Kazexa
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KAZEXA (CAZEXA)
Composition:
Active substance: cabazitaxel;
1 vial of concentrate (1.5 ml) contains cabazitaxel 60 mg;
1 ml of concentrate contains 40 mg of cabazitaxel; after initial dilution with the entire volume of solvent, 1 ml of solution contains 10 mg of cabazitaxel;
Excipient: polysorbate 80;
1 vial of solvent (4.5 ml) contains: ethanol 96%, water for injections.
Pharmaceutical form. Concentrate for solution for infusion.
Main physicochemical properties:
Concentrate: clear, viscous solution, yellow to brownish-yellow in color;
Solvent: clear, colorless solution, free from visible particles.
Pharmacotherapeutic group. Antineoplastic agents. ATC code L01C D04.
Pharmacological Properties
Pharmacodynamics
Mechanism of action. Cabazitaxel is an antineoplastic agent that acts by disrupting the microtubule system in cells. Cabazitaxel binds to tubulin and promotes tubulin aggregation into microtubules while simultaneously inhibiting their depolymerization. This leads to stabilization of microtubules, resulting in the inhibition of cellular functions during mitosis and interphase.
Pharmacodynamic effect. Cabazitaxel has demonstrated a broad spectrum of antitumor activity against human tumor xenografts in mice at advanced stages. Cabazitaxel is active against tumors sensitive to docetaxel. In addition, cabazitaxel has shown activity against models of tumors resistant to chemotherapy, including docetaxel.
Pharmacokinetics
Population pharmacokinetic analysis was conducted in 170 patients, including patients with advanced solid tumors (n = 69), metastatic breast cancer (n = 34), and metastatic prostate cancer (n = 67). These patients received cabazitaxel at doses ranging from 10 to 30 mg/m² once weekly or once every 3 weeks.
Absorption. After intravenous infusion over 1 hour of 25 mg/m² cabazitaxel in patients with hormone-refractory metastatic prostate cancer (n = 67), Cmax was 226 ng/mL (coefficient of variation (CV): 107%) and was achieved at the end of the 1-hour infusion (Tmax). Mean AUC was 991 ng*h/mL (CV: 34%).
No significant deviations from dose proportionality were observed across the dose range of 10 to 30 mg/m² in patients with advanced solid tumors (n = 126).
Distribution. The volume of distribution (Vss) at steady state was 4870 L (2640 L/m² for patients with a median body surface area of 1.84 m²).
In vitro, binding of cabazitaxel to human serum proteins was 89–92% and was not saturable up to a concentration of 50,000 ng/mL, which covers the maximum concentration observed in clinical studies. Cabazitaxel binds predominantly to human serum albumin (82%) and lipoproteins (87.9% for HDL, 69.8% for LDL, and 55.8% for VLDL). In vitro, the blood-to-plasma concentration ratio of cabazitaxel ranged from 0.9 to 0.99, indicating that cabazitaxel was evenly distributed between blood and plasma.
Metabolism. Cabazitaxel is extensively metabolized in the liver (>95%), primarily by the CYP3A isoenzyme (80–90%). Cabazitaxel is the main circulating compound in human plasma. Seven metabolites (including three active metabolites formed by O-demethylation) have been identified in plasma, with one major metabolite accounting for 5% of the administered parent compound. Approximately 20 metabolites of cabazitaxel are excreted in urine and feces.
Based on in vitro studies, cabazitaxel at clinically relevant concentrations has the potential to inhibit drugs that are primarily substrates of CYP3A. However, there is no potential risk of inhibiting drugs that are substrates of other CYP enzymes (1A2, 2B6, 2C9, 2C8, 2C19, 2E1, and 2D6), nor is there a potential risk of cabazitaxel inducing drugs that are substrates of CYP1A, CYP2C9, or CYP3A. In vitro, cabazitaxel did not inhibit the major biotransformation pathway of warfarin to 7-hydroxywarfarin, which is mediated by CYP2C9. Therefore, no pharmacokinetic interaction between cabazitaxel and warfarin is expected in vivo. Cabazitaxel may be affected by strong inducers or inhibitors of CYP3A, as it is primarily metabolized by CYP3A. Prednisone or prednisolone, administered at 10 mg once daily, influenced the pharmacokinetics of cabazitaxel.
In vitro, cabazitaxel did not inhibit multidrug resistance proteins (MRP [Multidrug-Resistant Protein]): MRP1 and MRP2.
Cabazitaxel inhibited P-glycoprotein (PgP) (digoxin, vinblastine) and breast cancer resistance protein (BCRP [Breast-Cancer-Resistant-Proteins]) at concentrations at least 38 times higher than those observed under clinical conditions. Therefore, the risk of in vivo interaction with substrates of MRP, PgP, and BCRP at a dose of 25 mg/m² is unlikely.
In vitro, cabazitaxel did not inhibit multidrug resistance proteins (Multidrug-Resistant Proteins – MRP) MRP1 and MRP2 or organic cation transporter (Organic Cation Transporter – OCT1). Cabazitaxel caused inhibition of P-glycoprotein (PgP) (digoxin, vinblastine), breast cancer resistance proteins (Breast Cancer Resistant Proteins – BCRP) (methotrexate), and organic anion transporting polypeptide OATP1B3 (CCS8) when administered at concentrations at least 15 times higher than those used clinically; meanwhile, the drug inhibited OATP1B1 (estradiol-17β-glucuronide) transport at concentrations only 5 times higher than those used clinically. Thus, the risk of in vivo interaction with substrates of MRP, OCT1, PgP, BCRP, and OATP1B3 is unlikely at a dose of 25 mg/m². However, the risk of interaction with the transporter protein OATP1B1 is possible, particularly during infusion (lasting 1 hour) and within 20 minutes after completion of the infusion (see section "Interaction with other medicinal products and other forms of interaction").
