INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PACLITAXEL «EBEWE»

Composition:

Active substance: paclitaxel;

1 ml of concentrate contains 6 mg of paclitaxel;

Excipients: polyoxyethylated castor oil, anhydrous ethanol.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear colorless or light-yellow solution.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Taxanes.

ATC code L01C D01.

Pharmacological Properties

Pharmacodynamics

Paclitaxel is an antimicrotubule agent that acts on the microtubular apparatus of the cell. It promotes the assembly of microtubules from tubulin dimers and stabilizes them by preventing depolymerization. As a result, the normal dynamic reorganization of microtubular networks, essential for cellular functions during interphase and mitosis, is disrupted. In addition, paclitaxel induces the formation of abnormal aggregates or "bundles" of microtubules throughout the cell cycle, as well as multiple microtubule "asters" during mitosis.

Pharmacokinetics

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

The pharmacokinetics of paclitaxel have been studied following intravenous infusion over 3 and 24 hours at doses of 135 mg/m² and 175 mg/m² of body surface area. The mean terminal half-life ranges from 3 to 52.7 hours, and the mean total systemic clearance ranges from 11.6 to 24.0 L/h·m². Total clearance of paclitaxel from the body is likely reduced as its plasma concentration increases. The mean steady-state volume of distribution of paclitaxel is 198–688 L/m², indicating extensive extravascular distribution and/or tissue binding. With 3-hour infusions, the pharmacokinetics of paclitaxel are nonlinear. When the dose was increased by 30% (from 135 mg/m² to 175 mg/m² of 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 via 3-hour intravenous infusions, the mean Cmax in 19 patients with Kaposi’s sarcoma was 1530 ng/mL (range: 761–2860 ng/mL), the mean AUC was 5619 ng·h/mL (range: 2609–9428 ng·h/mL), clearance was 20.6 L/h·m² (range: 11–38 L/h·m²), volume of distribution was 291 L/m² (range: 121–638 L/m²), and terminal half-life was 23.7 hours (range: 12–33 hours).

Intrasubject variability in systemic exposure to paclitaxel was minimal. There was no evidence of paclitaxel accumulation after multiple treatment cycles.

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

The metabolism of paclitaxel in humans has not been fully elucidated. Between 1.3% and 12.6% of the administered dose is excreted unchanged in urine, indicating extensive non-renal clearance. Paclitaxel is likely metabolized primarily in the liver by cytochrome P450 isoenzymes and excreted in bile. After administration of radiolabeled paclitaxel, approximately 26%, 2%, and 6% of radioactivity were excreted in 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 the combination of CYP2C8 + CYP3A4, respectively.

The impact of renal or hepatic impairment on the pharmacokinetics of paclitaxel during 3-hour infusions has not been formally studied. Pharmacokinetic parameters in one patient requiring hemodialysis and treated with paclitaxel at 135 mg/m² via 3-hour infusions did not differ from those observed in patients without renal impairment.

When paclitaxel and doxorubicin are used in combination, an increased distribution and elimination time of doxorubicin and its metabolites has been observed. 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 advanced disease or residual tumors (>1 cm in size) after laparotomy; second-line chemotherapy of metastatic ovarian cancer in cases of failure of standard platinum-based therapy).
• Breast cancer (adjuvant chemotherapy in patients with lymph node involvement following 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 cases of immunohistochemically confirmed HER-2 protein overexpression (3+) or in cases of contraindications to anthracycline therapy; monotherapy for metastatic breast cancer in patients who are not candidates for standard anthracycline therapy or in whom prior anthracycline therapy has failed).
• Advanced non-small cell lung cancer (NSCLC) (combination chemotherapy with cisplatin when surgical treatment and/or radiotherapy are not feasible).
• Kaposi’s sarcoma in AIDS patients (second-line therapy for advanced Kaposi’s sarcoma when prior therapy with liposomal anthracyclines has failed).

Contraindications.

