Paclitaxel-aar: detailed information

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PACLITAXEL-AAR (PACLITAXEL-AAR)

Composition:

Active substance: paclitaxel;

1 ml of concentrate contains 6 mg of paclitaxel;

Excipients: polyoxyethylated castor oil, anhydrous ethanol.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, particle-free, viscous solution ranging from colorless to slightly yellowish.

Pharmacotherapeutic group. Antineoplastic agents. Plant alkaloids and other natural agents. Taxanes.

ATC code: L01CD01.

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 microtubules by inhibiting depolymerization, thereby suppressing the normal dynamic reorganization of the microtubule network, which is essential for cellular functions during mitosis and interphase of the cell cycle. 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, the plasma concentration of paclitaxel declines according to a biphasic kinetic pattern.

Pharmacokinetics of paclitaxel were determined after infusion of the drug at doses of 135 and 175 mg/m² over 3 and 24 hours, respectively. The mean terminal half-life ranges from 3 to 52.7 hours, and mean values of total clearance vary between 11.6 and 24 L/h/m²; total clearance tends to decrease at higher plasma concentrations of paclitaxel. The mean steady-state volume of distribution ranges from 198 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding.

During 3-hour infusions, the pharmacokinetics of paclitaxel become nonlinear with increasing dose. 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 plasma concentration-time curve (AUC) increased by 75% and 81%, respectively.

After administration of paclitaxel at a dose of 100 mg/m² body surface area 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 the terminal half-life was 23.7 hours (range: 12–33 hours).

Variations in systemic exposure to paclitaxel among individual patients were minimal. No accumulation of paclitaxel was observed after multiple treatment cycles.

In vitro studies show 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. The mean total urinary excretion of unchanged drug ranges from 1.3% to 12.6% of the administered dose, indicating extensive non-renal clearance. The primary metabolites are hydroxylated derivatives. Paclitaxel is likely metabolized predominantly in the liver by cytochrome P450 isoenzymes and excreted in bile.

After administration of radiolabeled paclitaxel, an average of 26%, 2%, and 6% of radioactivity was 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 combined CYP2C8+CYP3A4 isoenzymes, respectively. The impact of renal or hepatic impairment on the metabolism of paclitaxel after 3-hour infusions has not been studied. Pharmacokinetic parameters in one patient requiring hemodialysis and treated with paclitaxel at a dose of 135 mg/m² body surface area via 3-hour infusions did not differ from those in patients without renal impairment.

When paclitaxel is used concomitantly with doxorubicin, an increased distribution and elimination time of doxorubicin and its metabolites has been observed. When paclitaxel was administered immediately after doxorubicin, total plasma exposure to doxorubicin was 30% higher than when paclitaxel was administered 24 hours after doxorubicin.

For use of paclitaxel in combination with other therapies, refer to the respective prescribing information for cisplatin, doxorubicin, and trastuzumab for further details 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 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 therapy in patients with lymph node involvement following standard combination therapy with anthracyclines or cyclophosphamide;
- primary chemotherapy of locally advanced or metastatic breast cancer in combination with anthracyclines or with trastuzumab when HER-2 protein overexpression (3+) is confirmed by immunohistochemical testing, or when anthracycline therapy is contraindicated;
monotherapy for metastatic breast cancer in patients not eligible for standard anthracycline-based therapy or in whom prior anthracycline therapy has failed.
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 (second-line therapy for extensive Kaposi's sarcoma when prior liposomal anthracycline therapy has failed).

Contraindications.

Hypersensitivity to paclitaxel or to any other component of the medicinal product (especially to polyethoxylated castor oil).
Pregnancy and breastfeeding period.
Neutropenia prior to initiation of treatment (baseline neutrophil count <1.5×10⁹/L; in AIDS patients with Kaposi's sarcoma, neutrophil count <1×10⁹/L), thrombocytopenia (<100×10⁹/L).
Severe hepatic dysfunction.
Concurrent severe uncontrolled infections in patients with Kaposi's sarcoma.

Special safety precautions.