Elimination. After a 1-hour intravenous infusion of 25 mg/m² [14C]-cabazitaxel, approximately 80% of the administered dose was eliminated within 2 weeks. Cabazitaxel is primarily excreted in feces as numerous metabolites (76% of dose); renal excretion of cabazitaxel and metabolites accounts for less than 4% of the dose (2.3% of unchanged drug in urine).
Cabazitaxel is characterized by high plasma clearance of 48.5 L/h (26.4 L/h/m² for patients with a median body surface area of 1.84 m²) and a prolonged terminal half-life of 95 hours.
Special populations.
Elderly. In the population pharmacokinetic analysis of 70 patients aged 65 years or older (57 patients aged 65–75 years and 13 patients over 75 years), no effect of age on the pharmacokinetics of cabazitaxel was observed.
Children. The safety and efficacy of Cabazitaxel (brand name: Jevtana) in children and adolescents (under 18 years of age) have not been established.
Hepatic impairment. Cabazitaxel is primarily eliminated via hepatic metabolism.
A dedicated study involving 43 oncology patients with hepatic dysfunction showed no effect of mild (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) or moderate (total bilirubin >1.5 to ≤3.0 × ULN) hepatic dysfunction on the pharmacokinetics of cabazitaxel. The maximum tolerated dose (MTD) in these patients was 20 mg/m² and 15 mg/m², respectively.
In three patients with severe hepatic dysfunction (total bilirubin >3 × ULN), a 39% reduction in drug clearance was observed compared to patients with mild hepatic dysfunction, indicating some impact of severe hepatic dysfunction on the pharmacokinetics of cabazitaxel. The MTD of cabazitaxel in patients with severe hepatic dysfunction has not been established.
Due to safety and tolerability data, the dose of cabazitaxel should be reduced in patients with mild hepatic dysfunction (see sections "Dosage and administration" and "Special precautions"). Jevtana is contraindicated in patients with severe hepatic dysfunction (see section "Contraindications").
Renal impairment. Cabazitaxel is minimally excreted by the kidneys (2.3% of the administered dose). Population pharmacokinetic analysis conducted in 170 patients, including 14 patients with moderate renal impairment (creatinine clearance between 30 and 50 mL/min) and 59 patients with mild renal impairment (creatinine clearance between 50 and 80 mL/min), showed that mild and moderate renal impairment did not have a significant effect on the pharmacokinetics of cabazitaxel. This was confirmed by a dedicated comparative pharmacokinetic study in patients with solid malignant tumors who had normal renal function (8 patients), moderate renal dysfunction (8 patients), or severe renal dysfunction (9 patients), and who received multiple cycles of cabazitaxel as single intravenous infusions at doses up to 25 mg/m².
Environmental risk assessment. Results of environmental risk assessment studies indicate that the use of Jevtana does not pose a significant risk to the aquatic environment (see section "Special precautions" for information on disposal of unused medicinal product).
Clinical characteristics.
Indications.
Indicated in combination with prednisone or prednisolone for the treatment of adult patients with hormone-refractory metastatic prostate cancer who have previously received docetaxel-based therapy.
Contraindications.
Hypersensitivity reactions to cabazitaxel or to other taxanes, polysorbate 80, or any of the excipients in the patient's history.
Neutrophil count less than 1500/mm³.
Severe hepatic impairment (total bilirubin > 3 × ULN).
Concomitant vaccination with yellow fever vaccine (see section "Interaction with other medicinal products and other types of interactions").
Interaction with other medicinal products and other types of interactions.
In vitro studies have shown that cabazitaxel is metabolized predominantly by CYP3A (from 80% to 90%) (see section "Pharmacokinetics").
CYP3A inhibitors. Repeated co-administration of cabazitaxel with ketoconazole (dosed at 400 mg daily), a potent CYP3A inhibitor, results in a 20% reduction in cabazitaxel clearance and a corresponding 25% increase in AUC. Concomitant use of the drug with potent CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) will lead to increased cabazitaxel concentrations. Therefore, concomitant administration of cabazitaxel with potent CYP3A inhibitors should be avoided (see sections "Special precautions" and "Method of administration and dosage").
Concomitant administration of the drug with aprepitant, a moderate CYP3A inhibitor, does not affect cabazitaxel clearance.
CYP3A inducers. Repeated co-administration of cabazitaxel with rifampicin (dosed at 600 mg daily), a potent CYP3A inducer, results in a 21% increase in cabazitaxel clearance and a corresponding 17% decrease in AUC. Concomitant use of the drug with potent CYP3A inducers (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital) will lead to decreased cabazitaxel concentrations. Therefore, concomitant administration of cabazitaxel with potent CYP3A inducers should be avoided (see sections "Special precautions" and "Method of administration and dosage"). In addition, patients should also refrain from taking St. John's wort (Hypericum perforatum) preparations.
OATP1B1. In vitro studies have also demonstrated that cabazitaxel inhibits the organic anion transporting polypeptides OATP1B1. There is a risk of interaction with OATP1B1 substrates (e.g., statins, valsartan, repaglinide), particularly during infusion (lasting 1 hour) and for 20 minutes after completion of the infusion. A 12-hour interval before infusion and at least a 3-hour interval after completion of infusion are recommended before administering OATP1B1 substrates.
Vaccinations. Administration of live or live attenuated vaccines to patients whose immune systems are weakened by chemotherapeutic agents may result in severe or fatal infections. Patients receiving cabazitaxel should avoid live attenuated vaccines. Inactivated or killed vaccines may be administered, but the immune response to such vaccines may be diminished.
