Universal reference book for medicines
Name of the drug: PACLITAXEL-EBEVE (PACLITAXEL-EBEWE)

Active substance: paclitaxel

Type: Antitumor preparation

Manufacturer: EBEWE PHARMA (Austria)
Composition, form of production and packaging
Concentrate for the preparation of solution for infusions
from colorless to light yellow color, transparent.

1 ml

paclitaxel 6 mg

Excipients: macrogol glycerylricinoleate (castor oil polyoxyethylated) - 522.396 mg, ethanol - 401.664 mg.

5 ml - bottles of colorless glass (1) - packs of cardboard.

16.7 ml - vials of colorless glass (1) - packs of cardboard.

25 ml - vials of colorless glass (1) - packs cardboard.

35 ml - vials of colorless glass (1) - packs cardboard.

50 ml - vials of colorless glass (1) - packs cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2014.

PHARMACHOLOGIC EFFECT

An antineoplastic preparation of natural origin, obtained semi-synthetically from the plant Taxus baccata.

The mechanism of action is associated with the ability to stimulate the assembly of microtubules from dimeric tubulin molecules, stabilize their structure and inhibit dynamic reorganization in the interphase, which disrupts the mitotic function of the cell.

Causes a dose-dependent depression of bone marrow hematopoiesis.

PHARMACOKINETICS

Distribution

With iv introduction for 3 hours at a dose of 135 mg / m 2 C max is 2170 ng / ml, AUC - 7952 ng / h / ml;
with the same dose administered for 24 hours - 195 ng / ml and 6300 ng / h / ml, respectively. The values ​​of C max and AUC are dose-dependent: when infused for 3 hours, increasing the dose to 175 mg / m 2 leads to an increase in these parameters by 68% and 89%; within 24 hours - by 87% and 26% respectively.
Binding to plasma proteins is 88-98%.
The average V d is 198-688 l / m 2 . The time of half-distribution from the blood in the tissue is 30 minutes. Easily penetrates the tissues of the body, mainly in the liver, spleen, pancreas, stomach, intestines, heart, muscles. With repeated infusions in the body does not cumulate.
Metabolism

It is metabolized in the liver by hydroxylation with the participation of cytochrome P 450 CYP2D8 isoenzymes (with the formation of the metabolite 6-alpha-hydroxypaclitaxel) and CYP3CA4 (with the formation of metabolites 3-para-hydroxypaclitaxel and 6-alpha, 3-para-dihydroxy paclitaxel).

Excretion

It is excreted mainly with bile - 90%.
T 1/2 and total clearance are variable and depend on the dose and duration of IV administration: 13.1-52.7 h and 12.2-23.8 l / h / m 2 , respectively. After intravenous infusion (1-24 hours), the total excretion by the kidneys is 1.3-12.6% of the dose (15-275 mg / m 2 ), which indicates the presence of intensive extrarenal clearance. The total ground clearance is 11-24 l / m 2 .
INDICATIONS

- ovarian cancer (first-line therapy in combination with platinum drugs and second-line therapy in metastases after standard therapy, which did not give a positive result);

- Breast cancer (as first-line and second-line therapy, as well as adjuvant treatment);

- non-small cell lung cancer (first-line therapy for patients who do not plan surgical treatment and / or radiation therapy (in combination with cisplatin);

- Kaposi's sarcoma in AIDS patients (second-line therapy, after ineffective therapy with liposomal anthracyclines).

DOSING MODE

Enter the / in.

Paclitaxel can be used both as a monotherapy and in combination with other antitumor drugs.
The dose and scheme of the drug is selected individually.
To prevent severe reactions of hypersensitivity, all patients should be premedicated using corticosteroids, blockers of histamine H 1 - and H 2 -receptors.
The recommended premedication schedule is 20 mg of dexamethasone (or its equivalent) inside approximately 12 hours and 6 hours before the administration of the Paclitaxel-Ebweve preparation, 50 mg of diphenhydramine (or its equivalent) IV and 300 mg of cimetidine or 50 mg of ranitidine IV for 30-60 minutes prior to the administration of the drug Paclitaxel-Ebene.
Chemotherapy for the first line of ovarian cancer

A combined treatment regimen for paclitaxel and cisplatin is recommended.
Paclitaxel is administered at a dose of 175 mg / m 2 of the body surface for a 3-hour intravenous infusion or at a dose of 135 mg / m 2 for a 24-hour IV infusion, after which cisplatin is administered at a dose of 75 mg / m 2 . Intervals between courses - 3 weeks.
Chemotherapy of the second line of ovarian cancer

Paclitaxel is recommended to be administered at a dose of 175 mg / m 2 of the body surface by a 3-hour IV infusion.
Intervals between courses - 3 weeks.
Adjuvant chemotherapy for breast cancer

Paclitaxel is administered after chemotherapy with anthracyclines and cyclophosphamide.
Paclitaxel is recommended to be administered at a dose of 175 mg / m 2 IV for 3 h. 4 courses with intervals between courses - 3 weeks.
Chemotherapy first line of breast cancer

In the case of combined use with doxorubicin (at a dose of 50 mg / m 2 body surface), paclitaxel should be administered 24 hours after doxorubicin.

