Paclitaxel dosage. Medicinal reference book geotar

One of the most popular anticancer drugs today is Paclitaxel. This medicine plant origin, which is isolated from the bark of a yew tree. Also, it is obtained by synthesis and semi-synthesis.

Clinical research and anti-cancer properties

"Paclitaxel" has a cytotoxic antimycotic effect. It belongs to the taxanes that have begun to be used to treat oncological diseases in the 90s of the twentieth century. The introduction of Paclitaxel into the treatment regimen for ovarian cancer made it possible to increase the effectiveness of such therapy up to 79%, and the number of complete regressions reached 46%.

Paclitaxel is the first drug that has demonstrated high efficacy (16% to 50%) in the treatment of patients suffering from malignant neoplasms of the ovaries, in whom platinum therapy has previously been ineffective.

In the US, it has been widely used for ovarian cancer since 1992, and in 1998 it was approved by the FDA as a first-line treatment for this disease. Its combination with Carboplatin has become the standard treatment regimen.

"Paclitaxel" began to be widely introduced into everyday clinical practice. He was prescribed in combination with Cisplatin or Carboplatin. But in 1995-1998, a study was conducted that showed that the separate use of Carboplatin is not inferior in effectiveness when it is co-administered with Paclitaxel, and if we take into account how many adverse reactions occur against the background of such a combination, then monotherapy " Carboplatin" for ovarian cancer stage I-III was preferable.

The benefit of treatment regimens that included Paclitaxel was only apparent in patients with residual tumor greater than 1 cm.

During clinical research, an increase in the therapeutic effect was found with the simultaneous use of "Paclitaxel" with the following drugs:

• "Gemcitabine";
• "Topotecan";
• "Fluorouracil";
• "Cisplatin";
• "Cyclophosphamide";
• "Etoposide";
• "Vincristine".

In the course of clinical studies, "Paclitaxel" proved to be highly effective, especially in the treatment of patients with an unfavorable prognosis, when the residual size of the neoplasm is more than 1 cm.

After intravenous administration the drug binds to plasma proteins, the half-distribution time from the bloodstream to the tissues is half an hour. It quickly penetrates and is absorbed by tissues, is deposited in many internal organs. Passing through the liver, it undergoes metabolism, and does not accumulate upon repeated administration. Excreted through the kidneys.

For what types of cancer is Paclitaxel indicated?

The drug is prescribed to patients suffering from:

• breast cancer;
• Kaposi's sarcoma.

Composition and active substance

The drug is produced in the form of a concentrate for the manufacture of an infusion solution, which, as active substance contains 6 mg of paclitaxel. As additional components, the drug contains:

• anhydrous ethyl alcohol;
• nitrogen;
• Cremophor EL.

Dosage and rules of administration

The treatment regimen is selected on an individual basis. Each patient, in order to prevent severe hypersensitivity reactions, is given premedication before starting therapy. For this purpose, the following drugs are administered:

1. “ ” in tablets at a dosage of 20 mg (with Kaposi's sarcoma at a dosage of 8 to 20 mg) 12 hours and 6 hours before the infusion of Paclitaxel or injections 0.5-1 hours before the administration of the antitumor agent.
2. Diphenhydramine at a dosage of 300 mg, Chlorpheniramine 10 mg, Ranitidine 50 mg, Cimetidine 300 mg as intravenous injections 30-60 minutes before Paclitaxel infusions.

The drug for ovarian cancer is administered as an intravenous infusion in the following dosages:

1. As first-line chemotherapy: at a dosage of 175 mg / m 2 for 3 hours, after that, “Cisplatin” is administered every 21 days, or at a dosage of 135 mg / m 2 during the day, after which “Cisplatin” is also administered every 3 weeks ”(In the same dosages, Paclitaxel is prescribed for non-small cell lung cancer).
2. As a second line therapy: at a dosage of 175 mg/m 2 every 3 weeks.

"Paclitaxel" for breast cancer is prescribed at a dosage of 175 mg / m 2 for 3 hours, 1 time in 3 weeks:

1. carried out after the completion of the standard complex treatment, a total of 4 infusions of medication are given.
2. First-line therapy is given after completion of adjuvant treatment.
3. Second-line therapy is given to patients who have failed chemotherapy.

With angiosarcoma in AIDS patients, Paclitaxel is recommended to be prescribed as a second-line therapy, after unsuccessful chemotherapy. It is prescribed at a dose of 135 mg/m 2 every 21 days or at a dosage of 100 mg/m 2 every 14 days. Enter the drug in the form of a 3-hour infusion.

Depending on the severity of immunosuppression in AIDS patients, it is recommended to prescribe treatment only when the number of neutrophils is at least 1000/µl, platelets - 75000/µl.

If the patient has a decrease in the number of platelets below 500 / μl for a week or a pronounced form of neutropenia, mucositis, then the dosage should be reduced by 25% until it reaches 75 mg / m 2.

For patients suffering from impaired liver function, the dosage is selected depending on the activity of its enzymes and the level of bilirubin in the blood.

Before administering the drug, the concentrate must be diluted in saline solution, 5% glucose solution, 5% dextrose solution in saline solution or Ringer's solution to obtain a concentration of 0.3-1.2 mg per 1 ml. The resulting solution may be opalescent.

Prepare the solution should be specially trained personnel in compliance with aseptic conditions. In this case, hands must be protected with gloves. It is necessary to avoid contact of the drug with the skin and mucous membranes, but if this happens, the drug should be washed off with water.

Mechanism of action

"Paclitaxel" disrupts the process of cell division. It stimulates the assembly of microtubules from the dimeric protein tubulin, inhibits their depolymerization, as a result, they are stabilized, their dynamic reorganization is blocked in the interphase and during mitosis. Induces pathological accumulation of microtubules in the form of bundles cell cycle and simultaneously promotes the formation of multiple microtubule stars during cell division.

Contraindications and important restrictions for use

The drug is contraindicated if there is:

• individual intolerance to the composition of the drug;
• severe liver pathology;
• the period of bearing a child;
• lactation;
• age under 18;
• the initial number of neutrophils is less than 1.5 10 9/l in patients with large neoplasms;
• severe uncontrolled infectious diseases in patients suffering from Kaposi's sarcoma;
• initial or recorded during therapy, the content of neutrophils is less than 1·10 9/l in patients with Kaposi's angiosarcoma.

With caution, it is prescribed to cancer patients suffering from such pathologies as:

• decrease in the level of platelets (below 100 10 9 / l);
• violation in the liver of mild and moderate severity;
• infections in the acute stage, including those caused by the herpes virus;
• oppression of bone marrow hematopoiesis;
• severe course of ischemic heart disease;
• arrhythmia;
• experienced myocardial infarction.

Side effects

During treatment with the drug, the following adverse reactions from the system may occur:

1. Hematopoiesis: myelosuppression; decrease in the number of neutrophils, hemoglobin, platelets, leukocytes; bleeding; neutropenic fever; ; acute non-lymphoblastic leukemia;
2. Metabolism: tumor decay syndrome.
3. Auditory: hearing loss; tinnitus; dizziness.
4. Nervous: neurotoxicity; peripheral and autonomic neuropathy; convulsions; cephalgia; violations of coordination of movement; encephalopathy.
5. visual: damage to the optic nerve; eye migraine; yellow spot; photopsy; the appearance of flies before the eyes.
6. Respiratory: dyspnea; respiratory failure; pulmonary embolism; fibrosis of the lung; accumulation of fluid in the pleural cavity; interstitial lung inflammation; cough.
7. Musculoskeletal system: joint and muscle pain; systemic lupus erythematosus.
8. Cardiovascular: cardiomyopathy; hypotension or hypertension; "tides"; slowing or increased heart rate; shock; myocardial infarction; phlebitis and thrombophlebitis; atrioventricular blockade and fainting; vein thrombosis; heart failure; ventricular fibrillation.
9. Digestion : liquid stool; constipation; stomatitis; vomit; nausea; esophagitis; ischemic and pseudomembranous colitis; inflammation of the pancreas; intestinal obstruction; rupture of the intestinal walls; liver necrosis; complete refusal to eat; thrombosis of the mesenteric artery; abdominal dropsy; hepatic encephalopathy, which can lead to the death of the patient.
10. Immune: rashes; angioedema; anaphylaxis; chills; excessive sweating; generalized urticaria.
11. Skin and subcutaneous tissue: pathological hair loss; reversible changes in nails and skin; malignant exudative erythema; erythema multiforme; dermatitis; detachment of nails from the nail bed; scleroderma.