Special precautions for use.
Hypersensitivity reactions. All patients should be premedicated prior to the start of Casex infusion (see section "Dosage and administration").
Patients should be closely monitored for hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions may occur within minutes after starting Casex infusion; therefore, equipment and medications for treatment of hypotension and bronchospasm should be readily available. Severe reactions may include generalized rash/erythema, hypotension, and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of Casex and appropriate therapy. Patients who experience hypersensitivity reactions must discontinue treatment with Casex (see section "Contraindications").
Bone marrow suppression. Bone marrow suppression manifests as neutropenia, anemia, thrombocytopenia, and pancytopenia (see subsections "Neutropenia" and "Anemia" below).
Neutropenia. Prophylactic use of G-CSF may be considered in patients receiving Casex according to recommendations of the American Society of Clinical Oncology (ASCO) and/or institutional guidelines to reduce the risk of neutropenic complications (febrile neutropenia, prolonged neutropenia, or neutropenic infection) or for their treatment.
Primary prophylaxis with G-CSF should be considered for patients with clinical characteristics placing them at high risk (age ≥ 65 years, poor performance status, prior episodes of febrile neutropenia, history of extensive radiation fields, poor nutritional status, or other serious comorbidities) and increased susceptibility to complications from prolonged neutropenia. The use of G-CSF has been shown to reduce the frequency and severity of neutropenia.
Neutropenia is the most common adverse reaction associated with Casex (see section "Adverse reactions"). Complete blood counts should be monitored weekly during the first cycle and prior to each subsequent treatment cycle. Dose adjustments may be necessary as needed. Dose reduction is required in cases of febrile neutropenia or prolonged neutropenia despite appropriate treatment (see section "Dosage and administration"). Treatment may be resumed only when neutrophil counts return to ≥ 1500/mm³ (see section "Contraindications").
Gastrointestinal disorders. Symptoms such as abdominal pain and tenderness on palpation, fever, persistent constipation, and diarrhea—both with and without neutropenia—may be early signs of serious gastrointestinal toxicity and should be promptly recognized and treated. Temporary delay or discontinuation of cabazitaxel therapy may be necessary.
Risk of diarrhea, nausea, vomiting, and dehydration. If diarrhea develops after administration of Casex, standard anti-diarrheal agents may be used. Appropriate measures for rehydration should also be implemented. Diarrhea may occur more frequently in patients previously treated with abdominal-pelvic radiation. Dehydration is more commonly observed in patients aged 65 years and older. Adequate rehydration measures should be taken, along with monitoring and correction of serum electrolyte levels, particularly potassium. Delaying treatment or reducing the dose may be necessary in cases of diarrhea ≥ Grade III (see section "Dosage and administration"). Antiemetic agents commonly used for nausea and vomiting may be administered if these symptoms occur.
Risk of serious gastrointestinal reactions. Cases of gastrointestinal bleeding and perforation, intestinal obstruction, and colitis, including fatal outcomes, have been reported in patients treated with cabazitaxel (see section "Adverse reactions"). Caution is recommended when treating patients at highest risk of gastrointestinal complications: those with neutropenia, elderly patients, patients receiving concomitant nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelet agents, or anticoagulants, and patients with a history of pelvic radiation therapy or prior gastrointestinal disorders such as ulcers or gastrointestinal bleeding.
Peripheral neuropathy. Peripheral neuropathy, including peripheral sensory neuropathy (e.g., paresthesia, dysesthesia) and peripheral motor neuropathy, has been observed in patients receiving cabazitaxel. Patients receiving cabazitaxel who develop neuropathic symptoms such as pain, burning sensation, tingling, numbness, or weakness should inform their physician before continuing treatment. Physicians should assess patients for neuropathy symptoms or worsening prior to each drug administration. Treatment should be withheld until symptoms improve. In cases of persistent peripheral neuropathy ≥ Grade II, the cabazitaxel dose should be reduced from 25 mg/m² to 20 mg/m² (see section "Dosage and administration").
Anemia. Anemia has been observed in patients treated with cabazitaxel (see section "Adverse reactions"). Hemoglobin and hematocrit levels should be checked before initiating cabazitaxel therapy and whenever patients present signs or symptoms of anemia or blood loss. Caution is recommended when administering this medicinal product to patients with hemoglobin levels < 10 g/dL, and appropriate measures should be taken as clinically indicated.
Risk of renal impairment. Renal disorders have been reported in association with sepsis, severe dehydration due to diarrhea and vomiting, and obstructive uropathy. Cases of renal failure, including fatal outcomes, have occurred. In case of renal disorders, appropriate measures should be taken to determine the underlying cause, and intensive treatment should be initiated.
Adequate hydration should be maintained throughout cabazitaxel therapy. Patients should promptly report any significant changes in daily urine output. Serum creatinine levels should be measured before starting treatment, with each blood test, and whenever a patient reports changes in urine volume. Cabazitaxel treatment must be discontinued in case of any worsening of renal function to renal failure ≥ Grade III according to CTCAE (Common Terminology Criteria for Adverse Events) 4.0.
Respiratory system disorders. Interstitial pneumonia/pneumonitis and interstitial lung disease, which may be fatal, have been reported (see section "Adverse reactions").
In case of development or worsening of pulmonary symptoms, appropriate diagnostic measures should be taken and intensive treatment initiated. Interruption of cabazitaxel therapy is recommended until a diagnosis is established. Early supportive therapy may improve patient outcomes. The decision to resume cabazitaxel treatment should be carefully evaluated.
Risk of cardiac arrhythmias. Cases of cardiac arrhythmias, most commonly tachycardia and atrial fibrillation, have been reported (see section "Adverse reactions").
