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

Carboplatin is an inorganic complex compound containing a heavy metal - platinum. It is assumed,that the main mechanism of action of this drug is due to binding to DNA, resulting in the formation of predominantly intra-spiral crosslinks, which alter the structure of DNA and suppress its synthesis. This effect manifests itself regardless of the phase of the cell cycle. Hydration of carboplatin, as a result of which the active form (form) of the drug is formed, is slower than hydration of cisplatin.

Pharmacokinetics:

The pharmacokinetics of carboplatin is a complex process and involves the transformation of the original carboplatin, total platinum and platinum, which is amenable to ultrafiltration. The total platinum consists of protein-bound and unbound protein with platinum, while as platinum, amenable to ultrafiltration, consists of carboplatin and protein metabolites unbonded to carboplatin. In pharmacokinetic studies of carboplatin, the level of platinum that is amenable to ultrafiltration is usually measured, as only platinum, not bound to proteins or its metabolites containing platinum, is usually cytotoxic.

After a single injection of carboplatin in the form of intravenous infusion, the maximum concentrations of carboplatin,general platinum and platinum, which is amenable to ultrafiltration, are achieved almost immediately. Platinum is distributed in all tissues and body fluids, with the highest concentrations being observed in the tissues of the kidneys, liver, skin and tumor tissues.

Initial half-lives (T1/2) carboplatin, total platinum and platinum, which is amenable to ultrafiltration, are practically identical when administered intravenously; T1/2 carboplatin is 1-2 hours.

Actually carboplatin with proteins does not bind, but breaks down to products containing platinum, which very quickly bind to proteins. Within the first 4 hours after carboplatin administration, less than 24% of platinum binds to plasma proteins; after 24 hours the amount of bound platinum is 87%.

The concentration of carboplatin and platinum, amenable to ultrafiltration, decreases in accordance with the two-phase model. The concentration of total platinum is reduced in accordance with the three-phase model. With normal kidney function, the half-lives of carboplatin and platinum, amenable to ultrafiltration, are 2-3 hours. The final half-life of total platinum is 4-6 days.

Carboplatin and its platinum-containing metabolites are mainly excreted in the urine. With normal kidney function, about 65% of the dose of carboplatin is excreted in the urine for 12 hours; after 24 hours, 71% of the dose is withdrawn. A significant part is derived in the form of unchanged carboplatin. Carboplatin (in the form of carboplatin, amenable to ultrafiltration) is effectively eliminated by hemodialysis.

In urine, after 24 hours, all platinum is present in the form of carboplatin. Only 3-5% of the administered platinum is excreted in the urine in a period of 24-96 hours.

As carboplatin is eliminated almost completely by glomerular filtration, only a very small concentration of carboplatin is present in the renal tubules, which may explain the small nephrotoxic potential of the drug compared to cisplatin.

Indications:

- Ovarian cancer;

- germinogenous tumors of men and women;

- lung cancer;

- cervical cancer;

- malignant tumors of the head and neck;

- transitional cell carcinoma of the bladder.

Contraindications:

- Hypersensitivity to carboplatinum or other platinum-containing compounds;

- severe renal dysfunction (creatinine clearance is equal to or below 15 ml / min);

- expressed myelosuppression;

- heavy bleeding;

- pregnancy and the period of breastfeeding;

- children's age (safety and efficacy not well studied).

Carefully:When oppression of bone marrow hematopoiesis (including against concomitant radiation or chemotherapy), prior therapy with nephrotoxic drugs (eg, cisplatin), hearing impairment, acute infectious diseases of viral, fungal or bacterial nature, in the post-vaccination period.

Dosing and Administration:

Carboplatin can be used as a monotherapy or in combination with other antitumor drugs. When choosing a dose and treatment in each individual case, you should use special literature.

The drug is administered intravenously in the following dose regimens:

- 300-400 mg / m² intravenously drip for 15-60 minutes or as a 24-hour infusion;

- 100 mg / m² intravenously drip for 15-60 minutes daily for 5 days;

Introduction Carboplatin is repeated at intervals of at least 4 weeks with platelet counts of at least 100,000 cells / μL of blood and neutrophils of at least 2000 cells / μL of blood at the time of the next administration.

The introduction of fluid before or after the application of carboplatin, as well as the achievement of forced diuresis is not required.

Depending on the state of the bone marrow or kidney function, the therapeutic dose of carboplatin can be corrected as follows:

- with a decrease in the number of platelets to 50,000 / mm3 and / or neutrophils to 500 / μl, no previous dose adjustment is required for previous carboplatin therapy;

- with the observed minimum platelet counts of less than 50,000 / μL and / or neutrophils less than 500 / μL in the previous course of carboplatin therapy, consideration should be given to reducing the next dose by 25% in both monotherapy and combined treatment regimens;

- if the renal function is impaired (creatinine clearance less than 60 ml / min), the risk of toxic effects of carboplatin increases, and therefore recommended doses of carboplatin are at creatinine clearance of 41-59 ml / min - 250 mg / m², with the clearance of creatinine 16-40 ml / min - 200 mg / m²;

- patients with risk factors, such as, for example, previous courses of myelosuppressive therapy, age over 65 years, low functional status (ECOG-Zubrod 2-4 or the Karnovsky index below 80%), it is recommended to reduce the initial dose of carboplatin by 20-25%.