Instructions for healthcare personnel

When handling Paclitaxel-AAR, as with all cytotoxic agents, caution must be exercised. Preparation of infusion solutions should be performed by trained personnel in a designated area under strict aseptic conditions. All necessary precautions should be taken to prevent contact of paclitaxel solutions with skin or mucous membranes, including the use of protective clothing (gowns, caps, masks, goggles, and disposable gloves). If contact occurs, affected skin areas should be washed thoroughly with soap and water. Skin tingling, warmth, and redness may occur at the site of contact. Mucous membranes exposed to the drug should be rinsed thoroughly with copious amounts of water. Inhalation of paclitaxel solutions may cause dyspnea, chest pain, throat irritation, and nausea.

Upon cooling, unopened vials may develop a precipitate, which dissolves upon gentle swirling or even without agitation when the solution reaches room temperature. This phenomenon does not affect the quality of the drug. However, if the solution remains cloudy or contains undissolved precipitate, the product must not be used and should be disposed of according to established hazardous waste disposal procedures.

Pregnant women should not handle cytotoxic drugs.

Disposal

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

Interaction with other medicinal products and other forms of interaction.

Pre-medication with cimetidine does not affect paclitaxel clearance.

In combined therapy with paclitaxel and cisplatin for ovarian cancer, paclitaxel should be administered before cisplatin. In this sequence, the safety profile is similar to paclitaxel monotherapy. If paclitaxel is administered after cisplatin, more severe myelosuppression occurs, and paclitaxel clearance is reduced by approximately 20%. The risk of renal impairment in ovarian cancer patients receiving combination therapy with paclitaxel and cisplatin is higher than with cisplatin monotherapy.

Since the elimination of doxorubicin and its active metabolites may be reduced 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 cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Clinical studies have shown 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. 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 possible 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 used concurrently, but not with indinavir. Data on interactions between paclitaxel and other protease inhibitors are insufficient; therefore, paclitaxel should be used with caution in patients receiving concomitant protease inhibitor therapy.

Special precautions for use.

Paclitaxel-AAR 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 available.

Due to the risk of extravasation during drug 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-AAR should be administered before cisplatin.

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

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of the drug. During treatment, complete blood counts should be monitored at least twice weekly. The drug should not be re-administered until neutrophil counts recover to ≥1.5×10⁹/L (≥1.0×10⁹/L in Kaposi’s sarcoma patients) and platelet counts reach ≥100×10⁹/L (≥75×10⁹/L in Kaposi’s sarcoma patients). In clinical trials, most patients with Kaposi’s sarcoma received granulocyte colony-stimulating factor (G-CSF).

The risk of toxic effects (particularly grade III–IV myelosuppression) is higher in patients with impaired liver function. When paclitaxel is administered via 3-hour infusions, no increased toxicity has been observed in patients with mild hepatic impairment. However, with longer infusions, 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 severe myelosuppression. Currently, there is insufficient data to recommend dose adjustments for patients with mild or moderate hepatic impairment. There is no information available on paclitaxel use in patients with severe cholestasis. Patients with severe renal insufficiency should not be treated with paclitaxel.

Severe cardiac conduction disorders have been rarely reported. In case of severe conduction disturbances during treatment, appropriate therapy should be initiated, and continuous cardiac monitoring is required if further drug administration is considered. Vital signs should be monitored during the first hour of paclitaxel infusion. Hypotension, hypertension, and bradycardia may occur during 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 after 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 must be carefully monitored. Patients scheduled 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 treatment (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 assessments. If test results indicate cardiac dysfunction—even asymptomatic—potential benefits of continuing therapy must be carefully weighed against the risk of irreversible cardiac damage. If combination chemotherapy is continued, cardiac monitoring should be increased in frequency (every 1–2 cycles).

Although peripheral neuropathy is common, severe symptoms are rare. In cases of severe peripheral neuropathy, the paclitaxel dose should be reduced by 20% in subsequent treatment cycles (by 25% in Kaposi’s sarcoma patients). 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 paclitaxel chemotherapy as a 3-hour infusion combined 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. Pre-existing neuropathy due to prior chemotherapy is not a contraindication for paclitaxel treatment.

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

Severe hepatic dysfunction

The drug is not recommended for patients with severe hepatic impairment due to increased risk of toxic effects, particularly grade III–IV myelosuppression.

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 or severe hepatic dysfunction. 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 for patients with mild or moderate hepatic impairment. Information on paclitaxel use in patients with severe cholestasis is lacking.

Intra-arterial administration

All 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

Pseudomembranous colitis, including cases in patients not concurrently receiving antibiotics, has been rarely reported during paclitaxel therapy. 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 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 must be considered.

