Expiration date: 01/2025
Composition
Concentrate for preparation of solution for infusions of 1 ml
active substance: paclitaxel 6 mg
macrogol glycerrizinic (Cremophor® EL) 527 mg; ethanol 396 mg; nitrogen
Description of dosage form
Transparent colorless or slightly yellowish non-aqueous viscous solution. Before/in the drug is diluted with an appropriate solution for parenteral use.
Pharmacological action
The drugs — anticancer, antitumoral
Pharmacodynamics
It stimulates the Assembly of microtubules from tubulin dimers and stabilizes microtubules by suppressing depolymerization, which disrupts the normal process of dynamic reorganization of the microtubule network, which is important for cell functions at the stage of mitosis and interphase of the cell cycle. Induces the formation of abnormal clusters or" ligaments "of microtubules throughout the cell cycle and causes the formation of multiple" stars " of microtubules during mitosis.
Pharmacokinetics
The concentration of paclitaxel in the blood plasma after/in the reduced in accordance with the two-phase kinetics.
Pharmacokinetics of paclitaxel was determined after drug infusion at doses of 135 and 175 mg/m2 over 3 and 24 h During infusion for 3 h pharmacokinetics with increasing doses acquired non-linear. With an increase in dose by 30% (from 135 to 175 mg/m2 ) Cmax and AUC0-? increased by 75 and 81%, respectively.
When multiple courses of the treatment was not given directions to the accumulation of paclitaxel.
Studies in vitro show that 89-98% of the drug is in a bound state. Cimetidine, ranitidine, dexamethasone or diphenhydramine do not affect the binding of paclitaxel to proteins.
Metabolism in humans is not fully investigated. From 1.3 to 12.6% of the administered dose of the drug is excreted in the urine unchanged. T1/2 is 3-52,7 h. the Main metabolic products are hydroxylated metabolites. Perhaps the main mechanism of metabolism is biotransformation in the liver and excretion of bile. The effect of impaired renal or liver function on the metabolism of paclitaxel in the body after a three-hour infusion was not formally investigated. Pharmacokinetic parameters obtained in one patient indicate that dialysis has no effect on the rate of excretion of the drug from the body.
The testimony of the drug Taxol®
Ovarian cancer: therapy of the 1st line (in combination with cisplatin) in patients with a common metastatic process or residual tumor (more than 1 cm) after laparotomy and therapy of the 2nd line in patients with advanced metastatic ovarian cancer after standard therapy, which did not give a positive result.
Breast cancer: adjuvant therapy in patients with lymph node metastases after standard combined treatment;
therapy of the 1st line of metastatic cancer and the progression of the disease after adjuvant therapy with anthracycline drugs; therapy of the 2nd line with the progression of the disease after combined chemotherapy with the use of antitumor antibiotics of the anthracycline series.
Non-small cell lung cancer: 1st line therapy in combination with cisplatin or monotherapy for patients who are not planned for surgical treatment and/or radiation therapy with the possibility of cure.
Kaposi's sarcoma in AIDS patients: 2nd line therapy.
Contraindications
Severe hypersensitivity reactions to paclitaxel or any other component of the drug, especially polyoxyethylated castor oil; during pregnancy and lactation, in patients with solid tumors with an initial neutrophil content of less than 1500/mm3, as well as in patients with Kaposi's sarcoma developed against the background of AIDS, with an initial (or registered during treatment) neutrophil content of less than 1000/mm3.
Side effect
When using a combination of Taxol with platinum preparations, there were no significant clinically significant changes in the safety profile of the drug compared to its use in the form of monotherapy.
Bone marrow hematopoiesis: suppression of bone marrow function was the main toxic effect limiting the dose of Taxol.
Neutropenia, depending to a lesser extent on the dose and more-on the duration of infusion, observed in 90% of patients. Pronounced neutropenia (less than <500 cells/mm3 blood) — approximately half of the patients, with a third it is accompanied by an increase in temperature. Infectious complications were observed in 30% of patients. Lethal outcome was registered in 1% of patients with diagnoses of sepsis, pneumonia and peritonitis.
