Paclitaxel amaksa: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Paclitaxel Amaxa

Composition:

Active substance: paclitaxel;

1 ml of concentrate contains 6 mg of paclitaxel;

Excipients: polyethoxylated castor oil, citric acid, anhydrous ethanol.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, yellowish, viscous solution.

Pharmacotherapeutic group. Antineoplastic agents. Plant alkaloids and other natural agents. Taxanes. ATC code L01C D01.

Pharmacological Properties.

Pharmacodynamics.

Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by inhibiting depolymerization. This stabilization interferes with the normal dynamic reorganization of the microtubule network, which is essential for mitosis and interphase stages of the cell cycle. Additionally, paclitaxel induces the formation of abnormal microtubule structures or bundles throughout the cell cycle, as well as multiple microtubule asters during mitosis.

Pharmacokinetics.

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

The pharmacokinetics of paclitaxel have been studied following 3- and 24-hour intravenous infusions at doses of 135 mg/m² and 175 mg/m² body surface area. The mean terminal half-life ranges from 3 to 52.7 hours, and the mean total body clearance ranges from 11.6 to 24.0 L/h·m². Total body clearance of paclitaxel likely decreases as its plasma concentration increases. The mean steady-state volume of distribution ranges from 198 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding. With 3-hour infusions, the pharmacokinetics of paclitaxel are nonlinear. When doses were increased by 30% (from 135 to 175 mg/m² body surface area), the maximum plasma concentration (Cmax) and the area under the pharmacokinetic curve (AUC_0→∞) 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 terminal half-life was 23.7 hours (range: 12–33 hours).

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

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

The metabolism of paclitaxel in humans has not been fully elucidated. Between 1.3% and 12.6% of the administered dose is excreted unchanged in urine, indicating extensive non-renal clearance. Paclitaxel is likely metabolized primarily in the liver by cytochrome P450 isoenzymes and excreted via bile. After administration of radiolabeled paclitaxel, approximately 26%, 2%, and 6% of radioactivity were excreted in feces as 6α-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel, and 6α-3'-p-dihydroxypaclitaxel, respectively. The formation of these hydroxylated metabolites is catalyzed by the isoenzymes CYP2C8, CYP3A4, and CYP2C8+CYP3A4, respectively. The impact of renal or hepatic impairment on the pharmacokinetics of paclitaxel during 3-hour infusions has not been formally studied. Pharmacokinetic parameters in one patient requiring hemodialysis who was treated with paclitaxel at 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 phases of doxorubicin and its metabolites has been observed. When paclitaxel was administered immediately after doxorubicin, systemic exposure to doxorubicin in plasma was 30% higher than when paclitaxel was administered 24 hours after doxorubicin.

For use of paclitaxel in combination with other therapies, refer to the appropriate prescribing information for cisplatin, doxorubicin, and trastuzumab for further details on the use of these medicinal products.

Clinical characteristics.

Indications.

Ovarian cancer:

as a first-line agent for the treatment of ovarian cancer, as well as in combination with cisplatin for advanced-stage ovarian cancer or for residual tumors larger than 1 cm after laparotomy;
as a second-line agent for the treatment of metastatic ovarian cancer when standard platinum-based therapy has proven ineffective.

Breast cancer:

as adjuvant therapy in patients with lymph node involvement following standard combination therapy with anthracyclines or cyclophosphamide;
primary treatment of locally advanced or metastatic breast cancer, either as monotherapy or in combination with anthracyclines or trastuzumab, in cases with immunohistochemically confirmed HER-2 protein overexpression (3+) or when anthracycline therapy is contraindicated;
monotherapy for metastatic breast cancer after failure of standard therapy.

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:

when prior therapy with liposomal anthracyclines has been ineffective.

Contraindications.

Hypersensitivity to paclitaxel or to any of the components of the drug (particularly to polyoxyethylated castor oil).
Neutropenia (baseline neutrophil count < 1,500/mm³; in AIDS patients with Kaposi's sarcoma, neutrophil count < 1,000/mm³), thrombocytopenia (< 100,000/mm³).
Concurrent severe uncontrolled infections in patients with Kaposi's sarcoma.
Severe hepatic dysfunction.
Pregnancy and breastfeeding (see section "Use during pregnancy or breastfeeding").
Viral infections.
Cardiovascular diseases.

