Paxovar

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

Composition:

Active substance: paclitaxel;

1 ml of solution contains 6 mg of paclitaxel;

Excipients: macrogolglycerol ricinoleate; anhydrous ethanol; citric acid monohydrate.

Pharmaceutical form. Concentrate for solution for infusion.

Main physico-chemical properties: clear, viscous solution ranging from colorless to pale yellow, free from particles.

Pharmacotherapeutic group. Antineoplastic agents. Taxanes. ATC code L01C D01.

Pharmacological Properties

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

Pharmacokinetics.

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

Pharmacokinetics of paclitaxel were determined after infusions at doses of 135 mg/m² 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 from 11.6 to 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 body surface area), the maximum plasma concentration (Cmax) and the area under the 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), mean AUC was 5619 ng·h/mL (range: 2609–9428 ng·h/mL), clearance was 20.6 L/h·m² (range: 11–38 L/h·m²), volume of distribution was 291 L/m² (range: 121–638 L/m²), and terminal half-life was 23.7 hours (range: 12–33 hours).

Variability in systemic exposure to paclitaxel among individual patients was minimal. No accumulation of paclitaxel was observed after multiple 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 protein binding of paclitaxel.

The metabolism of paclitaxel in humans has not been fully elucidated. The mean total excretion of unchanged drug in urine 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 CYP2C8 + CYP3A4 together. The impact of renal or hepatic impairment on the metabolism of paclitaxel after a 3-hour infusion has not been studied. Pharmacokinetic parameters in one patient requiring hemodialysis who was 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 is used concomitantly with doxorubicin, an increased duration of distribution and elimination of doxorubicin and its metabolites has been observed. When paclitaxel was administered immediately after doxorubicin, total plasma exposure to doxorubicin was 30% higher than when paclitaxel was administered 24 hours after doxorubicin.

When paclitaxel is used in combination with other therapies, refer to the appropriate guidelines for the use of cisplatin, doxorubicin, and trastuzumab.

Clinical Characteristics

Indications

• Ovarian cancer: First-line chemotherapy for the treatment of ovarian cancer, as well as use in combination with cisplatin in advanced disease or in cases of residual tumors (larger than 1 cm) following laparotomy; second-line chemotherapy for metastatic ovarian cancer when standard platinum-based therapy has been ineffective.
• Breast cancer: Adjuvant chemotherapy in patients with lymph node involvement following standard combination therapy with anthracyclines or 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 when anthracycline therapy is contraindicated; monotherapy for metastatic breast cancer in patients who are not candidates for standard anthracycline therapy or in whom prior anthracycline therapy has failed.
• Extensive-stage 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 when prior treatment with liposomal anthracyclines has been ineffective.

Contraindications

Hypersensitivity to paclitaxel or any other component of the medicinal product, especially to polyoxyethylated castor oil. Pregnancy and lactation. Neutropenia prior to treatment initiation (baseline neutrophil count < 1.5 × 10⁹/L; in AIDS patients with Kaposi’s sarcoma, neutrophil count < 1 × 10⁹/L), thrombocytopenia (< 100 × 10⁹/L). Concurrent severe uncontrolled infections in patients with Kaposi’s sarcoma. Severe hepatic dysfunction.

Safety precautions

Instructions for healthcare personnel. When handling this medicinal product, 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 with skin occurs, affected areas should be washed thoroughly with soap and water. Skin tingling, burning, and redness may occur at the site of contact. If the solution contacts 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; this precipitate dissolves upon gentle agitation or even without mixing when the solution reaches room temperature. This phenomenon does not affect the quality of the medicinal product. However, if the solution remains cloudy or contains undissolved precipitate, the product must not be used and the vial should be discarded according to established hazardous waste disposal procedures.

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

Preparation of infusion solution. The medicinal product must be diluted under aseptic conditions prior to infusion. Paclitaxel should be diluted with 0.9% sodium chloride isotonic solution, 5% glucose solution, 5% glucose with 0.9% sodium chloride (1:1), or Ringer’s solution with 5% glucose to a concentration between 0.3 and 1.2 mg/mL.

