Paklitaksel

General characteristics. Structure:

Active agent: paklitakset 6 mg
Excipients: макроголглицерол the ricinoleate purified; ethanol anhydrous, q.s nitrogen.

Description: transparent solution of light yellow color.

Pharmacological properties:

Pharmacodynamics. Paklitaksel is the antineoplastic drug of a natural origin received in the semi-synthetic way from Taxus Baccata plant.
The mechanism of action is connected with ability of drug to stimulate "assembly" of microtubules from dimeric molecules of a tubulin, to stabilize their structure and to slow down dynamic reorganization in interphase that breaks mitotic function of a cell.
Causes dozozavisimy suppression of a marrowy hemopoiesis. On experimental data has mutagen and embriotoksichesky properties, causes decrease in reproductive function.

Pharmacokinetics. At intravenous (in) introduction within 3 hours in a dose of 135 mg/sq.m the maximum concentration (Cmax) makes 2170 ng/ml, the area under a curve "concentration time" (AUC) - 7952 нг/ч/мл; at introduction of the same dose within 24 hours - 195 ng/ml and 6300 нг/ч/мл, respectively. Cmax and AUC of a dozozavisima: at the 3rd hour infusion increase in a dose up to 175 mg/sq.m leads to increase in these parameters for 68% and 89%, respectively, at 24 hour - for 87% and 26%, respectively.
Communication with proteins of plasma - 88-98%. The average volume of distribution – 198-688 l/sq.m. Semi-distribution time from blood in fabric - 30 min. Easily gets and it is adsorbed by fabrics, collects preferential in a liver, a spleen, a pancreas, a stomach, intestines, heart, muscles.
It is metabolized in a liver by a hydroxylation with participation of isoenzymes of P450 CYP2D8 cytochrome (with formation of a metabolite - 6 - alpha гидроксипаклитаксел) and CYP3CA4 (with formation of metabolites 3 - couple - gidroksipaklitaksel and 6 alpha, 3 - couple - digidroksipaklitaksel). It is removed preferential with bile - 90%. At repeated infusions does not kumulirut.
The elimination half-life and the general clearance are variable and depend on a dose and duration in/in introductions: 13.1-52.7 h and 12.2-23.8 l/h/sq.m, respectively. Later in/in infusion (1-24 h) the general removal by kidneys makes 1.3-12.6% of a dose (15-275 mg/sq.m) that indicates existence of intensive extrarenal clearance. The general clearance - 11-24 l/sq.m.

Indications to use:

• Ovarian cancer (therapy of the first line of patients with a common form of a disease or a residual tumor (more than 1 cm) after a laparotomy (in a combination with Cisplatinum) and therapy of the second line at metastasises after the standard therapy which did not yield a positive take).
• A breast cancer (existence of the affected lymph nodes after a standard combination therapy (adjuvant treatment); after the disease recurrence, within 6 months after the beginning of adjuvant therapy - therapy of the first line; a metastatic breast cancer after inefficient standard therapy - therapy of the second line).
• Not small-celled lung cancer (therapy of the first line of patients to whom performing surgical treatment and/or radiation therapy is not planned (in a combination with Cisplatinum).
• Kaposha's sarcoma at patients with AIDS (therapy of the second line, after inefficient therapy by liposomal anthracyclines).

Route of administration and doses:

