating components, as they may theoretically reduce the antitumor activity of carboplatin. However, experimental and clinical studies have shown that diethyldithiocarbamate does not affect the antitumor activity of carboplatin.

Concomitant use of cyclosporine, as well as tacrolimus and sirolimus, may lead to lymphoproliferative disorders due to enhanced immunosuppression.

Special precautions for use.

Warnings.

Carboplatin therapy should be administered under the supervision of an experienced oncologist. Diagnostic facilities for patient monitoring must be available in the hospital to ensure proper treatment and prevention of complications.

Regular blood tests, as well as functional tests to assess kidney and liver function, must be performed. The use of the medicinal product should be discontinued if significant bone marrow suppression or abnormal kidney or liver function is detected.

Patients who have previously undergone intensive therapy (especially with cisplatin), patients in poor general health, patients aged 65 years or older, and patients receiving concomitant treatment with nephrotoxic medicinal products may, like patients with severe renal impairment, experience severe or prolonged myelosuppression.

For these patient groups, initial dosing should be reduced (see section "Dosage and administration").

Regular blood monitoring is necessary to observe the effects of carboplatin. Myelosuppressive effects of carboplatin are closely related to renal clearance. Renal function parameters must be monitored before and during treatment in patients with impaired renal function. Therapy should be discontinued if significant deviations from normal values in bone marrow function or in kidney or liver function occur.

The duration of intervals between treatment cycles should generally be at least 4 weeks. Administration of carboplatin causes thrombocytopenia, leucopenia, and anemia.

Hematological toxicity. Hemolytic anemia associated with serological antibodies to the drug has been reported in patients treated with carboplatin. Such reactions may lead to fatal outcomes.

Leukopenia, neutropenia, and thrombocytopenia are dose-dependent and represent dose-limiting factors in treatment. Frequent monitoring of peripheral blood parameters is required during and after carboplatin therapy. If toxic effects occur, carboplatin treatment should be discontinued until parameters normalize. In patients receiving carboplatin monotherapy, the nadir of neutrophil counts typically occurs on day 21, while in patients receiving combination therapy, it occurs on day 15. The next course of carboplatin therapy should not be initiated until leukocyte and platelet counts have normalized. The following thresholds apply: leukocytes – 2,000 cells/mm³, platelets – 100,000 platelets/mm³.

Anemia may be cumulative, and blood transfusions may be required in some cases.

Myelosuppressive effects may be cumulative when combined with concomitant chemotherapy. Patients with severe and persistent myelosuppression are at high risk of infectious complications, including fatal outcomes. Therapy with carboplatin should be discontinued immediately if such effects occur.

To minimize additive effects, combined therapy involving carboplatin and other myelosuppressive agents must be carefully planned, particularly regarding dosage and treatment schedule. Patients with severe bone marrow suppression may require supportive transfusion therapy.

Cases of acute promyelocytic leukemia and myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) have been reported several years after treatment with carboplatin and other antineoplastic agents.

Hemolytic-uremic syndrome (HUS) is a life-threatening adverse effect. Carboplatin therapy should be discontinued at the first signs of microangiopathic hemolytic anemia, such as rapid hemoglobin decline accompanied by thrombocytopenia, increased serum bilirubin, serum creatinine, blood urea nitrogen, or lactate dehydrogenase (LDH). Renal failure may be irreversible after discontinuation of therapy and may require dialysis.

Allergic reactions. Allergic reactions, such as erythema, unexplained fever, and pruritus, may occasionally occur with carboplatin. In some cases, anaphylaxis, angioedema, and anaphylactoid reactions, including bronchospasm, urticaria, and facial swelling, have occurred; very rarely, treatment has resulted in fatal outcomes. If such events occur, carboplatin therapy must be immediately discontinued and appropriate therapeutic measures initiated. Similar reactions have been observed with other platinum-containing agents and may occur within minutes after administration. The frequency of allergic reactions with carboplatin may increase in patients previously treated with platinum-containing agents. Patients should be closely monitored for possible allergic reactions, and supportive treatment, including administration of antihistamines, adrenaline, and/or glucocorticoids, should be provided.

Hypersensitivity reactions progressing to Kounis syndrome (acute allergic coronary artery spasm, which may lead to myocardial infarction) have been reported (see section "Adverse reactions").

