Таксол®

General characteristics. Structure:

Active ingredient: 6 mg of a paklitaksel in 1 ml of solution.

Excipients: macrogoal глицерилрицинолеат (^{кремофор®} EL), ethanol, nitrogen.

Pharmacological properties:

Pharmacodynamics. The antineoplastic drug received in the biosynthetic way. The mechanism of action is connected with ability to stimulate "assembly" of microtubules from dimeric molecules of a tubulin, to stabilize their structure due to suppression of a depolymerization and to slow down dynamic reorganization in interphase that breaks mitotic function of a cell.

Besides, paklitakset induces formation of abnormal accumulations or "linking" of microtubules throughout a cellular cycle and causes formation of multiple stars of microtubules during a mitosis.

Causes dozozavisimy suppression of a marrowy hemopoiesis.

In pilot studies it is shown that paklitakset has mutagen and embriotoksichesky properties, causes decrease in reproductive function.

Pharmacokinetics. The pharmacokinetics of a paklitaksel was studied later in/in infusion of drug in doses of 135 mg/sq.m and 175 mg/sq.m during 3 and 24 h.

Distribution. Later in/in introductions concentration of a paklitaksel in a blood plasma decreases according to two-phase kinetics.

Average Vd makes from 198 to 688 l/sq.m. The pharmacokinetics of a paklitaksel with increase in a dose gains nonlinear character. At increase in a dose of drug by 30% (from 135 mg/sq.m to 175 mg/sq.m) Cmax and AUC0-values ∞ increased by 75% and 81% respectively.

At repeated courses of therapy instructions on cumulation of a paklitaksel were not received. Linkng with proteins averages 89%.

Metabolism. In the researches in vitro it was shown that paklitakset it is metabolized in a liver with participation of an isoenzyme of CYP2C8 with formation of a metabolite 6 - alpha гидроксипаклитаксел and with participation of an isoenzyme of CYP3A4 with formation of metabolites 3 - couple - gidroksipaklitaksel and 6 alpha, 3 - couple - digidroksipaklitaksel.

Removal. T1/2 and the general clearance of a paklitaksel are variable, depend on a dose and duration of introduction and make 13-52.7 h and 12.2-23.8 l/h/sq.m respectively

From 1.3% to 12,6% of the entered dose (15-275 mg/sq.m in the form of 1-, 6-or 24-hour infusion) drug it is allocated with urine in not changed look that indicates existence of intensive extrarenal clearance.

Pharmacokinetics in special clinical cases. Influence of a renal failure on metabolism of a paklitaksel was not investigated.

Dialysis does not exert impact on the speed of removal of drug from an organism.

Indications to use:

Ovarian cancer:

— therapy of 1 line in a combination with Cisplatinum at patients with widespread metastatic process or a residual tumor (more than 1 cm) after carrying out an initial laparotomy;

— therapy 2 lines at patients with widespread metastatic ovarian cancer after the standard therapy which did not lead to a positive take.

Breast cancer:

— adjuvant therapy at patients with existence of metastasises in lymph nodes after performing the standard combined treatment;

— therapy of 1 line of metastatic cancer and when progressing a disease after adjuvant therapy using drugs of an anthracycline row;

— therapy 2 lines when progressing a disease after the combined chemotherapy using antineoplastic antibiotics of an anthracycline row in the absence of contraindications for their use;

— adjuvant therapy for treatment of patients after therapy by drugs of an anthracycline row and cyclophosphamide;

— therapy of 1 line of a metastatic breast cancer in a combination with trastuzumaby at patients with level 3+ expression of HER-2 according to an immunohistochemical research and in the presence of contraindications to therapy by drugs of an anthracycline row.

Not small-celled cancer of a lung:

— as therapy of 1 line in a combination with Cisplatinum or for monotherapy of not small-celled cancer of lung at patients to whom performing surgical treatment and/or radiation therapy is not planned.

Kaposha's sarcoma at patients AIDS:

— as therapy 2 lines.

Route of administration and doses:

For the prevention of heavy hypersensitivity reactions before administration of the drug Taxol it is necessary to carry out premedication using GKS, blockers of histamine H1 receptors and blockers histamine H2 receptors. For example, dexamethasone (or its equivalent) in a dose of 20 mg inside approximately for 12 h and 6 h before administration of the drug Taxol or dexamethasone in a dose of 20 mg in/in approximately in 30-60 min. prior to administration of the drug Taxol, дифенгидрамин (or an equivalent) in a dose of 50 mg in/in and Cimetidinum in a dose of 300 mg or ranitidine in a dose of 50 mg in/in in 30-60 min. prior to administration of the drug Taxol.

