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

Carboplatin is an inorganic complex compound containing heavy metal - platinum. The main mechanism of action is the binding of the drug to DNA, resulting in the formation of predominantly intra-spiral crosslinks, which alter the structure of DNA and suppress its synthesis (interfere with the separation of DNA strands). 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. Despite this, carboplatin and cisplatin cause the formation of the same number of cross-links in DNA and have an equivalent biological effect.

Pharmacokinetics:

When administered intravenously, the concentration of carboplatin in the blood plasma is dose-dependent in the range 20-500 mg / m² and decreases biphasic. The average time of carboplatin in

the blood plasma is 3.5 hours. In plasma, platinum concentrations in the carboplatin molecule significantly exceed the concentrations of free platinum. The half-life of free platinum after intravenous carboplatin injection at doses of 20-1600 mg / m² for 30-60 minutes is from 83-96 minutes. The volume of distribution is 16-20 liters.The highest concentrations of carboplatin accumulate in the liver, kidneys, skin and tumors. The maximum concentrations of platinum are found in the liver and lungs. Less than 10% of carboplatin binds to blood plasma proteins, about 24% of platinum binds to plasma proteins in the first 4 hours and up to 40-87% within 24 hours after the onset of carboplatin administration.

Initial products metabolism carboplatin may be mono- and dihydrated diamine platinum compounds. These metabolites are highly reactive and bind strongly to the sulfide groups of plasma proteins.

Carboplatin is displayed mainly kidneys. Most of the platinum is excreted in the first 6 hours. After 24 hours, carboplatin removal is reduced to 2% of the dose and less per day. About 50% of carboplatin is eliminated unchanged. Cumulative excretion in the urine does not depend on the dose, but decreases with increasing severity of renal dysfunction. Patients with creatinine clearance less than 60 ml / min dose should be reduced.

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

Indications:

- Germinogenic tumors of men and women;

- ovarian cancer;

- cervical cancer;

- transitional cell carcinoma of the bladder;

- lung cancer;

- malignant tumors of the head and neck.

Contraindications:

- Hypersensitivity to carboplatinum or other platinum-containing compounds;

- severe renal dysfunction (creatinine clearance less than 30 ml / min);

- expressed myelosuppression;

- profuse bleeding;

- pregnancy and the period of breastfeeding;

- simultaneous vaccination against yellow fever;

- Children's age (safety and effectiveness have not been adequately studied).

Carefully:Caution is used in patients with oppression of bone marrow hematopoiesis (including on the background of concomitant radiation and chemotherapy), impaired renal function; impaired function of the hearing aid; who receive treatment with nephrotoxic drugs (for example, cisplatin), acute infectious diseases of viral, fungal or bacterial nature, in the post-vaccination period.

Pregnancy and lactation:

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

It is not known whether the carboplatin in breast milk, so in order to avoid toxic effects of platinum on the baby, during the period of treatment should stop breastfeeding.

Dosing and Administration:

Intravenously.

Carboplatin can be used as a monotherapy or in combination with other antitumor drugs. The dose and scheme of taking the drug is selected individually.

Carboplatin is injected drip for 15-60 minutes according to one of the schemes:

- 300-400 mg / m² 1 time in 4 weeks;

- 100 mg / m² daily for 5 days with a repetition of the course every 4-5 weeks.

Introduction Carboplatin is repeated at intervals of at least 4 weeks with platelet counts of at least 100,000 cells /mm³ blood and neutrophils at least 2000 cells /mm³ blood.

Patients with risk factors, for example, after myelosuppressive therapy or at a low functional status (ECOG/WHO/Zubrod - 2-4 points or less than 80% on the Karnovsky scale), the initial dose should be reduced by 20-25%.

Patients over 65 years of age, and also in the case of combination therapy, may need to adjust the baseline and subsequent doses.

For patients who have symptoms of moderate or severe hematologic toxicity (ie, the number of platelets and neutrophils is less than 50,000 and 500 / mm³respectively), the possibility of dose reduction should be considered - in both monotherapy and combined treatment regimens - by 25%.

Patients with impaired renal function (creatinine clearance less than 60 ml / min) in connection with an increased risk of severe myelosuppression, the dose of carboplatin is reduced as follows:

Creatinine clearance	Dose of Carboplatinum
More than 40 ml / min	400 mg / m²
41-59 ml / min	250 mg / m²
16-40 ml / min	200 mg / m²

Calculation of the dose is recommended using the Calvert formula:

Dose (mg) = (required AUC) х (СГФ + 25),

Where AUC - the area under the curve (concentration / time), GFS - the speed of glomerular filtration. Values AUC in the range of 4-6 and 6-8 mg / ml x min create acceptable hematologic toxicity in previously treated patients and patients who have not previously received treatment, respectively.

All the above recommendations for dosing relate to the initial course of treatment. The subsequent doses should be adjusted depending on the tolerance of the drug to patients and the severity of myelosuppression.

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.

