Carboplatin-RONC, 10 mg/ml 15 ml

Pharmacotherapeutic group: antitumor drug, alkylating compound

ATC code: L01XA02

Pharmacodynamics:

Carboplatin is a complex compound containing the heavy metal platinum. The main mechanism of action of this drug is due to the formation of cross-links between neighboring pairs of guanine bases in DNA that leads to suppression of nucleic acid synthesis and cell death. Hydration of carboplatin resulting in the formation of the active form(s) of the drug is slower than hydration of cisplatin. Unlike cisplatin it is less nephrotoxic and ototoxic and more strongly suppresses hematopoiesis. Causes growth arrest and reverse development of many types of tumors. In experimental studies in vivo and in vitro it shows mutagenic embryotoxic and teratogenic properties.

Pharmacokinetics:

Weakly bound to blood proteins. T1/2 in the initial phase – 11-2 h in the final phase – 26-59 h; volume of distribution – 16 l. It is excreted by kidneys (at a KPI of 60 ml/min or more during 12 hours, 65% of the dose is excreted during 24 hours – 71%). Metabolized by hydrolysis to form active compounds that interact with DNA. Binding to plasma proteins is very low. Platinum released from carboplatin irreversibly binds to plasma proteins and is slowly excreted with a minimum T1/2 – 5 days.

Indications

– Ovarian cancer (primary treatment as part of combination chemotherapy and secondary treatment – palliative in advanced stages);

– germ cell tumors of men and women;

– head and neck tumors;

– lung cancer;

– cervical cancer;

– transitional cell cancer of the bladder.

Active ingredient

Composition

1 ml of the concentrate contains:

active ingredient: carboplatin 10 mg;

excipients: water for injection – to the required volume.

How to take, the dosage

Carboplatin-RONZ® can be used both as monotherapy and in combination with other antitumor drugs.

The drug is administered intravenously in the following dosage regimens:

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

– 100 mg/m2 v/v drip for 15-60 minutes daily for 5 days.

Injections of carboplatin are repeated at intervals of at least 4 weeks with platelet counts of at least 100,000 cells/μL of blood and neutrophil counts of at least 2,000 cells/μL of blood at the time of the next infusion.

The administration of fluids before or after administration of Carboplatin-RONZ® or forced diuresis is not required.

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

For patients who have symptoms of moderate to severe hematologic toxicity (i.e. platelet and neutrophil leukocyte counts less than 50,000 and 500/µL, respectively), a 25% dose reduction should be considered, both in cases of monotherapy and in combination regimens;

Patients with symptoms of renal dysfunction (CK< 60 mL/min) are at increased risk for toxic effects of carboplatin so the carboplatin dose should be reduced as follows

Creatinine clearance

(ml/min)

The recommended dose of carboplatin

(mg/m2)

41-59

250

16-40

200

Dose determination using the formula

The starting dose in milligrams can be determined using the Calvert formula to describe the relationship between glomerular filtration rate (GFR in ml/min) and the desired concentration of carboplatin versus time (AUC in mg/mL x min):

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

Desired

Planned chemotherapy

Patient status in

AUC value

with the drug Carboplatin-RONZ®

treatment relation

5-7 mg/mL.min

Monotherapy

Previously untreated

4-6 mg/mLmin

Monotherapy

Previously untreated

4-6 mg/mL.min

In combination with cyclophosphamide

Previously untreated

Rules for preparing solution for infusion

The contents of the vial should be dissolved immediately prior to use in sterile water for injection with 5% dextrose solution or 09% sodium chloride solution to a final concentration of 10-05 mg/ml.

The prepared solution should be used within 8 hours.

Interaction

It is not recommended to use simultaneously with other drugs with myelosuppressive nephrotoxic or neurotoxic effects.

It potentiates (mutually) nephrotoxicity of aminoglycosides and other nephrotoxic drugs.

Decreases the production of antibodies to the introduction of inactivated viral vaccine and live viral vaccine (in addition, intensification of replication of the vaccine virus is possible increase of its side effects). The interval between discontinuation of treatment with carboplatin and vaccination should be 3 to 12 months (depends on the dose and type of the drug of the underlying disease and other factors).

Special Instructions

The administration of Carboplatin-RONZ® should be supervised by a physician experienced in the use of cytotoxic drugs. Continuous monitoring of possible toxic effects during treatment with carboplatin is mandatory, especially when using high doses of the drug.

Please do not use needles, catheters or infusion systems containing aluminum which may react with carboplatin leading to sludge formation or loss of drug activity for preparing and administering the drug.

Peripheral blood counts and renal function (creatinine clearance is the most sensitive indicator) and liver function should be monitored regularly (once a week).

