Paclitaxel Ebeve concentrate for solution for infusion 300 mg bottle 50 ml No. 1

Instructions Paclitaxel Ebeve concentrate for solution for infusion 300 mg bottle 50 ml No. 1

Composition

active ingredient: paclitaxel;

1 ml of concentrate contains 6 mg of paclitaxel;

excipients: polyethoxylated castor oil, anhydrous ethanol.

Dosage form

Concentrate for solution for infusion.

Main physicochemical properties: transparent colorless or light yellow solution.

Pharmacotherapeutic group

Antineoplastic and immunomodulatory agents. Taxanes. ATC 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 during interphase and mitosis, is disrupted. In addition, paclitaxel causes the formation of abnormal clusters or "bundles" of microtubules during the cell cycle, as well as multiple "stars" of microtubules during mitosis.

Pharmacokinetics

After intravenous administration of the drug, a biphasic decrease in paclitaxel plasma concentration is observed.

The pharmacokinetics of paclitaxel have been studied following intravenous administration over 3 and 24 hours at doses of 135 mg/m2 and 175 mg/m2 of body surface area. The mean terminal elimination half-life ranged from 3 to 52.7 hours, and the mean total body clearance ranged from 11.6 to 24.0 l/h·m2. It is likely that the total body clearance of paclitaxel decreases with increasing plasma concentrations. The mean steady-state volume of distribution of paclitaxel was 198 to 688 l/m2, indicating extensive extravascular distribution and/or tissue binding. Paclitaxel pharmacokinetics were non-linear following 3-hour infusions. With a 30% increase in dose (from 135 mg/m2 to 175 mg/m2 body surface area), the maximum plasma concentration 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 body surface area by 3-hour intravenous infusions in 19 patients with Kaposi's sarcoma, the mean Cmax was 1530 ng/mL (range 761-2860 ng/mL), the mean area under the pharmacokinetic curve was 5619 ng h/mL (range 2609-9428 ng h/mL), the clearance was 20.6 l/h/m2 (range 11-38 l/h/m2), the volume of distribution was 291 l/m2 (range 121-638 l/m2), and the terminal phase half-life was 23.7 h (range 12-33 h).

Intrasubject variability in systemic paclitaxel exposure was minimal. There was no evidence of paclitaxel accumulation over multiple courses of treatment.

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

The metabolism of paclitaxel in humans has not been fully studied. From 1.3% to 12.6% of the administered dose is excreted unchanged in the urine, indicating extensive non-renal clearance. Paclitaxel is likely to be metabolized primarily in the liver by cytochrome P450 isoenzymes 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 as 6α-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel and 6α-3'-p-dihydroxypaclitaxel, respectively. The formation of these hydroxylated metabolites is catalyzed by CYP2C8, CYP3A4 and CYP2C8+CYP3A4 isoenzymes, respectively. The effect of renal and hepatic impairment on the pharmacokinetics of paclitaxel given as a 3-hour infusion has not been formally studied. The pharmacokinetics of paclitaxel in one patient requiring hemodialysis treated with 135 mg/m2 of paclitaxel as a 3-hour infusion were not different from those in patients without renal impairment.

When paclitaxel and doxorubicin were administered together, an increase in the distribution and elimination time of doxorubicin and its metabolites was observed. When paclitaxel was administered immediately after doxorubicin, the total plasma exposure of doxorubicin was 30% higher than when paclitaxel was administered 24 hours after doxorubicin.

Indication

Ovarian cancer (first-line chemotherapy for the treatment of ovarian cancer, as well as in combination with cisplatin in advanced disease or 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 in patients with lymph node involvement after standard combination therapy with anthracyclines or cyclophosphamide; primary chemotherapy of locally advanced or metastatic breast cancer in combination with anthracyclines or in combination with trastuzumab in case of immunohistochemical overexpression of the oncoprotein HER-2 (3+) or in case 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 in case of impossibility of surgical treatment and/or radiotherapy). Kaposi's sarcoma in AIDS patients (second-line therapy of advanced Kaposi's sarcoma in case of ineffectiveness of previous therapy with liposomal anthracyclines).