In addition, against the background of therapy, the development of infectious diseases is possible, which can result in the death of the patient, local reactions, such as swelling, pain, redness and induration, hemorrhage at the injection site.

During treatment, general well-being may suffer: the temperature rises, peripheral edema develops, impotence.

Laboratory tests may show an increase in liver enzymes, bilirubin and creatinine levels.

special instructions

Treatment must be carried out under the supervision of a specialist who has experience in the use of antitumor agents.

With the appearance of dyspnea, a drop in pressure, the development of generalized urticaria, angioedema after the introduction of Paclitaxel, it is worth stopping and prescribing symptomatic treatment. The drug should not be re-introduced.

During the administration of the drug, you need to control blood pressure, pulse and breathing.

With the development of severe disorders of atrioventricular conduction, it is necessary to carry out appropriate therapy, and with the subsequent administration of the drug, it is necessary to constantly monitor the heart.

With the development of a severe form of peripheral neuropathy with a secondary administration, the dosage medicinal product should be reduced by 20%.

During therapy, it is necessary to constantly monitor the level of formed elements of blood cells at short intervals.

Help with overdose

In case of an overdose, the victim develops the following symptoms:

• mucositis (toxic-inflammatory disease of the oral mucosa and submucosal tissue);
• peripheral neurotoxicity;
• myelosuppression (decrease in the number of blood cells produced in the bone marrow).

There is no specific antidote. The victim is prescribed drugs that eliminate signs of intoxication.

Terms of sale, price, analogues

You can buy the drug strictly according to the doctor's prescription. On sale you can find an antitumor agent from various manufacturers:

• "Biolek";
• "Teva Private Co";
• "Pliva";
• Pharmachemy B.V.;
• “EBEWE PHARMA Ges.m.b.H.Nfg.KG.”.

The cost of the drug in pharmacies starts from 577 rubles.

In addition, on sale you can find analogues of the drug:

• "Mitotaks";
• "Taxol";
• "Intaxel".

Only a specialist should select an analogue!

Self-medication with Paclitaxel is unacceptable, only a doctor can choose an adequate therapy regimen.

Pharmacokinetics of the drug Paclitaxel "Ebeve"

After the administration of the drug, a two-phase decrease in the concentration of paclitaxel in the blood plasma is observed.

The pharmacokinetics of paclitaxel was studied with the introduction of the drug for 3 and 24 hours at doses of 135 mg/m 2 and 175 mg/m 2 . The average duration of the half-life in the terminal phase is 3-52.7 hours, and the average total clearance from the body is 11.6-24.0 l/h m 2 . It is likely that the total clearance of paclitaxel from the body decreases with an increase in its concentration in the blood plasma. The mean steady state volume of distribution of paclitaxel was 198-688 L/m 2 , indicating a wide extravascular distribution and/or tissue binding. With an infusion duration of 3:00, the pharmacokinetics of paclitaxel was non-linear. With an increase in doses by 30% (from 135 mg / m 2 to 175 mg / m 2), the maximum concentration in blood plasma, the maximum concentration and the area under the pharmacokinetic curve AUC → ∞ increased by 75% and 81%.

After the introduction of paclitaxel at a dose of 100 mg / m 2 by 3-hour infusion, the average Cmax in 19 patients with Kaposi's sarcoma was 1530 ng / ml (range 761-2860 ng / ml), the average area under the pharmacokinetic curve - 5619 ng h / ml (range 2609-9428 ng h / ml), clearance - 20.6 l / h m 2 (range 11-38 l / h m 2), volume of distribution - 291 l / m 2 (range 121-638 l / m 2 ), and the half-life in the terminal phase is 23.7 hours (range 12-33 hours).

Intrasubject variability in systemic exposure to paclitaxel was minimal. Signs of accumulation of paclitaxel were not found during several courses of treatment.

The results of in vitro studies indicate that 89-98% of paclitaxel binds to human plasma proteins. The presence of cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect protein binding of paclitaxel.

The metabolism of paclitaxel in humans has not been studied. From 1.3% to 12.6% of the administered dose is excreted unchanged in the urine, indicating extensive non-renal clearance. Probably, paclitaxel is metabolized in the liver with the participation of isoenzymes of the cytochrome P450 system and excreted in the bile. Following administration of radiolabeled paclitaxel, an average of 26%, 2%, and 6% of the radioactivity was excreted in the feces, respectively, as 6α-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel, and 6α-3'p-dihydroxypaclitaxel. The formation of these hydroxylated metabolites is catalyzed by CYP2C8 and CYP3A4 isoenzymes, respectively, and together by CYP2C8 + CYP3A4. The effect of impaired renal and hepatic function on the pharmacokinetics of paclitaxel following a 3-hour infusion has not been formally studied. Pharmacokinetic parameters in one patient who required hemodialysis and was treated with paclitaxel at a dose of 135 mg / m 2 by 3-hour infusion did not differ from those in patients without impaired renal function.

With the combined use of paclitaxel and doxorubicin, an increase in the duration of distribution and elimination of doxorubicin and its metabolites was noted. When paclitaxel was administered immediately after doxorubicin, total plasma exposure of doxorubicin was 30% higher than when paclitaxel was administered 24 hours after doxorubicin.

Basic physical and chemical properties

Clear colorless or light yellow solution.

Indications for use of the drug Paclitaxel

• Ovarian cancer (first-line chemotherapy for the treatment of ovarian cancer, as well as in combination with cisplatin for advanced disease or for residual tumors (>1 cm in size) after laparotomy; second-line chemotherapy for metastatic ovarian cancer when standard platinum therapy is ineffective).
• Breast cancer (adjuvant chemotherapy in patients with breast cancer) lymph nodes after standard combination therapy with anthracyclines or cyclophosphamides, primary chemotherapy for local or metastatic breast cancer in combination with anthracyclines or in combination with trastuzumab in case of immunohistochemically detected HER-2 (3+) oncoprotein overdexpression or in the presence of contraindications to anthracycline therapy; monotherapy of metastatic breast cancer in patients who are not candidates for standard anthracycline therapy, or in case of failure of previous anthracycline therapy).
• Advanced non-small cell lung cancer (NSCLC) (combined chemotherapy with cisplatin if surgery and / or radiation therapy cannot be used).
• Kaposi's sarcoma in patients with AIDS (second-line therapy for advanced Kaposi's sarcoma in case of failure of previous therapy with liposomal anthracyclines).

Contraindications when using the drug Paclitaxel

Hypersensitivity to paclitaxel or other components of the drug, especially polyethoxylated castor oils. Paclitaxel is contraindicated during pregnancy and lactation. Neutropenia before treatment (initial neutrophil count<1,5 × 109 / л, в случае саркомы Капоши у больных СПИДом количество нейтрофилов <1 × 109 / л), тромбоцитопения (<100 × 109 / л). Сопутствующие тяжелые неконтролируемые инфекции у больных саркомой Капоши. Тяжелые нарушения функции печени.

Dosing and Administration of Paclitaxel

Before starting treatment with the drug, all patients should receive premedication with corticosteroids, antihistamines and H2 receptor antagonists, for example, according to the following scheme:

Paclitaxel can be used as monotherapy or in combination with other anticancer drugs. The dose and regimen of the drug is selected individually.

To prevent severe hypersensitivity reactions, all patients should be premedicated with corticosteroids, histamine H1- and H2-receptor blockers. The recommended premedication regimen is 20 mg dexamethasone (or equivalent) orally approximately 12 hours and 6 hours before the administration of Paclitaxel Ebewe, 50 mg diphenhydramine (or equivalent) IV and 300 mg cimetidine or 50 mg ranitidine IV 30-60 minutes before the introduction of the drug Paclitaxel "Ebeve".

