Paclitaxel

When ATH:
L01CD01

Characteristic.

The antitumor agent of plant origin. Alkaloid, isolated from the bark of the yew tree (Taxus brevifolia), prepared as semisynthetic and synthetic by. White or almost white crystalline powder. Insoluble in water. The highly lipophilic. Melts at a temperature of 216-217° c. Molecular weight 853,9.

Pharmacological action.
Antitumor.

Application.

Ovarian Cancer, mammary cancer, non-small cell lung cancer, squamous head and neck cancer, perehodnokletochny bladder cancer, esophageal carcinoma, leukemia, Kaposi's sarcoma in AIDS patients.

Contraindications.

Hypersensitivity (incl. a polyoxyethylated castor oil), выраженная нейтропения — менее 1,5·10⁹/l (original or evolved in the course of treatment), у больных с саркомой Капоши — нейтропения менее 1,0·10⁹/l (original or evolved in the course of treatment).

Restrictions apply.

Thrombocytopenia (менее 100·10⁹/l), hepatic failure, viral infections (incl. enable vetryanaya, herpes zoster), inhibition of bone marrow hematopoiesis after prior chemotherapy- or radiotherapy, heart disorders (incl. CHD, myocardial infarction, cardiac conduction disturbances), childhood (safety and effectiveness in children have not identified).

Pregnancy and breast-feeding.

Contraindicated in pregnancy (possible embryo- and foetotoxic effects).

Category actions result in FDA - D. (There is evidence of the risk of adverse effects of drugs on the human fetus, obtained in research or practice, However, the potential benefits, associated with drugs in pregnant, may justify its use, in spite of the possible risk, if the drug is needed in life-threatening situations or severe disease, when safer agents should not be used or are ineffective.)

At the time of treatment should stop breastfeeding (unknown, Whether paclitaxel penetrates into breast milk).

Side effects.

In the combined data 10 research, involving 812 patients (493 -ovarian cancer, 319 - Mammary cancer), using different doses and different duration were observed following administration of paclitaxel side effects.

Hematologic: нейтропения менее 2·10⁹/l (90%), нейтропения менее 0,5·10⁹/l (52%), leukopenia less than 4 10⁹/l (90%), leukopenia less than 1 10⁹/l (17%), thrombocytopenia less than 100 10⁹/l (20%), thrombocytopenia less than 50 10⁹/l (7%), anemia is a hemoglobin level of less than 110 g / l (78%), anemia is a hemoglobin level of less than 80 g / l (16%).

Suppression of bone marrow function (mainly neutropenia) It is a major toxic effect, limiting the dose of paclitaxel.

Neutropenia depended less on dosage and more — from the length of the introduction (more pronounced in the 24-hour infusion). The lowest level of neutrophils is usually marked on the 8-11 day of treatment, normalization comes on 22 day. The temperature rise observed in 12% patients, infectious complications — 30% patients. Lethal outcome was registered in 1% Patients diagnosed with sepsis, pneumonia and peritonitis. The most common infections, associated neutropenia, They are urinary and upper respiratory tract.

With the development of thrombocytopenia lowest level of platelets is usually marked on the 8-9 day of treatment. Bleeding (14% cases) were local, the frequency of their occurrence was not related to the dose and time of administration.

The frequency and severity of anemia is not dependent on the dose and mode of administration of paclitaxel. Red blood cell transfusions needed 25% patients, transfusion of thrombocyte mass — 2% patients.

In patients with Kaposi's sarcoma, developed against AIDS, inhibition of bone marrow hematopoiesis, febrile neutropenia and infection can occur more frequently and be more severe.

Hypersensitivity reactions. The frequency and severity of hypersensitivity reactions are not dependent on the dose or schedule of administration of paclitaxel. All patients in the clinical trials conducted before the introduction of paclitaxel adequate premedication. Hypersensitivity reactions have been observed in 41% patients and mainly manifested as flares (28%), rash (12%), hypotension (4%), shortness of breath (2%), tachycardia (2%) and hypertension (1%). Severe hypersensitivity reactions, that require therapeutic intervention (breathlessness, requiring the use of expanding tools, hypotension, requiring therapeutic intervention, angioedema, generalized urticaria) observed in 2% cases. Probably, These reactions are histamine-indirect. In the case of severe hypersensitivity infusion reactions should cease immediately and start a symptomatic treatment, and enter the drug again should not be.

Cardiovascular. Hypotension (12%, n = 532) or hypertension and bradycardia (3%, n = 537) were observed during injection. IN 1% cases experienced severe side effects, that included fainting, heart rhythm disturbances (asymptomatic ventricular tachycardia, bigeminia and full AV blockade and fainting), hypertension and venous thrombosis. One patient with sinkope when the 24-hour infusion of paclitaxel at a dose 175 mg / m² developed progressive hypotension with fatal.

In clinical trials also deviated on ECG (23%). In most cases, there has not been any clear link between the use of paclitaxel and ECG changes, the changes were not clinically significant or had minimal clinical significance. In 14% patients with normal ECG parameters prior to inclusion in the study deviated on ECG, arising during treatment.

