Paclitaxel-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PAKLITAKSEL-VISTA (PACLITAXEL-VISTA)

Composition:

Active substance: paclitaxel;

1 ml of concentrate contains 6 mg of paclitaxel;

Excipients: citric acid anhydrous, polyoxyl 35 castor oil, ethanol anhydrous.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, slightly viscous solution ranging from colorless to pale yellow.

Pharmacotherapeutic group. Antineoplastic 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 microtubule structures or "bundles" throughout the cell cycle, as well as multiple microtubule "asters" during mitosis.

Pharmacokinetics

Plasma concentrations of paclitaxel decline according to a biphasic kinetic pattern following intravenous administration.

Paclitaxel pharmacokinetics were determined after infusion of the drug at doses of 135 mg/m² and 175 mg/m² over 3 and 24 hours, respectively. The mean terminal half-life ranged from 3 to 52.7 hours, and mean values of total clearance varied between 11.6 and 24 L/h/m²; total clearance tends to decrease at higher plasma concentrations of paclitaxel. The mean volume of distribution at steady state ranged 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), mean AUC was 5619 ng•h/mL (range: 2609–9428 ng•h/mL), clearance was 20.6 L/h•m² (range: 11–38 L/h•m²), volume of distribution was 291 L/m² (range: 121–638 L/m²), and terminal half-life was 23.7 hours (range: 12–33 hours).

Variations in systemic exposure to paclitaxel among individual patients were minimal. No drug accumulation was observed after multiple treatment courses. 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 elucidated. The mean total excretion of unchanged drug in urine ranges from 1.3% to 12.6% of the administered dose, indicating extensive non-renal clearance. The main metabolites are hydroxylated derivatives. Paclitaxel is likely metabolized primarily in the liver by cytochrome P450 isoenzymes and excreted in bile.

After administration of radiolabeled paclitaxel, on average 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 together, respectively. The impact of renal or hepatic impairment on paclitaxel metabolism following 3-hour infusions has not been studied. Pharmacokinetic parameters in one patient undergoing 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 increase in the distribution and elimination times 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 the use of paclitaxel in combination with other therapeutic agents, 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 if 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 when HER-2 protein overexpression (3+) is confirmed by immunohistochemical testing, or when anthracycline therapy is contraindicated;
• monotherapy for metastatic breast cancer in patients for whom standard anthracycline therapy is not planned, or in cases where prior anthracycline therapy has been ineffective.
• Advanced non-small cell lung cancer (combination chemotherapy with cisplatin when surgical treatment and/or radiotherapy are not feasible).
• Kaposi's sarcoma (KS) in AIDS patients (second-line treatment of advanced Kaposi's sarcoma when prior therapy with liposomal anthracyclines has been ineffective).

Contraindications.

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

Special safety precautions.

Instructions for medical personnel

When handling Paclitaxel-Vista, 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 techniques. All necessary precautions must 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. If the drug comes into contact with mucous membranes, they 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 agitation or even without mixing once room temperature is reached. This phenomenon does not affect the quality of the drug. However, if the solution remains cloudy or contains an undissolved precipitate, the product must not be used and the vial should be destroyed according to established hazardous waste disposal procedures.

Use of dosing devices or Chemo-type needles is not recommended, as they may damage the rubber stopper of the vial, leading to loss of sterility.

Preparation of infusion solution.

Prior to infusion, Paclitaxel-Vista must be diluted under aseptic conditions. Paclitaxel should be diluted with 0.9% sodium chloride isotonic solution, 5% glucose solution, 5% glucose solution with 0.9% sodium chloride solution (1:1), or Ringer's solution plus 5% glucose solution to a final concentration of 0.3 to 1.2 mg/mL.

Chemical and physical stability of the diluted solution has been demonstrated for 72 hours at temperatures not exceeding 25°C when diluted with 0.9% sodium chloride solution, 5% glucose solution, 5% glucose solution with 0.9% sodium chloride solution (1:1), or Ringer's solution with 5% glucose solution (1:1). From a microbiological standpoint, the product should be used immediately. If the solution is not administered immediately after preparation, the user is responsible for the storage conditions and duration prior to administration. Diluted solutions should not be refrigerated.

After preparation, the solution may appear cloudy due to the presence of solvent in the concentrate. Filtration to remove cloudiness is not recommended. Infusion of Paclitaxel-Vista should be administered through infusion sets equipped with in-line membrane filters having a pore size of not more than 0.22 µm. When administered through such systems, no significant loss of active ingredient has been observed.

