Carboplatin - instructions for use, dose, side effects, contraindications

Pharmacodynamics:Pharmacological action - antitumor, alkylating, cytostatic, immunosuppressive. Carboplatin - complex organometallic compound containing in the composition of platinum. The exact mechanism of action is unknown. It is assumed that carboplatin forms stable bonds with purine and pyrimidine bases of DNA and RNA, forming bonds within one filament with a change in the spatial structure of nucleic acids. This leads to a disruption in their function, suppression of biosynthesis and, ultimately, cell death.The effect of carboplatin does not depend on the phase of the cell cycle. It is also possible to stimulate the immune system under the influence of platinum, which is part of carboplatin. It causes a halt in the growth and reverse development of many types of tumors. Regression of primary tumors and metastases is associated with the effect of "platinization" on the body's immune system.

Pharmacokinetics:After intravenous administration (300-500 mg / m²), with the creatinine clearance of about 60 ml / min and above, the concentration of carboplatin in the plasma is reduced biphasic: the duration of the first phase is 1-2 hours, the second - 3-6 hours. Carboplatinum clearance 4.4 l / h, volume distribution 16 liters, average circulation time in the blood is 3.5 hours. Virtually does not bind to plasma proteins. The platinum released from carboplatin irreversibly combines with proteins, and its half-life is 5 days. In the liver, it hydrolyses to form active compounds that interact with DNA molecules. It is excreted mainly by the kidneys; at creatinine clearance values of 60 ml / min and above 65% of the dose is excreted in the urine for 12 hours.

Indications:Bladder cancer (transitional-cellular, common or metastatic). Ovarian cancer (epithelial).Locally spread cancer with lesions of the fallopian tubes or peritoneum - in combination with paclitaxel. Germinogenic tumors in men and women. Lung cancer is small cell and non-small cell. Malignant neoplasm of head and neck. Cancer of the cervix and the body of the uterus. Mammary cancer. Soft tissue sarcoma. Melanoma. Lymphogranulomatosis. Non-Hodgkin's lymphomas. Primary brain tumors. Soft tissue sarcomas.

ICD-10

II.C30-C39.C34 Malignant neoplasm of bronchi and lungs

II.C43-C44.C43.9 Malignant melanoma of skin, unspecified

II.C45-C49.C49 Malignant neoplasm of other types of connective and soft tissue

II.C50.C50 Malignant neoplasm of breast

II.C51-C58.C53 Malignant neoplasm of cervix

II.C51-C58.C54 Malignant neoplasm of uterine body

II.C51-C58.C56 Malignant neoplasm of ovary

II.C60-C63.C62 Malignant neoplasm of testis

II.C64-C68.C67 Malignant neoplasm of bladder

Contraindications:Hypersensitivity (including other drugs containing platinum), clinical signs of bleeding (including tumor tissue), severe renal dysfunction, expressed myelosuppression.

Carefully:Acute infectious diseases of viral, fungal or bacterial nature (including chicken pox, shingles), hearing impairment; oppression of bone marrow hematopoiesis (including on the background of previous radiation or chemotherapy), post-vaccination period; childhood; age over 65 years.

Pregnancy and lactation:Contraindicated in pregnancy. In experimental studies in vivo and in vitro shows mutagenic, embryotoxic and teratogenic properties. The action category for the fetus by FDA is D. For the duration of treatment, breastfeeding should be discontinued.

Dosing and Administration:To calculate individual doses of carboplatin, the Calvert formula is used:

Total dose, mg = AUC × (GFR + 25),

where AUC is the area under the curve "concentration in plasma-time" (mg / ml × min), GFR is the glomerular filtration rate (ml / min).

The following regimes of carboplatin treatment are possible:

- intravenously drip (for 15-60 minutes) - 400 mg / m² patients who had not previously received immunosuppressive therapy; on 300-320 mg / m² patients who had previously received immunosuppression. The introduction is repeated every 4 weeks.

- intravenously drip (for 15-60 minutes) at 100 mg / m² daily for 5 days every 4-5 weeks.

- intravenously drip (for 15-60 minutes) at 150 mg / m²Once a week for 4 weeks, then - a break 6 weeks.

Application in elderly patients

In elderly people, a reduction in renal filtration is very likely. It is necessary to adjust the dosage regimen and reduce the dose, since it is possible to accumulate and increase the time of exposure to the bone marrow with the development of thrombocytopenia and leukopenia.

