September 1, 2015
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Jevtana

"The U.S. Food and Drug Administration today expanded the approved use of Zytiga (abiraterone acetate) to treat men with late-stage (metastatic) castration-resistant prostate cancer prior to receiving chemotherapy.

The FDA initially appr"...

Jevtana




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Bone Marrow Suppression

Bone marrow suppression manifested as neutropenia, anemia, thrombocytopenia and/or pancytopenia may occur. Neutropenic deaths have been reported. In the randomized trial, five patients (1.3%) 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. Grade 3-4 neutropenia has been observed in 82% of patients treated with JEVTANA in the randomized trial.

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 is contraindicated in patients with neutrophils ≤ 1,500/mm³ [see CONTRAINDICATIONS].

Caution is recommended in patients with hemoglobin < 10 g/dl.

Hypersensitivity Reactions

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. Death related to diarrhea and electrolyte imbalance occurred in the randomized clinical trial. Intensive measures may be required for severe diarrhea and electrolyte imbalance. Antiemetic prophylaxis is recommended. Treat patients 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].

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, 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. JEVTANA treatment delay or discontinuation may be necessary.

Renal Failure

In the randomized clinical trial, 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.

Use In Elderly Patients

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].

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 x ULN) [see CONTRAINDICATIONS]. Dose should be reduced for patients with mild (total bilirubin > 1 to ≤ 1.5 x ULN or AST > 1.5 x ULN) and moderate (total bilirubin > 1.5 to ≤ 3.0 x ULN and any AST) hepatic impairment, based on tolerability data in these patients [see DOSAGE AND ADMINISTRATION and Use in Specific Populations]. Administration of cabazitaxel to patients with mild and moderate hepatic impairment should be undertaken with caution and close monitoring of safety.

Embryo-Fetal Toxicity

JEVTANA is not indicated for use in female patients.

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. Females of childbearing potential should be advised to avoid becoming pregnant during treatment with JEVTANA [see Use in Specific Populations].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Hypersensitivity Reactions

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.

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 vomiting or diarrhea, decreased urinary output, and hematuria to their healthcare provider [see WARNINGS AND PRECAUTIONS].

Drug Interactions

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].

Use 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].

Nonclinical Toxicology

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).

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 0.02-0.06 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 0.2-0.35 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).

Use In Specific Populations

Pregnancy

Pregnancy category D. See 'WARNINGS AND PRECAUTIONS' section.

JEVTANA is not indicated for use in female patients.

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 0.02-0.06 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.

Nursing Mothers

JEVTANA is not indicated for use in female patients.

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.

Pediatric Use

The safety and effectiveness of JEVTANA in pediatric patients have not been established.

Geriatric Use

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 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].

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).

Renal Impairment

No dose adjustment is necessary in patients with renal impairment not requiring hemodialysis. Patients presenting with end-stage renal disease (creatinine clearance CLCR < 15mL/min/1.73m²), should be monitored carefully during treatment [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

Cabazitaxel is extensively metabolized in the liver. Patients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 x ULN or AST > 1.5 x ULN) should have JEVTANA dose reduced to 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 x 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 > 3x ULN) [see CONTRAINDICATIONS].

Last reviewed on RxList: 7/8/2015
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions

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