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Composition:


active ingredient: carboplatin;


1 ml of the concentrate contains carboplatin 10 mg;


excipient: water for injection.


Dosage form. Concentrate for infusion solution.


Basic physical and chemical properties: clear, colorless or slightly yellowish solution.


Pharmacotherapeutic group.


Antineoplastic agents. Platinum compounds. ATX code L01X A02.


Pharmacological properties.


Pharmacodynamics.


Carboplatin is an antineoplastic agent, which is an inorganic complex compound of platinum. The antitumor activity of carboplatin is comparable to that of cisplatin for a wide range of tumors, regardless of their location. The mechanism of antitumor action of carboplatin is associated with inhibition of nucleic acid synthesis, which leads to cell death. The drug causes regression of primary tumors and metastases.


Studies by Alkaline DNA elution and DNA binding assays demonstrated qualitative similarity of the mechanisms of action of carboplatin and cisplatin. Carboplatin, like cisplatin, causes changes in the supercoiled conformation of DNA that are associated with the "DNA shortening effect". It also causes the formation of inter-thread and intra-thread crosslinks in DNA.


Pharmacokinetics.


After intravenous administration (300-500 mg/m2) with a creatinine clearance of about 60 mL/min or higher, the plasma concentration decreases biphasically: the duration of the first phase is 1.1 – 2 hours, the second–2.6 – 5.9 hours. The increase in plasma concentration as a function of dose and AUC (area under the curve) is described by linear pharmacokinetics. Clearance, volume of distribution, and average blood circulation time are 4.4 l/h, 16 L, and 3.5 hours, respectively. It practically does not bind to plasma proteins, but the Platinum released from carboplatin irreversibly binds to proteins, and its Half-Life is 5 days. It undergoes hydrolysis to form active compounds that interact with DNA molecules. The main route of elimination is renal excretion; with creatinine clearance values of 60 mL/min and above, 65% of the dose is excreted in the urine within 12 hours, 71% within 24 hours, and only 3-5% of platinum is excreted within 24-96 hours. For patients with impaired renal function and elderly patients (a decrease in renal filtration is likely), it is necessary to adjust the dosage regimen and reduce the dose, since accumulation and an increase in the time of exposure to the bone marrow are possible (for example, at AUC 4-5 mg/mL/min, thrombocytopenia and leukopenia are 16 and 13%, respectively, at AUC 6-7 mg/mL/min – 33 and 34 %).


Clinical characteristics.


Indications.


As monotherapy or in combination with other antineoplastic agents for the treatment of epithelial ovarian cancer and small cell lung cancer.


Contraindications.


Carboplatin is contraindicated:


with severe renal impairment (glomerular filtration rate 30 mL/min), except in cases where, according to the decision of the doctor and patient, the possible benefits of treatment prevail over the risks; with hypersensitivity to carboplatin and other platinum compounds in the Anamnesis; with severe forms of myelosuppression; with hearing disorders; with acute infections; with bleeding tumors and other significant blood loss; with simultaneous use of the yellow fever vaccine; during breast-feeding.

Special security measures.


Carboplatin-Vista should be used exclusively for the preparation of a single dose.


Skin and/or eye contact


In case of contact of carboplatin with the skin or eyes, the affected area should be thoroughly rinsed with water or saline solution. Skin irritation can be treated with a mild cream. In case of eye contact, consult a doctor.


Instructions for safe use of cytostatic substances


1.preparation of carboplatin Vista for its use can only be carried out by qualified personnel who have been trained in the safe handling of chemotherapeutic agents.


2. preparation of the drug for administration should be carried out in a specially designated place in compliance with aseptic conditions.


3.special protective gloves should be used when cooking.


4.precautions should be taken to avoid accidental contact of the product with the eyes. In case of contact of the product with the eyes, it is necessary to rinse them well with water and/or saline solution.


5. pregnant women should not come into contact with cytotoxic drugs.


6.disposal of materials (syringes, needles, etc.) that were used to prepare the cytostatic agent should be carried out with special care and in compliance with safety measures. The remaining product and solid waste should be placed in a plastic bag closed on both sides and burned at a temperature of 1000 °C. liquid waste can be washed off with plenty of water. 