Rarely, precipitation has been reported during 24-hour infusions. Although the exact cause of precipitation is unknown, it may result from solution supersaturation. To minimize the risk of precipitation, Paclitaxel-Vista should be administered as soon as possible after dilution, excessive agitation should be avoided, and the infusion set should be thoroughly flushed before use. The solution should be monitored regularly during infusion, and infusion should be discontinued if precipitation occurs.

Disposal.

Unused solutions, instruments, and materials that have come into contact with paclitaxel must be disposed of according to 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.

Premedication with cimetidine does not affect paclitaxel clearance.

When treating ovarian cancer with a combination of paclitaxel and cisplatin, paclitaxel should be administered before cisplatin. In this sequence, the safety profile is similar to that of paclitaxel monotherapy. However, if paclitaxel is administered after cisplatin, more severe myelosuppression occurs, and paclitaxel clearance decreases by approximately 20%. The risk of renal insufficiency in ovarian cancer patients receiving combination therapy with paclitaxel and cisplatin is higher than with cisplatin monotherapy.

Since 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 demonstrated that the primary metabolic transformation in humans is CYP2C8-mediated conversion of paclitaxel to 6α-hydroxypaclitaxel. Clinically significant interactions with other enzymes besides CYP2C8 are not expected. Concomitant administration of ketoconazole, a potent CYP3A4 inhibitor, does not slow 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 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 co-administered, 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.

The effect of other drugs may be altered due to the presence of alcohol in this medicinal product.

Special precautions for use.

Treatment with Paclitaxel-Vista should be carried out under the supervision of a qualified physician experienced in the use of anticancer chemotherapeutic agents. Since hypersensitivity reactions may occur, appropriate resuscitation equipment must be available.

Because extravasation may occur 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-Vista 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.

Mild secondary symptoms such as flushing or other skin reactions do not require discontinuation of therapy. The product contains polyoxyethylated castor oil, which may cause severe allergic reactions.

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of the drug. Complete blood counts should be monitored at least twice weekly during treatment. The drug should not be re-administered until 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 function impairment. The risk of toxic effects (particularly grade III–IV myelosuppression) is higher in patients with hepatic dysfunction. When paclitaxel is administered via 3-hour infusions, no increased toxicity has been observed in patients with mild hepatic impairment. However, with prolonged administration, more pronounced myelosuppression may occur in patients with moderate hepatic dysfunction. Paclitaxel is not recommended in patients with severe hepatic impairment. Patients should be closely monitored for signs of severe myelosuppression. Currently, there is insufficient data to provide dose adjustment recommendations for patients with mild or moderate hepatic impairment. Information on paclitaxel use in patients with severe cholestasis is lacking.

Severe cardiac conduction disorders have been reported rarely. In case of severe conduction disturbances during treatment, appropriate therapy should be initiated, and continuous cardiac monitoring is recommended 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 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 scheduled for such combination therapy should undergo thorough cardiac evaluation before treatment initiation, including ECG, echocardiography, and MUGA scanning. Cardiac function should be monitored regularly during treatment (e.g., every 3 months). This monitoring allows early detection of cardiac dysfunction. The cumulative dose of anthracyclines (in mg/m² body surface area) should be considered when determining the frequency of ventricular function assessment. If test results indicate cardiac dysfunction, even if asymptomatic, the potential benefits of continuing therapy versus the risk of irreversible cardiac damage must be carefully weighed. If combination chemotherapy is continued, cardiac monitoring should be increased in frequency (every 1–2 cycles).

Although peripheral neuropathy is common, severe symptoms occur rarely. 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 as a 3-hour infusion in combination with cisplatin, compared to those receiving paclitaxel alone or cyclophosphamide followed by cisplatin. Sensory disturbances usually improve or resolve within several months after discontinuation of paclitaxel. Pre-existing neuropathy due to prior chemotherapy is not a contraindication for paclitaxel treatment.

Ethanol. Since paclitaxel contains ethanol, its potential effects on the CNS and other possible interactions should be considered. The use of this drug may be harmful in patients with alcoholism. This information should be taken into account when administering the drug to children and patients at increased risk, such as those with liver disease or epilepsy. The amount of alcohol present in this medicinal product may alter the effects of other drugs.

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.