Hypersensitivity to paclitaxel or to any of the excipients of the medicinal product, particularly to polyethoxylated castor oil. Paclitaxel is contraindicated during pregnancy and lactation. Neutropenia prior to treatment initiation (baseline neutrophil count < 1.5 × 10⁹/L; in AIDS patients with Kaposi’s sarcoma, neutrophil count < 1 × 10⁹/L), thrombocytopenia (< 100 × 10⁹/L). Concurrent severe uncontrolled infections in patients with Kaposi’s sarcoma. Severe hepatic impairment.

Special safety precautions.

Instructions for healthcare personnel. Handling of Paclitaxel "Ebewe", as with other antineoplastic agents, requires caution. Reconstitution of infusion solutions under aseptic conditions in a designated area should be performed by trained personnel. All precautions must be taken to avoid contact of paclitaxel solutions with skin and mucous membranes, including use of protective clothing (gowns, caps, masks, goggles, and disposable gloves). If the drug comes into contact with the skin (local reactions such as stinging, burning, and erythema may occur), the affected area should be washed thoroughly with soap and water. In case of contact with mucous membranes, they should be rinsed thoroughly with copious amounts of water. Cases of dyspnea, chest pain, throat burning, and nausea following inhalation of aerosolized paclitaxel solutions have been reported.

Precipitation may occur in unopened vials when stored refrigerated; this precipitate dissolves upon gentle swirling or even without mixing upon reaching room temperature. This phenomenon does not affect the quality of the product. However, if the solution remains cloudy or contains undissolved precipitate, the product must not be used and the vial should be disposed of according to established hazardous waste disposal procedures.

Disposal. Unused solutions and all equipment and materials that have come into contact with paclitaxel must be destroyed in accordance with standard hospital procedures for disposal of cytotoxic waste, in compliance with applicable regulations for hazardous waste disposal.

Interaction with other medicinal products and other forms of interaction.

Premedication with cimetidine does not affect paclitaxel clearance.

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

Since elimination of doxorubicin and its active metabolites may be reduced when the interval between paclitaxel and doxorubicin administration is shortened, in primary chemotherapy of metastatic breast cancer, paclitaxel should be administered 24 hours after doxorubicin.

Paclitaxel metabolism is partially catalyzed by the CYP2C8 and CYP3A4 isoenzymes of the cytochrome P450 system. Clinical studies have demonstrated that the major metabolic transformation in humans is 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; therefore, both drugs can be used simultaneously without dose adjustment. Information on potential interactions between paclitaxel and CYP3A4 inducers or inhibitors is limited; therefore, caution is required when co-administering inhibitors (e.g., ketoconazole and other imidazole-derived 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.

Pharmacokinetic studies of paclitaxel in patients with Kaposi’s sarcoma receiving concomitant therapy with multiple drugs indicate a significant reduction in systemic paclitaxel clearance when nelfinavir and ritonavir are administered together, but not with indinavir. Data on interactions between paclitaxel and other protease inhibitors are insufficient. Therefore, paclitaxel should be administered with caution in patients receiving concomitant therapy with protease inhibitors.

Special precautions.

Paclitaxel therapy should be administered under the supervision of a qualified oncologist experienced in the use of antineoplastic chemotherapeutic agents. Since severe hypersensitivity reactions may occur, appropriate resuscitation equipment must be available.

Due to the risk of extravasation during drug administration, careful monitoring of the infusion site for signs of possible infiltration is recommended.

Patients must receive premedication with corticosteroids, antihistamines, and H2-receptor antagonists prior to paclitaxel administration.

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

Severe hypersensitivity reactions, characterized by dyspnea, hypotension (requiring therapeutic intervention), angioedema, and generalized urticaria, have been observed in less than 1% of patients receiving paclitaxel after adequate premedication. These symptoms are likely histamine-mediated reactions. In case of severe hypersensitivity reactions, the drug must be discontinued immediately and symptomatic treatment initiated; re-administration of the drug is not recommended.

