Paklitero

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PAKLITERO® (PACLITERO)

Composition:

Active substance: paclitaxel;

1 ml of solution contains paclitaxel 6 mg;

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

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, free from visible particles, colorless to slightly yellowish, viscous solution.

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

Pharmacological properties.

Pharmacodynamics.

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

Pharmacokinetics.

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

The pharmacokinetics of paclitaxel were studied following administration of the drug at doses of 135 mg/m² and 175 mg/m² over 3 and 24 hours. The mean terminal half-life ranged from 3 to 52.7 hours, and the mean total body clearance was 11.6–24 L/h/m². A trend toward decreased total body clearance of paclitaxel was observed with increasing plasma concentrations. The mean volume of distribution at steady state was 198–688 L/m², indicating extensive extravascular distribution and/or tissue binding. With 3-hour infusions, the pharmacokinetics of paclitaxel were nonlinear. When the dose was increased by 30% (from 135 to 175 mg/m²), the maximum concentration (Cmax) and the area under the concentration–time curve (AUC₀–∞) increased by 75% and 81%, respectively.

Variability in systemic exposure to paclitaxel across different treatment cycles was minimal. No accumulation of paclitaxel was observed with repeated treatment courses.

89–98% of paclitaxel is protein-bound in plasma. Administration of cimetidine, ranitidine, dexamethasone, or diphenhydramine does not affect the plasma protein binding of paclitaxel.

The metabolism of paclitaxel in humans has not yet been fully elucidated. Between 1.3% and 12% of the administered dose is excreted unchanged in urine, indicating extensive extrarenal clearance. Paclitaxel is metabolized primarily in the liver and is excreted mainly in feces—up to 70%. Metabolism of paclitaxel involves the cytochrome P450 enzyme system. To date, 11 metabolites of paclitaxel have been identified. Among them, 6α-hydroxypaclitaxel (26% of administered dose), 3'-p-dihydroxypaclitaxel (2%), and 6α-3'-p-dihydroxypaclitaxel (6%) have been characterized. The formation of these hydroxylated metabolites is catalyzed by the CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4 isoenzymes, respectively. The metabolites exhibit lower cytotoxic and myelotoxic activity compared to the parent drug. The impact of renal or hepatic impairment on paclitaxel metabolism during 3-hour infusions has not been formally studied. Pharmacokinetic parameters in one patient undergoing hemodialysis who received paclitaxel at a dose of 135 mg/m² via 3-hour infusions did not differ from those in patients with normal renal function.

When paclitaxel and doxorubicin are used concomitantly, an increased distribution and elimination time for 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.

Clinical characteristics.

Indications.

Ovarian cancer:

• as a first-line agent for the treatment of ovarian cancer, as well as in combination with cisplatin for progressive ovarian cancer or for residual tumors larger than 1 cm after laparotomy;
• as a second-line agent for the treatment of metastatic ovarian cancer if 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 alone or in combination with an anthracycline or trastuzumab, depending on the individual patient's suitability;
• 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 in AIDS patients:

• when prior therapy with liposomal anthracyclines has been ineffective.

Contraindications.

− Hypersensitivity to paclitaxel or to any of the components of the preparation (particularly to polyethoxylated castor oil).

• Neutropenia (baseline neutrophil count <1.5×10⁹/L; in AIDS patients with Kaposi's sarcoma, neutrophil count <1×10⁹/L), thrombocytopenia (<100×10⁹/L).
• Concurrent severe uncontrolled infections in patients with Kaposi's sarcoma.
• Severe hepatic dysfunction.
• Pregnancy or breastfeeding (see section "Use during pregnancy or breastfeeding").

Special safety precautions.

Instructions for medical personnel.

When handling paclitaxel, 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 the paclitaxel solution with skin and 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. Stinging, burning, and redness of the skin may occur at the site of contact. If the solution contacts mucous membranes, they should be rinsed thoroughly with water. Inhalation of paclitaxel solutions may cause dyspnea, chest pain, throat irritation, and nausea.

Pregnant women should not handle cytotoxic agents.

Disposal.

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

Preparation of intravenous infusion solutions.

It should be noted that a precipitate may form in unopened vials when cooled, which dissolves upon gentle shaking or even without agitation upon reaching room temperature. 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.