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 concurrently receiving antibiotics. This should be considered in the differential diagnosis in cases of severe or persistent diarrhea during or shortly after paclitaxel treatment.

Severe mucositis

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

Interstitial pneumonitis

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

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.

Teratogenicity, embryotoxicity, and mutagenicity.

Paclitaxel has demonstrated teratogenic, embryotoxic, and mutagenic effects in several experimental systems. Therefore, patients of reproductive potential and/or their partners should use contraception for at least 6 months after completion of paclitaxel treatment (see section "Use during pregnancy or breastfeeding").

Other warnings.

Patients with severe renal insufficiency should not be treated with paclitaxel. Paclitaxel contains polyoxyethylated castor oil, which may cause severe allergic reactions.

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

Use during pregnancy or breastfeeding.

Pregnancy

Paclitaxel has been shown to exhibit embryotoxic and fetotoxic effects in rabbit studies and to reduce fertility in rats. There are insufficient data on the use of paclitaxel in pregnant women. Like other cytotoxic drugs, paclitaxel poses a potential risk to the fetus. Therefore, paclitaxel is contraindicated during pregnancy. Women of reproductive age should not plan pregnancy during paclitaxel treatment and must immediately inform their physician if pregnancy occurs. Women and men of reproductive potential and/or their partners should use reliable contraception during treatment and for at least 6 months after completion of paclitaxel therapy, and must immediately inform their physician if pregnancy occurs.

Breastfeeding

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

Fertility

Paclitaxel has been shown to reduce fertility in rats. It is unknown whether this applies to humans. Male patients should undergo sperm cryopreservation prior to starting paclitaxel treatment due to the risk of infertility.

Ability to affect reaction speed when driving or operating machinery.

During paclitaxel treatment, patients should refrain from potentially hazardous activities requiring high concentration and rapid psychomotor responses. It should be noted that the medicinal product Paclitaxel-Vista contains alcohol, and certain adverse reactions may negatively affect the ability to drive or operate machinery.

Administration and Dosage.

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

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

The recommended treatment regimen is combination therapy with paclitaxel and cisplatin.

According to infusion duration, two paclitaxel dosing 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 should be 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. Administer 4 cycles at 3-week intervals.

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 trastuzumab infusion was well tolerated.

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.

First-line chemotherapy of advanced non-small cell lung cancer

A combination regimen of paclitaxel and cisplatin is recommended. Paclitaxel should be administered at a dose of 175 mg/m² body surface area by 3-hour intravenous 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.

Treatment of patients with hepatic impairment

There is insufficient data on dosing in patients with mild to moderate hepatic impairment. Paclitaxel is contraindicated in patients with severe hepatic impairment.

Treatment of patients with renal impairment

There is insufficient data on dose adjustment in patients with renal impairment. Subsequent paclitaxel doses should be adjusted according to individual patient tolerance.

Repeat administration is permitted only after neutrophil counts have recovered to ≥ 1.5×10⁹/L (≥ 1.0×10⁹/L in Kaposi's sarcoma) and platelet counts to ≥ 100×10⁹/L (≥ 75×10⁹/L in Kaposi's sarcoma). In patients who experienced severe neutropenia (neutrophil count < 0.5×10⁹/L for 7 days or more) or severe peripheral neuropathy, subsequent doses should be reduced by 20% (by 25% in Kaposi's sarcoma patients).

Preparation of infusion solution

Before use, the concentrate for infusion solution of Paclitaxel-Vista must be diluted under aseptic conditions with 0.9% sodium chloride solution, 5% glucose solution, 5% glucose in 0.9% sodium chloride solution, or 5% glucose in Ringer's solution to a final concentration of 0.3–1.2 mg/mL.

When multiple withdrawals are made from the same vial, the product maintains microbiological, physical, and chemical stability for up to 28 days at 25°C.

Infusion solutions prepared by diluting Paclitaxel-Vista with 0.9% sodium chloride solution or 5% glucose solution are physically and chemically stable for 51 hours when stored at temperatures not exceeding 25°C, and for 14 days when stored at 2–8°C. The cooled solution may form a precipitate but can redissolve at room temperature (25°C). The vial should be discarded if the solution is cloudy or if the precipitate does not redissolve. Freezing does not affect shelf life. From a microbiological standpoint, the infusion solution should be used immediately after preparation. If not used immediately, storage duration and conditions must be monitored by the user. Typically, storage should not exceed 24 hours at 2–8°C, unless the solution was prepared under controlled and validated aseptic conditions.

