NEOTAXEL

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEOTAXL (NEOTAXL)

Composition:

Active substance: paclitaxel;

1 ml of solution contains paclitaxel 6 mg;

Excipients: polyethylene glycol castor oil; anhydrous ethanol; citric acid monohydrate.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: colorless or pale yellow solution.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Taxanes.

ATC code L01C D01.

Pharmacological Properties

Pharmacodynamics

Paclitaxel is a plant-derived antimicrotubule agent that acts on the cellular microtubular apparatus. It promotes the formation of microtubules from tubulin dimers and stabilizes them by inhibiting depolymerization. As a result, the structure and function of the microtubule network, which is essential for vital cellular processes (such as mitosis), are disrupted. In addition, paclitaxel induces the formation of abnormal structures or "bundles" of microtubules throughout the cell cycle, as well as multiple microtubule "asters" during mitosis.

Pharmacokinetics

Following intravenous administration, a biphasic decline in plasma paclitaxel concentrations is observed.

The pharmacokinetics of paclitaxel were studied after 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 volume of distribution at steady state ranges from 198 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding. With 3-hour infusions, the pharmacokinetics of paclitaxel were nonlinear. When doses were 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 the protein binding of paclitaxel.

The metabolism of paclitaxel in humans has not been fully characterized. 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 via 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 the CYP2C8, CYP3A4, and CYP2C8+CYP3A4 isoenzymes, respectively.

The effects of renal or hepatic impairment on the pharmacokinetics of paclitaxel during 3-hour infusions have not been formally studied. Pharmacokinetic parameters in one patient undergoing hemodialysis who received paclitaxel at 135 mg/m² via 3-hour infusions were similar to those observed in patients without renal impairment.

When paclitaxel and doxorubicin are used in combination, an increased duration of distribution and elimination of doxorubicin and its metabolites has been observed. When paclitaxel was administered immediately after doxorubicin, systemic exposure (AUC) to doxorubicin in plasma was 30% higher compared to when paclitaxel was administered 24 hours after doxorubicin.

Clinical Characteristics.

Indications.

• Ovarian cancer:
  • first-line treatment of ovarian cancer, as well as in combination with cisplatin for advanced disease or residual tumors greater than 1 cm in size after laparotomy;
    – second-line treatment of metastatic ovarian cancer when standard platinum-based therapy has proven ineffective.
• Breast cancer:
  • adjuvant treatment of 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 with trastuzumab in cases of immunohistochemically confirmed HER-2 protein overexpression (3+) or in the presence of contraindications to anthracycline therapy;
  • monotherapy for metastatic breast cancer in patients who are not candidates for standard anthracycline therapy or in whom standard therapy has failed.
• Advanced non-small cell lung cancer (combined chemotherapy with cisplatin when surgical treatment and/or radiotherapy are not feasible).
• Kaposi’s sarcoma (KS) in AIDS patients (when prior therapy with liposomal anthracyclines has been ineffective).

Contraindications.

• Hypersensitivity to paclitaxel or to any of the excipients of the medicinal product, especially to polyethoxylated castor oil.
• Pregnancy and breastfeeding.
• Neutropenia prior to treatment initiation (baseline neutrophil count < 1.5 × 10⁹/L; in AIDS patients with Kaposi’s sarcoma, neutrophil count < 1.0 × 10⁹/L), thrombocytopenia (< 100 × 10⁹/L).
• Concomitant severe uncontrolled infections in patients with Kaposi’s sarcoma.
• Severe hepatic impairment.

Special safety precautions.

Instructions for medical personnel. As with all other antineoplastic agents, caution must be exercised when handling Neotaxel. Preparation 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 the use of protective clothing (gowns, caps, masks, goggles, and disposable gloves). In case of skin exposure (which may result in local reactions such as stinging, burning, or erythema), the affected area should be thoroughly washed with soap and water. If the solution contacts 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. Pregnant women should not handle cytotoxic drugs.