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

Before use, the solution of carboplatin should be visually inspected for mechanical inclusions and discoloration.

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

Side effects:

According to the World Health Organization (WHO), adverse reactions are classified according to their developmental frequency as follows: very often (≥1/10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, < 1/100), rarely (≥1 / 10000, <1/1000) and very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

Infections and parasitic diseases: often - infection.

Benign, malignant and unspecified neoplasms (including cysts and polyps): frequency unknown - treatment-related secondary malignancy of the neoplasm.Rare cases of development of acute myelogenous leukemia and myelodysplastic syndrome in patients who received carboplatin, especially when used in combination with other potentially leukemic preparations.

On the part of the blood and lymphatic system: very often - thrombocytopenia, neutropenia, leukopenia, anemia; often: bleeding *; frequency unknown - inhibition of bone marrow hematopoiesis, febrile neutropenia.

From the immune system: often - hypersensitivity, anaphylactoid reactions; frequency unknown - conjunctivitis, rhinitis.

From the side of metabolism and nutrition: frequency unknown - dehydration, anorexia.

From the nervous system: often - peripheral neuropathy (paresthesia, reduction of deep tendon reflexes, which is more likely for patients older than 65 years), taste disorders; frequency unknown - impaired cerebral circulation (including stroke *), headache, dizziness, meningism, depression, insomnia, increased nervousness.

Neurotoxicity is a dose-limiting dose. Often the symptoms of sensory neuropathy are provoked by cold.The duration of these symptoms, which are usually docked in the interval between courses, increases depending on the total dose of carboplatin. Functional disorders, which are expressed by the difficulty of performing precise movements, are possible consequences of sensory damage.

From the side of the organ of vision: Often - a temporary loss of vision (possible loss of the ability to distinguish color and see the light) reported in patients taking usual doses of carboplatin and cyclophosphamide. Improvement and / or complete restoration of vision, usually occurs within a few weeks after discontinuation of the drug; rarely - complete loss of vision (cortical blindness is described in patients with impaired renal function receiving the drug high doses).

From the side of the hearing organ and labyrinthine disorders: Often - ototoxicity (tinnitus, deterioration of hearing); very rarely - hearing loss.

From the heart: Often - cardiovascular complications (eg, myocardial infarction, heart failure, angina, myocardial ischemia) *; frequency unknown - heart failure *.

From the side of the vessels: the frequency is unknown - thromboembolism, increased blood pressure, lowering blood pressure (hypotension).

On the part of the respiratory system, the organs of the thorax and the mediastinum: often - violation of breathing, interstitial lung diseases, bronchospasm.

From the gastrointestinal tract: very often - nausea, vomiting, abdominal pain; often - diarrhea, constipation, inflammation of the oral mucosa; frequency unknown - stomatitis, mucositis, colitis, including pseudomembranous colitis.

From the skin and subcutaneous tissues: often - alopecia, skin rashes; very rarely: urticaria, reddening of the skin, erythema, itching of the skin, erythematous rash, anaphylactic reactions, exfoliative dermatitis.

From the musculoskeletal and connective tissue: often - arthralgia, myalgia.

From the side of the kidneys and urinary tract: rarely: acute renal failure, hemolytic-uremic syndrome (Gasser's syndrome - acute renal failure with oliguria, hemolytic anemia and thrombocytopenia).

From the genitals and mammary glands: frequency unknown - azoospermia, amenorrhea.

General disorders and disorders at the site of administration: often - asthenia; frequency unknown-allergic reactions, redness, pain, edema, directly at the site of administration, necrosis of tissues during extravasation, fever, intermittent fever.

Impact on laboratory and instrumental research results: very often - increasing the concentration of creatinine and urea in the blood plasma, increasing the activity of alkaline phosphatase and "liver" transaminases, reducing the sodium, potassium, calcium, magnesium in the blood plasma; often - an increase in the concentration of bilirubin, uric acid in the blood plasma.

* Lethal outcome was registered in less than 1% of patients with these complications.

Overdose:

Symptoms: marked manifestation of the above side effects, especially myelosuppression, violations of the liver and kidneys. When using high doses of carboplatin, loss of vision is possible.

Treatment: the antidote is not known. 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.

In connection with the increased risk of thrombosis in the treatment of tumors, anticoagulants are often used. Due to the high interindividual variability of the response to anticoagulant therapy, as well as the possible interaction of antitumor drugs and anticoagulants in combined use, coagulability of the blood, namely the International Normalized Ratio (MNO), should be regularly evaluated.

Contraindicated with the simultaneous use of yellow fever vaccine due to the possible risk of generalization of the infection.

It is not recommended simultaneous use of carboplatin with live attenuated vaccines because of the increased risk of developing systemic diseases with possible fatal outcome, especially in patients with immunosuppression. If necessary, an inactivated vaccine should be used (for example, with poliomyelitis). It should avoid simultaneous use with phenytoin because of increased risk of seizures because of increased toxicity or loss of cytotoxic drug effectiveness due to increased hepatic metabolism of phenytoin.