Periodic neurologic examinations are recommended especially in patients who have previously received cisplatin therapy and in patients older than 65 years.

Because Carboplatin-RONZ® may cause cumulative ototoxic effects, patients are advised to have audiographic studies before and during treatment. In the event of clinically significant hearing impairment, an appropriate change in drug dose or discontinuation of treatment may be required.

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

When using Carboplatin-RONZ®, all routine instructions for the use of cytotoxic drugs must be followed.

The presence of concomitant ascites or exudative pleurisy increases the toxicity of carboplatin.

The administration of subsequent doses of Carboplatin-RONZ® is not recommended until the platelet count reaches 100,000/μL and the neutrophil count reaches 2,000/μL.

In patients who develop thrombocytopenia while receiving carboplatin, special precautions should be taken to prevent bleeding and hemorrhage: caution when performing invasive procedures; regular inspection of the sites of IV drug administration of the skin and mucous membranes for bleeding and hemorrhage; limiting the frequency of venipuncture and avoiding IV injections; testing urine vomit feces and secretions for hidden blood; caution when using toothbrushes and dental floss safe shavers and scissors; prevention of constipation; avoiding falls or other Avoid taking ethanol and ASA.

People with bacterial infections should be avoided, especially if leukopenia has developed.

In case of fever or chills, coughing or hoarseness of voice, pain in the lower back or side, painful or difficult urination, see a physician immediately.

Patients or family members should not be vaccinated during treatment and should avoid contact with people who have received polio vaccine or wear a protective mask.

We should avoid driving vehicles and other work requiring concentration and quick psychomotor reactions while using Carboplatin-RONZ® given that peripheral neuropathy, visual and color perception disorders may occur in patients while the drug is being administered.

Contraindications

– Hypersensitivity to carboplatin and other platinum-containing compounds;

– Severe renal dysfunction (creatinine clearance equal to or below 15 ml/min);

– profuse bleeding;

– expressed myelosuppression;

– pregnancy and lactation;

– children (safety and efficacy have not been adequately studied).

Carboplatin should be used with caution in:

– acute infections of viral fungal or bacterial nature (including varicella herpes zoster);

– hearing impairment;

– inhibition of bone marrow hematopoiesis (including

– concomitant radiation or chemotherapy;

– prior therapy with nephrotoxic agents such as cisplatin;

– the post-vaccination period.

Side effects

Hematopoietic organs: the main toxic dose-limiting factor of carboplatin is suppression of medullary hematopoiesis function. Myelosuppression is dose-dependent. Maximal low level of thrombocytes and leukocytes/granulocytes is usually reached after 2-3 weeks from the start of the drug, with thrombocytopenia being more frequent. Adequate recovery to the levels allowed by the next dose of carboplatin usually takes at least 4 weeks. A fairly large number of patients may also show symptoms of anemia (hemoglobin less than 11 g/dL) intensity of which depends on the total 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 the possibility of clinical complications such as fever infections sepsis/septic shock and carboplatin (decreased clearance bleeding.

Gastrointestinal side effects: in the first 6-12 hours after taking the drug, there is a possibility of nausea and/or vomiting lasting up to 24 hours or longer. The risk of vomiting may be reduced by prophylactic therapy with anti-emetics. In some cases, other types of adverse effects on the gastrointestinal tract such as inflammation of the mucous membranes of the mouth diarrhea constipation and abdominal pain may also be observed.

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

With the kidneys: there may be a temporary increase in serum creatinine and urea concentrations. Acute renal damage may be observed. The risk of nephrotoxicity on admission may be mild and usually temporary increase in ACT creatinine concentrations) increases with increasing the dose of carboplatin and in patients who were previously treated with cisplatin.

Electrolyte balance: hypokalemia, hypocalcemia, hyponatremia and/or hypomagnesemia may occur.

Allergic reactions: erythematous rash fever pruritus urticaria bronchospasm arterial hypotension and anaphylactic reactions. These reactions may occur within minutes after administration of carboplatin. Exfoliative dermatitis may be observed.

Hearing organ: ototoxicity manifested as tinnitus and hearing impairment.

With the visual system: there is a possibility of temporary deterioration or complete loss of vision (possible loss of ability to distinguish colors and see light) as well as other disorders of visual function. 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.

Hepatobiliary system: there may be a temporary increase in alkaline phosphatase serum bilirubin concentration. In patients receiving high doses of carboplatin with autologous bone marrow transplantation significant liver dysfunction has been observed.

Local reactions: pain at the injection site allergic reactions.

Other side effects: changes in taste alopecia asthenia flu-like symptoms (elevated body temperature fever) hemolytic-uremic syndrome myalgia/arthralgia heart failure cerebrovascular disorders.

Overdose