Cabazitaxel

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# Black Box Warning

# Overview
Cabazitaxel is a antineoplasic agent that is FDA approved for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, and alopecia.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Indications
- Cabazitaxel is a 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.

### Dosage
- 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.
- Both the Cabazitaxel Injection and the diluent vials contain an overfill to compensate for liquid loss during preparation.
- The Cabazitaxel dose should be reduced if patients experience the following adverse reactions.
- Discontinue Cabazitaxel treatment if a patient continues to experience any of these reactions at 20 mg/m2.
- Concomitant drugs that are strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations of cabazitaxel. Avoid the coadministration of Cabazitaxel with these drugs. If patients require co-administration of a strong CYP3A inhibitor, consider a 25% Cabazitaxel dose reduction

### DOSAGE FORMS AND STRENGTHS
- Cabazitaxel (cabazitaxel) Injection 60 mg/1.5 mL is supplied as a kit consisting of the following:
- Cabazitaxel Injection 60 mg/1.5 mL: contains 60 mg cabazitaxel in 1.5 mL polysorbate 80,
- Diluent for Cabazitaxel Injection 60 mg/1.5 mL: contains approximately 5.7 mL of 13% (w/w) ethanol in water for injection.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cabazitaxel in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Cabazitaxel in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Cabazitaxel in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cabazitaxel in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Cabazitaxel in pediatric patients.

# Contraindications
- Cabazitaxel should not be used in patients with neutrophil counts of  1,500/mm3.
- Cabazitaxel is contraindicated in patients who have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80.

# Warnings
- Five patients experienced fatal infectious adverse events (sepsis or septic shock). All had grade 4 neutropenia and one had febrile neutropenia. One additional patient's death was attributed to neutropenia without a documented infection.
- G-CSF may be administered to reduce the 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.
- Monitoring of complete blood counts is essential on a weekly basis during cycle 1 and before each treatment cycle thereafter so that the dose can be adjusted, if needed.
- Cabazitaxel should not be administered to patients with neutrophils  1,500/mm3.
- 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.
- All patients should be premedicated prior to the initiation of the infusion of Cabazitaxel. 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, thus facilities and equipment for the treatment of hypotension and bronchospasm should be available. 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.
- Nausea, vomiting and severe diarrhea, at times, may occur. Death related to diarrhea and electrolyte imbalance occurred in the randomized clinical trial. 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, enterocolitis, neutropenic enterocolitis, including fatal outcome, have been reported in patients treated with Cabazitaxel. Risk may be increased with neutropenia, age, steroid use, concomitant use of NSAIDs, anti-platelet therapy or anti-coagulants, and patients with a prior history of pelvic radiotherapy, adhesions, ulceration and GI bleeding.
- 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 delay or discontinuation may be necessary.
- Renal failure, including four cases with fatal outcome, was reported in the randomized clinical trial. Most cases occurred in association with sepsis, dehydration, or obstructive uropathy. 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.
- In the randomized clinical trial, 3 of 131 (2%) patients < 65 years of age and 15 of 240 (6%)  65 years of age died of causes other than disease progression within 30 days of the last cabazitaxel dose. Patients  65 years of age are more likely to experience certain adverse reactions, including neutropenia and febrile neutropenia.
- No dedicated hepatic impairment trial for Cabazitaxel has been conducted. Patients with impaired hepatic function (total bilirubin  ULN, or AST and/or ALT  1.5  ULN) were excluded from the randomized clinical trial.
- 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).
- Pregnancy category D.
- Cabazitaxel can cause fetal harm when administered to a pregnant woman. In non-clinical studies in rats and rabbits, cabazitaxel was embryotoxic, fetotoxic, and abortifacient at exposures significantly lower than those expected at the recommended human dose level.
- There are no adequate and well-controlled studies in pregnant women using Cabazitaxel. 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 during treatment with Cabazitaxel