For the warning of heavy hypersensitivity reactions to all patients premedication with use of glucocorticosteroids, antihistaminic drugs and antagonists of H2 of histamine receptors has to be carried out. For example, 20 mg of dexamethasone (or its equivalent) inside approximately in 12 and 6 hours prior to administration of drug Paklitaksel, 50 mg of a difengidramin (or its equivalent) intravenously and 300 mg of Cimetidinum or 50 mg of ranitidine intravenously in 30-60 minutes prior to administration of drug Paklitaksel. At the choice of the mode and doses in each individual case it is necessary to be guided by data of special literature.
Paklitaksel is entered intravenously in the form of 3-hour or 24-hour infusion in a dose of 135-175 mg/sq.m with an interval between courses of 3 weeks. Drug is used in the form of monotherapy or in a combination with Cisplatinum (ovarian cancer and not small-celled lung cancer) or doxorubicine (breast cancer). The recommended drug dose Paklitaksel for treatment of Sarcoma of Kaposha at patients with AIDS makes 100 mg/sq.m in the form of 3-hour infusion each 2 weeks.
Administration of drug Paklitaksel should not be repeated until the maintenance of neutrophils does not make at least 1500/mkl blood, and the maintenance of thrombocytes at least 100000/mkl blood. Patients at whom after introduction Paklitaksela was observed the expressed neutropenia (the maintenance of neutrophils <500/mm3 blood within 7 days or longer time) or a severe form of peripheral neuropathy during the subsequent courses of treatment should lower Paklitaksel's dose by 20%.
Solution of drug is prepared just before introduction, parting a concentrate of 0,9% with chloride sodium solution, either 5% dextrose solution, or 5% dextrose solution in 0,9% chloride sodium solution for injections, or 5% dextrose solution in Ringer's solution to final concentration from 0,3 to 1,2 mg/ml. The prepared solutions can opalestsirovat because of the dosage form of a basis carrier which is present at structure, and after filtering opalescence of solution remains.
At preparation, storage and administration of drug Paklitaksel it is necessary to use the equipment which does not contain details from PVC.
Paklitaksel it is necessary to enter through system with the built-in membrane filter (the size of a time no more than 0,22 microns).

Features of use:

Paklitaksel's use has to be carried out under observation of the doctor having experience with antineoplastic chemotherapeutic drugs.
For the warning of heavy hypersensitivity reactions to all patients premedication with use of glucocorticosteroids, antihistaminic drugs and antagonists of H2 of histamine receptors has to be carried out: 20 mg of dexamethasone (or its equivalent) inside approximately in 12 and 6 hours prior to Paklitaksel's introduction, 50 mg of a difengidramin (or its equivalent) intravenously and 300 mg of Cimetidinum or 50 mg of ranitidine intravenously in 30-60 minutes prior to Paklitaksel's introduction.
In case of development of heavy reactions of hypersensitivity drug injection Paklitaksel it is necessary to stop and begin immediately a symptomatic treatment, and it is not necessary to administer the drug repeatedly. Makrogolglitserol the ricinoleate which is a part of drug Paklitaksel can cause extraction of DEGP [di - (2 hexyl) phthalate] from the plasticized polyvinyl chloride (PVC) containers, and extent of washing away of DEGP increases at increase in concentration of solution and over time. Therefore, at preparation, storage and administration of drug Paklitaksel it is necessary to use the equipment which does not contain details from PVC.
During treatment it is regularly necessary to control a pattern of peripheral blood, the ABP, ChSS and number of dykhaniye (especially for the first hour of infusion), ECG control (and prior to treatment). In cases of development of disturbances of atrioventricular conductivity, at repeated introductions it is necessary to carry out continuous cardiomonitoring.
If Paklitaksel is used in a combination with Cisplatinum, at first it is necessary to enter Paklitaksel, and then Cisplatinum.
Patients during treatment by Paklitaksel and, at least, within 3 months after the end of therapy should use reliable methods of contraception.
During treatment it is necessary to abstain from occupations potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.
Paklitaksel is cytotoxic substance during the work with which it is necessary to be careful, use gloves and to avoid its hit on skin or mucous membranes which in such cases need to be washed out carefully soap and water or (eyes) a large amount of water.

Side effects:

Frequency and expressiveness of side effects have dozozavisimy character.