Prior to administration, paclitaxel must be diluted under aseptic conditions with 0.9% sodium chloride solution, 5% glucose solution, or Ringer's solution with 5% glucose to a final concentration of 0.3–1.2 mg/mL.

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

To minimize leaching of diethylhexylphthalate (DEHP) from infusion bags, tubing, 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 bottles, polypropylene or polyolefin bags) and administered through polyethylene infusion sets. Filters may be connected using short PVC tubing, as this does not cause significant DEHP leaching.

Recommendations for storage of the diluted product.

The ready-to-use solution should be administered immediately after preparation. The solution is stable for 24 hours when stored at temperatures not exceeding 25°C. It should not be refrigerated, as precipitation may occur.

If the solution is not administered immediately, responsibility for the duration and conditions of storage of the ready-to-use solution lies with the user (medical personnel).

Interaction with other medicinal products and other forms of interaction.

Premedication with cimetidine does not affect paclitaxel clearance.

In combined treatment of ovarian cancer with paclitaxel and cisplatin, paclitaxel should be administered before cisplatin. In this sequence, the safety profile is similar to that of paclitaxel monotherapy. If paclitaxel is administered after cisplatin, more severe myelosuppression occurs, and paclitaxel clearance decreases by approximately 20%. The risk of renal impairment in patients with ovarian cancer 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 first-line chemotherapy of metastatic breast cancer, paclitaxel should be administered 24 hours after doxorubicin.

Paclitaxel metabolism is partially catalyzed by CYP2C8 and CYP3A4 isoenzymes of the cytochrome P450 system. Clinical studies have demonstrated that the main metabolic pathway in humans is CYP2C8-mediated conversion of paclitaxel to 6α-hydroxypaclitaxel. Concomitant administration of ketoconazole, a potent CYP3A4 inhibitor, does not slow paclitaxel elimination in humans; therefore, both drugs can be used simultaneously without dose adjustment. Information on potential interactions between paclitaxel and CYP3A4 inducers or inhibitors is limited; therefore, caution is required when co-administering inhibitors (e.g., 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.

Pharmacokinetic studies of paclitaxel in patients with Kaposi's sarcoma receiving concomitant therapy with multiple drugs indicate a significant reduction in systemic paclitaxel clearance when nelfinavir and ritonavir are used concurrently, but not with indinavir. Data on interactions between paclitaxel and other protease inhibitors are insufficient. Therefore, paclitaxel should be administered with caution in patients receiving concomitant protease inhibitor therapy.

Special precautions for use.

Paclitaxel therapy should be administered under the supervision of a qualified physician experienced in the use of antineoplastic chemotherapeutic agents. Since hypersensitivity reactions may occur, appropriate resuscitation equipment must be available. Because extravasation is possible, careful monitoring of the infusion site for signs of possible infiltration is recommended during drug administration. Patients must receive premedication with corticosteroids, antihistamines, and H2-receptor antagonists prior to paclitaxel administration. When used in combination with cisplatin, paclitaxel should be administered before cisplatin.

Severe hypersensitivity reactions.

Despite appropriate premedication, severe hypersensitivity reactions characterized by dyspnea and hypotension requiring therapeutic intervention, as well as angioneurotic edema and generalized urticaria, occur in less than 1% of patients. These reactions are likely histamine-mediated. In case of severe hypersensitivity reactions, paclitaxel infusion must be immediately discontinued and symptomatic treatment initiated. Paclitaxel must not be re-administered to such patients. Macrogolglycerol ricinoleate (polyoxyl 35 castor oil), an excipient of this medicinal product, may cause these reactions.

Bone marrow suppression.

Bone marrow suppression (mainly neutropenia) is the principal dose-limiting toxicity. Complete blood counts should be frequently monitored at least twice weekly during paclitaxel therapy. Re-administration of the drug is permitted only after neutrophil counts have recovered to levels >1.5×10⁹/L (>1.0×10⁹/L in Kaposi's sarcoma patients) and platelet counts to >100×10⁹/L (>75×10⁹/L in Kaposi's sarcoma patients). In clinical trials, most patients with Kaposi's sarcoma received granulocyte colony-stimulating factor (G-CSF).

