INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CARBOPLATIN (CARBOPLATIN)

Composition:

Active substance: carboplatin;

1 ml of solution contains carboplatin 10 mg;

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

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

Mechanism of action

The mechanism of its antitumor action is associated with inhibition of nucleic acid synthesis, leading to cell death. The ability of the drug to induce regression of primary tumors and metastases is also related to its effect on the body's immune system.

Studies analyzing DNA binding have demonstrated qualitative similarities in the mechanisms of action of carboplatin and cisplatin. Like cisplatin, carboplatin causes changes in the superhelical conformation of DNA, which are associated with the effect of DNA shortening. It also induces interstrand and intrastrand cross-links in DNA.

Pharmacokinetics

Distribution

Plasma concentrations of carboplatin and free platinum after intravenous administration decrease according to biphasic kinetics. The initial elimination half-life of free platinum is approximately 1–2 hours, and the terminal elimination half-life is 3–6 hours; total platinum has a similar initial elimination half-life, but a longer terminal elimination half-life (approximately 24 hours). With repeated dosing over four consecutive days, accumulation of platinum in plasma is not observed. Approximately 87% of plasma platinum binds to proteins within 24 hours after administration.

Elimination

Carboplatin is excreted in the urine, with recovery of approximately 70% of the administered platinum within 24 hours. The majority of the substance is excreted within the first 6 hours.
Total and renal clearance of free ultrafilterable platinum correlates with glomerular filtration rate, but not with tubular function.

Linearity / Non-linearity

After administration of carboplatin, there is a linear relationship between dose and plasma concentrations of total and free ultrafilterable platinum. The area under the plasma concentration–time curve (AUC) for total platinum also shows a linear dependence on dose when creatinine clearance is ≥ 60 mL/min.

Clinical Characteristics

Indications

Ovarian epithelial cancer and small cell lung cancer — as monotherapy or in combination with other antineoplastic agents.

Contraindications

Hypersensitivity to carboplatin or other platinum-containing compounds.
Severe renal impairment (creatinine clearance < 30 mL/min), except when, in the opinion of the physician and patient, potential benefits of treatment outweigh the risks.
Severe myelosuppression.
Bleeding tumors.
Recent significant blood loss.
Concomitant administration with yellow fever vaccine.
History of severe allergic reaction to platinum-containing components.
Pregnancy or breastfeeding period.
Hearing impairment.
Pediatric age.

Special Safety Measures

Carboplatin therapy should be administered under the supervision of an oncologist experienced in chemotherapy, preferably in a hospital setting equipped for adequate patient monitoring. Diagnostic and therapeutic resources must be readily available to manage potential complications. If bone marrow function or renal or hepatic function impairment is detected, the drug should be discontinued.

Standard precautions for handling cytotoxic agents must be observed during manipulations with the drug.

When preparing and administering the drug solution, as with other antineoplastic agents, caution must be exercised and gloves should be worn. In case of contact with skin or mucous membranes, the affected area should be immediately and thoroughly washed with soap and water; mucous membranes should be rinsed with water.

Preparation should be performed in a designated area. The work surface should be covered with absorbent paper with a plastic backing for single use.

Pregnant personnel should not handle cytotoxic medicinal products.

Disposal of materials (syringes, needles, liquid contents, etc.) used in the preparation of cytostatic agents must be carried out with special care and in accordance with safety precautions.

Any unused product or waste material must be destroyed in accordance with national regulations for the disposal of toxic waste.

Interaction with Other Medicinal Products and Other Types of Interactions

Carboplatin is generally used in combination with antineoplastic agents having similar cytotoxic effects. Under these circumstances, additive toxicity may occur.

When carboplatin is combined with other myelosuppressive agents, enhanced effects on bone marrow of carboplatin and/or the co-administered agents may occur. In patients receiving concomitant treatment with other nephrotoxic substances, there is an increased risk of more pronounced and prolonged myelotoxicity due to reduced renal clearance of carboplatin. When oral anticoagulants are used, intensified monitoring of the international normalized ratio (INR) is required due to the potential interaction between oral anticoagulants and carboplatin.

Concomitant use is contraindicated with yellow fever vaccine – risk of generalized vaccine-related disease leading to fatal outcomes.

Concomitant use with nephrotoxic or ototoxic agents such as aminoglycosides, vancomycin, capreomycin, and diuretics is not recommended, as such combined use may enhance toxicity due to carboplatin-induced changes in renal clearance of these agents, especially in patients with renal insufficiency.