# Adverse Reactions

## Clinical Trials Experience
- The following serious adverse reactions are discussed in greater detail in another section of the label:
- Neutropenia
- Hypersensitivity Reactions
- Gastrointestinal Disorders
- Renal Failure
- Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
- The safety of Cabazitaxel in combination with prednisone was evaluated in 371 patients with hormone-refractory metastatic prostate cancer treated in a single randomized trial, compared to mitoxantrone plus prednisone.
- Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (5%) Cabazitaxel-treated patients and 3 (< 1%) mitoxantrone-treated patients. The most common fatal adverse reactions in Cabazitaxel-treated patients were infections (n=5) and renal failure (n=4). The majority (4 of 5 patients) of fatal infection-related adverse reactions occurred after a single dose of Cabazitaxel. Other fatal adverse reactions in Cabazitaxel-treated patients included ventricular fibrillation, cerebral hemorrhage, and dyspnea.
- The most common ( 10%) grade 14 adverse reactions were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysguesia, cough, arthralgia, and alopecia.
- The most common ( 5%) grade 34 adverse reactions in patients who received Cabazitaxel were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia.
- Treatment discontinuations due to adverse drug reactions occurred in 18% of patients who received Cabazitaxel and 8% of patients who received mitoxantrone. The most common adverse reactions leading to treatment discontinuation in the Cabazitaxel group were neutropenia and renal failure. Dose reductions were reported in 12% of Cabazitaxel-treated patients and 4% of mitoxantrone-treated patients. Dose delays were reported in 28% of Cabazitaxel-treated patients and 15% of mitoxantrone-treated patients.
- Five patients experienced fatal infectious adverse events (sepsis or septic shock). All had grade 4 neutropenia and one had febrile neutropenia. One additional patient's death was attributed to neutropenia without a documented infection. Twenty-two (6%) patients discontinued Cabazitaxel treatment due to neutropenia, febrile neutropenia, infection, or sepsis. The most common adverse reaction leading to treatment discontinuation in the Cabazitaxel group was neutropenia (2%).
- Adverse events of hematuria, including those requiring medical intervention, were more common in Cabazitaxel-treated patients. The incidence of grade  2 hematuria was 6% in Cabazitaxel-treated patients and 2% in mitoxantrone-treated patients. Other factors associated with hematuria were well-balanced between arms and do not account for the increased rate of hematuria on the Cabazitaxel arm.
- The incidences of grade 34 increased AST, increased ALT, and increased bilirubin were each  1%.
- The following grade 14 adverse reactions were reported at rates  5% higher in patients 65 years of age or greater compared to younger patients: fatigue (40% vs. 30%), neutropenia (97% vs. 89%), asthenia (24% vs. 15%), pyrexia (15% vs. 8%), dizziness (10% vs. 5%), urinary tract infection (10% vs. 3%) and dehydration (7% vs. 2%), respectively.
- The incidence of the following grade 34 adverse reactions were higher in patients  65 years of age compared to younger patients; neutropenia (87% vs. 74%), and febrile neutropenia (8% vs. 6%)

## Postmarketing Experience
- The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.
- Gastrointestinal: Gastritis, intestinal obstruction.

# Drug Interactions
- No formal clinical drug-drug interaction trials have been conducted with Cabazitaxel.
- Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.
- CYP3A4 Inhibitors: Cabazitaxel is primarily metabolized through CYP3A. Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations of cabazitaxel. Avoid the co-administration of Cabazitaxel with strong CYP3A inhibitors. If patients require co-administration of a strong CYP3A inhibitor, consider a 25% Cabazitaxel dose reduction

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): D
- Cabazitaxel can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Cabazitaxel in pregnant women.
- Non-clinical studies in rats and rabbits have shown that cabazitaxel is embryotoxic, fetotoxic, and abortifacient. Cabazitaxel was shown to cross the placenta barrier within 24 hours of a single intravenous administration of a 0.08 mg/kg dose (approximately 0.02 times the maximum recommended human dose-MRHD) to pregnant rats at gestational day 17.
- Cabazitaxel administered once daily to female rats during organogenesis at a dose of 0.16 mg/kg/day (approximately 0.020.06 times the Cmax in patients with cancer at the recommended human dose) caused maternal and embryofetal toxicity consisting of increased post-implantation loss, embryolethality, and fetal deaths. Decreased mean fetal birth weight associated with delays in skeletal ossification were observed at doses  0.08 mg/kg (approximately 0.02 times the Cmax at the MRHD). In utero exposure to cabazitaxel did not result in fetal abnormalities in rats or rabbits at exposure levels significantly lower than the expected human exposures.
- 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.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cabazitaxel in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Cabazitaxel during labor and delivery.

