Structural formula

Russian name

Latin name of the substance Paclitaxel

Paclitaxelum ( genus. Paclitaxeli)

chemical name

]-beta-(Benzoylamino)-alpha-hydroxybenzenepropanoic acid 6,12b-bis(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,6,9,10,11,12,12a, 12b-dodecahydro -4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodecabenzoxet-9-yl ether

Gross formula

C 47 H 51 NO 14

Pharmacological group of the substance Paclitaxel

Nosological classification (ICD-10)

CAS code

33069-62-4

Characteristics of the substance Paclitaxel

An antitumor agent of plant origin. Alkaloid isolated from the bark of the yew tree (Taxus brevifolia), are also obtained semi-synthetically and synthetically. White or almost white crystalline powder. Insoluble in water. Highly lipophilic. Melts at a temperature of 216-217 °C. Molecular weight - 853.9.

Pharmacology

pharmachologic effect- antitumor.

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. It induces an abnormal arrangement of microtubules in the form of bundles throughout the cell cycle and the formation of multiple stellate condensations (asters) during mitosis.

Pharmacokinetic parameters of paclitaxel were determined after infusions of the drug at doses of 135 and 175 mg/m 2 for 3 and 24 hours during phase 3 randomized trials in patients with ovarian cancer. When administered intravenously for 3 hours at a dose of 135 mg / m 2 C max 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. C max and AUC are dose-dependent. With a 3-hour infusion, a dose increase of 30% (from 135 to 175 mg / m 2) leads to an increase in C max and AUC by 68 and 89%, respectively, with a 24-hour infusion, C max increases by 87%, AUC - by 26 %.

In research in vitro it has been 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 V ss at 24-hour infusion is 227-688 l/m 2 . Easily penetrates and is absorbed by tissues, mainly accumulates in the liver, spleen, pancreas, stomach, intestines, heart, muscles. After IV infusion (1-24 hours), the mean cumulative urinary excretion of unchanged substance is 1.3-12.6% of the dose (15-275 mg/m 2 ), indicating extensive extrarenal clearance. After an IV infusion of paclitaxel (15-275 mg/m) for 1; 6 or 24 hours 1.3-12.6% of the administered dose was excreted by the kidneys unchanged. After a 3-hour infusion of radioactive paclitaxel at doses of 225-250 mg/m 2 for 120 hours, 14% of the radiopharmaceutical was excreted by the kidneys, 71% by the intestines. The intestines excreted 5% of the administered radiopharmaceutical unchanged, the rest was metabolites, mainly 6-alpha-hydroxypaclitaxel.

In research in vitro on human liver microsomes, it was found that paclitaxel is metabolized in the liver with the participation of the isoenzyme CYP2C8 to 6-alpha-hydroxypaclitaxel and with the participation of the CYP3A4 isoenzyme to 3-para-hydroxypaclitaxel and 6-alpha-3-para-dihydroxypaclitaxel. The effect of impaired renal function on metabolism after a 3-hour infusion has not been studied. T 1/2 and total clearance are variable (depending on the dose and duration of intravenous administration): at doses of 135-175 mg / m 2 and an infusion duration of 3 or 24 hours, the average values ​​of T 1/2 are in the range of 13.1-52 .7 h, clearance - 12.2-23.8 l / h / m 2.

Carcinogenicity, mutagenicity, effect on fertility

Studies of the carcinogenicity of paclitaxel in tests on laboratory animals have not been conducted.

Paclitaxel was mutagenic in tests in vitro(chromosomal aberrations in human lymphocytes) and in vivo(micronucleus test in mice). Did not show mutagenic activity in the Ames test, when analyzing gene mutations on cells CHO/HGPRT(test with hypoxanthine-guanine phosphoribosyltransferase of Chinese hamster ovary cells).

In experimental studies, it has been shown that when administered intravenously to rats at a dose of 1 mg / kg (6 mg / m 2), paclitaxel causes a decrease in fertility and has a toxic effect on the fetus. When administered intravenously to rabbits at a dose of 3 mg / kg (33 mg / m 2), during organogenesis, it had a toxic effect on females and the embryo or fetus.

Application of the substance Paclitaxel

Ovarian cancer:

1st line therapy in combination with platinum drugs in patients with advanced ovarian cancer or with residual tumor (more than 1 cm) after the initial laparotomy;

2nd line therapy in patients with metastatic ovarian cancer after standard therapy that did not give a positive result.

Epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer in combination with carboplatin.