Concomitant use is not recommended

With live attenuated vaccines (except yellow fever vaccine) – risk of systemic disease that may lead to fatal outcomes. With inactivated vaccine (poliomyelitis).
With phenytoin, fosphenytoin.

Phenytoin, fosphenytoin: risk of seizure exacerbation due to reduced gastrointestinal absorption of the cytotoxic active substance or risk of toxic elevation or loss of efficacy of the cytotoxic active substance due to increased hepatic metabolism of phenytoin.

Caution is required when co-administering with the following agents.

Concomitant use with agents exhibiting myelosuppressive, nephrotoxic, neurotoxic, or ototoxic effects may lead to mutual enhancement of toxic effects. Cisplatin enhances the neuro- and ototoxicity of carboplatin. Concomitant administration with aminoglycoside antibiotics should be avoided.

Cyclosporines (also tacrolimus and sirolimus) – concomitant use leads to increased immunosuppression with risk of lymphoproliferative disorders.
Nephrotoxic or ototoxic agents – concomitant use with aminoglycoside antibiotics or loop diuretics enhances nephrotoxicity and/or ototoxicity.
Chelating agents – concomitant use should be avoided, as it may lead to reduced antitumor effect of carboplatin.

Experimentally, it has been established that carboplatin acts synergistically with etoposide and vindesine. Do not allow contact of carboplatin solutions with needles or other equipment containing aluminum (precipitation may occur upon contact of carboplatin with aluminum).

Special precautions for use

Warnings

Carboplatin should be administered in accordance with the instructions for handling cytotoxic agents.

In case of extravasation, the infusion must be immediately discontinued and local symptomatic treatment initiated.

Regular blood tests, as well as functional tests to assess kidney and liver function, are required. If significant suppression of bone marrow function or abnormal kidney or liver function is detected, the drug should be discontinued.

Patients who have previously undergone intensive therapy (especially with cisplatin), patients in poor general health or aged over 65 years, and patients receiving concomitant treatment with nephrotoxic drugs may, like patients with severe renal impairment, experience severe or prolonged myelosuppression. For these patient groups, initial dosing should be reduced (see section "Administration and dosage").

The interval between carboplatin treatment cycles should be at least 4 weeks.

Hematological toxicity

Hemolytic anemia associated with drug-specific serological antibodies has been reported in patients receiving carboplatin. Such reactions may be fatal.

Leukopenia, neutropenia, and thrombocytopenia are dose-dependent and dose-limiting factors in treatment.

Frequent monitoring of peripheral blood parameters is required during and after carboplatin treatment. If toxic effects occur, carboplatin therapy should be discontinued until parameters normalize. In patients receiving carboplatin monotherapy, nadir counts typically occur on day 21, and in combination therapy on day 15. A new cycle of carboplatin treatment should not be repeated until leukocyte and platelet counts have normalized (i.e. leukocyte levels ≥2000/mm³ and platelet levels ≥100,000/mm³). Administration of carboplatin causes thrombocytopenia, leukopenia, and anemia. Anemia is common and cumulative; in some cases, blood transfusions may be required.

The severity of myelosuppression, particularly thrombocytopenia, increases in patients previously treated with chemotherapy, especially cisplatin, and/or those with impaired renal function. Initial doses of carboplatin should be appropriately reduced for these patient groups. Combination therapy with carboplatin and other myelosuppressive treatments must be carefully planned regarding dosage and scheduling to minimize additive adverse effects. Myelosuppressive effects may be cumulative when combined with other chemotherapy. Patients with severe and persistent myelosuppression are at high risk of infectious complications, including fatal outcomes. If such complications occur, carboplatin therapy should be immediately discontinued.

To minimize additive effects, combination therapy involving carboplatin and other myelosuppressive agents must be carefully planned, particularly regarding dosage and treatment schedule.

Patients experiencing severe bone marrow suppression may require supportive transfusion therapy. Continuous monitoring for potential toxic effects during carboplatin treatment is mandatory. Before each treatment cycle, a neurological examination should be performed to detect signs of neurotoxicity.

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 therapies.