Upon cooling, unopened vials may develop a precipitate, which dissolves upon gentle agitation or even without mixing upon reaching room temperature. This phenomenon does not affect the quality of the medicinal product. However, if the solution remains cloudy or contains an 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 combination therapy with paclitaxel and cisplatin for ovarian cancer, paclitaxel should be administered before cisplatin. In this case, the safety profile is similar to that of paclitaxel monotherapy. If paclitaxel is administered after cisplatin, more severe myelosuppression occurs, and paclitaxel clearance is reduced by approximately 20%. The risk of renal insufficiency in ovarian cancer patients 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 shown that the primary metabolic pathway in humans is CYP2C8-mediated conversion of paclitaxel to 6α-hydroxypaclitaxel. Concomitant administration of ketoconazole, a potent CYP3A4 inhibitor, does not delay paclitaxel elimination; 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 the 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 used concurrently, but not with indinavir. Data on interactions between paclitaxel and other protease inhibitors are insufficient. Therefore, paclitaxel should be administered with caution to patients receiving concomitant protease inhibitor therapy.

Special precautions for use.

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

Extravasation may occur during drug infusion; therefore, the infusion site should be carefully monitored for signs of infiltration.

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

Despite appropriate premedication, severe hypersensitivity reactions characterized by dyspnea and hypotension may occur and require immediate treatment. Angioneurotic edema and generalized urticaria have been observed in less than 1% of patients.

These reactions are likely histamine-mediated. In case of severe hypersensitivity reactions, paclitaxel infusion must be stopped immediately, and symptomatic treatment initiated. Paclitaxel must not be re-administered to such patients.

Bone marrow suppression (predominantly neutropenia) is the principal dose-limiting toxicity of the drug. Blood cell 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 patients with Kaposi's sarcoma) and platelet counts to ≥100×10⁹/L (≥75×10⁹/L in Kaposi's sarcoma). 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, more pronounced myelosuppression may occur in patients with moderate hepatic dysfunction. Paclitaxel is contraindicated in patients with severe hepatic impairment. Patients should be closely monitored for signs of profound myelosuppression. Currently, there are insufficient data to recommend dose adjustments for patients with mild to moderate hepatic impairment. Information on paclitaxel use in patients with severe cholestasis is lacking. Patients with severe renal impairment should not be treated with paclitaxel.

Severe cardiac conduction disturbances

Severe cardiac conduction disturbances during paclitaxel therapy have been reported rarely. If such disturbances occur, appropriate treatment should be initiated, and continuous cardiac monitoring is recommended if further administration of the drug is considered. Vital signs should be monitored during the first hour of paclitaxel infusion. Arterial hypotension, arterial hypertension, and bradycardia may occur during infusion. These are usually asymptomatic and do not require therapeutic intervention. Frequent monitoring of vital signs is recommended, especially during the first hour of paclitaxel infusion.

Severe cardiovascular events are more frequently observed in patients with non-small cell lung cancer than in those with breast or ovarian cancer. One case of heart failure following 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 regularly monitored during therapy (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 benefit of continuing therapy must be carefully weighed against the risk of cardiac damage, which may be irreversible. If combination chemotherapy is continued, cardiac function should be monitored more frequently (every 1–2 cycles).

Peripheral neuropathy

Although peripheral neuropathy is a common adverse effect of paclitaxel therapy, severe neuropathy occurs rarely. In severe cases, subsequent paclitaxel doses should be reduced by 20% (by 25% in Kaposi's sarcoma). Peripheral neuropathy may develop after the first treatment cycle and worsen with continued paclitaxel therapy. Severe neurotoxicity occurred more frequently in patients with non-small cell lung cancer and ovarian cancer who received first-line chemotherapy with paclitaxel as a 3-hour infusion in combination with cisplatin, compared to those receiving paclitaxel alone or cyclophosphamide followed by cisplatin. Sensory disturbances usually diminish 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 contains ethanol, its potential effects on the central nervous system and other effects should be considered.