Elderly patients. In elderly patients (aged ≥ 65 years), the likelihood of certain adverse reactions, including neutropenia and febrile neutropenia, may be higher (see section "Adverse reactions").
Patients with hepatic impairment. Casex is contraindicated in patients with severe hepatic dysfunction (total bilirubin > 3 × ULN) (see sections "Contraindications" and "Pharmacokinetics"). Dose reduction is required in patients with mild hepatic dysfunction (total bilirubin > 1 to ≤ 1.5 × ULN or AST > 1.5 × ULN) (see sections "Dosage and administration" and "Pharmacokinetics").
Interactions. Concomitant use of Casex with strong CYP3A4 inhibitors should be avoided, as they may increase cabazitaxel plasma concentrations (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").
Concomitant use of Casex with strong CYP3A4 inducers should be avoided, as they may decrease cabazitaxel plasma concentrations (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").
Excipients. The solvent contains 573 mg of 96% ethanol, equivalent to 11 mL of beer or 5 mL of wine.
Harmful for individuals with alcohol dependence.
Should be considered when administering to high-risk groups, including patients with liver disease or epilepsy.
Use during pregnancy or breastfeeding.
Pregnancy. Data on the use of cabazitaxel in pregnant women are lacking. Animal studies have shown reproductive toxicity at doses toxic to the maternal organism, and cabazitaxel has been shown to cross the placental barrier. Like other cytotoxic medicinal products, cabazitaxel may have harmful effects on the fetus when administered to pregnant women.
Cabazitaxel is not recommended during pregnancy and in women of childbearing potential who are not using effective contraception.
Breastfeeding. Pharmacokinetic data from animal studies indicate excretion of cabazitaxel and its metabolites into milk. Risk to breastfed infants cannot be excluded. Cabazitaxel should not be used during breastfeeding.
Fertility. Animal studies have shown effects of cabazitaxel on the male reproductive system of rats and dogs without functional impact on fertility. However, due to the pharmacological activity of taxanes, their genotoxic potential, and effects of several compounds in this class on fertility in animal studies, effects on male fertility in humans cannot be excluded. Due to the potential impact on male germ cells and possible exposure via seminal fluid, men receiving cabazitaxel therapy should use effective contraception throughout the treatment period and continue its use for 6 months after the last dose of cabazitaxel. Due to potential exposure via seminal fluid, men receiving cabazitaxel therapy should avoid contact of another person with ejaculate throughout the treatment period. Men scheduled to receive cabazitaxel therapy are advised to seek consultation regarding sperm cryopreservation prior to starting treatment.
Ability to influence the ability to drive and use machines.
Based on the safety profile, Casex may affect the ability to drive or operate machinery, as it may cause increased fatigue and dizziness. Patients should refrain from driving and operating machinery if such adverse reactions occur during treatment.
Dosage and Administration
The use of Cabometyx may only occur in specialized facilities where cytotoxic therapy is administered, and its administration must be performed exclusively under the supervision of a physician experienced in anticancer chemotherapy. Appropriate means and equipment for the treatment of severe hypersensitivity reactions, such as arterial hypotension and bronchospasm, must be readily available (see section "Special Warnings and Precautions for Use").
Premedication. To reduce the risk and severity of hypersensitivity reactions, premedication should be administered intravenously at least 30 minutes prior to each infusion of Cabometyx, including:
- antihistamines (dexchlorpheniramine 5 mg or diphenhydramine 25 mg, or equivalent);
- corticosteroids (dexamethasone 8 mg or equivalent);
- H2-receptor antagonists (ranitidine or equivalent) (see section "Special Warnings and Precautions for Use").
Prophylactic oral or intravenous antiemetic agents are recommended as needed.
Adequate hydration should be maintained throughout the treatment period to prevent complications, including renal impairment.
Dosing. The recommended dose of Cabometyx for adults is 25 mg/m² administered as a one-hour intravenous infusion once every three weeks in combination with daily oral prednisone or prednisolone at a dose of 10 mg during the treatment period.
Dose Adjustment. Dose modifications are required if adverse reactions occur (see Table 1).
Recommended dose adjustments in patients experiencing adverse reactions during treatment with the drug
Table 1
Adverse reactions |
Dose adjustment |
| Prolonged grade ≥ III neutropenia (longer than 1 week), despite appropriate medical treatment including administration of granulocyte colony-stimulating factor (G-CSF). |
Delay treatment until neutrophil count is > 1,500 cells/mm3, then reduce the dose of Kyprolis from 25 mg/m2 to 20 mg/m2. |
| Febrile neutropenia or neutropenic infection. |
Delay treatment until improvement or recovery and until neutrophil count is > 1,500 cells/mm3, then reduce the dose of Kyprolis from 25 mg/m2 to 20 mg/m2. |
| Diarrhea ≥ grade III or persistent diarrhea, despite appropriate medical management, and correction of fluid and electrolyte imbalances. |
Delay treatment until improvement or recovery, then reduce the dose of Kyprolis from 25 mg/m2 to 20 mg/m2. |
| Peripheral neuropathy ≥ grade II. |
Delay treatment until reduction or resolution of adverse reaction, then reduce the dose of cabazitaxel from 25 mg/m2 to 20 mg/m2. |
Discontinue treatment with Cabazitaxel if any of the defined reactions persist in the patient at a dose of 20 mg/m².
Special patient groups.
Patients with hepatic impairment. Cabazitaxel is predominantly metabolized in the liver. In patients with mild hepatic dysfunction (total bilirubin exceeding the upper limit of normal (ULN) by >1 to ≤1.5 times or AST levels >1.5 × ULN), the cabazitaxel dose should be reduced to 20 mg/m². Administration of cabazitaxel to patients with mild hepatic dysfunction requires caution and careful monitoring of safety parameters.
