Sanofi-Aventis U.S. LLC
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.
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.
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)].
Reduce or discontinue JEVTANA dosing for adverse reactions as described in Table 1.
|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)].
- 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)].
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)].
JEVTANA is a cytotoxic 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.
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.
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
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)]
JEVTANA is contraindicated in patients with neutrophils ≤1,500/mm3 [see Contraindications (4)]. 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.
TROPIC Trial (JEVTANA 25 mg/m2)
In the TROPIC trial with G-CSF administered only at the investigator’s discretion, 5 patients (1.3%) died from neutropenic infection (sepsis or septic shock); 4 of these patients died in the first 30 days of treatment. 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. Grade 3–4 neutropenia occurred in 82% of patients treated with JEVTANA in the randomized trial [see Adverse Reactions (6.1)].
PROSELICA Trial (comparison of JEVTANA 20 mg/m2 versus 25 mg/m2)
In the PROSELICA trial comparing two doses of JEVTANA, primary prophylaxis with G-CSF was not allowed, but could be administered after development of neutropenia at investigators discretion. Eight 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. Clinically important neutropenia-related events occurred and included febrile neutropenia (2.1% on 20 mg/m2 arm and 9.2% on 25 mg/m2 arm), neutropenic infection/sepsis (2.1% on 20 mg/m2 arm and 6.4% on 25 mg/m2 arm), and neutropenic deaths (0.3% on 20 mg/m2 arm and 0.7% on 25 mg/m2 arm).
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 Adverse Reactions (6.1)].
CARD Trial (JEVTANA 25 mg/m2 + primary prophylaxis G-CSF)
In the CARD trial where JEVTANA 25 mg/m2 was administered with primary prophylaxis of G-CSF, 1 patient (0.8%) died from sepsis within the first 30 days of treatment. Grade 1–4 neutropenia-related adverse reactions were experienced in 33 patients (26%). Grade 3–4 neutropenias were experienced by 26 patients (21%). Clinically important neutropenia-related events occurred and included febrile neutropenia (3.2%), neutropenic infection/sepsis (0.8%) and neutropenic deaths (0.8%) [see Adverse Reactions (6.1)].
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. Consider primary prophylaxis with G-CSF in all patients receiving JEVTANA 25 mg/m2.
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 (2.2)].
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