Cabaxan

Cabazitaxel.

Each ml contains Cabazitaxel 20 mg, Dehydrated Alcohol 395 mg.
Excipients/Inactive Ingredients: Dehydrated Alcohol, Polysorbate 80.

Pharmacology: Pharmacodynamics: Cabazitaxel is a microtubule inhibitor. Cabazitaxel binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the inhibition of mitotic and interphase cellular functions.
Cabazitaxel demonstrated antitumor activity against advanced human tumors xenografted in mice. Cabazitaxel is active in docetaxel-sensitive tumors. In addition, cabazitaxel demonstrated activity in tumor models insensitive to chemotherapy including docetaxel.
Pharmacokinetics: A population pharmacokinetic analysis was conducted in 170 patients with solid tumors at doses ranging from 10 to 30 mg/m² weekly or every three weeks.
Absorption: Based on the population pharmacokinetic analysis, after an intravenous dose of cabazitaxel 25 mg/m² every three weeks, the mean Cmax in patients with metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end of the one hour infusion (T_max). The mean AUC in patients with metastatic prostate cancer was 991 ng.h/mL (CV 34%).
No major deviation from the dose proportionality was observed from 10 to 30 mg/m² in patients with advanced solid tumors.
Distribution: The volume of distribution (Vss) was 4,864 L (2,643 L/m² for a patient with a median BSA of 1.84 m²) at steady state. In vitro, the binding of cabazitaxel to human serum proteins was 89 to 92% and was not saturable up to 50,000 ng/mL, which covers the maximum concentration observed in clinical trials. Cabazitaxel is mainly bound to human serum albumin (82%) and lipoproteins (88% for HDL, 70% for LDL, and 56% for VLDL). The in vitro blood to-plasma concentration ratio in human blood ranged from 0.90 to 0.99, indicating that cabazitaxel was equally distributed between blood and plasma.
Metabolism: Cabazitaxel is extensively metabolized in the liver (>95%), mainly by the CYP3A4/5 isoenzyme (80% to 90%), and to lesser extent by CYP2C8. Cabazitaxel is the main circulating moiety in human plasma. Seven metabolites were detected in plasma (including the 3 active metabolites issued from O-demethylation), with the main one accounting for 5% of cabazitaxel exposure. Around 20 metabolites of cabazitaxel are excreted into human urine and feces.
Based on in vitro studies, the potential for cabazitaxel to inhibit drugs that are substrates of other CYP isoenzymes (1A2, -2B6, -2C9, -2C8, -2C19, -2E1, -2C6, and CYP3A4/5) is low. In addition, cabazitaxel did not induce CYP isozymes (-1A, -2C and -3A) in vitro.
Elimination: After a one-hour intravenous infusion [14C]-cabazitaxel 25 mg/m², approximately 80% of the administered dose was eliminated within 2 weeks. Cabazitaxel is mainly excreted in the feces as numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and metabolites account for 3.7% of the dose (2.3% as unchanged drug in urine).
Based on the population pharmacokinetic analysis, cabazitaxel has a plasma clearance of 48.5 L/h (CV 39%; 26.4 L/h/m² for a patient with a median BSA of 1.84 m²) in patients with metastatic prostate cancer. Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic mode with α-, β-, and γ-half-lives of 4 minutes, 2 hours, and 95 hours, respectively.

Cabazitaxel is microtubule inhibitor indicated in combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.

Recommended General Dosing Information: The individual dosage of Cabazitaxel is based on calculation of the Body Surface Area (BSA) and is 25 mg/m² administered as a one-hour intravenous infusion every three weeks in combination with oral prednisone 10 mg administered daily throughout Cabazitaxel treatment.
Premedication is recommended prior to treatment.
Cabazitaxel should be administered under the supervision of a qualified physician experienced in the use of antineoplastic medicinal products. Appropriate management of complications is possible only when the adequate diagnostic and treatment facilities are readily available.
Cabazitaxel Injection single-use vial requires two dilutions prior to administration.
Do not use PVC infusion containers and polyurethane infusions sets for preparation and administration of Cabazitaxel infusion solution.
Dose modifications: The Cabazitaxel dose should be reduced to 20 mg/m if patients experience the following adverse reactions. (See table.)