Use in patients aged 75 years or older

In patients aged 75 years or older, no benefit has been demonstrated with combination therapy of paclitaxel and gemcitabine compared to gemcitabine monotherapy. In elderly patients (≥75 years) receiving paclitaxel and gemcitabine, a higher incidence of serious adverse reactions and adverse reactions leading to treatment discontinuation was observed, including hematologic toxicity, peripheral neuropathy, anorexia, and dehydration.

Use in patients with 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.

Non-Caucasian patients

Limited data are available on the use of paclitaxel in non-Caucasian patients, and current data are insufficient to recommend additional dose adjustments.

Excipients

Since paclitaxel contains ethanol, its potential effects on the central nervous system and other possible effects should be considered. The drug may be harmful to patients with alcoholism. This information should be taken into account when administering the drug to high-risk patients, such as those with liver disease or epilepsy.

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

Use during pregnancy or breastfeeding

Pregnancy

There is no information on paclitaxel use in pregnant women. Like other cytotoxic agents, paclitaxel may be harmful to the fetus and is contraindicated during pregnancy. Women and men should use contraception to prevent pregnancy during paclitaxel therapy and for at least 6 months after completion of treatment. Pregnancy should be reported immediately to the physician if it occurs.

Breastfeeding

It is unknown whether paclitaxel is excreted in human breast milk. Paclitaxel is contraindicated in women who are breastfeeding. Breastfeeding must be discontinued during paclitaxel therapy.

Fertility

Paclitaxel has teratogenic, embryotoxic, and mutagenic effects.

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

Ability to affect reaction speed when driving or operating machinery.

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

Administration and Dosage.

The concentrate for solution for infusion must be diluted prior to administration and should be given intravenously. Prior to the initiation of paclitaxel therapy, all patients must receive premedication with corticosteroids, antihistamines, and H2-receptor antagonists according to the following regimen:

Drug	Dose	Time of administration
Dexamethasone	20 mg orally or intravenously (8–20 mg – for patients with Kaposi's sarcoma)	Oral administration: approximately 6 and 12 hours before paclitaxel infusion. Intravenous administration: 30–60 minutes before paclitaxel infusion.
Diphenhydramine (or equivalent antihistamine)	50 mg intravenously	30–60 minutes before paclitaxel infusion.
Cimetidine or ranitidine	300 mg intravenously, 50 mg intravenously	30–60 minutes before paclitaxel infusion.

Due to the possibility of developing severe hypersensitivity reactions, appropriate symptomatic treatment agents should be available.

Paclitaxel solution must be administered intravenously by infusion using infusion sets with integrated membrane filters with pore size ≤ 0.22 μm.

First-line chemotherapy of ovarian cancer

A combination regimen with paclitaxel and cisplatin is recommended.

Depending on the duration of infusion, two paclitaxel dosage regimens are recommended:

paclitaxel at a dose of 175 mg/m² body surface area should be administered by intravenous infusion over 3 hours, followed by cisplatin at a dose of 75 mg/m² body surface area. 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 body surface area. The interval between treatment cycles is 3 weeks.

Second-line chemotherapy of ovarian cancer

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

Adjuvant chemotherapy of breast cancer

Paclitaxel should be administered after anthracycline- or cyclophosphamide-based therapy. Paclitaxel is recommended at a dose of 175 mg/m² body surface area administered by 3-hour intravenous infusions. Four cycles should be administered at 3-week intervals, following anthracycline- or cyclophosphamide-based therapy.

First-line chemotherapy of breast cancer

When used in combination with doxorubicin (50 mg/m² body surface area), paclitaxel should be administered 24 hours after doxorubicin.

The recommended dose of paclitaxel is 220 mg/m² body surface area, administered by 3-hour intravenous infusions. The interval between treatment cycles is 3 weeks.

When used in combination with trastuzumab, paclitaxel is recommended at a dose of 175 mg/m² body surface area administered by 3-hour intravenous infusions every 3 weeks. Paclitaxel may be administered the day after the first dose of trastuzumab or immediately after subsequent doses of trastuzumab, provided the prior administration was well tolerated (for detailed trastuzumab dosing, refer to the trastuzumab product instruction).

