Paclitaxel-pharmex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PACLITAXEL-PHARMEKS (PACLITAXEL-PHARMEX)

Composition:

Active substance: paclitaxel;

1 ml of solution contains 6 mg of paclitaxel;

Excipients: polyethoxylated castor oil, anhydrous ethanol.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless or slightly yellowish viscous liquid without visible particles.

Pharmacotherapeutic group.
Antineoplastic 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 assembly of microtubules from tubulin dimers and stabilizes them by inhibiting depolymerization. As a result, the normal dynamic reorganization of microtubular networks, essential for cellular functions, is 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.

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

The pharmacokinetics of paclitaxel were studied after infusion at doses of 135 and 175 mg/m² of body surface area over 3 and 24 hours, respectively. The mean terminal half-life ranged from 3.0 to 52.7 hours, and the mean total body clearance was 11.6–24.0 L/hour•m². Variability in systemic exposure to paclitaxel across different treatment cycles was minimal. No accumulation of paclitaxel was observed with repeated treatment cycles.

In vitro studies indicate that 89–98% of paclitaxel is bound to plasma proteins.

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 primarily metabolized in the liver and mainly excreted via bile. Metabolism is likely mediated by cytochrome P450 isoenzymes. The mean steady-state volume of distribution ranges from 198 to 688 L/m², suggesting extensive extravascular distribution and/or tissue binding. With a 3-hour infusion, paclitaxel pharmacokinetics were nonlinear. When the dose was increased by 30% (from 135 to 175 mg/m² body surface area), the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) increased by 75% and 81%, respectively.

After intravenous administration of a 100 mg/m² dose as a 3-hour infusion in 19 patients with Kaposi’s sarcoma, the mean Cmax was 1.53 ng/mL (range: 761–2860 ng/mL), and the mean AUC was 5,619 ng•h/mL (range: 2,609–9,428 ng•h/mL). Clearance was 20.6 L/hour/m² (range: 11–38), and volume of distribution was 291 L/m² (range: 121–638). Terminal half-life averaged 23.7 hours (range: 12–33).

Inter-patient variability in systemic exposure to paclitaxel was minimal. There was no evidence of paclitaxel accumulation in the body after multiple treatment cycles.

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

The metabolism of paclitaxel in humans is not fully understood. Cumulative excretion data indicate that 1.3% to 12.6% of the administered dose is excreted unchanged in urine, suggesting extensive extrarenal clearance. Paclitaxel is predominantly metabolized in the liver and primarily excreted in bile. Metabolism is likely mediated primarily by cytochrome P450 isoenzymes. 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 isoenzymes CYP2C8, CYP3A4, and CYP2C8+CYP3A4, respectively.

The effect of renal or hepatic impairment on paclitaxel metabolism during a 3-hour infusion has not been studied. Pharmacokinetic parameters in a single patient undergoing hemodialysis who received paclitaxel at a dose of 135 mg/m² body surface area via 3-hour infusions were similar to those observed in patients without renal impairment.

In studies where paclitaxel and doxorubicin were administered concurrently, the distribution and elimination of doxorubicin and its metabolites were prolonged. Systemic exposure to doxorubicin was 30% higher when paclitaxel was administered immediately after doxorubicin, compared to a 24-hour interval between administrations.

For use of paclitaxel in combination with other agents, refer to the summary of product characteristics for cisplatin or trastuzumab for information on the use of these medicinal products.

Clinical characteristics.

Indications.

• Ovarian cancer:
  • first-line treatment of ovarian cancer, as well as in combination with cisplatin for advanced-stage ovarian cancer or for residual tumors larger than 1 cm 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 when anthracycline therapy is contraindicated;
  • monotherapy for metastatic breast cancer after ineffective standard therapy.
• Extensive non-small cell lung cancer (combined chemotherapy with cisplatin when surgical treatment and/or radiotherapy are not feasible).
• Kaposi's sarcoma in AIDS patients (in AIDS patients when previous therapy with liposomal anthracyclines has proven ineffective).

Contraindications.

• Hypersensitivity to paclitaxel or to any other components of the drug (especially to polyethoxylated castor oil).
• Neutropenia (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 dysfunction.
• Pregnancy and breastfeeding.

Special safety precautions.