Ovarian cancer. Therapy of 1 line: the recommended dose of the drug Taxol makes 175 mg/sq.m in a look in/in infusion during 3 h or 135 mg/sq.m in a look in/in infusion during 24 h with the subsequent introduction of Cisplatinum in a dose of 75 mg/sq.m; the interval between courses of treatment has to make 3 weeks.

Therapy 2 lines: in the monotherapy mode the dose of the drug Taxol makes 175 mg/sq.m in a look in/in infusion during 3 h each 3 weeks.

Breast cancer. Adjuvant therapy is carried out after a standard combination therapy. The dose of the drug Taxol makes 175 mg/sq.m in a look in/in infusion during 3 h. In total carrying out 4 courses of therapy with an interval of 3 weeks is recommended.

Therapy of 1 line. In the monotherapy mode: the dose of the drug Taxol makes 175 mg/sq.m in a look in/in infusion during 3 h each 3 weeks.

In the mode of a combination therapy:

- In a combination with trastuzumaby, the recommended dose of Taxol makes 175 mg/sq.m in a look in/in infusion during 3 h each 3 weeks. It is possible to begin Taxol use next day, after introduction of the first dose of a trastuzumab or, at good tolerance, in day of use of a trastuzumab.

- In a combination with doxorubicine (50 mg/m) Taxol each 3 weeks appoint in a dose 220 mg/sq.m in a look in/in infusion during 3 h. It is necessary to begin Taxol use in 24 hours after doxorubicine use.

Therapy 2 lines. For treatment of patients with the disseminated disease after the combined chemotherapy which did not yield a positive take of-175 mg/sq.m in a look in/in infusion during 3 h each 3 weeks.

Not small-celled lung cancer. In the mode of a combination therapy the recommended dose of the drug Taxol makes 175 mg/sq.m in a look in/in infusion during 3 h or 135 mg/sq.m in a look in/in infusion during 24 h with the subsequent introduction of Cisplatinum, the interval between courses makes 3 weeks;

- in the monotherapy mode the recommended dose of the drug Taxol makes from 175 mg/sq.m to 225 mg/sq.m in a look in/in infusion during 3 h each 3 weeks.

Kaposha's sarcoma at patients AIDS. At therapy 2 lines the recommended dose of the drug Taxol makes 135 mg/sq.m in a look in/in infusion during 3 h each 3 weeks or 100 mg/sq.m in/in kapelno during 3 h each 2 weeks.

Depending on the immunosuppression observed at patients with the developing AIDS form it is recommended:

1. to reduce a dexamethasone dose for intake (one of three components of premedication) to 10 mg;

2. to enter Taxol only at the maintenance of neutrophils not less 1000/mkl;

3. the patient with a heavy neutropenia (less 500/mkl within a week or more) at the subsequent courses to reduce a drug Taxol dose by 20%;

4. according to clinical indications at the same time to apply G-KSF.

Rules of preparation of solution for infusions. Before introduction a concentrate 5% solution of a dextrose, 5% dextrose solution in 0.9% solution of sodium of chloride or 5% dextrose solution in Ringer's solution dilute to concentration 0.3-1.2 mg/ml of 0.9% with solution of sodium of chloride.

Taxol should be entered through system with the built-in membrane filter with a size of time no more than 0.22 microns.

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 the drug Taxol it is necessary to use the equipment which does not contain details from polyvinylchloride.

Features of use:

Use at pregnancy and feeding by a breast. Taxol is contraindicated to use at pregnancy and in the period of a lactation (breastfeeding).

Patients of childbearing age during treatment with Taxol and, at least, within 3 months after the end of therapy should use reliable methods of contraception.

Use at abnormal liver functions. Change of metabolism of a paklitaksel at abnormal liver functions at three-hour injection formally was not investigated.

Use at renal failures. Change of metabolism of a paklitaksel at renal failures at three-hour injection formally was not investigated.

Use for children. Safety and efficiency of use of the drug Taksol® for children are not established.