Mammary cancer:

Adjuvant therapy in patients with lymph node metastases after standard combined treatment;

1st line therapy in patients with late-stage cancer or metastatic cancer after disease recurrence within 6 months after the start of adjuvant therapy with the inclusion of anthracycline drugs, in the absence of contraindications for their use;

1st line therapy in patients with advanced cancer or metastatic breast cancer in combination with anthracycline drugs in the absence of contraindications for their use or in combination with trastuzumab in patients with immunohistochemically confirmed 2+ or 3+ HER-2 expression level;

2nd line therapy in patients with advanced or metastatic breast cancer with disease progression after combination chemotherapy. Prior therapy should include anthracycline drugs in the absence of contraindications for their use.

Non-small cell lung cancer:

1st line therapy in combination with a platinum drug or as monotherapy in patients who are not scheduled for surgery and / or radiation therapy.

Kaposi's sarcoma due to AIDS:

2nd line therapy.

Contraindications

Hypersensitivity; the initial content of neutrophils is less than 1.5 10 9 /l in patients with solid tumors; initial or registered during treatment, the content of neutrophils is less than 1·10 9 /l in patients with Kaposi's sarcoma caused by AIDS; concomitant serious uncontrolled infections in patients with Kaposi's sarcoma; severe liver dysfunction; pregnancy and lactation period; children's age (safety and efficacy in children have not been determined).

Application restrictions

Inhibition of bone marrow hematopoiesis (including after previous chemotherapy or radiation therapy); thrombocytopenia (less than 100 10 9 /l); mild to moderate liver failure; acute infectious diseases (including herpes zoster, chickenpox, herpes), severe coronary artery disease; a history of myocardial infarction; arrhythmia.

Use during pregnancy and lactation

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).

Side effects of Paclitaxel

Side effects generally do not differ in frequency and severity with treatment for ovarian cancer, breast cancer, non-small cell lung cancer, or Kaposi's sarcoma. However, in patients with AIDS-related Kaposi's sarcoma, infections (including opportunistic ones), hematopoietic depression, and febrile neutropenia are more common and more severe than usual.

Clinical trial experience (with monotherapy)

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 administration of paclitaxel.

Hematological: neutropenia less than 2 10 9 /l (90%), neutropenia less than 0.5 10 9 /l (52%), leukopenia less than 4 10 9 /l (90%), leukopenia less than 1 10 9 /l ( 17%), thrombocytopenia less than 100 10 9 /l (20%), thrombocytopenia less than 50 10 9 /l (7%), anemia - Hb level less than 110 g / l (78%), anemia - Hb 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 observed on the 8-11th 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 (shortness of breath requiring the use of bronchodilators, arterial hypotension requiring therapeutic intervention, angioedema, generalized urticaria) were observed in 2% of cases. It is likely that these reactions are 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/m 2 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 was the reason for discontinuation of 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, 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. Usually, the symptoms were transient, appeared 2-3 days after the administration of paclitaxel and disappeared within a few days.

Hepatotoxicity. An increase in the level of AST, ALP 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, were mild or 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 the 14th and 21st 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.

Post-approval data on side effects of paclitaxel (with monotherapy)

The frequency of occurrence of side effects is given in accordance with the following scale: very often (≥1 / 10); often (≥1/100-<1/10); нечасто (≥1/1000-<1/100); редко (≥1/10000-<1/1000); очень редко (<1/10000); частота неизвестна (не может быть оценена при помощи доступных данных).

In addition to the reactions identified in clinical trials, the following effects have been reported in the post-marketing period.

From the side of the hematopoietic organs: very rarely - acute myeloid leukemia, myelodysplastic syndrome.

From the immune system: rarely - anaphylactic reactions (including fatal); very rarely - anaphylactic shock.

From the nervous system: rarely - motor neuropathy (leading to slight weakness of the limbs); very rarely - confusion, convulsions, dizziness, headache.

From the CCC: very rarely - atrial fibrillation, supraventricular tachycardia, shock.

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

From the digestive tract: rarely - pancreatitis; very rarely - pseudomembranous colitis, esophagitis, constipation, ascites, anorexia.

From the side of the organ of vision: very rarely - reversible damage to the optic nerve and / or visual impairment (atrial scotoma, or ocular migraine), photopsia, destruction of the vitreous body of the eye; frequency unknown - macular edema.

From the organ of hearing: very rarely - hearing loss, tinnitus, vertigo (vestibular dizziness), ototoxicity.

From the side of the skin, subcutaneous tissue and skin appendages: rarely - itching, rash, skin exfoliation, necrosis and fibrosis of the skin, skin lesions resembling the effects of radiation therapy; very rarely - Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme exudative, exfoliative dermatitis, urticaria, onycholysis; frequency unknown - scleroderma, cutaneous lupus erythematosus.

From the musculoskeletal system: frequency unknown - systemic lupus erythematosus.

From the side of laboratory indicators: rarely - an increase in serum creatinine concentration.

Others: rarely - pneumonia, sepsis, asthenia, general malaise, fever, dehydration, peripheral edema; frequency unknown - tumor lysis syndrome.