Chemical and physical stability of the diluted solution has been demonstrated for 72 hours at temperatures not exceeding 25°C when diluted with 0.9% sodium chloride, 5% glucose, 5% glucose with 0.9% sodium chloride (1:1), or Ringer’s solution with 5% glucose (1:1). From a microbiological standpoint, the product should be used immediately. If the solution is not administered immediately after preparation, the user is responsible for the storage conditions and duration prior to administration. Diluted solutions should not be refrigerated.

After preparation, the solution may appear cloudy due to the presence of solvent in the concentrate. Filtration to remove cloudiness is not recommended. The drug should be administered through infusion sets equipped with in-line membrane filters with pore size no larger than 0.22 μm. No significant loss of active ingredient has been observed when administered through such systems.

Rarely, precipitation has been reported during 24-hour infusions. Although the exact cause is unknown, it may result from solution supersaturation. To minimize the risk of precipitation, the drug should be administered as soon as possible after dilution, and excessive agitation should be avoided. The infusion system should be thoroughly flushed before use. The solution should be monitored regularly during infusion, and infusion should be discontinued if precipitation occurs.

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

Interaction with other medicinal products and other forms of interaction

Premedication with cimetidine does not affect paclitaxel clearance.

In the combination 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 is reduced by approximately 20%. The risk of renal impairment in patients with ovarian cancer receiving combination therapy with paclitaxel and cisplatin is higher than with cisplatin monotherapy.

Since 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.

When paclitaxel is used in combination with doxorubicin, and paclitaxel is administered before doxorubicin using a longer-than-recommended infusion duration (paclitaxel infused over 24 hours; doxorubicin over 48 hours), stomatitis and episodes of neutropenia have been observed.

Paclitaxel metabolism is partially catalyzed by the CYP2C8 and CYP3A4 isoenzymes of the cytochrome P450 system. Clinical studies have demonstrated that the primary 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 using paclitaxel concomitantly with inhibitors (e.g., ketoconazole and other imidazole-derived antifungals, erythromycin, fluoxetine, gemfibrozil, deferasirox, trimethoprim, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine, St. John’s wort) of CYP2C8 and CYP3A4 isoenzymes.

When the above-mentioned inhibitors are used concomitantly with paclitaxel, paclitaxel toxicity may increase; when paclitaxel is used with the above-mentioned inducers, paclitaxel efficacy may be reduced.

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

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

Special precautions for use

Treatment 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 infiltration is recommended.

Prior to paclitaxel administration, patients must receive premedication with corticosteroids, antihistamines, and H2-receptor antagonists. When paclitaxel 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.

Despite premedication, fatal hypersensitivity reactions have been reported in patients. These symptoms are likely histamine-mediated reactions. In the event of severe hypersensitivity reactions, paclitaxel infusion must be immediately discontinued and symptomatic treatment initiated; re-administration of the drug is not recommended.

Mild symptoms such as flushing or other skin reactions do not require discontinuation of therapy. The medicinal product contains polyoxyethylated castor oil (macrogolglycerides of ricinoleic acid), which may cause severe allergic reactions.

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of the drug. The lowest neutrophil count is typically observed on average on day 11. 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 levels 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. 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 paclitaxel administration, more pronounced myelosuppression may occur in patients with moderate hepatic impairment. Paclitaxel is contraindicated in patients with severe hepatic dysfunction. Patients should be closely monitored for signs of severe myelosuppression. Currently, there are insufficient data to provide dosage adjustment recommendations for patients with mild or moderate hepatic impairment. Information on paclitaxel use in patients with severe cholestasis is lacking.

Severe cardiac conduction disorders have been reported rarely. In case of severe conduction disturbances during paclitaxel therapy, appropriate treatment should be initiated, and careful cardiac monitoring is required if further drug administration is considered. Vital signs should be monitored during the first hour of paclitaxel infusion. Arterial hypotension, arterial hypertension, and bradycardia may occur during 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.

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 frequency of ventricular function assessment should consider the cumulative anthracycline dose (in mg/m² body surface area). If test results indicate cardiac dysfunction—even if asymptomatic—the potential benefit of continuing therapy must be carefully weighed against the risk of cardiac damage, which may be irreversible. If combination chemotherapy is continued, cardiac monitoring should be increased (every 1–2 cycles).