First line chemotherapy for ovarian cancer
A combination regimen of paclitaxel and cisplatin is recommended. Paclitaxel is administered at a dose of 175 mg/m 2 body surface area during a 3-hour IV infusion or at a dose of 135 mg/m 2 during a 24-hour IV infusion, followed by cisplatin at a dose of 75 mg/m 2 . Intervals between courses - 3 weeks.

Second line chemotherapy for ovarian cancer

Adjuvant chemotherapy for breast cancer

Paclitaxel is prescribed after chemotherapy with anthracyclines and cyclophosphamide. Paclitaxel is recommended to be administered at a dose of 175 mg/m 2 IV for 3 hours 4 courses with intervals between courses - 3 weeks.

First line chemotherapy for breast cancer

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

In the case of combined use with trastuzumab, paclitaxel is recommended to be administered at a dose of 175 mg / m 2 body surface area by 3-hour IV infusion with an interval between courses of 3 weeks. Paclitaxel may be given the day after the first dose of trastuzumab, or immediately after subsequent doses if previous doses of trastuzumab have been well tolerated.

Second line chemotherapy for breast cancer

Chemotherapy for advanced non-small cell lung cancer

A combination regimen of paclitaxel and cisplatin is recommended. Paclitaxel is administered at a dose of 175 mg/m 2 of the body surface by a 3-hour IV infusion, followed by cisplatin at a dose of 80 mg/m 2. The intervals between courses are 3 weeks.

Chemotherapy for Kaposi's sarcoma on the background of AIDS

Paclitaxel is recommended to be administered at a dose of 100 mg/m 2 by 3-hour IV infusion. Intervals between courses - 2 weeks.
Subsequent doses of paclitaxel are set individually depending on the tolerability of therapy. The next dose of paclitaxel can be administered only after the 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 the level of > 100,000 cells/mm3 (> 75,000 cells/mm3 in the case of Kaposi's sarcoma) . Patients who have experienced severe neutropenia (neutrophil count less than 500 cells / μl for 7 days or more) or severe peripheral neuropathy, the following doses are reduced by 20% (25% in the case of Kaposi's sarcoma).

There are currently insufficient data to make recommendations for dose adjustments in patients with mild or moderate hepatic impairment.

Patients with severe hepatic impairment should not be given paclitaxel.

Rules for preparing a solution for infusion

When preparing, storing and administering Paclitaxel Ebeve, equipment that does not contain PVC should be used, such as 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 dilution 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's solution. Prepared solutions may become opalescent due to the carrier base present in the dosage form. When administering the drug, a system with a membrane filter (pore size no more than 0.22 µm) should be used.

Solutions for infusion prepared by diluting Paclitaxel "Ebeve", 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 if stored at 5 ° C FROM. From a microbiological point of view, the solution for infusion should be administered immediately after preparation. If the solution is not used immediately after preparation, the storage time should not exceed 24 hours at 2° to 8°C, unless the solution has been prepared under controlled aseptic conditions.

To reduce the risk of sedimentation, the solution for infusion should be administered immediately after dilution and excessive shaking, vibration and shaking should be avoided.
The infusion set must be thoroughly flushed before use. During the introduction, it is necessary to regularly monitor the appearance of the solution and, if a precipitate is detected, stop the infusion.

Side effects of Paclitaxel

The use of the drug Paclitaxel "Ebeve", may cause side effects:

From the hematopoietic system: very often - myelosuppression, neutropenia, thrombocytopenia, anemia, leukopenia, bleeding; rarely - febrile neutropenia; very rarely - acute myeloid leukemia, myelodysplastic syndrome.

From the nervous system: very often - neurotoxic effects (mainly peripheral neuropathy), paresthesia; rarely - motor neuropathy (moderate weakness of the distal muscles, difficulty in performing precise movements); very rarely - autonomic neuropathy (leading to paralytic ileus and orthostatic hypotension), grand mal seizures (grand mal), convulsions, encephalopathy, dizziness, headache, confusion, ataxia.

From the side of 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 - damage to the optic nerve and / or visual impairment (atrial scotoma), hearing loss, tinnitus, dizziness.

From the respiratory system: rarely - shortness of breath, pleural effusion, interstitial pneumonia, pulmonary fibrosis, pulmonary embolism, respiratory failure, radiation pneumonitis in patients simultaneously undergoing radiation therapy; very rare - cough.

From the digestive system: very common - 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 death).

From the skin and skin appendages: very often - alopecia; often - transient small changes in nails and skin (pigmentation disorder, 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 musculoskeletal system: very often - arthralgia, myalgia.

From the immune system: very frequent - infections (mainly of 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.

From the side 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 pigmentation of the skin at the injection site; extravasation can cause inflammation and necrosis of the subcutaneous tissue.

Others: rarely - asthenia, fever, dehydration, general weakness.

Contraindications for the use of Paclitaxel

Contraindications to the use of the drug Paclitaxel "Ebeve", are:

• hypersensitivity to the components of the drug;
• hypersensitivity to other drugs, the dosage form of which includes polyoxyl castor oil;
• the initial content of neutrophils is less than 1500/µl in patients with solid tumors;
• initial (or registered during treatment) neutrophil content less than 1000/µl in Kaposi's sarcoma in AIDS patients; pregnancy;
• lactation (breastfeeding);
• children's age (safety and effectiveness have not been established).

Use with caution in patients with inhibition of bone marrow hematopoiesis (including after chemotherapy or radiation therapy), liver failure, acute infectious diseases (including herpes zoster, chickenpox, herpes), severe coronary artery disease, with a heart attack myocardium in history, with arrhythmias.

Use during pregnancy or lactation

Information on the treatment of pregnant women with paclitaxel is not available. As with other cytotoxic drugs, paclitaxel can cause harm to the fetus and should therefore not be used during pregnancy.

Women and men should use contraceptives to prevent pregnancy during treatment with paclitaxel and for at least 6 months after the end of treatment with paclitaxel and inform the doctor immediately if pregnancy does occur.

During treatment with paclitaxel, breast-feeding should be discontinued.

If necessary, perform cryopreservation of sperm in men before starting treatment with paclitaxel due to the possible development of infertility.

Children and drug

The safety and efficacy of paclitaxel in children have not been established, therefore paclitaxel is not recommended for use in this category of patients.

Features of the use of the drug Paclitaxel

Treatment with paclitaxel should be carried out under the supervision of a qualified oncologist experienced in the use of anticancer chemotherapeutic agents. Since serious hypersensitivity reactions are possible, appropriate resuscitation equipment must be available.

Since extravasation during drug administration is possible, it is recommended to carefully monitor the infusion area for signs of possible infiltration.

Before the introduction of paclitaxel, patients should receive premedication with corticosteroids, antihistamines and H2 receptor antagonists.

When combined with cisplatin, paclitaxel should be administered in addition to cisplatin.

Severe hypersensitivity reactions characterized by dyspnoea, arterial hypotension (requiring appropriate therapeutic measures), angioedema and generalized urticaria were observed in less than 1% of patients receiving paclitaxel after adequate premedication. These symptoms are probably histamine-mediated reactions. In the event of severe hypersensitivity reactions, the use of the drug should be stopped immediately and symptomatic treatment should be started, and the drug should not be re-administered.

Bone marrow suppression (mainly neutropenia) is the main toxic effect that limits the dose of the drug. During treatment with paclitaxel, it is necessary to control the content of blood cells at least 2 times a week. Re-administration of the drug is allowed only after an increase in the number of neutrophils to a level of ≥ 1.5 × 109 / l (≥ 1.0 × 109 / l in the case of Kaposi's sarcoma), and platelets - to a level of ≥ 100 × 109 / l (≥ 75 × 109 / l in the case of Kaposi's sarcoma). During clinical trials, most patients with Kaposi's sarcoma received granulocyte colony-stimulating factor (GCSF).