The recommended dose of paclitaxel is 220 mg / m 2 of the body surface when administered by a 3-hour IV infusion.
Intervals between courses - 3 weeks.
In the case of combined use with trastuzumab, paclitaxel is recommended to be administered at a dose of 175 mg / m 2 body surface by a 3-hour IV infusion with an interval between courses of 3 weeks.
Paclitaxel can be administered the next day after the administration of the first dose of trastuzumab, or immediately after the administration of subsequent doses if previous doses of trastuzumab are well tolerated.
Chemotherapy second line of breast cancer

Paclitaxel is recommended to be administered at a dose of 175 mg / m 2 by a 3-hour intravenous infusion.
Intervals between courses - 3 weeks.
Chemotherapy for advanced non-small cell lung cancer

A combined treatment regimen for paclitaxel and cisplatin is recommended.
Paclitaxel is administered at a dose of 175 mg / m 2 body surface by 3-hour IV infusion, after which cisplatin is administered at a dose of 80 mg / m 2 . Intervals between courses - 3 weeks.
Chemotherapy for Kaposi's sarcoma against AIDS

Paclitaxel is recommended to be administered at a dose of 100 mg / m 2 by 3-hour IV infusion.
Intervals between the courses - 2 weeks.
Subsequent doses of paclitaxel are set individually, depending on the tolerability of the therapy.
The next dose of paclitaxel can be administered only after an increase in the number of neutrophils to a level of? 1500 cells / μl (? 1000 cells / μl in the case of Kaposi's sarcoma), and platelets to> 100,000 cells / mm3 (> 75,000 cells / mm 3 in the case of Kaposi's sarcoma ). Patients who have had severe neutropenia (neutrophil counts less than 500 cells / μl for 7 days or more) or severe peripheral neuropathy, the following dose is reduced by 20% (25% in the case of Kaposi's sarcoma).
At present, there is insufficient data to develop recommendations for dose adjustment for patients with impaired liver function of mild or moderate severity .Patients with severe impairment of liver function should not be prescribed paclitaxel.

Rules for the preparation of a solution for infusions

When preparing, storing and administering the Paclitaxel-Ebweze preparation, you should use equipment that does not contain PVC: for example, glass, polypropylene or polyolefin.

The drug solution is prepared by diluting the concentrate to a final concentration of paclitaxel from 0.3 to 1.2 mg / ml.
As a diluting solution, 0.9% sodium chloride solution, 5% dextrose solution, 5% dextrose solution in 0.9% sodium chloride solution, 5% dextrose solution in Ringer's solution can be used. The prepared solutions may be opalescent due to the carrier base present in the formulation. When administering the drug should use a system with a membrane filter (pore size is not more than 0.22 microns).
Infusion solutions prepared by diluting Paclitaxel-Ebweve with 0.9% sodium chloride solution or 5% dextrose solution are physically and chemically stable for 51 hours if stored at 25 ° C and 14 days in the case of storage at 5 ° C.
From a microbiological point of view, the infusion solution should be administered immediately after preparation. If the solution is not used immediately after preparation, the storage time should not exceed 24 hours at a temperature of 2 ° to 8 ° C unless the solution is prepared under controlled aseptic conditions.
To reduce the risk of sediment formation, the infusion solution must be administered immediately after dilution and avoid excessive shaking, vibration and shaking.

The infusion system should be thoroughly rinsed before use.
During the introduction, the appearance of the solution should be regularly monitored and, if sediment is detected, stop the infusion.
SIDE EFFECT

The frequency and severity of side effects are dose-dependent.

Determination of the frequency of side effects: very often -> 10%, often - from 1 to 10%, infrequently - from 0.1% to 1%, rarely - from 0.01 to 0.1%, very rarely - less than 0.01%.