Special safety precautions.

Instructions for medical personnel.

Extreme caution must be exercised when handling this medicinal product, as with all other cytotoxic agents. Pregnant women should not handle cytotoxic drugs. Preparation of infusion solutions should be performed by appropriately trained personnel in a specially designated area, under strict aseptic conditions. Protective clothing (gowns, caps, masks, goggles, and disposable gloves) must be worn, and contact between the drug and skin or mucous membranes must be avoided. If contact occurs with skin or mucous membranes, the area should be immediately washed with soap and water. Localized stinging, burning, or erythema may occur after local contact. Inhalation of paclitaxel solutions may cause dyspnea, chest pain, throat irritation, and nausea.

Precipitation may occur when sealed vials are cooled; this precipitate dissolves upon gentle agitation or when the solution reaches room temperature. This does not affect the quality of the medicinal product. If the solution remains cloudy or insoluble precipitate is observed, 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 Amaksa must be diluted under aseptic conditions. Paclitaxel is diluted with 0.9% sodium chloride isotonic solution, 5% glucose solution, or 5% glucose solution with 0.9% sodium chloride (1:1), or in Ringer's solution plus 5% glucose solution to a concentration between 0.3 and 1.2 mg/mL.

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

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 Amaksa should be administered through infusion sets equipped with in-line membrane filters with pore size no larger than 0.22 µm. No significant loss of active ingredient has been observed when administered through such systems.

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 Amaksa should be administered as soon as possible after dilution, and excessive agitation should be avoided. The infusion set should be thoroughly flushed before use. The solution should be visually inspected regularly during infusion, and infusion should be discontinued if precipitation occurs.

To minimize patient exposure to DEHP (di(2-ethylhexyl)phthalate), which may leach from polyvinyl chloride (PVC) bags, tubing, or other medical devices, diluted paclitaxel solutions should be stored only in vials (glass, polypropylene) or plastic containers (polypropylene, polyolefin) that do not contain polyvinyl chloride, and administered through polyethylene-based infusion systems. Use of filters (e.g., IVEX-2®) with short PVC inlet or outlet ports does not cause significant DEHP leaching.

Disposal

Unused drug and all materials used in the preparation and administration of infusion solutions, or otherwise in 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.

No formal studies have been conducted on drug interactions involving paclitaxel. Prior treatment with cimetidine does not affect paclitaxel clearance.

Paclitaxel should be administered before cisplatin when used as first-line therapy for ovarian carcinoma. In this sequence, the safety profile of paclitaxel is consistent with that observed during monotherapy. If paclitaxel is administered after cisplatin, patients experience more severe myelosuppression and a reduction in paclitaxel clearance by approximately 20%. In patients receiving both paclitaxel and cisplatin, the risk of nephrotoxicity increases, as observed with cisplatin monotherapy in oncogynecology.

Elimination of doxorubicin and its active metabolites may be reduced if paclitaxel and doxorubicin are administered in close succession. Therefore, for initial treatment of metastatic breast carcinoma, paclitaxel should be administered 24 hours after doxorubicin (see section "Pharmacokinetics").

Paclitaxel metabolism is catalyzed primarily by the CYP2C8 and CYP3A4 isoenzymes of the cytochrome P450 system. Clinical studies have demonstrated that the major metabolic pathway in humans is CYP2C8-mediated conversion of paclitaxel to 6α-hydroxypaclitaxel. Concomitant administration of ketoconazole, a potent CYP3A4 inhibitor, does not delay paclitaxel elimination; therefore, both drugs can be used together without dose adjustment. Information on potential interactions between paclitaxel and CYP3A4 inducers or inhibitors is limited; therefore, caution is required when co-administering inhibitors (e.g., erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir, ketoconazole, and other imidazole-derived antifungals) or inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine) of CYP2C8 and CYP3A4 isoenzymes.

Studies on paclitaxel use in Kaposi's sarcoma patients receiving concomitant multi-drug therapy indicate that systemic clearance of paclitaxel was significantly lower in the presence of nelfinavir and ritonavir, but not indinavir. There is insufficient information regarding interactions with other protease inhibitors. Therefore, paclitaxel should be administered with caution to patients receiving protease inhibitors as concomitant therapy.