Second-line chemotherapy of breast cancer

Paclitaxel is recommended at a dose of 175 mg/m² body surface area administered by 3-hour intravenous infusions. The interval between treatment cycles is 3 weeks.

Chemotherapy of advanced non-small cell lung cancer

A combination regimen with paclitaxel and cisplatin is recommended. Paclitaxel should be 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. The interval between treatment cycles is 3 weeks.

Chemotherapy of 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.

Repeat administration is permitted only after neutrophil count has increased to ≥ 1.5×10⁹/L (≥ 1.0×10⁹/L in Kaposi’s sarcoma) and platelet count to ≥ 100×10⁹/L (≥ 75×10⁹/L in Kaposi’s sarcoma). 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).

Dose adjustment during treatment of patients with metastatic breast cancer, ovarian cancer, and advanced non-small cell lung cancer

The next dose of paclitaxel may be administered only after neutrophil count has increased to ≥ 1500/mm³ and platelet count to ≥ 10000/mm³.

For patients who experienced severe neutropenia (neutrophil count < 500/mm³ for 1 week or longer) or severe peripheral neuropathy, subsequent doses should be reduced by 20% (for patients with non-small cell lung cancer and first-line ovarian cancer therapy) or by 25% (for patients with metastatic breast cancer, ovarian cancer, and Kaposi’s sarcoma). For patients who develop mucositis (grade II or higher severity) during paclitaxel treatment, subsequent paclitaxel doses should be reduced by 25%.

Treatment of patients with hepatic impairment

Insufficient data are available on dosing for patients with mild or moderate hepatic impairment. Paclitaxel is contraindicated in patients with severe hepatic impairment.

Treatment of patients with renal impairment

Insufficient data are available on dose adjustment for patients with renal impairment.

Subsequent paclitaxel doses should be adjusted according to individual patient tolerance.

Preparation of infusion solution

Prior to administration, the concentrate for infusion solution Paclitaxel-AAR 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.

Infusion solutions prepared by diluting Paclitaxel-AAR with 0.9% sodium chloride solution or 5% glucose solution are physically and chemically stable for 24 hours at temperatures not exceeding 25°C and do not require protection from light. From a microbiological standpoint, the solution should be administered immediately after dilution. The cooled solution may precipitate but can re-dissolve at room temperature (25°C). The vial should be discarded if the solution is cloudy or if the precipitate does not re-dissolve. Freezing does not affect shelf life. From a microbiological standpoint, the infusion solution should be administered immediately after preparation. If not used immediately, storage duration and conditions must be monitored by the user (healthcare personnel). Usually, storage should not exceed 24 hours at 2–8°C, unless the solution was prepared under controlled and certified aseptic conditions.

The prepared infusion solutions may be cloudy due to the composition of the vehicle. Filtration does not eliminate cloudiness. Paclitaxel solution must be administered through infusion sets with integrated membrane filters with pore size < 0.22 μm. No significant loss of active ingredient activity has been observed when administered through such systems.

There have been isolated reports of precipitation in the infusion solution during administration (usually at the end of a 24-hour infusion period). Although the exact causes of precipitation have not been established, 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 infusion, and infusion should be discontinued if precipitation is observed.

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

Children

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

Overdose

Symptoms: the main expected complications of overdose are bone marrow suppression, peripheral neuropathy, and mucositis.

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

Adverse Reactions

Unless otherwise stated, the data below are based on safety data pooled from 812 patients with solid tumours who received paclitaxel monotherapy in clinical trials. Because patients with Kaposi's sarcoma represent a distinct population, a separate section at the end of this chapter describes a clinical study involving 107 patients with Kaposi's sarcoma.

Unless otherwise stated, the frequency and severity of reported adverse events were generally similar among 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.

Adverse Reactions with Paclitaxel Monotherapy

The most common adverse effect of paclitaxel therapy is bone marrow suppression: severe neutropenia (<500/mm³) occurred in 28% of patients but was not associated with fever. Only 1% of patients experienced severe neutropenia lasting ≥7 days. Thrombocytopenia 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 the baseline hemoglobin level).

Neurotoxicity, predominantly peripheral neuropathy, is likely to occur more frequently and severely with a 3-hour infusion of paclitaxel at 175 mg/m² (neurotoxicity in 85% of cases, severe in 15%) compared to a 24-hour infusion of paclitaxel at 135 mg/m² (peripheral neuropathy in 25% of cases, severe in 3%) in combination with cisplatin. A clear increase in the frequency of severe neurotoxicity has been observed in patients with non-small cell lung cancer and ovarian carcinoma treated with a 3-hour paclitaxel infusion followed by cisplatin. Peripheral neuropathy may develop after the first treatment cycle 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.