The risk of toxic effects (in particular myelosuppression III-IV severity) is higher in patients with impaired liver function. With the introduction of paclitaxel by 3-hour infusion, there is no increase in toxic effects in patients with mild hepatic impairment. However, with more prolonged administration of paclitaxel in patients with moderate hepatic impairment, more pronounced myelosuppression may be observed. Patients with severe hepatic impairment should not be given paclitaxel. Patients should be closely monitored for signs of profound myelosuppression. To date, insufficient data are available to develop dose adjustment recommendations for patients with mild or moderate hepatic impairment. Information on the treatment of patients with severe cholestasis with paclitaxel is not available. Patients with severe renal insufficiency should not be treated with paclitaxel.

Severe cardiac conduction disturbances have rarely been reported with paclitaxel treatment. When they appear, it is necessary to prescribe appropriate treatment, and in the case of further administration of the drug, continuous monitoring of cardiac function should be carried out. It is recommended that vital signs be monitored during the first hour of paclitaxel administration. With the introduction of paclitaxel, the development of arterial hypotension, arterial hypertension and bradycardia is possible.

Severe cardiovascular events are more common in patients with non-small cell lung cancer than in those with breast or ovarian cancer. During clinical trials, one case of heart failure was noted after paclitaxel therapy in a patient with Kaposi's sarcoma with AIDS.

When paclitaxel is used in combination with doxorubicin or trastuzumab for primary chemotherapy in metastatic breast cancer, consideration should be given to monitoring cardiac function. Patients who are candidates for such combination therapy should undergo a thorough cardiac examination, including ECG and echocardiography studies, as well as MUGA scanning, before starting treatment. During treatment, it is necessary to regularly monitor the function of the heart (for example, every 3 months). Such monitoring allows timely detection of the development of cardiac dysfunction. When deciding on the frequency of ventricular function monitoring, the cumulative dose of anthracyclines (in mg/m2) must be taken into account. If test results suggest cardiac dysfunction, even if asymptomatic, the potential benefit of continuing treatment should be carefully weighed against the possible risk of heart damage, sometimes irreversible. In case of continuation of combined chemotherapy, it is necessary to monitor the function of the heart more often (every 1-2 courses).

Although peripheral neuropathy is a common side effect of paclitaxel treatment, severe neuropathy is rare. In severe cases, it is recommended to reduce all subsequent doses of paclitaxel by 20% (25% in the case of Kaposi's sarcoma). Peripheral neuropathy may develop after the first course of therapy and become more severe with continued treatment with paclitaxel. Severe neurotoxicity occurred more frequently in patients with non-small cell lung cancer and ovarian cancer who received first-line chemotherapy with paclitaxel as a 3-hour infusion in combination with cisplatin than in patients who received paclitaxel or cyclophosphamide alone followed by cisplatin. Sensory disturbances usually improve or disappear within a few months after paclitaxel therapy is discontinued. Pre-existing neuropathy due to previous chemotherapy is not a contraindication for treatment with paclitaxel.

Since Paclitaxel "Ebeve" contains ethanol, it is necessary to take into account its possible effect on the central nervous system, as well as other effects.

The preparation contains polyoxyl castor oil, which can cause severe allergic reactions.

All measures should be taken to prevent intra-arterial administration of paclitaxel, since animal experiments have shown severe tissue reactions after intra-arterial administration of the drug.

There have been isolated cases of pseudomembranous colitis, especially in patients who did not receive concomitant antibiotic therapy. This should be considered in the differential diagnosis if severe or persistent diarrhea develops during or shortly after treatment with paclitaxel.

During chemotherapy with paclitaxel in combination with radiation therapy to the lung region, regardless of their sequence, cases of interstitial pneumonitis have been noted.

In patients with Kaposi's sarcoma, severe inflammation of the mucous membranes is rare. In case of severe reactions, the dose of paclitaxel is reduced by 25%.

When using paclitaxel in combination with other antineoplastic drugs (cisplatin, doxorubicin, trastuzumab), the recommendations for the use of these drugs should be taken into account.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms

During the period of treatment with paclitaxel, one should refrain from potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions. It should be borne in mind that Paclitaxel "Ebeve" contains ethanol, and some side effects may adversely affect the ability to drive vehicles or work with mechanisms.

Interaction with other medicinal products and other forms of interaction

Premedication with cimetidine does not affect the clearance of paclitaxel.

In first-line combination chemotherapy for ovarian cancer, paclitaxel must be administered in cisplatin. In this case, the safety profile of paclitaxel does not differ from that of monotherapy. If paclitaxel is administered after cisplatin, more severe myelosuppression is observed, and the clearance of paclitaxel is reduced by approximately 20%. The risk of developing renal failure in patients with ovarian cancer receiving combination therapy with paclitaxel and cisplatin is higher than with cisplatin monotherapy.

Because the elimination of doxorubicin and its active metabolites may be reduced by shortening the time between paclitaxel and doxorubicin doses, paclitaxel should be administered 24 hours after doxorubicin in primary chemotherapy for metastatic breast cancer.

The metabolism of paclitaxel is partially catalyzed by the CYP2C8 and CYP3A4 isoenzymes of the cytochrome P450 system. Clinical studies have shown that the major metabolic transformation in humans is the CYP2C8-mediated conversion of paclitaxel to 6α-hydroxypaclitaxel. Concomitant use of ketoconazole, a potent inhibitor of CYP3A4, does not slow down the elimination of paclitaxel from the body, so both drugs can be used simultaneously without dose adjustment. Information on the potential interaction of paclitaxel with inducers and inhibitors of CYP3A4 is limited, so caution is necessary when prescribing inhibitors (eg, ketoconazole and other antifungal imidazole derivatives, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir and nelfinavir) or inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine) CYP2C8 and CYP3A4 isoenzymes.

Pharmacokinetic studies of paclitaxel in patients with Kaposi's sarcoma who received concomitant therapy with several drugs indicate a significant decrease in the systemic clearance of paclitaxel with simultaneous use of nelfinavir and ritonavir, but not indinavir. There is insufficient information on the interaction of paclitaxel with other protease inhibitors. Therefore, paclitaxel should be used with caution in patients receiving concomitant therapy with protease inhibitors.

Incompatibility with Paclitaxel

Polyoxyl castor oil, which is part of Paclitaxel Ebewe, can cause leaching of dietylhexyl phthalate (DEHP) from plasticized PVC. The intensity of this process depends on the duration of action and the concentration of castor oil. Therefore, it is necessary to prepare, store and administer solutions for infusion using containers and systems that do not contain PVC.

Do not use with other solvents, except those indicated in the section "Method of application and dosage".

Storage conditions

Does not require special storage conditions.

Keep out of the reach of children.

Package

Clear glass bottle stoppered with a fluoropolymer coated halobutyl rubber stopper and aluminum crimp cap; 5 ml (30 mg) or 16.7 ml (100 mg), or 25 ml (150 mg), or 35 ml (210 mg) or 50 ml (300 mg) in a vial; 1 bottle in a cardboard box.

Antitumor agent. It is an inhibitor of mitosis. Paclitaxel binds specifically to microtubule beta-tubulin, disrupting the depolymerization of this key protein, which leads to the suppression of the normal dynamic reorganization of the microtubule network, which plays a crucial role during interphase and without which cellular functions cannot be carried out in the mitotic phase. In addition, paclitaxel induces the formation of abnormal microtubule bundles throughout the cell cycle and the formation of multiple centrioles during mitosis.

Pharmacokinetics

Release form

5 ml - bottles (1) from a glass tube - packs of cardboard.
5 ml - glass bottles (1) - cardboard packs.
16.7 ml - glass bottles (1) - cardboard packs.
25 ml - glass bottles (1) - cardboard packs.
35 ml - glass bottles (1) - cardboard packs.
41 ml - glass bottles (1) - cardboard packs.
50 ml - glass bottles (1) - cardboard packs.

Dosage

They are set individually, depending on the indications and the stage of the disease, the state of the hematopoietic system, and the scheme of antitumor therapy.