Bone marrow suppression (predominantly neutropenia) is the main dose-limiting toxic effect of the drug. Blood counts should be monitored at least twice weekly during paclitaxel therapy. Re-administration of the drug is permitted only after neutrophil counts have recovered to ≥ 1.5×10⁹/L (≥ 1.0×10⁹/L in Kaposi's sarcoma patients) and platelet counts to ≥ 100×10⁹/L (≥ 75×10⁹/L in Kaposi's sarcoma patients). In clinical trials, most patients with Kaposi's sarcoma received granulocyte colony-stimulating factor (G-CSF).

The risk of toxic effects (particularly grade III–IV myelosuppression) is higher in patients with impaired liver function. When paclitaxel is administered via 3-hour infusions, no increased toxicity has been observed in patients with mild hepatic impairment. However, with longer infusions in patients with moderate hepatic impairment, more pronounced myelosuppression may occur. Paclitaxel is not recommended for patients with severe hepatic impairment. Patients should be closely monitored for signs of severe myelosuppression. Currently, there is insufficient data to provide dose adjustment recommendations for patients with mild to moderate hepatic impairment. There is no information on paclitaxel treatment in patients with severe cholestasis. Patients with severe renal impairment should not be treated with paclitaxel.

Severe cardiac conduction disorders during paclitaxel therapy have been reported rarely. In such cases, appropriate treatment should be initiated, and if further administration of the drug is considered, continuous cardiac monitoring is required. Vital signs should be monitored during the first hour of paclitaxel infusion. Hypotension, hypertension, and bradycardia may occur during paclitaxel infusion.

Severe cardiovascular events are more frequently observed in patients with non-small cell lung cancer than in patients with breast or ovarian cancer. One case of heart failure after paclitaxel therapy was reported in a patient with Kaposi's sarcoma and AIDS during clinical trials.

When paclitaxel is used in combination with doxorubicin or trastuzumab for primary chemotherapy of metastatic breast cancer, cardiac function monitoring is essential. Patients eligible for such combination therapy should undergo thorough cardiac evaluation before treatment initiation, including ECG, echocardiography, and MUGA scanning. Cardiac function should be monitored regularly during treatment (e.g., every 3 months). This monitoring allows early detection of cardiac dysfunction. When determining the frequency of ventricular function assessment, the cumulative dose of anthracyclines (in mg/m² body surface area) should be considered. If test results indicate cardiac dysfunction—even if asymptomatic—the potential benefits of continuing treatment should be carefully weighed against the risk of irreversible cardiac damage. If combination chemotherapy is continued, cardiac monitoring should be performed more frequently (every 1–2 cycles).

Although peripheral neuropathy is a common adverse effect during paclitaxel therapy, severe neuropathy is rare. In severe cases, subsequent paclitaxel doses should be reduced by 20% (by 25% in Kaposi's sarcoma patients). Peripheral neuropathy may develop after the first treatment cycle and worsen with continued paclitaxel therapy. Severe neurotoxicity has been more frequently observed in patients with non-small cell lung cancer and ovarian cancer who received first-line paclitaxel chemotherapy as a 3-hour infusion in combination with cisplatin, compared to patients receiving paclitaxel alone or cyclophosphamide followed by cisplatin. Sensory disturbances usually improve or resolve within several months after discontinuation of paclitaxel therapy. Pre-existing neuropathy due to prior chemotherapy is not a contraindication for paclitaxel treatment.

Since Paclitaxel "Ebewe" contains ethanol, its potential effects on the central nervous system and other effects should be considered.

The drug contains polyoxyl 35 castor oil, which may cause severe allergic reactions.

All necessary precautions should be taken to prevent intra-arterial administration of paclitaxel, as animal studies have shown severe tissue reactions following intra-arterial injection.

Isolated cases of pseudomembranous colitis have been reported, including in patients not receiving concomitant antibiotic therapy. This should be considered in differential diagnosis if severe or persistent diarrhea develops during or shortly after paclitaxel therapy.