Click on icon to see table/diagram/image

Discontinue Cabazitaxel treatment if a patient continues to experience any of these reactions at 20 mg/m².
Premedication: Premedicate at least 30 minutes prior to each dose of Cabazitaxel with the following intravenous medications to reduce risk and/or severity of hypersensitivity:
antihistamine (dexchlorpheniramine 5 mg, or diphenhydramine 25 mg or equivalent antihistamine), corticosteroid (dexamethasone 5 mg, or diphenhydramine 25 mg or equivalent steroid), H2 antagonist (ranitidine 50 mg or equivalent H2 antagonist).
Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed.
Administration Precautions: Cabazitaxel is a cytotoxic anticancer drug and caution should be exercised when handling and preparing Cabazitaxel solutions, taking into account the use of containment devices, personal protective equipment (e.g., gloves), and preparation procedures.
If Cabazitaxel Injection, diluted solutions for intravenous infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Cabazitaxel Injection, diluted solution for intravenous infusion should come into contact with mucosa, immediately and thoroughly wash with water.
Route of Administration: Cabazitaxel Injection, 60 mg per 3 mL requires NO prior dilution with a diluent and is ready to add to the infusion solution.
Do not use PVC infusion containers or polyurethane infusions sets for preparation and administration of Cabazitaxel infusion solution.
Read this entire section carefully before diluting. Cabazitaxel requires dilutions prior to administration. Please follow the preparation instructions provided as follows.
The following dilution process must be carried out under aseptic conditions to prepare the infusion solution.
Inspect the Cabazitaxel Injection vial. The Cabazitaxel Injection is a clear colorless to pale yellow to brownish-yellow solution.
Withdraw the recommended dose from the Cabazitaxel Injection 60 mg/3 mL vial using a calibrated syringe and dilute into a sterile 250 mL PVC-free container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion. If a dose greater than 65 mg of Cabazitaxel Injection is required, use a larger volume of the infusion vehicle so that a concentration of 0.26 mg/mL Cabazitaxel Injection is not exceeded.
The concentration of the Cabazitaxel Injection final infusion solution should be between 0.10 mg/mL and 0.26 mg/mL.
Cabazitaxel Injection should not be mixed with any other drugs.
Remove the syringe and thoroughly mix the final infusion solution by gently inverting the bag or bottle.
Cabazitaxel Injection final infusion solution (in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 4 hours at ambient temperature (including the one-hour infusion) or within a total of 24 hours if refrigerated (including the one-hour infusion).
As the final infusion solution is supersaturated, it may crystallize over time. Do not use if this occurs and discard.
Inspect visually for particulate matter, any crystals and discoloration prior to administration. If the Cabazitaxel Injection infusion solution is not clear or appears to have precipitation, it should be discarded.
Administration: The final Cabazitaxel infusion solution should be administered intravenously as a one-hour infusion at room temperature.
Use an in-line filter of 0.22 micrometer nominal pore size (also referred to as 0.2 micrometer) during administration.
The final Cabazitaxel infusion solution should be used immediately. However, in-use storage time can be longer under specific conditions, i.e. 8 hours under ambient conditions (including the one-hour infusion) or for a total of 24 hours if refrigerated (including the one-hour infusion).

There is no known antidote for Cabazitaxel overdose. Anticipated complications of overdose include exacerbation or adverse reactions such as bone marrow suppression and gastrointestinal disorders.
In case of overdose, the patient should be kept in a specialized unit where vital signs, chemistry and particular functions can be closely monitored. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.

Cabazitaxel should not be used in patients with neutrophil counts of ≤ 1,500/mm³. It is contraindicated in patients who have a history of severe hypersensitivity reactions to cabazitaxel or any of its excipients or related group of drugs.