In patients with moderate hepatic dysfunction (total bilirubin >1.5 to ≤3.0 × ULN), the maximum tolerated dose (MTD) of the drug was 15 mg/m². If treatment with the drug is considered in patients with moderate hepatic dysfunction, the cabazitaxel dose should not exceed 15 mg/m². However, data on efficacy with this dose level are currently limited.
Cabazitaxel is contraindicated in patients with severe hepatic dysfunction (total bilirubin >3 × ULN) (see sections "Contraindications", "Special precautions", and "Pharmacokinetics").
Patients with renal impairment. Cabazitaxel is minimally excreted via the kidneys. Dose adjustment is not required in patients with renal impairment who do not require hemodialysis. In patients with end-stage renal disease (creatinine clearance (CLCR) <15 ml/min/1.73 m²), the drug should be administered with caution and under close monitoring due to their clinical condition and limited available data (see sections "Special precautions" and "Pharmacokinetics").
Elderly patients. No specific dose adjustment recommendations for Cabazitaxel are available for elderly patients (see also sections "Side effects", "Special precautions", and "Pharmacokinetics").
Concomitant use of medicinal products. Concomitant use of strong inducers or strong inhibitors of CYP3A should be avoided (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").
Children. Cabazitaxel should not be administered to children. The safety and efficacy of Cabazitaxel in children and adolescents have not been established.
Method of administration.
Precautions to be taken prior to handling or administering the medicinal product. Cabazitaxel should only be handled by personnel specifically trained in the use of cytotoxic agents. Pregnant personnel should not handle this drug. Specific precautions for handling Cabazitaxel are described in the subsection "Special precautions for disposal and other handling of the medicinal product".
Instructions for preparation and administration of the drug are provided in the subsection "Special precautions for disposal and other handling of the medicinal product".
Special precautions for disposal and other handling of the medicinal product. As with any other antineoplastic agent, caution should be exercised during handling and preparation of Cabazitaxel solutions. Closed-system devices, personal protective equipment (e.g., gloves), and appropriate preparatory procedures should be used. In case of skin contact at any stage of handling, wash immediately and thoroughly with soap and water. In case of contact with mucous membranes, rinse immediately and thoroughly with water.
The concentrate for infusion solution must always be diluted with the complete contents of the vial of solvent supplied in the pack before adding the drug to the infusion solution.
Before beginning mixing and dilution procedures, this section must be read carefully and in its ENTIRETY. Preparation of the ready-to-use Cabazitaxel solution requires a two-step dilution process. The following instructions for solution preparation must be strictly followed.
Note. Both the vial containing the 60 mg/1.5 ml concentrate of Cabazitaxel (fill volume: 73.2 mg cabazitaxel/1.83 ml) and the vial containing the solvent (fill volume: 5.67 ml) contain overages designed to compensate for liquid loss during solution preparation. This overfill allows, after adding the ENTIRE contents of the solvent vial supplied in the pack, to obtain a solution containing 10 mg/ml cabazitaxel.
The concentrate for infusion solution must be diluted in two steps under aseptic conditions according to the instructions below.
Step 1. First dilution of the concentrate for infusion solution using the solvent supplied in the pack.
Step 1.1. Visually inspect the vial of concentrate and the vial of solvent supplied in the pack. The concentrated solution and the solvent should be clear.
Step 1.2. Under aseptic conditions, using a syringe with a needle, withdraw the entire contents of the solvent vial, tilting the vial slightly.
Step 1.3. Transfer the entire volume of solvent into the corresponding vial of concentrate. During transfer, foam formation should be minimized as much as possible. To achieve this, the solvent should be added slowly, directing the stream against the inner wall of the concentrate vial. After dilution, the resulting solution contains 10 mg/ml of cabazitaxel.
Step 1.4. Remove the syringe with the needle and gently mix the vial contents by inverting it in the hands until a clear, homogeneous solution is obtained. This may take approximately 45 seconds.
Step 1.5. Allow the solution to stand for about 5 minutes, then confirm that it is homogeneous and clear. Foam may persist after this period; this is normal.
This resulting mixture of concentrate and solvent contains 10 mg/ml of cabazitaxel (at least 6 ml of volume that can be withdrawn). The second dilution must be performed immediately thereafter (no later than 1 hour) according to the instructions in section "Step 2".
More than one vial of the concentrate-solvent mixture may be required to prepare the patient's prescribed dose.
Step 2. Second (final) dilution to obtain the ready-to-use infusion solution.
Step 2.1. Under aseptic conditions, withdraw the required volume of the concentrate-solvent mixture (10 mg/ml cabazitaxel) using a graduated syringe with a needle. For example, to prepare a 45 mg dose of Cabazitaxel, 4.5 ml of the concentrate-solvent mixture prepared according to the instructions in "Step 1" is required.
After preparation of the pre-diluted solution as described in "Step 1", foam may remain on the vial walls; therefore, when withdrawing the solution, it is advisable to insert the syringe needle deeply into the solution.
Step 2.2. Transfer the drug into a sterile, non-polyvinyl chloride (PVC) infusion container containing either 5% glucose for infusion solution or 9 mg/ml (0.9%) sodium chloride for infusion solution. The concentration of the infusion solution should be between 0.10 mg/ml and 0.26 mg/ml.
Step 2.3. Detach the syringe and mix the contents of the infusion bag or vial by gently rocking it in the hands.
Step 2.4. Prior to administration, as with all parenteral medicinal products, the solution should be visually inspected. Do not use solutions in which precipitate is observed.
