Included as part of the "PRECAUTIONS" Section
Bone Marrow Suppression
JEVTANA is contraindicated in patients with neutrophils ≤1,500/mm3 [see CONTRAINDICATIONS]. Closely monitor patients with hemoglobin <10 g/dL.
Bone marrow suppression manifested as neutropenia, anemia, thrombocytopenia and/or pancytopenia may occur. Neutropenic deaths have been reported.
In a randomized trial (TROPIC) in previously treated patients with metastatic castration-resistant prostate cancer, five patients (1.3%) died from infection (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 JEVTANA treatment due to neutropenia, febrile neutropenia, infection, or sepsis. The most common adverse reaction leading to treatment discontinuation in the JEVTANA group was neutropenia (2%). Grade 3-4 neutropenia has been observed in 82% of patients treated with JEVTANA in the randomized trial.
In a randomized trial (PROSELICA) comparing two doses of JEVTANA in previously treated metastatic castration-resistant prostate cancer, 8 patients (1%) on the 20 mg/m2 arm and 15 patients (3%) on the 25 mg/m2 arm died from infection; of these, 4 deaths on the 20 mg/m2 arm and 8 deaths on the 25 mg/m2 arm occurred within the first 30 days of treatment.
Fewer patients receiving JEVTANA 20 mg/m2 were reported to have infectious adverse reactions. Grade 1-4 infections were experienced by 160 patients (28%) on the 20 mg/m2 arm and 227 patients (38%) on the 25 mg/m2 arm. Grade 3-4 infections were experienced by 57 patients (10%) on the 20 mg/m2 arm and 120 patients (20%) on the 25 mg/m2 arm. Noninferiority for overall survival was demonstrated between these two arms [see Clinical Studies].
Based on guidelines for the use of G-CSF and the adverse reactions profile of JEVTANA, primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features (older patients, 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. The effectiveness of primary prophylaxis with G-CSF in patients receiving JEVTANA has not been studied. Therapeutic use of G-CSF and secondary prophylaxis should be considered in all patients 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 [see DOSAGE AND ADMINISTRATION].
Increased Toxicities In Elderly Patients
In a randomized trial (TROPIC), 2% of patients (3/131) <65 years of age and 6% (15/240) ≥65 years of age died of causes other than disease progression within 30 days of the last JEVTANA dose. Patients ≥65 years of age are more likely to experience certain adverse reactions, including neutropenia and febrile neutropenia. The incidence of the following grade 3-4 adverse reactions were higher in patients ≥65 years of age compared to younger patients; neutropenia (87% vs 74%), and febrile neutropenia (8% vs 6%).
In a randomized clinical trial (PROSELICA) comparing two doses of JEVTANA, deaths due to infection within 30 days of starting JEVTANA occurred in 0.7% (4/580) patients on the 20 mg/m2 arm and 1.3% (8/595) patients on the 25 mg/m2 arm; all of these patients were >60 years of age.
In PROSELICA, on the 20 mg/m2 arm, 3% (5/178) of patients <65 years of age and 2% (9/402) ≥65 years of age died of causes other than disease progression within 30 days of the last JEVTANA dose. On the 25 mg/m2 arm, 2% (3/175) patients <65 years of age and 5% (20/420) ≥65 years of age died of causes other than disease progression within 30 days of the last JEVTANA dose [see ADVERSE REACTIONS and Use In Specific Populations].
Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of JEVTANA, 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.
Premedicate all patients prior to the initiation of the infusion of JEVTANA [see DOSAGE AND ADMINISTRATION]. Observe patients closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions require immediate discontinuation of the JEVTANA infusion and appropriate therapy. JEVTANA is contraindicated in patients with a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 [see CONTRAINDICATIONS].
Gastrointestinal Adverse Reactions
Nausea, vomiting and severe diarrhea, at times, may occur. Deaths related to diarrhea and electrolyte imbalance occurred in the randomized clinical trials. Intensive measures may be required for severe diarrhea and electrolyte imbalance. Antiemetic prophylaxis is recommended. Treat patients with rehydration, antidiarrheal or antiemetic medications as needed. Treatment delay or dosage reduction may be necessary if patients experience Grade ≥3 diarrhea [see DOSAGE AND ADMINISTRATION].
Gastrointestinal (GI) hemorrhage and perforation, ileus, enterocolitis, neutropenic enterocolitis, including fatal outcome, have been reported in patients treated with JEVTANA [see ADVERSE REACTIONS]. Risk may be increased with neutropenia, age, steroid use, concomitant use of NSAIDs, antiplatelet therapy or anticoagulants, 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. JEVTANA treatment delay or discontinuation may be necessary.