Nephrotoxicity and effects on liver function. Carboplatin may cause impaired kidney and liver function. Very high doses of carboplatin (exceeding the recommended dose by five times in monotherapy) have led to severe abnormalities in liver and kidney function. It has not yet been established whether adequate hydration can counteract this effect on renal function. In cases of moderate to severe kidney or liver dysfunction, dose reduction or treatment interruption is required (see section "Adverse reactions").

Patients with pre-existing renal impairment are more likely to experience nephrotoxic effects, which may be more frequent and severe. Additionally, the occurrence of renal dysfunction is more likely in patients who previously experienced nephrotoxicity with cisplatin. Although there are no clinical data indicating enhanced nephrotoxicity, carboplatin is not recommended to be combined with aminoglycosides or other nephrotoxic substances.

Veno-occlusive liver disease. Cases of hepatic venous obstruction (hepatic sinusoidal obstruction syndrome), some with fatal outcomes, have been reported. Patients should be monitored for signs and symptoms of liver dysfunction or portal hypertension that are unlikely to be due to liver metastases.

Neurological toxicity. Regular neurological examinations and hearing tests should be performed, especially in patients receiving high doses of carboplatin. Neurotoxic effects such as paresthesia, decreased deep tendon reflexes, and ototoxicity, usually mild, may occasionally occur. These symptoms are more likely in patients aged 65 years or older or in those previously treated with platinum-containing agents or other ototoxic drugs. Visual disturbances, including vision loss, have been reported with high-dose carboplatin. Vision typically recovers fully or with minor limitations within several weeks after completion of high-dose therapy.

Cases of reversible posterior leukoencephalopathy syndrome (RPLS) have been reported in patients receiving carboplatin as part of combination chemotherapy. RPLS is a rare, reversible neurological disorder that develops rapidly after discontinuation of treatment and may include seizures, hypertension, headache, confusion, blindness, and other visual and neurological disturbances. Diagnosis of RPLS is confirmed by brain imaging, preferably using MRI (magnetic resonance imaging).

Tumor lysis syndrome (TLS). Post-marketing experience has documented cases of tumor lysis syndrome in patients treated with carboplatin as monotherapy or in combination with other chemotherapeutic agents. Patients at high risk of TLS—those with tumors characterized by high proliferative activity, extensive tumor burden, or high sensitivity to cytotoxic agents—should be monitored, and appropriate preventive measures should be taken.

Studies investigating combination therapy with carboplatin and cyclophosphamide have shown that thrombocytopenia occurs more frequently in elderly patients than in younger ones. Since renal function is often reduced in elderly patients, this factor must be considered when determining the drug dosage (see section "Dosage and administration").

Administration of live or attenuated live vaccines in patients with impaired immune function during chemotherapy, including treatment with carboplatin, may lead to severe or fatal infections. Therefore, vaccination with live vaccines should be avoided during carboplatin therapy. Inactivated or non-live vaccines may be administered, but the immune response to such vaccines may be diminished (see also section "Interaction with other medicinal products and other forms of interaction").

Data on the carcinogenic potential of carboplatin are lacking. However, there are reports of carcinogenic effects of substances with a similar mechanism of action and similar mutagenicity.

The safety and efficacy of carboplatin in children and adolescents have not been established.

Carboplatin may cause nausea and vomiting. Pre-medication with antiemetic agents may reduce the frequency and intensity of adverse effects.

Aluminum-containing materials must not be used for the preparation or administration of carboplatin solution (see section "Incompatibilities").

Use during pregnancy or breastfeeding.

Pregnancy. Administration of carboplatin during pregnancy may result in congenital developmental abnormalities. Reproductive toxicity has been observed in animal studies. In rat experiments, carboplatin demonstrated embryotoxic and teratogenic effects, and in vitro and in vivo studies have shown carboplatin to be mutagenic. No controlled studies in pregnant women have been conducted. If carboplatin is used during pregnancy or if a patient becomes pregnant during treatment, the potential risk to the fetus must be explained. Carboplatin may be used during pregnancy only if clearly indicated. Women of reproductive age should be advised to avoid pregnancy during carboplatin therapy. Pregnant women should not use carboplatin.

Period of breastfeeding. It is currently unknown whether carboplatin is excreted in human milk. Due to the potential adverse effects on the infant, breastfeeding should be discontinued during carboplatin therapy.

Carboplatin is contraindicated during breastfeeding.

