Carboplatin (Lyophilisate, Concentrate) Instructions for Use

ATC Code

L01XA02 (Carboplatin)

Active Substance

Carboplatin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Carboplatin is an inorganic complex compound containing a heavy metal – platinum.

The main mechanism of action of this drug is assumed to be due to binding with DNA, resulting primarily in the formation of intrastrand cross-links, which alter the structure of DNA and suppress its synthesis. This effect is manifested regardless of the cell cycle phase. The hydration of carboplatin, which results in the active form(s) of the drug, occurs more slowly than the hydration of cisplatin.

Pharmacokinetics

After a single intravenous infusion of carboplatin over 1 hour, the plasma concentration of total platinum and free (ultrafilterable) platinum decreases according to a two-phase first-order kinetic model. The initial T_1/2 of free platinum is about 1-2 hours, and the terminal T_1/2 is 3-6 hours; total platinum has a similar initial T_1/2, but its terminal T_1/2 is longer (about 24 hours). No accumulation of platinum in plasma is observed with repeated doses for four consecutive days. Twenty-four hours after dose administration, more than 85% of platinum in plasma is in a protein-bound state.

Carboplatin is excreted primarily by the kidneys, and about 30% of the administered dose is excreted unchanged. In patients with a CrCl of 60 ml/min or more, approximately 65% and 70% of the administered dose is excreted within 12 and 24 hours after administration, respectively. Since Carboplatin is excreted almost entirely by glomerular filtration, only a very low concentration of carboplatin is present in the renal tubules, which may explain the low nephrotoxic potential of the drug compared to cisplatin.

Indications

Treatment of the following solid tumors

• Ovarian cancer;
• Germ cell tumors in men and women;
• Lung cancer;
• Cervical cancer;
• Head and neck tumors;
• Osteogenic sarcomas;
• Medulloblastoma.

ICD codes

Dosage Regimen

Concentrate

Carboplatin can be used both as monotherapy and in combination with other antineoplastic drugs. When choosing the dose and regimen in each individual case, specialized literature should be used. The drug is administered intravenously in the following dosage regimens

• 300-400 mg/m² IV drip over 15-60 minutes or as a 24-hour infusion;
• 100 mg/m² IV drip over 15-60 minutes daily for 5 days.

Carboplatin administration is repeated at intervals of at least 4 weeks with platelet counts of at least 100,000 cells/mm³ and neutrophil counts of at least 2,000 cells/mm³. Fluid administration before or after carboplatin use, as well as forced diuresis, is not required.

Depending on the bone marrow status or renal function, the therapeutic dose of Carboplatin may be adjusted as follows

• For patients with risk factors, e.g., after myelosuppressive therapy or with low functional status (ECOG-Zubrod 2-4 or Karnofsky score below 80%), the initial dose should be reduced by 20-25%.
• For patients over 65 years of age, adjustment of the initial and subsequent doses may be required.
• For patients who experience symptoms of moderate or severe hematological toxicity (i.e., platelet and neutrophil counts less than 50,000 and 500/mm³, respectively), a dose reduction of 25% should be considered – both in cases of monotherapy and in combination treatment regimens.
• For patients with impaired renal function (CrCl less than 60 ml/min), due to the increased risk of severe myelosuppression, the dose of Carboplatin is reduced as follows

All the above dosing recommendations refer to the initial course of treatment. Subsequent doses should be adjusted depending on patient tolerance to the drug and the development of myelosuppression.

Dose determination by formula

The initial dose of the drug in mg can be determined by the Calvert formula, which describes the dependence on the glomerular filtration rate (GFR in ml/min) and the desired area under the curve (AUC in mg/ml × min):

Total Dose (mg) = AUC x (GFR + 25)

Preparation for intravenous administration

Before administration, the drug is diluted to a concentration of 0.5 mg/ml with 5% dextrose solution or 0.9% sodium chloride solution.

The diluted drug solutions are stable for 8 hours at 25°C (77°F) and for 24 hours when stored refrigerated at 4°C (39.2°F).

Lyophilisate

Carboplatin can be used both as monotherapy and in combination with other antineoplastic drugs. The drug is administered IV in the following dosage regimens

• 300 – 400 mg/m² IV drip over 15-60 minutes or as a 24-hour infusion;
• 100 mg/m² IV drip over 15-60 minutes daily for 5 days.

Carboplatin administration is repeated at intervals of at least 4 weeks with platelet counts of at least 100,000 cells/mm³ and neutrophil counts of at least 1,500 cells/mm³.

Fluid administration before or after carboplatin use, as well as forced diuresis, is not required.

Depending on the bone marrow status or renal function, the therapeutic dose of carboplatin may be adjusted as follows

• For patients who experience symptoms of moderate or severe hematological toxicity (i.e., platelet and neutrophil counts less than 50,000 and 500/mm³, respectively), a dose reduction of 25% should be considered – both in cases of monotherapy and in combination treatment regimens;
• In patients with symptoms of impaired renal function (CrCl < 60 ml/min), the risk of toxic effects of carboplatin increases, therefore the dose of carboplatin should be reduced as follows

In the presence of risk factors, such as previously administered courses of myelosuppressive therapy and/or age over 65 years, a dose reduction of 20-25% is recommended; cautious use of carboplatin is also recommended if the patient has previously been treated with nephrotoxic drugs such as cisplatin.

Before use, the carboplatin solution must be visually inspected for the presence of mechanical inclusions and color changes. Carboplatin should be diluted in saline or 5% glucose solution to a concentration of 1-0.5 mg/ml immediately before use – the infusion must be performed no later than 24 hours after solution preparation.