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

Prepared infusion solutions do not require protection from light.

There have been isolated reports of precipitate formation in the infusion solution during administration (usually at the end of a 24-hour infusion period). Although the exact cause of precipitate formation has not been fully elucidated, it is likely due to supersaturation of the infusion solution. To minimize the risk of precipitate formation, the infusion solution should be administered immediately after dilution, and excessive shaking, vibration, or agitation should be avoided. The infusion system should be thoroughly flushed before use. The solution should be visually inspected regularly during administration, and infusion should be discontinued if precipitate is observed.

To minimize leaching of diethylhexylphthalate (DEHP) from infusion bags, systems, or other medical equipment made of plasticized polyvinyl chloride (PVC), diluted infusion solutions should be stored in containers made of non-PVC materials (glass bottles, polypropylene, polyolefin bags) and administered through polyethylene infusion systems. Filters may be connected using short PVC tubing without causing significant DEHP leaching.

Geriatric patients

No additional dose reductions are recommended for patients aged 65 years and older beyond those applicable to all patients. Among 229 patients receiving paclitaxel monotherapy for breast cancer, 13% were aged ≥ 65 years and 2% were aged ≥ 75 years. No increased incidence of toxicity was observed in patients aged ≥ 65 years. However, further analysis of 981 patients receiving paclitaxel monotherapy for metastatic breast cancer, of whom 15% were aged ≥ 65 years and 2% were aged ≥ 75 years, revealed higher rates of epistaxis, diarrhea, dehydration, malaise, and peripheral edema compared to younger patients. Among 421 patients with pancreatic adenocarcinoma receiving paclitaxel and gemcitabine in a randomized trial, 41% were aged ≥ 65 years and 10% were aged ≥ 75 years. Patients aged ≥ 75 years receiving paclitaxel and gemcitabine experienced higher rates of serious adverse reactions and adverse events leading to treatment discontinuation. Patients with pancreatic adenocarcinoma aged ≥ 75 years 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 and 3.5% were aged ≥ 75 years. Myelosuppression, peripheral neuropathy, and arthralgia occurred more frequently in patients aged ≥ 65 years compared to younger patients. Experience with paclitaxel/carboplatin in patients aged ≥ 75 years is limited. Pharmacokinetic/pharmacodynamic modeling based on data from 125 patients with advanced solid tumors indicated that patients aged ≥ 65 years may be more susceptible to neutropenia during the first treatment cycle. Administration method. Paclitaxel must be administered only in specialized oncology centers under the supervision of a qualified oncologist.

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 presented below refer to the pooled safety database of 812 patients with solid tumours who received paclitaxel as monotherapy in clinical trials. Because patients with Kaposi's sarcoma represent a distinct population, a separate subsection at the end of this section provides data from clinical studies involving 107 patients with Kaposi's sarcoma.

The frequency and intensity of adverse reactions in patients with ovarian cancer, breast cancer, and non-small cell lung cancer do not differ significantly. Age did not influence any of the observed types of toxicity.

Monotherapy

The most common adverse effect of paclitaxel therapy is bone marrow suppression. Severe neutropenia (< 500/mm³) was observed in 28% of patients, but no cases of febrile neutropenia were reported. Severe neutropenia lasting ≥ 7 days occurred in only 1% of patients. Thrombocytopenia with platelet counts < 50,000/mm³ was observed in a small number of patients at least once during the study, and anaemia (frequency and severity of anaemia depend on baseline haemoglobin levels). Disseminated intravascular coagulation (DIC) syndrome has been reported, often in association with sepsis or multi-organ failure. Neurotoxicity, primarily peripheral neuropathy, is likely to occur more frequently and be more severe with a 3-hour infusion of 175 mg/m² paclitaxel (neurotoxicity in 85% of cases, severe in 15%) compared to a 24-hour infusion of 135 mg/m² paclitaxel (peripheral neuropathy in 25% of cases, severe in 3%) when paclitaxel is combined with cisplatin. In patients with non-small cell lung cancer and ovarian carcinoma receiving paclitaxel over 3 hours followed by cisplatin, the incidence of severe neurotoxicity was significantly higher. 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 to paclitaxel treatment. Furthermore, peripheral neuropathy may persist for up to 6 months after discontinuation of paclitaxel.