Contraindication

Hypersensitivity to paclitaxel or to any of the excipients, especially polyethoxylated castor oil. Paclitaxel is contraindicated during pregnancy and lactation. Neutropenia before treatment (baseline neutrophil count < 1.5 × 109/l, in the case of Kaposi's sarcoma in AIDS patients, neutrophil count < 1 × 109/l), thrombocytopenia (< 100 × 109/l). Concomitant severe uncontrolled infections in patients with Kaposi's sarcoma. Severe liver dysfunction.

Interaction with other medicinal products and other types of interactions

Premedication with cimetidine does not affect paclitaxel clearance.

In combination chemotherapy for first-line ovarian cancer, paclitaxel should be administered before 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 paclitaxel clearance is reduced by approximately 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 be reduced by shortening the time interval between paclitaxel and doxorubicin administration, in the primary chemotherapy of metastatic breast cancer, paclitaxel should be administered 24 hours after doxorubicin.

The metabolism of paclitaxel is partially catalyzed by the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. 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 CYP3A4 inhibitor, does not slow 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, therefore caution should be exercised when co-administering inhibitors (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir and nelfinavir) or inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine) of CYP2C8 and CYP3A4 isoenzymes.

Studies of the pharmacokinetics of paclitaxel in patients with Kaposi's sarcoma receiving concomitant therapy with several drugs have shown a significant decrease in the systemic clearance of paclitaxel when administered concomitantly with nelfinavir and ritonavir, but not indinavir. There is insufficient information on the interaction of paclitaxel with other protease inhibitors. Therefore, paclitaxel should be administered with caution to patients receiving concomitant therapy with protease inhibitors.

Application features

Paclitaxel treatment should be supervised by a qualified oncologist experienced in the use of anticancer chemotherapeutic agents. Since serious hypersensitivity reactions are possible, appropriate resuscitation equipment should be available.

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

Patients should be premedicated with corticosteroids, antihistamines, and H2-receptor antagonists before administration of paclitaxel.

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

Bone marrow suppression (mainly neutropenia) is the main dose-limiting toxic effect. During treatment with paclitaxel, it is necessary to monitor the content of formed blood elements at least twice a week. Re-administration of the drug is allowed only after the number of neutrophils has increased 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 studies, the majority of patients with Kaposi's sarcoma received granulocyte colony-stimulating factor (GCSF).

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, no increase in toxic effects is observed in patients with mild liver function impairment. However, with longer administration of paclitaxel in patients with moderate liver function impairment, more pronounced myelosuppression may be observed. Patients with severe liver function impairment should not be prescribed paclitaxel. Patients should be closely monitored for signs of profound myelosuppression. Currently, there are insufficient data to develop recommendations for dosage adjustments in patients with mild or moderate liver function impairment. Information on the treatment of paclitaxel in patients with severe cholestasis is missing. Patients with severe renal failure should not be treated with paclitaxel.

Severe cardiac conduction disturbances have been reported rarely during treatment with paclitaxel. If they occur, appropriate treatment should be administered, and continuous cardiac monitoring should be performed with continued administration of the drug. It is recommended to monitor vital functions during the first hour of paclitaxel administration. Hypotension, hypertension, and bradycardia may occur during paclitaxel administration.

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

When paclitaxel is used in combination with doxorubicin or trastuzumab for the initial chemotherapy of metastatic breast cancer, attention should be paid to monitoring cardiac function. Patients who are candidates for such combination therapy should undergo a thorough cardiac evaluation, including ECG and echocardiography, as well as MUGA scanning, before starting treatment. Cardiac function should be monitored regularly during treatment (e.g. every 3 months). Such monitoring allows for early detection of the development of cardiac dysfunction. When deciding on the frequency of monitoring of ventricular function, the cumulative dose of anthracyclines (in mg/m2 body surface area) should be taken into account. If the results of the study indicate impaired cardiac function, even asymptomatic ones, the potential benefit of continuing treatment should be carefully weighed against the possible risk of cardiac damage, sometimes irreversible. In the case of continued combination chemotherapy, cardiac function should be monitored more frequently (every 1-2 courses).