Severe cardiac conduction disorders.

Severe cardiac conduction disorders during paclitaxel monotherapy are rare. In cases of significant conduction abnormalities, appropriate treatment should be initiated, and continuous cardiac monitoring is required during subsequent paclitaxel infusions. For all other patients, vital signs should be closely monitored, especially during the first hour of paclitaxel infusion. Arterial hypotension/hypertension and bradycardia may occur during infusion; these 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 has been 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 cardiologic evaluation before treatment initiation, including ECG, echocardiography, and MUGA scanning. Cardiac function should be regularly monitored during therapy (e.g., every 3 months). This monitoring allows early detection of cardiac dysfunction. When determining the frequency of ventricular function assessment, the cumulative dose of anthracyclines (in mg/m² body surface area) should be considered. If test results indicate cardiac dysfunction—even if asymptomatic—the potential benefit of continuing therapy versus the risk of cardiac damage, sometimes irreversible, must be carefully weighed. 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 may 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 therapy. Although peripheral neuropathy is a common adverse effect of paclitaxel, 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 been associated with increased frequency of severe neurotoxicity compared to paclitaxel monotherapy. In ovarian cancer patients, the use of paclitaxel as a 3-hour infusion in combination with cisplatin has led to increased frequency of severe neurotoxicity compared to the combination of cyclophosphamide and cisplatin.

Severe hepatic impairment.

Paclitero should not be administered to patients with severe hepatic impairment, as this may increase the risk of toxic effects, including grade III–IV myelosuppression.

With 3-hour infusions of paclitaxel, no increased toxicity has been observed in patients with mild hepatic impairment. However, with longer infusions, more pronounced myelosuppression may occur in patients with moderate or severe hepatic impairment. Paclitaxel should not be administered to patients with severe hepatic dysfunction. Patients should be closely monitored for signs of severe myelosuppression. Currently, there are insufficient data to recommend dose adjustments for patients with mild or moderate hepatic impairment. Information on paclitaxel use in patients with severe cholestasis is lacking.

Ethanol.

Since paclitaxel contains ethanol, its potential effects on the central nervous system and other systems should be considered. The use of this drug may be harmful to patients with alcoholism. This information should be taken into account when administering the drug to children and adult 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.

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

Intra-arterial administration.

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

Pseudomembranous colitis.

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

Cases 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 rare in patients with Kaposi's sarcoma. In case of severe reactions, paclitaxel doses should be reduced by 25%.

Interstitial pneumonitis.

Interstitial pneumonitis has been reported in patients receiving concurrent radiotherapy and paclitaxel therapy (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 been shown to have teratogenic, embryotoxic, and mutagenic effects in several experimental systems (see section "Use during pregnancy or breastfeeding").

Unopened vials stored in the refrigerator may develop a precipitate, which redissolves upon warming to room temperature with gentle agitation (or without agitation). Product quality is not impaired. If the solution in the vial remains cloudy or contains insoluble precipitate, the vial should be destroyed according to established hazardous waste disposal procedures.

The prepared solution is stable for 24 hours when stored at 2–8°C. It should not be frozen, as precipitation may occur.

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

Use during pregnancy or breastfeeding.

Pregnancy.

There is no information on paclitaxel use in pregnant women. Like other cytotoxic agents, paclitaxel may be harmful to the fetus and therefore should not be administered during pregnancy. Women and men should use effective contraception during paclitaxel therapy and for at least 6 months after completion of treatment. Patients should inform their physician immediately if pregnancy occurs.

Breastfeeding.

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 therapy.

Fertility.

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

Ability to influence reaction rate while 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 impair the ability to drive or operate machinery.

Administration and Dosage.

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

Ovarian cancer.

As first-line therapy. Combination therapy is recommended.

According to 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. The interval between treatment cycles is 3 weeks;
• paclitaxel 135 mg/m² administered as a 24-hour intravenous infusion, followed by cisplatin 75 mg/m². The interval between treatment cycles is 3 weeks.

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 cycles 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. Administer 4 treatment cycles with a 3-week interval between cycles. This should be performed after anthracycline- or cyclophosphamide-based therapy.

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 cycles is 3 weeks.

