Paclitaxel-mb

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Paclitaxel-MB (Paclitaxel-MB)

Composition:

Active ingredient: paclitaxel;

1 ml of concentrate for solution for infusion contains 6.0 mg of paclitaxel;

Excipients: polyoxyl 35 hydrogenated castor oil; ethanol anhydrous.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, slightly yellowish, viscous liquid.

Pharmacotherapeutic group. Antineoplastic agents. Taxanes.

ATC code: L01CD01.

Pharmacological Properties.

Pharmacodynamics.

Paclitaxel is a plant-derived antimitotic 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 "stars" during mitosis.

Pharmacokinetics.

After intravenous administration, the plasma concentration of paclitaxel decreases according to biphasic kinetics.

Paclitaxel pharmacokinetics were evaluated following infusions 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 steady-state volume of distribution ranged from 198 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding.

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

After administration of paclitaxel at a dose of 100 mg/m² body surface area via 3-hour intravenous infusions, the mean Cmax in 19 patients with Kaposi’s sarcoma was 1530 ng/mL (range: 761–2860 ng/mL), 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 elimination half-life was 23.7 hours (range: 12–33 hours).

Variations in systemic exposure to paclitaxel among individual patients were minimal. No accumulation of paclitaxel was observed with repeated treatment courses.

In vitro studies show that 89–98% of paclitaxel is bound to human plasma proteins. The presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine does not affect the 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 main metabolites are hydroxylated derivatives. Paclitaxel is likely metabolized primarily in the liver via cytochrome P450 isoenzymes and excreted in bile.

After administration of radiolabeled paclitaxel, an average of 26%, 2%, and 6% of radioactivity was excreted in feces as 6α-hydroxypaclitaxel, 3’-p-hydroxypaclitaxel, and 6α-3’-p-dihydroxypaclitaxel, respectively. The formation of these hydroxylated metabolites is catalyzed by the isoenzymes CYP2C8, CYP3A4, and the combination of CYP2C8 + CYP3A4, respectively. The effects of renal or hepatic impairment on paclitaxel metabolism after 3-hour infusions have not been studied. Pharmacokinetic parameters in one patient requiring hemodialysis and treated with paclitaxel at a dose of 135 mg/m² body surface area via 3-hour infusions did not differ from those in patients without renal impairment.

When paclitaxel 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 than when paclitaxel was administered 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 when standard platinum-based therapy has proven ineffective.

Breast cancer:

• Adjuvant treatment of patients with lymph node involvement following standard combination therapy with anthracyclines or cyclophosphamide;
• Primary chemotherapy of locally advanced or metastatic breast cancer in combination with anthracyclines or with trastuzumab in cases of immunohistochemically confirmed 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 when prior anthracycline therapy has failed.

Advanced non-small cell lung cancer

• Combination chemotherapy with cisplatin when surgical treatment and/or radiotherapy are not feasible.

Kaposi's sarcoma (KS) in AIDS patients

• Second-line therapy for advanced Kaposi's sarcoma when prior therapy with liposomal anthracyclines has been ineffective.

Contraindications.

− Hypersensitivity to paclitaxel or to any other component of the medicinal product (especially to polyoxyethylated castor oil).

− Neutropenia prior to treatment initiation (baseline neutrophil count < 1.5×10⁹/L; in AIDS-related Kaposi's sarcoma, neutrophil count < 1×10⁹/L), thrombocytopenia < 100×10⁹/L (in Kaposi's sarcoma, platelet count < 75×10⁹/L).

− Severe hepatic dysfunction.

− Concurrent severe uncontrolled infections in patients with Kaposi's sarcoma.

− Pregnancy or breastfeeding.

Special safety precautions.

Instructions for medical personnel.

When handling Paclitaxel-MB, as with all cytotoxic agents, caution must be exercised. Reconstitution 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. Localized stinging, burning, and erythema 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.

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

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 management.

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 insufficiency in ovarian cancer patients receiving combination therapy with paclitaxel and cisplatin is higher than with cisplatin monotherapy.

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

Paclitaxel metabolism is partially catalyzed by the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Clinical studies have shown that the major metabolic transformation in humans is CYP2C8-mediated conversion of paclitaxel to 6α-hydroxypaclitaxel. Clinically significant interactions with other enzymes besides CYP2C8 are not expected. Concurrent 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 the CYP2C8 and CYP3A4 isoenzymes.