The presence of alcohol in this medicinal product may alter the effects of other drugs.

Special precautions for use.

Paclitaxel should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapeutic agents; appropriate resuscitation equipment must be available due to the potential for serious hypersensitivity reactions.

Since extravasation may occur, the infusion site should be closely monitored during administration for signs of possible infiltration. Premedication with corticosteroids, antihistamines, and H2-receptor antagonists should be administered to patients prior to paclitaxel administration (see section "Administration and dosage"). If paclitaxel is used in combination with cisplatin, paclitaxel should be administered before cisplatin (see section "Interaction with other medicinal products and other forms of interaction").

Severe hypersensitivity reactions.

Despite appropriate premedication, severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, as well as angioedema and generalized urticaria, occur in less than 1% of patients. These reactions are likely histamine-mediated. In the event of severe hypersensitivity reactions, paclitaxel infusion must be immediately discontinued and symptomatic treatment initiated. Paclitaxel must not be re-administered to such patients. Minor 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.

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of the drug. Complete blood counts should be frequently monitored, at least twice weekly during treatment. The drug should not be re-administered until neutrophil counts have recovered to ≥1500/mm³ (≥1000/mm³ for patients with Kaposi's sarcoma) and platelet counts to ≥100,000/mm³ (≥75,000/mm³ for patients with Kaposi's sarcoma). In a clinical study, most patients with Kaposi's sarcoma received granulocyte colony-stimulating factor (G-CSF).

Severe cardiac conduction disorders.

Severe cardiac conduction disorders have been observed rarely during paclitaxel monotherapy. In cases of significant conduction abnormalities, appropriate treatment should be initiated, and continuous cardiac monitoring should be performed during subsequent paclitaxel infusions. For all other patients, vital signs should be frequently monitored, especially during the first hour of paclitaxel infusion. Arterial hypotension/hypertension and bradycardia may occur during infusion, which are usually asymptomatic and do not require therapeutic intervention. Severe cardiovascular events are more frequently observed in patients with non-small cell lung cancer than in those with breast or ovarian cancer. One case of heart failure following paclitaxel therapy was reported in a patient with Kaposi's sarcoma and AIDS.

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

Peripheral neuropathy.

Peripheral neuropathy may develop after the first treatment cycle and worsen with continued paclitaxel therapy. 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. Although peripheral neuropathy is a common adverse effect of paclitaxel therapy, severe forms are rare. In severe cases, subsequent paclitaxel doses should be reduced by 20% (by 25% in patients with Kaposi's sarcoma).

In patients with non-small cell lung cancer, the use of paclitaxel in combination with cisplatin has led to increased frequency of severe neurotoxicity compared to paclitaxel monotherapy. In first-line ovarian cancer patients, the use of paclitaxel as a 3-hour infusion in combination with cisplatin resulted in increased frequency of severe neurotoxicity compared to the combination of cyclophosphamide and cisplatin.

Severe hepatic dysfunction.

Paclitaxel 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, 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 impairment. Paclitaxel should not be administered to patients with severe hepatic dysfunction. Close monitoring for signs of severe myelosuppression is required. Currently, there are insufficient data to provide dosing recommendations for patients with mild to moderate hepatic impairment. Information on paclitaxel use in patients with severe cholestasis is lacking.

Ethanol.

Since paclitaxel contains ethanol (50.17% v/v), its potential effects on the central nervous system and other effects should be considered. The use of this medicinal product may be harmful to 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.

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 administration.

Pseudomembranous colitis.

Pseudomembranous colitis has been rarely reported during paclitaxel therapy, including cases where patients were not concurrently receiving antibiotics.

The possibility of pseudomembranous colitis, particularly in patients not receiving concomitant antibiotic therapy, should be considered in the differential diagnosis if severe or persistent diarrhea develops during or shortly after paclitaxel treatment.

Severe mucositis.

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

Interstitial pneumonitis.

Interstitial pneumonitis has been observed in patients receiving concurrent radiotherapy and paclitaxel treatment (regardless of treatment 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 medicinal products should be followed.

Teratogenicity, embryotoxicity, and mutagenicity.