Although peripheral neuropathy is a common side effect of paclitaxel, severe neuropathy is rare. In severe cases, it is recommended to reduce all subsequent doses of paclitaxel by 20% (25% in Kaposi's sarcoma). Peripheral neuropathy may develop after the first course of therapy and become more severe with continued paclitaxel treatment. Severe neurotoxicity has been reported 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 alone or cyclophosphamide followed by cisplatin. Sensory disturbances usually improve or resolve within a few months after discontinuation of paclitaxel. Existing neuropathy due to previous chemotherapy is not a contraindication to treatment with paclitaxel.

Since Paclitaxel "Ebewe" contains ethanol, its possible effects on the central nervous system, as well as other effects, must be taken into account.

The drug contains polyethoxylated castor oil, which can cause severe allergic reactions.

Every precaution should be taken to avoid intra-arterial administration of paclitaxel, as animal experiments have shown severe tissue reactions following intra-arterial administration of the drug.

Isolated cases of pseudomembranous colitis have been reported, particularly in patients not receiving concomitant antibiotic therapy. This should be considered in the differential diagnosis in case of severe or persistent diarrhoea 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, regardless of their sequence.

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

Ability to influence reaction speed when driving vehicles or other mechanisms

During treatment with paclitaxel, one should refrain from potentially hazardous activities that require increased concentration 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 or operate other mechanisms.

Use during pregnancy or breastfeeding

There is no information on the use of paclitaxel in pregnant women. As with other cytotoxic drugs, paclitaxel may cause foetal harm and should not be used during pregnancy. Women and men should use contraception to prevent pregnancy during treatment with paclitaxel and for at least 6 months after treatment with paclitaxel and should inform their doctor immediately if pregnancy occurs. Breast-feeding should be discontinued during treatment with paclitaxel.

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

Method of administration and doses

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

Paclitaxel solution should be administered intravenously via infusion systems with built-in membrane filters with a pore size ≤ 0.22 μm.

First-line chemotherapy of ovarian cancer. A combination regimen of paclitaxel and cisplatin is recommended. Two doses of paclitaxel are recommended, depending on the duration of infusion:

Paclitaxel at a dose of 175 mg/m2 of body surface area should be administered by intravenous infusion over 3 hours, followed by cisplatin at a dose of 75 mg/m2 of body surface area; Paclitaxel at a dose of 135 mg/m2 of body surface area should be administered as a 24-hour intravenous infusion, followed by cisplatin at a dose of 75 mg/m2 of body surface area.

The intervals between treatment courses are 3 weeks.

Second-line chemotherapy of ovarian cancer. Paclitaxel is recommended to be administered at a dose of 175 mg/m2 body surface area by 3-hour intravenous infusion. Usually, no more than 4 courses should be administered at 3-week intervals.

Adjuvant chemotherapy for breast cancer. Paclitaxel is given after chemotherapy with anthracyclines or cyclophosphamide. Paclitaxel is recommended to be administered at a dose of 175 mg/m2 of body surface area by 3-hour intravenous infusion. Usually 4 courses are prescribed with 3-week intervals between them.

First-line chemotherapy of breast cancer. When used in combination with doxorubicin (50 mg/m2 body surface area), paclitaxel should be administered 24 hours after doxorubicin. The recommended dose of paclitaxel is 220 mg/m2 body surface area administered as a 3-hour intravenous infusion. The treatment interval is 3 weeks.