Special instructions. The doctor having experience with antineoplastic chemotherapeutic drugs has to carry out by Taxol treatment.

At use of Taxol in combinations with Cisplatinum, at first it is necessary to enter Taxol, and then Cisplatinum.

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 case of development of heavy reactions of hypersensitivity injection of the drug Taxol it is necessary to stop and begin immediately a symptomatic treatment, and it is not necessary to administer the drug repeatedly.

In cases of development of disturbances of AV conductivity, at repeated introductions it is necessary to carry out continuous cardiomonitoring.

Taxol 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.

Influence on ability to driving of motor transport and to control of mechanisms. During treatment patients have to abstain from occupations potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Use in pediatrics. Safety and efficiency of use of the drug Taksol® for children are not established.

Side effects:

At use of a combination of the drug Taxol with drugs of platinum any essential changes of a profile of safety of drug in the clinical relation, in comparison with its use in the form of monotherapy were not noted.

At patients with sarcoma of Kaposha who developed against the background of AIDS arise more often and heavier oppression of a hemopoiesis, an infection (including opportunistic infections) and a febrile neutropenia proceed. The dose decline of drug and a maintenance therapy is required from these patients.

Determination of frequency of side effects: very often (≥1/10), it is frequent (≥1/100, <1/10), sometimes (≥1/1000, <1/100), is rare (≥1/10 000, <1/1000), is very rare (<1/10 000).

From system of a hemopoiesis: very often - a miyelosupressiya, a neutropenia, anemia, thrombocytopenia, a leukopenia, fever, bleedings; seldom - a febrile neutropenia; very seldom - an acute myeloid leukosis, a miyelodisplastichesky syndrome.

The neutropenia (90%) depending to a lesser extent on a dose of drug and in bigger - from infusion duration; the expressed neutropenia (less 500/mkl) is more often observed at 24-hour infusions, than at 3-hour approximately at a half of patients, at the same time at 1/3 it is followed by temperature increase; development of infectious complications (30%); at 1% of patients with diagnoses sepsis, pneumonia, peritonitis is registered a lethal outcome.

Thrombocytopenia (20%) with the maintenance of thrombocytes less than 100 000/mkl; the expressed thrombocytopenia with the minimum content of thrombocytes below 50 000/mkl (7%); anemia (78%); heavy anemia with hemoglobin less than 8 g/dl (16%).

Frequency and weight of anemia depended on an initial hemoglobin content and did not depend on a dose and the mode of administration of the drug Taxol.

Allergic reactions: very often - insignificant manifestations, generally in the form of feeling of heat ("inflows"), skin rash; sometimes - the expressed hypersensitivity reactions (decrease in the ABP, a Quincke's disease, tachycardia, breath dysfunction, a generalized small tortoiseshell), dorsodynias, a fever; seldom - anaphylactic reactions (including with a lethal outcome); very seldom - an acute anaphylaxis.

From cardiovascular system: very often - changes on an ECG, decrease in the ABP; often - bradycardia; sometimes - a cardiomyopathy, symptomless ventricular tachycardia, tachycardia with a bigeminal pulse, AV - blockade and a faint, a myocardial infarction, increase in the ABP, fibrinferments, tromboflefit; very seldom - atrial fibrillation, supraventricular tachycardia, shock.

From respiratory system: seldom - an asthma, a pleural exudate, respiratory insufficiency, intersticial pneumonia, a pneumosclerosis, an embolism of a pulmonary artery; very seldom - cough. More frequent development of a beam pneumonitis in the patients who are at the same time taking a course of radiation therapy is noted.

From TsNS and peripheral nervous system: very often - a peripheral touch neuropathy; seldom - a motive neuropathy (weakness of extremities); very seldom - the vegetative neuropathy which is shown paralytic impassability of intestines and orthostatic hypotension, attacks like grand mal, spasms, encephalopathy, dizziness, a headache, an ataxy.

From a musculoskeletal system: very often - an arthralgia, a mialgiya.

From the alimentary system: very often - nausea, vomiting, diarrhea, mukozit; often - substantial increase of level of nuclear heating plant, ShchF; sometimes - substantial increase of level of bilirubin; seldom - intestinal impassability, perforation of intestines, ischemic colitis, pancreatitis; very seldom - thrombosis of a mesenteric artery, pseudomembranous colitis, an esophagitis, a lock, ascites, гепатонекроз with a lethal outcome, hepatic encephalopathy with a lethal outcome.