Paclitaxel has demonstrated teratogenic, embryotoxic, and mutagenic effects in several experimental systems; therefore, patients of reproductive age 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.

Hormonal contraception is contraindicated in cases of HR+ tumors.

Use during pregnancy or breastfeeding.

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 therapy due to the risk of infertility.

Pregnancy

Paclitaxel has demonstrated embryotoxic and fetotoxic effects in rabbit studies and reduced fertility in rats. There are insufficient data on the use of paclitaxel in pregnant women. Like other cytotoxic medicinal products, paclitaxel poses a potential risk to the fetus. Therefore, paclitaxel is contraindicated during pregnancy. Women of reproductive age should not plan pregnancy during paclitaxel therapy, and should immediately inform their physician if pregnancy occurs. Women and men of reproductive age and/or their partners must 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 period

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

Ability to influence reaction speed when driving or operating machinery.

Patients should refrain from driving or operating machinery during paclitaxel therapy. It should be noted that the product contains ethanol, and certain adverse reactions may negatively affect the ability to drive or operate machinery (see sections "Excipients" and "Special precautions for use").

Administration and Dosage.

The concentrate for preparing infusion solution must be diluted prior to administration and given intravenously. Prior to initiating paclitaxel therapy, all patients should receive premedication with corticosteroids, antihistamines, and H2-receptor antagonists, for example, according to the regimen outlined in the table.

Medicinal product	Dose	Time of administration prior to paclitaxel
Dexamethasone	20 mg orally or intravenously (8–20 mg for patients with Kaposi's sarcoma)	For oral administration: approximately 6 and 12 hours prior. For intravenous administration: 30–60 minutes prior.
Diphenhydramine (or equivalent antihistamine)	50 mg intravenously	30–60 minutes prior.
Cimetidine or ranitidine	300 mg intravenously 50 mg intravenously	30–60 minutes prior.

Due to the possibility of severe hypersensitivity reactions, appropriate symptomatic therapy medications should be available.

Paklitaksel Amaksa should be administered through an in-line filter with a microporous membrane ≤ 0.22 μm (see section "Special precautions").

Ovarian cancer.

As first-line therapy. A combination treatment regimen is recommended.

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

paclitaxel 175 mg/m² administered as a 3-hour intravenous infusion, followed by cisplatin 75 mg/m². Treatment cycles should be repeated every 3 weeks;
paclitaxel 135 mg/m² administered as a 24-hour intravenous infusion, followed by cisplatin 75 mg/m². Treatment cycles should be repeated every 3 weeks (see section "Pharmacodynamics").

As second-line therapy. The recommended dose of paclitaxel 175 mg/m² should be administered as a 3-hour intravenous infusion. A total of 4 treatment cycles are recommended, with a 3-week interval between cycles.

Breast cancer.

Adjuvant chemotherapy for breast cancer.

The recommended dose of paclitaxel 175 mg/m² should be administered as a 3-hour intravenous infusion. Four treatment cycles should be administered at 3-week intervals. This regimen should be administered after combination therapy with anthracyclines/cyclophosphamide.

As first-line therapy. When used in combination with doxorubicin (50 mg/m²), paclitaxel should be administered 24 hours after doxorubicin. The recommended dose of paclitaxel 220 mg/m² should be administered as a 3-hour intravenous infusion. The interval between treatment cycles is 3 weeks (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

When used in combination with trastuzumab, the recommended dose of paclitaxel 175 mg/m² should be administered as a 3-hour intravenous infusion. The interval between treatment cycles is 3 weeks. Paclitaxel infusion may be initiated one day after the first dose of trastuzumab or immediately after subsequent doses of trastuzumab, provided the previous dose of trastuzumab was well tolerated (for detailed dosing information on trastuzumab, see the trastuzumab product leaflet).

As second-line therapy. The recommended dose of paclitaxel 175 mg/m² should be administered as a 3-hour intravenous infusion. The interval between treatment cycles is 3 weeks.

Treatment of non-small cell lung cancer.

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

Treatment of Kaposi's sarcoma in AIDS patients.

The recommended dose of paclitaxel 100 mg/m² should be administered as a 3-hour intravenous infusion every 2 weeks.