### Nursing Mothers
- Cabazitaxel or cabazitaxel metabolites are excreted in maternal milk of lactating rats. It is not known whether this drug is excreted in human milk. Within 2 hours of a single intravenous administration of cabazitaxel to lactating rats at a dose of 0.08 mg/kg (approximately 0.02 times the maximum recommended human dose), radioactivity related to cabazitaxel was detected in the stomachs of nursing pups. This was detectable for up to 24 hours post-dose. Approximately 1.5% of the dose delivered to the mother was calculated to be delivered in the maternal 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.

### Pediatric Use
- The safety and effectiveness of Cabazitaxel in pediatric patients have not been established.

### Geriatic Use
- Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of cabazitaxel between patients < 65 years (n=100) and older (n=70).
- Of the 371 patients with prostate cancer treated with Cabazitaxel every three weeks plus prednisone, 240 patients (64.7%) were 65 years of age and over, while 70 patients (18.9%) were 75 years of age and over. No overall differences in effectiveness were observed between patients  65 years of age and younger patients. 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

### Gender
There is no FDA guidance on the use of Cabazitaxel with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Cabazitaxel with respect to specific racial populations.

### Renal Impairment
- No dedicated renal impairment trial for Cabazitaxel has been conducted. Based on the population pharmacokinetic analysis, no significant difference in clearance was observed in patients with mild (50 mL/min  creatinine clearance (CLcr) < 80 mL/min) and moderate renal impairment (30 mL/min  CLcr < 50 mL/min). No data are available for patients with severe renal impairment or end-stage renal disease . Caution should be used in patients with severe renal impairment (CLcr < 30 mL/min) and patients with end-stage renal diseases.

### Hepatic Impairment
No dedicated hepatic impairment trial for Cabazitaxel has been conducted. The safety of Cabazitaxel has not been evaluated in patients with hepatic impairment .
- As cabazitaxel is extensively metabolized in the liver, hepatic impairment is likely to increase the cabazitaxel concentrations. Patients with impaired hepatic function (total bilirubin  ULN, or AST and/or ALT  1.5  ULN) were excluded from the randomized clinical trial.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cabazitaxel in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Cabazitaxel in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Premedicate at least 30 minutes prior to each dose of Cabazitaxel with the following intravenous medications to reduce the risk and/or severity of hypersensitivity:
- 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. Please refer to HANDLING AND DISPOSAL (16.3).
- If Cabazitaxel Injection, first diluted solution, or second (final) dilution for intravenous infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Cabazitaxel Injection, first diluted solution, or second (final) dilution for intravenous infusion should come into contact with mucosa, immediately and thoroughly wash with water.
- Do not use PVC infusion containers or polyurethane infusions sets for preparation and administration of Cabazitaxel infusion solution.
- Read this entire section carefully before mixing and diluting. Cabazitaxel requires two dilutions prior to administration. Please follow the preparation instructions provided below, as improper preparation may lead to overdose.
- Note: Both the Cabazitaxel Injection and the diluent vials contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with the entire contents of the accompanying diluent, there is an initial diluted solution containing 10 mg/mL Cabazitaxel.
- The following two-step dilution process must be carried out under aseptic conditions to prepare the second (final) infusion solution.
- Inspect the Cabazitaxel Injection and supplied diluent vials. The Cabazitaxel Injection is a clear yellow to brownish-yellow viscous solution.
- Step 1  First Dilution
- Each vial of Cabazitaxel (cabazitaxel) 60 mg/1.5 mL must first be mixed with the entire contents of supplied diluent. Once reconstituted, the resultant solution contains 10 mg/mL of Cabazitaxel.
- When transferring the diluent, direct the needle onto the inside wall of Cabazitaxel vial and inject slowly to limit foaming. Remove the syringe and needle and gently mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full mixing of the drug and diluent. Do not shake.
- Let the solution stand for a few minutes to allow any foam to dissipate, and check that the solution is homogeneous and contains no visible particulate matter. It is not required that all foam dissipate prior to continuing the preparation process.
- The resulting initial diluted Cabazitaxel solution (cabazitaxel 10 mg/mL) requires further dilution before administration. The second dilution should be done immediately (within 30 minutes) to obtain the final infusion as detailed in Step 2.
- Step 2  Second (Final) Dilution
- Withdraw the recommended dose from the Cabazitaxel solution containing 10 mg/mL as prepared in Step 1 using a calibrated syringe and further 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 is required, use a larger volume of the infusion vehicle so that a concentration of 0.26 mg/mL Cabazitaxel is not exceeded. The concentration of the Cabazitaxel final infusion solution should be between 0.10 mg/mL and 0.26 mg/mL.
- Cabazitaxel 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 final infusion solution (in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 8 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 first diluted solution or second (final) infusion solution is not clear or appears to have precipitation, it should be discarded.
- Discard any unused portion.
- 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)