Instructions for medical personnel

When handling the medicinal product Paclitaxel-Farmex, as with other cytotoxic agents, caution must be exercised. Preparation of infusion solutions should be performed by trained personnel in a specially designated area, following all aseptic procedures.

Contact of paclitaxel solutions with skin and mucous membranes must be avoided; protective clothing (gowns, caps, masks, goggles, and disposable gloves) should be used. If contact occurs, affected skin areas should be washed thoroughly with soap and water. Skin irritation, such as tingling, burning, and redness, may occur at the site of contact. If the drug comes into contact with mucous membranes, they should be rinsed thoroughly with large amounts of water. Inhalation of aerosolized paclitaxel solutions may cause dyspnea, chest pain, throat irritation, and nausea.

Unused solutions, instruments, and materials that have come into contact with paclitaxel must be disposed of according to established procedures for the disposal of waste containing cytotoxic substances.

Preparation of infusion solutions for intravenous administration

Before administration, the concentrate for infusion solution Paclitaxel-Farmex 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.

The prepared infusion solutions may appear cloudy due to the composition of the vehicle. Filtration does not eliminate cloudiness. The paclitaxel solution must be administered through infusion systems equipped with in-line membrane filters with pore size ≤ 0.22 μm. No significant loss of active ingredient has been observed when administered through such systems.

To minimize leaching of diethylhexylphthalate (DEHP) from infusion bags, systems, or other medical equipment made of plasticized polyvinyl chloride (PVC), the diluted infusion solution 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 PVC tubing, as this does not cause significant DEHP leaching.

Recommendations for storage of the drug after opening the vial

After opening the vial, prior to dilution: chemical and physical stability has been demonstrated for 28 days at temperatures not exceeding 25 °C.

From a microbiological standpoint, after the first opening, the concentrated infusion solution may be stored for no more than 28 days at temperatures not exceeding 25 °C. If the solution is not administered immediately, responsibility for the duration and conditions of storage of the ready-to-use solution lies with the user (medical personnel).

After dilution: the infusion solution is chemically and physically stable for 27 hours at temperatures not exceeding 25 °C.

Interaction with other medicinal products and other types of interactions.

Premedication with cimetidine does not affect paclitaxel clearance.

In combined treatment of ovarian cancer with paclitaxel and cisplatin, 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 decreases by approximately 20%. The risk of renal insufficiency in patients with ovarian cancer receiving combined paclitaxel and cisplatin therapy is higher than with cisplatin monotherapy.

Since the 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 CYP2C8 and CYP3A4 isoenzymes of cytochrome P450. Clinical studies have demonstrated that the primary metabolic transformation in humans is CYP2C8-mediated conversion of paclitaxel to 6α-hydroxypaclitaxel.

Clinically significant interactions with enzymes other than CYP2C8 are not expected. Concurrent 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 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 concurrently, but not with indinavir. Information on interactions between paclitaxel and other protease inhibitors is insufficient; therefore, paclitaxel should be used with caution in patients receiving concomitant protease inhibitor therapy.

Special precautions for use.

Treatment with Paclitaxel-Pharmex should be carried out 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 available.

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

Prior to paclitaxel administration, patients must receive premedication with corticosteroids, antihistamines, and H2-receptor antagonists. When used in combination with cisplatin, Paclitaxel-Pharmex should be administered before cisplatin.

Severe hypersensitivity reactions

Despite appropriate premedication, severe hypersensitivity reactions characterized by dyspnea and hypotension may occur and require immediate management. Angioneurotic edema 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 the event of severe hypersensitivity reactions, paclitaxel infusion must be immediately discontinued and symptomatic treatment initiated. Paclitaxel should not be re-administered to such patients.

Bone marrow suppression

Bone marrow suppression (primarily neutropenia) is the main dose-limiting toxicity. During treatment with Paclitaxel-Pharmex, complete blood counts should be monitored at least twice weekly. Repeat administration 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).

Hepatic impairment

The risk of toxic effects (particularly grade III–IV myelosuppression) is higher in patients with impaired liver function. With 3-hour infusions of paclitaxel, 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 impairment. Paclitaxel is contraindicated in patients with severe hepatic impairment. Patients should be closely monitored for signs of severe myelosuppression. Currently, there is insufficient data to recommend dose adjustments in patients with mild or moderate hepatic impairment. There is no information on the use of paclitaxel in patients with severe cholestasis. Patients with severe renal impairment should not be treated with paclitaxel.