Severe hypersensitivity reactions, which may be fatal (hypotension requiring therapeutic intervention; angioedema; respiratory dysfunction requiring bronchodilators; generalized urticaria), were observed in 2 patients (< 1% of all patients). Mild hypersensitivity reactions occurred in 34% of patients (17% of all treatment cycles). These mild reactions, primarily flushing and rash, did not require therapeutic intervention or discontinuation of paclitaxel therapy.

Arthralgia or myalgia was observed in 60% of patients, and was severe in 13% of patients.

Local swelling, pain, erythema, and induration may occur at the injection site. Accidental extravasation may lead to cellulitis. There have been isolated reports of skin desquamation and/or necrosis associated with extravasation. Skin colour changes may also occur. Isolated reports of skin reactions, so-called local inflammatory reactions at the site of prior extravasation, have been reported after subsequent administration of paclitaxel at another site. There is currently no specific treatment for extravasation reactions. In some cases, infusion site reactions began during prolonged infusion or 7–10 days later.

Alopecia was observed in 87% of patients receiving paclitaxel. Most cases of alopecia occurred within the first month of starting paclitaxel therapy. Most patients experiencing alopecia can expect to lose ≥ 50% of their hair. The list below includes adverse reactions observed during monotherapy with paclitaxel administered as a 3-hour infusion in the treatment of metastatic cancer (812 patients treated in clinical trials), and adverse reactions from post-marketing experience. The latter may be attributed to paclitaxel regardless of treatment regimen.

The frequency of adverse events is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data). Within each frequency group, adverse effects are listed in order of decreasing severity.

Infections and infestations

Very common: infections (predominantly of the urinary tract and upper respiratory tract, including herpes simplex, oral candidiasis, pharyngitis, rhinitis), occasionally with fatal outcome.

Uncommon: severe infections, septic shock.

Rare: pneumonia*, peritonitis*, sepsis*.

Very rare: pseudomembranous colitis.

Blood and lymphatic system disorders

Very common: myelosuppression, neutropenia, anaemia, thrombocytopenia, leucopenia, tendency to bleeding.

Common: febrile neutropenia*.

Uncommon: severe anaemia.

Rare: febrile neutropenia*.

Very rare: acute myeloid leukaemia*, myelodysplastic syndrome*.

Frequency not known: disseminated intravascular coagulation (DIC), often in combination with sepsis or multi-organ failure*.

Immune system disorders

Very common: mild hypersensitivity reactions (primarily flushing and rash).

Uncommon: delayed-type hypersensitivity reactions, serious hypersensitivity reactions requiring therapeutic intervention (including arterial hypotension, angioedema, respiratory distress, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, limb pain, profuse sweating, and arterial hypertension).

Rare: anaphylactic reactions*.

Very rare: anaphylactic shock* (including fatal hypersensitivity reactions).

Frequency not known: bronchospasm.

Metabolism and nutrition disorders

Uncommon: weight loss and weight gain.

Very rare: anorexia*.

Frequency not known: tumour lysis syndrome*.

Psychiatric disorders

Very rare: confusion*.

Nervous system disorders

Very common: neurotoxicity** (predominantly peripheral neuropathy), paraesthesia, somnolence.

Common: depression, severe neuropathy (predominantly peripheral neuropathy), nervousness, insomnia, cognitive impairment, hypokinesia, gait disturbance, hypoaesthesia, taste alteration.

Rare: motor neuropathy (manifested as moderate distal muscle weakness)*.

Very rare: autonomic neuropathy (leading to paralytic ileus and orthostatic hypotension)*, grand mal seizures*, convulsions*, encephalopathy*, dizziness*, headache*, ataxia*.

Eye disorders

Uncommon: dry eyes, blurred vision, visual field defect.

Very rare: optic nerve damage and/or visual disturbances (scintillating scotoma)*, particularly in patients receiving doses above the recommended levels.

Frequency not known: macular oedema*, 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 combined with bigeminy, arrhythmia, extrasystoles.

Rare: heart failure.

Very rare: atrial fibrillation*, supraventricular tachycardia*.

Vascular disorders

Very common: arterial hypotension.

Common: vasodilation (flushing).

Uncommon: thrombosis, arterial hypertension, thrombophlebitis.

Very rare: shock*.

Frequency not known: phlebitis*.

Respiratory, thoracic and mediastinal disorders

Common: epistaxis.