When used in combination with trastuzumab, paclitaxel is recommended to be administered at a dose of 175 mg/m2 body surface area by 3-hour intravenous infusion at 3-week intervals. Paclitaxel may be administered the day after the first dose of trastuzumab or immediately after subsequent doses of trastuzumab if the previous doses were well tolerated.

Second-line chemotherapy of breast cancer. Paclitaxel is recommended to be administered at a dose of 175 mg/m2 body surface area by 3-hour intravenous infusion. The intervals between courses of treatment are 3 weeks.

Chemotherapy of advanced non-small cell lung cancer (NSCLC). A combination regimen of paclitaxel and cisplatin is recommended. Paclitaxel should be administered at a dose of 175 mg/m2 body surface area by 3-hour intravenous infusion, followed by cisplatin at a dose of 80 mg/m2 body surface area. The intervals between courses of treatment are 3 weeks.

Chemotherapy of Kaposi's sarcoma in AIDS patients. Paclitaxel is recommended to be administered at a dose of 100 mg/m2 of body surface area by 3-hour intravenous infusion. The intervals between courses of treatment are 2 weeks.

Treatment of patients with renal impairment: There are insufficient data on dosage adjustments for patients with renal impairment.

Subsequent doses of paclitaxel should be determined individually, depending on the tolerability of therapy. The next dose of paclitaxel should be administered only after the neutrophil count has increased to ≥ 1.5 × 109/l (≥ 1.0 × 109/l in the case of Kaposi's sarcoma) and the platelet count to ≥ 100 × 109/l (≥ 75 × 109/l in the case of Kaposi's sarcoma). In patients who have experienced severe neutropenia (neutrophil count < 0.5 × 109/l for 7 days or more) or severe peripheral neuropathy, subsequent doses should be reduced by 20% (25% in the case of Kaposi's sarcoma).

Preparation of solution for intravenous infusions

The concentrate for solution for infusion should be diluted aseptically with 0.9% sodium chloride solution or 5% glucose solution, or 5% glucose solution in 0.9% sodium chloride solution, or 5% glucose solution in Ringer's solution to a final concentration of 0.3-1.2 mg/ml.

With repeated withdrawal of the concentrate from the vial, the drug retains microbiological, physical and chemical stability for up to 28 days at a temperature of 25 °C.

Infusion solutions prepared by diluting Paclitaxel Ebewe with 0.9% sodium chloride solution or 5% glucose solution are physically and chemically stable for 51 hours when stored at a temperature not exceeding 25 °C and 14 days when stored at 2-8 °C. The refrigerated product may precipitate, but can be reconstituted at room temperature (25 °C). The vial should be discarded if the solution is cloudy or if the precipitate does not re-dissolve. Freezing does not affect the shelf life. From a microbiological point of view, the infusion solution should be administered immediately after preparation. If the solution is not used immediately, storage times and conditions should be monitored by the user. Storage times would normally not be longer than 24 hours at 2-8 °C, unless the solution has been prepared in controlled and validated aseptic conditions.

Ready-to-use infusion solutions may be turbid due to the composition of the diluent. Filtration does not eliminate this turbidity. The infusion solution should be administered through a membrane filter with a pore size ≤ 0.22 μm built into the infusion system. No significant loss of activity of the active substance is observed when administered through such a system.

Prepared infusion solutions do not require protection from light.

There have been isolated reports of precipitation in the infusion solution during administration (usually at the end of the 24-hour administration period). Although the exact cause of precipitation is not known, it is likely to be due to oversaturation of the infusion solution. To reduce the risk of precipitation, the infusion solution should be administered immediately after dilution and excessive shaking, vibration and agitation should be avoided. The infusion system should be thoroughly flushed before use. The appearance of the solution should be regularly monitored during administration and the infusion should be stopped if precipitation is observed.