Side effects of combination therapy

Paclitaxel + cisplatin in the 1st line of ovarian cancer therapy

The frequency and severity of neurotoxicity, arthralgia/myalgia and hypersensitivity are higher compared with cyclophosphamide and cisplatin therapy. On the contrary, manifestations of myelosuppression are observed less frequently and are less pronounced than with the use of cyclophosphamide and cisplatin. Manifestations of severe neurotoxicity when used in combination with cisplatin at a dose of 75 mg / m 2 are observed less frequently when using paclitaxel at a dose of 135 mg / m 2 in the form of a 24-hour infusion than when it is administered at a dose of 175 mg / m 2 in the form of 3- hourly infusion.

Paclitaxel + trastuzumab in the treatment of breast cancer

When using paclitaxel in combination with trastuzumab in the 1st line of therapy for metastatic breast cancer, the following side effects were observed more often than with paclitaxel monotherapy: heart failure, infections, chills, fever, cough, rash, arthralgia, tachycardia, diarrhea, increased blood pressure. epistaxis, acne, herpetic eruptions, accidental trauma, insomnia, rhinitis, sinusitis, reactions at the injection site.

The use of paclitaxel in combination with trastuzumab in the 2nd line of therapy (after anthracycline drugs) led to an increase in the frequency and severity of cardiac events (in rare cases with a fatal outcome) compared with paclitaxel monotherapy. In most cases, side effects were reversible after the appointment of appropriate treatment.

Paclitaxel + doxorubicin in the treatment of breast cancer

There have been cases of congestive heart failure in patients who have not previously received chemotherapy. Patients who received previous chemotherapy courses, especially with the use of anthracyclines, often experienced cardiac dysfunction, a decrease in left ventricular ejection fraction and ventricular failure. In rare cases, myocardial infarction has been noted.

Paclitaxel + radiotherapy

Cases of radiation pneumonitis have been reported in patients treated concomitantly with paclitaxel and radiation therapy.

Interaction

Cisplatin. 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).

Doxorubicin. The use of paclitaxel with doxorubicin may increase the content of doxorubicin and its active metabolite doxorubicinol in the blood serum. Side effects such as neutropenia and stomatitis are more pronounced with the use of paclitaxel before the administration of doxorubicin, as well as with a longer infusion than recommended.

Substrates, inducers and inhibitors of isoenzymes CYP2C8 and CYP3A4. Paclitaxel is metabolized with the participation of isoenzymes CYP2C8 and CYP3A4, therefore, caution should be exercised when using paclitaxel during treatment with substrates (eg midazolam, buspiron, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, triazolam, repaglinide and rosiglitazone), inducers (eg rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) or inhibitors (eg erythromycin, fluoxetine, gemfibrozil, ketoconazole, ritonavir, indinavir, nelfinavir) of these isoenzymes.

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

Overdose

Symptoms: myelosuppression, peripheral neurotoxicity, mucositis.

Treatment: symptomatic. The specific antidote is unknown.

Routes of administration

I/V(infusion).

Precautions Substance Paclitaxel

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 corticosteroids, antihistamines and histamine H 2 receptor blockers before infusion.

Anaphylaxis and serious hypersensitivity reactions

When using paclitaxel, despite premedication, less than 1% of patients experienced serious hypersensitivity reactions. The frequency and severity of such reactions did not depend on the dose and regimen of drug administration. With the development of severe reactions, dyspnea, hot flashes, chest pain, tachycardia, as well as abdominal pain, pain in the extremities, increased sweating, and increased blood pressure were most often observed. With the development of severe hypersensitivity reactions, the administration of paclitaxel should be stopped immediately and, if necessary, symptomatic treatment should be prescribed. In such cases, repeated courses of treatment with paclitaxel should not be prescribed.

Reactions at the injection site

During intravenous administration of paclitaxel, the following reactions (usually mild) at the injection site were observed: swelling, pain, erythema, tenderness, induration, hemorrhage, which can lead to the development of cellulitis. Such reactions were more frequently observed with a 24-hour infusion than with a 3-hour one. In some cases, the onset of such reactions was observed both during the infusion and 7-10 days after it.

Myelosuppression

Bone marrow suppression (mainly neutropenia) is dose and dose dependent and is the main dose-limiting toxic reaction. In patients with previous radiotherapy in history, neutropenia developed less frequently and to a milder degree and did not worsen as the drug accumulated in the body.

In patients with ovarian cancer, the risk of renal failure is higher with the combination of paclitaxel + cisplatin compared with cisplatin alone.

Infections have been very common and sometimes fatal, including sepsis, pneumonia, and peritonitis. Urinary and upper respiratory tract infections were noted as the most common complicated infections. In immunosuppressed patients (patients with HIV infection and patients with AIDS-related Kaposi's sarcoma), at least one opportunistic infection has been noted.