Severe cardiac conduction disturbances

Severe cardiac conduction disturbances during treatment with Paclitaxel-Pharmex have been reported rarely. In cases of significant conduction abnormalities, appropriate treatment should be initiated, and continuous cardiac monitoring is required during subsequent paclitaxel infusions. In all other patients, vital signs should be monitored frequently, especially during the first hour of infusion. Arterial hypotension, arterial 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 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.

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 therapy (e.g., every 3 months). This monitoring allows early detection of cardiac dysfunction. The cumulative dose of anthracyclines (in mg/m² body surface area) should be considered when determining the frequency of ventricular function monitoring. If test results indicate cardiac dysfunction—even if asymptomatic—the potential benefit of continuing therapy should be carefully weighed against the risk of irreversible cardiac damage. If combination chemotherapy is continued, cardiac function should be monitored more frequently (every 1–2 cycles).

Sepsis

Sepsis has been reported in 5% of patients, with or without neutropenia, receiving paclitaxel in combination with gemcitabine. Complications associated with pancreatic adenocarcinoma, particularly biliary obstruction or presence of a biliary stent, were identified as significant risk factors. If fever occurs (regardless of neutrophil count), broad-spectrum antibiotic therapy should be initiated promptly. In cases of febrile neutropenia, paclitaxel and gemcitabine should be withheld until fever resolves and ANC ≥1500 cells/mm³; treatment may then be resumed at reduced doses.

Peripheral neuropathy

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

Ethanol

Since Paclitaxel-Pharmex contains ethanol, its potential effects on the central nervous system and other possible effects should be considered.

Paclitaxel 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.

Intra-arterial administration

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

Pseudomembranous colitis

Pseudomembranous colitis has been rarely reported during paclitaxel therapy, including in patients not receiving concomitant antibiotics. This should be considered in the differential diagnosis of severe or persistent diarrhea occurring during or shortly after paclitaxel therapy.

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 radiotherapy to the lung area, regardless of sequence.

Combination with other antineoplastic agents

When paclitaxel is used in combination with other antineoplastic agents (cisplatin, doxorubicin, trastuzumab), recommendations for the use of these drugs should be followed.

CNS metastases

The efficacy and safety of paclitaxel in patients with CNS metastases have not been established. CNS metastases are generally poorly controlled by systemic chemotherapy.

Gastrointestinal symptoms

Nausea, vomiting, and diarrhea occurring after paclitaxel administration can be managed with standard antiemetic medications.

Visual disturbances

Macular edema has been reported in patients receiving paclitaxel. Patients experiencing visual disturbances should undergo urgent and complete ophthalmologic evaluation. If macular edema is diagnosed, paclitaxel should be discontinued and appropriate treatment initiated.

Patients aged 75 years or older

In patients aged 75 years or older, no benefit has been demonstrated for combination therapy with paclitaxel and gemcitabine compared to gemcitabine monotherapy. In this age group, treatment with paclitaxel and gemcitabine was associated with a higher incidence of serious adverse reactions and events leading to treatment discontinuation, including hematologic toxicity, peripheral neuropathy, decreased appetite, and dehydration. Patients aged 75 years or older with pancreatic adenocarcinoma should be carefully monitored for their ability to tolerate paclitaxel in combination with gemcitabine, with mandatory consideration of overall health status and comorbidities.

Other warnings

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

Paclitaxel contains polyoxyethylated castor oil, which may cause severe allergic reactions.

Use during pregnancy or breastfeeding.

Fertility. Animal studies have shown that paclitaxel is embryotoxic and fetotoxic in animals and adversely affects fertility. Additionally, based on literature data, paclitaxel is considered a potentially carcinogenic and genotoxic agent at therapeutic doses, due to its pharmacodynamics and mechanism of action.

Pregnancy. There is no information on paclitaxel use in pregnant women. Like other cytotoxic drugs, paclitaxel may harm the fetus and therefore should not be administered 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. If a woman becomes pregnant during treatment, she must inform her physician immediately.

Male patients should undergo sperm cryopreservation prior to starting paclitaxel therapy due to the risk of infertility.

Lactation. It is unknown whether paclitaxel is excreted in human milk; therefore, breastfeeding must be discontinued during treatment with this drug.

Ability to drive or operate machinery.