From an urinary system: at patients with Kaposha's sarcoma and AIDS cases of a renal failure with reversible increases in level of serumal creatinine are described.

Dermatological reactions: very often - an alopecia; seldom - an itch, rash, an erythema, fibrosis, it is very rare - Stephens-Johnson's syndrome, an epidermal necrolysis, an exudative mnogoformny erythema, exfoliative dermatitis, a small tortoiseshell, онихолизис.

Local reactions: often - pain, hypostasis, an erythema, an induration and a xanthopathy in the place of an injection, it is rare - phlebitis, a skin peeling; the ekstravazation can cause an inflammation and a necrosis of hypodermic cellulose.

Others: anorexia, confusion of consciousness, adynamy and febricula.

Interaction with other medicines:

Cisplatinum reduces the general clearance of a paklitaksel by 33% (at the same time more expressed miyelosupressiya is observed in case paklitakset enter after Cisplatinum).

At use of Taxol in a combination with doxorubicine increase in concentration of doxorubicine (and its active metabolite of a doksorubitsinol) in a blood plasma is possible. At administration of the drug Taxol (infusion during 24 h) before administration of doxorubicine (infusion during 48 h) more expressed neutropenia and cases of stomatitis were observed. However at jet administration of doxorubicine and administration of the drug Taxol during 3 h any changes of nature of the toxic effects connected with the sequence of administration of drugs it was not noted.

Simultaneous use with Cimetidinum, ranitidine, dexamethasone or difengidraminy does not influence linkng of a paklitaksel with proteins of a blood plasma.

Metabolism of a paklitaksel is catalyzed by isoenzymes of CYP2C8 and CYP3A4 in this connection care at use of Taxol against the background of treatment is required by substrates, inductors (for example, rifampicin, carbamazepine, phenobarbital, Phenytoinum, эфавиренз, not Virapinum) or inhibitors (for example, erythromycin, fluoxetine, gemfibrozit) isoenzymes of CYP2C8 and CYP3A4.

In vitro inhibitors of a microsomal oxidation (including кетоконазол, verapamil, diazepam, quinidine, cyclosporine) in the concentration exceeding at use in therapeutic doses of in vivo and also testosterone, 17α-этинилэстрадиол, retinoic acid and meletin suppress metabolism of a paklitaksel.

Macrogoal глицерилрицинолеат, being a part of the drug Taxol, can cause extraction of DEGP [di - (2 ethylhexyl) phthalate] from the plasticized polyvinyl chloride containers, and extent of washing away of DEGP increases at increase in concentration of solution and over time.

Contraindications:

— 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 AIDS;
— the accompanying, serious, uncontrollable infections at patients with Kaposha's sarcoma;
— pregnancy;
— lactation (breastfeeding);
— hypersensitivity to drug components (including to the polyhydroxyethylated castor oil).

With care it is necessary to use drug at thrombocytopenia (less 100000/mkl), a liver failure, acute infectious diseases (including shingles, chicken pox, herpes), a heavy current of an ischemic heart disease, at a myocardial infarction (in the anamnesis), at arrhythmia.

Overdose:

Symptoms: marrow aplasia, peripheral neuropathy, mukozita.

Treatment: carry out symptomatic therapy. The specific antidote of a paklitaksel is unknown.

Storage conditions:

List B. It is necessary to store drug in the unavailable to children, protected from light place at a temperature from 15 ° to 30 °C. A period of validity - 2 years.

At storage of not opened bottles in the refrigerator drug can drop out in a deposit which is dissolved when warming a bottle to room temperature at insignificant stirring again (or without it). Quality of drug at the same time does not worsen. If drug in a bottle remains muddy or the insoluble deposit is observed, drug should be thrown out. Freezing does not influence quality of drug.

Weak solutions are stable during 27 h at storage at a temperature not above 25 °C and room lighting (taking into account infusion time).

The solutions received at cultivation of drug of 5% by dextrose solution are stable within 7 days; the solutions received by cultivation of 0.9% chloride sodium solution are stable within 14 days at storage at a temperature from 5 ° to 25 °C.

Weak solutions should not be stored in the refrigerator.

Issue conditions:

According to the recipe

Packaging:

16.7 ml - bottles of 20 ml (1) - packs cardboard.