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

Paclitaxel-Teva (paclitaxel) is an antitumor preparation of plant 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.

Pharmacokinetics:

With intravenous (IV) administration for 3 hours at a dose of 135 mg / m² maximum concentration (С_max) is 2170 ng / ml, the area under the curve "concentration-time" (AUC) - 7952 ng / h / ml; with the same dose administered for 24 hours at 195 ng / ml and 6300 ng / h / ml, respectively. FROM_max and AUC dose-dependent: with a 3-hour infusion, increasing the dose to 175 mg / m² leads to an increase in these parameters by 68% and 89%, and at 24 hours - by 87% and 26%, respectively.

The connection with plasma proteins is 88-98%. The time of half-distribution from the blood in the tissue is 30 minutes. Easily penetrates and absorbs 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-hydroxy-paclitaxel) and CYP3CA4 (with the formation of metabolites of 3-para-hydroxy-paclitaxel and 6-alpha, 3-para-dihydroxy paclitaxel). It is excreted mainly with bile - 90%. With repeated infusions do not cumulate.

The half-life 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 / m² , respectively. After intravenous infusion (1-24 hours), the total excretion by the kidneys is 1.3-12.6% of the dose (15-275 mg / m²), which indicates the presence of intensive extrarenal clearance.

Indications:Ovarian Cancer

- first-line therapy in combination with cisplatin in patients with latedays of ovarian cancer or residual ovary(more than 1 cm) after surgery interventions;

- second-line therapy in patients with metaStatic ovarian cancer if standard therapy with platinum preparations is ineffective.

Mammary cancer

- adjuvant therapy in patients with lymph node metastases after therapy with anthracyclines and cyclophosphamide (AC). Adjuvant therapy with paclitaxel should be considered as an alternative to prolonged therapy with AC;

- first-line metastatic therapy

rabreast cancer after relapsewithin 6 months after the commencement of adjuvant therapy withtreatment of anthracycline-based drugs, in the absence of contraindications for their application;

- first-line treatment of locally advanced or metastatic breast cancer in combination with anthracycline-based drugs in the absence of contraindications for their use, or with trastuzumab in patients with immunohistochemically confirmed2+ or 3+ levels of expression of type 2 receptors of human epidermal growth factor (HER-2) if there are contraindications to anthracyclines;

- second-line therapy (monotherapy) of metastatic breast cancer in case of ineffectiveness of standard therapy including anthracycline-based drugs in the absence of contraindications for their use.

Non-small cell lung cancer

- tThe first line of advanced non-small cell lung cancer in combination with cisplatin in the case ofsurgical treatment and / or radiotherapy.

Sarcoma Kaposhiu patients with AIDS

- second line therapy of progressive Kaposi's sarcoma in patients with AIDS after ineffective therapy with liposomal anthracyclines.

Contraindications:Hypersensitivity to paclitaxlu or other constituents of the drug (in including polyoxyethylated casto(macrogol glycerylriciniloleat)); original absolute quantity neutrophils (AKN) less than 1500 / μl of blood patients with solid tumors; the original (or registered during treatment) AKN less than 1000 / μL of blood in patients with capcoma of Kaposi; accompanying heavy notcontrolled infections in patients withcapcoma of Kaposi; severe function disruption liver; pregnancy and the period of the breast feeding; children's age (lack of sufficient data on the safety and efficacy of the drug).

Carefully:Inhibition of bone marrow hematopoiesis, thrombocytopenia (less than 100,000 / μl of blood), slight and moderate disturbance of the oven functionneither, acute infectious diseases (incl. shingles, chicken pox, herpes), severe course of ischemic heart diseasea myocardial infarction (in the anamnesis), an arrhythmia.

Dosing and Administration:

When choosing the regimen and doses in each individual case, one should be guided by the literature data.

To prevent severe hypersensitivity reactions, all patients should undergo premedication with glucocorticosteroids, antihistamines and antagonists of H1 and H2-histamine receptors. The recommended mode of premedication is Table 1.