Hemolytic-uremic syndrome (HUS)

Hemolytic-uremic syndrome (HUS) is a life-threatening adverse effect. Administration of carboplatin should be discontinued at the first signs of microangiopathic hemolytic anemia, such as rapid hemoglobin decline with concomitant thrombocytopenia, elevated serum bilirubin, serum creatinine, blood urea nitrogen, or lactate dehydrogenase. 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 occur during carboplatin administration. In some cases, anaphylaxis, angioedema, and anaphylactoid reactions, including bronchospasm, urticaria, and facial swelling, have occurred; very rarely, treatment has been fatal. Therapy must be immediately discontinued and appropriate treatment initiated. Reactions are similar to those observed with other platinum-containing compounds and may occur within minutes after administration. The frequency of allergic reactions may increase with prior exposure to platinum-containing agents, even if reactions occurred only after carboplatin use.

Patients with a history of allergic reactions to other platinum compounds should be monitored for allergic symptoms and provided supportive treatment, including administration of antihistamines, adrenaline, and/or glucocorticoids. Further use of carboplatin after allergic reactions is contraindicated. Cross-reactions with all platinum compounds have been reported, sometimes with fatal outcomes. Hypersensitivity reactions progressing to Kounis syndrome (acute allergic coronary artery spasm that may lead to myocardial infarction) have been reported (see section "Adverse reactions").

Renal toxicity and hepatic function effects

Carboplatin may cause renal and hepatic dysfunction. 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 is currently unknown whether adequate hydration can counteract this renal effect. In cases of moderate to severe renal or hepatic impairment, dose reduction or treatment interruption is required (see section "Adverse reactions").

Patients with pre-existing renal impairment are more likely to experience nephrotoxic effects more frequently and severely. Additionally, renal dysfunction is more likely in patients who experienced nephrotoxicity during cisplatin treatment. Although there are no clinical data indicating enhanced nephrotoxicity, carboplatin is not recommended to be combined with aminoglycosides or other nephrotoxic substances.

Renal function parameters should be monitored before and during treatment in patients with impaired renal function.

The myelosuppressive effect of carboplatin is largely dependent on its renal clearance.

The hematopoietic effects of carboplatin are more pronounced and prolonged in patients with renal impairment compared to those with normal renal function; therefore, carboplatin therapy should be administered with particular caution in this risk group.

Initial dosing should be reduced for these patient groups (see section "Administration and dosage").

Hepatic veno-occlusive 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 assessments are required, particularly in patients receiving high doses of carboplatin.

Patients should be informed about the possibility of persistent peripheral sensory neuropathy symptoms after completion of treatment. Localized moderate paresthesia with functional impairment may persist for up to 3 years after adjuvant treatment.

The frequency of peripheral neurological toxicity increases in patients aged 65 years and older and in those previously treated with platinum-containing agents or who previously received cisplatin or other ototoxic drugs.

Visual disturbances, including vision loss, have been reported after administration of carboplatin at higher than recommended doses in patients with renal insufficiency. Vision usually recovers fully or substantially after discontinuation of therapy. Regular monitoring and neurological examination are recommended.

Gastrointestinal toxicity

Carboplatin causes vomiting. The frequency and severity of vomiting can be reduced by premedication with antiemetics or by administering continuous 24-hour infusion or fractionated infusions over 5 days instead of a single infusion. Selective serotonin 5-HT3 receptor antagonists (e.g., ondansetron) or substituted benzamides (e.g., metoclopramide) may be particularly effective antiemetics, and combination therapy may be prescribed for patients with refractory or severe vomiting.

Reversible posterior leukoencephalopathy syndrome (RPLS)

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 rapidly develops 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, primarily using MRI (magnetic resonance imaging).

Tumor lysis syndrome (TLS)

Post-marketing reports have described cases of tumor lysis syndrome (TLS) in patients treated with carboplatin or carboplatin 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 implemented.

Use in elderly patients

When using combination therapy with carboplatin and cyclophosphamide, elderly patients were more prone to severe thrombocytopenia than younger patients.

Since renal function is often reduced in elderly patients, this factor must be considered when determining drug dosage (see section "Administration and dosage").

Carboplatin dosing

Cockcroft-Gault glomerular filtration rate estimation, which is important in treatment, should be supplemented with standard measurement methods (i.e., inulin, 51Cr–EDTA, 99mTc–DTPA, 125I–iothalamate, or iohexol) whenever possible in certain subgroups (e.g., age 40–59 years or body mass index (BMI) 20–25).

