Paclitaxel accord

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PAKLITAKSEL AKKORD (PACLITAXEL ACCORD)

Composition:

Active substance: paclitaxel;

1 ml of concentrate contains 6 mg of paclitaxel;

Excipients: polyethoxylated castor oil, anhydrous ethanol.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless or slightly yellowish solution, free from visible mechanical particles.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Taxanes.

ATC code L01C D01.

Pharmacological properties.

Pharmacodynamics.

Paclitaxel is an 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 normal dynamic reorganization of microtubular networks, essential for cellular functions during interphase and mitosis, is disrupted. In addition, paclitaxel induces the formation of abnormal aggregates or "bundles" of microtubules throughout the cell cycle, as well as multiple microtubule "asters" during mitosis.

Pharmacokinetics.

Absorption

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

The pharmacokinetics of paclitaxel were studied following intravenous infusions over 3 and 24 hours at doses of 135 mg/m² and 175 mg/m² of body surface area, respectively. The mean terminal half-life ranged from 3.0 to 52.7 hours, and the mean total body clearance was 11.6–24.0 L/h×m². Total body clearance of paclitaxel is likely reduced as its plasma concentration increases. The mean steady-state volume of distribution 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 mg/m² to 175 mg/m² of body surface area), the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC→∞) increased by 75% and 81%, respectively.

Distribution

Following administration of paclitaxel at a dose of 100 mg/m² 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 half-life was 23.7 hours (range: 12–33 hours).

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

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

Metabolism

The metabolism of paclitaxel in humans has not been fully elucidated. Between 1.3% and 12.6% of the administered dose is excreted unchanged in urine, indicating extensive non-renal clearance. Paclitaxel is likely metabolized primarily in the liver via the cytochrome P450 isoenzymes and excreted in bile. After administration of radiolabeled paclitaxel, approximately 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 CYP2C8, CYP3A4, and CYP2C8+CYP3A4 isoenzymes, respectively. The effects of renal or hepatic impairment on the pharmacokinetics of paclitaxel following 3-hour infusions have not been formally studied. Pharmacokinetic parameters in one patient undergoing hemodialysis and treated with paclitaxel at a dose of 135 mg/m² via 3-hour infusions were similar to those observed in patients without renal impairment.

Excretion

When paclitaxel and doxorubicin were administered concomitantly, an increase in the distribution and elimination half-lives of doxorubicin and its metabolites was 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 chemotherapy for advanced disease or residual tumors (>1 cm) after laparotomy, in combination with cisplatin; second-line chemotherapy for metastatic ovarian cancer in cases of failure of standard platinum-based therapy).

Breast cancer (adjuvant chemotherapy in patients with lymph node-positive breast cancer after treatment with anthracyclines and cyclophosphamide; primary chemotherapy for locally advanced or metastatic breast cancer in combination with anthracyclines or in combination with trastuzumab in cases of immunohistochemically confirmed HER-2 protein overexpression (3+) or in cases of contraindications to anthracycline therapy; monotherapy for metastatic breast cancer in patients who are not candidates for standard anthracycline therapy or in cases of prior anthracycline therapy failure).

Advanced non-small cell lung cancer (NSCLC) (combination chemotherapy with cisplatin when surgical treatment and/or radiotherapy are not feasible).

Kaposi’s sarcoma in AIDS patients (second-line therapy for advanced Kaposi’s sarcoma in cases of prior therapy failure with liposomal anthracyclines).

Contraindications.

Hypersensitivity to paclitaxel or to any of the excipients, particularly polyoxyethylated 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 impairment.

Pregnancy or breastfeeding (see section "Use during pregnancy or breastfeeding").

Special precautions.

Instructions for healthcare personnel. As with all cytotoxic agents, caution must be exercised when handling paclitaxel. Preparation of infusion solutions should be performed by personnel experienced in handling such agents, in a specially designated area under strict aseptic conditions. Protective clothing (gowns, caps, masks, goggles, and disposable gloves) must be worn. Contact between paclitaxel solutions and skin or mucous membranes should be avoided. In case of accidental contact, affected skin areas should be washed thoroughly with soap and water. Transient stinging, burning, and redness of the skin may occur at the site of contact. Mucous membranes exposed to the drug 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 drugs.