Pharmacokinetic studies of paclitaxel in patients with Kaposi's sarcoma receiving concomitant multi-drug therapy indicate a significant reduction in systemic paclitaxel clearance when nelfinavir and ritonavir are co-administered, but not with indinavir. Data on interactions between paclitaxel and other protease inhibitors are limited; therefore, paclitaxel should be used with caution in patients receiving concomitant protease inhibitor therapy.

Vaccination. Administration of live vaccines to immunocompromised patients due to chemotherapy, including paclitaxel, may lead to severe infections. Immune response to vaccines may be diminished. Live vaccines should be avoided in patients receiving paclitaxel. Live viral vaccination is recommended no earlier than 3 months after the last dose of chemotherapy.

Special precautions for use.

Paclitaxel-MB 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 may occur during drug administration, careful monitoring of the infusion site for signs of possible infiltration is recommended.

Prior to paclitaxel administration, patients must receive premedication with corticosteroids, antihistamines, and H2-receptor antagonists. When used in combination with cisplatin, Paclitaxel-MB should be administered before cispllatin.

Severe hypersensitivity reactions, characterized by dyspnea, hypotension (requiring appropriate therapeutic interventions), 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; the drug should not be re-administered.

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of the drug. Blood cell counts should be monitored at least twice weekly during treatment. The drug should not be re-administered 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 patients with Kaposi’s sarcoma). In clinical trials, most patients with Kaposi’s sarcoma received granulocyte colony-stimulating factor (G-CSF).

Hepatic function impairment.

Patients with severe renal insufficiency should not be treated with paclitaxel.

The risk of toxic effects (particularly grade III–IV myelosuppression) is higher in patients with hepatic dysfunction. When paclitaxel is administered via 3-hour infusions, no increased toxicity has been observed in patients with mild hepatic impairment. However, with prolonged administration of paclitaxel in patients with moderate to severe hepatic dysfunction, more pronounced myelosuppression may occur. Paclitaxel should not be administered to patients with severe hepatic impairment. Patients should be closely monitored for signs of developing severe myelosuppression. Currently, there is insufficient data to provide dosage adjustment recommendations for patients with mild to moderate hepatic impairment.

There is no available information on paclitaxel treatment in patients with severe cholestasis.

Severe cardiac conduction disorders have been rarely reported. In case of severe conduction disturbances during treatment with this drug, appropriate therapy should be initiated, and if further administration of the drug is considered, continuous cardiac monitoring should be performed. 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 planned 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. When determining the frequency of ventricular function monitoring, 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 treatment should be carefully weighed against the risk of cardiac damage, which may sometimes be irreversible. 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 who received paclitaxel alone or cyclophosphamide followed by cisplatin.

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

Ethanol.

Since Paclitaxel-MB contains ethanol, its potential effects on the central nervous system (CNS) and other possible effects should be considered. The use of the drug may be harmful in patients with alcohol-related disorders. 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.

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

Pseudomembranous colitis.

Rarely, pseudomembranous colitis has been reported during paclitaxel treatment, including cases where patients were not concurrently receiving antibiotics. This should be considered in differential diagnosis if severe or persistent diarrhea develops during or shortly after paclitaxel therapy.

Severe mucositis.

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

Interstitial pneumonitis.

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

Teratogenicity, embryotoxicity, and mutagenicity.

Paclitaxel has been shown to have teratogenic, embryotoxic, and mutagenic effects in several experimental systems. Therefore, both women and men should use contraceptive methods to prevent pregnancy during paclitaxel treatment and for at least 6 months after completion of therapy. Sperm cryopreservation is recommended for men prior to starting paclitaxel treatment due to the potential risk of infertility (see section "Use during pregnancy or breastfeeding").

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

Use during pregnancy or breastfeeding.

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

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

Ability to affect reaction speed when driving or operating machinery.

During paclitaxel treatment, patients should refrain from potentially hazardous activities requiring increased attention and psychomotor speed. It should be noted that Paclitaxel-MB contains alcohol, and some adverse effects may negatively affect the ability to drive or operate machinery.

Administration and dosage.

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

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 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 3-hour intravenous infusions. Typically, no more than 4 cycles should be administered, with intervals of 3 weeks.