The use of maintenance therapy, including granulocyte colony-stimulating factor, is recommended for patients who have experienced severe neutropenia.

A decrease in the number of platelets below 100·10 9 /l was noted at least 1 time during therapy with paclitaxel, sometimes the platelet count was below 50·10 9 /l. There were also cases of bleeding, most of which were local, and the frequency of their occurrence was not associated with the dose of paclitaxel and the regimen of administration.

When using paclitaxel, it is necessary to regularly monitor the blood picture. It should not be prescribed to patients with a neutrophil count of less than 1.5 10 9 /l and less than 1.0 10 9 /l with AIDS-related Kaposi's sarcoma and platelet counts of less than 100 10 9 /l (75 10 9 / l in patients with AIDS-related Kaposi's sarcoma). With the development of severe neutropenia (the number of neutrophils less than 0.5 10 9 /l) for more than 7 days during subsequent courses of treatment, the dose of paclitaxel should be reduced by 20% (in patients with AIDS-related Kaposi's sarcoma - by 25%).

Impact on CCC

The decrease, increase in blood pressure and bradycardia observed during the administration of paclitaxel are usually asymptomatic and in most cases do not require treatment. A decrease in blood pressure and bradycardia were usually observed during the first 3 hours of infusion.

There have also been cases of ECG disturbances in the form of repolarization disorders, such as sinus tachycardia, sinus bradycardia and early extrasystoles.

In severe cases, treatment with paclitaxel should be suspended or discontinued. Monitoring of vital signs is recommended, especially during the first hour of drug infusion. If paclitaxel is used in combination with trastuzumab or doxorubicin for the treatment of metastatic breast cancer, monitoring of cardiac function is recommended.

In the treatment of paclitaxel, there have been cases of severe cardiac conduction disorders. If symptoms of cardiac conduction disorders are detected, patients should be prescribed appropriate therapy along with constant ECG monitoring of the cardiovascular system.

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

Effect on the nervous system

The frequency and severity of disorders of the nervous system were mainly dose-dependent. In the treatment of paclitaxel, peripheral neuropathy is often noted, usually moderately severe. The incidence of peripheral neuropathy increased with the accumulation of the drug in the body. Cases of paresthesia were often observed in the form of hyperesthesia. In severe neuropathy, it is recommended to reduce the dose of paclitaxel by 20% in subsequent courses of treatment (in patients with AIDS-related Kaposi's sarcoma, by 25%). Peripheral neuropathy may be the reason for discontinuation of paclitaxel therapy. Symptoms of neuropathy decreased or completely disappeared within a few months after discontinuation of drug therapy. The development of neuropathy is not a contraindication for the appointment of paclitaxel.

There have been rare cases of impaired optic nerve evoked potential in patients with persistent damage to the optic nerve.

Consideration should be given to the possible effects of the ethanol contained in the paclitaxel concentrate for solution for infusion.

Influence on the gastrointestinal tract

Cases of nausea/vomiting/diarrhea, mild to moderate mucositis were very common in all patients. The incidence of mucositis was dependent on the paclitaxel regimen and was more common with 24-hour infusion than with 3-hour infusion. Rare cases of neutropenic enterocolitis (typhlitis), despite the co-administration of granulocyte colony-stimulating factor, have been observed in patients using paclitaxel as monotherapy and in combination with other chemotherapeutic drugs.

Liver failure

Patients with hepatic insufficiency represent a special risk group for the development of toxicity-related side effects, especially myelosuppression grade 3-4. Careful monitoring of the patient's condition should be established and, if necessary, consideration should be given to adjusting the dose of paclitaxel.

Radiation pneumonitis

Radiation pneumonitis was registered with concomitant radiation therapy.

Contraception. Patients should use reliable methods of contraception during treatment with paclitaxel and for at least 3 months after the end of therapy.

Influence on the ability to engage in potentially hazardous activities. 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.

special instructions

When working with paclitaxel, as with other anticancer drugs, care must be taken. The preparation of solutions should be carried out by trained personnel in a specially designated area for this purpose in compliance with protective measures (including gloves, masks). In case of contact of the drug with the skin or mucous membranes, it is necessary to thoroughly wash the mucous membranes with water, and the skin with soap and water.

Paclitaxel is a drug with antitumor properties, produced in a semi-synthetic way on the basis of natural raw materials obtained from Taxus baccata, yew berry - mahogany from the yew family.

The main area of ​​its application lies in the plane of those medications that are prescribed for chemotherapy in patients with cancer. This antitumor agent is included in the treatment regimens for malignant lesions of the lungs, larynx, mucous membranes of the nasopharynx and oral cavity, for breast cancer, ovarian oncology, etc.