To minimize the leaching of diethylhexyl phthalate (DEHP) from plasticized polyvinyl chloride (PVC) infusion bags, systems, or other medical equipment, diluted infusion solutions should be stored in PVC-free containers (glass, polypropylene, polypropylene bags, polyolefin) and administered through polyethylene infusion sets. Filters can be connected with short lengths of polyvinyl chloride tubing, which does not result in significant leaching of DEHP.

Children

The safety and efficacy of paclitaxel in children have not been established, therefore 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 inflammation of the mucous membranes.

Treatment: In case of overdose, the drug should be discontinued immediately and symptomatic treatment should be carried out, with monitoring of blood cell counts and vital organ function. There is no known antidote for paclitaxel.

Adverse reactions

Unless otherwise stated, the results presented below are based on pooled safety data from 812 patients with solid tumors treated with paclitaxel monotherapy in clinical trials. Because the Kaposi's sarcoma patient population has significant unique characteristics, a dedicated section describing a clinical trial involving 107 patients with Kaposi's sarcoma is provided at the end of this section.

Unless otherwise stated, the frequency and severity of adverse events reported were generally similar in patients receiving paclitaxel for the treatment of ovarian, breast, or non-small cell lung cancer. Age did not significantly influence any of the toxicities reported.

The most common adverse reaction with paclitaxel is bone marrow suppression. Severe neutropenia (< 500/mm3) was observed in 28% of patients, but was not accompanied by fever. Only 1% of patients had severe neutropenia for ≥ 7 days. Thrombocytopenia was observed in 11% of patients. In 3% of patients, platelet counts decreased to < 50,000/mm3 at least once during the study. Anemia was observed in 64% of patients, including severe (Hb < 5 mmol/L) in 6% of patients. The incidence and severity of anemia depended on baseline hemoglobin levels.

Arthralgia or myalgia were observed in 60% of patients, with severe symptoms occurring in 13% of patients.

There have been isolated reports of disseminated intravascular coagulation syndrome, often in association with sepsis or multi-organ dysfunction.

Alopecia was observed in 87% of patients treated with paclitaxel. The majority of cases of alopecia occurred within the first month after initiation of paclitaxel treatment. Significant hair loss of ≥ 50% is expected in the majority of patients who experience alopecia.

Local reactions - Local swelling, pain, erythema and induration may occur at the injection sites. Accidental extravasation may cause cellulitis. Skin peeling has been reported, sometimes associated with extravasation. Changes in skin pigmentation may occur. There have been isolated reports of skin reactions reoccurring at sites of previous paclitaxel extravasation following subsequent administrations. Specific treatment for extravasation reactions is currently unknown. In some cases, the onset of injection site reactions has been immediate following prolonged infusion or has been delayed for 7-10 days.

The following adverse reactions have been observed with paclitaxel monotherapy as a 3-hour infusion in the treatment of metastatic cancer (812 patients treated in clinical trials) and have also been identified during post-marketing surveillance*.

Adverse reactions are classified according to frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), not known (frequency cannot be estimated from the available data).

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

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

Immune system disorders: very common: minor hypersensitivity reactions (mainly flushing and rash); uncommon: delayed-type hypersensitivity reactions, serious hypersensitivity reactions requiring therapeutic measures (including hypotension, angioedema, respiratory distress, generalised urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, pain in the extremities, profuse sweating, hypertension); rare*: anaphylactic reactions; very rare*: anaphylactic shock.

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

Mental disorders: very rare* – confusional state.

Nervous system disorders: very common: neuropathy (predominantly peripheral neuropathy), paresthesia, drowsiness; common: depression, severe neuropathy (predominantly peripheral neuropathy), nervousness, insomnia, thinking disorders, hypokinesia, gait disturbance, hypoesthesia, taste perversion; rare: motor neuropathy (manifested in moderate distal muscle weakness); very rare: autonomic neuropathy (leading to paralytic ileus and orthostatic hypotension), grand mal seizures, convulsions, encephalopathy, dizziness, headache, ataxia.