Use in children

Efficiency and safety have not been studied. Use with caution under the supervision of a pediatric oncologist and a specialist in chemotherapy.

Side effects:The system of hematopoiesis: oppression of bone marrow hematopoiesis.

Digestive system: nausea, vomiting, stomatitis, diarrhea or constipation, abdominal pain, decreased appetite, impaired liver function (increased activity of AST, alkaline phosphatase and serum bilirubin concentration).

From the nervous system: asthenia, peripheral polyneuropathy (paresthesia, reduction of deep tendon reflexes), reduction of visual acuity up to complete loss of vision or loss of ability to distinguish colors (improvement or complete restoration of vision, as a rule,occurs within a few weeks after discontinuation of the drug; in patients with impaired renal function treated with high doses of carboplatin, cortical blindness was observed), hearing loss, tinnitus; long-term therapy can lead to cumulative neurotoxicity.

From the urinary system: increased serum creatinine and urea concentrations (acute kidney lesions were rare, the risk of nephrotoxicity in patients receiving carboplatin increased with increasing doses of carboplatin, as well as in patients who had previously been treated with cisplatin).

On the part of the reproductive system: azoospermia, amenorrhea.

From the side of the water-electrolyte balance: hypokalemia, hypocalcemia, hyponatremia and hypomagnesemia.

Allergic reactions: erythematous rash, fever, itching, urticaria, bronchospasm, lowering blood pressure, anaphylactoid reactions, allergic reactions at the injection site; rarely - exfoliative dermatitis.

Other: changes in taste, alopecia, flu-like symptoms (fever, fever), hemolytic-uremic syndrome, myalgia / arthralgia, heart failure,cerebrovascular disorders.

Overdose:Not described. They suggest the development of pronounced side effects. Antidote does not exist. Treatment is symptomatic (colony-stimulating factors, antibacterial drugs, blood transfusion and transfusion of platelet mass).

Interaction:Pharmaceutically incompatible with aluminum salts (in the interaction, precipitation is formed, leading to a decrease in efficiency).

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

Weaken the effectiveness of immunization with inactivated vaccines; when using vaccines containing live viruses, enhances the replication of the virus and the side effects of vaccination.

There is a cross-resistance with cisplatin, increases the neurotoxic and ototoxic effect caused earlier by this drug (observed in 30% of patients).

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

Special instructions:Monitoring: audiometric indicators (before and during treatment for suspected development of ototoxicity), neurological status (before and periodically during treatment), urea, creatinine and creatinine clearance (before treatment and before each cycle of chemotherapy for dose adjustment and diagnosis of nephrotoxicity), Ca2 +, Mg2 +, Na +, K +, uric acid in the blood (before and periodically during treatment), in blood plasma (periodically during treatment), hematocrit or hemoglobin, leukocytes, platelets (before and Periodically during treatment).

When using combination cisplatin + cyclophosphamide and carboplatin + cyclophosphamide in the treatment of patients with ovarian cancer III-IV stage, the objective effect was 50-75% and 59-61%, respectively, with an equal lifespan.

With long-term use, it is possible to display a distant effect - the development of secondary malignant tumors, degenerative changes in the sex glands, leading to amenorrhea or azoospermia, a decrease in fertility.

Unlike cisplatin, carboplatin has less nephrotoxicity and ototoxicity, but more severely inhibits hemopoiesis.

The recommended duration of a prolonged infusion of carboplatin is more than 15-60 minutes. Hyperhydration or forced diuresis before the introduction of carboplatin is not required.

It is possible to administer carboplatin as a 24-hour infusion or to divide the dose into 5 parts administered for 5 consecutive days. This reduces the severity of nausea and vomiting, but neuro- and ototoxicity remain the same.

It is recommended to conduct repeated courses of carboplatin treatment not earlier than 4 weeks (to ensure bone marrow recovery).

The introduction of a regular dose of carboplatin is not recommended with a platelet count of less than 100 × 109 / L and leukocytes less than 2 × 109 / L.

When administered to elderly patients (over 65 years of age), a dose reduction of carboplatin may be required. Careful monitoring of peripheral blood parameters is necessary.

For the dilution and infusion of carboplatin, instruments (needles, syringes, catheters and sets for intravenous administration) that do not contain aluminum (a black precipitate will come into contact with carboplatin).

Instructions

Carboplatin (Carboplatinum)