During treatment with paclitaxel, patients should refrain from driving or operating machinery requiring high concentration and rapid psychomotor responses. It should be noted that the drug contains alcohol, and certain adverse reactions may negatively affect the ability to drive or operate machinery.

Administration and Dosage.

Prior to initiating treatment with Paclitaxel-Farmex, all patients must receive premedication with corticosteroids, antihistamines, and H2-receptor antagonists according to the following regimen:

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

First-line treatment of ovarian cancer

According to the duration of infusion, two dosage regimens of Paclitaxel-Farmex are recommended:

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

Second-line treatment of ovarian cancer

Paclitaxel is recommended to be administered at a dose of 175 mg/m² body surface area by 3-hour intravenous infusions. Typically, no more than 4 cycles should be administered at 3-week intervals.

Adjuvant chemotherapy for breast cancer

Paclitaxel should be administered after therapy with anthracyclines or cyclophosphamide. Paclitaxel is recommended to be administered at a dose of 175 mg/m² body surface area by 3-hour intravenous infusions. Administer 4 cycles at 3-week intervals.

First-line chemotherapy for breast cancer

When used in combination with doxorubicin (50 mg/m² body surface area), paclitaxel is administered 24 hours after doxorubicin. The recommended dose of paclitaxel – 220 mg/m² body surface area – is administered by intravenous infusion over 3 hours. The interval between cycles is 3 weeks.

When used in combination with trastuzumab, the recommended dose of paclitaxel – 175 mg/m² body surface area – should be administered by intravenous infusion over 3 hours. 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 dose of trastuzumab well.

Second-line chemotherapy for breast cancer

Paclitaxel is recommended to be administered at a dose of 175 mg/m² body surface area by 3-hour intravenous infusions. Treatment intervals are 3 weeks.

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

A combination regimen of paclitaxel and cisplatin is recommended. Paclitaxel is administered at a dose of 175 mg/m² body surface area by 3-hour intravenous infusions, followed by cisplatin at a dose of 80 mg/m² body surface area. Treatment intervals are 3 weeks.

Chemotherapy for Kaposi’s sarcoma in AIDS patients

The recommended dose is 100 mg/m² body surface area administered by 3-hour intravenous infusions every 2 weeks.

Treatment of patients with hepatic impairment

There is insufficient data regarding dose adjustment in patients with mild or moderate hepatic impairment. Paclitaxel should not be administered to patients with severe hepatic impairment.

The following paclitaxel doses should be adjusted according to individual patient tolerance. Repeat administration is possible only after neutrophil count has increased to ≥ 1.5×10⁹/L and platelet count to ≥ 100×10⁹/L. 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% for patients with Kaposi’s sarcoma).

Treatment of patients with renal impairment

There is insufficient data regarding dose adjustment in patients with renal impairment.

Preparation of solution for intravenous infusion

Prior to administration, the Paclitaxel-Farmex 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, 5% glucose in Ringer’s solution to a final paclitaxel concentration of 0.3–1.2 mg/mL.

Ready-to-use infusion solutions may appear cloudy due to the composition of the vehicle. Filtration does not eliminate cloudiness. The paclitaxel solution must be administered through in-line membrane filters with a pore size of ≤ 0.22 μm. No significant loss of active ingredient activity is observed when administered through such systems.

To minimize leaching of DEHP from infusion bags, systems, or other medical equipment made of plasticized 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 via short PVC tubing; this does not cause significant DEHP leaching.

Ready-to-use solutions should be administered immediately after preparation. Solutions are stable for 27 hours when stored at room temperature (approximately 25 °C). They should not be refrigerated, as precipitation may occur.