When paclitaxel chemotherapy is combined with radiotherapy to the lung area, regardless of sequence, cases of interstitial pneumonitis have been observed.

Severe mucosal inflammation is rare in patients with Kaposi's sarcoma. In cases of severe reactions, paclitaxel doses should be reduced by 25%.

When paclitaxel is used in combination with other antineoplastic agents (cisplatin, doxorubicin, trastuzumab), the recommendations for use of these medicinal products should be taken into account.

Use during pregnancy or breastfeeding.

There is no information on paclitaxel treatment in pregnant women. Like other cytotoxic agents, paclitaxel may harm the fetus; therefore, it should not be administered during pregnancy. Both women and men should use effective contraception during paclitaxel therapy and for at least 6 months after completion of treatment. Pregnancy should be reported to the physician immediately if it occurs. Breastfeeding must be discontinued during paclitaxel therapy.

Sperm cryopreservation should be considered for men prior to starting paclitaxel therapy due to the potential risk of infertility.

Ability to affect reaction speed when driving or operating machinery.

During paclitaxel therapy, patients should refrain from potentially hazardous activities requiring high concentration and rapid psychomotor responses. It should be noted that Paclitaxel "Ebewe" contains ethanol, and certain adverse effects may negatively affect the ability to drive or operate machinery.

Route of administration and dosage.

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

Paclitaxel solution must be administered intravenously by infusion using infusion systems equipped with in-line membrane filters with a pore size of ≤ 0.22 μm.

First-line chemotherapy for ovarian cancer. A combination regimen of paclitaxel and cisplatin is recommended. Depending on the duration of infusion, two paclitaxel dosing regimens are recommended:

• paclitaxel 175 mg/m² body surface area administered as a 3-hour intravenous infusion, followed by cisplatin 75 mg/m² body surface area;
• paclitaxel 135 mg/m² body surface area administered as a 24-hour intravenous infusion, followed by cisplatin 75 mg/m² body surface area.

Treatment cycles should be repeated every 3 weeks.

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

Adjuvant chemotherapy for breast cancer. Paclitaxel should be administered following anthracycline- or cyclophosphamide-based chemotherapy. Paclitaxel is recommended at a dose of 175 mg/m² body surface area administered as a 3-hour intravenous infusion. Typically, 4 cycles are administered at 3-week intervals.

First-line chemotherapy for breast cancer. When used in combination with doxorubicin (at a dose of 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. Treatment cycles should be repeated every 3 weeks.

When used in combination with trastuzumab, paclitaxel is recommended at a dose of 175 mg/m² body surface area administered as a 3-hour intravenous infusion every 3 weeks. Paclitaxel may be administered the day after the first dose of trastuzumab or immediately after subsequent doses of trastuzumab, provided prior doses were well tolerated.

Second-line chemotherapy for breast cancer. Paclitaxel is recommended at a dose of 175 mg/m² body surface area administered as a 3-hour intravenous infusion. Treatment cycles should be repeated every 3 weeks.

First-line chemotherapy for 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 as a 3-hour intravenous infusion, followed by cisplatin at a dose of 80 mg/m² body surface area. Treatment cycles should be repeated every 3 weeks.

Chemotherapy for Kaposi’s sarcoma in AIDS patients. Paclitaxel is recommended at a dose of 100 mg/m² body surface area administered as a 3-hour intravenous infusion. Treatment cycles should be repeated every 2 weeks.

Treatment of patients with hepatic impairment. Insufficient data are available regarding dose adjustment in patients with mild to moderate hepatic impairment. Paclitaxel should not be administered to patients with severe hepatic impairment.

Treatment of patients with renal impairment. Insufficient data are available regarding dose adjustment in patients with renal impairment.