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

Repeated administration is permitted only after neutrophil counts have increased to ≥ 1500/mm³ and platelet counts to ≥ 100,000/mm³. For patients who experienced severe neutropenia (neutrophil count < 500/mm³ 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 counts have increased to ≥ 1500/mm³ and platelet counts to ≥ 100,000/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). Patients who develop mucositis (grade II severity or higher) during paclitaxel treatment should have subsequent paclitaxel doses reduced by 25%.

Treatment of patients with hepatic impairment.

Insufficient data are available regarding dose adjustment for patients with mild or moderate hepatic impairment (see sections "Pharmacokinetics" and "Special warnings and precautions for use"). Paclitaxel should not be administered to patients with severe hepatic impairment.

Treatment of patients with renal impairment.

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

Geriatric patients

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

Method of administration

Paclitaxel must be administered only in specialized facilities for cytotoxic drugs under the supervision of a qualified oncologist.

Children.

The safety and efficacy of paclitaxel in children under 18 years of age have not been established. It is not recommended for use in this patient population.

Overdose.

Symptoms: bone marrow suppression, peripheral neuropathy, mucositis.

Treatment: in case of overdose, administration of the drug should be immediately discontinued and symptomatic treatment initiated, with monitoring of blood cell counts and vital organ function. The antidote for paclitaxel is unknown.

Adverse Reactions

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

The frequency and intensity of adverse effects 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) occurred in 28% of patients, but no cases of fever were recorded. Severe neutropenia lasting ≥ 7 days was observed in only 1% of patients. Thrombocytopenia with platelet counts < 50,000/mm³ occurred in a small number of patients at least once during the study, and anemia (frequency and severity of anemia depend on the initial hemoglobin level).

Disseminated intravascular coagulation (DIC syndrome) has been reported, often in association with sepsis or multiorgan failure.

Neurotoxicity, primarily peripheral neuropathy, is likely to occur more frequently and severely 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%) in combination 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 diminish or resolve within several months after stopping paclitaxel. Pre-existing neuropathy due to prior therapy is not a contraindication for paclitaxel treatment. Furthermore, peripheral neuropathy may persist for up to 6 months after discontinuation of paclitaxel.

Severe hypersensitivity reactions, which may be fatal (hypotension requiring therapeutic intervention; angioedema; respiratory distress 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 courses). 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, with severe symptoms in 13%.

Local swelling, pain, erythema, and induration may occur at the injection site. Accidental extravasation may cause cellulitis. Isolated reports of skin desquamation and/or necrosis associated with extravasation have been reported. Skin discoloration may also occur. Isolated reports of skin reactions, so-called local inflammatory reactions at the site of previous extravasation, have been reported after paclitaxel administration 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 occurred in 87% of patients receiving paclitaxel. Most cases of hair loss occurred within the first month of starting paclitaxel therapy. Most patients experiencing alopecia can expect significant hair loss ≥ 50%.

The list below includes adverse reactions observed during monotherapy with paclitaxel administered via 3-hour infusion in the treatment of metastatic cancer (812 patients treated in clinical trials), and adverse reactions obtained from post-marketing experience. The latter may be attributed to paclitaxel regardless of the treatment regimen.

Adverse reaction frequencies are 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, anemia, thrombocytopenia, leukopenia, tendency to bleeding.

Common: febrile neutropenia*.

Uncommon: severe anemia.

Rare: febrile neutropenia*.

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

Frequency not known: disseminated intravascular coagulation (DIC syndrome), often in association with sepsis or multiorgan failure*.

Immune system disorders

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

Uncommon: delayed-type hypersensitivity reactions, severe hypersensitivity reactions requiring therapeutic measures (including arterial hypotension, angioedema, respiratory distress, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, limb pain, profuse sweating, 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: tumor lysis syndrome*.

Psychiatric disorders

Very rare: confusion*.

Nervous system disorders

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

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

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 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 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: 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 pneumonitis*, dyspnea*, pleural effusion*.

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*, neutropenic colitis*, ascites*, esophagitis*, constipation*, dehydration*.

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

Very common: alopecia.

Common: transient and minor 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

Very common: pain, swelling, including peripheral and facial edema.

Common: injection site reactions (including localized swelling, pain, erythema, induration, weakness, discoloration, and skin swelling; accidental extravasation may cause cellulitis, skin fibrosis, and skin necrosis).