Interaction

When conducting laboratory studies in patients receiving sequential infusions of paclitaxel and cisplatin, a more pronounced myelotoxic effect was revealed when paclitaxel was administered after cisplatin; while the average values ​​of the total clearance of paclitaxel decreased by about 20%.

Previous intake of cimetidine does not affect the average values ​​of the total clearance of paclitaxel.

Based on the data obtained in vivo and in vitro, it can be assumed that in patients treated with ketoconazole, there is a suppression of the metabolism of paclitaxel.

Side effects

From the hemopoietic system: leukopenia, thrombocytopenia, anemia.

From the digestive system: nausea, vomiting, diarrhea, mucositis, loss of appetite, constipation (rarely - intestinal obstruction), increased blood activity of liver enzymes and bilirubin levels.

Allergic reactions: skin rash, angioedema, rarely - bronchospasm.

From the side of the cardiovascular system: arterial hypotension, bradycardia, conduction disturbances, peripheral edema.

Others: arthralgia, myalgia, peripheral neuropathy.

Local reactions: thrombophlebitis, with extravasation - necrosis.

Indications

Ovarian cancer (including with the ineffectiveness of platinum drugs), breast cancer, lung cancer, esophageal cancer, head and neck cancer, bladder cancer.

Contraindications

Severe neutropenia (less than 1500/µl), pregnancy, hypersensitivity to paclitaxel.

Application features

Use during pregnancy and lactation

Paclitaxel is contraindicated for use in pregnancy. If necessary, use during lactation, breastfeeding should be discontinued.

Women of childbearing age should use reliable methods of contraception while using paclitaxel.

In experimental studies, it was found that paclitaxel has a teratogenic and embryotoxic effect.

Application for violations of liver function

special instructions

Paclitaxel is used with caution in patients with angina pectoris, arrhythmias and conduction disorders, chronic heart failure, chickenpox (including recent or after contact with sick people), herpes zoster and other acute infectious diseases, as well as within 6 months after myocardial infarction.

When using paclitaxel in patients with impaired liver function, dosage adjustment may be required.

To prevent the occurrence of hypersensitivity reactions, all patients should be given premedication (glucocorticosteroids, histamine H 1 and H 2 receptor blockers).

In the process of treatment, systematic monitoring of the picture of peripheral blood, control of blood pressure, ECG is necessary. The next infusion of paclitaxel should not be carried out until the number of neutrophils exceeds 1500 / μl, and the platelet count - 100,000 / μl.

When using paclitaxel in patients with impaired liver function, dosage adjustment may be required.

Do not use PVC infusion sets when preparing and administering paclitaxel solution.

In experimental studies, it was found that paclitaxel has a mutagenic effect.

Instructions for the medical use of the drug

Description of the pharmacological action

Indications for use

Ovarian cancer, breast cancer, non-small cell lung cancer, squamous cell head and neck cancer, transitional cell bladder cancer, esophageal cancer, leukemia, Kaposi's sarcoma in AIDS patients.

Release form

Substance-powder 20-1000 g; package (bag) polyethylene multilayer metal container 1;

Substance-powder; package (bag) polyethylene two-layer 100 g can (jar) 1;

Pharmacodynamics

It has a cytotoxic antimitotic effect.

Activates the assembly of microtubules from tubulin dimers and stabilizes them, preventing depolymerization.

As a result, it inhibits the dynamic reorganization of the microtubular network in the interphase and during mitosis.

Induces an abnormal arrangement of microtubules in the form of bundles throughout the cell cycle and multiple stellate thickenings (asters) during mitosis.

Pharmacokinetics

Pharmacokinetic parameters of paclitaxel were determined after infusions of the drug at doses of 135 and 175 mg/m2 for 3 and 24 hours in phase 3 randomized trials in patients with ovarian cancer. When administered intravenously for 3 hours at a dose of 135 mg / m2, Cmax was 2170 ng / ml, AUC - 7952 ng / h / ml; with the introduction of the same dose for 24 hours - 195 ng / ml and 6300 ng / h / ml, respectively. Cmax and AUC are dose-dependent. With a 3-hour infusion, a dose increase of 30% (from 135 to 175 mg / m2) leads to an increase in Cmax and AUC by 68 and 89%, respectively, with a 24-hour infusion, Cmax increases by 87%, AUC - by 26%.

In vitro studies have shown that at concentrations of paclitaxel 0.1–50 μg / ml, 89–98% of the substance binds to serum proteins.

After intravenous administration of paclitaxel, the dynamics of the decrease in plasma concentration is biphasic: the initial rapid decrease reflects distribution in the tissue and its significant excretion. The later phase is partly due to the relatively slow release of paclitaxel from tissues.

With intravenous administration, the half-distribution time from the blood to the tissues is an average of 30 minutes. The apparent volume of distribution at steady state with a 24-hour infusion is 227-688 l / m2. It easily penetrates and is absorbed by tissues, mainly accumulates in the liver, spleen, pancreas, stomach, intestines, heart, muscles.

The metabolism of paclitaxel in humans is not fully understood. After IV infusion (1–24 h), mean cumulative urinary excretion of unchanged substance is 1.3–12.6% of the dose (15–275 mg/m2), indicating extensive extrarenal clearance. It has been shown that the metabolism of paclitaxel in animals is carried out in the liver. Probably the main mechanism of metabolism of paclitaxel in the human body is biotransformation in the liver and excretion in the bile. The main metabolites are hydroxylation products.

The effect of impaired renal or hepatic function on metabolism after a 3-hour infusion has not been studied.

Pharmacokinetic parameters obtained from one patient indicate that dialysis does not affect the rate of excretion of the drug from the body. T1 / 2 and total clearance are variable (depending on the dose and duration of intravenous administration): at doses of 135–175 mg / m2 and an infusion duration of 3 or 24 hours, the average values ​​of T1 / 2 are in the range of 13.1–52.7 hours , clearance - 12.2–23.8 l / h / m2. With repeated infusions does not accumulate.

Use during pregnancy

Contraindicated in pregnancy (possibly embryo- and fetotoxic effects).

At the time of treatment, breastfeeding should be stopped (it is not known whether paclitaxel passes into breast milk).

Contraindications for use

Hypersensitivity (including to polyoxyethylated castor oil), severe neutropenia - less than 1.5 109 / l (initial or developed during treatment), in patients with Kaposi's sarcoma - neutropenia less than 1.0 109 / l (initial or developed during treatment).

Side effects

Based on pooled data from 10 studies including 812 patients (493 ovarian cancer, 319 breast cancer), the following side effects were observed at different doses and for different durations of paclitaxel administration.

Hematological: neutropenia less than 2 109/l (90%), neutropenia less than 0.5 109/l (52%), leukopenia less than 4 109/l (90%), leukopenia less than 1 109/l (17% ), thrombocytopenia less than 100 109/l (20%), thrombocytopenia less than 50 109/l (7%), anemia - hemoglobin level less than 110 g/l (78%), anemia - hemoglobin level less than 80 g/l ( 16%).

Bone marrow suppression (mainly neutropenia) is the main toxic effect limiting the dose of paclitaxel.

Neutropenia depends to a lesser extent on the dose of the drug and to a greater extent on the duration of administration (more pronounced with a 24-hour infusion). The lowest level of neutrophils is usually noted on the 8th-11th day of treatment, normalization occurs on the 22nd day. An increase in temperature was noted in 12% of patients, infectious complications - in 30% of patients. Lethal outcome was registered in 1% of patients diagnosed with sepsis, pneumonia and peritonitis. The most common infections associated with neutropenia are urinary and upper respiratory tract infections.

With the development of thrombocytopenia, the lowest level of platelets is usually observed on the 8-9th day of treatment. Bleeding (14% of cases) was local, the frequency of their occurrence was not related to the dose and time of administration.

The frequency and severity of anemia did not depend on the dose and mode of administration of paclitaxel. RBC transfusion was required in 25% of patients, platelet transfusion - in 2% of patients.

In patients with Kaposi's sarcoma, which developed on the background of AIDS, bone marrow hematopoiesis suppression, infections and febrile neutropenia may occur more frequently and have a more severe course.