Precipitation may occur in closed vials stored in the refrigerator or in a frozen state; this precipitate dissolves upon gentle shaking or without shaking upon warming to room temperature. This does not affect the quality of the drug. Vials with persistently cloudy solutions or undissolved precipitate must be discarded.

Safety instructions for preparation of paclitaxel infusion solution

1. A biological safety cabinet should be used, and protective gloves and gown must be worn. In the absence of a safety cabinet, a protective mask and goggles should be used.
2. Pregnant women or women who may become pregnant should not handle this drug.
3. Opened containers such as injection vials and infusion bottles, as well as used cannulas, syringes, catheters, test tubes, and residual cytostatic agents, should be considered hazardous waste and disposed of according to local regulations for handling hazardous waste.
4. In case of drug spillage, follow the instructions below:
   • Always wear protective clothing;
   • Collect broken glass and place it in a container for hazardous waste;
   • Clean contaminated surfaces thoroughly with a large amount of cold water;
   • Wipe the cleaned surface thoroughly, and dispose of wiping materials as hazardous waste.
5. In case of skin contact with paclitaxel, the affected area should be washed immediately with copious amounts of running water and then cleansed with soap. In case of contact with mucous membranes, the area should be rinsed thoroughly with water. Medical advice should be sought if any discomfort occurs.
6. In case of eye contact, eyes should be rinsed thoroughly with copious amounts of cold water and an ophthalmologist should be consulted immediately.

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

Disposal. Unused solution, instruments, and materials that have come into contact with paclitaxel should be destroyed in accordance with standard hospital procedures for disposal of cytotoxic waste, in compliance with current regulations regarding the destruction of hazardous waste.

Interaction with other medicinal products and other forms of interaction.

Premedication with cimetidine does not affect paclitaxel clearance.

In first-line combination chemotherapy for ovarian cancer, paclitaxel should be administered before cisplatin. In this case, the safety profile of paclitaxel does not differ from that observed during monotherapy. However, if paclitaxel is administered after cisplatin, more severe myelosuppression is observed, and paclitaxel clearance is reduced by approximately 20%. The risk of renal insufficiency 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 primary chemotherapy for metastatic breast cancer, paclitaxel should be administered 24 hours after doxorubicin.

Paclitaxel metabolism is partially catalyzed by the CYP2C8 and CYP3A4 isoenzymes of the cytochrome P450 system. Therefore, due to the lack of interaction studies, concomitant use of paclitaxel with known inhibitors of CYP2C8 and CYP3A4 (e.g., ketoconazole or other imidazole antifungal agents, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) should be approached with caution because of the potential for increased paclitaxel toxicity due to elevated exposure. Concomitant use of paclitaxel with known inducers of CYP2C8 or CYP3A4 (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended due to the potential for reduced efficacy resulting from decreased paclitaxel exposure.

Clinical studies have demonstrated that CYP2C8-mediated metabolism of paclitaxel to 6α-hydroxypaclitaxel is the major metabolic pathway in humans. Concurrent administration of ketoconazole, a known potent inhibitor of CYP3A4, does not inhibit paclitaxel elimination in patients. Thus, both drugs can be used together without dose adjustment.

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

Vaccination with live vaccines in patients receiving paclitaxel may result in severe infection. Antibody response to vaccines may be reduced in these patients. Therefore, live viral vaccines should be avoided during chemotherapy. It is recommended to use live viral vaccines cautiously after discontinuation of chemotherapy, and vaccination should not be performed earlier than 3 months after the last dose of chemotherapy. Live vaccines should be avoided in the post-chemotherapy period, and individual consultation with a specialist is advised.

Concomitant administration of live vaccines increases the risk of fatal systemic vaccine-related disease. Live vaccines are not recommended for immunosuppressed patients.

Premedication with cimetidine does not affect paclitaxel clearance.

For use of paclitaxel in combination with other medicinal products such as cisplatin, doxorubicin, or trastuzumab, refer to the instructions for medical use of these medicinal products.