Other

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

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

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

Appropriate contraceptive measures should be used during treatment and for at least 6 months after treatment. Men should also use contraception during treatment and for at least 3 months after treatment due to the mutagenic potential of carboplatin, which may damage sperm chromosomes. Sperm cryopreservation is recommended before starting therapy. Pregnant women should avoid contact with carboplatin.

Premedication with antiemetics may help reduce the frequency and severity of nausea and vomiting caused by carboplatin.

Hepatotoxic lesions associated with nephrotoxic lesions have been observed with very high-dose carboplatin treatment.

Instruments containing aluminum must not be used during the preparation and administration of carboplatin (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding

Pregnancy

Carboplatin may cause fetal harm if used during pregnancy. Carboplatin demonstrated embryotoxic and teratogenic effects in rat studies when administered during organogenesis. Controlled studies in pregnant women have not been conducted.

Carboplatin should not be administered to pregnant women. If use during pregnancy is necessary, the patient must be informed of the potential risk to the fetus. Women of reproductive potential should use effective contraception during treatment and for at least 6 months after treatment.

Breastfeeding

It is unknown whether carboplatin or its platinum-containing metabolites are excreted in human milk. However, due to the potential for serious adverse reactions in infants, breastfeeding should be discontinued during carboplatin treatment (see section "Contraindications").

Fertility

Carboplatin is genotoxic; therefore, patients of reproductive potential (both women and men) and their partners must use effective contraception during treatment and for at least 6 months after therapy completion. Men are advised to undergo sperm cryopreservation before starting carboplatin therapy due to the risk of irreversible infertility.

Effect on ability to drive and use machines

Carboplatin may cause nausea, vomiting, visual disturbances, and ototoxicity; therefore, driving and operating machinery are not recommended during treatment. Depending on individual sensitivity, carboplatin may impair the ability to drive or operate machinery.

Administration and Dosage

Carboplatin is intended for intravenous use only, after dilution.

For adult patients who have not been previously treated and who have normal renal function, carboplatin injections should be administered at a dose of 400 mg/m² body surface area via short intravenous infusions lasting 15–60 minutes.

Doses may also be calculated using the Calvert formula based on the patient's glomerular filtration rate (GFR) and the desired area under the pharmacokinetic concentration-time curve (AUC). It is important to note that doses calculated by the Calvert formula are expressed in milligrams, not mg/m².

Dose (mg) = desired AUC (mg/ml × min) × [GFR (ml/min) + 25]

Target AUC	Chemotherapy	Patient status
5–7 mg/ml × h	Carboplatin monotherapy	Previously untreated
4–6 mg/ml × h	Carboplatin monotherapy	Previously treated
4–6 mg/ml × h	Carboplatin + cyclophosphamide	Previously untreated

Do not use the Calvert formula to calculate doses for patients who have received prior prolonged therapy with the following agents:

Mitomycin C;
Nitrosourea;
Combination therapy with doxorubicin / cyclophosphamide / cisplatin;
Combination therapy with 5 or more agents;
Radiation therapy ≥ 4500 rad, delivered to an area of 20×20 cm or larger at more than one site.

Carboplatin therapy must be discontinued if the tumor does not respond to treatment, the disease progresses, or unacceptable adverse reactions occur.

Treatment courses may be repeated at intervals of at least 4 weeks, provided blood counts are: neutrophils ≥ 2000/mm³ and platelets ≥ 100,000/mm³.

A 20–25% reduction in the initial dose is recommended for patients with risk factors such as prior myelosuppressive therapy or poor performance status (ECOG–Zubrod 2–4 or Karnofsky score below 80%).

All the above dosing recommendations apply to the initial treatment course; subsequent doses should be adjusted based on weekly blood test results.

Renal Impairment

If patients have a creatinine clearance < 60 mL/min, the risk of developing myelosuppression increases.

Optimal use of carboplatin injections in patients with impaired renal function requires appropriate dose adjustment and continuous monitoring of hematological parameters and renal function. If glomerular filtration rate (GFR) ≤ 20 mL/min, carboplatin should not be administered at all.

Combination Therapy

The use of carboplatin in combination with other antineoplastic agents requires individual dose adjustments and must be determined according to the specific regimen and schedule.

Pediatric Population

There is insufficient experience with the use of carboplatin in children; therefore, no dosing recommendations can be made for this age group.

Elderly Patients

Carboplatin doses during the first and subsequent treatment courses should be adjusted according to the patient's overall health status.