Sepsis. Sepsis has been reported in 5% of patients receiving paclitaxel in combination with gemcitabine, with or without neutropenia. Complications associated with adenocarcinoma of the pancreas, particularly biliary obstruction or presence of a biliary stent, have been identified as significant risk factors. If fever occurs (regardless of neutrophil count), broad-spectrum antibiotic therapy should be initiated promptly. In cases of febrile neutropenia, paclitaxel and gemcitabine should be withheld until fever resolves and absolute neutrophil count (ANC) reaches ≥1500 cells/mm³, after which treatment may be resumed at reduced doses.

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

Ethanol. Since paclitaxel contains ethanol, its potential effects on the central nervous system (CNS) and other possible effects should be considered. The drug may be harmful to patients with alcoholism. The ethanol content should be taken into account when administering the drug to children and patients at increased risk, such as those with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter the effects of other drugs.

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

Pseudomembranous colitis. Rarely, pseudomembranous colitis has been 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 with paclitaxel chemotherapy combined with radiotherapy to the lung area, regardless of sequence.

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

Teratogenicity, embryotoxicity, and mutagenicity. Paclitaxel has demonstrated teratogenic, embryotoxic, and mutagenic effects in several experimental systems. Therefore, patients of reproductive age and/or their partners should use contraception for at least 6 months after completion of paclitaxel therapy (see section "Use during pregnancy or breastfeeding").

Male patients are advised to consult on sperm preservation prior to treatment initiation due to the potential for irreversible infertility caused by paclitaxel therapy.

CNS metastases. The efficacy and safety of paclitaxel in patients with CNS metastases have not been established. CNS metastases are generally poorly controlled by systemic chemotherapy.

Gastrointestinal symptoms. Nausea, vomiting, and diarrhea occurring after paclitaxel administration can be managed with standard antiemetic medications.

Visual disturbances. Macular edema has been reported in patients receiving paclitaxel. Patients experiencing visual disturbances should undergo immediate comprehensive ophthalmologic evaluation. If macular edema is diagnosed, paclitaxel should be discontinued and appropriate treatment initiated.

Patients aged 75 years and older. No benefit of combination therapy with paclitaxel and gemcitabine over gemcitabine monotherapy has been demonstrated in patients aged 75 years and older. In patients aged 75 years and older receiving paclitaxel and gemcitabine, a higher incidence of serious adverse reactions and reactions requiring treatment discontinuation was observed, including hematologic toxicity, peripheral neuropathy, decreased appetite, and dehydration. Patients with pancreatic adenocarcinoma aged 75 years and older should be carefully monitored for their ability to tolerate paclitaxel in combination with gemcitabine, with mandatory consideration of overall health status and comorbidities.

Other warnings. Patients with severe renal impairment should not be treated with paclitaxel.

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

Hormonal contraception is contraindicated in cases of HR+ tumors.

Use during pregnancy or breastfeeding

Pregnancy. Paclitaxel has shown embryotoxic and fetotoxic effects in rabbits and reduced fertility in rats in experimental studies. There are insufficient data on the use of paclitaxel in pregnant women. Like other cytotoxic drugs, paclitaxel poses a potential risk to the fetus. Therefore, paclitaxel is contraindicated during pregnancy. Women of reproductive age should not plan pregnancy during paclitaxel therapy and must immediately inform their physician if pregnancy occurs. Women and men of reproductive age and/or their partners must use reliable contraception during treatment and for at least 6 months after completion of paclitaxel therapy and must immediately inform their physician if pregnancy occurs.

Breastfeeding. It is unknown whether paclitaxel is excreted in human breast milk. Paclitaxel is contraindicated in breastfeeding women. Breastfeeding must be discontinued during paclitaxel therapy.

Fertility. Paclitaxel has been shown to reduce fertility in rats. It is unknown whether these findings are applicable to humans. Male patients should undergo sperm cryopreservation prior to starting paclitaxel therapy due to the risk of infertility.

Ability to influence reaction speed when driving or operating machinery

During paclitaxel therapy, patients should refrain from potentially hazardous activities requiring high concentration and rapid psychomotor responses. It should be noted that the medicinal product contains alcohol, and certain adverse reactions may negatively affect the ability to drive or operate machinery.