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 cycles is 3 weeks. Paclitaxel infusion may be initiated 24 hours after the first dose of trastuzumab or immediately after subsequent doses of trastuzumab, provided the previous dose of trastuzumab was well tolerated.

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

Treatment of non-small cell lung cancer (NSCLC).

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 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.

Repeat administration is allowed only after neutrophil counts have increased to ≥ 1500/mm³ and platelet counts to ≥ 100000/mm³. In patients who experienced severe neutropenia (neutrophil count below 500/mm³ for 7 days or longer) or severe peripheral neuropathy, subsequent doses should be reduced by 20% (in patients with Kaposi's sarcoma – by 25%).

Dose adjustment during treatment course.

Metastatic breast cancer (MBC), ovarian cancer, or advanced NSCLC.

The next dose of paclitaxel may be administered only after neutrophil counts have increased to ≥ 1500/mm³ and platelet counts to ≥ 100000/mm³.

In 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% (in patients with NSCLC and first-line ovarian cancer chemotherapy) or by 25% (in patients with MBC and ovarian cancer). In patients who experienced mucositis (grade II or higher), subsequent doses should be reduced by 25%.

Treatment of patients with hepatic impairment.

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

Treatment of patients with renal impairment.

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

Children.

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

Overdose.

Symptoms: bone marrow suppression, peripheral neuropathy, mucositis.

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

Adverse Reactions

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

The frequency and severity of adverse effects in patients with ovarian cancer, breast cancer, and NSCLC do not differ significantly. Patient age did not substantially influence any of the observed drug toxicities.

Adverse Reactions with Paclitaxel Monotherapy

The most common adverse effect of paclitaxel treatment is bone marrow suppression: severe neutropenia (<0.5×10⁹/L), not associated with febrile episodes; thrombocytopenia: in a small number of patients, platelet counts were <50×10⁹/L at least once during the study; anemia (frequency and severity of anemia episodes depend on baseline hemoglobin levels).

Neurotoxicity, predominantly peripheral neuropathy, is likely to occur more frequently and in a more severe form with the 3-hour infusion of paclitaxel at a dose of 175 mg/m² (neurotoxicity in 85% of cases, severe in 15%) compared to the 24-hour infusion of paclitaxel at a dose of 135 mg/m² (peripheral neuropathy in 25% of cases, severe in 3%) in combination with cisplatin. A clear increase in the frequency of severe neurotoxicity has been observed in patients with NSCLC and ovarian carcinoma treated with a 3-hour paclitaxel infusion followed by cisplatin. Peripheral neuropathy may develop after the first treatment cycle and worsen with subsequent paclitaxel administrations. Occasionally, it may necessitate discontinuation of paclitaxel therapy. Sensory symptoms usually improve or resolve within several months after stopping paclitaxel treatment. Pre-existing neuropathy due to prior therapy is not a contraindication to paclitaxel treatment. Additionally, peripheral neuropathy may persist for up to 6 months after discontinuation of paclitaxel.

Arthralgia or myalgia occurred in 60% of patients, with 13% experiencing severe symptoms.

Severe, potentially life-threatening hypersensitivity reactions (such as hypotension requiring treatment, angioedema, respiratory distress requiring bronchodilators, generalized urticaria) were observed in 2 patients (<1% of patients). 34% of patients (17% of all therapy cycles) experienced mild hypersensitivity reactions, primarily flushing and rash, which did not require therapeutic intervention or discontinuation of paclitaxel therapy.

Local reactions: Local swelling, pain, erythema, and induration may occur at the injection site. Accidental extravasation may lead to cellulitis. Skin desquamation and/or necrosis have been reported, sometimes associated with extravasation. Skin pigmentation changes are possible. There have been isolated reports of recurrence of skin reactions at sites of previous paclitaxel extravasation after subsequent drug administrations. In some cases, injection site reactions occurred during prolonged intravenous infusion or developed with a delay of 7–10 days after injection.

There have been isolated reports of cases of disseminated intravascular coagulation (DIC) syndrome, often in combination with sepsis or multi-organ dysfunction.

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

The adverse reactions listed below were observed during monotherapy with paclitaxel administered via 3-hour infusion in the treatment of metastatic cancers (812 patients treated in clinical trials), as well as identified during post-marketing surveillance*. The latter may be attributed to paclitaxel regardless of the treatment regimen.

