Paclitaxel-Ebwee - instructions for use, dose, side effects, contraindications

Paclitaxel is an antitumor drug of natural origin, obtained semi-synthetically from the plant Tis Yagodny (Taxus Baccata). The mechanism of action is related to the ability of the drug to stimulate the "assembly" of microtubules from dimeric tubulin molecules, to stabilize their structure and to inhibit dynamic reorganization in the interphase, which disrupts the mitotic function of the cell.

Dose-dependent suppression of bone marrow hemopoiesis. It has mutagenic and embryotoxic properties, causes a decrease in reproductive function.

Pharmacokinetics:After intravenous administration of paclitaxel, there is a two-phase decrease concentration of the drug in the blood plasma. When administered intravenously for 3 hours at a dose of 135 mg / m² the maximum concentration of the drug in the plasma is 2170 ng / ml. When the administered dose is increased by 30% (175 mg / m2), the maximum concentration of the drug in the blood plasma increases by 75%. With repeated infusions do not cumulate. FROMligament with plasma proteins - 89-98%. Reception cimetidine, ranitidine, dexamethasone, Diphenhydramine does not affect the binding of paclitaxel to blood plasma proteins. The volume of distribution is 198-688 l / m2. Easily penetrates into tissues, accumulates mainly in the liver, spleen, pancreas, stomach, intestines, heart, muscles.

Metabolized in the liver by hydroxylation with the participation of cytochrome P450 isoenzymes CYP2D8 (with the formation of a metabolite - 6-alpha-hydroxypaclitaxel) and CYP3CA4 (with the formation of metabolites 3-para-hydroxypaclitaxel and 6-alpha, 3-paradihydroxy paclitaxel).

The half-life and total clearance of paclitaxel are variable and depend on the dose and duration of intravenous administration: 13-52 hours and 12-23 l / h / m², respectively.After intravenous infusion (1-24 hours), the total excretion by the kidneys is 1.3-12.6% of the dose. It is excreted mainly with bile - 90%.

Indications:

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

- Breast cancer (as first 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).

Contraindications:

- Child age (safety and efficacy not established).

- Hypersensitivity to paclitaxel, as well as other drugs,

the dosage form of which includes polyoxyethylated castor oil.

- Pregnancy and lactation.

- The initial content of neutrophils is less than 1.5 * 10⁹/ l in patients with solid tumors.

- The initial (or registered in the treatment process) content of neutrophils is less than 1.0 * 10⁹/ L in patients with Kaposi's sarcoma in AIDS patients.

Carefully:

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 coronary heart disease, myocardial infarction (in the anamnesis), arrhythmias.

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, pregnant women should not use paclitaxel.

It is not known whether the paclitaxel in breast milk, so in order to avoid the toxic effect of the drug on the baby, during the period of treatment should stop breastfeeding.

Dosing and Administration:

Intravenously.

Paclitaxel can be used both as a monotherapy and in combination with other antitumor drugs. The dose and scheme of taking the drug is selected individually.

To prevent severe hypersensitivity reactions all patients should be premedication with the use of corticosteroids, antihistamines and antagonists of H2 receptors. The recommended premedication regimen is 20 mg dexamethasone (or its equivalent) orally approximately 12 and 6 hours before the administration of Paclitaxel-Ebweve, 50 mg of diphenhydramine (or its equivalent) intravenously and 300 mg of cimetidine or 50 mg of ranitidine intravenously 30-60 minutes before administration of the drug Paclitaxel-Ebwe.

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 / m2 of the body surface during a three-hour intravenous infusion or at a dose of 135 mg / m2 of the body surface during a 24-hour intravenous infusion, after which cisplatin in a dose of 75 mg / m2 body surface. 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 / m2 body surface by three-hour intravenous infusion. Intervals between courses - 3 weeks.

Adjuvant chemotherapy for breast cancer

Paclitaxel is administered after chemotherapy with anthracyclines and cyclophosphamide. Paclitaxel it is recommended to administer 175 mg / m2 of body surface, intravenously, for three hours. 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 / m2 body surface area), paclitaxel must be administered 24 hours after doxorubicin. The recommended dose of paclitaxel is 220 mg / m2 of body surface upon administration by three-hour intravenous infusion. Intervals between courses - 3 weeks.

