Paclitaxel phares

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PaclitaxelPhaRes (PaclitaxelPhaRes)

Composition:

Active substance: paclitaxel;

1 ml of concentrate contains 6 mg of paclitaxel;

Excipients: citric acid anhydrous, polyglyceryl ricinoleate, ethanol anhydrous.

Pharmaceutical form. Concentrate for solution for infusion.

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

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Taxanes. ATC code: L01CD01.

Pharmacological properties.

Pharmacodynamics.

Paclitaxel is a plant-derived antimicrotubule agent that acts on the cellular microtubular apparatus. It promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by inhibiting depolymerization, thereby suppressing the normal dynamic reorganization of the microtubule network, which is essential for cellular functions during mitosis and interphase of the cell cycle. In addition, paclitaxel induces the formation of abnormal structures or "bundles" of microtubules throughout the cell cycle, as well as multiple microtubule "asters" during mitosis.

Pharmacokinetics.

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

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

During 3-hour infusions, the pharmacokinetics of paclitaxel become nonlinear with increasing dose. When the dose was increased by 30% (from 135 to 175 mg/m² of body surface area), the maximum plasma concentration (Cmax) increased by 75%, and the area under the plasma concentration-time curve (AUC) increased by 81%.

After administration of paclitaxel at a dose of 100 mg/m² of body surface area via 3-hour intravenous infusions, the mean Cmax in 19 patients with Kaposi’s sarcoma was 1530 ng/mL (range: 761–2860 ng/mL), the mean AUC was 5619 ng·h/mL (range: 2609–9428 ng·h/mL), clearance was 20.6 L/h·m² (range: 11–38 L/h·m²), volume of distribution was 291 L/m² (range: 121–638 L/m²), and the terminal elimination half-life was 23.7 hours (range: 12–33 hours).

Variations in systemic exposure to paclitaxel among individual patients were minimal. No drug accumulation occurs with repeated treatment cycles.

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

The metabolism of paclitaxel in humans has not been fully elucidated. The mean total urinary excretion of unchanged drug ranges from 1.3 to 12.6% of the administered dose, indicating extensive non-renal clearance. The primary metabolites are hydroxylated derivatives. Paclitaxel is likely metabolized predominantly in the liver by cytochrome P450 isoenzymes and excreted in bile.

After administration of radiolabeled paclitaxel, 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 CYP2C8, CYP3A4, and combined CYP2C8+CYP3A4 isoenzymes, respectively. The effects of renal or hepatic impairment on paclitaxel metabolism following 3-hour infusions have not been studied. Pharmacokinetic parameters in one patient undergoing hemodialysis who was treated with paclitaxel at a dose of 135 mg/m² via 3-hour infusions were similar to those observed in patients without renal impairment.

When paclitaxel and doxorubicin are used concomitantly, an increased duration of distribution and elimination of doxorubicin and its metabolites has been observed. When paclitaxel was administered immediately after doxorubicin, systemic exposure to doxorubicin in plasma was 30% higher compared to administration of paclitaxel 24 hours after doxorubicin.

Clinical characteristics.

Indications.

• Ovarian cancer:
  • first-line treatment of ovarian cancer, as well as in combination with cisplatin for advanced-stage ovarian cancer or residual tumors larger than 1 cm after laparotomy;
  • second-line treatment of metastatic ovarian cancer if standard platinum-based therapy has proven ineffective.
• Breast cancer:
  • adjuvant treatment in patients with lymph node involvement following standard combination therapy with anthracyclines or cyclophosphamide;
  • primary chemotherapy of locally advanced or metastatic breast cancer in combination with anthracyclines or with trastuzumab when immunohistochemical testing confirms HER-2 protein overexpression (3+) or when anthracycline therapy is contraindicated;
  • monotherapy for metastatic breast cancer in patients for whom standard anthracycline therapy is not planned, or in cases where prior anthracycline therapy has been ineffective.
• Advanced non-small cell lung cancer (combined chemotherapy with cisplatin when surgical treatment and/or radiotherapy are not feasible).
• Kaposi's sarcoma (KS) in AIDS patients (second-line treatment of advanced Kaposi's sarcoma when prior therapy with liposomal anthracyclines has been ineffective).

Contraindications.

• Hypersensitivity to paclitaxel or to any other component of the drug, especially to polyethoxylated castor oil;
• neutropenia prior to treatment initiation (neutrophil count < 1.5 × 10⁹/L; in AIDS patients with Kaposi's sarcoma, neutrophil count < 1.0 × 10⁹/L);
• severe, uncontrolled infections in Kaposi's sarcoma;
• severe hepatic dysfunction;
• pregnancy or breastfeeding (see section "Use during pregnancy or breastfeeding").

Special safety precautions.

Instructions for healthcare personnel.

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

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

Waste disposal.