Fertility. Carboplatin is genotoxic. Women of reproductive age should use reliable contraceptive methods during carboplatin therapy and for at least 6 months after completion of treatment to prevent pregnancy. Pregnant women and patients who become pregnant during treatment should be referred for genetic counseling.

Patients receiving antineoplastic therapy may develop gonadal suppression, manifesting as amenorrhea or azoospermia. These effects are dose- and duration-dependent and may be irreversible. The prognosis regarding the degree of testicular or ovarian dysfunction is complicated by the frequent use of combinations of several antineoplastic agents, making it difficult to assess the individual contribution of each medicinal product.

Sexually mature men undergoing carboplatin therapy are advised to avoid conception during treatment and for 6 months thereafter. Due to the possibility of irreversible infertility, consideration should be given to sperm cryopreservation before starting carboplatin therapy.

Ability to influence the speed of reactions when driving vehicles or operating machinery.

The ability to influence the speed of reactions when driving vehicles or operating machinery has not been studied. However, carboplatin may cause nausea, vomiting, visual disturbances, and ototoxicity. Therefore, patients should be informed about the possible impact of these effects on their ability to drive vehicles or operate machinery.

Method of Administration and Dosage

The medicinal product is intended for intravenous use after dilution.

Carboplatin must be administered intravenously only.

Carboplatin should be used only under the supervision of a physician experienced in the use of chemotherapeutic agents.

For adult patients who have not previously undergone treatment and who have normal renal function, i.e., creatinine clearance > 60 mL/min, the recommended single intravenous dose of carboplatin is 400 mg/m², administered by short intravenous infusion (15 to 60 minutes).

The next treatment cycle must not be initiated until at least four weeks have elapsed since the previous carboplatin treatment cycle and until the neutrophil count has recovered to at least 2000 cells/mm³ and the platelet count to at least 100,000 cells/mm³.

For patients with risk factors such as prior treatment with myelosuppressive agents and a poor performance status (performance status according to Zubrod scale (ECOG [Eastern Cooperative Oncology Group] scale) 2–4 or Karnofsky index < 80), a 20–25% reduction in the initial dose is recommended.

During the initial treatment cycle with carboplatin, weekly blood tests are recommended to determine the nadir levels of hematological parameters for dose adjustment purposes.

The Calvert formula may also be used to determine the dose:

Dose (mg) = target AUC (mg/mL × min) × [GFR (mL/min) + 25]

AUC — area under the curve
GFR — glomerular filtration rate

Note. When using the Calvert formula, the total dose of carboplatin is calculated in mg, not in mg/m².

Do not use the Calvert formula to calculate doses for patients who have previously received intensive therapy**.

**Intensive therapy is considered to be:

• administration of mitomycin C;
• administration of nitrosourea;
• combination therapy with doxorubicin/cyclophosphamide/cisplatin;
• combination therapy using 5 or more active substances;
• radiation therapy ≥ 4500 rad focused on a field of 20 × 20 cm or more than one field.

Carboplatin administration should be discontinued in case of tumor resistance, disease progression, and/or occurrence of unacceptable adverse reactions.

Carboplatin must not be administered using infusion sets, syringes, or injection needles made from materials containing aluminum, as this may reduce the antineoplastic activity of the drug.

As with handling all cytostatic agents, special caution is required when handling carboplatin. The solution should be prepared only by specially trained personnel wearing protective gloves, protective mask, and protective clothing. Contact of the drug with skin and mucous membranes must be avoided. Pregnant individuals should avoid contact with carboplatin.

Impaired renal function. In patients with creatinine clearance less than 60 mL/min, there is an increased risk of bone marrow suppression.

The incidence of severe leukopenia, neutropenia, or thrombocytopenia at the following doses is consistently 25%:

Creatinine clearance Initial dose

41–59 mL/min 250 mg/m² body surface area

16–40 mL/min 200 mg/m² body surface area

For optimal use of carboplatin, appropriate dose adjustment and regular frequent monitoring of hematological parameters and renal function are required in patients with impaired renal function. Data on the use of carboplatin in patients with creatinine clearance less than 15 mL/min are insufficient to provide treatment recommendations.

All the above-mentioned dosage recommendations apply to the initial treatment course. Subsequent doses should be adjusted according to patient tolerance and acceptable myelosuppressive effect.

Combination therapy. For optimal use of carboplatin in combination with other myelosuppressive agents, dose adjustment is necessary depending on the selected regimen and treatment schedule.