The incidence of gastrointestinal adverse reactions is greater in the patients who have received prior radiation. In PROSELICA, diarrhea was reported in 41% (297/732) of patients who had received prior radiation and in 27% (118/443) of patients without prior radiation. Of the patients who had previously received radiation, more patients on the 25 mg/m2 arm reported diarrhea, compared to patients on the 20 mg/m2 arm.
In the randomized clinical trial (TROPIC), renal failure of any grade occurred in 4% of the patients being treated with JEVTANA, including four cases with fatal outcome. Most cases occurred in association with sepsis, dehydration, or obstructive uropathy [see ADVERSE REACTIONS]. 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.
Urinary Disorders Including Cystitis
Cystitis, radiation cystitis, and hematuria, including that requiring hospitalization, has been reported with JEVTANA in patients who previously received pelvic radiation [see ADVERSE REACTIONS]. In PROSELICA, cystitis and radiation cystitis were reported in 1.2% and 1.5% of patients who received prior radiation, respectively. Hematuria was reported in 19.4% of patients who received prior radiation and in 14.4% of patients who did not receive prior radiation. Cystitis from radiation recall may occur late in treatment with JEVTANA. Monitor patients who previously received pelvic radiation for signs and symptoms of cystitis while on JEVTANA. Interrupt or discontinue JEVTANA in patients experiencing severe hemorrhagic cystitis. Medical and/or surgical supportive treatment may be required to treat severe hemorrhagic cystitis.
Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome have been reported and may be associated with fatal outcome [see ADVERSE REACTIONS]. Patients with underlying lung disease may be at higher risk for these events. Acute respiratory distress syndrome may occur in the setting of infection.
Interrupt JEVTANA if new or worsening pulmonary symptoms develop. Closely monitor, promptly investigate, and appropriately treat patients receiving JEVTANA. Consider discontinuation. The benefit of resuming JEVTANA treatment must be carefully evaluated.
Use In Patients With Hepatic Impairment
Cabazitaxel is extensively metabolized in the liver.
JEVTANA is contraindicated in patients with severe hepatic impairment (total bilirubin >3 × ULN) [see CONTRAINDICATIONS]. Dose should be reduced for patients with mild (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) and moderate (total bilirubin >1.5 to ≤3.0 × ULN and any AST) hepatic impairment, based on tolerability data in these patients [see DOSAGE AND ADMINISTRATION and Use In Specific Populations]. Administration of JEVTANA to patients with mild and moderate hepatic impairment should be undertaken with caution and close monitoring of safety.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Educate patients about the risk of potential hypersensitivity associated with JEVTANA. 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 [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
Bone Marrow Suppression
Inform patients that JEVTANA decreases blood count such as white blood cells, platelets and red blood cells. Thus, it is important that periodic assessment of their blood count be performed to detect the development of neutropenia, thrombocytopenia, anemia, and/or pancytopenia [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever to their healthcare provider.
Increased Toxicities In Elderly Patients
Inform elderly patients that certain side effects may be more frequent or severe [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Importance Of Prednisone
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 [see DOSAGE AND ADMINISTRATION].
Infections, Dehydration, Renal Failure
Explain to patients that severe and fatal infections, dehydration, and renal failure have been associated with cabazitaxel exposure. Patients should immediately report fever, significant omiting or diarrhea, decreased urinary output, and hematuria to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Explain to patients that severe and fatal interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome have occurred with JEVTANA. Instruct patients to immediately report new or worsening pulmonary symptoms to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Inform patients about the risk of drug interactions and the importance of providing a list of prescription and non-prescription drugs to their healthcare provider [see DRUG INTERACTIONS].
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of cabazitaxel injection [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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).
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. In repeat-dose toxicology studies in rats with intravenous cabazitaxel administration once every three weeks for up to 6 months, 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).
In a fertility study in male rats, cabazitaxel did not affect mating performances or fertility at doses of 0.05, 0.1, or 0.2 mg/kg/day. In repeat-dose toxicology studies with intravenous cabazitaxel administration once every three weeks for up to 9 months, degeneration of seminal vesicle and seminiferous tubule atrophy in the testis were observed in rats at a dose of 1 mg/kg (approximately 0.2 times the AUC in patients at the recommended human dose), and minimal testicular degeneration (minimal epithelial single cell necrosis in epididymis) was observed in dogs treated at a dose of 0.5 mg/kg (approximately 0.1 times the AUC in patients at the recommended human dose).
Use In Specific Populations
JEVTANA is contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy. JEVTANA is not indicated for use in female patients. There are no human data on the use of cabazitaxel injection in pregnant women. In animal reproduction studies, intravenous administration of cabazitaxel in pregnant rats during organogenesis caused embryonic and fetal death at doses lower than the maximum recommended human dose [see Data].