### Monitoring
In order to monitor the occurrence of neutropenia, frequent blood cell counts should be performed on all patients receiving Cabazitaxel. Cabazitaxel should not be given to patients with neutrophil counts of 1,500 cells/mm3.

# IV Compatibility
There is limited information regarding IV Compatibility of Cabazitaxel in the drug label.

# Overdosage
- There is no known antidote for Cabazitaxel overdose. Overdose has resulted from improper preparation. Please read the entire section DOSAGE AND ADMINISTRATION (2) carefully before mixing or diluting. Complications of overdose include exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders. Overdose has led to fatal outcome.
- 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.

# Pharmacology

## Mechanism of Action
- 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.

## Structure
- Cabazitaxel (cabazitaxel) is an antineoplastic agent belonging to the taxane class. It is prepared by semi-synthesis with a precursor extracted from yew needles.
- The chemical name of cabazitaxel is (2,5,7,10,13)-4-acetoxy-13-({(2R,3S)-3--2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate  propan-2-one(1:1).
- Cabazitaxel has the following structural formula:
- Cabazitaxel is a white to almost-white powder with a molecular formula of C45H57NO14.C3H6O and a molecular weight of 894.01 (for the acetone solvate) / 835.93 (for the solvent free). It is lipophilic, practically insoluble in water and soluble in alcohol.
- Cabazitaxel (cabazitaxel) Injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution and is available in single-use vials containing 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 g polysorbate 80.
- Each mL contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80.
- DILUENT for Cabazitaxel is a clear, colorless, sterile, and non-pyrogenic solution containing 13% (w/w) ethanol in water for injection, approximately 5.7 mL.
- Cabazitaxel requires two dilutions prior to intravenous infusion. Cabazitaxel injection should be diluted only with the supplied DILUENT for Cabazitaxel, followed by dilution in either 0.9% sodium chloride solution or 5% dextrose solution.