The medicinal product contains polyoxyethylated castor oil, which may cause severe allergic reactions.

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

Pseudomembranous colitis

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

Severe mucositis

Severe mucositis has been rarely observed in patients with Kaposi's sarcoma. If such reactions occur, the paclitaxel dose should be reduced by 25%.

Interstitial pneumonitis

Cases of interstitial pneumonitis have been reported when paclitaxel chemotherapy was combined with radiation therapy to the lung area, regardless of sequence.

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.

Hormonal contraception is contraindicated in the case of HR+ tumors.

Use during pregnancy or breastfeeding

There is no information on paclitaxel use in pregnant women. Like other cytotoxic agents, paclitaxel may be harmful to the fetus and therefore should not be used during pregnancy. Women and men should use effective contraception to prevent pregnancy 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 should 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 rate when driving or operating machinery

During paclitaxel therapy, patients should avoid potentially hazardous activities requiring high concentration and rapid psychomotor responses. It should be noted that the medicinal product contains ethanol, and certain adverse reactions may negatively affect the ability to drive or operate machinery.

Administration and Dosage.

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

Table 1

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

As first-line treatment for ovarian cancer.

The recommended combination therapy regimen includes paclitaxel and cisplatin. Depending on the duration of infusion, two paclitaxel dosing regimens are recommended:

• Paclitaxel at a dose of 175 mg/m² body surface area administered as a 3-hour intravenous infusion, followed by cisplatin at a dose of 75 mg/m². The interval between treatment cycles is 3 weeks;
• Paclitaxel at a dose of 135 mg/m² body surface area administered as a 24-hour intravenous infusion, followed by cisplatin at a dose of 75 mg/m². The interval between treatment cycles is 3 weeks.

As second-line treatment 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, with intervals of 3 weeks between cycles.

Adjuvant chemotherapy for breast cancer.

The recommended dose of paclitaxel is 175 mg/m², administered as a 3-hour intravenous infusion. Four treatment cycles should be administered, with intervals of 3 weeks between cycles. Treatment should be administered following anthracycline- or cyclophosphamide-based therapy.

First-line chemotherapy for breast cancer.

When used in combination with doxorubicin (50 mg/m²), paclitaxel should be administered 24 hours after doxorubicin. The recommended dose of paclitaxel is 220 mg/m² administered as a 3-hour intravenous infusion. The interval between cycles is 3 weeks.

When used in combination with trastuzumab, the recommended dose of paclitaxel is 175 mg/m² administered as a 3-hour intravenous infusion. The interval between cycles is 3 weeks. Paclitaxel infusion may be initiated one day after the first dose of trastuzumab or immediately after subsequent doses of trastuzumab, provided the patient tolerated the previous trastuzumab dose well.

Second-line chemotherapy for breast cancer.

The recommended dose of paclitaxel—175 mg/m²—is administered as a 3-hour intravenous infusion. The interval between cycles is 3 weeks.

Chemotherapy for advanced non-small cell lung cancer (NSCLC).

The recommended dose of paclitaxel—175 mg/m²—is administered as a 3-hour intravenous infusion, followed by cisplatin at a dose of 80 mg/m². The interval between cycles is 3 weeks.

Chemotherapy for Kaposi’s sarcoma in AIDS patients.

The recommended dose is 135 mg/m² body surface area administered as a 3-hour intravenous infusion every 3 weeks, or 100 mg/m² body surface area administered as a 3-hour intravenous infusion every 2 weeks.

Subsequent doses of paclitaxel must be adjusted according to individual patient tolerance. Repeated administration is possible only after neutrophil counts have recovered to ≥ 1.5 × 10⁹/L and platelet counts to ≥ 100 × 10⁹/L. For 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% for patients with Kaposi’s sarcoma).

Treatment of patients with hepatic impairment.

There is insufficient data on dose adjustment for patients with mild to moderate hepatic impairment. Paclitaxel is contraindicated in patients with severe hepatic dysfunction.

