Dosage & Administration
Recommended Dose: JEVTANA 20 mg/m2 administered every three weeks as a one-hour intravenous infusion in combination with oral prednisone 10 mg administered daily throughout JEVTANA treatment.
A dose of 25 mg/m2 can be used in select patients at the discretion of the treating healthcare provider.
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Jevtana Prescribing Information
Neutropenia: Neutropenic deaths have been reported. Monitor for neutropenia with frequent blood cell counts. JEVTANA is contraindicated in patients with neutrophil counts of ≤1,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features. Consider primary prophylaxis with G-CSF in all patients receiving a dose of 25 mg/m2 [see Contraindications (4) and Warnings and Precautions (5.1, 5.2)].
Severe hypersensitivity: 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 administration of appropriate therapy. Patients should receive premedication. JEVTANA is contraindicated in patients who have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 [see Dosage and Administration (2.1), Contraindications (4), and Warnings and Precautions (5.3)].
JEVTANA® is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen.
Dosing Information
The recommended dose of JEVTANA is based on calculation of the Body Surface Area (BSA), and is 20 mg/m2 administered as a one-hour intravenous infusion every three weeks in combination with oral prednisone 10 mg administered daily throughout JEVTANA treatment.
A dose of 25 mg/m2 can be used in select patients at the discretion of the treating healthcare provider [see Warnings and Precautions (5.1, 5.2), Adverse Reactions (6.1), and Clinical Studies (14)].
Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features. Consider primary prophylaxis with G-CSF in all patients receiving a dose of 25 mg/m2 [see Contraindications (4) and Warnings and Precautions (5.1, 5.2)].
Premedicate at least 30 minutes prior to each dose of JEVTANA with the following intravenous medications to reduce the risk and/or severity of hypersensitivity [see Warnings and Precautions (5.3)]:
- antihistamine (dexchlorpheniramine 5 mg, or diphenhydramine 25 mg or equivalent antihistamine),
- corticosteroid (dexamethasone 8 mg or equivalent steroid),
- H2 antagonist.
Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed [see Warnings and Precautions (5.3)].
JEVTANA injection single-dose vial requires two dilutions prior to administration [see Dosage and Administration (2.5)].
Dose Modifications for Adverse Reactions
Reduce or discontinue JEVTANA dosing for adverse reactions as described in Table 1.
| Toxicity | Dosage Modification |
|---|---|
| Prolonged grade ≥3 neutropenia (greater than 1 week) despite appropriate medication including granulocyte-colony stimulating factor (G-CSF) | Delay treatment until neutrophil count is >1,500 cells/mm3, then reduce dosage of JEVTANA by one dose level. Use G-CSF for secondary prophylaxis. |
| Febrile neutropenia or neutropenic infection | Delay treatment until improvement or resolution, and until neutrophil count is >1,500 cells/mm3, then reduce dosage of JEVTANA by one dose level. Use G-CSF for secondary prophylaxis. |
| Grade ≥3 diarrhea or persisting diarrhea despite appropriate medication, fluid and electrolytes replacement | Delay treatment until improvement or resolution, then reduce dosage of JEVTANA by one dose level. |
| Grade 2 peripheral neuropathy | Delay treatment until improvement or resolution, then reduce dosage of JEVTANA by one dose level. |
| Grade ≥3 peripheral neuropathy | Discontinue JEVTANA. |
Patients at a 20 mg/m2 dose who require dose reduction should decrease dosage of JEVTANA to 15 mg/m2 [see Adverse Reactions (6.1)].
Patients at a 25 mg/m2 dose who require dose reduction should decrease dosage of JEVTANA to 20 mg/m2. One additional dose reduction to 15 mg/m2 may be considered [see Adverse Reactions (6.1)].
Dose Modifications for Hepatic Impairment
- Mild hepatic impairment (total bilirubin >1 to ≤1.5 × Upper Limit of Normal (ULN) or AST >1.5 × ULN): Administer JEVTANA at a dose of 20 mg/m2.
- Moderate hepatic impairment (total bilirubin >1.5 to ≤3 × ULN and AST = any): Administer JEVTANA at a dose of 15 mg/m2 based on tolerability data in these patients; however, the efficacy of this dose is unknown.