Administration 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)	For oral administration: approximately 6 and 12 hours before paclitaxel infusion. For 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 dosage regimens of paclitaxel 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 as a 3-hour intravenous infusion. Typically, no more than 4 cycles should be administered, with intervals of 3 weeks between cycles.

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 as a 3-hour intravenous infusion. 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 by 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 by 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 as a 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 as a 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.

Chemotherapy of Kaposi’s sarcoma in AIDS patients

The recommended dose is 100 mg/m² body surface area administered as a 3-hour intravenous infusion every 2 weeks.

Subsequent doses of paclitaxel must be adjusted according to individual patient tolerance. Repeated administration is possible only after neutrophil counts have increased to ≥ 1.5×10⁹/L (≥ 1.0×10⁹/L in Kaposi’s sarcoma patients) and platelet counts have increased 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 more) or severe peripheral neuropathy, subsequent doses should be reduced by 20% (by 25% for Kaposi’s sarcoma patients).

Treatment of patients with hepatic impairment

There is insufficient data on dosing for 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 on dose adjustment for patients with renal impairment.

Preparation of infusion solution

Before administration, the concentrate for infusion solution (Paxovar) 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 remains microbiologically, physically, and chemically stable for up to 28 days at 25°C.

Infusion solutions prepared by diluting Paxovar 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 re-dissolve 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 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. Typically, 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 has been observed when administered through such systems.

Prepared infusion solutions do not require protection from light.

There have been isolated reports of precipitate formation in the infusion solution during administration (usually toward the end of a 24-hour infusion). Although the exact cause of precipitate formation has not been determined, 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 infusion, 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, polypropylene or polyolefin bags) and administered through polyethylene infusion systems. Filters may be connected using short PVC tubing—this does not cause significant DEHP leaching.

Geriatric patients

No additional dose reduction is recommended for patients aged 65 years and older.

Among 229 patients receiving paclitaxel monotherapy for breast cancer, 13% were aged ≥ 65 years and 2% were aged ≥ 75 years. In patients aged ≥ 65 years, there was no increased incidence of toxicity. However, further analysis of data from 981 patients receiving paclitaxel monotherapy for metastatic breast cancer, of whom 15% were aged ≥ 65 years and 2% were aged ≥ 75 years, revealed higher frequencies of epistaxis, diarrhea, dehydration, malaise, and peripheral edema compared to younger patients. Among 421 patients with pancreatic adenocarcinoma receiving paclitaxel and gemcitabine in a randomized study, 41% were aged ≥ 65 years and 10% were aged ≥ 75 years. In patients aged ≥ 75 years receiving paclitaxel and gemcitabine, there was a higher incidence of serious adverse reactions and adverse reactions requiring treatment discontinuation. Patients with pancreatic adenocarcinoma aged ≥ 75 years should be carefully evaluated before initiating therapy. Among 514 patients with non-small cell lung cancer receiving paclitaxel in combination with carboplatin, 31% were aged ≥ 65 years and 3.5% were aged ≥ 75 years. Myelosuppression, peripheral neuropathy, and arthralgia occurred more frequently in patients aged ≥ 65 years compared to those under 65 years. There is some experience with paclitaxel/carboplatin use in patients aged ≥ 75 years. Pharmacokinetic/pharmacodynamic modeling using data from 125 patients with advanced solid tumors indicated that patients aged ≥ 65 years may be more susceptible to developing neutropenia during the first treatment cycle.

Administration method

The concentrate for infusion solution must be diluted before administration. Paclitaxel should be administered only in specialized oncology centers under the supervision of a qualified oncologist. The drug must be administered intravenously through an integrated filter with a microporous membrane ≤ 0.22 μm.

Pediatric use

The safety and efficacy of paclitaxel in children have not been established; therefore, paclitaxel is not recommended for use in children (under 18 years of age).

Overdose

Symptoms: The main expected complications of overdose are bone marrow suppression, peripheral neuropathy, and mucositis.

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

Adverse Reactions

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

The frequency and intensity of adverse reactions in patients with ovarian cancer, breast cancer, and non-small cell lung cancer do not differ significantly. Age did not influence any of the observed types of toxicity.