Hypersensitivity reactions. The frequency and severity of hypersensitivity reactions did not depend on the dose or mode of administration of paclitaxel. In all patients in clinical studies, adequate premedication was carried out before the introduction of paclitaxel. Hypersensitivity reactions were observed in 41% of patients and mainly manifested in the form of flushing to the face (28%), rash (12%), arterial hypotension (4%), shortness of breath (2%), tachycardia (2%) and arterial hypertension (one%). Severe hypersensitivity reactions that required therapeutic intervention (dyspnea requiring the use of bronchodilators, arterial hypotension requiring therapeutic intervention, angioedema, generalized urticaria) were observed in 2% of cases. These reactions are likely histamine-mediated. In case of severe hypersensitivity reactions, the infusion of the drug should be immediately stopped and symptomatic treatment should be started, and the drug should not be re-administered.

Cardiovascular. Arterial hypotension (12%, n=532) or hypertension and bradycardia (3%, n=537) were noted during drug administration. In 1% of cases, severe side effects were observed, which included syncope, cardiac arrhythmias (asymptomatic ventricular tachycardia, bigeminy and complete AV block and syncope), hypertension and venous thrombosis. One patient with syncope on a 24-hour infusion of 175 mg/m2 paclitaxel developed progressive hypotension with a fatal outcome.

ECG abnormalities were also observed during clinical trials (23%). In most cases, there was no clear association between the use of paclitaxel and ECG changes, changes were not clinically significant or had minimal clinical significance. In 14% of patients with normal ECG parameters before inclusion in the study, ECG abnormalities that occurred during treatment were noted.

Neurological. The frequency and severity of neurological manifestations were dose-dependent, but they were not affected by the duration of the infusion. Peripheral neuropathy, mainly manifested in the form of paresthesia, was observed in 60% of patients, in severe form - in 3% of patients, in 1% of cases it was the reason for discontinuing the drug. The incidence of peripheral neuropathy increased with increasing total dose of paclitaxel. Symptoms usually appear after repeated use and subside or disappear within a few months after stopping treatment. Prior neuropathy due to previous treatment is not a contraindication to paclitaxel therapy.

Other serious neurological disorders observed after the administration of paclitaxel (less than 1% of cases): grand mal seizures, ataxia, encephalopathy. There are reports of neuropathy at the level of the autonomic nervous system, which led to paralytic ileus.

Arthralgia/myalgia were observed in 60% of patients and were severe in 8% of patients. Typically, symptoms were transient, appearing 2–3 days after paclitaxel administration and resolving within a few days.

Hepatotoxicity. An increase in the level of AST, alkaline phosphatase and bilirubin in the blood serum was observed in 19% (n=591), 22% (n=575) and 7% (n=765) of patients, respectively. Cases of liver necrosis and encephalopathy of hepatic origin with a fatal outcome are described.

Gastrointestinal. Nausea/vomiting, diarrhea, and mucositis were reported in 52%, 38%, and 31% of patients, respectively, and were mild to moderate. Mucositis was more common with 24-hour infusion than with 3-hour infusion. In addition, there were phenomena of obstruction or perforation of the intestine, neutropenic enterocolitis (typhlitis), thrombosis of the mesenteric artery (including ischemic colitis).

Reactions at the injection site (13%): local edema, pain, erythema, induration. These reactions are more common after a 24-hour infusion than after a 3-hour one. Currently, no specific form of treatment for reactions associated with drug extravasation is known. There are reports of the development of phlebitis and cellulitis with the introduction of paclitaxel.

Other toxic manifestations. Reversible alopecia was observed in 87% of patients. Complete hair loss occurs in almost all patients between 14–21 days of therapy. There was a violation of pigmentation or discoloration of the nail bed (2%). Transient skin changes have also been observed due to hypersensitivity to paclitaxel. Edema was reported in 21% of patients, incl. in 1% - in a pronounced form, but these cases were not the reason for discontinuing the drug. In most cases, the edema was focal and caused by the disease. There are reports of recurrence of radiation-related skin reactions.

Dosage and administration

In / in, in the form of a 3-hour or 24-hour infusion (immediately before administration, the drug is diluted to a concentration of 0.3–1.2 mg / ml with appropriate solutions).

The dosage regimen is set individually, depending on the indications, previous chemotherapy (or lack thereof), the state of the hematopoietic system, and the chemotherapy regimen.

Overdose

Symptoms: myelosuppression, peripheral neurotoxicity, mucositis.

Treatment: symptomatic. The specific antidote is unknown.

Interactions with other drugs

According to clinical studies, with the introduction of paclitaxel after infusion of cisplatin, more pronounced myelosuppression and a decrease in clearance of paclitaxel by approximately 33% were observed compared with the reverse sequence of administration (paclitaxel before cisplatin).

In in vitro studies, ketoconazole inhibits the biotransformation of paclitaxel. Cimetidine, ranitidine, dexamethasone, diphenhydramine do not affect the binding of paclitaxel to plasma proteins.

Microsomal oxidation inhibitors (including ketoconazole, cimetidine, quinidine, cyclosporine) inhibit the metabolism of paclitaxel.

Precautions for use

Treatment should be carried out by a physician experienced in chemotherapy, and under the conditions necessary for the relief of complications. Mandatory constant monitoring of peripheral blood, blood pressure, heart rate and other parameters of vital functions (especially during the initial infusion or during the first hour of administration).

When using paclitaxel in combination with cisplatin, paclitaxel should be administered first, followed by cisplatin.

To avoid the development of severe hypersensitivity reactions (and to improve tolerability), all patients should be premedicated with glucocorticoids, antihistamines, and histamine H2 receptor blockers before infusion; exemplary regimen: dexamethasone (or equivalent) 20 mg orally or intramuscularly 6–12 hours before paclitaxel, diphenhydramine (or equivalent) 50 mg i.v., and cimetidine 300 mg (or ranitidine 50 mg) i.v. in 30-60 minutes before administration. If severe allergic reactions occur during the infusion, the administration is immediately stopped and symptomatic therapy is carried out.

With the development of neutropenia, patients should not be prescribed the drug again until the neutrophil content is restored to a level of at least 1.5 109 / l and at least 1 109 / l with Kaposi's sarcoma (see "Contraindications"). With the development of severe neuropathic peripheral disorders or severe neutropenia (less than 0.5 109 / l) due to paclitaxel infusion, incl. lasting 7 days or more or accompanied by infectious complications, if necessary, repeated courses are recommended to reduce the dose by 20%.

If significant cardiac conduction disturbances occur during treatment with paclitaxel, appropriate treatment should be prescribed, and subsequent administration of the drug should be followed by continuous monitoring of cardiac function.

During the treatment period, it is shown to refrain from engaging in potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.

** The Medication Guide is for informational purposes only. For more information, please refer to the manufacturer's annotation. Do not self-medicate; Before you start taking Paclitaxel, you should talk to your doctor. EUROLAB is not responsible for the consequences caused by the use of the information posted on the portal. Any information on the site does not replace the advice of a doctor and cannot serve as a guarantee of the positive effect of the drug.

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Active substance

Paclitaxel (paclitaxel)

Release form, composition and packaging

Concentrate for solution for infusion in the form of a clear, colorless or slightly yellowish, viscous solution.

Excipients: macrogol glyceryl ricinyl oleate - 527 mg, anhydrous citric acid - 2 mg, absolute ethanol - 396 mg (up to 933 mg, equivalent to 1 ml).

16.7 ml - glass bottles covered with a transparent polyethylene film (1) - cardboard packs.
50 ml - glass bottles covered with a transparent polyethylene film (1) - packs of cardboard.

Set #2: cardboard pack, elements of the device for infusion systems and syringes for diluting and administering drugs "Tevadaptor" (adapter for a vial, adapter for a syringe, adapter for syringe injection) with instructions for using the device in a cardboard box with or without a cardboard seal and with control of the first opening.

pharmachologic effect

An anticancer drug 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

Suction

When administered intravenously for 3 hours at a dose of 135 mg / m C max is 2170 ng / ml, AUC - 7952 ng / h / ml; with the introduction of the same dose for 24 hours - 195 ng / ml and 6300 ng / h / ml, respectively. C max and AUC are dose-dependent: with a 3-hour infusion, an increase in dose to 175 mg / m 2 leads to an increase in these parameters by 68% and 89%, and with a 24-hour infusion - by 87% and 26%, respectively.