7.the work surface should be covered with absorbent paper with a single-use plastic base.


8.for all syringes and infusion systems, it is necessary to use "luer-lock "type nozzles. To minimize pressure and possible aerosol formation, it is recommended to use large-diameter needles. Aerosol formation can also be reduced by using an air duct needle.


Recycling.


Unused vehicle residues or waste must be disposed of in accordance with national toxic waste disposal requirements.


Interactions with other drugs and other types of interactions.


Due to the increased risk of thrombosis in the case of cancer, anticoagulant therapy is often used. Due to the high individual variability of coagulation in patients and the possible interaction between oral anticoagulants and antitumor chemotherapy, it may be necessary to prescribe oral anticoagulants, increase the frequency of INR control (international normalized ratio). When taking carboplatin and warfarin at the same time, you should be very careful, since there have been cases of increased INR indicators.


Concomitant use is contraindicated:


- with the yellow fever vaccine – the risk of fatal generalized vaccine disease.

Concomitant use is not recommended:


- with live attenuated vaccines (with the exception of the yellow fever vaccine) – risk of systemic disease, possibly fatal. This risk increases in people who already have immunosuppression due to the underlying disease. An inactivated vaccine should be used if available (polio);


- with phenytoin, phosphophenytoin-the risk of exacerbation of seizures as a result of a decrease in the absorption of phenytoin in the digestive tract associated with the use of a cytotoxic drug, or the risk of increased toxicity xb loss of effectiveness of the cytotoxic drug due to an increase in hepatic metabolism caused by phenytoin;


- nephrotoxic and ototoxic agents, such as aminoglycosides, vancomycin, capreomycin and diuretics. Changes in renal clearance caused by the use of these drugs can lead to increased toxicity.


In case of simultaneous use, the following should be taken into account::


- cyclosporine (as well as tacrolimus and sirolimus): too high immunosuppression with the risk of lymphoproliferation;


- aminoglycosides: concomitant use of carboplatin with aminoglycoside antibiotics requires a balanced approach due to cumulative nephrotoxicity and toxicity to the hearing organs, in particular for patients with impaired renal function;


- loop diuretics: concomitant use of carboplatin with loop diuretics requires a balanced approach due to cumulative nephrotoxicity and toxicity to the hearing organs;


- chelating agents: concomitant use of carboplatin with chelating agents should be avoided, as they can theoretically weaken the antitumor effect of carboplatin. However, experimental and clinical studies have shown that diethyl Dithiocarbamate does not affect the antitumor effect of carboplatin.


When carboplatin is combined with other substances that inhibit bone marrow, it can enhance the effect of carboplatin and/or additionally prescribed medications on the bone marrow. When used concomitantly with other nephrotoxic agents, patients may develop severe and long-term myelotoxicity due to a decrease in renal clearance of carboplatin. Combination therapy with carboplatin and other myelosuppressive drugs may require dose reduction to prevent cumulative toxic effects.


Increases (mutually) the nephrotoxicity of propranolol, aminoglycosides, as well as the effects of other drugs that have nephrotoxic, neurotoxic, ototoxic and myelosuppressive effects.


Carboplatin weakens the effectiveness of immunization with inactivated vaccines; when using vaccines containing live viruses, it increases viral replication and side effects of vaccination.


Carboplatin enhances the neurotoxic and ototoxic effects previously caused by cisplatin.


Other myelotoxic drugs and radiation therapy increase bone marrow depression (potentiate neutropenia and thrombocytopenia).


Carboplatin acts synergistically with etoposide and vindesin.


Carboplatin interacts with components of needles, syringes, catheters, and kits for intravenous administration of drugs containing aluminum to form a black precipitate, and therefore such items should not be used for carboplatin administration.


Application features.


Administration of carboplatin should be carried out under the supervision of a doctor who has experience in the use of cytotoxic drugs. Constant monitoring of possible toxic effects during treatment with carboplatin is mandatory.