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 3-hour intravenous infusions. Four cycles should be administered with 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 previous 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 3-hour intravenous infusion. 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 infusion, followed by cisplatin at a dose of 80 mg/m² body surface area. The interval between treatment cycles is 3 weeks.

Kaposi’s sarcoma chemotherapy in AIDS patients.

The recommended dose of paclitaxel is 100 mg/m² body surface area administered via 3-hour intravenous infusion 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 must be adjusted according to individual patient tolerance.

Repeat administration is possible only after neutrophil counts have recovered to ≥ 1.5×10⁹/L (≥ 1.0×10⁹/L in Kaposi’s sarcoma patients) and platelet counts have recovered to ≥ 100×10⁹/L (≥ 75×10⁹/L in Kaposi’s sarcoma patients). 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 the infusion solution.

Prior to use, the concentrate for infusion solution preparation, Paclitaxel-MB, 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 vial, the concentrate maintains microbiological, physical, and chemical stability for up to 8 hours at a temperature not exceeding 25 °C.

Infusion solutions prepared by diluting Paclitaxel-MB with 0.9% sodium chloride solution or 5% glucose solution are physically and chemically stable for 24 hours when stored at temperatures not exceeding 25 °C. Refrigerated solutions may form a precipitate, but this may resolve upon standing at room temperature (25 °C). The vial should be discarded if the solution is cloudy or if the precipitate does not redissolve. 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. Typically, storage should not exceed 24 hours at 2–8 °C, unless the solution was prepared under controlled and validated aseptic conditions.

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

The prepared infusion solutions do not require protection from light.

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

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

Children.

The safety and efficacy of paclitaxel in pediatric patients 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 below are based on pooled safety data 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 special subsection at the end of this section presents data from a clinical study involving 107 patients with Kaposi's sarcoma.

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, angioedema, respiratory distress requiring bronchodilators, generalized urticaria) were observed in two patients (<1% of patients). Mild hypersensitivity reactions, primarily flushing and rash, occurred in 34% of patients (17% of all treatment cycles) and 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 (frequency and severity of anemia depend on baseline hemoglobin levels).

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

Isolated reports of disseminated intravascular coagulation (DIC) syndrome have been reported, often in association with sepsis or multi-organ dysfunction.

Hair loss was observed 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 the injection site. Accidental extravasation may lead to cellulitis. Reports of skin desquamation, sometimes associated with extravasation, have been reported. Skin pigmentation changes are possible. There have been isolated reports of recurrence of skin reactions at sites of previous paclitaxel extravasation after subsequent administrations. Specific treatment for extravasation reactions is currently unknown. In some cases, injection site reactions occurred 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 metastatic cancer treatment (812 patients treated in clinical trials), as well as those identified during post-marketing surveillance*.

Adverse reactions are categorized by frequency: 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 (primarily 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 (primarily flushing and rash); uncommon – delayed-type hypersensitivity reactions, serious hypersensitivity reactions requiring therapeutic intervention (e.g., hypotension, angioedema, respiratory distress, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, limb pain, profuse sweating, hypertension); rare* – anaphylactic reactions; very rare* – anaphylactic shock; frequency not known – bronchospasm.

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

Psychiatric disorders: very rare* – confusion.

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

Eye disorders: uncommon – dry eyes, blurred vision, visual field defect; very rare* – optic nerve damage and/or visual disturbances (scintillating scotoma), particularly in patients receiving doses above 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 – hypotension; common – vasodilation (flushing); uncommon – 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 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, hypohydration.

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

Skin and subcutaneous tissue disorders: very common – alopecia; common – transient mild nail and skin changes, dry skin, acne; uncommon – nail discoloration; rare* – pruritus, rash, erythema, swelling; very rare* – Stevens-Johnson syndrome, 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 erythrodysesthesia syndrome.

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

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

General disorders and administration site conditions: very common – mucositis; 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 administrations.

Laboratory investigations: 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.

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), signs of neurosensory toxicity, hypersensitivity reactions, arthralgia/myalgia, anemia, infections, fever, nausea/vomiting, and diarrhea were observed more frequently compared to patients receiving AC alone. 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 hematologic 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. Hematologic 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 1.3% of treatment cycles. Three septic episodes resulting in fatal outcomes were reported during paclitaxel therapy.