Paediatric patients. Since experience with carboplatin use in children and adolescents is limited, there are no dosage recommendations for this age group.

Geriatric patients (aged 65 years and older). Depending on the patient's general health status, dose adjustment may be required during the first or subsequent treatment courses.

Drug dilution. The concentrate must be diluted before infusion.

Children. Safety and efficacy in children and adolescents have not been established.

Overdose.

Symptoms of overdose. In early clinical trials, carboplatin was administered at doses up to 1600 mg/m² per course. At this dose, life-threatening hematological adverse reactions such as granulocytopenia, thrombocytopenia, and anemia were observed. The lowest values of granulocytes, platelets, and hemoglobin were recorded on days 9–25 (on average, on days 12–17). Granulocyte counts returned to ≥ 500/µL after 8–14 days (on average after 11 days), and platelet counts returned to ≥ 25,000/µL after 3–8 days (on average after 7 days).

In addition, the following non-hematological adverse reactions were observed: renal dysfunction with a 50% decrease in glomerular filtration rate, neuropathies, ototoxicity, vision loss, hyperbilirubinemia, mucositis, diarrhea, nausea and vomiting with headache, erythema, and severe infection. Hearing disturbances were mostly transient and reversible.

Treatment of overdose. There is no specific antidote for carboplatin overdose. Possible complications of overdose may involve bone marrow suppression as well as liver and kidney dysfunction. For treatment of hematological adverse reactions, bone marrow transplantation and transfusions (platelets, blood) may be effective.

Adverse Reactions

The frequency of adverse effects was determined based on data from 1893 patients who received carboplatin injections as monotherapy and post-marketing experience.

Adverse reactions are listed by MedDRA system organ classes, and the frequency of occurrence is classified as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated based on available data).

Benign, malignant and unspecified neoplasms (including cysts and polyps). Uncommon: recurrence of tumors (including promyelocytic leukemia, which developed 6 years after completion of carboplatin monotherapy and prior radiotherapy); secondary acute malignant neoplasms have also been reported after combination chemotherapy containing carboplatin (causal relationship not established).

Infections and infestations. Common: infections*. Frequency not known: pneumonia.

Blood and lymphatic system disorders. Very common: thrombocytopenia, neutropenia, leukopenia, anemia.

Myelosuppression is the dose-limiting factor in carboplatin therapy. Myelosuppression may be more severe and prolonged in patients with impaired renal function, prior radiotherapy, poor general health status, and in patients aged 65 years or older. Additionally, bone marrow suppression is enhanced when carboplatin is combined with other agents having similar myelosuppressive effects. When carboplatin is used as monotherapy at the recommended dose according to the indication (frequency of administration), bone marrow suppression is usually reversible and noncumulative.

When maximum tolerated doses of carboplatin were used in monotherapy, thrombocytopenia with platelet counts decreasing to a nadir of less than 50,000/mm³ was observed in approximately 30% of patients. The nadir is usually reached on days 14–21 of therapy, with normalization occurring within 35 days after the start of treatment. Leukopenia with leukocyte concentrations below 2,000/mm³ occurred in approximately 20% of patients; recovery begins from the day of reaching the nadir (on days 14–28) and occurs more slowly, usually within 42 days after the start of therapy.

In some cases, platelet and leukocyte counts return to baseline only after 35 and 42 days, respectively. In such cases, carboplatin treatment should be repeated only when platelet count has increased to over 100,000/mm³ and leukocyte count exceeds 2,000/mm³.

Neutropenia with granulocyte counts below 1,000/mm³ was observed in approximately 18% of patients. Low hemoglobin levels (below 8 g/dL) occurred in 15% of patients with normal baseline values. Anemia frequently develops and may be cumulative. The incidence of anemia increases with higher carboplatin exposure. Myelotoxicity is more pronounced in patients who have undergone extensive prior therapy (especially with cisplatin) or in patients with impaired renal function. In patients with poor general health status receiving carboplatin injections, increased frequencies of leukopenia and thrombocytopenia were observed. These adverse effects, although usually reversible, led to infectious and hemorrhagic complications in 4% and 5% of patients receiving carboplatin injections, respectively. These complications resulted in death in less than 1% of patients. Overall, transient hemorrhagic complications were also observed.

Common: hemorrhage*. Rare: fever, sepsis/septic shock. Frequency not known: bone marrow failure, blood dyscrasias, febrile neutropenia, hemolytic-uremic syndrome.

Immune system disorders. Common: hypersensitivity reactions, anaphylactoid reactions (rarely fatal), which may occur within minutes after injection. Symptoms include bronchospasm, urticaria, facial swelling and flushing, dyspnea, hypotension, dizziness, anaphylactic shock, wheezing, and tachycardia (see section "Special precautions").

Allergic reactions occurred in less than 2% of patients and manifested as skin rashes, urticaria, erythematous rashes without obvious etiology, or pruritus. Some allergic reactions require additional treatment (e.g., antihistamines, glucocorticoids, or adrenaline). Such reactions include anaphylaxis/anaphylactoid reactions (sometimes fatal), anaphylactic shock, Quincke's edema, facial swelling and hyperemia, low blood pressure, bronchospasm, dizziness, wheezing, syncope, tachycardia, and pyrexia. Hypersensitivity reactions may occur within minutes after injection.

Metabolism and nutrition disorders. Very common: following carboplatin therapy, decreased serum electrolytes were reported (magnesium (29%), potassium (20%), sodium (29%), and calcium (22%)); however, these manifestations were not severe enough to cause clinical signs or symptoms. Early hyponatremia has also been reported. Rare: anorexia, hyponatremia. Frequency not known: dehydration, tumor lysis syndrome.

Nervous system disorders. Common: peripheral neuropathy, paresthesia, decreased deep tendon reflexes, sensory disturbances, dysgeusia.

The incidence of peripheral neuropathy after carboplatin therapy is 4%. In most patients, neurotoxicity is limited to paresthesias and decreased deep tendon reflexes. The frequency and intensity of adverse effects are increased in patients aged 65 years or older or in those previously treated with cisplatin. Paresthesias present before the start of carboplatin therapy, primarily due to prior cisplatin therapy, may persist or worsen during carboplatin treatment.

In isolated cases, symptoms related to the central nervous system have been reported, although these are often attributable to concomitant antiemetic medications.

Clinically significant sensory disturbances (e.g., visual disturbances, taste changes) were observed in 1% of patients.

The incidence of neurological adverse effects was higher in patients receiving carboplatin as part of combination therapy. This may be related to cumulative effects.

Very rare: cerebral stroke*. Frequency not known: cerebrovascular disorders, reversible posterior leukoencephalopathy syndrome#. Hallucinations, anxiety, and nightmares (terrible dreams) are possible.

Eye disorders. Common: during treatment with platinum-containing agents, transient visual disturbances up to complete vision loss have been reported. These disturbances usually occur only with high-dose therapy in patients with impaired renal function. Cases of optic neuritis development were reported during post-marketing surveillance studies.

Ear and labyrinth disorders. Very common: based on audiometric studies, subclinical hearing disturbances in the high-frequency range (4000–8000 Hz) were observed in 15% of patients after carboplatin therapy. Common: clinical ototoxicity. Clinical symptoms occurred in only 1% of patients and were predominantly manifested as tinnitus. Hearing disturbances may persist or worsen in patients with pre-existing hearing loss due to cisplatin therapy.

Clinically significant hearing loss was observed in children who received higher doses of carboplatin than recommended, in combination with other ototoxic agents.

Frequency not known: hearing loss.

Cardiac disorders. Common: cardiovascular disorders*. Very rare: cardiovascular disorders (heart failure, embolism), cerebrovascular disorders (stroke) (causal relationship with carboplatin use not established), arrhythmia, hypertension. Frequency not known: heart failure*, ischemic heart disease (e.g., myocardial infarction, cardiac arrest, angina, myocardial ischemia), Kounis syndrome.

Vascular disorders. Frequency not known: embolism*, hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders. Common: respiratory disorders, pulmonary fibrosis with constrictive chest pain and dyspnea, interstitial lung disease, bronchospasm; these should be considered if pulmonary hypersensitivity can be excluded.

Gastrointestinal disorders. Very common: vomiting, nausea, abdominal pain; nausea without vomiting was observed in approximately 15% of patients. 65% of patients reported vomiting, with severe vomiting in one-third of them. Nausea and vomiting usually occur 6–12 hours after carboplatin administration. These symptoms generally resolve with antiemetic treatment and usually disappear within the first 24 hours after therapy. One-quarter of patients experienced neither nausea nor vomiting. Only 1% of patients experienced vomiting unresponsive to medical treatment. Vomiting occurs more frequently in patients who have previously received therapy, especially with cisplatin. The incidence of vomiting also increases when carboplatin is administered simultaneously with other emetogenic drugs.

17% of patients reported gastrointestinal pain.

Common: diarrhea (8%), constipation (6%), mucositis, esophagitis. Frequency not known: stomatitis, pancreatitis#.

Hepatobiliary disorders. Very common: changes in liver function of mild to moderate severity were reported in approximately one-third of patients with normal baseline values receiving carboplatin therapy. Alkaline phosphatase levels increased more frequently (in 24% of patients) than serum glutamic-oxaloacetic transaminase levels (in 15% of patients), serum alanine aminotransferase levels, or total bilirubin levels (in 5% of patients). Most deviations from normal spontaneously normalized during the treatment course. In half of the patients, these changes were mainly mild and reversible.

In a limited group of patients receiving high-dose carboplatin injections and undergoing autologous bone marrow transplantation, disturbances in liver function parameters were observed. Rare: severe liver function disorders (including acute liver necrosis) occur after administration of higher carboplatin doses than recommended.

Skin and subcutaneous tissue disorders. Common: alopecia, skin disorders. Rare: exfoliative dermatitis. Frequency not known: urticaria, rash, erythema, pruritus.

Musculoskeletal and connective tissue disorders. Common: musculoskeletal disorders. Rare: myalgia, arthralgia.

Renal and urinary disorders. Very common: renal function impairment with creatinine clearance < 60 ml/min, increased blood urea nitrogen levels.

Common: urogenital disorders, hyperuricemia, increased serum creatinine occurred in 6% of patients, increased blood urea nitrogen in 14%, and increased uric acid in 5% of patients. However, these phenomena were usually mild and reversible in approximately half of the patients. Creatinine clearance proved to be the most sensitive indicator of renal function in patients receiving carboplatin injections: a decrease in creatinine clearance occurred in 27% of patients with a baseline value of 60 ml/min or higher during carboplatin therapy.

Nephrotoxic effects may occur more frequently or be more severe in patients with limited renal function prior to starting carboplatin therapy.

It is unknown whether this effect can be compensated by adequate hydration. In cases of moderate (creatinine clearance 41–59 ml/min) or severe (creatinine clearance 16–40 ml/min) renal impairment, the dose should be reduced or treatment discontinued.

Carboplatin is contraindicated in patients with creatinine clearance ≤ 15 ml/min. With standard dosing, renal function disturbances are uncommon. Overall, nephrotoxic effects do not require dose reduction or preventive measures such as large-volume fluid administration or forced diuresis.

Doses should be reduced or carboplatin therapy discontinued in case of significant deviations in renal test results; see sections "Contraindications" and "Special precautions." Hyperuricemia is frequently observed in patients. Allopurinol may be used to reduce serum uric acid concentration. Cases of hematuria and edema have been reported.

General disorders and administration site conditions. Common: asthenia. Uncommon: influenza-like symptoms, chills, headache. Frequency not known: fever without signs of infection, injection site reactions such as burning, pain, redness, erythema, swelling, urticaria, and necrosis, malaise, extravasation at injection site.

Investigations. Very common: decreased creatinine clearance, increased blood urea levels, increased alkaline phosphatase levels, increased aspartate aminotransferase levels, liver function test abnormalities, decreased sodium, potassium, calcium, and magnesium levels in blood. Common: increased blood bilirubin levels, increased creatinine and blood urea levels.

* Fatal outcome in <1%, fatal cardiovascular events in <1%, including heart failure, embolism, and stroke.

From post-marketing data.

Shelf life. 18 months.

Storage conditions.

Store below 25°C in the original packaging to protect from light and in a place inaccessible to children.

Incompatibilities.

The medicinal product must not be mixed with other medicinal products except those specified in the sections "Special precautions for handling" and "Method of administration and dosage."

Infusion systems, syringes, and injection needles made of materials containing aluminum must not be used for administration, as this may reduce the antitumor activity of the product.

Packaging.

5 ml (50 mg) or 15 ml (150 mg) or 45 ml (450 mg) or 60 ml (600 mg) in a vial; 1 vial with patient information leaflet in a carton.

Prescription status. Prescription only.

Manufacturer.

(Responsible for batch release)

EBEWE Pharma GmbH & Co KG

or

Fresenius Kabi Austria GmbH

Manufacturer's address and place of business.

Mondseestrasse 11, 4866 Unterach am Attersee, Austria.