Treatment of patients with renal impairment.

There is insufficient data on dose adjustment for patients with renal impairment. 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 medicinal product maintains microbiological, physical, and chemical stability for up to 28 days at 25 °C.

Infusion solutions prepared by diluting paclitaxel 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 solution may precipitate upon cooling but can redissolve upon return to 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 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 pore size ≤ 0.22 μm. No significant loss of active ingredient has been observed when administered through such systems.

Prepared infusion solutions do not require protection from light.

There have been isolated reports of precipitation 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 set 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 diethylhexyl phthalate (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, polypropylene or polyolefin bags) and administered through polyethylene infusion sets. Filters may be connected using short polyvinyl chloride tubing—this does not cause significant DEHP leaching.

Children.

The safety and efficacy of paclitaxel in pediatric patients have not been established. The medicinal product is not recommended for use in this patient population.

Overdose.

Symptoms: bone marrow suppression, peripheral neuropathy, 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 safety data listed below were obtained from clinical trials involving 812 patients with solid tumours who received paclitaxel monotherapy. At the end of this section, data from a separate clinical study involving 107 patients with Kaposi's sarcoma are presented.

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

Severe, 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 for ≥7 days. Thrombocytopenia was observed 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 manifestations in 13% of patients.

Gastrointestinal adverse effects associated with paclitaxel were mild or moderate. Nausea, vomiting, diarrhea, and mucositis were reported; rarely, intestinal obstruction, perforation, ischemic colitis, pseudomembranous colitis, esophagitis, constipation, pancreatitis.

Marked elevations (≥5 times the upper limit of normal) in aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin were observed in 5%, 4%, and <1% of patients, respectively.

There have been reports of liver necrosis and hepatic encephalopathy in patients treated with paclitaxel.

Isolated cases of disseminated intravascular coagulation (DIC) syndrome have been reported, often in association 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 initiation of paclitaxel therapy. Most patients experiencing alopecia can expect ≥50% hair loss.

Local reactions: Local swelling, pain, erythema, and induration may occur at the injection site. Accidental extravasation may lead to cellulitis. Cases of skin desquamation have been reported, sometimes associated with extravasation. Skin pigmentation changes are possible. There have been isolated reports of recurrence of skin reactions at sites of previous paclitaxel extravasation following subsequent drug 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 via 3-hour infusion in the treatment of metastatic cancers (812 patients treated in clinical trials).

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), unknown (frequency cannot be estimated from available data).

Infections and infestations: very common – infections (predominantly 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, severe hypersensitivity reactions requiring therapeutic intervention (e.g., hypotension, angioedema, respiratory distress, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, limb pain, profuse sweating, hypertension); rare* – anaphylactic reactions; very rare* – anaphylactic shock; unknown* – bronchospasm.

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 disturbances, hypokinesia, gait disturbances, hypoesthesia, taste disturbances; 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.

Eye disorders: uncommon – dry eyes, blurred vision, visual field defects; very rare* – optic nerve involvement and/or visual disturbances (scintillating scotoma), particularly 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 with 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 – hypotension; common – vasodilation (flushing); uncommon – hypertension, thrombosis, thrombophlebitis; very rare* – shock; unknown* – phlebitis.

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

Gastrointestinal disorders: very common – nausea, vomiting, diarrhea, mucositis, 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 (fatal cases reported).

Skin and subcutaneous tissue disorders: very common – alopecia; common – transient mild skin and nail 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.

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 have been isolated reports of recurrence of skin reactions at sites of previous paclitaxel extravasation following subsequent drug administrations.

Laboratory findings: common – marked (≥5 times upper limit of normal) elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase; uncommon – marked elevation in bilirubin; rare* – elevated serum creatinine.

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 following standard combination therapy with anthracyclines or cyclophosphamide (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 corresponded to that observed with paclitaxel monotherapy as described above.

* As reported in post-marketing surveillance.