## Pharmacodynamics
- 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.
- 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 (Tmax). The mean AUC in patients with metastatic prostate cancer was 991 ngh/mL (CV 34%).
- No major deviation from the dose proportionality was observed from 10 to 30 mg/m2 in patients with advanced solid tumors.
- 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.
- Cabazitaxel is extensively metabolized in the liver (> 95%), mainly by the CYP3A4/5 isoenzyme (80% to 90%), and to a 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.
- After a one-hour intravenous infusion -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 model with -, -, and - half-lives of 4 minutes, 2 hours, and 95 hours, respectively.
- Cabazitaxel is minimally excreted via the kidney. No formal pharmacokinetic trials have been conducted with cabazitaxel in patients with renal impairment. The population pharmacokinetic analysis carried out in 170 patients including 14 patients with moderate renal impairment (30 mL/min  CLcr < 50 mL/min) and 59 patients with mild renal impairment (50 mL/min  CLcr < 80 mL/min) showed that mild to moderate renal impairment did not have meaningful effects on the pharmacokinetics of cabazitaxel. No data are available for patients with severe renal impairment or end-stage renal disease.
- No formal trials in patients with hepatic impairment have been conducted. As cabazitaxel is extensively metabolized in the liver, hepatic impairment is likely to increase the cabazitaxel concentrations.
- A drug interaction study of Cabazitaxel in 23 patients with advanced cancers has shown that repeated administration of ketoconazole (400 mg orally once daily), a strong CYP3A inhibitor, increased the exposure to cabazitaxel (5 mg/m2 intravenous) by 25%.
- A drug interaction study of Cabazitaxel in 13 patients with advanced cancers has shown that repeated administration of aprepitant (125 or 80 mg once daily), a moderate CYP3A inhibitor, did not modify the exposure to cabazitaxel (15 mg/m2 intravenous).
- A drug interaction study of Cabazitaxel in 21 patients with advanced cancers has shown that repeated administration of rifampin (600 mg once daily), a strong CYP3A inducer, decreased the exposure to cabazitaxel (15 mg/m2 intravenous) by 17%.
- A drug interaction study of Cabazitaxel in 11 patients with advanced cancers has shown that cabazitaxel (25 mg/m2 administered as a single 1-hour infusion) did not modify the exposure to midazolam, a probe substrate of CYP3A.
- Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.
- 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, -2D6, and CYP3A4/5) is low.
- In addition, cabazitaxel did not induce CYP isozymes (-1A, -2C9 and -3A) in vitro.
- In vitro, cabazitaxel did not inhibit the multidrug-resistance protein 1 (MRP1) 2 (MRP2) or organic cation transporter (OCT1). In vitro, cabazitaxel inhibited P-gp, BRCP, and organic anion transporting polypeptides (OATP1B1, OATP1B3). However the in vivo risk of cabazitaxel inhibiting MRPs, OCT1, P-gp, BCRP, OATP1B1 or OATP1B3 is low at the dose of 25 mg/m2.
- In vitro, cabazitaxel is a substrate of P-gp, but not a substrate of MRP1, MRP2, BCRP, OCT1, OATP1B1 or OATP1B3.
- The effect of cabazitaxel following a single dose of 25 mg/m2 administered by intravenous infusion on QTc interval was evaluated in 94 patients with solid tumors. No large changes in the mean QT interval (i.e., > 20 ms) from baseline based on Fridericia correction method were detected. However, a small increase in the mean QTc interval (i.e., < 10 ms) cannot be excluded due to study design limitations.

## Nonclinical Toxicology
- Long-term animal studies have not been performed to evaluate the carcinogenic potential of cabazitaxel.
- Cabazitaxel was positive for clastogenesis in the in vivo micronucleus test, inducing an increase of micronuclei in rats at doses  0.5 mg/kg. Cabazitaxel increased numerical aberrations with or without metabolic activation in an in vitro test in human lymphocytes though no induction of structural aberrations was observed. Cabazitaxel did not induce mutations in the bacterial reverse mutation (Ames) test. The positive in vivo genotoxicity findings are consistent with the pharmacological activity of the compound (inhibition of tubulin depolymerization).
- Cabazitaxel may impair fertility in humans. In a fertility study performed in female rats at cabazitaxel doses of 0.05, 0.1, or 0.2 mg/kg/day there was no effect of administration of the drug on mating behavior or the ability to become pregnant. There was an increase in pre-implantation loss at the 0.2 mg/kg/day dose and an increase in early resorptions at doses  0.1 mg/kg/day (approximately 0.020.06 times the human clinical exposure based on Cmax). In multi-cycle studies following the clinically recommended dosing schedule, atrophy of the uterus was observed at the 5 mg/kg dose level (approximately the AUC in patients with cancer at the recommended human dose) along with necrosis of the corpora lutea at doses  1 mg/kg (approximately 0.2 times the AUC at the clinically recommended human dose).
- Cabazitaxel did not affect mating performances or fertility of treated male rats at doses of 0.05, 0.1, or 0.2 mg/kg/day. In multiple-cycle studies following the clinically recommended dosing schedule, however, degeneration of seminal vesicle and seminiferous tubule atrophy in the testis were observed in rats treated intravenously with cabazitaxel at a dose of 1 mg/kg (approximately 0.20.35 times the AUC in patients with cancer at the recommended human dose), and minimal testicular degeneration (minimal epithelial single cell necrosis in epididymis) was observed in dogs treated with a dose of 0.5 mg/kg (approximately one-tenth of the AUC in patients with cancer at the recommended human dose).