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

There have been isolated reports of disseminated intravascular coagulation (DIC) syndrome, often in association with sepsis or multiorgan dysfunction.

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

Severe hypersensitivity reactions with potentially fatal outcomes (such as hypotension requiring treatment, angioedema, respiratory distress requiring bronchodilators, 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.

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 rare 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 after injection.

The list below includes adverse reactions observed in patients receiving paclitaxel monotherapy via 3-hour infusions for metastatic cancer treatment (812 patients treated in clinical trials), as well as those identified during post-marketing surveillance*.

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

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

Blood and lymphatic system disorders: very common – myelosuppression, neutropenia, anemia, thrombocytopenia, leukopenia, tendency to bleeding; 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 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; frequency not known – bronchospasm.

Metabolism and nutrition disorders: very rare – anorexia, weight loss and weight gain; frequency not known* – tumor lysis syndrome.

Psychiatric disorders: very rare* – confusion.

Nervous system disorders: very common – neurotoxicity** (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 (manifesting 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 damage and/or visual disturbances (scintillating scotoma), especially in patients receiving doses above the recommended levels; frequency not known* – macular edema, photopsia, floaters in the vitreous body.

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

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

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 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, dry skin, acne; 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 long-sleeved clothing and long pants to protect arms and legs 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.

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, fever, dehydration, swelling, malaise. There have been rare reports of recurrence of skin reactions at sites of previous paclitaxel extravasation after subsequent drug administrations.

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

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

* Reported during post-marketing surveillance of paclitaxel.

** May persist for up to 6 months after discontinuation 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 more frequently observed compared to patients who received only AC. However, the frequency of these events corresponded to that observed with paclitaxel monotherapy as described above.

Hematologic and lymphatic system toxicity

Myelosuppression is the main dose-limiting toxic effect. The most significant manifestation of hematologic 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 was observed in 39% of patients. Neutropenia lasting more than 7 days was recorded in 41% of patients, and neutropenia lasting 30–35 days occurred in 8% of patients. In all monitored patients, hematologic parameters returned to normal within 35 days. The frequency of grade 4 neutropenia lasting 7 days or more was 22%.

Febrile neutropenia associated with paclitaxel therapy was observed in patients during 1.3% of treatment cycles. Three septic episodes leading to fatal outcomes were observed during paclitaxel therapy.

Thrombocytopenia was observed in 50% of patients, and severe thrombocytopenia (<50×10⁹/L) in 9%. Platelet counts decreased below 75×10⁹/L at least once during treatment in only 14% of patients. Bleeding episodes associated with paclitaxel therapy were observed in less than 3% of patients, but were localized.

Anemia (Hb < 11 g/dL) was observed in 61% of patients, and severe anemia (Hb < 8 g/dL) in 10%. Erythrocyte transfusions were required in 21% of patients.

Adverse Reactions with Combination Chemotherapy

Paclitaxel with Cisplatin

With combination therapy using paclitaxel and cisplatin, the frequency and severity of neurotoxic effects, predominantly peripheral neuropathy, were higher when paclitaxel was 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 24-hour intravenous infusions of paclitaxel at 135 mg/m² body surface area (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 receiving paclitaxel over 3 hours followed by cisplatin, an increased frequency of severe neurotoxicity was observed. Peripheral neuropathy may develop after the first treatment cycle 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 patients receiving cisplatin alone for gynecological tumors.

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

In ovarian cancer patients receiving 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 compared to treatment with cyclophosphamide in combination with cisplatin. The frequency and severity of myelosuppression were lower in the group receiving paclitaxel via 3-hour intravenous infusions in combination with cisplatin compared to the group receiving cyclophosphamide in combination with cisplatin.

In first-line chemotherapy for metastatic breast cancer, the frequency and severity of neutropenia, anemia, peripheral neuropathy, arthralgia/myalgia, asthenia, fever, and diarrhea were higher with administration of paclitaxel 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 FAC regimen. This may be partly explained by the use of corticosteroids.