Reconstitution

Before administration, the drug should be diluted with 5% glucose solution or 0.9% sodium chloride solution to a concentration of 0.5 mg/mL.

The diluted solution is stable for 24 hours when stored refrigerated (4°C).
From a microbiological standpoint, the diluted solution should be administered immediately.

Carboplatin must not be administered through infusion systems containing aluminum parts or needles containing aluminum (precipitation may occur).

The solution should be drawn from the vial immediately before use.

Single withdrawal of the medicinal product from the vial is permitted.

Standard precautions for handling cytotoxic agents should be followed when manipulating the drug.

Children

There is insufficient data on the use of the medicinal product in the pediatric population; therefore, it should not be used in children.

Overdose

Symptoms of overdose. During initial studies, carboplatin was administered at doses up to 1600 mg/m² per course. At this dosage, life-threatening hematological adverse reactions such as granulocytopenia, thrombocytopenia, and anemia were observed. The lowest granulocyte, platelet, and hemoglobin levels were recorded on days 9–25 (average on days 12–17). Granulocyte counts returned to ≥ 500/µL within 8–14 days (average within 11 days), and platelet counts returned to ≥ 25,000/µL within 3–8 days (average within 7 days).

In addition, the following non-hematological adverse reactions were observed: renal dysfunction with a 50% reduction 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 include bone marrow suppression, as well as liver and kidney dysfunction. In the treatment of hematological adverse reactions, bone marrow transplantation and transfusions (platelets, blood) may be effective.

Adverse Reactions

The frequency of adverse reactions 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), frequency not known (cannot be estimated based on available data).

Infections and infestations

Common – infectious complications*.

Frequency not known – pneumonia.

Benign and malignant neoplasms (including cysts and polyps)

Uncommon – development of recurrent tumours (including promyelocytic leukaemia occurring 6 years after monotherapy with carboplatin and prior radiotherapy) observed after completion of carboplatin monotherapy and combination therapy (causal relationship not established).

Frequency not known – secondary malignancies related to treatment.

Blood and lymphatic system disorders

Very common – thrombocytopenia, neutropenia, leucopenia, anaemia.

Common – haemorrhage*, infection-related complications in patients with poor general health status (<1% lead to fatal outcome).

Frequency not known – haematopoietic disorders, febrile neutropenia, haemolytic-uraemic syndrome.

Bone marrow suppression may be more severe and prolonged in patients aged 65 years and older.

Myelosuppression is the dose-limiting factor in carboplatin treatment. With carboplatin monotherapy at maximally tolerated doses, thrombocytopenia (platelet count <50,000/mm³) occurs in 25% of patients. Neutropenia (granulocyte count <1,000/mm³) occurs in 18% of patients. Leucopenia (white blood cell count <2,000/mm³) occurs in 14% of patients. The lowest levels of platelets, granulocytes, and white blood cells are usually observed on day 21 after initiation of treatment. Myelosuppression may be intensified when carboplatin is used in combination with other myelosuppressive agents.

Myelotoxicity is more severe in patients previously treated with cisplatin, patients with impaired renal function, and those with more severe somatic status. These effects, although usually reversible, led to infectious and haemorrhagic complications in 4% and 5% of patients receiving carboplatin injections, respectively. These complications resulted in fatal outcomes in less than 1% of patients.

Anaemia (haemoglobin level <8 g/dL) occurs in 15% of patients with normal baseline values.

Anaemia (haemoglobin level <8 g/dL), the severity of which increases with cumulative carboplatin dose, occurs in 15% of patients with normal baseline values.

Myelosuppression may be more serious and prolonged in patients with impaired renal function, those who have undergone intensive prior treatment, those with low performance status, and in individuals aged over 65 years.

At maximally tolerated doses of carboplatin administered as monotherapy, thrombocytopenia with the lowest platelet count below 50×10⁹/L develops in approximately one-third of patients. The nadir usually occurs between days 14 and 21, with recovery within 35 days from the start of therapy.

In leucopenia, white blood cell count may decrease to approximately 20% of normal levels, but recovery from the nadir (days 14–28) may be slower and usually occurs within 42 days from the start of therapy.

Neutropenia with granulocyte count below 1×10⁹/L may occur in one-fifth of patients.

Haemoglobin levels below 9.5 mg/100 mL were observed in 48% of individuals with normal baseline values.

With carboplatin monotherapy at recommended doses, myelosuppression is usually reversible and non-cumulative.