# Clinical Studies
- The efficacy and safety of Cabazitaxel in combination with prednisone were evaluated in a randomized, open-label, international, multi-center study in patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.
- A total of 755 patients were randomized to receive either Cabazitaxel 25 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone 10 mg orally daily (n=378), or to receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for 10 cycles with prednisone 10 mg orally daily (n=377) for a maximum of 10 cycles.
- This study included patients over 18 years of age with hormone-refractory metastatic prostate cancer either measurable by RECIST criteria or non-measurable disease with rising PSA levels or appearance of new lesions, and ECOG (Eastern Cooperative Oncology Group) performance status 02. Patients had to have neutrophils >1,500 cells/mm3, platelets > 100,000 cells/mm3, hemoglobin > 10 g/dL, creatinine < 1.5  upper limit of normal (ULN), total bilirubin < 1ULN, AST < 1.5  ULN, and ALT < 1.5  ULN. Patients with a history of congestive heart failure, or myocardial infarction within the last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study.
- Demographics, including age, race, and ECOG performance status (02) were balanced between the treatment arms. The median age was 68 years (range 4692) and the racial distribution for all groups was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others in the Cabazitaxel group.
- Efficacy results for the Cabazitaxel arm versus the control arm are summarized in Table 3 and Figure 1.
- Investigator-assessed tumor response of 14.4% (95%CI: 9.619.3) was higher for patients in the Cabazitaxel arm compared to 4.4% (95%CI: 1.67.2) for patients in the mitoxantrone arm, p=0.0005.

# How Supplied
- Cabazitaxel is supplied as a kit containing one single-use vial of Cabazitaxel (cabazitaxel) Injection (clear glass vial with a grey rubber closure, aluminum cap and light green plastic flip-off cap) and one vial of Diluent for Cabazitaxel (13% (w/w) ethanol in water for injection) in a clear glass vial with a grey rubber closure, gold-color aluminum cap and colorless plastic flip-off cap. Both items are in a blister pack in one carton.

## Storage
- Store at 25C (77F); excursions permitted between 1530C (5986F).
- Do not refrigerate.
- Stability of the First Diluted Solution in the Vial:
- First diluted solution of Cabazitaxel should be used immediately (within 30 minutes). Discard any unused portion .
- Stability of the Second (Final) Dilution Solution in the Infusion Bag:
- Fully prepared Cabazitaxel infusion solution (in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 8 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 both the first diluted solution and the second (final) infusion solution are supersaturated, the solutions may crystallize over time. If crystals and/or particulates appear, the solutions must not be used and should be discarded .
- Procedures for proper handling and disposal of antineoplastic drugs should be followed. Several guidelines on this subject have been published . Any unused product or waste material should be disposed of in accordance with local requirements.

