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Composition:


active ingredient: paclitaxel;


1 ml of the concentrate contains paclitaxel 6 mg;


excipients: polyethoxylated castor oil, anhydrous ethanol.


Dosage form. Concentrate for infusion solution.


Basic physical and chemical properties: transparent colorless or light yellow solution.


Pharmacotherapeutic group. Antineoplastic and immunomodulatory agents. Taxanes.


ATX code L01C D01.


Pharmacological properties.


Pharmacodynamics.


Paclitaxel is an antimitotic agent that acts on the microtubule apparatus of the cell. It stimulates the assembly of microtubules from tubulin dimers and stabilizes them, preventing depolymerization. As a result, the normal process of dynamic reorganization of microtubule networks, which is important for cellular functions at the stages of interphase and mitosis, is disrupted. In addition, paclitaxel causes abnormal clusters or "connections" of microtubules during the cell cycle, as well as multiple "stars" of microtubules during mitosis.


Pharmacokinetics.


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


The pharmacokinetics of paclitaxel were studied by intravenous administration of the drug for 3 and 24 hours at doses of 135 mg/m2 and 175 mg/m2 of body surface area. The average 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·M2. Probably, the total clearance of paclitaxel from the body decreases with an increase in its concentration in blood plasma. The average equilibrium volume of distribution of paclitaxel was 198-688 L/M2, which indicates a wide extravascular distribution and/or binding to tissues. With infusions lasting 3 hours, the pharmacokinetics of paclitaxel were non-linear. With a 30% increase in doses (from 135 mg/m2 to 175 mg/m2 of body surface area), the maximum plasma concentration of Cmax and the area under the pharmacokinetic curve AUC→∞ increased by 75% and 81%, respectively.


After administration of paclitaxel at a dose of 100 mg/m2 of body surface area by 3-hour intravenous infusions, 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 was 5619 ng·H/ML (range 2609-9428 ng·H/ML), and the clearance was 20.6 L/H·m2 (range 11-38 L/H·m2), the volume of distribution is 291 l/m2 (range 121-638 L/m2), and the terminal phase Half – Life is 23.7 hours (range 12-33 hours).


Intra-subject variability in systemic exposure to paclitaxel was minimal. There were no signs of accumulation of paclitaxel 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 the Binding of paclitaxel to proteins.


The metabolism of paclitaxel in the human body has not been definitively studied. From 1.3% to 12.6% of the administered dose is excreted unchanged in the urine, which indicates intensive non-renal clearance. Paclitaxel is probably metabolized in the liver with the participation of cytochrome P450 isoenzymes and is excreted in the bile. After administration of paclitaxel labeled with a radioactive isotope, an average of 26%, 2%, and 6% of the radioactivity was excreted in the faeces as 6α-hydroxypaclitaxel, 3’-p-hydroxypaclitaxel, and 6α-3’-p-dihydroxypaclitaxel, respectively. The formation of these hydroxylated metabolites is catalyzed by the isoenzymes CYP2C8, CYP3A4, and together CYP2C8+CYP3A4, respectively. The effect of impaired renal and hepatic function on the pharmacokinetics of paclitaxel with 3-hour infusions has not been formally studied. Pharmacokinetic parameters in one patient who required hemodialysis and was treated with paclitaxel at a dose of 135 mg/m2 of body surface area by 3-hour infusions 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 to doxorubicin was 30% higher than when paclitaxel was administered 24 hours after doxorubicin.


Clinical characteristics.


Indications.


* Ovarian cancer (first-line chemotherapy for the treatment of ovarian cancer, as well as in combination with cisplatin for a common form of the disease or for residual tumors (larger than 1 cm) after laparotomy; second-line chemotherapy for metastatic ovarian cancer in case of ineffectiveness of standard platinum therapy).


* Breast cancer (adjuvant chemotherapy of patients with lymph node involvement after standard combination therapy with anthracyclines or cyclophosphamides; primary chemotherapy of locally advanced or metastatic breast cancer in combination with anthracyclines or in combination with trastuzumab in the case of immunohistochemical overexpression of oncoprotein HER-2 (3+) 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 ineffectiveness of previous anthracycline therapy).


* Advanced non-small cell lung cancer (NSCLC) (combined chemotherapy with cisplatin if surgical treatment and/or radiation therapy are not possible).


* Kaposi's sarcoma in AIDS patients (second-line therapy of advanced Kaposi's sarcoma in case of ineffectiveness of previous therapy with liposomal anthracyclines).


Contraindications.


Hypersensitivity to paclitaxel or other components of the drug, especially to polyethoxylated castor oil. Paclitaxel is contraindicated during pregnancy and lactation. Neutropenia before treatment (initial neutrophil count 9/L, in the case of Kaposi's sarcoma in AIDS patients, neutrophil count 9/l), thrombocytopenia (9 / l). Concomitant severe uncontrolled infections in patients with Kaposi's sarcoma. Severe liver function disorders.