Elderly patients

No additional dose reduction is recommended for patients aged 65 years and older beyond what is standard for all patients. Among 229 patients receiving paclitaxel monotherapy for breast cancer, 13% were at least 65 years old and 2% were 75 years or older. No increased incidence of toxicity was observed in patients aged 65 years and older. However, further analysis of 981 patients receiving paclitaxel monotherapy for metastatic breast cancer, of whom 15% were aged 65 years or older and 2% were 75 years or older, revealed a higher frequency of epistaxis, diarrhea, dehydration, malaise, and peripheral edema compared to younger patients. Among 421 patients with pancreatic adenocarcinoma who received paclitaxel and gemcitabine in a randomized trial, 41% were aged 65 years or older and 10% were 75 years or older. In patients aged 75 years and older receiving paclitaxel and gemcitabine, a higher frequency of serious adverse reactions and adverse reactions leading to treatment discontinuation was observed. Patients with pancreatic adenocarcinoma aged 75 years and older should be carefully evaluated before initiating therapy. Among 514 patients with non-small cell lung cancer receiving paclitaxel in combination with carboplatin, 31% were aged 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia occurred more frequently in patients aged 65 years and older compared to younger patients. Experience with paclitaxel/carboplatin in patients aged 75 years and older is limited. Pharmacokinetic/pharmacodynamic modeling using data from 125 patients with advanced solid tumors indicated that patients aged 65 years and older may be more susceptible to neutropenia during the first treatment cycle.

Metastases to the CNS

The efficacy and safety of the medicinal product in patients with CNS metastases have not been established. Treatment of CNS metastases is generally poorly controlled by systemic chemotherapy.

After opening the vial prior to dilution: chemical and physical stability has been demonstrated for 28 days at temperatures not exceeding 25 °C.

From a microbiological standpoint, after the first opening, the concentrated infusion solution may be stored for up to 28 days at temperatures not exceeding 25 °C. If the solution is not administered immediately, responsibility for the duration and storage conditions of the ready-to-use solution lies with the user (healthcare personnel).

After dilution: the infusion solution is chemically and physically stable for 27 hours at temperatures not exceeding 25 °C.

Children

The safety and efficacy of paclitaxel in children have not been established. It is not recommended for use in this patient population.

Overdose

Symptoms: bone marrow suppression, peripheral neuropathy, mucositis.

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 frequency and intensity of adverse reactions in patients with ovarian cancer, breast cancer, and non-small cell lung cancer do not differ significantly. Patient age did not significantly affect any of the observed types of drug toxicity. Severe hypersensitivity reactions with potentially fatal outcomes (such as hypotension requiring treatment, angioedema, respiratory dysfunction requiring bronchodilator therapy, generalized urticaria) were observed in 2 patients (<1% of patients). Mild hypersensitivity reactions, primarily flushing and rash, occurred in 34% of patients (17% of all treatment cycles), which did not require therapeutic intervention or discontinuation of paclitaxel therapy.

The most common adverse effect of paclitaxel treatment is bone marrow suppression: severe neutropenia (<500/mm³) was observed 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 was observed in 64% of patients, including severe anemia (Hb <5 mmol/L) in 6% of patients (frequency and severity of anemia depend on baseline hemoglobin levels).

Arthralgia or myalgia occurred in 60% of patients, with severe forms in 13% of patients. Isolated cases of disseminated intravascular coagulation (DIC) syndrome, often in combination with sepsis or multiorgan dysfunction, have been reported.

Hair loss was observed in 87% of patients receiving paclitaxel. Most cases of alopecia 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 injection sites. Accidental extravasation may lead to cellulitis. Cases of skin desquamation, sometimes associated with extravasation, have been reported. Skin pigmentation changes are possible. There have been isolated reports of recurrence of skin reactions at sites of previous paclitaxel extravasation after subsequent drug administrations. Specific treatment for extravasation reactions is currently unknown. In some cases, injection site reactions began immediately after prolonged infusion or developed with a delay of 7–10 days.

Adverse Reactions During Paclitaxel Monotherapy

Below is a list of adverse reactions observed in clinical trials and those reported from post-marketing experience. The latter may be attributed to paclitaxel regardless of treatment regimen.

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 frequency not known (cannot be estimated from available data).

The most common adverse effect of paclitaxel treatment is bone marrow suppression: thrombocytopenia; anemia (frequency and severity of anemia depend on baseline hemoglobin levels).

Peripheral neuropathy may develop after the first treatment cycle and intensify with subsequent paclitaxel administrations. It may sometimes necessitate discontinuation of paclitaxel therapy. Sensory symptoms typically diminish or resolve several months after stopping paclitaxel. Pre-existing neuropathy due to prior therapy is not a contraindication for paclitaxel treatment. Furthermore, peripheral neuropathy may persist for more than 6 months after discontinuation of paclitaxel.

Severe hypersensitivity reactions with potentially fatal outcomes: hypotension requiring therapeutic intervention; angioedema; respiratory dysfunction requiring bronchodilators; generalized urticaria. Mild hypersensitivity reactions, primarily flushing and rash, which do not require therapeutic intervention or discontinuation of paclitaxel therapy.

