WARNINGS AND PRECAUTIONS
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 JEVTANA 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 [see Dosage and Administration].
JEVTANA should not be administered to patients with neutrophils ≤ 1,500/mm3
[see Contraindications (4) ].
If a patient experiences febrile neutropenia or prolonged neutropenia (greater than one week) despite appropriate medication (e.g., G-CSF), the dose of JEVTANA should be reduced [see Dosage and Administration]. Patients can restart treatment with JEVTANA only when neutrophil counts recover to a level > 1,500/mm3
[see Contraindications (4) ].
All patients should be premedicated prior to the initiation of the infusion of JEVTANA [see Dosage and Administration]. 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 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. Severe hypersensitivity reactions require immediate discontinuation of the JEVTANA infusion and appropriate therapy. Patients with a history of severe hypersensitivity reactions should not be re-challenged with JEVTANA [see Contraindications (4) ].
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 [see Dosage and Administration].
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 [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.
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 [see Adverse Reactions and Use in Specific Populations].
No dedicated hepatic impairment trial for JEVTANA 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 JEVTANA. JEVTANA should not be given to patients with hepatic impairment (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 — ULN).
Pregnancy category D.
JEVTANA 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 JEVTANA. 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 JEVTANA [see Use in Specific Populations].
USE IN SPECIFIC POPULATIONS
Pregnancy category D. See ' Warnings and Precautions ' section.
JEVTANA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of JEVTANA 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 JEVTANA.
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 JEVTANA, 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 and effectiveness of JEVTANA in pediatric patients have not been established.
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 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 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 [see Adverse Reactions].
No dedicated renal impairment trial for JEVTANA 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 [see Clinical Pharmacology]. Caution should be used in patients with severe renal impairment (CLcr < 30 mL/min) and patients with end-stage renal diseases.
No dedicated hepatic impairment trial for JEVTANA has been conducted. The safety of JEVTANA has not been evaluated in patients with hepatic impairment [see Warnings and Precautions].
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.