Adverse Reactions

From the hematopoietic system: the main dose-limiting toxic factor of carboplatin is suppression of bone marrow hematopoiesis. Myelosuppression is dose-dependent. The lowest level of platelets and leukocytes/granulocytes is usually reached 2-3 weeks after starting the drug, with thrombocytopenia being more common. Adequate recovery to a level allowing the next dose of carboplatin usually takes at least 4 weeks. A significant number of patients may also experience symptoms of anemia (hemoglobin level less than 11 g/dl), the intensity of which depends on the cumulative dose of the drug. Transfusion therapy may be necessary, especially in patients undergoing long-term treatment (e.g., more than 6 cycles of the drug). There is also a possibility of clinical complications such as fever, infectious diseases, sepsis/septic shock and bleeding.

From the gastrointestinal tract: within 6-12 hours after drug administration, there is a possibility of nausea and/or vomiting (mild to moderate), lasting up to 24 hours or more. The risk of emetic effects can be reduced by prior therapy with antiemetics, continuous IV infusion of carboplatin over 24 hours, or fractional dose administration over 5 consecutive days. Other types of adverse effects on the gastrointestinal tract, such as inflammation of the oral mucosa, diarrhea, constipation and abdominal pain, have also been observed in some cases.

From the central and peripheral nervous system: there is a possibility of peripheral neuropathies, mainly in the form of paresthesia and decreased deep tendon reflexes, which is more likely in patients over 65 years of age with long-term or prior treatment with cisplatin. Symptoms of CNS dysfunction may also occur. Long-term therapy with the drug may lead to cumulative neurotoxicity.

From the hearing organs: ototoxicity manifests as tinnitus and hearing impairment.

From the organs of vision: there is a possibility of temporary deterioration or complete loss of vision (possible loss of color discrimination and light perception), as well as other visual function disorders. Improvement and/or complete recovery of vision usually occurs within a few weeks after discontinuation of the drug. Cortical blindness has been observed in patients with impaired renal function treated with high doses of carboplatin.

From the kidneys: mild and temporary increases in serum creatinine and urea concentrations may be observed. Acute kidney damage has been rarely observed. The risk of nephrotoxicity while taking carboplatin (decrease in creatinine clearance) increases with increasing carboplatin dose, as well as in patients who have previously been treated with cisplatin.

From the liver: mild and usually temporary increases in serum AST, bilirubin and alkaline phosphatase concentrations may be observed. Significant liver function impairment has been observed in patients treated with high doses of carboplatin with autologous bone marrow transplantation.

From electrolyte balance: hypokalemia, hypocalcemia, hyponatremia and/or hypomagnesemia are possible.

Allergic reactions: erythematous rash, fever, pruritus, urticaria, bronchospasm, arterial hypotension and anaphylactic reactions. These reactions may occur within minutes of carboplatin administration. In rare cases, exfoliative dermatitis may also be observed.

Other side effects: alopecia, asthenia, flu-like symptoms, hemolytic-uremic syndrome, myalgia/arthralgia, heart failure, cerebrovascular disorders and allergic reactions directly at the injection site.

Contraindications

• Severe renal impairment;
• Severe myelosuppression;
• Profuse bleeding;
• Pregnancy and breastfeeding period;
• Hypersensitivity to carboplatin or other platinum-containing compounds.

Use in Pregnancy and Lactation

Contraindication: pregnancy and breastfeeding period.

Use in Renal Impairment

In patients with symptoms of impaired renal function (CrCl < 60 ml/min), the risk of toxic effects of carboplatin increases, therefore the dose of carboplatin should be reduced as follows

Geriatric Use

In the presence of risk factors, such as age over 65 years, a dose reduction of 20-25% is recommended.

Special Precautions

Carboplatin administration should be carried out under the supervision of a physician experienced in the use of cytotoxic drugs. Constant monitoring for possible toxic effects during treatment with carboplatin is mandatory, especially when using high doses of the drug.

Do not use aluminum-containing needles, syringes, catheters and infusion systems for preparation and administration of the drug. Aluminum can react with carboplatin, leading to precipitate formation or loss of drug activity.

In patients, peripheral blood cell counts and renal function (the most sensitive indicator is CrCl) should be regularly monitored (e.g., once a week).

Periodic neurological examinations are recommended, especially in patients previously treated with cisplatin and in patients over 65 years of age. Carboplatin may cause cumulative ototoxic effects. Audiographic studies should be performed before and during treatment or in case of symptoms of hearing impairment. In case of clinically significant hearing impairment, appropriate dose adjustment or discontinuation of treatment may be required.

Women and men during treatment with Carboplatin and for 3 months thereafter should use reliable methods of contraception.

If the drug gets into the eyes, they should be immediately rinsed with plenty of water or sodium chloride solution. If the drug gets on the skin, the area of contact with the drug should be immediately rinsed with plenty of water. If the drug is inhaled or enters the mouth, a doctor should be consulted immediately.

Overdose

There are no specific antidotes used in case of carboplatin overdose. In case of overdose, more pronounced above-mentioned adverse reactions should be expected. Treatment is symptomatic. Hemodialysis is possible within the first 3 hours after drug administration.

Drug Interactions

The use of carboplatin in combination with other myelosuppressive drugs or radiation therapy may increase the risk of hematological toxicity.

The use of carboplatin in combination with aminoglycosides, as well as with other nephrotoxic drugs, increases the risk of nephrotoxic and/or ototoxic effects.

Storage Conditions

Store out of reach of children at room temperature 15-25°C (-13°F). Protect from light.

Shelf Life

Shelf life for solution – 2 years, for lyophilized powder 50 mg and 450 mg – 3 years, 150 mg – 4 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.