Special precautions for use

Treatment with paclitaxel should be administered under the supervision of a qualified oncologist experienced in the use of cytotoxic anticancer agents. Since severe hypersensitivity reactions may occur, appropriate resuscitation equipment must be available. Because extravasation may occur during administration of the drug, careful monitoring of the infusion site for signs of possible infiltration is recommended. Prior to administration of paclitaxel, patients must receive premedication with corticosteroids, antihistamines, and H2-receptor antagonists.

When used in combination with cisplatin, paclitaxel should be administered before cisplatin.

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

Myelosuppression (predominantly neutropenia) is the main dose-limiting toxic effect of the drug. During treatment with paclitaxel, blood cell counts should be monitored at least twice weekly. Re-administration of the drug is permitted only after neutrophil counts have recovered to ≥ 1.5×10⁹/L (≥ 1.0×10⁹/L in Kaposi's sarcoma), and platelet counts have recovered to ≥ 100×10⁹/L (≥ 75×10⁹/L in Kaposi's sarcoma). In clinical trials, most patients with Kaposi's sarcoma received granulocyte colony-stimulating factor (G-CSF).

Severe cardiac conduction disturbances during treatment with paclitaxel have been reported rarely. In such cases, appropriate treatment should be initiated, and if further administration of the drug is considered, continuous cardiac monitoring is required. During paclitaxel infusion, arterial hypotension, arterial hypertension, and bradycardia have been observed, usually asymptomatic and not requiring therapeutic intervention. Frequent monitoring of vital signs is recommended, especially during the first hour of paclitaxel infusion. Severe cardiovascular events are more frequently observed in patients with NSCLC than in those with breast or ovarian cancer. One case of heart failure following paclitaxel therapy was reported in a patient with Kaposi's sarcoma and AIDS.

When paclitaxel is used in combination with doxorubicin or trastuzumab for first-line chemotherapy of metastatic breast cancer, cardiac function monitoring is essential. Patients eligible for such combination therapy should undergo thorough cardiac evaluation prior to treatment initiation, including ECG, echocardiography, and MUGA scanning. Cardiac function should be monitored regularly during treatment (e.g., every 3 months). This monitoring allows timely 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 treatment versus the risk of irreversible cardiac damage must be carefully weighed. If combination chemotherapy is continued, cardiac monitoring should be performed more frequently (every 1–2 cycles). For further information, refer to the prescribing information for doxorubicin and trastuzumab.

Although peripheral neuropathy is a common adverse effect during paclitaxel treatment, severe neuropathy develops rarely. In severe cases, subsequent paclitaxel doses should be reduced by 20% (by 25% in Kaposi's sarcoma). 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 treatment. In patients with NSCLC or ovarian cancer receiving first-line therapy, severe neurotoxicity was observed more frequently with the 3-hour infusion of paclitaxel in combination with cisplatin compared to paclitaxel alone or cyclophosphamide followed by cisplatin.

Pseudomembranous colitis

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

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, with longer infusions, more pronounced myelosuppression may occur in patients with moderate hepatic impairment. Paclitaxel should not be administered to patients with severe hepatic impairment. Patients should be closely monitored for signs of profound 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.

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

Severe mucosal inflammation is rare in patients with Kaposi's sarcoma. In case of severe reaction, the paclitaxel dose should be reduced by 25%.

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

The drug must not be frozen, as precipitation may occur.

Such precipitate usually dissolves upon warming the vial to room temperature (25°C). However, if the solution in a previously frozen vial remains cloudy or contains insoluble precipitate, the drug must not be used and the vial should be discarded. Freezing does not shorten the shelf life of Paclitaxel Accord.

Intra-arterial administration of paclitaxel should be avoided, as severe tissue reactions were observed in animal local tolerance studies following intra-arterial administration.

Since paclitaxel has teratogenic, embryotoxic, and mutagenic properties, patients of reproductive age and/or their partners should use contraception for at least 6 months after completion of paclitaxel treatment (see section "Use during pregnancy or breastfeeding").