Local reactions: Local swelling, pain, erythema, and induration may occur at injection sites. Accidental extravasation may lead to cellulitis. Skin pigmentation changes are possible. Isolated reports exist of recurrence of skin reactions at sites of prior paclitaxel administration after subsequent drug infusions.

Cardiovascular system: Bradycardia, cardiomyopathy, asymptomatic ventricular tachycardia, arterial hypotension, thrombosis, thrombophlebitis.

Gastrointestinal tract effects of paclitaxel were mild or moderate. Nausea, vomiting, diarrhea, mucositis were observed; rarely – intestinal obstruction, perforation, ischemic colitis, pseudomembranous colitis, esophagitis, constipation, pancreatitis. Significant increases (≥5 times above normal) in aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin levels were also recorded.

Cases of liver necrosis and hepatic encephalopathy have also been reported in patients treated with paclitaxel.

Musculoskeletal system: Arthralgia, myalgia.

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

Benign, malignant and unspecified neoplasms (including cysts and polyps): Metastases (may present with pain symptoms), tumor necrosis.

Blood and lymphatic system disorders: Very common – myelosuppression, severe neutropenia, anemia, thrombocytopenia, severe leukopenia, hemorrhage; common – febrile neutropenia*; uncommon – severe anemia; rare – febrile neutropenia*; very rare – acute myeloid leukemia*, myelodysplastic syndrome*; frequency not known – disseminated intravascular coagulation (DIC) syndrome, often in combination with sepsis or multiorgan failure*.

Immune system disorders: Very common – mild hypersensitivity reactions (mainly flushing and rash); uncommon – delayed-type hypersensitivity reactions; serious hypersensitivity reactions requiring therapeutic measures (including 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* (including fatal hypersensitivity reactions); frequency not known – bronchospasm.

Metabolic and nutritional disorders: Uncommon – weight loss and weight gain; very rare – anorexia*; frequency not known – tumor lysis syndrome*.

Psychiatric disorders: Very rare – confusion*.

Nervous system disorders: Very common – neuropathy** (predominantly peripheral neuropathy), paresthesia, somnolence; common – depression, severe neuropathy (predominantly peripheral), nervousness, insomnia, cognitive disturbance, hypokinesia, gait disturbance, hypoesthesia, taste alteration; rare – motor neuropathy (manifested as moderately pronounced 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 defect; very rare – optic nerve damage and/or visual disturbances (scintillating scotoma)*, especially in patients receiving doses above recommended; frequency not known – macular edema*, photopsia*, floaters in 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*.

Vascular disorders: Very common – arterial hypotension; common – vasodilation (flushing); uncommon – arterial hypertension, thrombosis, thrombophlebitis; very rare – shock*; frequency not known – 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* (fatal cases reported).

Skin and subcutaneous tissue disorders: Very common – alopecia; common – transient mild nail and skin changes, acne, dry skin; uncommon – nail discoloration; rare – pruritus*, rash*, erythema*, swelling*; very rare – Stevens-Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme*, exfoliative dermatitis*, urticaria*, onycholysis* (patients receiving paclitaxel should wear appropriate clothing to protect from sunlight), folliculitis*; frequency not known – scleroderma*, hand-foot syndrome**.

Musculoskeletal and connective tissue disorders: Very common – arthralgia, myalgia, bone pain, leg cramps, myasthenia, back pain; frequency not known – systemic lupus erythematosus*.

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

In patients with Kaposi's sarcoma and AIDS, cases of renal dysfunction with reversible increase in serum creatinine levels have been described.

General disorders and administration site conditions: Very common – pain, swelling, including peripheral and facial edema; common – injection site reactions (including localized swelling, pain, erythema, induration, weakness, discoloration, and skin swelling; accidental extravasation may lead to cellulitis, skin fibrosis, and skin necrosis); rare – chest pain, chills, pyrexia*, dehydration*, asthenia*, edema*, malaise*. Isolated reports exist of recurrence of skin reactions at sites of prior paclitaxel extravasation after subsequent drug administrations.

Laboratory findings: Common – significant (≥5 times above normal) increases in liver enzymes – aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase; uncommon – significant increase in bilirubin levels; rare – increased blood creatinine levels*.