# Images

## Drug Images

## Package and Label Display Panel

### PRINCIPAL DISPLAY PANEL
NDC 0024-5824-11
Cabazitaxel 
(cabazitaxel)
Injection
60 mg/1.5 mL Before First Dilution*
This carton contains: 1 Cabazitaxel vial and 1 Diluent vial
- Requires two dilutions before administration-See back panel for details
FOR INTRAVENOUS INFUSION ONLY AFTER SECOND DILUTION
CYTOTOXIC AGENT
RX ONLY
SANOFI
Cabazitaxel 
(cabazitaxel) Injection 
NDC 0024-5823-15
RX ONLY 
60 mg/1.5 mL Before First Dilution*
- FOR INTRAVENOUS INFUSION ONLY AFTER SECOND DILUTION
CAUTION: Reconstitute this vial using the entire contents of the diluent 
vial (approx. 5.7 mL). Following this first dilution, the resultant solution 
contains a concentration of 10 mg/mL. Withdraw only the required 
amount of the first dilution to prepare the final infusion solution prior 
to administration. See package insert for full dilution information.
Store at 25C (77F); excursions permitted between 15-30C 
(59-86F). Do not refrigerate. 
Single-dose vial. 
CYTOTOXIC AGENT 
sanofi-aventis U.S. LLC / Origin France 50110242
DILUENT 
NDC 0024-5822-01
5.7 mL of 13 % (w/w) ethanol in water for injection.
Use ONLY for dilution of Cabazitaxel.
See package insert for full preparation instructions.
Store at 25C (77F); excursions permitted
between 15-30C (59-86F). Do not refrigerate.
Single-dose vial.
RX ONLY
sanofi-aventis U.S. LLC / Origin Germany

### Ingredients and Appearance

# Patient Counseling Information
- Educate patients about the risk of potential hypersensitivity associated with Cabazitaxel. Confirm patients do not have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80. Instruct patients to immediately report signs of a hypersensitivity reaction.
- Explain the importance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever to the treating oncologist.
- Explain that it is important to take the oral prednisone as prescribed. Instruct patients to report if they were not compliant with oral corticosteroid regimen.
- Explain to patients that severe and fatal infections, dehydration, and renal failure have been associated with cabazitaxel exposure. Patients should immediately report fever, significant vomiting or diarrhea, decreased urinary output, and hematuria to the treating oncologist.
- Inform patients about the risk of drug interactions and the importance of providing a list of prescription and non-prescription drugs to the treating oncologist.
- Inform elderly patients that certain side effects may be more frequent or severe.