Table №1. Recommended mode of premedication

Medicinal preparation	Dose, mg	Mode of application
Dexamethasone	20^*	Inside, approximately 12 and 6 hours before the administration of the drug Paclitaxel-Teva or in / in 30-60 minutes prior to the administration of Paclitaxel-Teva
Diphenhydramine^**	50	In / in, 30-60 minutes prior to the administration of Paclitaxel-Teva
Cimetidine / ranitidine	300/50	In / in, 30-60 minutes prior to the administration of Paclitaxel-Teva

* 8-20 mg for patients with Kaposi's sarcoma;

** or its equivalent, for example, chlorfeniumRamin 10 mg IV.

Ovarian Cancer

Thosefirst-line ration

In a dose of 175 mg / m² in the form of a 3-hour intravenous infusion with subsequent administration of cisplatin every 3 weeks or at a dose of 135 mg / m² in the form of a 24-hour IV infusion followed by cisplatin every 3 weeks.

Therapy of the second line (monotherapy)

In a dose of 175 mg / m² in the form of a 3-hour intravenous infusion once every 3 weeks.

Mammary cancer

Adjuvant therapy

After a standard combined cure4 courses of drug therapy Paclitaxel-Teva in a dose of 175 mg /m² in the form of 3 hour IV infusion every 3 weeks.

Therapy of the first line

Monotherapy: in a dose of 175 mg /m² in the form of 3 hoursI consume IV infusion every 3 weeks.

In combination with doxorubicin: after 24 hours after the administration of doxorubicin - in a dose of 220 mg /m² in the form of a 3-hour intravenous infusion every 3 of the week.

In combination with trastuzumab: on the nextday after the first dose was given to the trustzoumab - in a dose of 175 mg /m² in the form of 3 hours intravenous infusion every 3 weeks, with good tolerability of trastuzumab immediately after administration of subsequent doses of trastuzumab.

Therapy of the second line

In a dose of 175 mg /m² in the form of 3 hours in / in infuevery 3 weeks.

Non-small cell lung cancer

In a dose of 175 mg /m² in the form of 3 hours in / in infuwith subsequent administration of cisplatin every 3 weeks or at a dose of 135 mg /m² as 24-hour IV infusion followed by injectioncisplatin every 3 weeks.

Kaposi's sarcoma in patients with AIDS

Therapy of the second line

The recommended dose is 135 mg /m² in the form of 3 hoursinfusion every 3 weeks or 100 mg /m²in the form of a 3-hour infusion every 2 weeks. Depending on the severity of immunosuppression in patients with AIDS, the administration of the drug Paclitaxel-Teva is recommended only if the AKN is not less than 1000 / μl of blood and the amount of platelets is not less than 75,000 / μl of blood. Patients with severe neutropenia (AKH less than 500 / μL blood for 7 days or more), or with severe peripheral polyneuropathy, or with mucositis (grade III or higher) with subsequent courses are recommendeddose of 25% to a dose of 75 mg / m. It is necessary to consider the possibility of mobilizing peripheral blood stem cells by the administration of a granulocyte colony-stimulating factor.

Dosing in the treatment of breast cancer, ovarian cancer, non-small cell lung cancer

The administration of Paclitaxel-Teva should not be repeated until ACN reaches at least 1500 / μL of blood, and the platelet count is 100,000 / μL of blood. Patients who had severe neutropenia (AKH less than 500 / μL blood for 7 days or longer) or severe peripheral neuropathy after the administration of Paclitaxel-Teva, in the course of subsequent courses of treatment, the dose of Paclitaxel-Tevait decreases by 20% (with the treatment of non-small cell lung cancer and first-line treatment of ovarian cancer) or by 25% (in the treatment of breast cancer and ovarian cancer). In patients with mucositis (grade II or higher), a dose reduction of 25% is recommended.

Patients with impaired hepatic function

Patients with hepatic insufficiency and associated increased risk of toxicity (in particular, myelosuppression III-IV degree), a dose adjustment is recommended. The condition of patients must be carefully monitored. Recommended doses for patients with impaired liver function, see table 2.

Table number 2. Recommended doses for patients with impaired liver function

Degree of hepatic impairment			Dose^* of the drug Paclitaxel-Teva, mg / m²
Activity of "liver" enzymes	-	Bilirubin concentration in blood serum, μmol / l	Dose^* of the drug Paclitaxel-Teva, mg / m²
24 hour infusion
<2×VGN	and	≤26	135
2-<10×VGN	and	≤26	100
<10×VGN	and	28-129	50
≥10×VGN	or	>129	Not recommended
3 hour infusion
<10×VGN	and	≤22×VGN	175
<10×VGN	and	22-35×VGN	135
<10×VGN	and	35-86×VGN	90
≥10×VGN	or	>86×VGN	Not recommended

*Recommended doses for the first course of therapy; dose adjustment in subsequent courses should be based on individual drug tolerance.

VGN - the upper limit of the norm.