Paclitaxel with Trastuzumab

In first-line chemotherapy with paclitaxel via 3-hour intravenous infusions in combination with trastuzumab, the frequency of the adverse effects listed below (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%), fever (47% vs. 23%), cough (42% vs. 22%), rash (39% vs. 18%), arthralgia (37% vs. 21%), tachycardia (12% vs. 4%), diarrhea (45% vs. 30%), arterial hypertension (11% vs. 3%), epistaxis (18% vs. 4%), acne (11% vs. 3%), herpes simplex (12% vs. 3%), accidental injuries (13% vs. 3%), insomnia (25% vs. 13%), rhinitis (22% vs. 5%), sinusitis (21% vs. 7%), injection site reactions (7% vs. 1%). Differences in the frequency of some adverse effects may be explained by the greater number and 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 cardiac contractility (a decrease in left ventricular ejection fraction by more than 20%) was observed in patients with metastatic breast cancer receiving doxorubicin in combination with paclitaxel, as well as in patients receiving standard therapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen). The incidence of congestive heart failure was <1% both with paclitaxel plus doxorubicin and with standard FAC regimen therapy. With combination chemotherapy using 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 functional class I-II in 10% of patients vs. 0%, heart failure NYHA functional class III-IV in 2% of patients vs. 1%). In rare cases, these disorders were associated with fatal outcomes. In all cases except the rare fatal ones, patients responded to appropriate therapy.

Special Patient Populations

Radiation pneumonitis has been reported in patients undergoing concurrent radiotherapy.

Adverse Effects in AIDS Patients with Kaposi's Sarcoma

Except for hematologic 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 tumors receiving paclitaxel monotherapy.

Bone marrow suppression was the main dose-limiting toxic effect. The most significant manifestation of hematologic toxicity was neutropenia. During the first treatment cycle, severe neutropenia (<0.5×10⁹/L) occurred in 20% of patients. Throughout the entire treatment period, severe neutropenia was observed in 39% of patients. The duration of neutropenia was more than 7 days in 41% of patients and 30–35 days in 8% of patients. In all monitored patients, hematologic parameters normalized within 35 days. The frequency of grade 4 neutropenia lasting more than 7 days was 22%.

Febrile neutropenia associated with paclitaxel therapy was observed in 14% of patients during 1.3% of treatment cycles. Three septic episodes (2.8%) leading to fatal outcomes were observed during paclitaxel therapy.

Anemia (Hb < 11 g/dL) was observed in 61% of patients, and severe anemia (Hb < 8 g/dL) in 10%. Erythrocyte transfusions were required in 21% of patients.

Hepatobiliary disorders: increased levels of bilirubin, alkaline phosphatase, and AST were observed in 28%, 43%, and 44% of patients, respectively, who had normal baseline liver function tests (more than half of these patients were receiving protease inhibitors). Significant increases in these parameters were observed in 1% of cases.

During post-marketing surveillance of paclitaxel, cranial nerve paralysis has been reported.

Paclitaxel with Gemcitabine

Renal and urinary system disorders: Hemolytic uremic syndrome may develop in patients receiving paclitaxel and gemcitabine.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after drug authorization 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 efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

After reconstitution, the infusion solution is chemically and physically stable for 24 hours at a temperature not exceeding 25°C and does not require protection from light.

From a microbiological standpoint, the solution should be administered immediately after reconstitution. If not administered immediately, the responsibility for the duration and conditions of storage of the ready-to-use solution lies with the user (healthcare personnel).

Storage conditions.

Store at a temperature not exceeding 30°C in the original packaging to protect from light.

Keep out of reach of children.

Incompatibilities.

Polyethoxylated castor oil, a component of Paclitaxel-AAR, may cause leaching of diethylhexyl phthalate (DEHP) from plasticized PVC. The intensity of this process depends on the duration of exposure and the concentration of castor oil. Therefore, reconstitution, storage, and administration of infusion solutions must be performed using containers and systems that do not contain PVC.

Do not use with other solvents except those specified in the section "Instructions for Use 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 or 10 vials per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Venus Remedies Limited.

Manufacturer's address and place of business.

Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh, 173205, India.

Marketing Authorization Holder.

AAR PHARMA FZ-LLC.

Address of Marketing Authorization Holder.

Premises 702, 7th Floor, Building: DSC Tower, Post Box – 478837, Dubai, United Arab Emirates.