In an early embryonic developmental toxicity study in rats, cabazitaxel was administered intravenously for 15 days prior to mating through Day 6 of pregnancy, which resulted in an increase in pre-implantation loss at 0.2 mg/kg/day and an increase in early resorptions at ≥0.1 mg/kg/day (approximately 0.06 and 0.02 times the Cmax in patients at the recommended human dose, respectively).
In an embryo-fetal developmental toxicity study in rats, cabazitaxel caused maternal and embryo-fetal toxicity consisting of increased postimplantation loss, embryolethality, and fetal deaths when administered intravenously at a dose of 0.16 mg/kg/day (approximately 0.06 times the Cmax in patients at the recommended human dose). Decreased mean fetal birthweight associated with delays in skeletal ossification was observed at doses ≥0.08 mg/kg. Cabazitaxel crossed the placenta barrier within 24 hours of a single intravenous administration of 0.08 mg/kg to pregnant rats at gestational day 17. A dose of 0.08 mg/kg in rats resulted in a Cmax approximately 0.02 times that observed in patients at the recommended human dose. Administration of cabazitaxel did not result in fetal abnormalities in rats or rabbits at exposure levels significantly lower than the expected human exposures.
JEVTANA is not indicated for use in female patients. There is no information available on the presence of cabazitaxel in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Cabazitaxel or cabazitaxel metabolites are excreted in maternal milk of lactating rats [see Data].
In a milk excretion study, radioactivity related to cabazitaxel was detected in the stomachs of nursing pups 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 Cmax in patients at the recommended human dose). This was detectable 24 hours post dose. Approximately 1.5% of the dose delivered to the mother was calculated to be delivered in the maternal milk.
Females And Males Of Reproductive Potential
Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of JEVTANA [see Pregnancy].
Based on animal toxicology studies, cabazitaxel injection may impair human fertility in males of reproductive potential [see Nonclinical Toxicology].
The safety and effectiveness of JEVTANA in pediatric patients have not been established.
JEVTANA was evaluated in 39 pediatric patients (ages 3 to 18 years) receiving prophylactic GCSF. The maximum tolerated dose (MTD) was 30 mg/m2 intravenously over 1 hour on Day 1 of a 21 day cycle in pediatric patients with solid tumors based on the dose-limiting toxicity (DLT) of febrile neutropenia. No objective responses were observed in 11 patients with refractory high grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). One patient had a partial response among the 9 patients with ependymoma.
Infusion related/hypersensitivity reactions were seen in 10 patients (26%). Three patients experienced serious adverse events of anaphylactic reaction. The incidence of infusion related/hypersensitivity reactions decreased with steroid pre-medication. The most frequent treatment-emergent adverse events were similar to those reported in adults.
Based on the population pharmacokinetics analysis conducted with data from 31 pediatric patients with cancer (ages 3 to 18 years), the clearances by body surface area were comparable to those in adults.
In the TROPIC study, of the 371 patients with prostate cancer treated with JEVTANA 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 death due to causes other than disease progression within 30 days of the last cabazitaxel dose were higher in patients who were 65 years of age or greater compared to younger patients [see WARNINGS AND PRECAUTIONS]. The incidence of grade 3-4 neutropenia and febrile neutropenia were higher in patients who were 65 years of age or greater compared to younger patients. The following grade 1-4 adverse reactions were reported at rates ≥5% higher in patients 65 years of age or older 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.
In the PROSELICA study, the grade 1-4 adverse reactions reported at rates of at least 5% higher in patients 65 years of age or older compared to younger patients were diarrhea (43% vs 33%), fatigue (30% vs 19%), asthenia (22% vs 13%), constipation (20% vs 13%), clinical neutropenia (13% vs 6%), febrile neutropenia (11% vs 5%), and dyspnea (10% vs 3%).
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).
No dose adjustment is necessary in patients with renal impairment not requiring hemodialysis. Patients presenting with end-stage renal disease (creatinine clearance CLCR <15 mL/min/1.73 m2), should be monitored carefully during treatment [see CLINICAL PHARMACOLOGY].
Cabazitaxel is extensively metabolized in the liver. Patients with mild hepatic impairment (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) should have JEVTANA dose of 20 mg/m2. Administration of cabazitaxel to patients with mild hepatic impairment should be undertaken with caution and close monitoring of safety [see CLINICAL PHARMACOLOGY]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 to ≤3.0 × ULN and AST = any) was 15 mg/m2, however, the efficacy at this dose level was unknown. JEVTANA is contraindicated in patients with severe hepatic impairment (total bilirubin >3 × ULN) [see CONTRAINDICATIONS].