Thrombocytopenia was observed in 50% of patients, with severe thrombocytopenia (<50×10⁹/L) in 9%. Only 14% of patients had platelet counts decrease below 75×10⁹/L at least once during treatment. Bleeding episodes related to 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

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

In patients with non-small cell lung cancer and ovarian cancer receiving paclitaxel over 3 hours followed by cisplatin, the frequency of severe neurotoxicity increased. Peripheral neuropathy may develop after the first treatment cycle and worsen with subsequent paclitaxel administrations. It may sometimes necessitate discontinuation of paclitaxel therapy. Sensory symptoms usually improve or resolve within several months after stopping paclitaxel. Pre-existing neuropathy from 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 paclitaxel with doxorubicin (paclitaxel + doxorubicin; 267 patients), another combining paclitaxel 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 patients with ovarian cancer receiving first-line chemotherapy with paclitaxel via three-hour intravenous infusions in combination with cisplatin, the frequency and severity of neurotoxic effects, arthralgia/myalgia, and hypersensitivity reactions were higher compared to treatment with cyclophosphamide plus cisplatin. The frequency and severity of myelosuppression were lower in the group receiving paclitaxel via three-hour intravenous infusions plus cisplatin compared to the group receiving cyclophosphamide plus 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 220 mg/m² administered as a 3-hour intravenous infusion 24 hours after doxorubicin 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, partly due to corticosteroid use.

Paclitaxel with Trastuzumab

In first-line chemotherapy with paclitaxel administered via 3-hour intravenous infusions in combination with trastuzumab, the frequency of the following adverse effects (regardless of causal relationship to paclitaxel or trastuzumab) was higher in patients with metastatic breast cancer compared to 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%), 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 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 was comparable 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 patients with metastatic breast cancer receiving doxorubicin in combination with paclitaxel and in patients receiving standard therapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen). The incidence of congestive heart failure was <1% with both paclitaxel plus doxorubicin and standard FAC therapy. In patients previously treated with anthracyclines, the frequency and severity of cardiac dysfunction were higher with combination chemotherapy using trastuzumab and paclitaxel compared to paclitaxel monotherapy (NYHA class I-II heart failure in 10% of patients vs. 0%, NYHA class III-IV heart failure in 2% of patients vs. 1%). In isolated cases, these events were associated with fatal outcomes. In all cases except the isolated fatal cases, patients responded to appropriate therapy.

Special Patient Groups

Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.

Adverse Effects in AIDS Patients with Kaposi's Sarcoma

Except for hematological and hepatic adverse effects, the frequency and severity of adverse reactions in patients with Kaposi's sarcoma were comparable to those in patients with other solid tumors receiving paclitaxel monotherapy.

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

Reporting of Suspected Adverse Reactions

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

Shelf Life. 30 months.

After opening the vial prior to dilution.

Chemical and physical stability has been demonstrated for 8 hours at a temperature not exceeding 25°C. From a microbiological standpoint, after the first opening, the injection solution may be stored for no more than 8 hours at a temperature not exceeding 25°C. If the solution is not administered immediately, responsibility for storage duration and conditions of the ready-to-use solution lies with the user (healthcare personnel).

After dilution

The infusion solution is chemically and physically stable for 24 hours when stored at 5°C to 25°C.

Storage Conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 25°C. Freezing does not adversely affect the product. Precipitates may form in the cooled medicinal product, which redissolve upon reaching room temperature with or without slight agitation. If the solution remains cloudy or contains insoluble residue, the vial should be discarded.

Keep out of reach of children.

Incompatibilities.

Polyoxyl 35 castor oil, included in Paclitaxel-MB, may cause leaching of diethylhexyl phthalate (DEHP) from plasticized PVC. The extent of this process depends on duration of exposure and 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 in a vial; 1 or 10 vials per cardboard box; or 25 vials per tray in a cardboard box, covered with thick heat-shrink film;

16.7 mL in a vial; 1 or 5 vials per cardboard box; or 16 vials per tray in a cardboard box, covered with thick heat-shrink film;

25 mL in a vial; 1 or 4 vials per cardboard box;

50 mL in a vial; 1 or 4 vials per cardboard box.

Prescription Status. Prescription only.

Manufacturer.

Biolyse Pharma Corporation

Manufacturer's Address.

59 Welland Vale Road, St. Catharines, Ontario, Canada, L2S 3Y2

Marketing Authorization Holder.

M.BIOTECH LIMITED

Address of Marketing Authorization Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom