Carboplatin, 10 mg/ml 45 ml

Pharmacotherapeutic group: Antitumor agent, alkylating compound.

ATX code: L01XA2

Pharmacological properties

Pharmacodynamics

Carboplatin is an inorganic complex compound containing the heavy metal – platinum. The main mechanism of action is the drug’s binding to DNA, as a result of which mainly intraspiral cross-links are formed, which change the structure of DNA and inhibit its synthesis (prevent DNA strands separation). This effect appears regardless of the phase of the cell cycle. Hydration of carboplatin, which produces the active form(s) of the drug, is slower than hydration of cisplatin. Despite this, carboplatin and cisplatin cause the same amount of cross-linking in DNA and have equivalent biological effects.

Pharmacokinetics

In intravenous administration, the plasma concentration of carboplatin is dose-dependent in the range of 20-500 mg/m2 and decreases biphasically. Average retention time of carboplatin in plasma is 3.5 hours. In blood plasma concentrations of platinum in carboplatin molecule are much higher than concentrations of free platinum. Half-life period of free platinum after intravenous injection of carboplatin in doses of 20-1600 mg/m2 for 30-60 minutes is 83-96 minutes. Volume of distribution is 16-20 liters. The highest concentrations of carboplatin accumulate in the liver, kidneys, skin and tumors. Maximum concentrations of platinum are found in liver and lungs. Less than 10% of carboplatin binds to plasma proteins, about 24% of platinum binds to plasma proteins in the first 4 hours and up to 40-87% within 24 hours after administration of carboplatin.

The initial metabolic products of carboplatin can be mono- and dihydrated diamine-platinum compounds. These metabolites are highly reactive and bind firmly to the sulfide groups of plasma proteins.

Carboplatin is excreted primarily by the kidneys. Most of the platinum is excreted in the first 6 hours. After 24 hours the excretion of carboplatin decreases to 2% of the dose or less per day. About 50% of carboplatin is eliminated unchanged. Cumulative urinary excretion is independent of the dose, but decreases with increasing severity of renal impairment. In patients with creatinine clearance less than 60 ml/min, the drug doses should be reduced.

The pharmacokinetic parameters of carboplatin in children are similar to those in adults. Because elderly patients may have impaired renal function, doses of carboplatin should be reduced.

Indications

Active ingredient

Composition

How to take, the dosage

Carboplatin can be used both as monotherapy and in combination with other anticancer drugs. The dose and regimen of the drug are chosen individually.

Carboplatin is given as a capelain for 15-60 minutes according to one of the regimens:

The administration of Carboplatin is repeated at intervals of at least 4 weeks with platelet counts of at least 100000 cells/mm3 of blood and neutrophils of at least 2000 cells/mm of blood.

Patients with risk factors, e.g., after myelosuppressive therapy or with low functional status (ECOG/WHO/Zubrod score of 2-4 or less than 80% on the Karnofsky scale), should have the initial dose reduced by 20-25%.

Patients over 65 years of age, and in case of combination therapy, adjustment of initial and subsequent doses may be required.

For patients who have symptoms of moderate to severe hematologic toxicity (i.e., platelet and neutrophil counts less than 50000 and 500/mm3, respectively), a 25% dose reduction should be considered, both in monotherapy and in combination regimens.

Patients with impaired renal function (creatinine clearance less than 60 mL/min) due to the increased risk of severe myelosuppression, the dose of Carboplatin is reduced as follows:

The Calvert formula is recommended for dose calculation:
Dose (mg)= (required AUC) x (SGF + 25), where AUC is the area under the curve (concentration/time), SGF is glomerular filtration rate. AUC values between 4-6 and 6-8 mg/ml x min create acceptable hematologic toxicity in previously treated patients and previously untreated patients, respectively.

All of the above dosing recommendations apply to the initial course of treatment. Subsequent doses should be adjusted according to patient tolerance and the severity of myelosuppression.

Regulations for preparation of the infusion solution
Before injection the drug is diluted to a concentration of 0.5 mg/ml with 5% dextrose solution or 0.9% sodium chloride solution.

Diluted solutions of the drug are stable for 8 hours at 25°C and for 24 hours if stored in refrigerator at 4°C.

Before use, carboplatin solution must be visually inspected for mechanical inclusions and color abnormalities. Fluid administration before or after administration of carboplatin and forced diuresis are not required.

Interaction

The use of carboplatin in combination with other myelosuppressive drugs or radiation therapy may increase the risk of hematologic toxicity. Concomitant therapy with aminoglycosides and other nephrotoxic and ototoxic drugs potentiates the toxic effects of carboplatin on these organs.

Carboplatin may interact with aluminum to form a black precipitate.

Special Instructions

The administration of Carboplatin-Ebeve should be performed under the supervision of a physician experienced in the use of cytotoxic drugs. Continuous monitoring of possible toxic effects during treatment with Carboplatin-Ebeve is mandatory, especially when using high doses of the drug.

No needles, syringes, catheters or infusion systems containing aluminum, which may react with carboplatin, resulting in precipitate formation or loss of drug activity, should be used for preparation and administration of the drug. Clinical blood tests, renal function (creatinine clearance) and liver function should be monitored regularly (once a week).

Nausea and vomiting develop 6-12 hours after administration of Carboplatin-Ebeve and continue for 24 hours (anti-emetics must be administered). Periodic neurological examinations are recommended, especially in elderly patients (over 65 years of age) and those previously treated with drugs containing platinum.

Since Carboplatin-Ebeve may cause ototoxic effects (manifested by decreased hearing threshold in the upper frequencies), patients are advised to have audiographic studies before and during treatment. In the event of clinically significant hearing loss, an appropriate dose change of Carboplatin-Ebeve or discontinuation of treatment may be required.

Patients should not be vaccinated during treatment with Carboplatin-Ebeve and for at least 3 months thereafter.

Women and men should use reliable contraception during treatment with Carboplatin-Ebeve and for at least 6 months after treatment ends.

In case of contact of Carboplatin-Ebeve with skin or mucous membranes – rinse thoroughly with water (mucous membranes) or soap and water (skin). Dissolution, dilution and administration of the drug is carried out by trained medical personnel with observance of protective measures (gloves, masks, clothing, etc.).

The remains of the drug and all instruments and materials that have been used to prepare Carboplatin-Ebeve infusion solutions must be disposed of in accordance with the standard hospital procedure for the disposal of cytotoxic waste, taking into account the applicable regulations for the disposal of hazardous waste.

Information on possible effects of Carboplatin-Ebeve on driving and operating ability
Due to the possibility of side effects such as nausea, vomiting, drowsiness, caution should be exercised when engaged in potentially hazardous activities requiring increased concentration and rapid psychomotor reactions.

Contraindications

With caution, use in patients with inhibition of medullary hematopoiesis function (including in the background of concomitant radiation and chemotherapy), impaired renal function; with impaired function of the auditory system; patients treated with nephrotoxic drugs (e.g., cisplatin), acute infectious diseases of viral, fungal or bacterial nature, in the post-vaccination period.

Side effects

The incidence of side effects is stated according to the following gradation: very frequent – >10%, frequent – >1%0.1%0.01%

Hematopoietic disorders: very frequent: suppression of medullary hematopoiesis function (dose-dependent). Maximum low levels of platelets and leukocytes/granulocytes are usually reached after 2-3 weeks from the start of the drug, with thrombocytopenia being more common. Adequate recovery to the level allowing the next dose of Carboplatin usually takes at least 4 weeks.

Anemia (hemoglobin level less than 11 g/dL). Transfusion therapy may be necessary, especially in patients undergoing long-term treatment (e.g., more than 6 cycles of the drug). Leukopenia, neutropenia usually occurs on day 42 after initiation of therapy.

Gastrointestinal tract:

On the central nervous system:

Neurotoxicity is a dose-limiting side effect. Symptoms of sensory neuropathy are often triggered by cold. The duration of these symptoms, which usually resolve between courses, increases with the total dose of carboplatin. Functional impairment, which is expressed by difficulty in performing precise movements, is a possible consequence of sensory damage.

Hearing and vision:

Urinary system disorders:

With electrolyte balance:

Other:

Overdose

Pregnancy use

Controlled studies of carboplatin use in pregnant women have not been conducted. Animal studies have shown embryotoxic, teratogenic and mutagenic effects of carboplatin. Therefore, pregnant women should not use carboplatin.

It is not known whether carboplatin penetrates into breast milk, so to avoid toxic effects of platinum on the infant, breastfeeding should be stopped during treatment.