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

Interaction with other medicinal products and other forms of interaction.

Premedication with cimetidine does not affect paclitaxel clearance.

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

Since the elimination of doxorubicin and its active metabolites may be reduced when the interval between paclitaxel and doxorubicin administration is shortened, in primary chemotherapy of metastatic breast cancer, paclitaxel should be administered 24 hours after doxorubicin.

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

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

Special precautions for use.

Paclitaxel Pharos therapy should be administered under the supervision of a qualified physician experienced in the use of anticancer chemotherapeutic agents. Since hypersensitivity reactions may occur, appropriate resuscitation equipment must be readily available.

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

Patients must receive premedication with corticosteroids, antihistamines, and H2-receptor antagonists prior to paclitaxel administration. When Paclitaxel Pharos is used in combination with cisplatin, paclitaxel should be administered before cisplatin.

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

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of the drug. Blood counts should be monitored at least twice weekly during treatment. Re-administration of the drug should not occur until neutrophil levels have recovered to ≥1.5×10⁹/L (≥1.0×10⁹/L in patients with Kaposi's sarcoma) and platelet counts to ≥100×10⁹/L (≥75×10⁹/L in Kaposi's sarcoma). During clinical trials, most patients with Kaposi's sarcoma received granulocyte colony-stimulating factor (G-CSF).

The risk of toxic effects (particularly grade III–IV myelosuppression) is higher in patients with impaired liver function. With 3-hour infusions of paclitaxel, no increased toxicity has been observed in patients with mild hepatic impairment. However, prolonged administration of paclitaxel in patients with moderate liver dysfunction may result in more pronounced myelosuppression. Paclitaxel is contraindicated in patients with severe hepatic impairment. Patients should be closely monitored for signs of severe myelosuppression. Currently, there is insufficient data to provide dose adjustment recommendations for patients with mild or moderate hepatic impairment. Information on paclitaxel use in patients with severe cholestasis is lacking. Patients with severe renal impairment should not be treated with paclitaxel.

Severe cardiac conduction disturbances have been reported rarely. In case of severe conduction disturbances during treatment with this drug, appropriate therapy should be initiated, and continuous cardiac monitoring is recommended if further administration is considered. Vital signs should be monitored during the first hour of paclitaxel infusion. Hypotension, hypertension, and bradycardia may occur during paclitaxel infusion.

Severe cardiovascular events are more frequently observed in patients with non-small cell lung cancer than in those with breast or ovarian cancer. One case of heart failure following paclitaxel therapy was reported in a patient with Kaposi's sarcoma and AIDS during clinical trials.

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

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

Since paclitaxel contains ethanol, its potential effects on the central nervous system (CNS) and other possible effects should be considered.

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

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. This should be considered in differential diagnosis if severe or persistent diarrhea develops during or shortly after paclitaxel treatment.

Severe mucositis.

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

Interstitial pneumonitis.

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

When paclitaxel is used in combination with other antineoplastic agents (cisplatin, doxorubicin, trastuzumab), recommendations for the use of these medicinal products should be taken into account.

Use during pregnancy or breastfeeding.

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

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

Ability to affect reaction speed when driving or operating machinery.

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

Administration method and dosage.

Before starting paclitaxel treatment, all patients must receive premedication with corticosteroids, antihistamines, and H2-receptor antagonists according to the following regimen:

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

The paclitaxel solution must be administered intravenously by infusion using infusion systems equipped with integrated membrane filters with a pore size ≤ 0.22 μm.

First-line chemotherapy of ovarian cancer.

A combination regimen of paclitaxel and cisplatin is recommended.

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

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

Second-line chemotherapy of ovarian cancer.

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

Adjuvant chemotherapy of breast cancer.

Paclitaxel should be administered after therapy with anthracyclines or cyclophosphamide. Paclitaxel is recommended at a dose of 175 mg/m² body surface area administered via three intravenous infusions. Four cycles should be administered at 3-week intervals.

First-line chemotherapy of breast cancer.

When used in combination with doxorubicin (50 mg/m² body surface area), paclitaxel should be administered 24 hours after doxorubicin. The recommended dose of paclitaxel is 220 mg/m² body surface area administered via 3-hour intravenous infusions. The interval between treatment cycles is 3 weeks.

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

Second-line chemotherapy of breast cancer.

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

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

A combination regimen of paclitaxel and cisplatin is recommended. Paclitaxel should be administered at a dose of 175 mg/m² body surface area via 3-hour intravenous infusions, followed by cisplatin at a dose of 80 mg/m² body surface area. The interval between treatment cycles is 3 weeks.

Kaposi's sarcoma in AIDS patients.

The recommended dose is 100 mg/m² body surface area administered via intravenous infusions every 2 weeks.

Treatment of patients with hepatic impairment.

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

Treatment of patients with renal impairment.

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

The following paclitaxel doses should be adjusted according to individual patient tolerance.