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

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

Blood and lymphatic system disorders: very common – myelosuppression, neutropenia, anemia, thrombocytopenia, leukopenia, bleeding tendency; rare* – febrile neutropenia; very rare* – acute myeloid leukemia, myelodysplastic syndrome; frequency not known – disseminated intravascular coagulation (DIC) syndrome.

Immune system disorders: very common – mild hypersensitivity reactions (mainly 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, arterial hypertension); rare* – anaphylactic reactions; very rare* – anaphylactic shock; frequency not known – bronchospasm.

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

Psychiatric disorders: very rare* – confusion.

Nervous system disorders: very common – neuropathy (predominantly peripheral neuropathy**), paraesthesia, somnolence; common – depression, severe neuropathy (predominantly peripheral neuropathy), nervousness, insomnia, cognitive disturbances, hypokinesia, gait disturbances, hypoesthesia, taste disturbances; rare* – motor neuropathy (manifested as moderate distal muscle weakness); very rare* – autonomic neuropathy (leading to paralytic ileus and orthostatic hypotension), grand mal seizures, convulsions, encephalopathy, dizziness, headache, ataxia.

Eye disorders: uncommon – dry eyes, blurred vision, visual field defects; very rare* – optic nerve damage and/or visual disturbances (scintillating scotoma), particularly in patients receiving doses higher than recommended; 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, AV block and syncope, cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy, arrhythmia, extrasystoles; rare – heart failure; very rare* – atrial fibrillation, supraventricular tachycardia.

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

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

Gastrointestinal disorders: very common – nausea, vomiting, diarrhea, mucositis, stomatitis, abdominal pain; common – dry mouth, oral ulcers, melena, dyspepsia; rare* – intestinal obstruction, intestinal perforation, ischemic colitis, acute pancreatitis; very rare* – mesenteric thrombosis, pseudomembranous colitis, esophagitis, constipation, ascites, neutropenic colitis, dehydration.

Hepatobiliary disorders: very rare* – liver necrosis, hepatic encephalopathy (fatal cases reported).

Skin and subcutaneous tissue disorders: very common – alopecia; common – transient mild nail and skin changes, acne; uncommon – nail discoloration; rare* – pruritus, rash, erythema, swelling; very rare* – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients receiving paclitaxel should wear appropriate clothing to protect against sun exposure), 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.

General disorders and administration site conditions: common – injection site reactions (localized swelling, pain, erythema, induration, weakness, skin discoloration and swelling, accidental extravasation may cause cellulitis, fibrosis, and skin necrosis); rare* – asthenia, fever, dehydration, edema, malaise. There have been isolated reports of recurrence of skin reactions at sites of previous paclitaxel extravasation after subsequent drug administrations.

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

*: as reported in post-marketing surveillance.

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

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

Description of selected adverse reactions.

In patients with breast cancer who received paclitaxel as adjuvant therapy following standard combination therapy with anthracyclines or cyclophosphamide (AC), compared to patients receiving AC alone, higher incidences of neurosensory toxicity, hypersensitivity reactions, arthralgia/myalgia, anemia, infections, fever, nausea/vomiting, and diarrhea were observed. However, the frequency of these events was consistent with that observed with paclitaxel monotherapy as described above.

Toxic effects on blood and lymphatic system.

Myelosuppression is the main dose-limiting toxic effect. The most significant manifestation of hematological toxicity was neutropenia. During the first treatment cycle, severe neutropenia (<500 cells/mm³) occurred in 20% of patients. Throughout the entire treatment period, severe neutropenia was observed in 39% of patients. Neutropenia lasting more than 7 days was recorded in 41% of patients, and neutropenia lasting 30–35 days occurred in 8% of patients. Hematological parameters normalized within 35 days in all monitored patients. The frequency of grade 4 neutropenia lasting 7 days or more was 22%.

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

Thrombocytopenia was observed in 50% of patients and was severe (<50,000 cells/mm³) in 9% of cases. Platelet counts decreased to <75,000 cells/mm³ at least once during treatment in 14% of patients. Bleeding episodes related to paclitaxel were reported in <3% of patients; these were localized.