### PATIENT PACKAGE INSERT
Patient Information
Cabazitaxel (JEV-TA-NA)
(cabazitaxel)
Injection
- Read this Patient Information before you start receiving Cabazitaxel and each time before you receive your infusion. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.
- Cabazitaxel may cause serious side effects including:
- Low white blood cells. Low white blood cells can cause you to get serious infections, and may lead to death. People who are 65 years or older may be more likely to have these problems. Your doctor:
- will do blood tests regularly to check your white blood cell counts during your treatment with Cabazitaxel.
- may lower your dose of Cabazitaxel, change how often you receive it, or stop Cabazitaxel until your doctor decides that you have enough white blood cells.
- may prescribe a medicine for you called G-CSF, to help prevent complications if your white blood cell count is too low.
- Tell your doctor right away if you have any of these symptoms of infection while receiving Cabazitaxel:
- fever. Take your temperature often during treatment with Cabazitaxel.
- cough
- burning on urination
- muscle aches
- Also, tell your doctor if you have any diarrhea during the time that your white blood cell count is low. Your doctor may prescribe treatment for you as needed.
- Severe allergic reactions. Severe allergic reactions can happen within a few minutes after your infusion of Cabazitaxel starts, especially during the first and second infusions. Your doctor should prescribe medicines before each infusion to help prevent severe allergic reactions.
Tell your doctor or nurse right away if you have any of these symptoms of a severe allergic reaction during or soon after an infusion of Cabazitaxel:
- rash or itching
- skin redness
- feeling dizzy or faint
- breathing problems
- chest or throat tightness
- swelling of face
- Severe stomach and intestine (gastrointestinal) problems. Cabazitaxel can cause severe stomach and intestine problems, which may lead to death. You may need to go to the hospital for treatment.
- Vomiting and diarrhea can happen when you take Cabazitaxel. Severe vomiting and diarrhea with Cabazitaxel can lead to loss of too much body fluid (dehydration), or too much of your body salts (electrolytes). Death has happened from having severe diarrhea and losing too much body fluid or body salts with Cabazitaxel. Your doctor will prescribe medicines to prevent or treat vomiting and diarrhea, as needed with Cabazitaxel.
- Tell your doctor if:
- you have vomiting or diarrhea
- your symptoms get worse or do not get better.
- Cabazitaxel can cause a leak in the stomach or intestine, intestinal blockage, infection, and bleeding in the stomach or intestine. This can lead to death.
- Tell your doctor if you get any of these symptoms:
- severe stomach-area (abdomen) pain
- constipation
- fever
- blood in your stool or changes in the color of your stool.
- Kidney failure. Kidney failure may happen with Cabazitaxel, because of severe infection, loss of too much body fluid (dehydration), and other reasons, which may lead to death. Your doctor will check you for this problem and treat you if needed.
- Tell your doctor if you develop these signs or symptoms:
- swelling of your face or body
- decrease in the amount of urine that your body makes each day.
- Cabazitaxel is a prescription anti-cancer medicine used with the steroid medicine prednisone. Cabazitaxel is used to treat people with prostate cancer that has worsened (progressed) after treatment with other anti-cancer medicines, including docetaxel.
- It is not known if Cabazitaxel is safe and effective in children.
- Do not receive Cabazitaxel if:
- your white blood cell (neutrophil count) is too low
- you have had a severe allergic reaction to cabazitaxel or other medicines that contain polysorbate 80. Ask your doctor if you are not sure.
- Before receiving Cabazitaxel, tell your doctor if you:
- had allergic reactions in the past
- have kidney or liver problems
- are over the age of 65
- have any other medical conditions
- if you are a female and:
- are pregnant or plan to become pregnant. Cabazitaxel can harm your unborn baby. Talk to your doctor about the best way for you to prevent pregnancy while you are receiving Cabazitaxel.
- are breastfeeding or plan to breastfeed. It is not known if Cabazitaxel passes into your breast milk. You and your doctor should decide if you will take Cabazitaxel or breastfeed. You should not do both.
- Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Cabazitaxel can interact with many other medicines. Do not take any new medicines without asking your doctor first. Your doctor will tell you if it is safe to take the new medicine with Cabazitaxel.
- Cabazitaxel will be given to you by an intravenous (IV) infusion into your vein.
- Your treatment will take about 1 hour.
- Cabazitaxel is usually given every 3 weeks. Your doctor will decide how often you will receive Cabazitaxel .
- Your doctor will also prescribe another medicine called prednisone, for you to take by mouth every day during treatment with Cabazitaxel. Your doctor will tell you how and when to take your prednisone.
- It is important that you take prednisone exactly as prescribed by your doctor. If you forget to take your prednisone, or do not take it on schedule, make sure to tell your doctor or nurse. Before each infusion of Cabazitaxel, you may receive other medicines to prevent or treat side effects.
- Cabazitaxel may cause serious side effects including:
- See "WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT Cabazitaxel?"
- Common side effects of Cabazitaxel include:
- Low red blood cell count (anemia). Your doctor will regularly check your red blood cell count. Symptoms of anemia include shortness of breath and tiredness.
- Low blood platelet count. Tell your doctor if you have any unusual bruising or bleeding.
- Tell your doctor if you have any side effect that bothers you or that does not go away.
- These are not all the possible side effects of Cabazitaxel. For more information, ask your doctor or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.
- This leaflet summarizes the most important information about Cabazitaxel. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Cabazitaxel that is written for health professionals.
- For more information, go to www.sanofi-aventis.us or call 1-800-633-1610.
- Active ingredient: cabazitaxel
- Inactive ingredient: polysorbate 80

# Precautions with Alcohol
- Alcohol-Cabazitaxel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- JEVTANA 

# Look-Alike Drug Names
There is limited information regarding Cabazitaxel Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price