Composition, form of production and packaging
Concentrate for the preparation of solution for infusions is transparent, colorless or slightly yellowish, viscous solution.
1 ml of 1 fl.
paclitaxel 6 mg 30 mg
[PRING] macrogol, glycerylricinoleate (cremophor В® EL), ethanol, nitrogen.
5 ml - vials in volume of 5 ml (1) - packs cardboard.
Concentrate for the preparation of solution for infusions is transparent, colorless or slightly yellowish, viscous solution.
1 ml of 1 fl.
paclitaxel 6 mg 100 mg
[PRING] macrogol, glycerylricinoleate (cremophor В® EL), ethanol, nitrogen.
16.7 ml - bottles of 20 ml (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2010.
PHARMACHOLOGIC EFFECT
Antitumor drug obtained by biosynthetic pathway. The mechanism of action is related to the ability to stimulate the "assembly" of microtubules from dimer tubulin molecules, to stabilize their structure by suppressing depolymerization, and to inhibit dynamic reorganization in the interphase, which disrupts the mitotic function of the cell.
In addition, paclitaxel induces the formation of abnormal clusters or "bundles" of microtubules throughout the cell cycle and causes the formation of multiple microtubule stars during mitosis.
Causes a dose-dependent suppression of bone marrow hematopoiesis.
In experimental studies, it was shown that paclitaxel has mutagenic and embryotoxic properties, causing a decrease in reproductive function.
PHARMACOKINETICS
The pharmacokinetics of paclitaxel were studied after intravenous infusion of the drug at doses of 135 mg / m 2 and 175 mg / m 2 for 3 and 24 hours.
Distribution
After intravenous administration, the concentration of paclitaxel in the blood plasma decreases in accordance with two-phase kinetics.
The average V d is between 198 and 688 l / m 2 .
The pharmacokinetics of paclitaxel with increasing doses acquires a nonlinear character. With an increase in the dose of the drug by 30% (from 135 mg / m 2 to 175 mg / m 2 ), the values ​​of C max and AUC 0-? increased by 75% and 81% respectively.
At repeated courses of therapy, no indication was given of the cumulation of paclitaxel.
The binding with proteins is on average 89%.
Metabolism
In vitro studies, it was shown that paclitaxel is metabolized in the liver with the participation of the CYP2C8 isoenzyme with the formation of the metabolite 6-alpha-hydroxypaclitaxel and with the participation of the CYP3A4 isoenzyme with the formation of metabolites of 3-para- hydroxypaclitaxel and 6-alpha, 3-para-dihydroxy paclitaxel.
Excretion
T 1/2 and total clearance of paclitaxel are variable, depend on the dose and duration of administration and are 13-52.7 h and 12.2-23.8 l / h / m 2, respectively
From 1.3% to 12.6% of the administered dose (15-275 mg / m 2 in the form of 1-, 6- or 24-hour infusion) the drug is excreted unchanged in the urine, which indicates the presence of an intensive extrarenal clearance.
Pharmacokinetics in special clinical cases
The effect of impaired renal function on the metabolism of paclitaxel has not been investigated.
Dialysis has no effect on the rate of excretion of the drug from the body.
INDICATIONS
Ovarian Cancer:
- 1 line therapy in combination with cisplatin in patients with a common metastatic process or residual tumor (more than 1 cm) after the initial laparotomy;
- Therapy of 2 lines in patients with advanced metastatic ovarian cancer after standard therapy, which did not lead to a positive result.
Mammary cancer:
- adjuvant therapy in patients with the presence of metastases in the lymph nodes after the standard combined treatment;
- therapy of 1 line of metastatic cancer and with progression of the disease after adjuvant therapy with the use of anthracycline drugs;
- 2 lines therapy for progression of the disease after combined chemotherapy with antitumor antibiotics of anthracycline series in the absence of contraindications for their use;
- adjuvant therapy for the treatment of patients after therapy with anthracycline drugs and cyclophosphamide;
- treatment of 1 line of metastatic breast cancer in combination with trastuzumab in patients with a level of 3+ HER-2 expression according to immunohistochemical data and in the presence of contraindications to therapy with anthracycline-based drugs.
Non-small cell lung cancer:
- as a first-line therapy in combination with cisplatin or for monotherapy of non-small cell lung cancer in patients who do not plan surgical treatment and / or radiation therapy.