This drug, being a powerful mitotic inhibitor, has a stimulating effect on the processes in which dimeric tubulin molecules are involved in microtubule assembly. The use of Paclitaxel also contributes to the stabilization of their structure and leads to a decrease in the rate of dynamic reorganization at the interphase stage, which causes a violation of cellular myotic function. As a result of its application, the occurrence of abnormal accumulations created by microtubules during the entire life cycle of cells is induced, and in addition, during mitosis, multiple stellate accumulations of microtubules are formed.

Further development of new modes and combinatorial features of the administration of this drug is underway, which is very promising in terms of ensuring high individualization of chemotherapy based on molecular genetic typing of tumor formations.

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ATX code

L01CD01 Paclitaxel

Active ingredients

Paclitaxel

Pharmacological group

Anticancer agents of plant origin

pharmachologic effect

Cytostatic drugs

Anticancer drugs

Indications for use Paclitaxel

Indications for the use of Paclitaxel are determined by the high degree of its effectiveness as a drug among those used to treat all kinds of oncologists.

So it is advisable to use it in ovarian cancer. In this case, the drug is included in the first-line therapy for the widespread form of this malignant lesion, or for residual tumor formation not exceeding 1 centimeter. In addition, the combination of Paclitaxel and cisplatin is used after laparotomy. Ovarian cancer with second-line therapy involves the use of the drug in the presence of metastases and insufficiently achieved measure of therapeutic effect produced by standard therapeutic measures.

The indication for the use of Paclitaxel may be the presence of breast cancer. Mainly when lymph node involvement occurs after adjuvant treatment, standard combination therapy; if the disease recurred within a six-month period from the moment when adjuvant therapy was started. As a second-line therapy - for metastatic phenomena of breast cancer in the event that the standard therapeutic measures taken have shown their failure.

Paclitaxel is also indicated for use in non-small cell lung cancer in first-line therapy. Here, cystoplatin is included in combination with it. But the drug is prescribed only to those patients who are not expected to be treated surgically and are not provided for x-ray therapy.

Other cases where the use of Paclitaxel may be justified include, in addition, squamous cell type of neck and head cancer, bladder cancer in the transitional cell form, malignant tumors in the esophagus, leukemia.

Thus, on the basis of all the above, it becomes obvious that the indications for the use of Paclitaxel cover a considerable number of cases of oncological diseases. In each of them, the drug exhibits one or another, but, as a rule, a rather high degree of its effectiveness as part of a complex cancer treatment.

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Release form

The release form of Paclitaxel is presented in the form of a concentrate, which is used in the preparation of a solution for the purpose of its subsequent administration by intravenous infusion.

1 milliliter of the drug contains paclitaxel 6 milligrams. In addition to this main active component, the composition contains the presence of various excipients: nitrogen, anhydrous ethanol, purified macrogolglycerol ricinoleate.

The concentrate is contained in a bottle made of transparent class I hydrolytic glass. The capacity of the bottle can be different and is 5 or 16.7 milliliters, respectively. The cork on the bottle is made of bromobutyl, an aluminum shell is rolled over it forming a cap, in which there is a polypropylene cap.

The bottle is placed in a cardboard box, where the manufacturer also puts a folded sheet containing instructions for using Paclitaxel. As for the number of bottles in such a package, in this regard it should be noted that it also differs in a certain variety. So if you open the box, there is only a single 30-milligram vial containing 5 ml. the drug, or, in a larger package, there can be 10 bottles of a similar capacity. An option is also offered as 1 bottle per 100 mg - 16.7 milliliters, respectively. The treatment regimen in which Paclitaxel is used, the prescribed dosage, the frequency of use may be different and purely individual for each individual patient, due to which one or another form of release of the drug can be the most convenient.

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Pharmacodynamics

Pharmacodynamics Paclitaxel is manifested in the antitumor pharmacological action of the drug. Its use has the effect of inhibiting the processes of mitosis, and also has a cytotoxic effect. Entering into specific bonds with microtubule beta-tubulin, it causes disturbances in the depolymerization of this protein, which is of key importance.

The effect of Paclitaxel is that the normal dynamic reorganization of the network formed by microtubules is suppressed. This is extremely important when the interphase stage occurs, and without which cells become incapable of performing functions during mitosis.

A characteristic feature of the pharmacology of the drug is also that in the phase of mitosis leads to the formation of several centrioles. Paclitaxel contributes to the fact that microtubules form abnormal bundles throughout the entire period when the cell cycle lasts, and during mitosis they form clusters that look like stars in their appearance - asters.

Pharmacodynamics Paclitaxel is also characterized by inhibition of hematopoietic processes in the bone marrow. In addition, as is obvious from the results of experimental studies, the drug has embryotoxic properties and can lead to a decrease in reproductive function.