Monotherapy

The most common adverse effect of paclitaxel therapy is bone marrow suppression. Severe neutropenia (< 500/mm³) was observed in 28% of patients, but no cases of febrile neutropenia were reported. Severe neutropenia lasting ≥ 7 days occurred in only 1% of patients. Thrombocytopenia with platelet counts < 50,000/mm³ occurred in a small number of patients at least once during the study, and anemia (frequency and severity of anemia depend on baseline hemoglobin levels). Disseminated intravascular coagulation (DIC) syndrome has been reported, often in combination with sepsis or multiorgan failure. Neurotoxicity, primarily peripheral neuropathy, is likely to occur frequently and is a more severe adverse effect with a 3-hour infusion of paclitaxel 175 mg/m² (neurotoxicity in 85% of cases, severe in 15%) compared to a 24-hour infusion of paclitaxel 135 mg/m² (peripheral neuropathy in 25% of cases, severe in 3%) when paclitaxel is combined with cisplatin. In patients with non-small cell lung cancer and ovarian carcinoma receiving paclitaxel over 3 hours followed by cisplatin, the incidence of severe neurotoxicity was significantly higher. Peripheral neuropathy may develop after the first treatment cycle and worsen with subsequent paclitaxel administrations. Occasionally, it may necessitate discontinuation of paclitaxel therapy. Sensory symptoms usually improve or resolve within several months after stopping paclitaxel. Pre-existing neuropathy due to prior therapy is not a contraindication to paclitaxel treatment. Furthermore, peripheral neuropathy may persist for up to 6 months after discontinuation of paclitaxel.

Severe hypersensitivity reactions, potentially fatal (hypotension requiring therapeutic intervention; angioedema; respiratory dysfunction requiring bronchodilators; generalized urticaria), were observed in 2 patients (< 1% of all patients). Mild hypersensitivity reactions occurred in 34% of patients (17% of all treatment courses). These mild reactions, primarily flushing and rash, did not require therapeutic intervention or discontinuation of paclitaxel therapy.

Arthralgia or myalgia was observed in 60% of patients, with severe symptoms in 13%. At the injection site, local swelling, pain, erythema, and induration may occur. Accidental extravasation may cause cellulitis. There have been isolated reports of skin desquamation and/or necrosis associated with extravasation. Skin color changes may also occur. Isolated reports of skin reactions, so-called local inflammatory reactions at the site of previous extravasation, have been reported after paclitaxel administration at another site. There is currently no specific treatment for extravasation reactions. In some cases, infusion site reactions began during prolonged infusion or 7–10 days later. Alopecia was observed in 87% of patients receiving paclitaxel. Most cases of hair loss occurred within the first month after starting paclitaxel therapy. Most patients experiencing hair loss expect significant hair loss ≥ 50%. The list below includes adverse reactions observed during monotherapy with paclitaxel via 3-hour infusion in metastatic cancer (812 patients treated in clinical trials) and adverse reactions identified during post-marketing use of paclitaxel regardless of treatment regimen. Frequency of adverse events is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data). Within each frequency group, adverse effects are listed in order of decreasing severity.

Infections and infestations

Very common: infections (predominantly of the urinary tract and upper respiratory tract, including herpes simplex, oral candidiasis, pharyngitis, rhinitis), occasionally with fatal outcome; injection site infections.

Uncommon: severe infections, septic shock.

Rare: pneumonia*, peritonitis*, sepsis*.

Very rare: pseudomembranous colitis*.

Blood and lymphatic system disorders

Very common: myelosuppression, neutropenia, anemia, thrombocytopenia, leukopenia, tendency to bleeding.

Common: febrile neutropenia*.

Uncommon: severe anemia.

Rare: febrile neutropenia*.

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

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

Immune system disorders

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

Uncommon: delayed-type hypersensitivity reactions, serious hypersensitivity reactions requiring therapeutic intervention (including arterial hypotension, angioedema, respiratory distress, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, limb pain, profuse sweating, and arterial hypertension).

Rare: anaphylactic reactions*.

Very rare: anaphylactic shock* (including fatal hypersensitivity reactions).

Frequency not known: bronchospasm*.

Metabolism and nutrition disorders

Rare: weight loss and weight gain, dehydration*.