Distribution

Protein binding - 88-98%. The half-distribution time from blood to tissue is 30 minutes. Easily penetrates and absorbed by tissues, accumulates mainly in the liver, spleen, pancreas, stomach, intestines, heart, muscles.

Metabolism and excretion

It is metabolized in the liver by hydroxylation with the participation of CYP2D8 isoenzymes (with the formation of a metabolite - 6-alpha-hydroxypaclitaxel) and CYP3A4 (with the formation of metabolites 3-para-hydroxypaclitaxel and 6-alpha, 3-para-dihydroxypaclitaxel). It is excreted mainly with bile - 90%. With repeated infusions does not accumulate.

T 1/2 and total clearance are variable and depend on the dose and duration of intravenous 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.

Indications

ovarian cancer

- first-line therapy in combination with cisplatin in patients with advanced ovarian cancer or residual tumor (more than 1 cm) after surgery;

- second-line therapy in patients with metastatic ovarian cancer in case standard therapy with platinum drugs is ineffective.

Mammary cancer

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

- first-line therapy of metastatic breast cancer after a relapse of the disease within 6 months after the start of adjuvant therapy with the inclusion of anthracycline drugs, in the absence of contraindications for their use;

- first-line therapy for locally advanced or metastatic breast cancer in combination with anthracycline drugs in the absence of contraindications for their use, or with trastuzumab in patients with immunohistochemically confirmed 2+ or 3+ levels of human epidermal growth factor receptor type 2 (HER- 2) in the presence of contraindications to anthracyclines;

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

Non-small cell lung cancer

- first-line therapy for advanced non-small cell lung cancer in combination with cisplatin in case of impossibility of using surgical treatment and / or radiation therapy.

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

Contraindications

- hypersensitivity to paclitaxel or to other components of the drug, incl. to polyoxyethylated (macrogol glyceryl ricinyl oleate);

- initial ANC less than 1500/µl in patients with solid tumors;

- initial (or registered during treatment) ANC less than 1000/µl in patients with Kaposi's sarcoma;

- concomitant severe uncontrolled infections in patients with Kaposi's sarcoma;

- severe liver dysfunction;

— pregnancy;

- lactation period (breastfeeding);

- children's age (safety and effectiveness have not been established).

FROM caution: oppression of bone marrow hematopoiesis, thrombocytopenia (less than 100,000 / μl), mild and moderate liver dysfunction, acute infectious diseases (including herpes zoster, chicken pox, herpes), severe coronary artery disease, myocardial infarction (history), arrhythmias .

Dosage

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

To prevent severe hypersensitivity reactions, all patients should undergo premedication with the use of corticosteroids, antihistamines and histamine H 1 and H 2 receptor antagonists. The recommended premedication regimen is presented in Table 1.

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

** or equivalent, such as chlorpheniramine 10 mg IV.

ovarian cancer

First line therapy

Second line therapy (monotherapy)

At a dose of 175 mg / m 2 as a 3-hour intravenous infusion 1 time in 3 weeks.

Mammary cancer

adjuvant therapy

After the standard combined treatment, 4 courses of therapy with Paclitaxel-Teva at a dose of 175 mg/m 2 are carried out as a 3-hour intravenous infusion every 3 weeks.

First line therapy

Monotherapy: at a dose of 175 mg / m 2 as a 3-hour intravenous infusion every 3 weeks.

In combination with doxorubicin: 24 hours after the administration of doxorubicin - at a dose of 220 mg / m 2 as a 3-hour intravenous infusion every 3 weeks.

In combination with trastuzumab: the next day after the first dose of trastuzumab - at a dose of 175 mg/m 2 as a 3-hour IV infusion every 3 weeks; with good tolerability of trastuzumab - immediately after the introduction of subsequent doses of trastuzumab.

Second line therapy

At a dose of 175 mg/m 2 as a 3-hour IV infusion every 3 weeks.

Non-small cell lung cancer

At a dose of 175 mg/m 2 as a 3-hour IV infusion followed by cisplatin every 3 weeks or at a dose of 135 mg/m 2 as a 24-hour IV infusion followed by cisplatin every 3 weeks.

Kaposi's sarcoma in AIDS patients

Depending on the severity of immunosuppression in patients with AIDS, it is recommended to administer Paclitaxel-Teva only if the absolute neutrophil count (ANC) is at least 1000/µl and the platelet count is at least 75,000/µl. Patients with severe neutropenia (ACN less than 500/μl for 7 days or more), or with severe peripheral neuropathy, or with mucositis (grade III or higher) in subsequent courses, a dose reduction of 25% to a dose of 75 mg/m is recommended. 2. It is necessary to consider the possibility of carrying out the mobilization of peripheral stem cells by the introduction of granulocyte colony-stimulating factor.

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

The introduction of the drug Paclitaxel-Teva should not be repeated until the ANC reaches at least 1500 / µl, and the platelet count is at least 100,000 / µl. Patients who experience severe neutropenia (ANC less than 500/mcL for 7 days or longer) or severe peripheral neuropathy after administration of Paclitaxel-Teva should have the dose of Paclitaxel-Teva reduced by 20% during subsequent courses of treatment. during treatment non-small cell lung cancer and first line therapy ovarian cancer or 25% on treatment breast cancer And ovarian cancer. In patients with mucositis (grade II or higher), a dose reduction of 25% is recommended.

Patients with impaired liver function

Dosage adjustments are recommended in patients with hepatic insufficiency and an associated increased risk of toxicity (particularly grade III-IV myelosuppression).

The condition of patients must be carefully monitored. Recommended doses are presented in Table 2.

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. Dose adjustment is not required.

Rules for preparing a solution for infusion

The solution for infusion is prepared immediately before administration, diluting the concentrate with 0.9% solution, or 5% dextrose solution, or 5% dextrose solution in 0.9% sodium chloride solution for injection, or 5% dextrose solution to a final concentration of 0.3 to 1.2 mg / ml . The prepared solutions may become opalescent due to the carrier base present in the composition of the dosage form, and after filtration, the opalescence of the solution is preserved.

When preparing, storing and administering Paclitaxel-Teva, use equipment that does not contain plasticized PVC parts. The plasticizer diethylhexyphthalate (DEHP) contained in plasticized PVC can be released when exposed to macrogolaglyceryl ricinyl oleate, which is an auxiliary component of the drug.

Paclitaxel-Teva should be administered through a system with a built-in membrane filter (pore size no more than 0.22 microns).

If unopened vials are placed in a refrigerator, a precipitate may form which will re-dissolve with little (or no) stirring when room temperature is reached. The quality of the product does not deteriorate. If the solution remains cloudy, or if an insoluble precipitate is noted, the vial should be destroyed.

Side effects

The frequency and severity of adverse reactions with paclitaxel monotherapy are generally similar when used in patients with various solid tumors (ovarian cancer, breast cancer, non-small cell lung cancer). There was no relationship between the manifestation of paclitaxel toxicity and the age of patients.

The incidence of side effects is classified according to WHO recommendations: very often (at least 10%), often (at least 1%, but less than 10%), infrequently (at least 0.1%, but less than 1%), rarely (at least 0.01% , but less than 0.1%), very rarely, including isolated cases (less than 0.01%).

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

From the hematopoietic system: very often - myelosuppression, neutropenia, anemia, thrombocytopenia, leukopenia, bleeding; rarely - febrile neutropenia; very rarely - acute myeloid leukemia, myelodysplastic syndrome. Inhibition of bone marrow function, mainly granulocytic lineage, was the main toxic effect limiting the dose of the drug. The maximum decrease in ANC is usually observed on days 8-11, normalization occurs on day 22.