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

Preparation of infusion solution.

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

When multiple withdrawals are made from the same vial, the concentrate remains microbiologically, physically, and chemically stable for up to 28 days at 25°C.

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

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

Prepared infusion solutions do not require protection from light.

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

To minimize leaching of diethylhexyl phthalate (DEHP) from infusion bags, systems, or other medical equipment made of plasticized polyvinyl chloride (PVC), diluted infusion solutions should be stored in containers made of non-PVC materials (glass bottles, polypropylene bottles, polypropylene or polyolefin bags) and administered through polyethylene infusion systems. Filters may be connected using short PVC tubing, which does not cause significant DEHP leaching.

Children.

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

Overdose.

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

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

Adverse Reactions.

Unless otherwise stated, the findings listed below are based on pooled safety data from 812 patients with solid tumors who received paclitaxel monotherapy in clinical trials. Since the group of patients with Kaposi's sarcoma has significant peculiarities, a special subsection describing a clinical study involving 107 patients with Kaposi's sarcoma is presented at the end of this section.

Unless otherwise indicated, the frequency and severity of reported adverse events were generally similar among patients receiving paclitaxel for the treatment of ovarian, breast, or non-small cell lung cancer. Patient age did not significantly influence any of the observed types of drug toxicity.

Severe, potentially life-threatening hypersensitivity reactions (such as hypotension requiring treatment, angioneurotic edema, 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.

The most common adverse effect of paclitaxel treatment is bone marrow suppression: severe neutropenia (<500/mm³) was observed in 28% of patients but was not associated with fever. Only 1% of patients experienced severe neutropenia lasting ≥7 days. Thrombocytopenia occurred in 11% of patients. Platelet counts decreased to <50,000/mm³ at least once during the study in 3% of patients. Anemia was observed in 64% of patients, including severe anemia (Hb <5 mmol/L) in 6% of patients (the frequency and severity of anemia depend on the initial hemoglobin level).

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

There were isolated reports of cases of disseminated intravascular coagulation syndrome, often in combination with sepsis or multi-organ dysfunction.

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

Local reactions: local swelling, pain, erythema, and induration may occur at injection sites. Accidental extravasation may lead to cellulitis. Cases of skin desquamation 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. Specific treatment for extravasation reactions is currently unknown. In some cases, injection site reactions began immediately after prolonged infusion or developed with a delay of 7–10 days.

Adverse Reactions with Paclitaxel Monotherapy.

Below is a list of adverse reactions observed in patients receiving paclitaxel monotherapy via 3-hour infusions for the treatment of metastatic cancer (812 patients treated in clinical trials), as well as those identified from 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 (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data).

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 – septic shock; rare* – pneumonia, peritonitis, sepsis.

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 syndrome.

Immune system disorders: very common – mild hypersensitivity reactions (primarily flushing and rash); uncommon – delayed-type hypersensitivity reactions, serious hypersensitivity reactions requiring therapeutic intervention (including hypotension, angioneurotic edema, respiratory distress, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, limb pain, profuse sweating, hypertension); rare* – anaphylactic reactions; very rare* – anaphylactic shock.

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

Psychiatric disorders: very rare* – confusion.

Nervous system disorders: very common – numbness, tingling, or weakness in hands and feet (all symptoms of peripheral neuropathy)*1, paresthesia, 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. Additionally, peripheral neuropathies may persist for more than 6 months after discontinuation of paclitaxel.

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 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 combined with bigeminy, arrhythmia, extrasystoles; rare – heart failure; very rare* – atrial fibrillation, supraventricular tachycardia; frequency not known* – phlebitis.

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

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

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

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

Skin and subcutaneous tissue disorders: very common – alopecia; common – transient mild nail and skin changes, dry skin, acne; uncommon – nail discoloration; rare* – pruritus, rash, erythema, edema; very rare* – Stevens-Johnson syndrome, 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; frequency not known – hand-foot syndrome (erythrodysesthesia) (redness and swelling of palms or soles of feet, which may lead to skin desquamation)*2.

Musculoskeletal and connective tissue disorders: very common – arthralgia, myalgia; frequency not known* – systemic lupus erythematosus.

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

General disorders and administration site conditions: common – injection site reactions (localized swelling, pain, erythema, induration, weakness, skin discoloration and swelling; accidental extravasation may cause cellulitis, fibrosis, and skin necrosis); rare* – asthenia, fever, dehydration, 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 – marked (≥5 times above normal) increases in AST, ALT, and alkaline phosphatase levels; uncommon – marked increase in bilirubin levels; rare* – increased blood creatinine levels.

Description of selected adverse reactions.

In women with breast cancer who received paclitaxel as adjuvant therapy following standard combination therapy with anthracyclines or cyclophosphamide (AC), compared to those 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 corresponded to that observed with paclitaxel monotherapy as described above.