Very rare: anorexia*, hypokalemia, hypophosphatemia, fluid retention, hypoalbuminemia, polydipsia, hyperglycemia, hypocalcemia, hypoglycemia, hyponatremia.

Frequency not known: tumor lysis syndrome*.

Psychiatric disorders

Very rare: confusion*, anxiety, restlessness.

Nervous system disorders

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

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

Rare: motor neuropathy (manifested as moderately pronounced distal muscle weakness)*, dyskinesia, hyporeflexia, neuralgia, loss of sensation, dizziness, neuropathic pain, tremor.

Very rare: autonomic neuropathy (leading to paralytic ileus and orthostatic hypotension)*, grand mal seizures*, convulsions*, encephalopathy*, dizziness*, headache*, ataxia*.

Eye disorders

Common: increased lacrimation.

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.

Frequency not known: macular edema*, photopsia*, floaters*.

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*.

Vascular disorders

Very common: arterial hypotension.

Common: vasodilation (flushing).

Uncommon: thrombosis, arterial hypertension, thrombophlebitis.

Very rare: shock*.

Frequency not known: phlebitis*.

Respiratory, thoracic and mediastinal disorders

Common: epistaxis, throat/esophagus pain, rhinitis, rhinorrhea, productive cough, exertional dyspnea, sinus congestion, decreased breath sounds, allergic rhinitis, hoarseness, nasal congestion, dryness of nasal mucosa.

Rare: respiratory failure*, pulmonary embolism*, lung fibrosis*, interstitial pneumonitis*, dyspnea*, pleural effusion*.

Very rare: cough*, pulmonary hypertension*.

Gastrointestinal disorders

Very common: nausea, vomiting, diarrhea, mucosal inflammation, stomatitis, abdominal pain.

Common: dry mouth, oral ulcers, melena, dyspepsia, flatulence, gastroesophageal reflux disease, oral hypoesthesia, dysphagia, glossalgia, gum pain, loose stools, oral cavity pain, rectal bleeding.

Rare: intestinal obstruction*, intestinal perforation*, ischemic colitis*, acute pancreatitis*.

Very rare: mesenteric thrombosis*, pseudomembranous colitis*, neutropenic colitis*, ascites*, esophagitis*, constipation*, hypohydration*.

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

Very common: alopecia.

Common: transient and minor changes in nails and skin, dry skin, acne.

Uncommon: nail discoloration.

Rare: pruritus*, rash*, erythema*, swelling*.

Very rare: Stevens-Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme*, exfoliative dermatitis*, urticaria*, onycholysis* (patients receiving paclitaxel should wear long-sleeved clothing and long pants to protect arms and legs from sunlight), folliculitis*.

Frequency not known: scleroderma*, hand-foot syndrome*.

Musculoskeletal and connective tissue disorders

Very common: arthralgia, myalgia, bone pain, leg cramps, myasthenia, back pain, limb pain, bone pain.

Frequency not known: systemic lupus erythematosus*.

Renal and urinary disorders

Common: dysuria, frequent urination, hematuria, nocturia, polyuria, urinary incontinence.

Rare: renal failure.

General disorders and administration site conditions

Very common: mucosal inflammation.

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

Rare: hyperthermia, chest pain, chills, increased body temperature*, dehydration*, asthenia*, swelling*, malaise*, influenza-like illness; there are isolated reports of recurrence of skin reactions at sites of previous paclitaxel extravasation after subsequent administrations of the drug.

Laboratory findings

Common: significant (≥ 5 times above normal) elevation of liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and alkaline phosphatase), decreased hematocrit, decreased erythrocyte count, increased gamma-glutamyl transferase.

Uncommon: significant elevation of bilirubin, significant elevation of lactate dehydrogenase, significant elevation of blood glucose, significant elevation of blood phosphorus, decreased blood potassium.

Rare: increased blood creatinine*.

Injury, poisoning and procedural complications: hematoma, local inflammatory reaction in previously irradiated area, radiation pneumonitis.

* Reported during post-marketing use of paclitaxel.