Kaposi's sarcoma in AIDS patients:
- As a therapy, 2 lines.
DOSING MODE
To prevent severe hypersensitivity reactions prior to administration of Taxol, premedication should be performed using GCS, histamine H 1 -receptor blockers and histamine H 2 -receptor blockers. For example, dexamethasone (or its equivalent) at a dose of 20 mg orally for about 12 hours and 6 hours prior to administration of Taxol or dexamethasone 20 mg IV in about 30-60 minutes before administration of Taxol, diphenhydramine (or equivalent) in dose 50 mg IV and cimetidine 300 mg or ranitidine at a dose of 50 mg IV for 30-60 minutes before the administration of Taxol.
Ovarian Cancer
Line 1 therapy: The recommended dose of Taxol is 175 mg / m 2 as an IV infusion for 3 hours or 135 mg / m 2 as an IV infusion for 24 hours, followed by cisplatin at a dose of 75 mg / m 2 ; the interval between treatment courses should be 3 weeks.
Therapy of 2 lines: in the monotherapy regimen, the dose of the drug Taxol is 175 mg / m 2 as an IV infusion for 3 hours every 3 weeks.
Mammary cancer
Adjuvant therapy is performed after standard combination therapy. The dose of Taxol is 175 mg / m 2 as an IV infusion for 3 hours. In total, 4 courses of therapy are recommended with an interval of 3 weeks.
Therapy of 1 line
In monotherapy: the dose of the drug Taxol is 175 mg / m 2 as an IV infusion for 3 hours every 3 weeks.
In the mode of combined therapy:
- In combination with trastuzumab, the recommended dose of Taxol is 175 mg / m 2 in the form of an IV infusion for 3 hours every 3 weeks. You can start using Taxol the next day, after the first dose of trastuzumab or, with good tolerability, on the day of trastuzumab.
- In combination with doxorubicin (50 mg / m) Taxol is administered at a dose of 220 mg / m 2 as an IV infusion for 3 hours every 3 weeks. Begin the use of Taxol should be 24 hours after the use of doxorubicin.
Therapy 2 lines
For treatment of patients with disseminated disease after combined chemotherapy, which did not give a positive result -175 mg / m 2 in the form of IV infusion for 3 hours every 3 weeks.
Non-small cell lung cancer
- in the combined therapy, the recommended dose of Taxol is 175 mg / m 2 as an IV infusion for 3 hours or 135 mg / m 2 as an IV infusion for 24 hours followed by cisplatin, the interval between courses is 3 weeks;
- In the monotherapy regimen, the recommended dose of Taxol is 175 mg / m 2 to 225 mg / m 2 as an IV infusion for 3 hours every 3 weeks.
Kaposi's sarcoma in patients with AIDS
In 2-line therapy, the recommended dose of Taxol is 135 mg / m 2 as an IV infusion for 3 hours every 3 weeks or 100 mg / m 2 IV drip for 3 hours every 2 weeks.
Depending on the immunosuppression observed in patients with developing form of AIDS, it is recommended:
1. reduce the dose of dexamethasone for oral administration (one of the three components of premedication) to 10 mg;
2. Enter Taxol only if the neutrophil content is not less than 1000 / ОјL;
3. For patients with severe neutropenia (less than 500 / ОјL for a week or more), in subsequent courses, reduce the dose of Taxol by 20%;
4. Clinical indications simultaneously apply G-CSF.
Rules for the preparation of a solution for infusions
Before administration, the concentrate is diluted to a concentration of 0.3-1.2 mg / ml with 0.9% sodium chloride solution, 5% dextrose solution, 5% dextrose solution in 0.9% sodium chloride solution or 5% dextrose solution in Ringer's solution.
Taxol should be injected through a system with a built-in membrane filter with a pore size of not more than 0.22 microns.
The prepared solutions may be opalescent due to the carrier base present in the formulation, after which the opalescence of the solution is retained.
When preparing, storing and administering Taxol, you should use equipment that does not contain PVC parts.
SIDE EFFECT
When using the combination of Taxol with platinum preparations, there were no significant clinical changes in the safety profile of the drug compared to its use as monotherapy.
In patients with Kaposi's sarcoma that develops against AIDS, oppression of hematopoiesis, infections (including opportunistic infections) and febrile neutropenia occur more often and more severely. These patients require a reduction in the dose of the drug and maintenance therapy.
Determination of the frequency of side effects: very often (? 1/10), often (? 1/100, <1/10), sometimes (? 1/1000, <1/100), rarely (? 1/10 000, <1 / 1000), very rarely (<1/10 000).
From the hemopoietic system: very often - myelosuppression, neutropenia, anemia, thrombocytopenia, leukopenia, fever, bleeding; rarely - febrile neutropenia; very rarely - acute myeloid leukemia, myelodysplastic syndrome.
Neutropenia (90%), depending to a lesser extent on the dose of the drug and more on the duration of the infusion; Severe neutropenia (less than 500 / Ојl) is more frequent with 24-hour infusions than in 3-hour patients in about half of patients, while in 1/3 it is accompanied by an increase in temperature; development of infectious complications (30%); 1% of patients with diagnoses of sepsis, pneumonia, peritonitis have a lethal outcome.
Thrombocytopenia (20%) with a platelet count of less than 100,000 / ОјL; marked thrombocytopenia with a minimum platelet count below 50,000 / ОјL (7%); anemia (78%); severe anemia with hemoglobin less than 8 g / dL (16%).
The frequency and severity of anemia depended on the initial hemoglobin content and did not depend on the dose and mode of administration of Taxol.
Allergic reactions: very often - minor manifestations, mainly in the form of sensation of heat ("hot flashes"), skin rashes; sometimes - pronounced hypersensitivity reactions (decreased blood pressure, angioedema, tachycardia, respiratory failure, generalized urticaria), back pain, chills; rarely - anaphylactic reactions (including fatal); very rarely - anaphylactic shock.
From the cardiovascular system: very often - changes in the ECG, a decrease in blood pressure; often bradycardia; sometimes - cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with biigemia, AV - blockade and syncope, myocardial infarction, increased blood pressure, thrombosis, thrombophlebitis; very rarely - atrial fibrillation, supraventricular tachycardia, shock.
On the part of the respiratory system: rarely - shortness of breath, pleural effusion, respiratory failure, interstitial pneumonia, pulmonary fibrosis, pulmonary embolism; very rarely - cough. The more frequent development of radiation pneumonitis in patients who are simultaneously undergoing radiotherapy is noted.
From the side of the central nervous system and peripheral nervous system: very often - peripheral sensory neuropathy; rarely - motor neuropathy (weakness of the limbs); very rarely - vegetative neuropathy, manifested by paralytic intestinal obstruction and orthostatic hypotension, seizures such as grand mal, convulsions, encephalopathy, dizziness, headache, ataxia.
From the osteomuscular system: very often - arthralgia, myalgia.
From the digestive system: very often - nausea, vomiting, diarrhea, mucositis; often - a significant increase in the level of AST, APF; sometimes - a significant increase in the level of bilirubin; rarely - intestinal obstruction, intestinal perforation, ischemic colitis, pancreatitis; very rarely - thrombosis of the mesenteric artery, pseudomembranous colitis, esophagitis, constipation, ascites, hepatonecrosis with fatal outcome, hepatic encephalopathy with lethal outcome.
From the side of the urinary system: in patients with Kaposi's sarcoma and AIDS, cases of renal dysfunction with reversible increases in serum creatinine levels have been described.
Dermatological reactions: very often - alopecia; rarely - itching, rash, erythema, fibrosis, very rarely - Stevens-Johnson syndrome, epidermal necrolysis, exudative erythema multiforme, exfoliative dermatitis, urticaria, onycholysis.
Local reactions: often - pain, swelling, erythema, induration and pigmentation of the skin at the injection site, rarely - phlebitis, skin peeling; Extravasation can cause inflammation and necrosis of subcutaneous tissue.
Other: anorexia, confusion, asthenia and general malaise.
CONTRAINDICATIONS
- initial neutrophil count less than 1500 / ОјL in patients with solid tumors;
- initial (or registered in the treatment) neutrophil count less than 1000 / Ојl in patients with Kaposi's sarcoma in AIDS patients;
- Concomitant, serious, uncontrolled infections in patients with Kaposi's sarcoma;
- Pregnancy;
- lactation (breastfeeding);
- Hypersensitivity to the components of the drug (including polyoxyethylated castor oil).
With caution should be used in patients with thrombocytopenia (less than 100,000 / Ојl), liver failure, acute infectious diseases (including herpes zoster, chicken pox, herpes), severe coronary heart disease, myocardial infarction (history), arrhythmia .
PREGNANCY AND LACTATION
Taxol is contraindicated for use in pregnancy and lactation (breastfeeding).
Patients of childbearing age during treatment with Taxol and at least 3 months after the end of therapy should use reliable methods of contraception.
APPLICATION FOR FUNCTIONS OF THE LIVER
Changes in the metabolism of paclitaxel in cases of impaired renal function with a three-hour infusion were not formally investigated.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Changes in the metabolism of paclitaxel for violations of liver function with a three-hour infusion were not formally investigated.
APPLICATION FOR CHILDREN
Safety and efficacy of Taxol В® in children have not been established.
SPECIAL INSTRUCTIONS
Treatment Taxol should be carried out by a doctor who has experience working with antitumor chemotherapeutic drugs.
When Taxol is used in combination with cisplatin, Taxol should first be administered, followed by cisplatin.
During treatment, it is necessary to regularly monitor the picture of peripheral blood, blood pressure, heart rate and the number of breaths (especially during the first hour of infusion), ECG control (and before treatment).
In case of severe hypersensitivity reactions, the infusion of Taxol should be stopped immediately and symptomatic treatment started, and the drug should not be re-administered.
In cases of development of violations of AV-conduction, with repeated administration it is necessary to conduct continuous cardiomonitoring.
Taxol is a cytotoxic substance that should be used with care, use gloves and avoid contact with skin or mucous membranes, which in such cases must be thoroughly washed with soap and water or (eyes) with plenty of water.
Impact on the ability to drive vehicles and manage mechanisms
During the treatment period, patients should refrain from engaging in potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions.
Use in Pediatrics
Safety and efficacy of Taxol В® in children have not been established.
OVERDOSE
Symptoms: bone marrow aplasia, peripheral neuropathy, mucositis.
Treatment: conduct symptomatic therapy. The specific antidote of paclitaxel is unknown.
DRUG INTERACTION
Cisplatin reduces the total clearance of paclitaxel by 33% (with more pronounced myelosuppression observed when paclitaxel is administered after cisplatin).
When Taxol is used in combination with doxorubicin, an increase in the concentration of doxorubicin (and its active metabolite of doxorubicinol) in blood plasma is possible. With the introduction of Taxol (infusion for 24 hours) before the administration of doxorubicin (infusion for 48 hours), more severe neutropenia and cases of stomatitis were observed. However, with jet administration of doxorubicin and administration of Taxol preparation for 3 h, no changes in the nature of the toxic effects associated with the sequence of drug administration were noted.
Simultaneous use with cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the binding of paclitaxel to blood plasma proteins.
The metabolism of paclitaxel is catalyzed by the isoenzymes CYP2C8 and CYP3A4, and caution is required when using Taxol against the background of treatment with substrates, inducers (eg, rifampicin, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine) or inhibitors (eg erythromycin, fluoxetine, gemfibrozil) isoenzymes CYP2C8 and CYP3A4.
In vitro inhibitors of microsomal oxidation (including ketoconazole, verapamil, diazepam, quinidine, cyclosporine) in concentrations higher than those used in therapeutic doses in vivo, as well as testosterone, 17? -ethynylestradiol, retinoic acid and quercetin inhibit paclitaxel metabolism.
Macrogol glycerylricinoleate, which is a part of the Taxol preparation, can cause extraction of DEHP [di- (2-ethylhexyl) phthalate] from plasticized polyvinyl chloride containers, the degree of leaching of the DEHP increases with increasing solution concentration and with time.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
List B. The drug should be kept out of the reach of children, protected from light at a temperature of from 15 В° to 30 В° C. Shelf life - 2 years.
When stored in a refrigerator unopened vials drug may precipitate which redissolves at a vial warming to room temperature with slight agitation (or without it). The quality of the drug will not be degraded. If the drug vial is cloudy or there is an insoluble precipitate, the preparation should be discarded. Freezing does not affect the quality of the drug.
Dilute solutions are stable for 27 hours if stored at a temperature not higher than 25 В° C and room lighting (with the infusion time).
The solutions obtained by dilution of the preparation is 5% dextrose solution, are stable for 7 days; solutions obtained by diluting 0.9% sodium chloride solution, stable for 14 days when stored at temperatures from 5 В° to 25 В° C.
Dilute solutions should not be stored in the refrigerator.