From the hemopoietic system: very often - myelosuppression, neutropenia, thrombocytopenia, anemia, leukopenia, bleeding;
rarely - febrile neutropenia; very rarely - acute myeloid leukemia, myelodysplastic syndrome.
From the side of the nervous system: very often - neurotoxic effects (mainly peripheral neuropathy), paresthesia;
rarely - motor neuropathy (moderately pronounced weakness of distal muscles, difficulty in performing precise movements); very rarely - vegetative neuropathy (resulting in paralytic obstruction of the intestine and orthostatic hypotension), large epileptic seizures (grand mal), convulsions, encephalopathy, dizziness, headache, confusion, ataxia.
From the cardiovascular system: often - bradycardia, lowering blood pressure;
infrequently - cardiomyopathy, asymptomatic ventricular tachycardia, AV-blockade, syncope, increased blood pressure, myocardial infarction, vascular thrombosis, thrombophlebitis; very rare - atrial fibrillation, supraventricular tachycardia, shock.
From the sense organs: very rarely - lesions of the optic nerve and / or visual impairment (ciliary scotoma), hearing loss, tinnitus, dizziness.

On the part of the respiratory system: rarely - shortness of breath, pleural effusion, interstitial pneumonia, pulmonary fibrosis, pulmonary embolism, respiratory failure, radiation pneumonitis in patients undergoing radiotherapy;
very rare - cough.
On the part of the digestive system: very frequent - nausea, vomiting, diarrhea, inflammation of the mucous membranes;
rarely - pancreatitis, intestinal perforation, ischemic colitis; Very rarely - anorexia, constipation, mesenteric thrombosis, pseudomembranous colitis, esophagitis, ascites, neutropenic colitis, liver necrosis, hepatic encephalopathy (there are isolated reports of a lethal outcome).
From the skin and skin appendages: very often - alopecia;
often - transient small changes in nails and skin (violation of pigmentation, discoloration of the nail bed);rarely - itching of the skin, rashes, erythema; very rarely - Stevens-Johnson syndrome (ulceration of the mucous membrane of the mouth, throat, eyes, genital organs, other areas of the skin and mucous membranes), epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis.
From the osteomuscular system: very often - arthralgia, myalgia.

On the part of the immune system: very frequent - infections (mainly the urinary tract and upper respiratory tract);
infrequently, serious hypersensitivity reactions requiring therapeutic measures (namely, lowering blood pressure, angioedema, respiratory distress syndrome, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, pain in the extremities, severe sweating, increased blood pressure); rarely anaphylatoid reactions.
On the part of laboratory indicators: often - an increase in the activity of hepatic transaminases, an increase in the concentration of alkaline phosphatase, bilirubin, creatinine in the blood serum.

Local reactions: often - pain, localized edema, erythema, induration and skin pigmentation at the injection site;
Extravasation can cause inflammation and necrosis of subcutaneous tissue.
Other: rarely - asthenia, fever, dehydration, general weakness.

CONTRAINDICATIONS

- hypersensitivity to the components of the drug;

- hypersensitivity to other drugs, the dosage form of which includes polyoxyethylated castor oil;

- initial neutrophil count less than 1500 / μL in patients with solid tumors;

- the initial (or registered in the treatment) neutrophil content of less than 1000 / μl with Kaposi's sarcoma in AIDS patients;

- Pregnancy;

- lactation (breastfeeding);

- Children's age (safety and efficacy not established).

With caution apply in patients with oppression of bone marrow hematopoiesis (including after chemotherapy or radiation therapy), liver failure, acute infectious diseases (including herpes zoster, chicken pox, herpes), severe course of ischemic heart disease, with a heart attack a myocardium in the anamnesis, at an arrhythmia.

PREGNANCY AND LACTATION

Controlled studies of paclitaxel in pregnant women have not been conducted.
Studies in animals have shown embryotoxic, teratogenic and mutagenic effects of paclitaxel. Therefore, in pregnancy, paclitaxel should not be used.
It is not known whether paclitaxel is excreted in breast milk, so in order to avoid the toxic effect of the drug on the infant, during the period of treatment it should stop breastfeeding

Patients should be provided with reliable contraceptive methods during treatment with the drug Paclitaxel-Ebwe and, at least 3 months after the end of therapy.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

With caution appoint with liver failure.

At present, there is insufficient data to develop recommendations for dose adjustment for patients with impaired liver function of mild or moderate severity .Patients with severe impairment of liver function should not be prescribed paclitaxel.

APPLICATION FOR CHILDREN

The safety and effectiveness of the drug Paclitaxel-Ebwee in children is not established.

SPECIAL INSTRUCTIONS

The use of Paclitaxel-Ebweve should be carried out under the supervision of a physician with experience in working with antitumor chemotherapeutic drugs.