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

In patients with breast cancer who received paclitaxel for adjuvant therapy following standard combination therapy with anthracyclines and cyclophosphamide (AC), neurotoxicity, hypersensitivity reactions, arthralgia/myalgia, anemia, infection, fever, nausea/vomiting, and diarrhea were observed more frequently compared to patients who received only AC. The frequency of these adverse reactions was consistent with that observed during paclitaxel monotherapy as described above.

Effects on blood and lymphatic system

Myelosuppression is the main dose-limiting toxic effect. The most significant manifestation of hematological toxicity was neutropenia. During the first treatment cycle, severe neutropenia (< 500/mm³) was observed 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. Hematological parameters normalized within 35 days in all monitored patients. The incidence of grade IV neutropenia lasting 7 days or more was 22%.

Febrile neutropenia associated with paclitaxel therapy was observed in 14% of patients, during 1.3% of treatment courses. Three episodes of sepsis (2.8%) related to paclitaxel therapy, resulting in fatal outcome, were recorded during treatment.

Thrombocytopenia was observed in 50% of patients and was severe (< 50,000/mm³) in 9% of cases. Platelet counts decreased to < 75,000/mm³ at least once during treatment in 14% of patients. Bleeding events related to paclitaxel occurred in < 3% of patients, but these were localized. Anemia (Hb < 11 g/dL) was observed in 61% of patients and was severe (Hb < 8 g/dL) in 10% of cases. 21% of patients required erythrocyte transfusions.

Combination therapy

When paclitaxel is combined with cisplatin, neurotoxicity, primarily peripheral neuropathy, occurs more frequently and is more severe with a 3-hour infusion of paclitaxel 175 mg/m² (neurotoxic effects reported in 85% of patients, severe in 15%) compared to a 24-hour infusion of paclitaxel 135 mg/m² (neurotoxic effects in 25% of patients, severe in 3%).

In patients with non-small cell lung cancer and ovarian cancer who received paclitaxel over 3 hours followed by cisplatin, the frequency of severe neurotoxicity increased. Peripheral neuropathy may develop after the first treatment cycle and worsen with subsequent paclitaxel administrations. Occasionally, it may necessitate discontinuation of paclitaxel therapy. Sensory symptoms usually improve or resolve within several months after stopping paclitaxel. Pre-existing neuropathy due to prior therapy is not a contraindication to paclitaxel treatment. Patients receiving paclitaxel and cisplatin have an increased risk of developing renal failure compared to patients receiving cisplatin alone for gynecological tumors.

The data below are from:

• Two large first-line chemotherapy trials in ovarian cancer (paclitaxel + cisplatin; over 1050 patients);
• Two phase III trials in first-line chemotherapy of metastatic breast cancer—one trial combining with doxorubicin (paclitaxel + doxorubicin; 267 patients); the second trial combining with trastuzumab (planned subgroup analysis of paclitaxel + trastuzumab; 188 patients);
• Two phase III trials in advanced non-small cell lung cancer (paclitaxel + cisplatin; over 360 patients).

In patients with ovarian cancer receiving first-line chemotherapy with paclitaxel via 3-hour intravenous infusions combined with cisplatin, the frequency and severity of neurotoxic effects, arthralgia/myalgia, and hypersensitivity reactions were higher compared to treatment with cyclophosphamide combined with cisplatin. The frequency and severity of myelosuppression were lower in the group receiving paclitaxel via 3-hour intravenous infusions combined with cisplatin compared to the group receiving cyclophosphamide combined with cisplatin.

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

Paclitaxel with trastuzumab

In first-line chemotherapy with paclitaxel via 3-hour intravenous infusions combined with trastuzumab, the frequency of the following adverse reactions (regardless of causal relationship to paclitaxel or trastuzumab) in patients with metastatic breast cancer was higher than with paclitaxel monotherapy: heart failure (8% vs 1%), infection (46% vs 27%), chills (42% vs 4%), fever (47% vs 23%), cough (42% vs 22%), rash (39% vs 18%), arthralgia (37% vs 21%), tachycardia (12% vs 4%), diarrhea (45% vs 30%), arterial hypertension (11% vs 3%), epistaxis (18% vs 4%), acne (11% vs 3%), herpes simplex (12% vs 3%), accidental injury (13% vs 3%), insomnia (25% vs 13%), rhinitis (22% vs 5%), sinusitis (21% vs 7%), and injection site reactions (7% vs 1%). Some of these frequency differences may be attributed to the greater number and duration of treatment cycles with the paclitaxel/trastuzumab combination compared to paclitaxel monotherapy. The frequency of serious adverse effects was similar between combination chemotherapy with paclitaxel and trastuzumab and paclitaxel monotherapy.