When combined use with trastuzumab, paclitaxel it is recommended to administer 175 mg / m2 of the body surface by three-hour intravenous infusions with three-week intervals between courses. 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 / m2 body surface by three-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 / m2 body surface by three-hour intravenous infusion, after which the cisplatin in a dose of 80 mg / m2 body surface. Intervals between courses - 3 weeks.

Chemotherapy for Kaposi's sarcoma against AIDS.

Paclitaxel is recommended to be administered at a dose of 100 mg / m2 body surface by three-hour intravenous infusion. Intervals between the courses - 2 weeks.

Subsequent doses paclitaxel is set individually, depending on the tolerability of therapy. The next dose of paclitaxel can be administered only after an increase in the number of neutrophils to a level of ≥ 1500 cells / mm³ (≥1000 cells / mm³ in the case of Kaposi's sarcoma), and platelets to a level of ≥ 100,000 cells / mm³ (≥ 75,000 cells / mm³ in the case of Kaposi's sarcoma). Patients with severe neutropenia (neutrophil count less than 500 cells / mm³ for 7 days or more) or severe peripheral neuropathy, the following doses are reduced by 20% (25% in the case of Kaposi's sarcoma).

Treatment of patients with impaired liver function. Currently, 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, use equipment that does not contain polyvinyl chloride (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 the drug is administered, a system with a membrane filter should be used (pore size not more than 0.22 μm).

Infusion solutions prepared by diluting Paclitaxel-Ebweve with a 0.9% solution of sodium chloride or 5% dextrose solution are physically and chemically stable for 51 hours in the case of storage at a temperature of 25 ° C and 14 days in the case of storage at a temperature of 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 2-8 ° C, unless the solution has been 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 effects:

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

Frequency of development of side effects is stated in accordance with the following gradation: very frequent - more than 10%, frequent - from 1 to 10%, not frequent - from 0,1% to 1%, rare - from 0.01 to 0.1%, very rare - less than 0.01%.

On the part of the blood and lymphatic system

very frequent: myelosuppression, neutropenia, thrombocytopenia, anemia, leukopenia, bleeding;

rare: fibrillar neutropenia;

very rare: acute myeloid leukemia, myelodysplastic syndrome.

From the nervous system

very frequent: neurotoxic effects (mainly peripheral

neuropathy), paresthesia;

rare: motor neuropathy (moderately pronounced weakness of distal muscles, difficulty in performing precise movements);

very rare: vegetative neuropathy (leading to paralytic obstruction of the intestine and orthostatic hypotension), large epileptic seizures ("grand mal"), convulsions, encephalopathy, dizziness, headache, confusion, ataxia.

From the side of the cardiovascular system

Frequent: bradycardia, lowering blood pressure;

infrequent: cardiomyopathy, asymptomatic ventricular tachycardia, atrioventricular blockade, syncope, increased arterial pressure, myocardial infarction, vascular thrombosis, thrombophlebitis;

very rare: atrial fibrillation, supraventricular tachycardia, shock.

From the sense organs

very rare: lesions of the optic nerve and / or visual impairment (ciliary scotoma), hearing loss, tinnitus, dizziness.

From the respiratory system

rare: dyspnea, pleural effusion, interstitial pneumonia, pulmonary fibrosis, pulmonary embolism,respiratory insufficiency, radiation pneumonitis in patients concomitantly undergoing radiotherapy; very rare: cough.

From the digestive system

very frequent: nausea, vomiting, diarrhea, inflammation of the mucous membranes; rare: pancreatitis, intestinal perforation, ischemic colitis;

very rare: anorexia, constipation, mesenteric thrombosis, pseudomembranous colitis, esophagitis, ascites, neutropenic colitis, liver necrosis, hepatic encephalopathy (there are isolated reports of death).

From the skin and skin appendages

very frequent: alopecia;

Frequent: transient small changes in nails and skin (violation of pigmentation, discoloration of the nail bed);

rare: itching of the skin, rashes, erythema;

very rare: 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 musculoskeletal system

very frequent: arthralgia, myalgia.

From the immune system

very frequent: infection (mainly the urinary tract and upper respiratory tract);

not frequent: serious hypersensitivity reactions that require therapeutic measures (namely, lowering arterial pressure, angioedema, respiratory distress syndrome, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, pain in the extremities, severe sweating, increased blood pressure);

rare: anaphylatoid reactions.

Laboratory indicators

Frequent: an increase in the activity of "liver" transaminases, an increase in the concentration of alkaline phosphatase, bilirubin, creatinine in the blood serum.

Local Reakits

frequent: pain, localized edema, erythema, induration and skin pigmentation at the injection site; Extravasation can cause inflammation and necrosis of subcutaneous tissue.

Other

rare: asthenia, fever, dehydration, general weakness.

Overdose:

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

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

Interaction:

Cisplatinum reduces the total clearance of paclitaxel by 20%, so with combined chemotherapy paclitaxel must be administered prior to cisplatin. More pronounced myelosuppression is observed in the case when paclitaxel is administered after cisplatin. With combined chemotherapy (paclitaxel and cisplatin), the risk of developing renal failure is higher than with monotherapy with cisplatin.

Simultaneous appointment with cimetidine, ranitidine, dexamethasone with sheep diphenhydramine does not affect the association of paclitaxel with plasma proteins.

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

Information on the potential interaction of paclitaxel with inhibitors and inductors of cytochrome P 450 isoenzymes (in particular isoenzyme CYP3A4) limited, so caution is needed when using inhibitors at the same time (for example, erythromycin, fluoxetine, gemfibrozil) or inducers (for example, rifampicin, carbamazepine, phenytoin, phenobarbital) of cytochrome P 450 isoenzymes.

Inhibitors of macrosomal oxidation (incl. ketoconazole, cimetidine, verapamil, diazepam, quinidine, ciclosporin and others) suppress the metabolism of paclitaxel. However, it is known that with the simultaneous administration of ketoconazole and paclitaxel, the elimination of the latter does not slow down, so both drugs can be used without correction of the doses. With the simultaneous use of paclitaxel and nelfinavir or ritonavir (but not indinavir) the systemic clearance of paclitaxel is significantly reduced. Insufficient information on the interaction of paclitaxel and other protease inhibitors with simultaneous application.

Polyoxyethylated castor oil, (2-hexyl) phthalate (DEGP) from plasticized polyvinylchloride containers, where the degree of leaching of the DEHP increases with increasing solution concentration and time. Therefore, when preparing, storing and administering the Paclitaxel-Ebweve preparation, you should use equipment that does not contain PVC parts.

Special instructions:

The use of Paclitaxel-Ebweve should be carried out under the supervision of a qualified physician with experience in working with antitumor chemotherapeutic drugs. Paclitaxel-Ebwee can be used both as a monotherapy and in combination with other antitumor drugs. The dose and scheme of taking the drug is selected individually.

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.

In case of severe hypersensitivity reactions, the infusion of Paclitaxel-Ebweve should be stopped immediately and symptomatic treatment started. Do not re-administer the drug.

During treatment it is necessary to regularly monitor the clinical analysis of blood, blood pressure, heart rate and respiration (especially at the beginning of infusion), electrocardiogram.

In cases of development of violations of atrioventricular conduction, with repeated administration, continuous monitoring of the electrocardiogram is necessary.

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

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.

Since the safety and effectiveness of Paclitaxel-Ebwee in children is not established, it is not recommended to use the drug in this age group of patients.

Effect on the ability to drive transp. cf. and fur:

Because of the likelihood of side effects such as headache, dizziness, drowsiness, one should refrain from engaging in potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Concentrate for the preparation of a solution for infusions of 30 mg / 5 ml, 100 mg / 16.7 ml, 150 mg / 25 ml, 210 mg / 35 ml or 300 mg / 50 ml (6 mg / ml).

Packaging:

5 ml, 16.7 ml, 25 ml, 35 ml or 50 ml in vials of colorless glass (type I, Hept. F.), sealed with bromobutyl rubber stoppers under aluminum rolling, closed with a protective Teflon cap.

One bottle together with instructions for use in a cardboard tutu.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Special precautions for the destruction of unused medications

Remains of the drug and all tools, and materials,which were used to prepare a solution for infusion and the administration of Paclitaxel-Ebwe, must be destroyed in accordance with the standard hospital procedure for the disposal of cytotoxic substances, taking into account the existing regulatory acts on the destruction of hazardous waste.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N 015197/01

Date of registration:07.05.2008

The owner of the registration certificate:Ebewe Pharma Gesmb.b. Nfg. KGEbewe Pharma Gesmb.b. Nfg. KG Austria

Manufacturer: & nbsp

EBEWE PHARMA, Ges.m.b.H.Nfg.KG Austria

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp16.10.2015

Illustrated instructions

Instructions

Paclitaxel-Ebwee (Paclitaxel-Ebewe)