- Severe hepatic impairment (total bilirubin >3 × ULN): JEVTANA is contraindicated in patients with severe hepatic impairment [see Warning and Precautions (5.8) and Clinical Pharmacology (12.3)].
Dose Modifications for Use with Strong CYP3A Inhibitors
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 JEVTANA with these drugs. If patients require coadministration of a strong CYP3A inhibitor, consider a 25% JEVTANA dose reduction [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Preparation and Administration
JEVTANA is a hazardous anticancer drug. Follow applicable special handling and disposal procedures [see References (15)]. If JEVTANA first diluted solution, or second (final) dilution for intravenous infusion should come into contact with the skin or mucous, immediately and thoroughly wash with soap and water.
Do not use PVC infusion containers or polyurethane infusions sets for preparation and administration of JEVTANA infusion solution.
JEVTANA should not be mixed with any other drugs.
Preparation
Read this entire section carefully before mixing and diluting. JEVTANA requires two dilutions prior to administration. Follow the preparation instructions provided below, as improper preparation may lead to overdose [see Overdosage (10)].
Note: Both the JEVTANA 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 JEVTANA.
Inspect the JEVTANA injection and supplied diluent vials. The JEVTANA injection is a clear yellow to brownish-yellow viscous solution.
Step 1 – first dilution
Each vial of JEVTANA (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 JEVTANA.
When transferring the diluent, direct the needle onto the inside wall of JEVTANA 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 JEVTANA 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 JEVTANA 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 JEVTANA is required, use a larger volume of the infusion vehicle so that a concentration of 0.26 mg/mL JEVTANA is not exceeded. The concentration of the JEVTANA final infusion solution should be between 0.10 mg/mL and 0.26 mg/mL.
Remove the syringe and thoroughly mix the final infusion solution by gently inverting the bag or bottle.
As the final infusion solution is supersaturated, it may crystallize over time. Do not use if this occurs and discard.
Fully prepared JEVTANA 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.
Discard any unused portion.
Administration
Inspect visually for particulate matter, any crystals and discoloration prior to administration. If the JEVTANA first diluted solution or second (final) infusion solution is not clear or appears to have precipitation, it should be discarded.
Use an in-line filter of 0.22 micrometer nominal pore size (also referred to as 0.2 micrometer) during administration.
The final JEVTANA infusion solution should be administered intravenously as a one-hour infusion at room temperature.
JEVTANA (cabazitaxel) injection is supplied as a kit consisting of the following:
- Cabazitaxel injection: 60 mg/1.5 mL; a clear yellow to brownish-yellow viscous solution
- Diluent: 5.7 mL of 13% (w/w) ethanol in water; a clear colorless solution
Pregnancy
Risk Summary
The safety and efficacy of JEVTANA have not been established in females. There are no human data on the use of JEVTANA in pregnant women to inform the drug-associated risk. 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].
Data
Animal 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.
Lactation
Risk Summary
The safety and efficacy of JEVTANA have not been established in females. 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].
Data
Animal 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
Contraception
Males
Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of JEVTANA [see Use in Specific Populations (8.1)].
Infertility
Males
Based on animal toxicology studies, JEVTANA may impair human fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].
Pediatric Use
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 G-CSF. 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 premedication. 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.
Geriatric Use
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 (5.2)]. 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%).
In the CARD 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 decreased appetite (16% vs 7%), hypertension (5% vs 0), constipation (18% vs 7%), paresthesia (6% vs 0), stomatitis (10% vs 3%), musculoskeletal pain (5% vs 0), fatigue (31% vs 23%), asthenia (30% vs 19%), and edema peripheral (11% vs 0).
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 <15 mL/min/1.73 m2), should be monitored carefully during treatment [see Clinical Pharmacology (12.3)].
Hepatic Impairment
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 (12.3)]. 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 (4)].
JEVTANA is contraindicated in patients with:
- neutrophil counts of ≤1,500/mm3 [see Warnings and Precautions (5.1)]
- history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 [see Warnings and Precautions (5.3)]
- severe hepatic impairment (total bilirubin >3 × ULN) [see Warnings and Precautions (5.8)]