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

Pharmacodynamics:Carboplatin is a complex compound containing a heavy metal platinum.It is suggested 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

Pharmacokinetics:

After a 30-minute infusion of 300-500 mg / m² carboplatin in patients with creatinine clearance (CK) of 60 ml / min and more plasma concentration of unchanged carboplatin decreases biphasic. Initial half-life (T_1/2-alpha) is 1.1-2 hours after the end of the distribution T_1/2-beta - 2,6-5,9 h. The total clearance is 4,4 l / h, the apparent volume of distribution is 16 l, the average time of constant carboplatin in plasma is 3.5 h. The maximum concentration (C_max) and the area under the concentration-time curve (AUC) increase linearly with increasing dose, so the pharmacokinetics of carboplatin in the range 300-500 mg / m² is linear in nature.

Carboplatin does not bind to plasma proteins. Platinum-containing metabolites of carboplatin, not associated with plasma proteins, are contained in it only in small amounts.However, platinum, released from carboplatin, irreversibly binds to plasma proteins and is slowly eliminated from it with minimal T_1/2 - 5 days.

The main way of elimination is kidney excretion. At CC 60 ml / min and more than 65% of the administered dose is excreted within 12 hours, 71% - within 24 hours. In daily urine, all platinum is present in carboplatin. In the next 72 h only 3-5% of the administered platinum is excreted in the urine. Information on the possible elimination of feces is not enough.

In patients with SC less than 60 ml / min, the renal clearance of carboplatin decreases in proportion to the degree of renal failure. In such patients, the dose of carboplatin should be reduced.

The main indicator of renal carboplatin excretion is the glomerular filtration rate (GFR), which is often reduced in elderly patients, so when calculating AUC In elderly patients, the degree of GFR reduction should be adjusted.

Indications:

Ovarian cancer, germ cell tumors of men and women, lung cancer, cervical cancer, malignant head and neck tumors, transitional cell carcinoma of the bladder.

Contraindications:

Hypersensitivity to carboplatinum or other platinum-containingconnections; severe renal dysfunction (creatinine clearance is equal to or below 15 ml / min); severe oppression of bone marrow hematopoiesis; heavy bleeding; pregnancy and the period of breastfeeding; children's age (safety and efficacy not well studied).

Carefully:

With oppression of bone marrow hematopoiesis of mild and moderate severity (including on the background of concomitant radiation or chemotherapy), previous therapy with nephrotoxic drugs (eg, cisplatin), violations of liver function, visual impairment, hearing impairment, acute infectious diseases of viral, fungal or bacterial nature, in the post-vaccination period.

Dosing and Administration:

The drug Carboplatin-Teva can be used both in the form of monotherapy, and in combination with other antitumor drugs. When choosing a dose and dosage regimen, special literature should be used in each individual case.

The drug is administered intravenously according to the following scheme:

- 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.

The administration of Carboplatin-Teva is repeated at intervals of not less than 4 weeks with a platelet count 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 use of the drug Carboplatin-Teva, as well as the achievement of forced diuresis is not required.

Depending on the condition of the bone marrow or kidney function, the therapeutic dose of Carboplatin-Teva can be corrected as follows:

- with a decrease in the number of platelets to 50,000 / μL and / or neutrophils to 500 / μl with previous courses of carboplatin therapy, dose adjustment is not required;

- 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 kidney function is impaired (CC less than 60 ml / min.), the risk of toxic effects of carboplatin increases, and therefore recommended doses of carboplatin are at a CK of 41-59 ml / min - 250 mg / m², with SC 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 (according to the scale of the Eastern United Group of Oncologists (ECOG) 2-4 points 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

Determine the initial dose of the drug in milligrams, according to Calvert's formula describing the dependence of the glomerular filtration rate (GFR in ml / min) and the desired carboplatin concentration on time (AUC in mg / ml x min):

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

Preferred	Planned chemotherapy	Status of the patient in
value AUC	drug Carboplatin-Teva	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

A 5% dextrose solution or 0.9% sodium chloride solution is added to the vial with lyophilizate until a solution with a concentration of 10 mg / ml is obtained. Before administration, the solution is diluted to a concentration of 0.5 mg / ml with 5% dextrose solution or 0.9% sodium chloride solution.

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

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 content of platelets and white blood cells / granulocytes is usually achieved two to three weeks after the start of the drug, with thrombocytopenia occurring more often. Adequate recovery to a value 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 (hemoglobin content less than 110 g / l), 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 by fractional dose administration for 5 consecutive days), stomatitis, diarrhea or constipation, abdominal pain, decreased appetite, impaired hepatic function (increased activity of aspartate aminotransferase , alkaline phosphatase and serum bilirubin concentration).

Co hand 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, usually occurs within a few weeks after discontinuation of the drug; renal dysfunction, 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 when taking carboplatin increases with an increase in the dose of carboplatin, as well as 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, pruritus, urticaria, bronchospasm, lowering blood pressure, anaphylactoid reactions, allergic reactions at the site of administration, exfoliative dermatitis.

Other: changes in taste, alopecia, influenza-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 the drug Carboplatin-Teva should be carried out under the supervision of a doctor who has 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 monitor the content of the formed elements in the peripheral blood and the renal function (the most sensitive indicator is the creatinine clearance) and the liver.

It is recommended that the neurologist regularly monitor, especially patients who have previously been treated with cisplatin, as well as patients older than 65 years.

Since Carboplatin-Teva 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 should be treated with reliable methods of contraception during treatment with Carboplatin-Teva.

When using the drug Carboplatin-Teva, all 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.

In the time of treatment is not recommended to vaccinate patients.

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

Taking into account the possibility of developing side effects from the nervous system, during the treatment period one should refrain from driving and potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Lyophilizate for the preparation of a solution for infusions of 50 mg, 150 mg and 450 mg.

Packaging:For 50 mg, 150 mg and 450 mg of active substance in a vial of dark glass (type I, Hept., Pharm.) With a capacity of 5 ml, 15 ml or 45 ml respectively, with an elastomer cap of chlorobutyl aluminum cap equipped with a protective cap made of colored polypropylene. The bottle is covered with a transparent film of PVC or OPS. 1 bottle with instructions for use in a pack of cardboard.

Storage conditions:

At a temperature of 15 to 30 ° C in the dark place.

Keep out of the reach of children.

Shelf life:

50 mg - 3 years, 150 mg - 4 years, 450 mg - 3 years. Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N012288 / 02

Date of registration:25.09.2008 / 18.09.2017

Expiration Date:Unlimited

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

PHARMACHEMIE, B.V. Netherlands

Representation: & nbspTeva Teva Israel

Information update date: & nbsp08.12.2017

Illustrated instructions

Instructions

Carboplatin-Teva (Carboplatin-Teva)