Rare: chest pain, chills, pyrexia*, dehydration*, asthenia*, edema*, malaise*. Isolated reports of recurrence of skin reactions at sites of previous paclitaxel extravasation after subsequent administrations have been reported.

Laboratory findings

Common: significant (≥ 5 times the upper normal limit) elevation of liver enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase).

Uncommon: significant elevation of bilirubin levels.

Rare: elevated serum creatinine*.

* 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, anemia, infection, fever, nausea/vomiting, and diarrhea occurred more frequently compared to patients receiving 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 hematological toxicity was neutropenia. During the first treatment cycle, severe neutropenia (< 500/mm³) occurred in 20% of patients. Over 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. All patients under observation had hematological parameters return 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 courses. Three episodes of sepsis (2.8%) occurred during paclitaxel therapy, leading to 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 episodes related to paclitaxel were reported in < 3% of patients, but these were localized.

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

Combination therapy

When paclitaxel is used in combination 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 in 85% of patients, severe in 15%) compared to a 24-hour infusion of 135 mg/m² paclitaxel (neurotoxic effects 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 diminish 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.

The data below refer to:

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

In patients with ovarian cancer who received first-line chemotherapy with paclitaxel via 3-hour intravenous infusions in combination with cisplatin, the frequency and severity of neurotoxic effects, arthralgia/myalgia, and hypersensitivity reactions were higher than with cyclophosphamide 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 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 therapy. 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 following adverse effects (regardless of their 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%), diarrhea (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 attributed to the greater number and duration of treatment cycles with the paclitaxel/trastuzumab combination compared to paclitaxel monotherapy. The frequency of serious adverse effects was similar between combination chemotherapy with paclitaxel and trastuzumab and 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 both paclitaxel therapy and paclitaxel with doxorubicin, as well as with standard FAC therapy. With combination chemotherapy using trastuzumab and paclitaxel, the frequency and severity of cardiac dysfunction were higher in patients previously treated with anthracyclines compared to 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 using 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 hematological and hepatic adverse effects, the frequency and severity of adverse effects in patients with Kaposi's sarcoma were comparable to those in patients with other solid tumors receiving paclitaxel monotherapy.

Bone marrow suppression was the main dose-limiting toxic effect. The most significant manifestation of hematological toxicity was neutropenia. During the first treatment course, severe neutropenia (< 500 cells/mm³) occurred in 20% of patients. Over the entire treatment period, severe neutropenia was observed in 39% of patients. Neutropenia lasted > 7 days in 41% of patients and 30–35 days in 8% of patients. Neutropenia resolved within 35 days in all monitored patients. 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 courses. Three cases of drug-related sepsis (2.8%) with fatal outcomes occurred during paclitaxel therapy. Thrombocytopenia occurred in 50% of patients, with 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 observed in less than 3% of patients, but were localized.

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

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

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

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

Reporting suspected adverse reactions

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

Shelf life. 3 years.

After opening the vial: from microbiological, chemical, and physical perspectives, this product may be stored for 28 days at a temperature not exceeding 25 °C. The user is responsible for the duration and conditions of storage after opening the vial.

After dilution: the diluted infusion solution has been shown to be chemically and physically stable for 72 hours at a temperature not exceeding 25 °C.

Diluted solutions should not be stored in a refrigerator.

From a microbiological standpoint, the diluted solution should be used immediately.

Storage conditions.

Keep out of reach of children. Store in the original packaging protected from light at a temperature not exceeding 25 °C.

Incompatibilities.

Polyoxyethylated castor oil, a component of the drug, may leach DEHP from plasticized polyvinyl chloride (PVC). The extent of this process depends on the duration of exposure and the concentration of castor oil. Therefore, equipment containing PVC should not be used for dilution, storage, or administration of the drug.

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

Packaging.

5 ml, 16.7 ml, or 50 ml in a vial; 1 vial per cardboard box.

Prescription category.

By prescription.

Manufacturer.

AqVida GmbH.

Manufacturer's address and place of business.

Kaiser-Wilhelm-Str. 89, 20355 Hamburg, Germany.

Marketing authorization holder.

Amaxa Ltd.

Address of the marketing authorization holder.

31 John Islip Street, London SW1P 4FE, United Kingdom.