Patients with impaired renal function

There is insufficient data on the manifestation of the toxic effect of the drug Paclitaxel-Teva in patients with impaired renal function. Correction of the dose is not required.

Rules for the preparation of a solution for infusion

Solution for infusion is prepared immediately before administration, diluting the concentrate with 0.9% solution of sodium chloride, or 5% solution of dextrose,or 5% dextrose solution in a 0.9% solution of sodium chloride for injection, or 5% dextrose solution in Ringer's solution to a final concentration of 0.3 to 1.2 mg / ml. 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 Paclitaxel-Teva, equipment should be used that does not contain plasticized polyvinyl chloride (PVC) parts. Plasticiser diethylhexyl phthalate (DEHP/ DEHP) contained in plasticized PVC can be released by the action of macrogolglycerylriciniloleate, which is an auxiliary component of the preparation. The drug Paclitaxel-Teva should be administered through a system with an integrated membrane filter (pore size not more than 0.22 microns).

If unopened vials are placed in the refrigerator, a precipitate may form which dissolves again with little stirring (or without stirring) when room temperature is reached. The quality of the product does not deteriorate.If the solution remains cloudy, or if there is an insoluble deposit, the vial should be destroyed.

Side effects:Frequency and severity of adverse reactionspaclitaxel in general are similar in application in patients with differentlead tumors (ovarian cancer, cancernon-small cell lung cancerth). There was no dependence of manifestation toxicity of paclitaxel on the age of patients.

The incidence of side effects is classified according to the recommendations of the World Health Organization: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely (including isolated cases) - less than 0.01%.

Infectious diseases: Often - infection (mainly the urinary tract and upper respiratory tract), including reports of death; infrequently septic shock; rarely - sepsis, peritonitis, pneumonia.

From the side of blood and lymphatic systemwe: Often - myelosuppression, neutropeniaanemia, thrombocytopenia, leukopenia, bleeding; rarely - febrile neutropeniation; rarely acute myeloblastic leukemia, myelodysplastic syndrome. The inhibition of bone marrow function, mainly of the granulocyte germ, was the main toxic effect limiting the dose of the drug. The maximum decrease in ACN is usually observed on day 8-11, normalization occurs on day 22.

From the immune system: Often - minor hypersensitivity reactions (mainly skin rash); infrequently - expressed hypersensitivity reactions requiring medication (lowering blood pressure (BP), angioedema, respiratory distress syndrome, generalized urticaria, chills, back pain, chest pain, tachycardia, pain in the extremities, increased sweating and increased blood pressure); rarely - anaphylactic reactions, confusion; very rarely - anaphylactic shock.

From the side of metabolism and nutrition: unknown frequency - tumor lysis syndrome.

From the nervous system: Often - neurotoxicity, mainly peripheral polyneuropathy; rarely - peripheral motor neuropathy (leading to distal weakness); rarely - convulsive seizures of the type grand mal, vegetative neuropathy, leading to paralytic obstruction of the intestine and orthostatic hypotension, encephalopathy, convulsions, dizzinessataxia, headache.

From the side of the organ of vision: rarely - byoptic nerve and / or disturbance vision ("scintillating scotoma"), especially in patients who received doses higher than recommended;unknown frequency - maa catarrhal edema, a photopsy, a "floating puffinessvitreous body.

On the part of the hearing organ and labyrinthine violations: rarely - loss of hearing, noise in ears, vertigo.

From the cardiovascular system: Often - reduction of blood pressure, "hot flashes"; chahundred - bradycardia; infrequently - myocardial infarctioncardia, atrioventricular blockade, obmorock, cardiomyopathy, asymptomatic stomachdacha tachycardia, including with bigeminiher, venous thrombosis, increased Blood pressure, thrombophlebitis; rarely -heart failurestatochnost; rarely - fibrillationstroke, supraventricular tachycardia, shock; unknown frequency - phlebitis.

From the respiratory system, organs thorax and mediastinum: rarely - thesevere insufficiency, pulmonary embolism,fibrosis of the lung, interstitial pneumonia, dyspnea, pleural effusion; rarely - cough.

From the digestive system: Often - diarrhea, vomiting, nausea, inflammation of the oral mucosa; rarely - intestinal obstruction, intestinal perforation, ischemic colitis, pancreatitis; rarely - anorexia, thrombosis of mesenteric arteries of the mesentery, pseudomembranous colitis, neutropenic colitis, ascites, oesophagitis, constipation, hepatic necrosis, hepatic encephalopathy with fatal consequences.