Ethanol

This medicinal product contains 391 mg/mL of anhydrous ethanol; thus, the maximum dose (220 mg/m²) is equivalent to 646 mL of beer or 258 mL of wine.

A dose of 220 mg/m² of this medicinal product administered to a 70 kg adult results in an ethanol exposure of 368.66 mg/kg, which may increase blood alcohol concentration (BAC) by approximately 61.44 mg/100 mL. For comparison, drinking a glass of wine or 500 mL of beer typically results in a BAC of about 50 mg/100 mL.

Concomitant use with medicinal products containing, for example, propylene glycol or ethanol may lead to ethanol accumulation and cause adverse effects. Since this medicinal product is usually administered slowly over 3–24 hours, the effect of alcohol may be reduced.

Harmful for patients with alcoholism. Caution is advised in pregnant women, breastfeeding women, children, patients with liver disease, and patients with epilepsy.

The amount of alcohol in this medicinal product may affect the action of other drugs.

The amount of alcohol in this medicinal product may affect the ability to drive or operate machinery.

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

Use during pregnancy or breastfeeding

Women of reproductive age/Contraception in women and men

Women of reproductive age must use effective contraception during treatment and for six months after treatment. Male patients receiving paclitaxel are advised not to father children during treatment and for six months after treatment.

Pregnancy

There is no information on the use of paclitaxel in pregnant women. Paclitaxel may be harmful to the fetus during pregnancy. Paclitaxel is genotoxic and has shown reproductive toxicity in animal studies. Paclitaxel should not be used during pregnancy and should not be administered to women of reproductive potential unless effective contraception is used, except when the patient's clinical condition necessitates its use.

Breastfeeding

Paclitaxel and its metabolites penetrate into rat milk. Paclitaxel is also excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, paclitaxel is contraindicated during breastfeeding (see section "Contraindications"). Breastfeeding should be avoided for at least 6 to 10 days after paclitaxel therapy.

Fertility

Paclitaxel has been shown to reduce fertility in rats.

Sperm cryopreservation should be considered in 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 activities requiring high concentration and rapid psychomotor responses. It should be noted that the drug contains ethanol (see section "Special precautions for use"), and certain adverse effects may negatively affect the ability to drive or operate machinery.

Administration and Dosage.

Before starting treatment, all patients must receive premedication with corticosteroids, antihistamines, and H2-receptor antagonists, for example 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: approximately 12 and 6 hours before paclitaxel administration. Intravenous: 30–60 minutes before paclitaxel administration.
Diphenhydramine (or equivalent antihistamine)	50 mg intravenously	30–60 minutes before paclitaxel administration
Cimetidine or ranitidine	300 mg intravenously 50 mg intravenously	30–60 minutes before paclitaxel administration

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 for ovarian cancer. A combination regimen of paclitaxel and cisplatin is recommended. According to infusion duration, two paclitaxel dosing regimens are recommended:

• paclitaxel 175 mg/m² body surface area administered as a 3-hour intravenous infusion, followed by cisplatin 75 mg/m² body surface area;
• paclitaxel 135 mg/m² body surface area administered as a 24-hour intravenous infusion, followed by cisplatin 75 mg/m² body surface area.

Treatment cycles should be repeated every 3 weeks.

Second-line chemotherapy for ovarian cancer. Paclitaxel is recommended at a dose of 175 mg/m² body surface area administered as a 3-hour intravenous infusion. Typically, no more than 4 cycles are administered at 3-week intervals.

Adjuvant chemotherapy for breast cancer. Paclitaxel should be administered after anthracycline-based or cyclophosphamide-based chemotherapy. Paclitaxel is recommended at a dose of 175 mg/m² body surface area administered as a 3-hour intravenous infusion. Typically, 4 cycles are administered at 3-week intervals.

First-line chemotherapy for breast cancer. When used in combination with doxorubicin (at a dose of 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 as a 3-hour intravenous infusion. Treatment cycles should be repeated every 3 weeks.

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

Second-line chemotherapy for breast cancer. Paclitaxel is recommended at a dose of 175 mg/m² body surface area administered as a 3-hour intravenous infusion. Treatment cycles should be repeated every 3 weeks.