Rare: respiratory failure*, pulmonary embolism*, pulmonary fibrosis*, interstitial pneumonia*, dyspnoea*, pleural effusion*.

Very rare: cough*, pulmonary hypertension*.

Gastrointestinal disorders

Very common: nausea, vomiting, diarrhoea, mucositis, stomatitis, abdominal pain.

Common: dry mouth, oral ulcers, melena, dyspepsia.

Rare: intestinal obstruction*, intestinal perforation*, ischaemic colitis*, acute pancreatitis*.

Very rare: mesenteric thrombosis*, pseudomembranous colitis*, neutropenic colitis*, ascites*, oesophagitis*, constipation*, dehydration*.

Hepatobiliary disorders

Very rare: liver necrosis*, hepatic encephalopathy* (fatal cases reported).

Skin and subcutaneous tissue disorders

Very common: alopecia.

Common: transient and mild nail and skin changes, dry skin, acne.

Uncommon: nail discoloration.

Rare: pruritus*, rash*, erythema*, oedema*.

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

Very common: pain, oedema, including peripheral and facial oedema.

Common: injection site reactions (including localized oedema, pain, erythema, induration, weakness, pallor, and skin oedema; accidental extravasation may lead to cellulitis, skin fibrosis, and skin necrosis).

Rare: chest pain, chills, pyrexia*, dehydration*, asthenia*, oedema*, malaise*. There have been isolated reports of recurrence of skin reactions at sites of prior paclitaxel extravasation after subsequent administrations.

Laboratory findings

Common: significant (≥ 5 times above normal) elevation of liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and alkaline phosphatase).

Uncommon: significant elevation of bilirubin levels.

Rare: increased blood creatinine levels*.

* Reported during post-marketing surveillance of paclitaxel.

** May persist for up to 6 months after discontinuation of paclitaxel.

In patients with breast cancer who received paclitaxel for adjuvant therapy following standard combination therapy with anthracyclines and cyclophosphamide (AC), neurotoxicity, hypersensitivity reactions, arthralgia/myalgia, anaemia, infection, fever, nausea/vomiting, and diarrhoea occurred more frequently compared to patients who received AC alone. The frequency of these adverse reactions was consistent 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 haematological toxicity was neutropenia. During the first treatment cycle, severe neutropenia (< 500/mm³) was observed in 20% of patients. Over 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. In all monitored patients, haematological parameters returned to normal within 35 days. The incidence of grade IV neutropenia lasting 7 days or longer 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%) 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. Anaemia (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 therapy

When paclitaxel is combined with cisplatin, neurotoxicity, primarily peripheral neuropathy, occurs more frequently and is more severe with a 3-hour infusion of 175 mg/m² paclitaxel (neurotoxic effects reported in 85% of patients, severe in 15%) compared to a 24-hour infusion of 135 mg/m² paclitaxel (neurotoxic effects reported in 25% of patients, severe in 3%).

In patients with non-small cell lung cancer and ovarian cancer who received paclitaxel over 3 hours followed by cisplatin, the frequency of severe neurotoxicity increased. Peripheral neuropathy may develop after the first treatment 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 to paclitaxel treatment.

Patients receiving paclitaxel and cisplatin have an increased risk of developing renal failure compared to patients receiving cisplatin alone in the treatment of gynaecological tumours.

The data below are derived from:

• two large first-line chemotherapy trials in ovarian cancer (paclitaxel + cisplatin; over 1050 patients);
• two phase III trials of first-line chemotherapy in metastatic breast cancer – one trial combining with doxorubicin (paclitaxel + doxorubicin; 267 patients); the second trial combining with trastuzumab (planned subgroup analysis of paclitaxel + trastuzumab; 188 patients);
• two phase III trials in advanced non-small cell lung cancer (paclitaxel + cisplatin: over 360 patients).

In patients with ovarian cancer 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 as 3-hour intravenous infusions combined with cisplatin compared to the group receiving cyclophosphamide combined with cisplatin.

In first-line chemotherapy for metastatic breast cancer, the frequency and severity of neutropenia, anaemia, peripheral neuropathy, arthralgia/myalgia, asthenia, fever, and diarrhoea were higher with paclitaxel administered at 220 mg/m² body surface area as 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 corticosteroid premedication.