Thrombocytopenia was recorded in 20% of patients. In 7% of patients, the minimum platelet count was reduced to less than 50,000 / mm3 of blood.
Anemia was observed in 78% of patients, but was severe (hemoglobin less than 8 g/DL) only in 16% of patients. The frequency and severity of anemia depended on the initial level of hemoglobin and did not depend on the dose and mode of administration of the drug paclitaxel.
In patients with Kaposi's sarcoma, developed against the background of AIDS, oppression of bone marrow hematopoiesis, infections and febrile neutropenia may occur more often and have a more severe course. Therefore, such patients require lower doses and maintenance therapy.
Hypersensitivity reactions: the frequency and severity of hypersensitivity reactions did not depend on the dose or mode of administration of the drug. Severe hypersensitivity reactions-hypotension requiring therapeutic intervention, angioedema, respiratory dysfunction requiring the use of bronchodilators, or generalized urticaria — were observed in less than 1% of cases. In 41% of patients there were minor hypersensitivity reactions, mainly manifested in the form of tides of blood to the face, rash, hypotension, shortness of breath, tachycardia and hypertension, which did not require therapeutic intervention and did not interfere with the continuation of treatment with paclitaxel. Isolated cases of chills and back pain were reported, which were also attributed to hypersensitivity reactions.
From the cardiovascular system: hypotension or hypertension and bradycardia are usually noted during the administration of the drug. The severity of these symptoms was usually insignificant, therapeutic intervention was not required. During the first hour of paclitaxel infusion is recommended frequent monitoring of the vital functions of the body. Clinical trials also showed abnormalities in the ECG. In most cases, there was no clear link between paclitaxel administration and ECG changes, and these changes were either not clinically significant or had minimal clinical significance. In one patient (less than 1%) during treatment with paclitaxel, arterial hypertension was registered. In addition, two patients (less than 1%) had serious thrombotic episodes (upper limb thrombosis and thrombophlebitis). Clinically significant disorders of the cardiovascular system (hypotension against septic shock, cardiomyopathy and tachycardia against fever) were observed in less than 1% of patients. In the early stages of clinical trials, conducted with different dosages and infusion schemes of the drug, 2% of patients had severe side effects from the cardiovascular system, probably associated with paclitaxel, including asymptomatic ventricular tachycardia, tachycardia in combination with bigeminia, AV blockade and fainting.
Respiratory system: in rare cases, interstitial pneumonia, pulmonary fibrosis and pulmonary embolism were reported, as well as radiation pneumonitis in patients undergoing simultaneous radiation therapy.
From the nervous system: peripheral neuropathy, mainly manifested in the form of paresthesia, was observed in 60% of patients, in severe form — in 3% of patients, and only in 1% of cases was the cause of drug withdrawal. The frequency of peripheral neuropathy increased with the increase of the total dose of paclitaxel. Sensory symptoms usually improved or resolved within a few months after discontinuation of treatment. Previous neuropathies due to previous treatment are not a contraindication for the treatment of paclitaxel.
Grand mal seizures, changes in vision, ataxia, encephalopathy, neuropathy at the level of the autonomic nervous system, leading to paralytic intestinal obstruction and orthostatic hypotension were reported.
From the musculoskeletal system: arthralgia or myalgia were observed in 60% of patients and were severe in 8% of patients. Usually symptoms were transient in nature, appeared 2-3 days after administration of the drug Taxol® and stopped for several days.
From the gastrointestinal tract: nausea, vomiting/diarrhea and mucositis were observed in 52, 38 and 31% of patients, respectively, and were mild or moderate. In addition, there were phenomena of obstruction or perforation of the intestine, neutropenic enterocolitis (tiflitis), mesenteric artery thrombosis (including ischemic colitis).
On the part of liver function: an increase in AST, alkaline phosphatase and bilirubin values in serum was observed in 19, 22 and 7% of patients, respectively. Cases of liver necrosis and encephalopathy of hepatic origin are described.
From the genitourinary system: five patients with Kaposi's sarcoma in the treatment of Taxol® developed the phenomenon of renal toxicity III or IV severity. One patient suspected of HIV-associated nephropathy grade IV required discontinuation of treatment. Other patients had renal insufficiency with reversible increases in serum creatinine.
Reactions at the injection site: possible local swelling, pain, erythema, induration; occasional extravasation can cause cellulite. Skin pigmentation may also occur. Currently, any specific forms of treatment of reactions associated with extravasation of the drug are unknown.
From the skin: alopecia was observed in almost all patients. Pigmentation disorders or discoloration of the nail bed were rare (2%). Transient skin changes were observed due to increased sensitivity to paclitaxel, maculopapular rash and itching.
Other adverse reactions: asthenia and General malaise.
Interaction
Cimetidine premedication does not affect the clearance of paclitaxel. According to clinical studies, a more pronounced myelosuppression and a decrease in the clearance of paclitaxel by about 33% were observed when the drug Taxol® was administered after cisplatin compared with the reverse sequence of administration (Taxol® before cisplatin).
The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised while using the drug Taxol® and known substrates or inhibitors of these isoenzymes. It has been shown that the metabolism of paclitaxel in vitro is suppressed by drugs such as ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporine, teniposide, etoposide and vincristine. However, the concentrations used in the experiments were higher than those found in vivo after administration of normal therapeutic doses. Testosterone, 17alpha-ethinyl estradiol, retinoic acid and quercetin, a specific CYP2C8 inhibitor — also suppressed the formation of 6alpha-hydroxypaclitaxel in vitro. As a result of interaction with substrates, inducers or inhibitors of CYP2C8 and/or CYP3A4, the pharmacokinetics of paclitaxel in vivo can also be changed.
When using paclitaxel in combination with doxorubicin, side effects associated with the sequence of administration of these drugs were noted. When the first drug Taxol® (Taxol® was administered within 24 hours, doxorubicin-within 48 hours) observed more pronounced neutropenia and cases of stomatitis. When using Taxol® in combination with doxorubicin may increase the content of doxorubicin (and its active metabolite doxorubicinol) in serum. However, the jet administration of doxorubicin and the introduction of the drug Taxol® for 3 hours any changes in the nature of the toxic effects associated with the sequence of administration of drugs was not noted.
Dosage and administration
intravenously, drip.
To prevent severe hypersensitivity reactions, all patients should be sedated using GCS, H1 - and H2-histamine receptor blockers. For example, 20 mg of dexamethasone (or its equivalent) orally approximately 12 and 6 hours before administration of the drug Taxol® or 20 mg of dexamethasone/about 30-60 min before administration of the drug Taxol®, 50 mg diphenhydramine (or its equivalent) I/o, and 300 mg cimetidine or 50 mg ranitidine/in 30-60 min. before administration of the drug Taxol®.
Patients with solid tumors repeated courses of treatment with Taxol® are prescribed only after reaching the neutrophil content of 1500 / µl (1000/µl in patients with Kaposi's sarcoma due to AIDS), and the platelet content — 100 000/µl. For patients who have developed severe neutropenia (the number of neutrophils was less than 500/µl for more than one week) or with severe peripheral neuropathy in subsequent courses of treatment with Taxol® should reduce the dose by 20%. Neurotoxicity and neutropenia are dose-dependent.
When choosing the mode and doses in each individual case should be guided by the data of the literature.
Ovarian cancer:
First-line therapy: the recommended dose of Taxol® is 175 mg / m2 by 3-hour in / infusion or 135 mg / m2 by 24-hour infusion followed by the introduction of the drug platinum, the interval between courses of treatment should be 3 weeks.
Second-line therapy: monotherapy at a dose of 175 mg / m2 as a 3-hour in / infusion every 3 weeks.
Breast cancer:
Adjuvant therapy is performed after standard combined treatment. Taxol® is administered at a dose of 175 mg / m2 as a 3-hour in / infusion. In total, it is recommended to conduct 4 courses of therapy with an interval of 3 weeks.
First-line therapy:
monotherapy: 175 mg / m2 as a 3-hour in / infusion every 3 weeks;
combination therapy: when using the drug in combination with trastuzumab, the recommended dose of Taxol® is 175 mg/m2 in the form of a 3-hour in / infusion every 3 weeks. To begin the use of Taxol® can be the next day, after the first dose of the patient trastuzumab or, with good tolerance, on the day of trastuzumab; when using the drug in combination with doxorubicin (50 mg / m2) Taxol® is used at a dose of 220 mg/m2 in the form of 3-hour in/infusion every 3 weeks. Start using Taxol ® should be 24 hours after the use of doxorubicin.
Second-line therapy 175 mg / m2 in the form of 3-hour in / infusion every 3 weeks.
Non-small cell lung cancer:
In the mode of combination therapy, the recommended dose of the drug is 175 mg/m2 by 3-hour in/infusion or 135 mg / m2 by 24-hour infusion followed by the introduction of platinum, the interval between courses of treatment should be 3 weeks.
In the mode of monotherapy, the recommended dose of the drug is from 175 mg/m2 to 225 mg/m2 in the form of a 3-hour in / infusion every 3 weeks.
Kaposi's sarcoma in AIDS patients:
Second-line therapy-the recommended dose of Taxol® is 135 mg/m2 in the form of a 3-hour in/infusion every 3 weeks or 100 mg/m2 in / drip for 3 hours every 2 weeks.
Depending on the level of immunosuppression observed in patients with advanced form of AIDS, it is recommended:
- reduce the oral dose of dexamethasone (one of the three components of premedication) to 10 mg;
- enter Taxol® only if the content of neutrophils is not less than 1000 cells / µl of blood;
- patients with severe neutropenia (less than 500 cells / µl blood for a week or more) in subsequent courses to reduce the dose of Taxol® 20%;
- according to clinical indications at the same time to use hematopoietic growth factor (G-CSF).
Application in violation of liver function
Patients with liver failure and associated increased risk of toxicity (in particular, myelosuppression III–IV) recommended dose adjustment Taxol®.
It is necessary to establish careful monitoring of the condition of patients.
Rules of preparation of solution for infusions
The solution of the drug is prepared by diluting the concentrate to the final concentration of paclitaxel from 0.3 to 1.2 mg / ml.as a diluting solution can be used: 0.9% sodium chloride solution, 5% dextrose solution, 5% dextrose solution in 0.9% sodium chloride solution, 5% dextrose solution in ringer solution. The prepared solutions can opalestiruty due to the presence in the composition of the dosage form the foundations of the carrier, and after filtration opalescence of the solution is preserved.
In the preparation, storage and administration of the drug Taxol® should use equipment that does not contain PVC parts.
Taxol® should be administered through a system with a built-in membrane filter (pore size-no more than 0.22 MK).
Overdose
Symptoms: bone marrow suppression, peripheral neurotoxicity, mucositis.
Antidotes for use in case of an overdose of Taxol® are unknown.
Precautionary measures
Taxol® should be administered through a system with a built-in membrane filter (pore size less than 0.22 microns). During the simulated injection of the solution through the I / V tube with a built-in filter, no noticeable loss of activity was observed.
Taxol® should be used under the guidance of a doctor with experience in the use of anticancer chemotherapy drugs.
When using Taxol® in combination with cisplatin, Taxol® should be administered first, and then cisplatin.