First-line chemotherapy for advanced non-small cell lung cancer (NSCLC). A combination regimen of paclitaxel and cisplatin is recommended. Paclitaxel should be administered at a dose of 175 mg/m² body surface area as a 3-hour intravenous infusion, followed by cisplatin 80 mg/m² body surface area. Treatment cycles should be repeated every 3 weeks.

Chemotherapy for Kaposi's sarcoma in AIDS patients. Paclitaxel is recommended at a dose of 100 mg/m² body surface area administered as a 3-hour intravenous infusion. Treatment cycles should be repeated every 2 weeks.

Subsequent doses of paclitaxel should be individually adjusted based on treatment tolerability. The next dose of paclitaxel may be administered only after neutrophil counts have recovered to ≥ 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). For 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).

Treatment of patients with hepatic impairment. Insufficient data are available 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. Insufficient data are available regarding dose adjustment in patients with renal impairment.

Preparation of solution for intravenous infusion.

Paclitaxel must be diluted prior to infusion using aseptic techniques. The following infusion solutions may be used as diluents:

• 0.9% sodium chloride solution,
• 5% glucose solution,
• a mixture of 5% glucose solution and 0.9% sodium chloride solution,
• 5% glucose solution and Ringer's solution.

Sufficient diluent should be added to achieve a final paclitaxel concentration between 0.3 and 1.2 mg/mL.

Chemical and physical stability of the solution during use has been demonstrated at 5°C and 25°C for 7 days when diluted with 5% glucose, and for 14 days when diluted with 0.9% sodium chloride solution.

From a microbiological standpoint, the preparation should be used immediately. If not used immediately, the duration and conditions of storage prior to use are the sole responsibility of the user and should not exceed 24 hours at 2°C to 8°C, except when dilution is performed under properly controlled and validated aseptic conditions.

After dilution, the solution should be used only once.

During preparation, the solution may appear slightly cloudy due to the excipient in the formulation. This cloudiness does not resolve upon filtration. Paclitaxel should be administered through systems equipped with a microporous filter membrane ≤ 0.22 μm in diameter. Simulated infusion studies using filtered tubing showed no significant loss of activity.

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

To minimize leaching of diethylhexyl phthalate (DEHP) from infusion bags, systems, or other medical equipment made of plasticized polyvinyl chloride (PVC), the diluted infusion solution 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.

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, administration of the drug should be immediately discontinued, 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 following results are based on pooled safety data from 812 patients with solid tumours who received paclitaxel monotherapy in clinical trials. Because patients with Kaposi's sarcoma have 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 types of drug toxicity.

Adverse Reactions with Paclitaxel Monotherapy

The most common adverse effect of paclitaxel therapy is bone marrow suppression. Severe neutropenia (< 500/mm³) occurred 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. Anaemia occurred in 64% of patients, including severe anaemia (Hb < 5 mmol/L) in 6% of patients. The frequency and severity of anaemia depend on the initial haemoglobin level.

Neurotoxicity (mainly peripheral neuropathy) occurs more frequently and severely with a 3-hour infusion of paclitaxel at 175 mg/m² (neurotoxicity in 85% of cases, severe in 15%) compared to a 24-hour infusion of paclitaxel at 135 mg/m² in combination with cisplatin (peripheral neuropathy in 25% of cases, severe in 3%). 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. It may sometimes necessitate discontinuation of paclitaxel therapy. Sensory symptoms usually diminish or resolve within several months after stopping paclitaxel. Pre-existing neuropathy due to prior therapy is not a contraindication for paclitaxel treatment. Additionally, peripheral neuropathy may persist for more than 6 months after discontinuation of paclitaxel.

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

Severe hypersensitivity reactions with potentially fatal outcomes (hypotension requiring therapeutic intervention; angioedema; respiratory dysfunction requiring bronchodilators; generalized urticaria) were observed in 2 patients (<1% of patients). 34% of patients (17% of all treatment cycles) experienced mild hypersensitivity reactions, mainly 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 injection sites. Accidental extravasation may lead to cellulitis. Skin pigmentation changes are possible. There have been isolated reports of recurrence of skin reactions at previous extravasation sites after subsequent paclitaxel administrations. There is currently no specific treatment for transudation reactions. In some cases, injection site reactions occurred either during prolonged drug infusion or as late as 7–10 days afterward.

