Cabazitaxel Injection

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Before receiving cabazitaxel injection,

• tell your doctor and pharmacist if you are allergic to cabazitaxel injection, any other medications, polysorbate 80, or any of the other ingredients in cabazitaxel injection. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: anticoagulants ('blood thinners') such as warfarin (Coumadin); antifungals such as ketoconazole (Nizoral), itraconazole (Sporanox), and voriconazole (Vfend); antiplatelet medications; aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn); clarithromycin (Biaxin); certain medications for human immunodeficiency virus (HIV) such as atazanavir (Reyataz), indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), and saquinavir (Invirase); certain medications for seizures such as carbamazepine (Carbatrol, Equetro, Tegretol), phenytoin (Dilantin), and phenobarbital; nefazodone; rifabutin (Mycobutin), rifapentine (Priftin); rifampin (Rimactin, in Rifamate, in Rifater); steroid medication; and telithromycin (Ketek). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with cabazitaxel injection, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor what herbal products you are taking, especially St. John's wort.
• tell your doctor if you have or have ever had liver disease. Your doctor may probably tell you not to receive cabazitaxel injection.
• tell your doctor if you have or have ever had kidney disease or anemia (a lower than normal number of red blood cells).
• you should know that cabazitaxel injection is usually used in men with prostate cancer. If used by pregnant women, cabazitaxel injection can cause harm to the fetus. Women who are or may become pregnant or are breast-feeding should not receive cabazitaxel injection. If you receive cabazitaxel injection while you are pregnant, call your doctor. You should use birth control to prevent pregnancy during your treatment with cabazitaxel injection.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are receiving cabazitaxel injection.

Talk to your doctor about eating grapefruit and drinking grapefruit juice while taking this medication.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

• sore throat, cough, fever, chills, muscle aches, burning on urination, or other signs of infection
• unusual bruising or bleeding
• pale skin
• shortness of breath
• excessive tiredness or weakness
• nausea
• vomiting
• diarrhea

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.

Pharmacodynamics

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.

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 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.

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 [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 model with α-, β-, and γhalf-lives of 4 minutes, 2 hours, and 95 hours, respectively.

Cabazitaxel is minimally excreted via the kidney. A 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. This was confirmed by a dedicated comparative pharmacokinetic study in patients with solid tumors with normal renal function (n=8, CLCR >80 mL/min/1.73 m²), or moderate (n=8, 30 mL/min/1.73 m² ≤ CLCR <50 mL/min/1.73 m²) and severe (n=9, CLCR <30 mL/min/1.73 m²) renal impairment, who received several cycles of cabazitaxel in single IV infusion up to 25 mg/m². Limited pharmacokinetic data were available in patients with end-stage renal disease (n=2, CLCR <15 mL/min/1.73 m²).

Cabazitaxel is extensively metabolized in the liver.

A dedicated study in 43 cancer patients with hepatic impairment showed no influence of mild (total bilirubin >1 to ≤ 1.5 x ULN or AST >1.5 x ULN) or moderate (total bilirubin >1.5 to ≤ 3.0 x ULN) hepatic impairment on cabazitaxel pharmacokinetics. The maximum tolerated dose (MTD) of cabazitaxel was 20 and 15 mg/m², respectively. In 3 patients with severe hepatic impairment (total bilirubin >3 x ULN), a 39% decrease in clearance was observed when compared to patients with mild hepatic impairment (ratio=0.61, 90% CI: 0.36-1.05), indicating some effect of severe hepatic impairment on cabazitaxel pharmacokinetics. The MTD of cabazitaxel in patients with severe hepatic impairment was not established. Based on safety and tolerability data, cabazitaxel dose should be maintained at 20 mg/m² in patients with mild hepatic impairment and reduced to 15 mg/m² in patients with moderate hepatic impairment [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. Cabazitaxel is contraindicated in patients with severe hepatic impairment [see CONTRAINDICATIONS and Use In Specific Populations].

Drug Interactions

A drug interaction study of JEVTANA 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 JEVTANA 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 JEVTANA 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 JEVTANA 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.

Clinical Studies

TROPIC Trial (JEVTANA + Prednisone Compared To Mitoxantrone)

The efficacy and safety of JEVTANA in combination with prednisone were evaluated in a randomized, open-label, international, multi-center study in patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen (TROPIC, NCT00417079).

A total of 755 patients were randomized to receive either JEVTANA 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 0-2. Patients had to have neutrophils >1,500 cells/mm³, platelets >100,000 cells/mm³, hemoglobin >10 g/dL, creatinine <1.5 x upper limit of normal (ULN), total bilirubin <1 x ULN, AST <1.5 x ULN, and ALT <1.5 x 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 (0-2) were balanced between the treatment arms. The median age was 68 years (range 46-92) and the racial distribution for all groups was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others in the JEVTANA group.

Efficacy results for the JEVTANA arm versus the control arm are summarized in Table 5 and Figure 1.

Table 5: Efficacy of JEVTANA in TROPIC in the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer (intent-to-treat analysis)

Figure 1: Kaplan-Meier Overall Survival Curves (TROPIC)

Investigator-assessed tumor response of 14.4% (95% CI: 9.6-19.3) was higher for patients in the JEVTANA arm compared to 4.4% (95% CI: 1.6-7.2) for patients in the mitoxantrone arm, p=0.0005.

In a noninferiority, multicenter, randomized, open-label study (PROSELICA, NCT01308580), 1200 patients with metastatic castration-resistant prostate cancer, previously treated with a docetaxel-containing regimen, were randomized to receive either JEVTANA 25 mg/m² (n=602) or 20 mg/m² (n=598) dose. Overall survival (OS) was the major efficacy outcome.

Demographics, including age, race, and ECOG performance status (0-2) were balanced between the treatment arms. The median age was 68 years (range 45-89) and the racial distribution for all groups was 87% Caucasian, 6.9% Asian, 2.3% Black, and 3.8% Others in the JEVTANA 20 mg/m² group. The median age was 69 years (range 45-88) and the racial distribution for all groups was 88.7% Caucasian, 6.6% Asian, 1.8% Black, and 2.8% Others in the JEVTANA 25 mg/m² group.

The study demonstrated noninferiority in overall survival (OS) of JEVTANA 20 mg/m² in comparison with JEVTANA 25 mg/m² in an intent-to-treat population (see Table 6 and Figure 2). Based on the per-protocol population, the estimated median OS was 15.1 months on JEVTANA 20 mg/m² and 15.9 months on JEVTANA 25 mg/m², the observed hazard ratio (HR) of OS was 1.042 (97.78% CI: 0.886, 1.224). Among the subgroup analyses intended for assessing the heterogeneity, no notable difference in OS was observed on the JEVTANA 25 mg/m² arm compared to the JEVTANA 20 mg/m² arm in subgroups based on the stratification factors of ECOG performance status score, measurability of disease, or region.

Table 6: Overall Survival in PROSELICA for JEVTANA 20 mg/m² versus JEVTANA 25 mg/m² (intent-to-treat analysis)

Figure 2: Kaplan-Meier Overall Survival Curves (intent-to-treat population) (PROSELICA)

Call your doctor for instructions if you miss an appointment for your cabazitaxel injection.

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