Subsequent doses of paclitaxel should be individually adjusted based on treatment tolerability. The next dose of paclitaxel may be administered only after the neutrophil count has recovered to ≥ 1.5×10⁹/L (≥ 1.0×10⁹/L in Kaposi’s sarcoma) and platelet count to ≥ 100×10⁹/L (≥ 75×10⁹/L in Kaposi’s sarcoma). In patients who experienced severe neutropenia (neutrophil count < 0.5×10⁹/L for 7 days or longer) or severe peripheral neuropathy, subsequent doses should be reduced by 20% (by 25% in Kaposi’s sarcoma).

Preparation of infusion solution

The concentrate for infusion solution must be diluted under aseptic conditions with 0.9% sodium chloride solution, 5% glucose solution, 5% glucose in 0.9% sodium chloride solution, or 5% glucose in Ringer’s solution to a final concentration of 0.3–1.2 mg/mL.

When multiple withdrawals are made from the same vial, the product maintains microbiological, physical, and chemical stability for up to 28 days at 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 temperatures not exceeding 25°C, and for 14 days when stored at 2–8°C. The cooled solution may precipitate but can redissolve upon standing at room temperature (25°C). The vial should be discarded if the solution is cloudy or if the precipitate does not redissolve. Freezing does not affect the shelf life. From a microbiological standpoint, the infusion solution should be administered immediately after preparation. If not used immediately, the user must monitor storage duration and conditions. Typically, storage should not exceed 24 hours at 2–8°C, unless the solution was prepared under controlled and validated aseptic conditions.

Ready-to-use infusion solutions may appear cloudy due to the composition of the solvent. Filtration does not eliminate this cloudiness. The infusion solution must be administered through an in-line membrane filter with a pore size of ≤ 0.22 μm. No significant loss of active ingredient has been observed when administered through such a system.

Prepared infusion solutions do not require protection from light.

There have been isolated reports of precipitation occurring in the infusion solution during administration (usually toward the end of a 24-hour infusion period). Although the exact causes of precipitation have not been fully elucidated, this phenomenon is likely due to supersaturation of the infusion solution. To minimize the risk of precipitation, the infusion solution should be administered immediately after dilution, and excessive shaking, vibration, or agitation should be avoided. The infusion system should be thoroughly flushed before use. The appearance of the solution should be monitored regularly during administration, and infusion should be discontinued if precipitation is observed.

To minimize leaching of diethylhexylphthalate (DEHP) from infusion bags, systems, or other medical equipment made of plasticized polyvinyl chloride (PVC), diluted infusion solutions should be stored in containers made of non-PVC materials (glass bottles, polypropylene bottles, polypropylene or polyolefin bags) and administered through polyethylene infusion sets. Filters may be connected using short polyvinyl chloride tubing, which does not cause 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 patient population.

Overdose

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

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

Adverse Reactions

Unless otherwise stated, the following results are based on pooled safety data from 812 patients with solid tumors treated with paclitaxel monotherapy in clinical trials. Because patients with Kaposi's sarcoma have significant characteristics, a separate subsection at the end of this section describes a clinical study involving 107 patients with Kaposi's sarcoma.

Unless otherwise indicated, the frequency and severity of observed adverse events were generally similar among patients receiving paclitaxel for the treatment of ovarian, breast, or non-small cell lung cancer. Patient age did not significantly influence any of the observed types of drug toxicity.

Severe, potentially life-threatening hypersensitivity reactions (such as hypotension requiring treatment, angioedema, respiratory dysfunction requiring bronchodilators, generalized urticaria) were observed in 2 patients (<1% of patients). 34% of patients (17% of all treatment cycles) experienced mild hypersensitivity reactions, primarily flushing and rash, which did not require therapeutic intervention or discontinuation of paclitaxel therapy.

The most common adverse effect during paclitaxel treatment is bone marrow suppression. Severe neutropenia (<500/mm³) occurred in 28% of patients but was not associated with fever. Only 1% of patients experienced severe neutropenia lasting ≥7 days. Thrombocytopenia occurred in 11% of patients. Platelet counts decreased to <50,000/mm³ at least once during the study in 3% of patients. Anemia occurred in 64% of patients, including severe anemia (Hb <5 mmol/L) in 6% of patients. The frequency and severity of anemia depend on baseline hemoglobin levels.