Each concentrate vial contains 60 mg of cabazitaxel in a nominal volume of 1.5 ml (actual fill volume: 73.2 mg cabazitaxel/1.83 ml). This fill volume was specifically designed during the development of Cabazitaxel to compensate for liquid loss during premix preparation. This overfill allows, after dilution with the complete contents of the solvent vial supplied in the pack, to obtain a minimum withdrawable premix volume of 6 ml containing 10 mg/ml of Cabazitaxel, corresponding to the declared amount of 60 mg per vial.
The nominal volume of each solvent vial is 4.5 ml (actual fill volume: 5.67 ml). This fill volume was specifically designed during the development of this medicinal product formulation, and this overfill allows, after adding the ENTIRE contents of the solvent vial to the concentrate vial for preparing Cabazitaxel solution, to obtain a premix with a concentration of 10 mg/ml of Cabazitaxel.
The infusion solution should be used immediately. However, if storage conditions described in the "Shelf life" section are maintained, the solution remains suitable for use for an additional period of time. Prior to administration of the ready-to-use infusion solution, as with all parenteral medicinal products, it should be visually inspected. Since this solution is supersaturated, crystallization may occur over time. Such solutions are unsuitable for administration and must be discarded.
During infusion, it is recommended to use an in-line filter with a nominal pore size of 0.22 µm (which may also be indicated as 0.2 µm).
Do not use infusion containers containing PVC or infusion systems containing polyurethane for the preparation and administration of Cabazitaxel.
Do not mix Cabazitaxel with any other medicinal products except those specified above.
Any unused portion of the medicinal product and waste materials should be disposed of in accordance with local requirements.
Children.
The safety and efficacy of Cabazitaxel in children (under 18 years of age) have not been established.
Overdose.
There are no known antidotes for Cabazitaxel. Expected complications of overdose may include exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders. In case of overdose, the patient should be hospitalized in a specialized facility and kept under close observation. Therapy with G-CSF should be initiated as soon as possible after overdose is detected. Other appropriate symptomatic measures should also be taken.
Adverse Reactions
Short description of safety profile
The safety of Cabometyx in combination with prednisone or prednisolone was evaluated in 371 patients with hormone-refractory metastatic prostate cancer who received 25 mg/m² of Cabometyx once every 3 weeks in a randomized, open-label, controlled Phase III trial. Patients received a median of
6 cycles of Cabometyx.
The most common (≥ 10%) adverse reactions of all grades included anemia (97.3%), leukopenia (95.7%), neutropenia (93.5%), thrombocytopenia (47.4%), and diarrhea (46.6%). The most common
(≥ 5%) adverse reactions of Grade ≥ III in the group of patients receiving Cabometyx were neutropenia (81.7%), leukopenia (68.2%), anemia (10.5%), febrile neutropenia (7.5%), and diarrhea (6.2%).
68 patients (18.3%) receiving Cabometyx discontinued treatment due to adverse reactions. The most common adverse reaction leading to discontinuation of Cabometyx was neutropenia.
List of adverse reactions in table format
Adverse reactions are presented in Table 2 according to MedDRA system organ classes and frequency of occurrence. Severity of adverse reactions was determined according to CTCAE 4.0 (Grade ≥ III = G ≥ 3). Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), not known (cannot be estimated from available data).
Adverse reactions and blood disorders observed with Cabometyx
in combination with prednisone or prednisolone in the TROPIC study (n = 371)
Table 2
| System Organ Class |
Adverse Reactions |
All Grades n (%) |
Grade ≥ III n (%) |
||
| Very Common |
Common |
Uncommon |
|||
| Infections and infestations |
Neutropenic infection / sepsis* |
48 (4.4) |
42 (3.8) |
||
| Septic shock |
10 (0.9) |
10 (0.9) |
|||
| Sepsis |
8 (0.7) |
3 (0.3) |
|||
| Cellulitis |
6 (1.6) |
2 (0.5) |
|||
| Urinary tract infection |
27 (7.3) |
4 (1.1) |
|||
| Influenza |
11 (3) |
0 |
|||
| Cystitis |
10 (2.7) |
1 (0.3) |
|||
| Upper respiratory tract infection |
10 (2.7) |
0 |
|||
| Herpes zoster |
5 (1.3) |
0 |
|||
| Candidiasis |
4 (1.1) |
0 |
|||