Paclitaxel with trastuzumab

In first-line chemotherapy with paclitaxel administered as 3-hour intravenous infusions in combination with trastuzumab, the frequency of the following adverse reactions (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%), infection (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%), diarrhoea (45% vs. 30%), arterial hypertension (11% vs. 3%), epistaxis (18% vs. 4%), acne (11% vs. 3%), herpes simplex (12% vs. 3%), accidental injury (13% vs. 3%), insomnia (25% vs. 13%), rhinitis (22% vs. 5%), sinusitis (21% vs. 7%), and injection site reactions (7% vs. 1%). Some of these differences in frequency may be attributable to the greater number and duration of treatment cycles with paclitaxel/trastuzumab combination compared to paclitaxel monotherapy. The frequency of serious adverse effects with combination chemotherapy paclitaxel/trastuzumab was similar 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% with paclitaxel, paclitaxel combined with doxorubicin, and standard FAC therapy. In combination chemotherapy with trastuzumab and paclitaxel, the frequency and severity of cardiac dysfunction in patients previously treated with anthracyclines were higher than with paclitaxel monotherapy (NYHA class I/II 10% vs. 0%; NYHA class III/IV 2% vs. 1%), and fatal outcomes were rare. In isolated cases, cardiac dysfunction (with combination chemotherapy trastuzumab and paclitaxel in patients previously treated with anthracyclines) was associated with fatal outcomes. All patients responded to appropriate treatment, except in the aforementioned isolated cases.

Special patient groups

Radiation pneumonitis has been observed in patients who received concomitant radiotherapy with the drug.

Adverse reactions in AIDS patients with Kaposi's sarcoma

Except for haematological and hepatic adverse effects, the frequency and severity of adverse effects in patients with Kaposi's sarcoma were comparable to those in patients with other solid tumours receiving paclitaxel monotherapy. Bone marrow suppression was the main dose-limiting toxic effect. The most significant manifestation of haematological toxicity was neutropenia. During the first treatment course, severe neutropenia (< 500 cells/mm³) was observed in 20% of patients. Over the entire treatment period, severe neutropenia occurred in 39% of patients. Neutropenia lasted > 7 days in 41% of patients and 30–35 days in 8% of patients. In all monitored patients, neutropenia resolved within 35 days. The incidence of grade IV neutropenia lasting ≥ 7 days was 22%. Febrile neutropenia associated with paclitaxel therapy was observed in 14% of patients during 1.3% of treatment cycles. Three cases of sepsis (2.8%) related to the drug, with fatal outcomes, were recorded during paclitaxel therapy. Thrombocytopenia was observed in 50% of patients, and severe thrombocytopenia (< 50,000 cells/mm³) in 9%. Platelet counts decreased below 75,000 cells/mm³ at least once during treatment in only 14% of patients. Bleeding episodes related to paclitaxel therapy were reported in less than 3% of patients, but bleeding was localized.

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

A total of 128 cases of DIC syndrome were identified, 31 of which were temporally associated. Additionally, 47 fatal cases due to disseminated intravascular coagulation were recorded.

Hepatobiliary disorders

Among patients with normal baseline liver function (more than 50% of whom received protease inhibitors), bilirubin levels increased in 28% of patients, alkaline phosphatase in 43%, and AST (SGOT – serum glutamate-oxaloacetate transaminase) in 44%. Significant elevation of each of these parameters was observed in 1% of cases.

Skin and subcutaneous tissue disorders

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

After opening the vial prior to dilution

Chemical and physical stability has been demonstrated for 28 days at a temperature not exceeding 25 °C.

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

After dilution

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

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of the reach of children.

Incompatibilities.

Polyoxyethylated castor oil, a component of Paclitaxel-Vista, may cause leaching of diethylhexylphthalate (DEHP) from plasticized PVC. The intensity of this process depends on the duration of exposure and the concentration of castor oil. Therefore, infusion solutions must be prepared, stored, and administered using containers and systems that do not contain PVC.

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

Packaging.

5 mL (30 mg), 16.7 mL (100 mg), 25 mL (150 mg), 43.33 mL (260 mg), or 50 mL (300 mg) in a vial; 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturers.

Actavis Italia S.p.A.

Sindan Pharma S.R.L.

Manufacturer locations and addresses of manufacturing sites.

Via Pasteur, 10 - 20014 Nerviano (Milan), Italy.

Bd. Ion Mihalache, 11, Sector 1, 011171, Bucharest, Romania.