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Pharmacokinetics

The essence of the processes that characterize the pharmacokinetics of Paclitaxel is as follows.

As a result of intravenous administration of the drug, its concentration in the blood plasma begins to decrease, in a way that occurs according to the two-phase kinetics.

In order to determine the specific pharmacokinetic features of Paclitaxel, studies were carried out on the processes that take place after 3, as well as after 24 hours after it was introduced. The doses used were 135 and 175 milligrams per square meter, respectively. Based on the results obtained, it became possible to state that with an increase in the dose in which the infusion was carried out, with the passage of more than 3 hours, the pharmacokinetics of the drug became characterized by non-linearity. A 30% increase in dosage, that is, from 135 to 175 mg / m², resulted in an increase in Cmax by 75 percent, and AUC by 81.

Conducting several repeated courses of treatment, as was also found, does not cause a tendency to a cumulative effect in connection with taking the drug.

In addition, it was found that Paclitaxel binds to proteins by 89-98 percent.

The pharmacokinetics of Paclitaxel have not been sufficiently studied to date. Available information only suggests that it is biotransformed in the liver, resulting in the formation of hydroxylated metabolites. The drug leaves the body along with the excretion of bile.

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Use of paclitaxel during pregnancy

The use of Paclitaxel during pregnancy should be of concern, at least due to the fact that, despite the proven effectiveness of the drug as a means of helping to cure many forms of cancer, all its mechanisms in the human body are not yet fully understood. And for a woman in a position where her body is especially vulnerable, any threat from outside influences acquires a value raised to the nth degree. The same statement is true for the future little man, for whom she is responsible.

This drug, based on the existing criteria for assessing the possible effect on the child during its prenatal development (FDA), has been assigned category D. This suggests that, despite the confirmed existence of a risk to the fetus, under a certain combination of factors and circumstances, Paclitaxel may be justified . The drug is prescribed only when the question is about the life and death of a woman expecting a baby, or if there is a high probability that the supposed positive changes for her to the least possible extent can have negative consequences for the fetus.

Since the drug has experimentally confirmed fetotoxic and embryotoxic properties, the use of Paclitaxel during pregnancy is prescribed only in exceptional cases. A woman during treatment with its use should use reliable methods of contraception, and during lactation, breastfeeding of the baby should be stopped throughout the treatment course.

Contraindications

Contraindications to the use of Paclitaxel can be caused, first of all, due to individual hypersensitivity, both to this drug and to those drugs in the dosage form of which there is the presence of macrogolglycerol ricinoleate.

Paclitaxel belongs to the list of those drugs that are subject to exclusion from the treatment regimen for Kaposi's sarcoma, which can occur with AIDS, if the neutrophil counts recorded during the course of treatment are characterized by a value not exceeding 1000 / μl.

What else needs to be noted in relation to the initial amount in which neutrophils are present is that if they do not reach 1500 / μl in solid tumor formations, this fact classifies the drug as unacceptable for use in treatment.

Paclitaxel should be used with all possible precautions if thrombocytopenia is less than 100,000/µl. If its quantitative indicator is under the lower limit of 1500 / μl, the drug is clearly contraindicated.

It is banned in case of liver failure, due to severe cardiac ischemia, arrhythmia and the patient's history of myocardial infarction less than six months ago.

It is also recommended to refuse the use of Paclitaxel during pregnancy and during lactation and lactation.

There are also some cases that are not direct contraindications, but require increased attention during the use of Paclitaxel. These are chronic heart failure, angina pectoris, cardiac arrhythmias. This also includes a number of infectious diseases.

Like any other drug, Paclitaxel has its strengths and weaknesses, showing aggressive radical action, which is precisely what distinguishes many of the drugs used in cancer therapy. But at the same time, all sorts of adverse side effects often become the price for the efficiency achieved in this way. And therefore, there are contraindications to the use of Paclitaxel and special prescriptions aimed at preventing and reducing the possibility of all sorts of associated negative phenomena.

Side effects of Paclitaxel

How often and with what degree of severity the side effects of Paclitaxel appear are largely due to the fact that they differ in a dose-dependent manner.

During the first hours after the drug was administered, it is possible to develop an allergic reaction such as bronchospasm, a decrease in blood pressure, flushing to the face, pain in the sternum, a rash on the skin.

Those organs in the human body that are involved in the processes associated with the execution of the hematopoietic function may show their specific reaction to the use of the drug in the form of developing anemia, thrombocytopenia and neutropenia. The main factor for which it is necessary to limit the increase in dosage is that the use of increased doses results in inhibition of bone marrow function, which, with its toxic effect, especially affects the granulocytic germ. The level of neutrophils reaches its lowest point in the time period from the 8th to the 11th day, with subsequent normalization after a three-week period.

