Karboplatin

General characteristics. Structure:

Active ingredient: 10 mg of a karboplatin.

Excipients: water for injections.

Pharmacological properties:

Pharmacodynamics. Karboplatin represents the inorganic complex compound containing heavy metal - platinum. Assume that the main mechanism of effect of this drug is caused by linkng with DNA therefore preferential intra spiral stitchings which change structure of DNA are formed and suppress its synthesis. This effect is shown regardless of a phase of a cellular cycle. Hydration of a karboplatin as a result of which the active form (forms) of drug is formed happens more slowly, than hydration of Cisplatinum.

Pharmacokinetics. The pharmacokinetics of a karboplatin is difficult process and includes transformations of an initial karboplatin, the general platinum and platinum which is giving in to ultrafiltration. The general platinum consists from connected with proteins and platinum, untied with proteins, while the platinum which is giving in to ultrafiltration consists of a karboplatin and metabolites of a karboplatin, untied with proteins. Level of the platinum which is giving in to ultrafiltration as only platinum, untied with proteins, or its metabolites containing platinum usually are cytotoxic is usually measured in pharmacokinetic researches of a karboplatin.

After single introduction of a karboplatin in the form of intravenous infusion the maximum concentration of a karboplatin, sheathe platinum and the platinum which is giving in to ultrafiltration is reached almost immediately. Platinum is distributed in all fabrics and liquids of an organism, and the highest concentration are observed in tissues of kidneys, a liver, skin and tumoral fabrics.

Initial stages of semi-removal (T1/2) of a karboplatin, the general platinum and platinum which is giving in to ultrafiltration at intravenous administration are almost identical; T1/2 of a karboplatin makes 1-2 hours.
 
Actually карбоплатин does not contact proteins, and breaks up to the products containing platinum which very quickly contact proteins. Within the first 4 hours after introduction of a karboplatin less than 24% of platinum contact proteins of plasma; in 24 hours the amount of the connected platinum makes 87%.
 
Concentration of a karboplatin and the platinum which is giving in to ultrafiltration decreases according to two-phase model. Concentration of the general platinum decreases according to three-phase model. At normal function of kidneys elimination half-lives of a karboplatin and the platinum which is giving in to ultrafiltration make 2-3 hours. The final elimination half-life of the general platinum makes 4-6 days.
 
Karboplatin and his platiniferous metabolites are generally removed with urine. At normal function of kidneys about 65% of a dose of a karboplatin are removed with urine within 12 hours; in 24 hours 71% of a dose are removed. A considerable part is removed in the form of not changed karboplatin. Karboplatin (in the form of the karboplatin which is giving in to ultrafiltration) is effectively brought by a hemodialysis.
 
In urine in 24 hours all platinum is present at a type of a karboplatin. Only 3-5% of the entered platinum are removed with urine during 24-96 hours.
 
As карбоплатин it is removed almost completely by means of glomerular filtering, only very small concentration of a karboplatin is present at renal tubules that, perhaps, explains the small nephrotoxic potential of drug in comparison with Cisplatinum.

Indications to use:

- ovarian cancer;
 
- germinogenny tumors of men and women;
 
- lung cancer;
 
- cancer of a neck of uterus;
 
- malignant tumors of the head and neck;
 
- bladder Schmincke's tumor.

Route of administration and doses:

Karboplatin can be applied both in the form of monotherapy, and in combination with other antineoplastic drugs. At the choice of a dose and mode in each individual case it is necessary to use special literature.
 
The drug is administered intravenously in the following dose modes:
 
- 300-400 mg/sq.m intravenously kapelno within 15-60 minutes or in the form of 24-hour infusion;
 
- 100 mg/sq.m intravenously kapelno within 15-60 minutes daily within 5 days;

Karboplatin's introduction not less than 4 weeks at indicators of thrombocytes repeat with an interval not less than 100000 cells / мкл blood and neutrophils not less than 2000 cells / мкл blood at the time of the following introduction.
 
Administration of liquid to or after Karboplatin's use, and also achievement of an artificial diuresis is not required.
 
Depending on a condition of marrow or function of kidneys the therapeutic dose of Karboplatin can korregirovatsya as follows:
 
- at decrease in quantity of thrombocytes to 50000/mkl and/or neutrophils to 500/mkl at the previous courses of therapy karboplatiny correction of a dose is not required;
 
- at the observed minimum values of thrombocytes less 50000/mkl and/or neutrophils less 500/mkl at the previous therapy course karboplatiny it is necessary to consider the possibility of decrease in the following dose for 25% both in monotherapy cases, and in the combined schemes of treatment;
 
- at a renal failure (clearance of creatinine less than 60 ml/min.) the risk of development of toxic effects of a karboplatin in this connection the recommended doses of a karboplatin make 41-59 ml/min. - 250 mg/sq.m at clearance of creatinine increases, at clearance of creatinine of 16-40 ml/min. - 200 mg/sq.m;
 
- to patients with risk factors, such as, for example, the courses of myelosuppressive therapy conducted earlier, age more than 65 years, the low functional status (ECOG-Zubrod 2-4 or an indicator across Karnovsky lower than 80%) is recommended decrease in an initial dose of a karboplatin by 20-25%.
 