Determination of the dose by the formula

The initial dose of the preparation in milligrams can be determined by the Calvert formula, which describes the dependence of the glomerular filtration rate (GFR in ml / min) and the desired drug concentration on timeAUC in mg / ml x min):

Total dose (mg) = AUC x (GF + 25)

Desired value AUC *	Planned chemotherapy with CARBOPLATIN	Status of the patient with regard to treatment
5-7 mg / ml.min	Monotherapy	Previously untreated
4-6 mg / ml. Min	Monotherapy	Previously treated
4-6 mg / ml. Min	In combination with cyclophosphamide	Previously untreated

Rules for the preparation of a solution for infusions

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

Dilute drug solutions are stable for 8 hours at 25 ° C and for 24 hours when stored in a refrigerator at 4 ° C.

Side effects:

On the part of the organs of hematopoiesis: the main toxic factor, limiting the dose of carboplatin, is the suppression of bone marrow hematopoiesis.Myelosuppression is dose-dependent. The lowest level of platelets and white blood cells / granulocytes is usually achieved two to three weeks after starting the drug, with thrombocytopenia occurring more often. Adequate recovery to a level that allows the next dose of carboplatin, usually takes at least 4 weeks. A sufficiently large number of patients may also exhibit symptoms of anemia (a hemoglobin level of less than 11 g / dl), the intensity of which depends on the total dose of the drug. It may be necessary to perform transfusion therapy, especially in patients undergoing long-term treatment (for example, more than 6 cycles of drug administration). There is also the possibility of complications such as fever, infectious diseases, sepsis / septic shock and bleeding.

From the side of the digestive system: nausea, vomiting (can be prevented by prescribing antiemetics, continuous intravenous infusion of carboplatin for 24 hours, or a fractional dose administration for 5 consecutive days), stomatitis, diarrhea or constipation, abdominal pain, decreased appetite,impaired liver function (increased activity of ACT, alkaline phosphatase and serum bilirubin concentration).

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

From the genitourinary system: increased concentrations of creatinine and urea in the blood serum (acute kidney damage was rare, the risk of nephrotoxicity with carboplatin increased with increasing doses of carboplatin and also in patients who had previously been treated with cisplatin), azoospermia, amenorrhea.

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

Allergic reactions: erythematous rash, fever, itching, urticaria, bronchospasm, decline arterial 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:

Special antidotes, used in case of carboplatin overdose, are unknown. In case of overdose, the more severe adverse reactions listed above should be expected. Treatment is symptomatic. In the first 3 hours after the administration of the drug, hemodialysis may be used.

Interaction:

The use of carboplatin in combination with other myelosuppressive drugs or radiotherapy can 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.

Special instructions:

Treatment with carboplatin should be performed under the supervision of a physician with experience in the use of cytotoxic drugs.

Do not use needles, syringes, catheters and infusion systems containing aluminum that can react with carboplatin, resulting in a precipitate or loss of activity of the preparation.

Regularly (once a week) it is necessary to carry out control of uniform, peripheral blood elements and renal function indicators (the most sensitive indicator is the creatinine clearance) and liver.

Periodically, it is recommended to perform neurologic examinations, especially in patients who have previously been treated with cisplatin, as well as in patients older than 65 years.

As Carboplatin can cause cumulative ototoxic effects, patients are advised to perform audiographic studies before and during treatment. In the case of a clinically significant impairment of the hearing function, an appropriate dose change or discontinuation of treatment may be required.

Women and men during treatment with carboplatin should use reliable methods of contraception.

When using carboplatin, all the usual instructions adopted for the use of cytotoxic drugs should be observed. If the product gets into the eyes, they must be washed immediately with a large amount of water or with 0.9% sodium chloride solution. In case of contact with the skin, immediately contact the product with plenty of water. If the product is inhaled or if it gets into the mouth, immediately consult a doctor.

During treatment, patients are not recommended to be vaccinated.

Form release / dosage:

Concentrate for solution preparation for infusions, 10 mg / ml.

Packaging:By 5, 15, 45 or 75 ml of the drug in bottles of dark neutral glass I hydrolytic class, sealed with rubber stoppers with a rolling aluminum caps.

For 1 bottle with instructions for use in a pack of cardboard.

Storage conditions:

In protected from light location at a temperature of 15 to 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the product after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-010186/08

Date of registration:15.12.2008

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

Representation: & nbspBIOCAD CJSC BIOCAD CJSC Russia

Information update date: & nbsp21.10.2014

Illustrated instructions

Instructions

Carboplatin (Carboplatin )