From the skin and subcutaneous tissues: Often - alopecia; infrequently - reversible changes in skin and nails; rarely - skin itching, skin rash, erythema; rarely - Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (recommended to apply sunscreen on the arms and legs); unknown frequency - scleroderma.

From the osteomuscular and connective tissue: Often - arthralgia, mialgia; unknown frequency - System lupus erythematosus.

Local reactions: often - reactions in place administration (edema, pain, erythema and individual cases of hemorrhage, which can cause inflammation of the subcutaneous fiber, skin fibrosis and skin necrosis).

Laboratory data: often - expressed aspartate aminotransferase activityferazy (ACT), alkaline phosphatase (AFP); infrequently - increased bilirubin concentrationBina; rarely - increasing the concentration of creaof tannin.

Other: rarely - fever, dehydration, asthenia, peripheral edema, total nedomafeces, increased body temperature.

Overdose:Symptoms: oppression of bone marrow functionha, peripheral neuropathy, mucositis.

Treatment: symptomatic. Antidote to paclitaxel is not known.

Interaction:When treating the first line of ovarian cancer paclitaxel should be used before administrationtion of cisplatin. When paclitaxel atchanges before cisplatin, profile withoutapplication of paclitaxelmonotherapy with paclitaxel. When, if paclitaxel applied after cisplatintine, patients have moreMyelosuppression and 25% decrease clearance of paclitaxel. In patients, takeThe combination of paclitaxel / cisplatin, risk of developing kidney failurecompared with cisplatin monotherapyin the treatment of small-pelvic women.

When treating breast cancerpaclitaxel / doxorubicin infusion paclitaxel should be administered through 24 hours after the administration of doxorubicin. When earlier administration of paclitaxel may to reduce the excretion of doxorubicin and its active metabolites.

The metabolism of paclitaxel is catalyzed, in particular, by isoenzymes CYP2C8 and CYP3A4 systems of cytochrome P450. Simultaneous use of potent inhibitors of isoenzymeCYP3A4, for example, ketoconazole, does not prevent the excretion of paclitaxel in patients, so there is no need to adjust the dose.

Other data on the potential drug interaction between paclitaxel and other isoenzyme inhibitors CYP3A4 are limited. Therefore, care should be taken when using paclitaxel concomitantly with known isozyme inhibitors CYP2C8 and CYP3A4 (eg, erythromycin, CYP3A4 (eg, rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine).

Simultaneous use with cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the binding of paclitaxel to blood plasma proteins.

The systemic clearance of paclitaxel was significantly lower when used with nelfinavir and ritonavir and did not change when used with indinavir. The interaction of paclitaxel with other protease inhibitors of information is not enough. Therefore, caution should be exercised when using paclitaxel in patients taking protease inhibitors.

Polyoxyethylated castor oil (macrogol glycerylriciniloleate), which is part of paclitaxel, can cause extraction of DEHP [di- (2-ethylhexyl) phthalate] from plasticized PVC containers, where the degree of leaching of DEHP increases with increasing solution concentration and over time.

Special instructions:Treatment with the drug Paclitaxel-Teva should be carried out under the supervision of a doctor who has experience with antitumor chemotherapeutic drugs. Taking into account the possibility of extravasation, it is necessary to control the introduction ofpaclitaxel-Teva.

It should be taken into account that in connection with the possibility of developing serious hypersensitivity reactions, appropriate precautions must be taken in advance. Serious hypersensitivity reactions, accompanied by shortness of breath, arterial hypotension, requiring therapeutic intervention, generalized urticaria, were observed in less than 1% of patients who received the drug Paclitaxel-Teva after adequate premedication. These reactions are probably histamine-mediated. In case of severe hypersensitivity reactions, the infusion of Paclitaxel-Teva should be stopped immediately and symptomatic treatment started. Re-administer the drug Paclitaxel-Teva to such patients should not.

If the Paclitaxel-Teva preparation is used in combination with cisplatin, the first drug should be Paclitaxel-Teva, and then cisplatin.

The inhibition of bone marrow function (primarily neutropenia) is the main toxic effect limiting the dose of the drug Paclitaxel-Teva. During the treatment it is necessary to regularly monitor the blood test.