Special security measures.


Instructions for medical personnel. When working with paclitaxel "Ebeve", as with other antineoplastic drugs, caution should be exercised. Preparation of solutions for infusions under aseptic conditions in a specially designated room should be carried out by trained personnel. It is necessary to take all measures to prevent paclitaxel solutions from getting on the skin and mucous membranes, in particular, wear protective clothing (dressing gowns, caps, masks, glasses and disposable gloves). If the drug gets on the skin (local reactions such as tingling, burning and redness of the skin are possible), the affected area is washed with soap and water. If the drug gets on the mucous membranes, they are thoroughly washed with plenty of water. Shortness of breath, chest pain, burning throat, and nausea have been reported when inhaling sprayed paclitaxel solutions.


When unopened vials are cooled, a precipitate may form in the preparation, which dissolves with careful shaking or even without stirring when reaching room temperature. This phenomenon does not affect the quality of the drug. If the solution remains cloudy or there is an undissolved precipitate in it, the drug should not be used and such a bottle should be destroyed in accordance with the established procedure for the disposal of hazardous waste.


Recycling. Unused solutions and all tools and materials in contact with paclitaxel should be disposed of in accordance with the standard hospital procedure for cytotoxic waste disposal, taking into account the current regulations for the disposal of hazardous waste.


Interactions with other drugs and other types of interactions.


Premedication with cimetidine does not affect the clearance of paclitaxel.


In combination chemotherapy for first-line ovarian cancer, paclitaxel should be administered with 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 decreases by about 20 %. The risk of developing renal failure in ovarian cancer patients receiving combination therapy with paclitaxel and cisplatin is higher than with cisplatin monotherapy.


Since the elimination of doxorubicin and its active metabolites may decrease with a shorter time interval between paclitaxel and doxorubicin injections, paclitaxel should be administered 24 hours after doxorubicin in primary chemotherapy for metastatic breast cancer.


Paclitaxel metabolism is partially catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. clinical studies have shown that the main metabolic transformation in humans is CYP2C8-mediated conversion of paclitaxel to 6α-hydroxypaclitaxel. Concomitant administration of ketoconazole, a potent CYP3A4 inhibitor, does not slow down the elimination of paclitaxel from the human 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 should be exercised when prescribing inhibitors (e.g. ketoconazole and other antifungal derivatives of imidazole, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir and nelfinavir) or inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, Efavirenz, Nevirapine) isoenzymes CYP2C8 and CYP3A4.


Studies of the pharmacokinetics 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 the 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.

Application features.


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


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


Patients should receive premedication with corticosteroids, antihistamines, and H2 receptor antagonists before taking paclitaxel.


When used in combination with cisplatin, paclitaxel should be administered before cisplatin.


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


Inhibition of bone marrow function (mainly neutropenia) is the main toxic effect that limits the dose of the drug. During treatment with paclitaxel, it is necessary to monitor the content of shaped blood elements at least 2 times a week. Repeated administration of the drug is allowed only after an increase in the number of neutrophils to the level of ≥ 1.5×109/L (≥ 1.0×109/L in the case of Kaposi's sarcoma), and platelets – to the 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 (ACSF).


The risk of toxic effects (in particular, Grade III-IV myelosuppression) is higher in patients with impaired liver function. When paclitaxel is administered by 3-hour infusions, there is no increase in toxic effects in patients with mild hepatic impairment. However, with longer administration of paclitaxel, patients with moderate hepatic impairment may experience more pronounced myelosuppression. Patients with severe hepatic impairment should not be prescribed paclitaxel. Patients should be closely monitored for signs of deep myelosuppression. To date, there is insufficient data to develop recommendations for dosage adjustment for patients with mild or moderate hepatic impairment. There is no information on the treatment of patients with severe cholestasis with paclitaxel. Patients with severe renal insufficiency should not be treated with paclitaxel.


Severe cardiac conduction disorders were rare during paclitaxel treatment. If they occur, appropriate treatment should be prescribed, and in case of further Administration of the drug, continuous monitoring of heart function should be carried out. It is recommended to monitor vital body functions during the first hour of paclitaxel administration. Hypotension, hypertension, and bradycardia may occur during paclitaxel administration.