| Blood and lymphatic system disorders |
Neutropeniaa* |
347 (93.5) |
303 (81.7) |
||
| Anemiaa |
361 (97.3) |
39 (10.5) |
|||
| Leukopeniaa |
355 (95.7) |
253 (68.2) |
|||
| Thrombocytopeniaa |
176 (47.4) |
15 (4) |
|||
| Febrile neutropenia |
28 (7.5) |
28 (7.5) |
|||
| Immune system disorders |
Hypersensitivity |
7 (0.6) |
0 |
||
| Metabolism and nutrition disorders |
Anorexia |
59 (15.9) |
3 (0.8) |
||
| Dehydration |
18 (4.9) |
8 (2.2) |
|||
| Hypoglycemia |
4 (1.1) |
3 (0.8) |
|||
| Hypokalemia |
4 (1.1) |
2 (0.5) |
|||
| Psychiatric disorders |
Insomnia |
45 (4.1) |
0 |
||
| Anxiety |
11 (3) |
0 |
|||
| Confusion |
5 (1.3) |
0 |
|||
| Nervous system disorders |
Dysgeusia |
64 (5.9) |
0 |
||
| Taste disturbance |
56 (5.1) |
0 |
|||
| Peripheral neuropathy |
30 (8.1) |
2 (0.5) |
|||
| Peripheral sensory neuropathy |
20 (5.4) |
1 (0.3) |
|||
| Polyneuropathy |
9 (0.8) |
2 (0.2) |
|||
| Dizziness |
30 (8.1) |
0 |
|||
| Headache |
28 (7.5) |
0 |
|||
| Paresthesia |
17 (4.6) |
0 |
|||
| Lethargy |
5 (1.3) |
1 (0.3) |
|||
| Hypoesthesia |
5 (1.3) |
0 |
|||
| Sciatica |
4 (1.1) |
1 (0.3) |
|||
| Eye disorders |
Conjunctivitis |
5 (1.3) |
0 |
||
| Increased lacrimation |
5 (1.3) |
0 |
|||
| Ear and labyrinth disorders |
Tinnitus |
5 (1.3) |
0 |
||
| Vertigo |
5 (1.3) |
0 |
|||
| Cardiac disorders* |
Atrial fibrillation |
4 (1.1) |
2 (0.5) |
||
| Tachycardia |
6 (1.6) |
0 |
|||
| Vascular disorders |
Arterial hypotension |
20 (5.4) |
2 (0.5) |
||
| Deep vein thrombosis |
8 (2.2) |
7 (1.9) |
|||
| Arterial hypertension |
6 (1.6) |
1 (0.3) |
|||
| Orthostatic hypotension |
5 (1.3) |
1 (0.3) |
|||
| Flushing |
5 (1.3) |
0 |
|||
| Hot flush |
4 (1.1) |
0 |
|||
| Respiratory, thoracic and mediastinal disorders |
Dyspnea |
44 (11.9) |
5 (1.3) |
||
| Cough |
40 (10.8) |
0 |
|||
| Oropharyngeal pain |
13 (3.5) |
0 |
|||
| Pneumonia |
9 (2.4) |
6 (1.6) |
|||
| Pulmonary embolism |
30 (2.7) |
23 (2.1) |
|||
| Gastrointestinal disorders |
Diarrhea |
173 (46.6) |
23 (6.2) |
||
| Nausea |
127 (34.2) |
7 (1.9) |
|||
| Vomiting |
84 (22.6) |
7 (1.9) |
|||
| Constipation |
76 (20.5) |
4 (1.1) |
|||
| Abdominal pain |
43 (11.6) |
7 (1.9) |
|||
| Dyspepsia |
25 (6.7) |
0 |
|||
| Upper abdominal pain |
20 (5.4) |
0 |
|||
| Hemorrhoids |
14 (3.8) |
0 |
|||
| Gastroesophageal reflux disease |
12 (3.2) |
0 |
|||
| Rectal hemorrhage |
8 (2.2) |
2 (0.5) |
|||
| Dry mouth |
8 (2.2) |
1 (0.3) |
|||
| Abdominal distension |
5 (1.3) |
1 (0.3) |
|||
| Stomatitis |
7 (0.6) |
5 (0.5) |
|||
| Paralytic ileus* |
10 (0.9) |
0 |
|||
| Gastritis |
10 (0.9) |
5 (0.5) |
|||
| Colitis* |
3 (0.3) |
1 (<0.1) |
|||
| Gastrointestinal perforation |
2 (0.2) |
1 (<0.1) |
|||
| Gastrointestinal hemorrhage |
7 (0.6) |
5 (0.5) |
|||
| Skin and subcutaneous tissue disorders |
Alopecia |
37 (10) |
0 |
||
| Skin dryness |
9 (2.4) |
0 |
|||
| Erythema |
5 (1.3) |
0 |
|||
| Nail disorder |
18 (1.6) |
0 |
|||
| Musculoskeletal and connective tissue disorders |
Back pain |
60 (16.2) |
14 (3.8) |
||
| Arthralgia |
39 (10.5) |
4 (1.1) |
|||
| Limb pain |
30 (8.1) |
6 (1.6) |
|||
| Muscle spasms |
27 (7.3) |
0 |
|||
| Myalgia |
14 (3.8) |
1 (0.3) |
|||
| Chest musculoskeletal pain |
11 (3) |
1 (0.3) |
|||
| Muscle weakness |
31 (2.8) |
1 (0.2) |
|||
| Flank pain |
7 (1.9) |
3 (0.8) |
|||
| Renal and urinary disorders |
Acute renal failure |
8 (2.2) |
6 (1.6) |
||
| Renal failure |
7 (1.9) |
6 (1.6) |
|||
| Dysuria |
25 (6.7) |
0 |
|||
| Renal colic |
5 (1.3) |
1 (0.3) |
|||
| Hematuria |
62 (16.7) |
7 (1.9) |
|||
| Frequency of urination |
13 (3.5) |
1 (0.3) |
|||
| Hydronephrosis |
9 (2.4) |
3 (0.8) |
|||
| Urinary retention |
9 (2.4) |
3 (0.8) |
|||
| Urinary incontinence |
9 (2.4) |
0 |
|||
| Ureteric obstruction |
7 (1.9) |
5 (1.3) |
|||
| Reproductive system and breast disorders |
Pelvic pain |
7 (1.9) |
1 (0.3) |
||
| General disorders and administration site conditions |
Increased fatigue |
136 (36.7) |
18 (4.9) |
||
| Asthenia |
76 (20.5) |
17 (4.6) |
|||
| Pyrexia |
45 (12.1) |
4 (1.1) |
|||
| Peripheral edema |
34 (9.2) |
2 (0.5) |
|||
| Mucosal inflammation |
22 (5.9) |
1 (0.3) |
|||
| Pain |
20 (5.4) |
4 (1.1) |
|||
| Chest pain |
9 (2.4) |
2 (0.5) |
|||
| Edema |
7 (1.9) |
1 (0.3) |
|||
| Chills |
6 (1.6) |
0 |
|||
| Malaise |
5 (1.3) |
0 |
|||
| Investigations |
Decreased weight |
32 (8.6) |
0 |
||
| Increased aspartate aminotransferase |
4 (1.1) |
0 |
|||
| Increased transaminases |
4 (1.1) |
0 |
|||
Based on laboratory parameter assessments.