# May persist for 6 months after paclitaxel discontinuation.

On the part of the organs of vision: infrequently - dry eyes, decreased vision, visual field defect; very rarely* - optic nerve damage and/or visual impairment (flickering scotoma), especially in patients who received doses higher than recommended; unknown* - macular edema, photopsia, floating vitreous haze.

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

From the side of the cardiovascular system: often - bradycardia, tachycardia, increased heart rate, fainting; infrequently - congestive heart failure, myocardial infarction, atrioventricular block and fainting, cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia combined with bigeminy, arrhythmia, extrasystole; rarely - heart failure; very rarely * - atrial fibrillation, supraventricular tachycardia; unknown * - phlebitis.

Respiratory system: often - epistaxis; rarely* - dyspnea, 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.

Hepatobiliary system: very rare* – liver necrosis, hepatic encephalopathy (fatal cases have been reported).

Skin and subcutaneous tissue disorders: very common - alopecia; common - transient minor changes in nails and skin, acne; uncommon - nail discoloration; rare* - itching, rash, erythema, edema; very rare* - Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients receiving paclitaxel should wear appropriate clothing to protect against sun exposure), folliculitis; unknown* - scleroderma, palmar-plantar erythrodysaesthesia syndrome.

Musculoskeletal system: very often - arthralgia, myalgia; unknown* - systemic lupus erythematosus.

General disorders and local reactions: common: injection site reactions (localised swelling, pain, erythema, induration, weakness, skin discolouration and oedema; accidental extravasation may cause cellulitis, fibrosis and skin necrosis); rare*: asthenia, fever, dehydration, oedema, malaise. There have been isolated reports of recurrence of skin reactions at sites of previous extravasation of paclitaxel after subsequent administrations.

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

From the kidneys and urinary system: often - dysuria; rarely - renal failure.

Description of some adverse reactions.

In breast cancer patients who received paclitaxel as adjuvant therapy after AC, neurosensory toxicity, hypersensitivity reactions, arthralgia/myalgia, anemia, infections, fever, nausea/vomiting, and diarrhea were more frequently observed compared to patients who received AC alone. However, the incidence of these events was consistent with that observed with paclitaxel monotherapy, as described above.

Toxic effect on the circulatory and lymphatic systems.

Myelosuppression is the main dose-limiting toxic effect. The most significant manifestation of hematological toxicity was neutropenia. During the first cycle of treatment, severe neutropenia (< 500 cells/mm3) was observed in 20% of patients. During the entire period of therapy, severe neutropenia was observed in 39% of patients. Neutropenia lasting more than 7 days was recorded in 41% of patients, and neutropenia lasting for 30-35 days in 8% of patients. In all patients under observation, hematological parameters normalized within 35 days. The incidence of grade 4 neutropenia lasting 7 days or more was 22%.

Neutropenic fever associated with paclitaxel treatment was reported in 14% of patients, during 1.3% of courses of therapy. Three septic episodes (2.8%) were reported during paclitaxel treatment, which resulted in a fatal outcome.

Thrombocytopenia occurred in 50% of patients and was severe (< 50,000 cells/mm3) in 9%. 14% of patients experienced a platelet count decrease to < 75,000 cells/mm3 at least once during treatment. Bleeding events associated with paclitaxel were reported in < 3% of patients and were localized.

Anemia (Hb < 11 g/dL) was noted in 61% of patients and was severe (Hb < 8 g/dL) in 10%. 21% of patients required packed red blood cell transfusions.

Combination chemotherapy.

Paclitaxel with cisplatin.

In combination therapy with paclitaxel and cisplatin, the frequency and severity of neurotoxic effects, mainly peripheral neuropathy, were higher when paclitaxel was administered at a dose of 175 mg/m2 of body surface area by 3-hour intravenous infusions (neurotoxic effects were noted in 85% of patients, severe in 15%) than when paclitaxel was administered at a dose of 135 mg/m2 of body surface area by 24-hour intravenous infusions.