From bodies of a hemopoiesis: neutropenia, thrombocytopenia, anemia. Suppression of function of marrow, mainly a granulotsitarny sprout, was the main toxic effect limiting a drug dose. The maximum decrease in level of neutrophils is usually observed for 8-11 day, normalization occurs for the 22nd day.
Allergic reactions: during the first hours after Paklitaksel's introduction the hypersensitivity reactions which are shown a bronchospasm, a lowering of arterial pressure, pains behind a breast, rushes of blood to the person, skin rashes, a generalized small tortoiseshell, a Quincke's disease can be observed. Isolated cases of a fever and dorsodynias are described.
From cardiovascular system: the lowering of arterial pressure, is more rare – increase in the ABP, bradycardia, tachycardia, an atrioventricular block, changes on an ECG, thrombosis of vessels and thrombophlebitis are possible.
From respiratory system: intersticial pneumonia, a pneumosclerosis, an embolism of a pulmonary artery, and also more frequent development of a beam pneumonitis in the patients who are at the same time taking a course of radiation therapy.
From a nervous system: mainly paresthesias. Seldom - convulsive attacks like grand mal, vision disorders, an ataxy, encephalopathy, the vegetative neuropathy which is shown paralytic impassability of intestines and orthostatic hypotonia. From a musculoskeletal system: arthralgia, mialgiya.
From the alimentary system: nausea, vomiting, diarrhea, mukozita, anorexia, lock. Single messages on acute intestinal impassability, perforation of intestines, fibrinferment of a mesenteric artery, ischemic colitis.
From function of a liver: increase in activity of "hepatic" transaminases (the nuclear heating plant is more often), an alkaline phosphatase and bilirubin in blood serum. Cases of development of a gepatonekroz and hepatic encephalopathy are described.
Local reactions: pain, hypostasis, an erythema, an induration and a xanthopathy in the place of an injection; the ekstravazation can cause an inflammation and a necrosis of hypodermic cellulose.
From skin and skin appendages: an alopecia, disturbance of pigmentation or decolouration of a nail bed is rare.
Other side reactions: adynamy and febricula.

Interaction with other medicines:

Cisplatinum reduces the general clearance of a paklitaksel by 20% (at the same time more expressed miyelosupressiya is observed in case paklitakset enter after Cisplatinum).
Co-administration with Cimetidinum, ranitidine, dexamethasone or difengidraminy does not influence communication of a paklitaksel with proteins of a blood plasma.
Inhibitors of a microsomal oxidation (including кетоконазол, Cimetidinum, verapamil, diazepam, quinidine, cyclosporine, etc.) suppress metabolism of a paklitaksel.

Contraindications:

• Hypersensitivity to drug, and also other drugs which dosage form includes макроголглицерол ricinoleate.
• Pregnancy and period of feeding by a breast.
• The initial maintenance of neutrophils less 1500/mkl at patients with solid tumors.
• Initial (or registered in the course of treatment) the maintenance of neutrophils less 1000/mkl at patients with Kaposha's sarcoma at patients with AIDS.
With care: thrombocytopenia (less 100000/mkl), a liver failure, acute infectious diseases (including shingles, chicken pox, herpes), the heavy course of coronary heart disease, a myocardial infarction (in the anamnesis), arrhythmias.
Use in pediatrics. Safety and efficiency of drug of Paklitaksel at children is not established.

Overdose:

Symptoms: marrow aplasia, peripheral neuropathy, mukozita.
Treatment: symptomatic. The antidote to a paklitaksel is not known.

Storage conditions:

List B. At a temperature not above 25 °C in protected from light and the place, unavailable to children. Period of validity 2 years. Drug should not be used after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 5 ml or 16,7 ml of a concentrate (6 mg/ml) in the bottle of colourless glass, a hydrolytic class I corked by a stopper from a brombutil and rolled by an aluminum cap with a polypropylene cover. On 1 or 10 bottles containing 5 ml of drug (30 mg) or 1 bottle containing 16,7 ml (100 mg) together with the application instruction is placed in a cardboard pack.