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

** Reported during post-marketing surveillance of paclitaxel.

Description of selected adverse reactions

In patients with breast cancer who received paclitaxel as adjuvant therapy after standard combination therapy with anthracyclines or cyclophosphamide (AC), signs of neurosensory toxicity, hypersensitivity reactions, arthralgia/myalgia, anemia, infections, fever, nausea/vomiting, and diarrhea were observed more frequently compared to patients who received only AC. However, the frequency of these events corresponded to that observed with 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 hematological toxicity was neutropenia. During the first treatment cycle, severe neutropenia (<500/mm³) was observed 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 incidence of grade IV neutropenia lasting 7 days or longer was 22%.

Febrile neutropenia associated with paclitaxel treatment was recorded 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/mm³) in 9% of cases. Platelet counts decreased to <75,000/mm³ at least once during treatment in 14% of patients. Bleeding events related to paclitaxel were reported in <3% of patients, but these 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

Neurotoxicity, primarily peripheral neuropathy, occurs more frequently and is more severe with 3-hour infusions of 175 mg/m² paclitaxel compared to 24-hour infusions of 135 mg/m² when paclitaxel is combined with cisplatin.

In ovarian cancer patients receiving first-line chemotherapy with paclitaxel administered as 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 patients with non-small cell lung cancer and ovarian cancer who received paclitaxel over 3 hours followed by cisplatin, the incidence of severe neurotoxicity increased. Peripheral neuropathy may develop after the first treatment cycle and intensify with subsequent paclitaxel administrations. It may sometimes necessitate discontinuation of paclitaxel therapy. Sensory symptoms typically diminish or resolve 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 patients receiving cisplatin alone for gynecological tumors.

In first-line chemotherapy of metastatic breast cancer, the frequency and severity of neutropenia, anemia, peripheral neuropathy, arthralgia/myalgia, asthenia, fever, and diarrhea were higher with paclitaxel administered at 220 mg/m² body surface area via 3-hour intravenous infusions 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 FAC regimen. This may be partly explained by corticosteroid use.

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, infections, chills, fever, cough, rash, arthralgia, tachycardia, diarrhea, arterial hypertension, epistaxis, acne, herpes simplex, accidental injuries, insomnia, rhinitis, sinusitis, injection site reactions. Differences in 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%) was observed 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 paclitaxel combined with doxorubicin and standard FAC therapy. When trastuzumab and paclitaxel were used in combination chemotherapy, 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 ones, patients responded to appropriate therapy.

Special Patient Groups

Radiation pneumonitis has been reported in patients undergoing concurrent radiotherapy.

Adverse Reactions in AIDS Patients with Kaposi's Sarcoma

Except for hematological and hepatic adverse reactions, 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.

Bone marrow suppression was the main dose-limiting toxic effect. The most significant manifestation of hematological toxicity was neutropenia. Other adverse reactions observed included severe neutropenia, febrile neutropenia, sepsis, thrombocytopenia, hemorrhage, and anemia.

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 received protease inhibitors). Significant increases in these parameters were occasionally observed.

Special Patient Groups

Radiation pneumonitis has been reported in patients undergoing concurrent radiotherapy.

Skin and subcutaneous tissue disorders

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

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in original packaging at temperatures not exceeding 25°C.

Keep out of reach of children.

When stored in a refrigerator, the solution in closed vials may precipitate; the precipitate redissolves upon warming to room temperature with slight agitation (or without agitation). The quality of the drug is not impaired. If the solution in the vial remains cloudy or contains insoluble precipitate, it should be discarded.

Incompatibilities.

Polyoxyl 35 castor oil contained in the drug may leach diethylhexyl phthalate (DEHP) from plasticized PVC. The intensity of this process depends on duration of exposure and concentration of castor oil. Therefore, equipment containing PVC should not be used during dilution, storage, or administration of the drug.

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

Packaging.

5 mL (30 mg), 16.7 mL (100 mg), 43.4 mL (260 mg), or 50 mL (300 mg) in a vial; 1 vial in a blister pack; 1 blister pack in a cardboard box.

Prescription category. Prescription only.

Manufacturer. LLC "FARMEX GROUP".

Manufacturer's address and place of business.

100 Shevchenko Street, Boryspil, Kyiv Oblast, 08301, Ukraine.