Neurologic. The frequency and severity of neurological signs were doses, but they did not influence the duration of infusion. Peripheral neuropathy, mainly manifested in the form of paresthesias, I observed in 60% patients, in its severe form- 3% patients, in 1% the cases led to the drug. Frequency of peripheral neuropathy has increased with increasing total dose of paclitaxel. Symptoms usually appear after repeated use and weaken or disappear within a few months after the end of treatment. Previous neuropathy due to previously conducted treatment is not a contraindication for paclitaxel therapy.

Other serious neurological disorders, observed after introduction of paclitaxel (less 1% cases): seizures type grand mal, ataxia, encephalopathy. There are reports of neuropathy at the level of autonomic nervous system, that led to paralysis bowel obstruction.

Arthralgia/myalgia were observed in 60% sick and had severe at 8% patients. Usually symptoms of transient character wore, appeared through 2-3 days after injection of paclitaxel and passed within a few days.

Gepatotoksichnostь. Increasing the level of AST, alkaline phosphatase and bilirubin in serum observed in 19% (n = 591), 22% (n = 575) and 7% (n = 765) patients, respectively. Cases of liver necrosis and encephalopathy hepatic origin fatal.

Gastrointestinal. Nausea, vomiting, diarrhoea and mucositis were observed in 52, 38 and 31% patients, respectively, and wore light or moderate. Mucositis was observed more frequently with the 24-hour infusion, than 3-hour. Besides, observed phenomena obstruction or perforation of the bowel, nejtropenicheskogo enterocolitis (tiflita), bryzheechnoj artery thrombosis (including ischemic colitis).

Reaction at the site in/in the injection (13%): local swelling, pain, эritema, induration. These reactions can be observed after 24-hour infusion, than after 3-hour. Currently any specific form of treatment responses, associated with drug jekstravazaciej, unknown. There are reports on the development of phlebitis and cellulite with the introduction of paclitaxel.

Other toxicities. Reversible alopecia was observed at 87% patients. Complete hair loss almost all patients between 14-21 day therapy. Met pigmentation or discoloration of the nail bed (2%). There were also transient skin change due to hypersensitivity to paklitakselu. About oteke reported at 21% patients, incl. in 1% — expressly, but these cases were not the cause of the drug. In most cases, the swelling was caused by disease and case. There have been reports of recidivist skin reactions, associated with radiation.

Cooperation.

According to clinical studies, with the introduction of paclitaxel after cisplatin infusion was observed more expressed mielosuprescia and reduced clearance of paclitaxel by approximately 33% compared to the reverse sequence introduction (before cisplatin, paclitaxel). The studies in vitro ketoconazole inhibits the biotransformation of paclitaxel.

Overdose.

Symptoms: mielosuprescia, peripheral neurotoxicity, mukozit.

Treatment: symptomatic. Spetsificheskiy antidote unknown.

Dosing and Administration.

B /, as a 3-hour or 24-hour infusion (immediately before the introduction of the drug dilute to concentrations of 0.3-1.2 mg/ml of relevant solutions). The mode set individually, depending on the evidence, carried out by earlier chemotherapy (or lack thereof), the state of the hematopoietic system, regimens.

Precautions.

Treatment should be performed by a doctor, with experience of chemotherapy, and if the conditions, needed for the relief of complications. Required constant monitoring of peripheral blood, FROM, HEART RATE and other parameters of the vital functions (especially when the primary infusion or during the first hours of the introduction).

When using paclitaxel in combination with cisplatin, paclitaxel you should enter, then cisplatin.

In order to avoid the development of heavy gipercuvstvenosti reactions (and to improve endurance) before infuziei all patients should be premedikatia using glucocorticoids, antihistamines and blockers gistaminovykh H₂-receptors; the approximate scheme: Dexamethasone (or equivalent) - 20 mg inside or/m for 6-12 hours prior to the introduction of paclitaxel, difengidramin (or equivalent) - 50 mg in/in and zimetidin- 300 mg (or ranitidine — 50 mg) in/in the 30-60 min before the introduction. If you experience severe allergic reactions during the infusion introduction immediately cease and simptomaticescuu therapy.

При развитии нейтропении больным не следует вновь назначать препарат до восстановления содержания нейтрофилов до уровня не менее 1,5·10⁹/л и не менее 1·10⁹/l when Kaposi Sarcoma (cm. "Contra"). While developing as a result of the infusion of paclitaxel heavy nejropaticheskih peripheral violations or expressed neutropenia (менее 0,5·10⁹/l), incl. lasting 7 days or more, or with infectious complications, If necessary, remedial courses dose reduction is recommended in 20%.

When you are prompted during treatment paclitaxel significant violations conductivity heart, you must assign the appropriate treatment, and the subsequent introduction of the drug should be continuous monitoring of the heart.

During the period of treatment is shown to refrain from activities potentially hazardous activities, require high concentration and speed of psychomotor reactions.

During the treatment it is recommended to use adequate methods of contraception.

Cautions.

When working with paclitaxel, as working with other anticancer drugs, Care must be taken. Preparation of solutions should be left to trained personnel in specially designed for this zone with the protection (gloves, masks, etc.). In case of contact with skin or mucous membrane must be thoroughly rinsed with water the mucous membranes, and skin - with soap and water.

When cooking, storage and the introduction of paclitaxel should use equipment, that contains no PVC parts.

Cooperation