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


When paclitaxel is used in combination with doxorubicin or trastuzumab for primary chemotherapy for metastatic breast cancer, attention should be paid to monitoring heart function. Patients who are candidates for such combination therapy should undergo a thorough Cardiological examination, including ECG and echocardiography, as well as Muga scans, before starting treatment. During treatment, it is necessary to regularly monitor heart function (for example, every 3 months). Such monitoring makes it possible to detect the development of cardiac disorders in time. When deciding on the frequency of ventricular function monitoring, the cumulative dose of anthracyclines (in mg/m2 of body surface area) should be taken into account. If the results of the study indicate cardiac dysfunction, even asymptomatic ones, it is necessary to carefully weigh the potential benefits of continuing treatment and the possible risk of heart damage, sometimes irreversible. If combined chemotherapy continues, it is necessary to monitor heart function more often (every 1-2 courses).


Although peripheral neuropathy is a common side effect of paclitaxel treatment, severe neuropathy is rare. In serious cases, it is recommended to reduce all subsequent doses of paclitaxel by 20 % (by 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 was more common in patients with non-small cell lung cancer and ovarian cancer who underwent 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 administration. Sensory impairments usually subside or disappear within a few months of discontinuation of paclitaxel therapy. 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 drug contains polyethoxylated castor oil, which can cause severe allergic reactions.


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


Isolated cases of pseudomembranous colitis have been reported, in particular in patients who did not receive concomitant antibiotic therapy. This should be taken into account in differential diagnosis if severe or persistent diarrhea develops during or shortly after treatment with paclitaxel.


Cases of interstitial pneumonitis have been reported with paclitaxel chemotherapy in combination with radiation therapy to the lung area, regardless of their sequence.


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


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


Use during pregnancy or lactation.


There is no information on the treatment of pregnant women with paclitaxel. Like other cytotoxic drugs, paclitaxel can have a harmful effect on the fetus, so it should not be prescribed during pregnancy. Women and men should use contraceptives to prevent pregnancy during treatment with paclitaxel and at least 6 months after the end of treatment with paclitaxel, and immediately inform the doctor if pregnancy still occurs. Breast-feeding should be discontinued during treatment with paclitaxel.


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


Ability to influence the reaction rate when driving vehicles or other mechanisms.


During treatment with paclitaxel, you should refrain from potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions. It should be borne in mind that paclitaxel "Ebeve" contains ethanol, and some side effects can negatively affect the ability to drive vehicles or work with other mechanisms.

Children.


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


Overdose.


Symptoms. The main expected complications of overdose are bone marrow suppression, peripheral neuropathy, and mucosal inflammation.


Treatment. In case of overdose, you should immediately stop using the drug and conduct symptomatic treatment with monitoring the content of shaped blood elements and the state of vital organ functions. The antidote to paclitaxel is unknown.


Adverse reactions.


Unless otherwise indicated, the following results are based on cumulative safety data for 812 patients with solid tumors treated with paclitaxel monotherapy in clinical trials. Since the group of patients with Kaposi's sarcoma has significant features, at the end of this section, a special subsection is presented describing a clinical trial involving 107 patients with Kaposi's sarcoma.


Unless otherwise indicated, the frequency and severity of reported side effects were generally the same in patients treated with paclitaxel for the treatment of ovarian, breast, or non-small cell lung cancer. The age of patients did not significantly affect any of the identified types of toxic effects of the drug.


Severe hypersensitivity reactions with a possible fatal outcome (such as hypotension requiring treatment, angioedema, respiratory disorders requiring the use of bronchodilators, generalized urticaria) were observed in 2 patients (


The most common side effect of paclitaxel treatment is bone marrow suppression. Severe neutropenia (3) was observed in 28% of patients, but was not accompanied by cases of fever. Only 1% of patients had severe neutropenia within ≥ 7 days. Thrombocytopenia was observed in 11% of patients. In 3% of patients, the platelet count decreased to 3 at least once during the study. Anemia was observed in 64% of patients, including severe (Hb


Arthralgia or myalgia was observed in 60% of patients, in severe form – in 13% of patients.


There have been isolated reports of cases of disseminated intravascular coagulation syndrome, often in combination with sepsis or multiple organ dysfunction.


Baldness was observed in 87% of patients treated with paclitaxel. Most cases of baldness were observed in the first month after starting treatment with paclitaxel. Significant hair loss ≥ 50% is expected by most patients who experience baldness.


Local reactions-local edema, pain, erythema, and induration may occur at the injection sites. Accidental extravasation can cause cellulite. There have been reports of cases of flaky skin, sometimes associated with extravasation. Possible changes in skin pigmentation. There are isolated reports of recurrent skin reactions at the sites of previous extravasation of paclitaxel after subsequent injections of the drug. The specific treatment for extravasation reactions is currently unknown. In some cases, the onset of the injection site reaction occurred immediately after prolonged infusion or occurred with a delay of 7-10 days.


The following are adverse reactions that were observed with paclitaxel monotherapy by 3-hour infusion in the treatment of metastatic cancer (812 patients treated in clinical trials), as well as identified during post-marketing follow-up*.