The characteristic symptomatology during the course of treatment with Paclitaxel is inherent in the cardiovascular system. Side effects are displayed as the appearance of unfavorable dynamics of changes occurring with blood pressure, mainly with a tendency to decrease it. An increase in blood pressure is noted in fewer cases. The result of the introduction of the drug can be the occurrence of palpitations, bradycardia, the phenomenon of atrioventricular blockade, the development of vascular thrombosis and thrombophlebitis. There are changes in the heart rate on the electrocardiogram.

Due to the active action of the drug in the body, the central nervous system is attacked by it. This takes place predominantly as the appearance of paresthesias. Occasionally, there are cases of grand mal seizures, the development of ataxia, encephalopathy, visual impairment, and autonomic neuropathy is noted. The latter, in turn, often acts as a cause of paralytic ileus and orthostatic hypotension.

Paclitaxel can adversely affect hepatic function, leading to the fact that liver transaminases (mainly AST), alkaline phosphatose and bilirubin are activated in the blood serum. Liver encephalopathy and hepatonecrosis are possible.

The respiratory system responds to the action of the drug with pulmonary fibrosis, interstitial pneumonia, and the appearance of pulmonary embolism. When Paclitaxel is used concomitantly with radiation therapy, there is an increased risk that radiation pneumonitis may develop.

The resulting dysfunctions of the digestive system are reflected in the appearance of nausea, vomiting, diarrhea, constipation, and the development of anorexia.

The musculoskeletal system can also be affected by the occurrence of side effects, one hundred manifests itself in myalgia and arthralgia.

Side effects of Paclitaxel can affect various organs and systems of the body and have quite serious consequences. Therefore, it is very important that the use of the drug is carried out under medical supervision and in compliance with a carefully selected dosage, which will lead to the maximum possible positive result and at the same time have the least negative impact on the patient's condition.

Dosage and administration

The route of administration and doses of Paclitaxel are regulated by a number of practical guidelines that must be followed when dealing with this drug.

It should be noted that the stage of treatment, when its direct administration begins, must be preceded by a certain preparatory period, during which each patient, without exception, who is prescribed Paclitaxel, must undergo premedication. Its essence lies in the fact that in order to prevent a severe hypersensitivity reaction, antihistamines and glucocorticosteroid drugs, antagonists of H2 histamine receptors, are used. As an example of this, dexamethasone at a dose of 20 milligrams is administered 12 to 6 hours before the infusion. An alternative to dexamethasone can be diphenhydramine (50 mg), or another drug of similar action. And also from 30 minutes to one hour - intravenous ranitidine 50 mg. or cimetidine 300 mg.

The solution for infusion is prepared before the actual start of the introduction of Paclitaxel.

To do this, the concentrate is combined with a 0.9% solution of sodium chloride. It is also allowed in combination with a 5% dextrose solution, dextrose in a solution with sodium chloride for injection, and in addition Ringer's solution with a 5% dextrose solution, the final concentration of which should be 0.3-1.2 mg / ml.

The introduction of Paclitaxel is carried out by intravenous infusion, in which the drug in a single dose of 135-175 mg / m2 should enter the body over a period of 3 to 24 hours. Each course is separated from the previous one by a break of at least 21 days. The drug is used until the levels of neutrophils and in the blood are at least 1500 / μl, and platelets, respectively, 100,000 / μl.

Treatment with this drug of Kaposi's sarcoma in AIDS occurs through the introduction of it at 100 mg / m2 for 3 hours with 14-day breaks.

The method of application and doses of this antitumor agent may be different based on the history, nature of the disease, stage and severity in each individual patient, factors of individual tolerance to the components of Paclitaxel.

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Overdose

To determine the optimal regimen and the required doses of Paclitaxel for each individual patient, the information contained in the special medical reference literature is used. The task of the medical specialist in this regard is to select the lowest possible dosage, which contributes to the achievement of a positive progress of the cure and at the same time to prevent the occurrence of negative consequences that may occur if the required optimal amount of the drug is exceeded.

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

Plasma protein binding 89-98%. Biotransformirovatsya mainly in the liver. It is excreted both by the kidneys in unchanged form and with bile (both unchanged and in the form of metabolites).

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

Installed individually, depending on the indications and stage of the disease, the state of the hematopoietic system, 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.

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 lymph node involvement 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 HER-2 oncoprotein overpressure (3+) detected by immunohistochemistry) 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:

A drug	Dose	Time of receipt
Dexamethasone	20 mg orally or (8-20 mg orally for Kaposi's sarcoma)	For oral administration: Approximately 6 and 12 hours before the administration of paclitaxel. With intravenous administration: 30-60 minutes before the introduction of paclitaxel.
Diphenhydramine (Or equivalent antihistamine)	50 mg IV	30-60 minutes before the introduction of paclitaxel
Cimetidine or ranitidine	300 mg IV 50 mg IV	30-60 minutes before the introduction of paclitaxel

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 WITH. 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 arrhythmia.