Definition of a dose on a formula. It is possible to determine an initial dose of drug in milligrams by Kalvert's formula describing dependence of values of speed of glomerular filtering (SGF in ml/min.) and desirable concentration of drug from time (AUC in mg/ml x mines):
 
General dose (mg) = AUC x (SGF + 25)

Desirable AUC value *	The planned chemotherapy drug KARBOPLATIN	The status of the patient concerning treatment
5-7 mg / мл.мин	Monotherapy	Earlier not treated
4-6 mg / мл.мин	Monotherapy	Earlier treated
4-6 mg / мл.мин	In a combination with cyclophosphamide	Earlier not treated

 

Rules of preparation of solution for infusions. Before introduction drug dilute to concentration 0,5 mg/ml of 5% with solution of a dextrose or 0,9% chloride sodium solution. Weak solutions of drug are stable within 8 hours at a temperature of 25 °C and within 24 hours at storage in the refrigerator at 4 °C.

Features of use:

Treatment by Karboplatin should be performed under control of the doctor having experience of use of cytotoxic drugs.
 
It is not necessary to apply to preparation and administration of drug of a needle, the syringes, catheters and infusional systems containing aluminum which can react with karboplatiny, leading to formation of a deposit or loss of activity of drug.
 
Regularly (weekly) it is necessary to carry out control uniform, elements of peripheral blood and indicators of function of kidneys (the most sensitive indicator the clearance of creatinine is) and a liver.
 
It is periodically recommended to perform neurologic inspections, especially at the patients who were earlier undergoing therapy by Cisplatinum and also at patients 65 years are more senior.
 
As Karboplatin can cause cumulative ototoksichesky effects, patients are recommended to conduct audiographic researches prior to the beginning of and during treatment. In case of clinically significant dysfunction of hearing corresponding change of a dose of drug or the termination of treatment can be required.
 
Women and men during treatment by Karboplatin should use reliable ways of contraception.
 
At Karboplatin's use all usual instructions accepted for use of cytotoxic drugs have to be observed. In case of hit of drug in their eyes it is necessary to wash out immediately a large amount of water or 0,9% chloride sodium solution. In case of hit of drug on skin it is necessary to wash out immediately the place of contact with drug a large amount of water. In case of inhalation of drug or its hit in a mouth it is necessary to see a doctor immediately.
 
During treatment do not recommend to carry out vaccination of patients.

Side effects:

From bodies of a hemopoiesis: the major toxic factor limiting a dose of a karboplatin is suppression of function of a marrowy hemopoiesis. Miyelosupressiya of a dozozavisim. The lowest level of thrombocytes and leukocytes/granulocytes is, as a rule, reached in two-three weeks after the beginning of administration of drug, at the same time thrombocytopenia meets more often. Adequate recovery to the level allowing reception of the following dose of a karboplatin, as a rule, takes not less than 4 weeks. At rather large number of patients anemia symptoms (hemoglobin level less than 11 g/dl) which intensity depends on a total dose of drug can be also shown. There can be a need for performing transfusion therapy, especially at the patients undergoing prolonged treatment (for example, more than 6 cycles of administration of drug). There is also a probability of development of such complications as fever, infectious diseases, sepsis / septic shock and bleeding.
 
From system of digestion: nausea, vomiting (it is possible to prevent preliminary purpose of antiemetics, continuous intravenous infusion of a karboplatin within 24 hours or fractional introduction of a dose within 5 days in a row), stomatitis, diarrhea or locks, abdominal pains, a loss of appetite, an abnormal liver function (increase in activity of ACT, an alkaline phosphatase and concentration of bilirubin in blood serum).
 
From a nervous system: an adynamy, peripheral polyneuropathy (paresthesias, decrease in deep tendon jerks), decrease in visual acuity up to total loss of sight or loss of ability to distinguish colors (improvement or a complete recovery of sight, as a rule, happens within several weeks after the termination of administration of drug; at the patients with a renal failure undergoing treatment by high doses of a karboplatin the cortical blindness), decrease in hearing, a sonitus was observed. Long therapy by drug can lead to a cumulative neurotoxicity.
 
From urinogenital system: increase in concentration of creatinine and urea in blood serum (acute damages of kidneys were observed seldom, the risk of emergence of nephrotoxicity against the background of reception of a karboplatin increases at increase in a dose of a karboplatin and also at patients who underwent treatment by Cisplatinum earlier), an azoospermism, an amenorrhea.
 
From water and electrolytic balance: hypopotassemia, hypocalcemia, hyponatremia and hypomagnesiemia.
 
Allergic reactions: erythematic rash, fever, an itch, a small tortoiseshell, a bronchospasm, a lowering of arterial pressure, anaphylactoid reactions, allergic reactions in a drug injection site. Seldom - exfoliative dermatitis.
 
Others: taste changes, alopecia, grippopodobny symptoms (temperature increase, fever), gemolitiko-uraemic syndrome, миалгия / arthralgia, heart failure, cerebrovascular disturbances.

Interaction with other medicines:

Use of a karboplatin in a combination with other myelosuppressive drugs or radiation therapy can increase risk of emergence of hematologic toxicity.
 
Use of a karboplatin in a combination with aminoglycosides, and also with other nephrotoxic drugs increases risk of emergence of nephrotoxic and/or ototoksichesky effects.

Contraindications:

Overdose:

The special antidotes applied in case of overdose of a karboplatin are unknown. At overdose it is necessary to expect more expressed above-mentioned side reactions. Symptomatic treatment. In the first 3 hours after administration of drug use of a hemodialysis is possible.

Storage conditions:

In the place protected from light at a temperature from 15 to 30 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to use drug after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 5, 15, 45 or 75 ml of drug in the bottles of dark neutral glass I of a hydrolytic class corked by rubber bungs with a running in aluminum caps. On 1 bottle with the application instruction in a pack from a cardboard.