Platelet counts usually recover within 35 days after administration of the drug.

White blood cell count recovery usually occurs somewhat slower than platelet recovery – within 42 days after administration of the drug.

Carboplatin treatment may be continued only if platelet count is at least 100,000/μL and white blood cell count is at least 4,000/μL. If cell counts are below these levels, therapy must be discontinued until normal values are restored (usually within 5–6 weeks). In severe cases, supportive transfusion therapy or blood transfusion may be required.

Respiratory, thoracic and mediastinal disorders

Very rare: pulmonary fibrosis presenting as chest tightness and dyspnoea. This should be considered if pulmonary hypersensitivity is excluded.

Immune system disorders

Common – hypersensitivity reactions (including skin rashes, urticaria, erythema, fever without apparent cause, or pruritus), anaphylactoid reactions, sometimes with fatal outcomes, especially within the first minutes after administration (angioneurotic oedema, dyspnoea, bronchospasm, urticaria, anaphylactic shock, hypotension, dizziness, tachycardia).

Allergic reactions to carboplatin have been reported in less than 2% of patients.

Treatment is symptomatic (see section "Special precautions for use").

Metabolism and nutrition disorders

Very common – following carboplatin treatment, decreased serum electrolyte levels (magnesium, potassium, sodium, calcium) have been reported; however, these manifestations were not severe enough to cause clinical signs or symptoms. Early hyponatraemia has also been reported.

Rare – anorexia, hyponatraemia.

Frequency not known – dehydration, tumour lysis syndrome.

Nervous system disorders

Common – peripheral neuropathy, paraesthesia, decreased tendon reflexes, sensory disturbances, taste disturbances.

The incidence of peripheral neuropathy after carboplatin treatment is 4%. In most patients, neurotoxicity is limited to paraesthesias and decreased deep tendon reflexes. In patients aged 65 years or older, or after prior treatment with cisplatin, the frequency and severity of adverse reactions increase. Paraesthesias present before the start of carboplatin treatment, primarily caused by prior cisplatin therapy, may persist or worsen during carboplatin treatment.

In isolated cases, symptoms related to the central nervous system have been reported, which are often attributable to concomitant use of antiemetic agents.

Clinically significant sensory disturbances (e.g., visual disturbances, taste changes) occurred 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.

Uncommon – central nervous system symptoms (often associated with antiemetic use).

Frequency not known – cerebrovascular disorders*, reversible posterior leukoencephalopathy syndrome (RPLS), possible hallucinations, anxiety, and frightening dreams, encephalopathy.

Eye disorders

Common – visual function disturbances. Isolated cases of vision loss.

Transient worsening of vision, including occasional transient vision loss, has been reported during treatment with platinum-containing agents. These disturbances usually occur only with high-dose therapy in patients with impaired renal function.

Frequency not known – optic neuritis.

Ear and labyrinth disorders

Very common – decreased hearing acuity in the high-frequency range (4000–8000 Hz) was observed in 15% of patients.

Common – ototoxicity.

Clinical symptoms were noted in only 1% of patients, predominantly manifesting as tinnitus.

In patients with hearing loss due to prior cisplatin treatment, hearing impairment may persist or worsen. Clinically significant hearing loss was observed in children who received higher-than-recommended doses of carboplatin in combination with other ototoxic agents.

Cardiac disorders

Common – cardiac disorders*.

Very rare – isolated cases of cardiovascular diseases (heart failure, embolism), cerebrovascular diseases (stroke) (causal relationship with carboplatin use not established), arrhythmia. Isolated cases of hypertension have been reported.

Frequency not known – heart failure*, ischaemic heart disease (e.g., myocardial infarction, cardiac arrest, angina, myocardial ischaemia), Kounis syndrome.

Vascular disorders

Frequency not known – embolism*, arterial hypertension, arterial hypotension.

Haemorrhagic complications may occur.

Respiratory, thoracic and mediastinal disorders

Common – pulmonary fibrosis with chest tightness and dyspnoea, interstitial lung disease, bronchospasm.

Gastrointestinal disorders

Very common – vomiting, nausea, abdominal pain.

Vomiting occurs in 65% of patients, with severe vomiting in one-third of them. Additionally, nausea occurs in 15% of patients. Patients previously treated with cisplatin are more prone to gastrointestinal symptoms. These symptoms usually resolve with antiemetic treatment and disappear within the first 24 hours after carboplatin administration. A quarter of patients experience neither nausea nor vomiting. Only 1% of patients experience vomiting unresponsive to medical treatment. Also, 17% of patients reported gastrointestinal pain.