Paclitaxel with doxorubicin

Impaired cardiac contractility (left ventricular ejection fraction decrease > 20%) was observed in 15% of patients with metastatic breast cancer receiving doxorubicin combined 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 paclitaxel therapy, 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 class [New York Heart Association] I/II—10% vs 0%; NYHA class III/IV—2% vs 1%), and fatal outcomes were rarely observed. In isolated cases, cardiac dysfunction (with combination chemotherapy using trastuzumab and paclitaxel in patients previously treated with anthracyclines) was associated with fatal outcome. All patients responded to appropriate treatment except in the aforementioned isolated cases.

Special patient groups

Radiation pneumonitis was observed in patients who received concomitant radiotherapy with the drug.

Adverse reactions in AIDS patients with Kaposi's sarcoma

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

Blood and lymphatic system disorders

Bone marrow suppression was the main dose-limiting toxic effect. The most significant manifestation of hematological toxicity was neutropenia. During the first treatment course, severe neutropenia (< 500 cells/mm³) was observed in 20% of patients. Throughout the entire treatment period, severe neutropenia occurred in 39% of patients. Neutropenia duration was > 7 days in 41% of patients and 30–35 days in 8% of patients. Neutropenia resolved within 35 days in all monitored patients. The frequency of grade IV neutropenia lasting ≥ 7 days was 22%. Febrile neutropenia associated with paclitaxel therapy was observed in 14% of patients and during 1.3% of treatment courses. Three cases of sepsis (2.8%) related to the drug, resulting in fatal outcome, were recorded during paclitaxel therapy. Thrombocytopenia was observed in 50% of patients, and severe thrombocytopenia (< 50,000 cells/mm³) in 9%. Platelet counts decreased below 75,000 cells/mm³ at least once during treatment in only 14% of patients. Bleeding episodes related to paclitaxel therapy were observed in less than 3% of patients, but bleeding was 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 by 21% of patients.

128 cases of DIC syndrome were identified, 31 of which were time-related. Additionally, 47 fatal cases due to disseminated intravascular coagulation were recorded.

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

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

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 2 years.

After opening the vial prior to dilution

Chemical and physical stability has been demonstrated for 28 days at a temperature not exceeding 25°C.

From a microbiological standpoint, after the first opening, the concentrated infusion solution may be stored for up to 28 days at a temperature not exceeding 25°C. If the solution is not used immediately, responsibility for the duration and conditions of storage of the ready-to-use solution lies with the user (healthcare personnel).

After dilution

Infusion solutions prepared by diluting paclitaxel with 0.9% sodium chloride solution or 5% glucose solution are physically and chemically stable for 27 hours when stored at a temperature not exceeding 25°C and for 7 days when stored at 2–8°C. The cooled solution may precipitate but can redissolve at room temperature (25°C). The vial should be discarded if the solution is cloudy or if the precipitate does not redissolve. Freezing does not affect shelf life. From a microbiological standpoint, the infusion solution should be administered immediately after preparation. If not used immediately, the user must monitor the duration and conditions of storage. Usually, storage time should not exceed 24 hours at 2–8°C unless the solution was prepared under controlled and validated aseptic conditions.

Storage conditions. The medicinal product does not require special storage conditions. Store out of reach of children.

Incompatibilities. Polyethylglycol ricinoleate, an ingredient of the medicinal product, may cause leaching of diethylhexylphthalate from plasticized PVC. The intensity of this process depends on the duration of exposure and the concentration of polyethylglycol ricinoleate. 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 "Method of administration and dosage."

Packaging. 5 mL (30 mg), or 16.7 mL (100 mg), 25 mL (150 mg), or 50 mL (300 mg) in a vial, 1 vial per pack.

Prescription category. Prescription only.

Manufacturer. Farmahem B.V.

Manufacturer's address and location of operations. Swensweg 5, Haarlem, 2031 GA, Netherlands.