From the immune system: very often - minor hypersensitivity reactions (mainly skin rash); infrequently - severe hypersensitivity reactions requiring drug therapy (decrease in blood pressure), 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: unknown frequency - tumor lysis syndrome.

From the nervous system: very often - neurotoxicity, mainly peripheral polyneuropathy; rarely - peripheral motor neuropathy (leading to distal weakness); very rarely - grand mal seizures, autonomic neuropathy leading to paralytic ileus and orthostatic hypotension, encephalopathy, convulsions, dizziness, ataxia, headache.

From the side of the organ of vision: very rarely - damage to the optic nerve and / or visual impairment ("flickering scotoma"), especially in patients who received doses higher than those recommended; unknown frequency - macular edema, photopsia, "floating" opacification of the vitreous body.

On the part of the organ of hearing and labyrinth disorders: very rarely - hearing loss, tinnitus, vertigo.

From the side of the cardiovascular system: very often - a decrease in blood pressure, "hot flashes"; often - bradycardia; infrequently - myocardial infarction, AV blockade, syncope, cardiomyopathy, asymptomatic ventricular tachycardia, incl. with bigeminia, thrombosis of venous vessels, increased blood pressure, thrombophlebitis; rarely - heart failure; very rarely - ventricular fibrillation, supraventricular tachycardia, shock; unknown frequency - phlebitis.

From the respiratory system: rarely - respiratory failure, pulmonary embolism, pulmonary fibrosis, interstitial pneumonia, shortness of breath, pleural effusion; very rarely - cough.

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

From the skin and subcutaneous tissues: very often - alopecia; infrequently - reversible changes in the skin and nails; rarely - pruritus, skin rash, erythema; very rarely - Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (it is recommended to apply sunscreen on the hands and feet); unknown frequency - scleroderma.

From the musculoskeletal system and connective tissue: very often - arthralgia, myalgia; unknown frequency - systemic lupus erythematosus.

Local reactions: often - reactions at the injection site (edema, pain, erythema and induration, in some cases - hemorrhage, which can cause inflammation of the subcutaneous tissue, skin fibrosis and skin necrosis).

Laboratory data: often - a pronounced increase in the activity of ACT, alkaline phosphatase; infrequently - an increase in the concentration of bilirubin; rarely - an increase in the concentration of creatinine.

Others: rarely - fever, dehydration, asthenia, peripheral edema, general malaise, fever.

Overdose

Symptoms: depression of bone marrow function, peripheral neuropathy, mucositis.

Treatment: conducting symptomatic therapy. There is no known antidote for paclitaxel.

drug interaction

In first-line therapy for ovarian cancer, paclitaxel should be used before cisplatin. When paclitaxel is used before cisplatin, the safety profile of paclitaxel is consistent with paclitaxel monotherapy. When paclitaxel is used after cisplatin, patients experience more pronounced myelosuppression and a 25% decrease in paclitaxel clearance. Patients taking the paclitaxel/cisplatin combination have an increased risk of developing renal failure compared with cisplatin alone in the treatment of pelvic cancer in women.

In the treatment of breast cancer with a combination of paclitaxel/doxorubicin, paclitaxel infusion should be carried out 24 hours after the administration of doxorubicin. In the case of earlier administration of paclitaxel, the excretion of doxorubicin and its active metabolites may be reduced.

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

Other data on potential drug interactions between paclitaxel and other inhibitors of the CYP3A4 isoenzyme are limited. Therefore, caution should be exercised when using paclitaxel concomitantly with known inhibitors of CYP2C8 and CYP3A4 isoenzymes (eg, erythromycin, fluoxetine, gemfibrozil) or inducers of CYP2C8 and CYP3A4 isoenzymes (eg, rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine).

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

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

The polyoxyethylated castor oil contained in paclitaxel can cause DEHP to leach out of plasticized PVC containers, with the DEHP leaching rate increasing with increasing solution concentration and over time.

special instructions

Treatment with Paclitaxel-Teva is carried out under the supervision of a physician experienced in working with anticancer chemotherapy drugs. Given the possibility of extravasation, it is necessary to control the introduction of the drug Paclitaxel-Teva.

It should be borne in mind that due to the possibility of developing serious hypersensitivity reactions, appropriate precautions should 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 Paclitaxel-Teva after adequate premedication. These reactions are likely histamine-mediated. In the event of severe hypersensitivity reactions, the infusion of Paclitaxel-Teva should be immediately discontinued and symptomatic treatment initiated. Re-introduction of the drug Paclitaxel-Teva in such patients should not be.

If Paclitaxel-Teva is used in combination with cisplatin, Paclitaxel-Teva should be administered first, followed by cisplatin.

Bone marrow suppression (primarily neutropenia) is the main toxic effect that limits the dose of Paclitaxel-Teva. During treatment, it is necessary to regularly monitor the blood test.

Patients with hepatic insufficiency are most at risk of developing the toxic effect of the drug Paclitaxel-Teva, which may manifest as grade 3-4 myelosuppression. There is no evidence that in patients with moderate hepatic impairment, the toxic effect may increase 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 and severe liver failure. There are insufficient data to recommend a dose change of Paclitaxel in patients with mild to moderate hepatic impairment. There are no data on the use of the drug Paclitaxel-Teva in patients with initially severe cholestasis. In patients with severe hepatic impairment, the use of Paclitaxel-Teva is not recommended.

With monotherapy with Paclitaxel-Teva, cardiac conduction disorders rarely develop. In cases of development of severe disorders of AV conduction with repeated injections, it is necessary to carry out appropriate therapy and continuous cardiac monitoring. The decrease and increase in blood pressure, bradycardia, recorded during cardiac monitoring, as a rule, are not accompanied by subjective symptoms and do not require treatment. Most often, a change in vital signs of cardiac activity is observed during the first hour of infusion of the drug Paclitaxel-Teva. Severe cardiac dysfunction is more common in patients with non-small cell lung cancer than in ovarian and breast cancers. No cases of heart failure have been reported in patients with Kaposi's sarcoma.

Before conducting first-line therapy for metastatic breast cancer with a combination of Paclitaxel-Teva with doxorubicin or trastuzumab, the patient's cardiac status should be carefully examined (history, physical examination data, ECG, echocardiography, multi-entry isotope arteriography). During treatment with these combinations, careful cardiac monitoring (eg, every 3 months) is required in order to be able to identify patients with progressive cardiac dysfunction and modify the cumulative dose (mg / m 2) of anthracyclines in time. With a decrease in the contractile function of the myocardium, even in the case of an asymptomatic course, the attending physician should carefully evaluate the ratio of the expected benefit from the duration of chemotherapy and the possible risk of worsening cardiac activity, incl. the risk of irreversible myocardial damage. If chemotherapy is continued, cardiac monitoring should be performed more frequently (for example, after 1-2 cycles). For more information, see the prescribing information for doxorubicin and trastuzumab.

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

Paclitaxel-Teva in combination with radiation therapy, regardless of the chronology of the use of this treatment regimen, can contribute to the development of interstitial pneumonitis.

Rare cases of pseudomembranous colitis in patients who did not receive antibiotics concomitantly with Paclitaxel should be differentiated from cases of severe or persistent diarrhea that may occur during or shortly after the end of Paclitaxel-Teva treatment.

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

Paclitaxel-Teva is a cytotoxic substance, when working with which care must be taken, use gloves and avoid contact with the skin or mucous membranes, which in such cases must be thoroughly washed with soap and water, or (eyes) with plenty of water.

After dilution of the concentrate, the physicochemical stability of the drug Paclitaxel-Teva is maintained for 96 hours at a temperature of less than 25°C. After dilution, the solution must not be frozen.

Influence on the ability to drive vehicles and control mechanisms

During the period of treatment with Paclitaxel-Teva, patients should be careful when driving vehicles and engaging in other potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions, due to the possible development of dizziness.

Pregnancy and lactation

The drug is contraindicated during pregnancy and during breastfeeding.

Men and women of reproductive age during treatment with Paclitaxel-Teva and for at least 6 months after the end of therapy, effective methods of contraception should be used.

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C. Shelf life - 2 years.