Arthralgia or myalgia occurred in 60% of patients, with severe cases in 13% of patients.

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

Hair loss occurred in 87% of patients receiving paclitaxel. Most cases of hair loss occurred within the first month after starting paclitaxel treatment. Most patients experiencing alopecia can expect significant hair loss ≥50%.

Local reactions – Local swelling, pain, erythema, and induration may occur at the injection site. Accidental extravasation may cause cellulitis. Cases of skin desquamation, sometimes associated with extravasation, have been reported. Skin pigmentation changes are possible. There are isolated reports of recurrence of skin reactions at sites of previous paclitaxel extravasation after subsequent administrations. Specific treatment for extravasation reactions is currently unknown. In some cases, injection site reactions occurred immediately after prolonged infusion or developed with a delay of 7–10 days.

The following adverse reactions were observed during monotherapy with paclitaxel administered as a 3-hour infusion for the treatment of metastatic cancer (812 patients treated in clinical trials), as well as identified during post-marketing surveillance*.

Adverse reactions are categorized by frequency as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), and unknown (frequency cannot be estimated from available data).

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

Blood and lymphatic system disorders: very common – myelosuppression, neutropenia, anemia, thrombocytopenia, leukopenia, bleeding tendency; rare* – febrile neutropenia; very rare* – acute myeloid leukemia, myelodysplastic syndrome; unknown – disseminated intravascular coagulation syndrome.

Immune system disorders: very common – mild hypersensitivity reactions (mainly flushing and rash); uncommon – delayed-type hypersensitivity reactions, serious hypersensitivity reactions requiring therapeutic intervention (e.g., arterial hypotension, angioedema, respiratory distress, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, limb pain, profuse sweating, arterial hypertension); rare* – anaphylactic reactions; very rare* – anaphylactic shock.

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

Psychiatric disorders: very rare* – confusion.

Nervous system disorders: very common – neuropathy# (mainly peripheral neuropathy), paresthesia, somnolence; common – depression, severe neuropathy# (mainly peripheral neuropathy), nervousness, insomnia, cognitive disturbance, hypokinesia, gait disturbance, hypoesthesia, taste alteration; rare* – motor neuropathy (manifested as 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 more than 6 months after discontinuation of paclitaxel.

Eye disorders: uncommon – dry eyes, blurred vision, visual field defect; very rare* – optic nerve damage and/or visual disturbances (scintillating scotoma), especially in patients receiving doses higher than recommended; unknown* – macular edema, photopsia, floaters in the vitreous body.

Ear and labyrinth disorders: very rare* – ototoxic effects, hearing loss, tinnitus, vertigo.

Cardiac disorders: common – bradycardia, tachycardia, palpitations, syncope; uncommon – congestive heart failure, myocardial infarction, atrioventricular block and syncope, cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy, arrhythmia, extrasystoles; rare – heart failure; very rare* – atrial fibrillation, supraventricular tachycardia; unknown* – phlebitis.

Vascular disorders: very common – arterial hypotension; common – vasodilation (flushing); uncommon – arterial hypertension, thrombosis, thrombophlebitis; very rare* – shock; unknown* – phlebitis.

Respiratory, thoracic and mediastinal disorders: common – epistaxis; rare* – dyspnea, pleural effusion, interstitial pneumonitis, pulmonary fibrosis, pulmonary artery embolism, respiratory failure; very rare* – cough, pulmonary hypertension.

Gastrointestinal disorders: very common – nausea, vomiting, diarrhea, mucositis, stomatitis, abdominal pain; common – dry mouth, oral ulcers, melena, dyspepsia; rare* – intestinal obstruction, intestinal perforation, ischemic colitis, acute pancreatitis; very rare* – mesenteric thrombosis, pseudomembranous colitis, esophagitis, constipation, ascites, neutropenic colitis, dehydration.