Patients with hepatic insufficiency are most at risk of toxic developmentthe effect of the drug Paclitaxel-Teva, which may manifest myelosuppression of 3-4 degrees. There is no evidence that patients with moderate liver dysfunction may have a toxic effect with a 3-hour infusion of Paclitaxel-Teva. With a longer administration of the drug Paclitaxel-Teva, the degree of myelosuppression increases in patients with moderate to severe hepatic impairment. There is insufficient data to recommend a change in the dose of Paclitaxel-Teva in patients with mild or moderate impairment of liver function. There is no data on the use of the drug Paclitaxel-Teva in patients with initially severe cholestasis. In patients with severe impairment of liver function, the use of Paclitaxel-Teva is not recommended.

With monotherapy with the drug Paclitaxel-Teva, cardiac conduction disorder rarely develops. In cases of development of severe atrioventricular conduction disorders with repeated administration, appropriate therapy and continuous cardiomonitoring should be carried out. Decrease and increase of blood pressure, bradycardia, recorded during cardiomonitoring, as a rule,are not accompanied by subjective symptoms and do not require treatment. The most frequent change in vital indicators cardiac activity is observed during the first hour of infusion of the drug Paclitaxel-Teva. Severe cardiac abnormalities are more common in patients with non-small cell lung cancer than in ovarian cancer and breast cancer. In patients with Kalosha's sarcoma, no cases of heart failure were recorded. Before the first-line treatment of metastatic breast cancer with a combination of Paclitaxel-Teva with doxorubicin or trastuzumab, the patient's cardiac activity should be carefully monitored (history, physical examination, electrocardiography, echocardiography, multiple input isotope arteriography). During treatment with these combinations, careful cardiomonitoring (eg every 3 months) is required in order to be able to identify patients with progressive cardiac dysfunction and to modify the cumulative dose in time (mg / m²) anthracyclines.With a decrease in the contractile function of the myocardium, even in the case of asymptomatic flow, the attending physician should carefully evaluate the ratio of the expected benefit to the duration of chemotherapy and the possible risk of worsening cardiac activity, including the risk of irreversible damage to the myocardium. When continuation of chemotherapy cardiomonitoring should be carried out more often (for example, through 1-2 cycles). For more information, see the instructions for medical use of medications doxorubicin and trastuzumab.

Despite the fact that with the use of the drug Paclitaxel-Teva symptoms of peripheral neuropathy occur frequently, severe manifestations of them are rare.

The drug Paclitaxel-Teva in combination with radiotherapy, regardless of the chronology of the application of this regimencan contribute to the development of interstitial pneumonitis.

Rare cases of pseudomembranous colitis in patients who did not use antibiotics simultaneously with Paclitaxel-Teva should be differentiated from cases of severe or persistent diarrhea,which can occur during or shortly after the end of treatment with the drug Paclitaxel-Teva.

Since the preparation Paclitaxel-Teva contains ethanol (396 mg / ml), it is necessary to take into account the possibility of developing unwanted reactions from the central nervous system.

Men and women of reproductive age should be treated with effective methods of contraception during treatment with Paclitaxel-Teva and at least 6 months after the end of therapy. Men should be advised to carry out cryopreservation of sperm before starting treatment with the drug Paclitaxel-Teva because of the possible development of infertility.

The drug Paclitaxel-Teva is a cytotoxic substance that should be used with caution, 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.

After diluting the concentrate, the physicochemical stability of the Paclitaxel-Teva preparation is maintained for 96 hours at a temperature of less than 25 ° C.

After dilution, the solution should not be frozen.

Effect on the ability to drive transp. cf. and fur:During the period of treatment with the drug Paclitaxel-Teva, care must be taken when driving vehicles and engaging in other potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions, in connection with the possible development of dizziness.

Form release / dosage:Concentrate for solution preparation for infusions of 6 mg / ml.

Packaging:At 30 mg / 5 mL, 100 mg / 16.7 mL, 150 mg / 25 mL and 300 mg / 50 ml in glass bottles with stoppers of rubber brombutyl, aluminum caps and protective cover-insert from color polypropylene. The vials are covered with a transparent film of p / e.

1 bottle together with the instructions for application in a cardboard bundle.

Storage conditions:

At a temperature of no higher than 25 ° C in a dark place.

List B.

Keep out of the reach of children!

Shelf life:

2 of the year.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-003654/09

Date of registration:15.05.2009

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

PHARMACHEMIE, B.V. Netherlands

Representation: & nbspTeva Teva Israel

Information update date: & nbsp14.10.2015

Illustrated instructions

Instructions

Paclitaxel-Teva (Paclitaxel-Teva)