Gastrointestinal adverse effects associated with paclitaxel were mild or moderate. Nausea, vomiting, diarrhoea, mucositis, and rarely intestinal obstruction, perforation, ischaemic colitis, pseudomembranous colitis, oesophagitis, constipation, and pancreatitis were reported.

Significant elevations (≥ 5 times above normal) in aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin levels were observed in 5%, 4%, and <1% of patients, respectively.

Cases of liver necrosis and hepatic encephalopathy have also been reported in patients treated with paclitaxel.

There have been isolated reports of disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure.

Hair loss (alopecia) occurred in 87% of patients receiving paclitaxel, with a sudden onset. Most patients experiencing alopecia can expect significant hair loss (≥ 50%).

Below is a list of adverse reactions regardless of severity associated with paclitaxel monotherapy administered via 3-hour infusions to patients with metastatic disease (812 patients treated in clinical trials), and adverse reactions reported in post-marketing surveillance of paclitaxel use. The latter may be characteristic of paclitaxel regardless of treatment regimen.

The following adverse reactions are categorized by frequency: 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 (frequency cannot be estimated from available data).

Infections and infestations: very common – infections (mainly urinary tract and upper respiratory tract), occasionally fatal; uncommon – septic shock; rare* – pneumonia, peritonitis, sepsis.

Blood and lymphatic system disorders: very common – myelosuppression, neutropenia, anaemia, thrombocytopenia, leucopenia, bleeding; rare* – febrile neutropenia; very rare* – acute myeloid leukaemia, myelodysplastic syndrome; frequency not known – disseminated intravascular coagulation.

Immune system disorders: very common – mild hypersensitivity reactions (mainly flushing and rash); uncommon – severe hypersensitivity reactions requiring therapeutic intervention (including 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: very rare* – anorexia; frequency not known* – tumour lysis syndrome.

Psychiatric disorders: very rare* – confusion.

Nervous system disorders: very common – neurotoxic effects (mainly peripheral neuropathy); rare* – motor neuropathy (manifesting as mild distal muscle weakness); very rare – autonomic neuropathy (leading to paralytic ileus and orthostatic hypotension), grand mal seizures, convulsions, encephalopathy, dizziness, headache, ataxia.

Eye disorders: very rare* – optic nerve damage and/or visual disturbances (scintillating scotoma), particularly in patients receiving doses above recommended levels; frequency not known* – macular oedema, photopsia, floaters in the vitreous body.

Ear and labyrinth disorders: very rare* – ototoxic effects, hearing loss, tinnitus, vertigo.

Cardiac disorders: common – bradycardia; uncommon – cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy, atrioventricular block and syncope, myocardial infarction; rare – heart failure; very rare* – atrial fibrillation, supraventricular tachycardia.

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

Respiratory, thoracic and mediastinal disorders: rare* – dyspnoea, pleural effusion, interstitial pneumonia, pulmonary fibrosis, pulmonary embolism, respiratory failure; very rare* – cough.

Gastrointestinal disorders: very common – nausea, vomiting, diarrhoea, mucositis; rare* – intestinal obstruction, intestinal perforation, ischaemic colitis, pancreatitis; very rare* – mesenteric thrombosis, pseudomembranous colitis, oesophagitis, constipation, ascites, neutropenic colitis.

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; rare* – pruritus, rash, erythema; very rare* – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients receiving paclitaxel should wear long-sleeved clothing and long pants to protect arms and legs from sun exposure); frequency not known* – scleroderma, hand-foot erythrodysesthesia syndrome.

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 (including localized swelling, pain, erythema, induration; accidental extravasation may cause cellulitis, skin fibrosis, and skin necrosis); rare* – asthenia, fever, dehydration, oedema, malaise.