Severe hypersensitivity reactions characterized by shortness of breath, hypotension (requiring therapeutic measures), angioedema and generalized urticaria were observed in approximately 2% of patients treated with Taxol® after adequate premedication. These symptoms are probably histamine-mediated reactions. In the case of severe hypersensitivity reactions infusion should immediately stop and start symptomatic treatment, and re-enter Taxol ® unacceptable.
Suppression of bone marrow function (mainly neutropenia) is a toxic effect that limits the dose of the drug. During treatment with the drug, it is necessary to determine the content of blood elements in the form in a short period of time. Patients should not re-prescribe the drug until the neutrophil content is restored to a level of not less than 1500/mm3 of blood (not less than 1000/mm3 of blood with Kaposi's sarcoma). With the development of severe neutropenia (less than 500/mm3 blood) dose Taxol® in subsequent courses is recommended to reduce by 20%.
Severe cardiac conduction disorders were rare. When they appear in the course of treatment with Taxol®, appropriate treatment should be prescribed, and with subsequent administration of the drug, continuous monitoring of heart functions should be carried out. The rest of the patients are recommended to monitor the vital functions of the body during the first hour of administration of Taxol®.
Peripheral neuropathy develops frequently and is usually moderate. In cases of severe peripheral neuropathy in subsequent courses of treatment, the dose of Taxol® is recommended to be reduced by 20%.
Safety and effectiveness of Taxol® in children has not been established.
Special instruction
When working with Taxol, as with other anticancer drugs, care must be taken. Preparation of solutions for infusion should be carried out by trained personnel in a specially designated area in compliance with aseptic conditions. Protective gloves must be worn. Precautions should be taken to avoid contact with skin and mucous membranes. In case of contact with mucous membranes — wash them with water, in case of contact with skin-with soap and water.
In the preparation, storage and administration of Taxa should use equipment that does not contain PVC parts.
The prepared solutions are stable for no more than 27 h (including preparation and infusion time) at a temperature of approximately 25 °C in room lighting conditions. Dilute solutions should not be placed in the refrigerator.
The prepared solutions can opalestiruty due to the presence in the composition of the dosage form the foundations of the carrier, and after filtration opalescence of the solution is preserved.
Form release
Concentrate for infusion solution, 30 mg/5 ml or 100 mg/16.7 ml (6 mg / ml). In bottles made of colorless glass, sealed with fluorine rubber or butyl rubber stopper with Teflon coating under aluminum running-in with a plastic cap or protective cap, with the control of the first opening. 1 bottle in a protective contour liner is placed in a cardboard box.
Manufacturer
Bristol-Myers Squibb S. R. L., Italy.
Bristol-Myers Squibb S. r.L., Italy.
Via del Murillo Km 2,800, 04010-Sermoneta (LT), Italy.
Via del Murillo Km 2,800, 04010-Sermoneta (LT), Italy.
Customer complaints may be sent to
Bristol-Myers Squibb LLC, Russia.
105064, Moscow, Zemlyanoy Val str., 9.
Phone:+7(495) 755-92-67, Fax:+7 (495) 755-92-62.
Comment
When storing unopened bottles in the refrigerator, there may be precipitation, which dissolves when the bottle is warmed to room temperature with little or no stirring. The quality of the drug does not deteriorate. If the drug in the bottle remains cloudy or there is an insoluble precipitate, the drug should be destroyed.
Freezing does not affect the quality of the drug. Dilute solutions are stable for 27 h when stored at a temperature not exceeding 25 °C and room lighting (taking into account the infusion time).
The solutions obtained by dilution of the drug with 5% dextrose solution are stable for 7 days, the solutions obtained by dilution with 0.9% sodium chloride solution are stable for 14 days at a temperature of 5 to 25 °C.
Dilute solutions should not be stored in the refrigerator.
Storage conditions of the drug Taxol®
In a dark place, at a temperature of 15-30 °C. Freezing does not affect the quality of the drug. Dilute solutions should not be placed in the refrigerator.
Keep out of reach of children.
The shelf life of the drug Taxol®
2 years.
Do not use after the expiration date specified on the package.