Regularly (1 time a week), as well as before each administration of carboplatin, it is necessary to monitor the level of formed elements of peripheral blood and laboratory parameters of kidney and liver function, and in case of significant suppression of spinal cord function or abnormal functioning of the kidneys or liver, the use of the drug should be discontinued.


Hematological toxicity.


Patients who have undergone serious previous treatment (especially with cisplatin), patients with severe general health or patients over 65 years of age, patients with impaired renal function, and patients receiving concomitant treatment with other nephrotoxic drugs may suffer from severe and long-term myelosuppression. For these groups of patients, the initial dosage should be reduced (see the section "dosage and administration"). Combination therapy with carboplatin injections with other myelosuppressive treatments should be very carefully planned in terms of doses and timing to minimize undesirable additive effects. In case of severe suppression of bone marrow function, the Drug Administration should be suspended. Patients with severe bone marrow suppression may need transfusion therapy. Acute promyelocytic leukemia and myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) have been reported several years after treatment with carboplatin and other antitumor drugs.


The myelosuppressive effect of carboplatin largely depends on its renal clearance, so renal function should be carefully evaluated before starting and during treatment with carboplatin. Administration of carboplatin causes thrombocytopenia, leukopenia, and anemia. Anemia that occurs is frequent and cumulative, and blood transfusions may be required in some cases. Hemolytic anemia with the presence of serological drug antibodies has been reported in patients treated with carboplatin. Such anemia can be fatal. Leukopenia, neutropenia, and thrombocytopenia are dose-dependent and dose-limiting. Usually, the duration of intervals between courses of therapy should be at least 4 weeks. It is necessary to carefully monitor the condition of peripheral blood during treatment with carboplatin to adjust the dosage regimen and therapy schedule in order to minimize side effects. In patients receiving carboplatin injections as part of monotherapy, the maximum decrease in neutrophil levels usually occurs on Day 21, and in patients receiving combination therapy-on Day 15. Do not start the next course of treatment with carboplatin until the indicators of white blood cells and platelets normalize. In this case, the following standards apply: for white blood cells – 2000 white blood cells/mm3, for platelets – 100,000 platelets/mm3.


Hemolytic-uremic syndrome (Hus) is a life-threatening side effect. Carboplatin should be discontinued at the first sign of microangiopathic hemolytic anemia, such as a rapid decrease in hemoglobin with concomitant thrombocytopenia, increased serum bilirubin, serum creatinine, blood urea nitrogen, or LDH. Renal failure may be irreversible after discontinuation of therapy and will require dialysis.


Renal toxicity and effects on liver function.


Carboplatin can lead to impaired kidney and liver function. Very high doses of carboplatin (exceeding the recommended dose by 5 times in monotherapy) led to severe abnormalities in liver and kidney function. To date, it has not been clarified whether appropriate hydration can combat this effect on kidney function. In case of changes in renal or hepatic function of moderate to severe severity, it is necessary to reduce the dose or interrupt treatment (see the section "adverse reactions").


In patients with limited renal function, even before starting treatment with carboplatin, the nephrotoxic effect may occur more often and have a more severe form. In addition, the occurrence of impaired renal function is more likely in those patients who have developed nephrotoxicity under the influence of cisplatin. Although there are currently no clinical data indicating an increased nephrotoxic effect, carboplatin is not recommended to be combined with aminoglycosides or other nephrotoxic substances.


Disorders of the hepatobiliary system as a whole are insignificant and reversible (levels of total bilirubin, aspartate aminotransferase, alkaline phosphatase may increase), in some cases, especially in the case of high doses of carboplatin, acute fulminant necrosis of liver cells may occur.

Dosage and administration.


For intravenous administration after dilution.


Carboplatin is administered exclusively intravenously.


For adult patients who have not previously been treated, with normal renal function (creatinine clearance > 60 mL/min), a dose of carboplatin is recommended, which is 400 mg/m2 of body surface area in the form of a single intravenous dose, which is administered by short intravenous infusions (from 15 to 60 Minutes). The course should be repeated no earlier than 4 weeks after the previous administration and/or until the neutrophil content is 2 × 109/L, and the platelet content is 100 × 109/L.


Patients with risk factors (after myelosuppressive therapy and/or radiation therapy), patients with a severe general condition (general condition according to Zubrod assessment (ECOG scale) 2-4 or Karnovsky index less than 80) carboplatin should be prescribed at an initial dose of 300-320 mg/m2 of body surface area.


During the initial courses of treatment with carboplatin, it is necessary to determine the content of shaped blood elements on a weekly basis in order to adjust the dose in subsequent courses of treatment.


Elderly patients


Patients over 65 years of age should adjust the dose of the drug in accordance with the general condition during the first and subsequent courses of treatment.


Carboplatin therapy should be discontinued if there is no response from the tumor, if the disease progresses, and/or if intolerant side effects occur.


Impaired renal function. Patients with creatinine clearance below 60 mL/min are at an increased risk of developing severe myelosuppression. If patients have impaired renal function, carboplatin doses should be reduced in accordance with the glomerular filtration rate.


The frequency of severe forms of Leukopenia, neutropenia or thrombocytopenia with the following doses is constant and amounts to 25 %:


Creatinine clearance initial dosage


41-59 mL/min 250 mg/m2 of body surface area


16-40 mL/min 200 mg/m2 of body surface area


For optimal use of carboplatin, appropriate dose adjustment is necessary, as well as regular frequent monitoring of hematological parameters and renal function in patients with limited renal function.


Do not use carboplatin at a glomerular filtration rate of ≤ 20 mL/min.


Combined treatment. Optimal use of carboplatin with other myelosuppressive drugs requires dose adjustment depending on the regimen and treatment regimen used.

Instructions for medical personnel


Carboplatin should be administered by short intravenous infusions lasting 15-60 minutes after preliminary dilution with 5% glucose solution to a carboplatin concentration of 0.4 mg/mL.


From a microbiological point of view, the diluted solution should be administered immediately. If immediate use of the product is not provided, the user is responsible for observing the time and storage conditions before use.


Since carboplatin Vista does not contain antibacterial preservatives, infusion solutions can be stored at a temperature of 2-8 °C for no more than 24 hours. From a microbiological point of view, the diluted solution should be administered immediately.


Carboplatin should not be administered through infusion systems that include aluminum parts, or through needles, syringes, or catheters containing aluminum. Sediment formation can lead to a decrease in antitumor activity.


Collect the solution from the bottle immediately before use.


It is allowed to collect the drug from the bottle only once.


When manipulating the drug, you should follow the rules for working with cytostatics.


Children.


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


Overdose.


At the first stage of the study, carboplatin was administered in doses up to 1600 mg/m2 per course. Life-threatening hematological adverse reactions such as granulocytopenia, thrombocytopenia, and anemia were observed at this dosage. On days 9-25 (on average, on days 12-17), the lowest values of granulocytes, platelets and hemoglobin were recorded. After 8-14 days (an average of 11 days), granulocytes again reached ≥ 500/µL, platelets again reached ≥ 25,000/µL after 3-8 days (an average of 7 days).


Non-hematological side effects may include: impaired renal function with a 50% decrease in glomerular filtration rate, neuropathy, ototoxicity, vision loss, hyperbilirubinemia, mucositis, diarrhea, nausea and vomiting with headache, erythema and severe infections. In most cases, hearing loss is temporary and reversible.


Treatment of overdose: if necessary, the doctor prescribes symptomatic therapy. Effective measures in case of hematological side effects can be bone marrow transplantation and transfusions (platelets, blood). The antidote to carboplatin is unknown.


Adverse reactions.


The frequency of adverse reactions is classified as follows:


very frequent (≥ 1/10), frequent (≥ 1/100 to


Infections and infestations:


Common: infections*.


Frequency unknown: pneumonia.


Neoplasms are benign, malignant, and undefined (including cysts and polyps):


Rare: the development of recurrent tumors (including promyelocytic leukemia, which developed 6 years after carboplatin monotherapy and previous radiation therapy) was observed after the end of carboplatin monotherapy, as well as combination therapy (no causal relationship has been established).


From the hematopoietic system and the lymphatic system:


Very common: thrombocytopenia, neutropenia, leukopenia, anemia; the dose-limiting factor in carboplatin treatment is limited bone marrow function. In patients with impaired renal function, after previous radiation therapy, with poor general health and over 65 years of age, myelosuppression may occur in a more severe and prolonged form. In addition, bone marrow suppression is enhanced when carboplatin is combined with other agents that have a similar myelosuppressive effect. If carboplatin is used as part of monotherapy and at the recommended dose and in accordance with the indications for use (frequency of administration of the drug), bone marrow suppression is usually reversible and non-cumulative.


When using the maximum tolerated doses of carboplatin as part of monotherapy, about 25% of patients experienced thrombocytopenia with a decrease in the number of platelets to the minimum value – less than 50,000/mm3. The minimum value is reached, as a rule, on 14-21 days of therapy, normalization occurs within 35 days after the start of treatment. Approximately 14% of patients experienced leukopenia with a white blood cell concentration > 2000/mm3, normalization of indicators begins on the day of reaching the minimum value (on days 14-28) and occurs more slowly, usually within 42 days after the start of therapy. Approximately 18% of patients had neutropenia with a granulocyte count of 3. 15% of patients with normal baseline values had low hemoglobin levels – less than 8 g/dL. Anemia develops frequently and can occur cumulatively.


Common: hemorrhage*, infectious-related complications in patients with poor general condition (


Frequency unknown: hematopoietic disorders, febrile neutropenia, hemolytic-uremic syndrome.


From the immune system:


Common: hypersensitivity reactions, anaphylactoid reactions, skin rashes, fever with no known cause, fever. Anaphylactoid reactions, which rarely lead to death, can occur within minutes after injection of the drug with the following manifestations: bronchospasm, urticaria, erythema and facial edema, shortness of breath, tachycardia, low blood pressure, dizziness, wheezing, anaphylactic shock (see the section "features of use").


Cross-reactions with all platinum compounds have been reported, sometimes fatal.


From the side of metabolism:


Very frequent: after carboplatin treatment, a decrease in serum electrolytes (magnesium, potassium, sodium, and calcium) was reported, but these manifestations were not so severe as to cause clinical signs or symptoms. Cases of early hyponatremia have also been reported.


Liquid: anorexia, hyponatremia.


Frequency unknown: dehydration, tumor lysis syndrome.


From the nervous system:


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


The incidence of peripheral neuropathy after carboplatin treatment is 4 %. In most patients, neurotoxicity is limited to paresthesia and decreased deep tendon reflexes. In patients over 65 years of age or after previous cisplatin treatment, the frequency and intensity of side effects increases. Paresthesias that occur even before the start of carboplatin treatment, caused primarily by previous cisplatin therapy, may persist or worsen during carboplatin treatment.


In some cases, symptoms from the central nervous system have been reported, which, however, can often be explained by the simultaneous use of antiemetic drugs.


1% of patients had clinically significant sensitivity disorders (for example, visual disturbances, changes in taste).


The incidence of neurological side effects was higher in patients treated with carboplatin as part of combination therapy. This may be due to cumulative exposure.


Very rare: brain stroke*.


Frequency unknown: reverse posterior leukoencephalopathy syndrome, possible hallucinations, anxiety and nightmares (terrible dreams).


From the side of the visual organs:


Frequent: temporary visual disturbances, up to complete loss of vision. These disorders usually occur only with high-dose therapy in patients with impaired renal function. Neuritis of the optic nerve.


From the side of the organs of hearing and balance:


Very frequent: based on audiometric studies, 15% of patients after carboplatin treatment had subclinical hearing impairments with restrictions in the upper frequency range (4000-8000 Hz).


Frequent: clinical ototoxicity. Only 1% of patients had clinical symptoms, which mainly manifested themselves in the form of tinnitus. In patients with reduced hearing acuity due to cisplatin treatment, hearing disorders may persist or worsen.


Clinically significant hearing loss was observed in children who received higher doses of carboplatin than recommended in combination with other drugs that have a negative effect on hearing.

Tags: Carboplatin