Investigations: common – significant increases in AST (SGOT) and alkaline phosphatase levels; uncommon – significant increase in bilirubin levels; rare* – increased blood creatinine levels.

* As reported in post-marketing surveillance.

In patients with breast cancer receiving paclitaxel as adjuvant therapy in combination with AC, symptoms such as severe neurosensory toxicity, hypersensitivity reactions, arthralgia/myalgia, anaemia, infections, fever, nausea/vomiting, and diarrhoea were observed more frequently than in patients treated with AC alone, although the frequency of these adverse reactions was comparable to that seen with paclitaxel monotherapy.

Adverse Effects with Combination Chemotherapy

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

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 in combination with cisplatin.

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

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) was higher in patients with metastatic breast cancer compared to paclitaxel monotherapy: heart failure (8% vs. 1%), infection (46% vs. 27%), chills (42% vs. 4%), fever (47% vs. 23%), cough (42% vs. 22%), rash (39% vs. 18%), arthralgia (37% vs. 21%), tachycardia (12% vs. 4%), diarrhoea (45% vs. 30%), hypertension (11% vs. 3%), epistaxis (18% vs. 4%), acne (11% vs. 3%), herpes simplex (12% vs. 3%), accidental injury (13% vs. 3%), insomnia (25% vs. 13%), rhinitis (22% vs. 5%), sinusitis (21% vs. 7%), 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 using paclitaxel and trastuzumab was comparable to that with paclitaxel monotherapy.

Impaired cardiac contractility (left ventricular ejection fraction decrease > 20%) occurred in 15% of patients with metastatic breast cancer receiving doxorubicin in combination with paclitaxel, and in 10% of patients receiving standard therapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen). The incidence of congestive heart failure was <1% with both paclitaxel plus doxorubicin and standard FAC therapy. With combination chemotherapy using trastuzumab and paclitaxel, the frequency and severity of cardiac dysfunction were higher in patients previously treated with anthracyclines compared to paclitaxel monotherapy (NYHA class I-II heart failure in 10% of patients vs. 0%; NYHA class III-IV heart failure in 2% of patients vs. 1%). In isolated cases, these disorders were fatal. Except for these isolated fatal cases, patients responded to appropriate therapy.

Radiation pneumonitis was observed in patients who received concurrent radiotherapy.

Adverse Effects in AIDS Patients with Kaposi's Sarcoma

Except for adverse effects related to the haematopoietic system and liver, the frequency and severity of adverse effects in patients with Kaposi's sarcoma were comparable to those in patients with other solid tumours receiving paclitaxel monotherapy.

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

Neutropenic fever associated with paclitaxel therapy occurred in 14% of patients during 1.3% of treatment cycles. Three septic episodes (2.8%) resulting in fatal outcomes were recorded during paclitaxel therapy.

Thrombocytopenia occurred in 50% of patients, and 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 and were localized.

Anaemia (Hb < 11 g/dL) occurred in 61% of patients, and severe anaemia (Hb < 8 g/dL) in 10%. 21% of patients required erythrocyte 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.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: http://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

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

Incompatibilities.

Polyoxyl 35 castor oil, an excipient in Paclitaxel Accord, may cause leaching of diethylhexyl phthalate (DEHP) from plasticized polyvinyl chloride (PVC). The extent 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 "Instructions for Use and Dosage."

Packaging.

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

Prescription status.

By prescription only.

Manufacturer. Accord Healthcare Polska Sp. z o.o. Importer's Address / Accord Healthcare Polska Sp. z o.o. Magazyn Importera.

Manufacturer's address and location of operations. ul. Lutomierska 50, Pabianice, 95-200, Poland / ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing Authorization Holder. Accord Healthcare Polska Sp. z o.o. / Accord Healthcare Polska Sp. z o.o.

Inquiries regarding substandard quality of the medicinal product, safety concerns, improper use, or complaints are accepted 24/7 via phone: +380993100335 or by email: [email protected].

Marketing Authorization Holder's address. 7 Tasmowa St., Warsaw, 02-677, Poland / 7 Tasmowa St., Warsaw, 02-677, Poland.