According to the frequency of adverse reactions, they are divided into the following categories: very often (≥ 1/10), often (≥ 1/100,


Infections and infestations: very often – infections (mainly of the urinary tract and upper respiratory tract, including herpes simplex, oral candidiasis, pharyngitis, rhinitis), in isolated cases – with a fatal outcome; infrequently – septic shock; rarely* – pneumonia, peritonitis, sepsis.


From the blood and lymphatic system: very often-myelosuppression, neutropenia, anemia, thrombocytopenia, leukopenia, tendency to bleeding; rarely* – febrile neutropenia; very rarely* – acute myeloid leukemia, myelodysplastic syndrome; unknown - disseminated intravascular coagulation syndrome.


From the immune system: very often – minor hypersensitivity reactions (mainly hot flashes and rashes); infrequently – delayed hypersensitivity reactions, serious hypersensitivity reactions requiring therapeutic measures (in particular, hypotension, angioedema, respiratory distress, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, pain in the extremities, profuse sweating, arterial hypertension); rarely* – anaphylactic reactions; very rarely* – anaphylactic shock.


Metabolic disorders: very rare – anorexia; unknown * - tumor lysis syndrome.


Mental disorders: very rare – - a state of confusion.


From the nervous system: very often-neuropathy# (mainly peripheral neuropathy), paresthesia, drowsiness; often-depression, severe neuropathy# (mainly peripheral neuropathy), nervousness, insomnia, thinking disorders, hypokinesia, gait disorders, hypesthesia, taste distortion; rarely* – motor neuropathy (manifested in moderate weakness of the distal muscles); very rarely* – autonomic neuropathy# (leading to paralytic intestinal obstruction and orthostatic hypotension), extensive epileptic seizures ("grand mal"), convulsions, encephalopathy, dizziness, headache, ataxia.


# May persist after 6 months of paclitaxel withdrawal.


From the side of the visual organs: infrequently – dry eyes, blurred vision, visual field defect; very rarely* – damage to the optic nerve and/or visual impairment (atrial fibrillation scotoma), especially in patients who received doses higher than recommended; unknown* – macular edema, photopsia, floating opacity in the vitreous body.


From the side of the organs of hearing and Labyrinth: very rarely* – ototoxic lesions, hearing loss, tinnitus, vertigo.


From the cardiac system: often – bradycardia, tachycardia, palpitations, syncope; infrequently – congestive heart failure, myocardial infarction, atrioventricular block and syncope, cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia in combination with bigeminia, arrhythmia, extrasystole; rarely – heart failure; very rarely* – atrial fibrillation, supraventricular tachycardia; unknown* – phlebitis.


From the vascular system: very often-hypotension; often-vasodilation (hot flashes); infrequently – arterial hypertension, thrombosis, thrombophlebitis; very rarely* – shock; unknown* – phlebitis.


From the respiratory system: often – nosebleeds; rarely* – shortness of breath, pleural effusion, interstitial pneumonitis, pulmonary fibrosis, pulmonary embolism, respiratory failure; very rarely* - cough, pulmonary hypertension.


From the digestive system: very often – nausea, vomiting, diarrhea, inflammation of the mucous membranes, stomatitis, abdominal pain; often – dry mouth, mouth ulcers, Melena, dyspepsia; rarely* – intestinal obstruction, intestinal perforation, ischemic colitis, acute pancreatitis; very rarely* – mesenteric thrombosis, pseudomembranous colitis, esophagitis, constipation, ascites, neutropenic colitis, hypohydration.


From the hepatobiliary system: very rarely* – liver necrosis, hepatic encephalopathy (cases with a fatal outcome have been noted).


From the skin and subcutaneous tissues: very often – alopecia; often – transient minor changes in nails and skin, acne; infrequently – changes in nail color; rarely* – pruritus, rash, erythema, edema; very rarely* – Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients receiving paclitaxel should wear appropriate clothing to protect from sun exposure), folliculitis; unknown* – scleroderma, Palmar syndrome-plantar erythrodysesthesia.


Musculoskeletal disorders: very common – arthralgia, myalgia; unknown* - systemic lupus erythematosus.


General disorders and local reactions: often – reactions at injection sites (localized edema, pain, erythema, induration, weakness, loss of color and swelling of the skin, accidental extravasation can cause cellulite, fibrosis and skin necrosis); rarely* – asthenia, fever, dehydration, edema, malaise. There are isolated reports of recurrent skin reactions at the sites of previous extravasation of paclitaxel after subsequent injections of the drug.


Laboratory parameters: often-a significant (5 times or more compared to the norm) increase in AST, ALT and alkaline phosphatase levels; infrequently – a significant increase in bilirubin levels; rarely* – an increase in blood creatinine levels.


From the side of the kidneys and urinary system: often – dysuria; rarely – renal failure.

Tags: Paclitaxel