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

Adverse Reactions with Combination Chemotherapy.

When paclitaxel is used in combination with cisplatin, the frequency and severity of neurotoxic effects, predominantly peripheral neuropathy, are higher with a 3-hour intravenous infusion of paclitaxel at a dose of 175 mg/m² body surface area (neurotoxic effects observed in 85% of patients, severe in 15%) compared to a 24-hour intravenous infusion of paclitaxel at a dose of 135 mg/m² body surface area (neurotoxic effects observed in 25% of patients, severe in 3%).

In patients with NSCLC 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. Occasionally, it may necessitate discontinuation of paclitaxel therapy. Sensory symptoms usually improve or resolve within several months after stopping paclitaxel treatment. 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 those receiving cisplatin alone in the treatment of gynecological tumors.

The findings below are from two large first-line chemotherapy trials in ovarian cancer (paclitaxel + cisplatin; over 1,050 patients); two phase III trials in first-line treatment of metastatic breast cancer: one trial combining with doxorubicin (paclitaxel + doxorubicin; 267 patients), another combining with trastuzumab (planned analysis of the trastuzumab + paclitaxel subgroup: 188 patients), and two phase III trials in advanced-stage NSCLC (paclitaxel + cisplatin; over 360 patients).

In patients with ovarian cancer receiving first-line chemotherapy with paclitaxel via 3-hour intravenous infusions in combination with cisplatin, the frequency and severity of neurotoxic effects, arthralgia/myalgia, and hypersensitivity reactions were higher 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 of metastatic breast cancer, the frequency and severity of neutropenia, anemia, peripheral neuropathy, arthralgia/myalgia, asthenia, fever, and diarrhea were higher with paclitaxel administered at 220 mg/m² body surface area via 3-hour intravenous infusions 24 hours after doxorubicin at 50 mg/m² body surface area, compared to standard therapy with 5-fluorouracil (500 mg/m²), doxorubicin (50 mg/m²), and cyclophosphamide (500 mg/m²) (FAC regimen). The frequency and severity of nausea and vomiting with paclitaxel (220 mg/m²) and doxorubicin (50 mg/m²) were lower than with the FAC regimen. This may be partly explained by corticosteroid use.

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, infections, chills, fever, cough, rash, arthralgia, tachycardia, diarrhea, arterial hypertension, epistaxis, acne, herpes simplex, accidental injuries, insomnia, rhinitis, sinusitis, injection site reactions. The frequency of serious adverse effects with combination chemotherapy of paclitaxel and trastuzumab was comparable to that with paclitaxel monotherapy.

Paclitaxel with Doxorubicin.

Impaired cardiac contractility was observed slightly more frequently in patients with metastatic breast cancer receiving doxorubicin in combination with paclitaxel than in those receiving standard therapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen). The incidence of congestive heart failure was similar with paclitaxel alone or in combination with doxorubicin and with standard FAC therapy. With combined chemotherapy using trastuzumab and paclitaxel, the frequency and severity of cardiac dysfunction in patients previously treated with anthracyclines were higher than with paclitaxel monotherapy (heart failure NYHA class I–II: 10% vs 0%; occasionally heart failure NYHA class III–IV: 2% vs 1%). In isolated cases, cardiac dysfunction (with combined trastuzumab and paclitaxel chemotherapy in patients previously treated with anthracyclines) was associated with fatal outcomes. In all cases except these rare fatal events, patients responded to appropriate therapy.

Special Patient Populations

Radiation pneumonitis was 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 and those with other solid tumors receiving paclitaxel monotherapy were comparable.

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

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

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

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

Elevations in bilirubin, alkaline phosphatase, and AST levels were observed in 28%, 43%, and 44% of patients with normal baseline liver function (more than half of these patients were receiving protease inhibitors). Significant elevations in these parameters occurred in 1% of cases.

Shelf life. 3 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25°C, out of reach of children.

Incompatibilities.

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

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

Packaging.

5 ml, 16.7 ml, or 50 ml of the drug in a vial. One vial per cardboard box.

Prescription category. Prescription only.

Manufacturer.

HETERO LABS LIMITED, India.

Manufacturer's address and location of operations.

Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.