Common – diarrhoea (8%), constipation (6%), mucositis, inflammation of the mucous membranes of the mouth and oesophagus.

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 treatment. Alkaline phosphatase increases more frequently (in 24% of patients) than serum glutamic-oxaloacetic transaminase (in 15% of patients), serum alanine aminotransferase, or total bilirubin (in 5% of patients). Most deviations from normal values spontaneously normalize during the course of treatment. In half of patients, these changes were mainly mild and reversible.

In a limited group of patients receiving high-dose carboplatin injections and after autologous bone marrow transplantation, disturbances in liver function parameters were observed.

Frequency not known – severe liver function impairment (including acute liver necrosis) occurring after administration of higher-than-recommended doses of carboplatin.

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.

Frequency not known – asthenia, myalgia, arthralgia.

Renal and urinary disorders

Very common – renal toxicity.

Renal toxicity generally does not require dose limitation for patients receiving carboplatin and does not require preventive measures such as hydration with large fluid volumes or forced diuresis. However, blood urea and serum creatinine levels may increase.

Renal insufficiency may occur, defined as a decrease in creatinine clearance below 60 mL/min. The likelihood and severity of nephrotoxicity may increase in patients with pre-existing renal impairment before starting carboplatin treatment. It is unknown whether this adverse effect can be overcome with appropriate hydration regimens, but dose reduction or discontinuation of carboplatin therapy is required if renal test results are abnormal (creatinine clearance 30–59 mL/min). Carboplatin is contraindicated in patients with creatinine clearance <30 mL/min.

Common – urogenital disorders, hyperuricaemia.

With standard doses of the drug, abnormal kidney function rarely developed, despite carboplatin injections being administered without hydration with large fluid volumes and/or forced diuresis. Increased serum creatinine levels were recorded in 6% of patients, increased blood urea nitrogen in 14%, and increased uric acid in 5% of patients. These disorders were generally mild and reversible in approximately half of patients. Creatinine clearance measurement proved to be the most accurate test of kidney function in patients receiving carboplatin injections. Among patients with baseline values of 60 mL/min or higher, 27% experienced decreased creatinine clearance during carboplatin therapy.

Hyperuricaemia occurs in approximately 25% of patients. Allopurinol may be used to reduce serum uric acid concentration.

Uncommon – renal insufficiency.

Reproductive system disorders

Frequency not known – azoospermia and amenorrhoea.

General disorders and administration site conditions

Common – asthenia.

Frequency not known – fever and chills without evident signs of infection, headache, malaise, injection site reactions such as erythema, swelling, urticaria, necrosis due to extravasation.

Investigations

Very common – decreased renal creatinine clearance, increased blood urea levels, increased blood alkaline phosphatase levels, increased aspartate aminotransferase levels, liver function test abnormalities, decreased blood sodium, potassium, calcium, and/or magnesium levels.

Common – increased blood bilirubin levels, increased blood creatinine levels, increased blood uric acid levels.

Other adverse reactions

Secondary acute malignant neoplasms after cytostatic combination therapy including carboplatin. Acute promyelocytic leukaemia 6 years after carboplatin monotherapy and prior radiotherapy.

Alopecia, alopecia, mucositis, asthenia, malaise, dysgeusia, anxiety, weight loss, tachycardia.

Haemolytic-uraemic syndrome has been reported in isolated cases.

Isolated cases of cardiovascular diseases (heart failure, embolism), isolated cases of strokes. Cases of increased blood pressure have been observed.

*Fatal outcomes <1%, fatal cardiovascular outcomes <1%, including heart failure, embolism, and cerebrovascular diseases.

Reporting of 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 and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C. Keep out of reach of children.

Incompatibilities. Since aluminium may react with carboplatin, leading to precipitate formation or loss of drug activity, needles and other intravenous administration equipment containing aluminium components are not recommended for preparing and administering carboplatin solution.

Do not mix with other drugs in the same container.

Packaging. 15 mL or 45 mL in a vial, 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. Venus Remedies Limited.

Manufacturer's location and address of place of business.

Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn.), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh 173205, India / Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn.), Bhatoli Kalan, Baddi, District Solan, Himachal Pradesh 173205, India.