** May persist for more than 6 months after discontinuation of paclitaxel.

Toxic effects on the hematopoietic and lymphatic systems.

Myelosuppression is the main dose-limiting toxic effect. The most significant manifestation of hematological toxicity is 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 in 8% of patients. Hematological parameters normalized within 35 days in all monitored patients. The frequency of grade 4 neutropenia lasting 7 days or longer was 22%.

Febrile neutropenia associated with paclitaxel treatment occurred in 14% of patients during 1.3% of treatment cycles. Three septic episodes (2.8%) occurred during paclitaxel therapy, which resulted in fatal outcomes.

Thrombocytopenia was observed 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. Paclitaxel-related bleeding occurred in <3% of patients; these bleedings 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 and cisplatin were used in combination, the frequency and severity of neurotoxic effects, mainly peripheral neuropathy, were higher with paclitaxel administered at 175 mg/m² body surface area via 3-hour intravenous infusions (neurotoxic effects observed in 85% of patients, severe in 15%) compared to paclitaxel administered at 135 mg/m² body surface area via 24-hour intravenous infusions (neurotoxic effects observed in 25% of patients, severe in 3%) in combination with cisplatin.

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

Patients receiving paclitaxel and cisplatin have an increased risk of developing renal failure compared to those receiving cisplatin alone in the treatment of gynecological tumors.

Below are results from two large first-line chemotherapy trials in ovarian cancer (paclitaxel + cisplatin; over 1050 patients); two phase III trials in first-line treatment of metastatic breast cancer: one trial combining with doxorubicin (paclitaxel + doxorubicin; 267 patients), another combining with trastuzumab (planned analysis of trastuzumab-paclitaxel subgroup: 188 patients); and two phase III trials in advanced-stage non-small cell lung cancer (paclitaxel + cisplatin; over 360 patients).

In patients with ovarian cancer who received first-line chemotherapy with paclitaxel via 3-hour intravenous infusions 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 via 3-hour intravenous infusions 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 when paclitaxel was administered at 220 mg/m² body surface area via 3-hour intravenous infusions 24 hours after doxorubicin at 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 be partly explained by corticosteroid premedication.

Paclitaxel with trastuzumab.

In first-line chemotherapy with paclitaxel administered via 3-hour intravenous infusions 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%), 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 higher number and longer duration of treatment cycles with paclitaxel and trastuzumab compared to paclitaxel monotherapy. The frequency of serious adverse effects with combination chemotherapy using paclitaxel and trastuzumab was comparable to that with paclitaxel monotherapy.

Paclitaxel with doxorubicin.

Impaired myocardial 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% both with paclitaxel combined with doxorubicin and with standard FAC therapy. 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 these rare fatal events, 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 hematological and hepatic adverse effects, the frequency and severity of adverse effects in patients with Kaposi's sarcoma were comparable to those in patients with other solid tumours receiving paclitaxel monotherapy.

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

Reporting of adverse reactions.

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30°C. Keep out of reach of children.

The prepared solution is stable for 27 hours when stored at 25°C. It should not be refrigerated, as precipitation may occur.

From a microbiological standpoint, the medicinal product should be used immediately. If the infusion solution is not used immediately, storage conditions and duration should be observed.

Incompatibilities. Polyoxyl 35 castor oil, a component of the medicinal product, may leach diethylhexyl phthalate (DEHP) from plasticized polyvinyl chloride. The extent of this process depends on the duration of exposure and the concentration of castor oil. Therefore, equipment containing polyvinyl chloride should not be used during dilution, storage, or administration of the drug.

Do not use with other solutions except those specified in the section "Instructions for use and dosage."

Packaging. Vials of 5 ml (30 mg), 16.67 ml (100 mg), 41.7 ml (250 mg), 25 ml (150 mg), 35 ml (210 mg), one vial per cardboard box with instructions for medical use.

Prescription category. Prescription only.

Manufacturer. Venus Remedies Limited.

Manufacturer's address and location of operations.
Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn.), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh 173205, India.