Hepatobiliary disorders: very rare* – liver necrosis, hepatic encephalopathy (cases with fatal outcome reported).

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

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

General disorders and administration site conditions: common – injection site reactions (localized swelling, pain, erythema, induration, weakness, skin discoloration and swelling, accidental extravasation may cause cellulitis, fibrosis, and skin necrosis); rare* – asthenia, pyrexia, dehydration, edema, malaise. There are isolated reports of recurrence of skin reactions at sites of previous paclitaxel extravasation after subsequent administrations.

Laboratory findings: common – marked (≥5 times above normal) increases in AST, ALT, and alkaline phosphatase levels; uncommon – marked increase in bilirubin levels; rare* – increased blood creatinine levels.

Renal and urinary disorders: common – dysuria; rare – renal failure.

Description of selected adverse reactions.

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

Toxic effects on blood and lymphatic system.

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

Neutropenic fever associated with paclitaxel therapy was observed in 14% of patients, during 1.3% of treatment cycles. Three septic episodes (2.8%) occurred during paclitaxel treatment, resulting in fatal outcomes.

Thrombocytopenia occurred in 50% of patients and was severe (<50,000 cells/mm³) in 9% of cases. Platelet counts decreased to <75,000 cells/mm³ at least once during treatment in 14% of patients. Bleeding events related to paclitaxel were reported in <3% of patients and were localized.

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

Combination chemotherapy.

Paclitaxel with cisplatin.

When paclitaxel is combined with cisplatin, the frequency and severity of neurotoxic effects, mainly peripheral neuropathy, are higher with a 175 mg/m² body surface area dose administered as a 3-hour intravenous infusion (neurotoxic effects observed in 85% of patients, 15% severe) compared to a 135 mg/m² body surface area dose administered as a 24-hour intravenous infusion (neurotoxic effects observed in 25% of patients, 3% severe) in combination with cisplatin.

In patients with non-small cell lung cancer and ovarian cancer receiving paclitaxel over 3 hours followed by cisplatin, the frequency of severe neurotoxicity increased. Peripheral neuropathy may develop after the first treatment cycle and worsen with subsequent paclitaxel administrations. Sometimes it leads to discontinuation of paclitaxel therapy. Sensory symptoms improve or resolve within several months after stopping paclitaxel treatment. Pre-existing neuropathy due to prior therapy is not a contraindication for paclitaxel treatment.

Patients receiving paclitaxel and cisplatin have an increased risk of renal failure compared to those receiving cisplatin alone for gynecological tumors.

The following results are from two large first-line ovarian cancer chemotherapy studies (paclitaxel + cisplatin: over 1,050 patients); two phase III studies of first-line metastatic breast cancer treatment: one study combining with doxorubicin (paclitaxel + doxorubicin: 267 patients), another combining with trastuzumab (planned analysis of paclitaxel + trastuzumab subgroup: 188 patients); and two phase III studies of advanced non-small cell lung cancer treatment (paclitaxel + cisplatin: over 360 patients).

In ovarian cancer patients receiving first-line chemotherapy with paclitaxel administered as a 3-hour intravenous infusion in combination with cisplatin, the frequency and severity of neurotoxic effects, arthralgia/myalgia, and hypersensitivity reactions were higher than with cyclophosphamide combined with cisplatin. The frequency and severity of myelosuppression were lower in the group receiving paclitaxel as a 3-hour intravenous infusion combined with cisplatin compared to the group receiving cyclophosphamide combined with cisplatin.

In first-line chemotherapy for metastatic breast cancer, the frequency and severity of neutropenia, anemia, peripheral neuropathy, arthralgia/myalgia, asthenia, chills, and diarrhea were higher with paclitaxel 220 mg/m² body surface area administered as a 3-hour intravenous infusion 24 hours after doxorubicin 50 mg/m² body surface area, compared to standard therapy with 5-fluorouracil (500 mg/m²), doxorubicin (50 mg/m²), and cyclophosphamide (500 mg/m²) (FAC regimen). The frequency and severity of nausea and vomiting with paclitaxel (220 mg/m²) and doxorubicin (50 mg/m²) were lower than with the FAC regimen. This may partly be explained by the use of corticosteroids.