Toxic effects on blood and lymphatic system.

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

Neutropenic fever associated with paclitaxel treatment was observed in 1.3% of treatment cycles. Three septic episodes resulting in fatal outcomes were reported during paclitaxel treatment.

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

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

Adverse Reactions with Combination Chemotherapy.

Paclitaxel with Cisplatin.

In combination therapy with paclitaxel and cisplatin, the frequency and severity of neurotoxic effects, primarily peripheral neuropathy, were higher when paclitaxel was administered at a dose of 175 mg/m² body surface area via 3-hour intravenous infusions (neurotoxic effects observed in 85% of patients, 15% severe) compared to paclitaxel administered at 135 mg/m² via 24-hour intravenous infusions (neurotoxic effects observed in 25% of patients, 3% severe) in combination with cisplatin.

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 course and worsen with subsequent paclitaxel administrations. It may sometimes necessitate discontinuation of paclitaxel therapy. Sensory symptoms diminish or resolve within several months after stopping paclitaxel treatment. 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 those receiving cisplatin alone for gynecological tumors.

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

In ovarian cancer patients receiving first-line chemotherapy with paclitaxel via three intravenous infusions in combination with cisplatin, the frequency and severity of neurotoxic effects, arthralgia/myalgia, and hypersensitivity reactions were higher than with cyclophosphamide combined with cisplatin. The frequency and severity of myelosuppression were lower in the group receiving paclitaxel via three intravenous infusions combined with cisplatin compared to the group receiving cyclophosphamide combined with cisplatin.

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

Paclitaxel with Trastuzumab.

In first-line chemotherapy with paclitaxel via 3-hour intravenous infusions combined 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%), infections (46% vs. 27%), chills (42% vs. 4%), fever (47% vs. 23%), cough (42% vs. 22%), rash (39% vs. 18%), arthralgia (37% vs. 21%), tachycardia (12% vs. 4%), diarrhea (45% vs. 30%), arterial hypertension (11% vs. 3%), epistaxis (18% vs. 4%), acne (11% vs. 3%), herpes simplex (12% vs. 3%), accidental injuries (13% vs. 3%), insomnia (25% vs. 13%), rhinitis (22% vs. 5%), sinusitis (21% vs. 7%), injection site reactions (7% vs. 1%). Differences in the frequency of some adverse effects may be explained by the greater number and duration of treatment cycles with paclitaxel and trastuzumab compared to paclitaxel monotherapy. The frequency of serious adverse effects with combination chemotherapy of paclitaxel and trastuzumab was comparable to that with paclitaxel monotherapy.

Paclitaxel with Doxorubicin.

Impaired cardiac contractility (left ventricular ejection fraction decrease >20%) was observed in patients with metastatic breast cancer receiving doxorubicin combined with paclitaxel and in those receiving standard therapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen). The incidence of congestive heart failure was <1% in both paclitaxel combined with doxorubicin and standard FAC therapy. With combination chemotherapy using trastuzumab and paclitaxel, the frequency and severity of cardiac dysfunction in patients previously treated with anthracyclines were higher than with paclitaxel monotherapy (NYHA functional class I-II heart failure in 10% of patients vs. 0%, NYHA functional class III-IV heart failure in 2% vs. 1%). In isolated cases, these disorders were associated with fatal outcomes. In all cases except the isolated fatal cases, patients responded to appropriate therapy.

Special Patient Groups.

Radiation pneumonitis was reported in patients undergoing concurrent radiotherapy.

Adverse Effects 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.

Hepatobiliary Disorders: increased levels of bilirubin, alkaline phosphatase, and AST were observed in patients with normal baseline liver function (more than half of these patients were receiving protease inhibitors). Marked increases in these parameters occurred in 1% of cases.

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

*2 As reported in post-marketing surveillance of paclitaxel.

Shelf Life. 3 years.

After Dilution. Infusion solutions are physically and chemically stable at temperatures not exceeding 25°C for 7 days when prepared by dilution with 5% glucose solution, and for 14 days when prepared by dilution with 0.9% sodium chloride solution. From a microbiological standpoint, the infusion solution should be used immediately after preparation. If not used immediately, storage duration and conditions must be controlled by the user. Typically, storage should not exceed 24 hours at 2–8°C unless the solution was prepared under controlled and validated aseptic conditions.

Storage Conditions.

Store in the original packaging, protected from light and out of reach of children.

Incompatibilities.

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

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

Packaging.

5 ml, 16.7 ml, 25 ml, or 50 ml in a vial; 1 vial per cardboard box.

Prescription Category. Prescription only.

Manufacturer.

Haupt Pharma Wolfenbüttel GmbH.

Manufacturer's Address and Place of Business.

Pfaffenrieder Strasse 5, Wolfratshausen, Bavaria, 82515, Germany.