With the development of severe hypersensitivity reactions, the administration of Paclitaxel-Ebweve should be stopped immediately and symptomatic therapy started, with no repeated administration of the drug.

If Paclitaxel-Ebweve is used in combination with cisplatin, you should first inject Paclitaxel-Ebweave, and then cisplatin.

Care should be taken when working with Paclitaxel-Ebweave (as with other cytotoxic agents), use gloves and avoid contact with skin or mucous membranes.
In case of contact with skin, wash thoroughly with soap and water; In case of contact with eyes, use plenty of water.
Control of laboratory indicators

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 monitoring should be performed before therapy and regularly during treatment.

In the development of violations of AV-conduction during the implementation of repeated injections, continuous monitoring of the ECG is necessary.

Use in Pediatrics

The safety and effectiveness of the drug Paclitaxel-Ebwee in children is not established.
Application in pediatrics is contraindicated.
Impact on the ability to drive vehicles and manage mechanisms

Because of the likelihood of side effects such as headache, dizziness, drowsiness, patients should refrain from engaging in potentially dangerous activities during the treatment period, which require an increased concentration of attention and speed of psychomotor reactions.

Precautions when working and destroying an unused product

Care should be taken when working with the drug Paclitaxel-Ebwe.
Dilute the drug in aseptic conditions in a specially designated room. This should be handled by trained personnel. It is necessary to take all measures to prevent the solution of paclitaxel from getting on the skin and mucous membranes, in particular to use protective clothing (gown, cap, mask, glasses and disposable gloves). When breathing in vapors or spray solutions of paclitaxel, there were reports of shortness of breath, chest pain, burning sensation in the throat, and nausea.
If you get paclitaxel on the skin or mucous membranes, rinse thoroughly with soap and water or (eyes) with plenty of water.

The drug should not be frozen, as it may form a precipitate.
Such a precipitate usually dissolves when the vial is heated to room temperature (25 ° C). If the solution in the previously frozen vial remains cloudy or there is an insoluble precipitate, the drug can not be used and such a vial must be destroyed. The prepared infusion solution does not need protection from light.
The remnants of the preparation and all tools and materials used to prepare the infusion solution and the introduction of Paclitaxel-Ebwee should be disposed of in accordance with the standard hospital procedure for the disposal of cytotoxic substances, taking into account existing regulations on hazardous waste disposal.

OVERDOSE

Symptoms: oppression of bone marrow function, peripheral neuropathy, inflammation and ulceration of mucous membranes.

Treatment: symptomatic.
The antidote to paclitaxel is not known.
DRUG INTERACTION

Cisplatin reduces the total clearance of paclitaxel by 20%, so with combined chemotherapy, paclitaxel should be administered prior to cisplatin.
More pronounced myelosuppression is observed when paclitaxel is administered after cisplatin. With combined chemotherapy (paclitaxel and cisplatin), the risk of developing kidney failure is higher than with monotherapy with cisplatin.
Simultaneous administration with cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the association of paclitaxel with plasma proteins.

Since the elimination of doxorubicin and its active metabolites may decrease with a shorter time interval between the administration of paclitaxel and doxorubicin, paclitaxel should be administered 24 hours after doxorubicin.

Information on potential interactions of paclitaxel with inhibitors and inducers of isoenzymes of cytochrome P450 (in particular isoenzyme CYP3A4) is limited, so caution is required while the use of inhibitors (e.g., erythromycin, fluoxetine, gemfibrozil) or inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital ) isoenzymes of cytochrome P450.
Inhibitors of microsomal oxidation (including ketoconazole, cimetidine, verapamil, diazepam, quinidine, cyclosporine) inhibit the metabolism of paclitaxel.
However, it is known that while receiving ketoconazole and paclitaxel, the elimination of the latter is not slowing down, so both drugs can be used without dose adjustment.
With simultaneous application of paclitaxel or nelfinavir and ritonavir (but not indinavir) significantly decreases the systemic clearance of paclitaxel. Insufficient information on the interaction of paclitaxel and other protease inhibitors when applied simultaneously.
Polyoxyethylated castor oil, which is part of paclitaxel can cause extraction di- (2-hexyl) phthalate (DEGP) of plasticized PVC containers, the degree of leaching DEGP increases with increasing solution concentration and time. Therefore, in the preparation, storage and administration of the drug Paclitaxel-Ebewe equipment must be used, which contains no parts of PVC.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of the reach of children, protected from light at a temperature of no higher than 25 ° C.
Shelf life - 3 years.
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