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-introduction 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), it is necessary to take into account the recommendations for the use of these drugs.

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 administration 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.

In this article, you can read the instructions for using the drug Paclitaxel. Reviews of site visitors - consumers of this medicine, as well as opinions of doctors of specialists on the use of Paclitaxel in their practice are presented. A big request to actively add your reviews about the drug: did the medicine help or not help get rid of the disease, what complications and side effects were observed, perhaps not declared by the manufacturer in the annotation. Analogues of Paclitaxel in the presence of existing structural analogues. Use for the treatment of breast, ovarian, lung cancer in adults, children, as well as during pregnancy and lactation. The composition of the drug.

Paclitaxel- an 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.

Compound

Paclitaxel + excipients.

Pharmacokinetics

Plasma protein binding 89-98%. Biotransformirovatsya mainly in the liver. It is excreted both by the kidneys in unchanged form and with bile (both unchanged and in the form of metabolites).

Indications

• ovarian cancer (including with the ineffectiveness of platinum drugs);
• mammary cancer;
• cancer of the lungs and bronchi;
• esophageal carcinoma;
• head and neck cancer;
• bladder cancer.

Release forms

Concentrate for solution for infusion (injections in ampoules for injections or droppers) 300 mg in a 50 ml vial.

There are no other dosage forms, whether capsules or tablets.

Instructions for use and dosing regimen

Intravenously in the form of a 3- or 24-hour infusion (droppers) at a dose of 135-175 mg / m2 with an interval between courses of 3 weeks.

To prevent severe hypersensitivity reactions, all patients should be premedicated with glucocorticosteroids (GCS), antihistamines, and histamine H2 receptor antagonists. For example, dexamethasone 20 mg (or equivalent) orally approximately 12 and 6 hours before Paclitaxel administration; 50 mg diphenhydramine (or equivalent) IV and 300 mg cimetidine or 50 mg ranitidine IV 30 to 60 minutes prior to Paclitaxel administration.

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

Paclitaxel is used alone or in combination with cisplatin (ovarian and non-small cell lung cancer) or doxorubicin (breast cancer).

The administration of Paclitaxel should not be repeated until the neutrophil count is at least 1500/µl of blood and the platelet count is at least 100,000/µl of blood. Patients who develop severe neutropenia (neutrophil count less than 500/mm3 of blood for 7 days or longer) or severe peripheral neuropathy after administration of Paclitaxel should have the dose of Paclitaxel reduced by 20% during subsequent courses of treatment.

The drug solution is prepared immediately before administration, diluting the concentrate with 0.9% sodium chloride solution, or 5% dextrose solution, or 5% dextrose solution in 0.9% sodium chloride solution for injection, or 5% dextrose solution in Ringer's solution to the final concentration from 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, use equipment that does not contain PVC parts.

Paclitaxel should be administered through a system with an integrated membrane filter (0.22 micron pore size).

Side effect

• leukopenia, thrombocytopenia, anemia;
• nausea, vomiting;
• diarrhea, constipation;
• mucositis;
• loss of appetite;
• phenomena of intestinal obstruction;
• increased blood activity of liver enzymes and bilirubin levels;
• skin rash;
• angioedema;
• bronchospasm;
• arterial hypotension;
• bradycardia;
• conduction disorders;
• peripheral edema;
• arthralgia;
• myalgia;
• peripheral neuropathy;
• thrombophlebitis;
• necrosis (with extravasation).

Contraindications

• severe neutropenia (less than 1500/µl);
• pregnancy;
• hypersensitivity to paclitaxel.

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.

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.

To prevent the occurrence of hypersensitivity reactions, all patients should be given premedication (glucocorticosteroids (GCS), histamine H1- and H2-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.

Patients during treatment with paclitaxel and for at least 3 months after the end of therapy should use reliable methods of contraception.

drug 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.

Analogues of the drug Paclitaxel

Structural analogues for the active substance:

• Abitaxel;
• Intaxel;
• Kanataxene;
• Mitotax;
• Paklikal;
• Paclitaxel semi-synthetic;
• Paclitaxel LENS;
• Paclitaxel Teva;
• Paclitaxel Phylaxis;
• Paclitaxel Ebewe;
• Paklitera;
• Paxen;
• Paktalek;
• Syndaxel;
• Taxacad;
• Taxol;
• Yutaxan.

In the absence of analogues of the drug for the active substance, you can follow the links below to the diseases that the corresponding drug helps with and see the available analogues for the therapeutic effect.