*See detailed description below.
Neutropenia and associated clinical manifestations. The incidence of laboratory-confirmed Grade ≥ III neutropenia was 81.7%. The incidence of adverse reactions of neutropenia with clinical manifestations and febrile neutropenia was 21.3% and 7.5%, respectively. Neutropenia was the most common adverse reaction leading to discontinuation of the medicinal product (2.4%). Neutropenic complications included neutropenic infections (0.5%), neutropenic sepsis (0.8%), and septic shock (1.1%), which in some cases led to fatal outcomes. It has been demonstrated that administration of granulocyte colony-stimulating factor (G-CSF) reduces the frequency and severity of neutropenia (see sections "Dosage and administration" and "Special precautions for use").
Cardiac disorders and arrhythmias. Cardiac disorders of all grades of severity were observed in patients receiving cabazitaxel. Among them, Grade ≥ III cardiac arrhythmias occurred in 6 patients (1.6%). The incidence of tachycardia in the cabazitaxel treatment group was 1.6%, with no cases of Grade ≥ III tachycardia reported. The incidence of atrial fibrillation in the cabazitaxel treatment group was 1.1%. Cases of heart failure were more frequently observed in the cabazitaxel treatment group, with the time of onset reported in 2 patients (0.5%). One patient in the cabazitaxel group died due to heart failure. Fatal ventricular fibrillation was reported in one patient (0.3%) and cardiac arrest in two patients (0.5%). None of these events were considered by the investigator to be related to cabazitaxel administration.
Other laboratory parameter abnormalities. The incidence of Grade ≥ III anemia, elevated AST, elevated ALT, and elevated bilirubin based on laboratory parameter abnormalities was 10.5%, 0.7%, 0.9%, and 0.6%, respectively.
Gastrointestinal disorders. Cases of colitis, enterocolitis, gastritis, and neutropenic enterocolitis have been reported. Gastrointestinal hemorrhage and perforation, as well as paralytic and mechanical bowel obstruction, have also been observed (see section "Special precautions for use").
Respiratory system disorders. Cases of interstitial pneumonia/pneumonitis and interstitial lung disease, which may be fatal, have been reported; the frequency is unknown (see section "Special precautions for use").
Renal and urinary disorders. Rare cases of cystitis due to a flare-up inflammatory reaction in a previously irradiated area, including cases of hemorrhagic cystitis, have been reported.
Children. (See section "Dosage and administration").
Elderly patients. Among 371 patients who received Cabomazyne in the prostate cancer study, 240 were aged 65 years or older, including 70 patients aged 75 years or older.
The following adverse reactions were reported more frequently by ≥5% in patients aged 65 years or older compared to younger patients: increased fatigue (40.4% vs. 29.8%), neutropenia with clinical manifestations (24.2% vs. 17.6%), asthenia (23.8% vs. 14.5%), hyperthermia (14.6% vs. 7.6%), dizziness (10.0% vs. 4.6%), urinary tract infections (9.6% vs. 3.1%), and dehydration (6.7% vs. 1.5%).
In patients aged ≥65 years compared to younger patients, the incidence of the following adverse reactions of Grade ≥ III severity was higher: neutropenia based on laboratory parameter abnormalities (86.3% vs. 73.3%), neutropenia with clinical manifestations (23.8% vs. 16.8%), and febrile neutropenia (8.3% vs. 6.1%) (see sections "Dosage and administration" and "Special precautions for use").
Reporting suspected adverse reactions.
Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk profile of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life.
Unopened vials – 2 years.
After opening. Vials of concentrate and solvent should be used immediately after opening. If the product is not used immediately after opening, the responsibility for the duration and conditions of storage of opened vials lies with the user.
After initial dilution of concentrate with solvent. The solution has been shown to remain chemically and physically stable for 30 minutes after initial dilution when stored at room temperature of 15–30 °C. From a microbiological standpoint, the concentrate diluted with solvent should be used immediately. If not used immediately after preparation, the responsibility for the duration and conditions of storage lies with the user. Generally, the concentrate diluted with solvent may be stored for no more than 24 hours at 2–8 °C, except when dilution was performed under controlled and validated aseptic conditions.
After final dilution in infusion bag/bottle. The infusion solution has been shown to remain chemically and physically stable for 8 hours (including 1 hour of infusion) when stored at room temperature, and for 48 hours when the infusion solution is stored refrigerated.
From a microbiological standpoint, the infusion solution should be used immediately. If the infusion solution is not used immediately after preparation, the responsibility for the duration and conditions of storage lies with the user. Generally, the infusion solution may be stored for no more than 24 hours at 2–8 °C, except when dilution was performed under controlled and validated aseptic conditions.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze. Keep out of the reach and sight of children.
Storage conditions after dilution see section "Shelf life".
Incompatibilities. The Cabomazyne medicinal product must always be diluted with the solvent provided in the pack before adding it to the infusion solution. This medicinal product must not be mixed with other medicinal products except as specified in the section "Special precautions for use".
Do not use polyvinyl chloride infusion containers or polyurethane infusion sets for the preparation and administration of the infusion solution.
Packaging.
1.5 ml of concentrate in a vial, 4.5 ml of solvent in a vial; 1 vial of concentrate and 1 vial of solvent in a cardboard box.
Prescription category. Prescription only.
Manufacturer. Hetero Labs Limited.
Manufacturer's address and location of manufacturing site.
Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.