Cabazitaxel should not be used in patients with neutrophils ≤ 1,500/mm³.
Monitoring of complete blood counts is essential on a weekly basis during cycle I and before each treatment cycle thereafter so that the dose can be adjusted, if needed.
G-CSF may be administered to reduce risks of neutropenia complications associated with Cabazitaxel use. Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features (age > 65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia. Therapeutic use of G-CSF and secondary prophylaxis should be considered in all patients considered to be at increased risk for neutropenia complications.
If a patient experiences febrile neutropenia or prolonged neutropenia (greater than one week) despite appropriate medication (e.g., G-CSF), the dose of cabazitaxel should be reduced. Patients can restart treatment with cabazitaxel only when neutrophil counts recover to a level > 1,500/mm³.
Hypersensitivity Reactions: Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of Cabazitaxel. Severe hypersensitivity reactions can occur and may include generalized rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of the Cabazitaxel infusion and appropriate therapy. Patients with a history of severe hypersensitivity reactions should not be re-challenged with Cabazitaxel.
Gastrointestinal Symptoms: Nausea, vomiting and severe diarrhea at times, may occur. Intensive measures may be required for severe diarrhea and electrolyte imbalance. Patients should be treated with rehydration, anti-diarrheal or anti-emetic medications as needed.
Treatment delay or dosage reduction may be necessary if patients experience Grade ≥ 3 diarrhea. Gastrointestinal (GI) hemorrhage and perforation, ileus, colitis, including fatal outcome, have been reported in patients treated with Cabazitaxel. Caution is advised with treatment of patients most at risk of developing gastrointestinal complications: those with neutropenia, the elderly, concomitant use of NSAIDs, anti-platelet therapy or anti-coagulants, and patients with a prior history of pelvic radiotherapy, gastrointestinal disease, such as ulceration and GI bleeding.
Symptoms such as abdominal pain and tenderness, fever, persistent constipation, diarrhea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly. Cabazitaxel treatment or delay or discontinuation may be necessary.
Renal Failure: Renal failure, including four cases with fatal outcome, was reported in the randomized clinical trial. Some deaths due to renal failure did not have a clear etiology. Appropriate measures should be taken to identify causes of renal failure and treat aggressively.
Hepatic Impairment: Cabazitaxel is extensively metabolized in the liver, and hepatic impairment is likely to increase Cabazitaxel concentrations.
Hepatic impairment increases the risk of severe and life-threatening complications in patients receiving other drugs belonging to the same class as Cabazitaxel. Cabazitaxel should not be given to patients with hepatic impairment (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 ULN).
Effects on ability to drive and use machines: Cabazitaxel may influence the ability to drive and use machines as it may cause fatigue and dizziness. Patients should be advised not to drive or use machines if they experience these adverse reactions during treatment.
Use in Children: The safety and effectiveness of Cabazitaxel in pediatric patients have not been established.
Use in the Elderly: Patients ≥ 65 years of age are more likely to experience certain adverse reactions, including neutropenia and febrile neutropenia.
Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of cabazitaxel between patients < 65 years and older.
Elderly patients (≥65 years of age) may be more likely to experience certain adverse reactions.
The incidence of neutropenia, fatigue, asthenia, pyrexia, dizziness, urinary tract infection and dehydration occurred at rates > 5% higher in patients who were 65 years of age or greater compared to younger patients.

Pregnancy (Pregnancy category D): Cabazitaxel can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking Cabazitaxel.
Nursing Mothers: It is not known whether Cabazitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cabazitaxel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The safety of Cabazitaxel in combination with prednisone or prednisolone was evaluated in 371 patients with metastatic castration resistant prostate cancer who were treated with 25 mg/m² cabazitaxel once every three weeks in randomised open label, controlled phase III study. Patients received a median duration of 6 cycles of cabazitaxel.
The most commonly (≥10%) occurring adverse reactions in all grades were anaemia (97.3%), leukopenia (95.7%), neutropenia (93.5%), thrombocytopenia (47.4%), and diarrhoea (46.6%). The most commonly (≥5%) occurring grade ≥3 adverse reactions in the cabazitaxel group were neutropenia (81.7%), leukopenia (68.2%), anaemia (10.5%), febrile neutropenia (7.5%), diarrhoea (6.2%).
Discontinuation of treatment due to adverse reactions occurred in 68 patients (18.3%) receiving cabazitaxel. The most common adverse reactions leading to cabazitaxel discontinuation was neutropenia.
The following serious adverse reactions are discussed in greater detail in another section (see Precautions): Neutropenia, Hypersensitivity Reactions, Gastrointestinal Disorders, Renal Failure.

Drugs That May Increase Cabazitaxel Plasma Concentrations: CYP3A4 Inhibitors: Cabazitaxel is primarily metabolized through CYP3A. Concomitant administration of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) is expected to increase concentrations of cabazitaxel. Therefore, co-administration with strong CVYP3A inhibitors should be avoided. Caution should be exercised with concomitant use of moderate CYP3A inhibitors.
Drugs That May Decrease Cabazitaxel Plasma Concentrations: CYP3A4 Inducers: Concomitant administration of strong CYP3A inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital) is expected to decrease cabazitaxel concentrations. Therefore, co-administration with strong CYP3A inducers should be avoided.

Incompatibilities: This medical product must not be mixed with other medicinal products. PVC infusion containers or polyurethane infusion sets should not be used for the preparation and administration of the infusion solution.
Special precautions for disposal and other handling: Procedure for proper handling and disposal of antineoplastic drugs should be followed. Any unused product or waste material should be disposed of in accordance with local requirements.

Store below 30°C. Do not refrigerate. Protect from light (keep in outer carton).
Shelf-life: Unopened vial: 3 years.
Stability of the Dilution Solution in the Infusion Bag: Fully prepared Cabazitaxel Injection infusion solution (in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 4 hours at ambient temperature (including the one-hour infusion), or for a total of 24 hours (including the one-hour infusion) under the refrigerated conditions.
In addition, chemical and physical stability of the infusion solution has been demonstrated for 24 hours under refrigerated conditions. As the final infusion solution is supersaturated, the solution may crystallize over time. If cystals and/or particulates appear, the solution must not be used and should be discarded.

Cytotoxic Chemotherapy

L01CD04 - cabazitaxel ; Belongs to the class of taxanes from plant alkaloids and other natural products. Used in the treatment of cancer.

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