Paclitaxel with trastuzumab.

In first-line chemotherapy with paclitaxel administered as a 3-hour intravenous infusion in combination with trastuzumab, the frequency of the following adverse effects (regardless of causal relationship to paclitaxel or trastuzumab) in patients with metastatic breast cancer was higher than with paclitaxel monotherapy: heart failure (8% vs 1%), infections (46% vs 27%), chills (42% vs 4%), chills (47% vs 23%), cough (42% vs 22%), rash (39% vs 18%), arthralgia (37% vs 21%), tachycardia (12% vs 4%), diarrhea (45% vs 30%), arterial hypertension (11% vs 3%), epistaxis (18% vs 4%), acne (11% vs 3%), herpes simplex (12% vs 3%), accidental injuries (13% vs 3%), insomnia (25% vs 13%), rhinitis (22% vs 5%), sinusitis (21% vs 7%), injection site reactions (7% vs 1%). Differences in the frequency of some adverse effects may be explained by a greater number and longer duration of treatment cycles with paclitaxel and trastuzumab compared to paclitaxel monotherapy. The frequency of serious adverse effects with combination chemotherapy of paclitaxel and trastuzumab was comparable to that with paclitaxel monotherapy.

Paclitaxel with doxorubicin.

Impaired cardiac contractility (left ventricular ejection fraction decrease >20%) occurred in 15% of patients with metastatic breast cancer receiving doxorubicin in combination with paclitaxel, and in 10% of patients receiving standard therapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen). The incidence of congestive heart failure was <1% in both the paclitaxel plus doxorubicin group and the standard FAC regimen group. In combination chemotherapy with trastuzumab and paclitaxel, the frequency and severity of cardiac dysfunction in patients previously treated with anthracyclines were higher than with paclitaxel monotherapy (heart failure NYHA class I-II: 10% vs 0%; occasionally NYHA class III-IV: 2% vs 1%). In isolated cases, these disorders were associated with fatal outcomes. In all cases except the rare fatal exceptions, patients responded to appropriate therapy.

Special patient groups

Radiation pneumonitis has been reported in patients undergoing concurrent radiotherapy.

Adverse effects in AIDS patients with Kaposi's sarcoma.

Except for adverse effects related to the hematopoietic system and liver, the frequency and severity of adverse effects in patients with Kaposi's sarcoma were comparable to those in patients with other solid tumors receiving paclitaxel monotherapy.

Hepatobiliary disorders: increased levels of bilirubin, alkaline phosphatase, and AST may occur in patients with normal baseline liver function (more than half of these patients were receiving protease inhibitors). Significant increases in these parameters were occasionally observed.

Shelf life. 3 years.

Storage conditions.

No special storage conditions required.

Keep out of reach of children.

Incompatibilities.

Polyoxyl 35 castor oil, an ingredient in Paclitaxel "Ebewe", may cause leaching of diethylhexyl phthalate (DEHP) from plasticized PVC. The extent of this process depends on the duration of exposure and the concentration of castor oil. Therefore, solutions for infusion must be prepared, stored, and administered using containers and systems that do not contain PVC.

Do not use with other solvents except those specified in the section "Dosage and administration".

Packaging.

Clear glass vial, stoppered with a halobutyl rubber plug with fluoropolymer coating and sealed with an aluminum crimp cap; 5 ml (30 mg), 16.7 ml (100 mg), 25 ml (150 mg), 35 ml (210 mg), or 50 ml (300 mg) per vial; 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Fareva Unterach GmbH

EBEWE Pharma Ges.m.b.H. Nfg. KG

Manufacturer's address and location of business operations.

Mondseestrasse 11, 4866 Unterach am Attersee, Austria

Mondseestrasse 11, 4866 Unterach am Attersee, Austria