With the simultaneous use of carboplatin and cyclosporine (as well as tacrolimus and sirolimus), it is possible to develop severe myelosuppression with an increased risk of developing lymphoproliferative diseases. Concomitant therapy with aminoglycosides, as well as other nephrotoxic (for example, loop diuretics) and ototoxic drugs potentiates the toxic effect of carboplatin on these organs.

Carboplatin can interact with aluminum to form a black precipitate.

Special instructions:

Carboplatin-Ebweve should be administered under the supervision of a physician with experience in the use of cytotoxic drugs. Continuous monitoring of possible toxic effects in the treatment with Carboplatin-Ebevé is mandatory, especially when using high doses of the drug.

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) should monitor the clinical blood test, kidney function (creatinine clearance) and liver.

Nausea and vomiting develop 6-12 hours after the administration of the drug Carboplatin-Ebwe and continue for 24 hours (antiemetics should be used).

Hematological toxicity

The severity of leukopenia, neutropenia, thrombocytopenia is dose-dependent and usually occurs on the 15th or 21st day after the use of the Carboplatin-Ebove drug with combined therapy with other cytotoxic drugs or in monotherapy, respectively. Treatment with the drug should not be resumed until the number of neutrophils is not less than 2000 cells / mm³, platelets - not less than 100 000 cells / mm³.

If severe anemia occurs, very rarely a transfusion of red blood cells of the blood may be required. When combined with other cytotoxic drugs, the dose of Carboplatin-Ebweve should be carefully adjusted (reduced) in order to minimize the summation effect.

Allergic reactions

As with other preparations containing platinum, allergic reactions most often occur during the infusion of the drug, sometimes requiring its discontinuation.There are reports of a cross-reaction to drugs with platinum compounds, sometimes with the development of a lethal outcome.

Nephrotoxicity

In patients with impaired renal function, the effect of Carboplatin-Ebweve on the hematopoietic system is more pronounced and prolonged than in patients with normal renal function.

Neurotoxicity

Neurotoxicity, due to the use of the Carboplatin-Ebove drug, is usually mild, and is manifested by paresthesia and a decrease in tendon reflexes. During treatment with Carboplatin-Ebove, especially in elderly patients (over 65 years) and previously treated with drugs containing platinum, neurologic examinations should be performed periodically.

Visual impairment, including visual loss, was reported in patients with renal insufficiency after the use of Carboplatin-Ebweve in doses higher than those recommended. Vision is restored almost completely or to a large extent within a few weeks after the cancellation of high doses of the drug.

Since the drug Carboplatin-Ebweave can cause ototoxic effects (manifested by a decrease in the audibility threshold at the upper frequencies), patients are advised to perform audiographic studies before and during treatment. In the case of a clinically significant impairment of the hearing function, a corresponding change in the dose of the Carboplatin-Ebove drug or discontinuation of treatment may be required.

Elderly patients (over 65 years of age)

With the combination therapy of Carboplatin-Ebweve and cyclophosphamide, elderly patients experienced more severe thrombocytopenia than younger patients. Since renal function is often reduced in elderly patients, this should be taken into account when determining the dose and regimen of the drug.

During treatment with Carboplatin-Ebeva and for at least 3 months after, it is not recommended to vaccinate patients.

Women and men should be treated with safe methods of contraception during treatment with Carboplatin-Ebeva and at least 6 months after the end of treatment.

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

Remains of the preparation and all instruments and materials used to prepare solutions for Carboplatin-Ebweve infusions must be disposed of in accordance with the standard hospital procedure for the disposal of cytotoxic substances, taking into account existing regulatory acts on the destruction of hazardous waste.

Effect on the ability to drive transp. cf. and fur:

Because of the likelihood of side effects, such as nausea, vomiting, drowsiness, caution should be exercised when practicing potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Concentrate for the preparation of a solution for infusions of 10 mg / ml (50 mg / 5 ml, 150 mg / 15 ml, 450 mg / 45 ml, 600 mg / 100 ml, 1000 mg / 100 ml).

Packaging:5 ml, 15 ml, 45 ml, 60 ml or 100 ml in brown glass bottles (type 1 Hept. F.), Sealed with chlorobutyl rubber stoppers, under an aluminum run-off, with a needle hole in the center, closed with a protective Teflon cap.

One bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015198 / 01-2003

Date of registration:11.08.2008 / 18.05.2012

Expiration Date:Unlimited

Date of cancellation:2016-10-17

The owner of the registration certificate:Ebewe Pharma Gesmb.b. Nfg. KGEbewe Pharma Gesmb.b. Nfg. KG Austria

Manufacturer: & nbsp

EBEWE PHARMA, Ges.m.b.H.Nfg.KG Austria

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp08.12.2017

Illustrated instructions

Instructions

Carboplatin-Ebene (Carboplatin-Ebewe)