Posology : מינונים

2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
The recommended dose of Cabazitaxel S.K. 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 Cabazitaxel S.K.
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.
Premedicate at least 30 minutes prior to each dose of Cabazitaxel S.K. 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 (ranitidine 50 mg or equivalent H2 antagonist).
Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed [see Warnings and Precautions (5.3)].
Cabazitaxel S.K. injection single-dose vial requires two dilutions prior to administration [see Dosage and Administration (2.5)].
2.2 Dose Modifications for Adverse Reactions
Reduce or discontinue Cabazitaxel S.K. dosing for adverse reactions as described in Table 1.


Table 1: Recommended Dosage Modifications for Adverse Reactions in Patients Treated with Cabazitaxel S.K.
Toxicity                                                    Dosage Modification Prolonged grade ≥ 3 neutropenia (greater than 1 week)       Delay treatment until neutrophil count is despite appropriate medication including granulocyte-       >1,500 cells/mm3, then reduce dosage of Cabazitaxel colony stimulating factor (G-CSF)                           S.K. 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 Cabazitaxel
S.K. by one dose level. Use G-CSF for secondary prophylaxis.
Grade ≥ 3 diarrhea or persisting diarrhea despite           Delay treatment until improvement or resolution, then appropriate medication, fluid and electrolytes              reduce dosage of Cabazitaxel S.K. by one dose replacement                                                 level.
Grade 2 peripheral neuropathy                               Delay treatment until improvement or resolution, then reduce dosage of Cabazitaxel S.K. by one dose level.
Grade ≥3 peripheral neuropathy                              Discontinue Cabazitaxel S.K.
Patients at a 20 mg/m2 dose who require dose reduction should decrease dosage of Cabazitaxel S.K. to 15 mg/m2 [see Adverse Reactions (6.1)].
Patients at a 25 mg/m2 dose who require dose reduction should decrease dosage of Cabazitaxel S.K. to 20 mg/m2. One additional dose reduction to 15 mg/m2 may be considered [see Adverse Reactions (6.1)].
2.3 Dose Modifications for Hepatic Impairment
•   Mild hepatic impairment (total bilirubin >1 to ≤1.5 × Upper Limit of Normal (ULN) or
AST >1.5 x ULN): Administer Cabazitaxel S.K. at a dose of 20 mg/m2.
•   Moderate hepatic impairment (total bilirubin >1.5 to ≤3 × ULN and AST = any): Administer Cabazitaxel S.K. 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): Cabazitaxel S.K. is contraindicated in patients with severe hepatic impairment [see Warning and Precautions (5.8) and Clinical Pharmacology (12.3)].
2.4 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 Cabazitaxel S.K. with these drugs. If patients require coadministration of a strong CYP3A inhibitor, consider a 25% Cabazitaxel S.K. dose reduction [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
2.5 Preparation and Administration
Cabazitaxel S.K. is a cytotoxic anticancer drug. Follow applicable special handling and disposal procedures. If Cabazitaxel S.K., 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 Cabazitaxel S.K. infusion solution.
Cabazitaxel S.K. should not be mixed with any other drugs.
Preparation
Read this entire section carefully before mixing and diluting. Cabazitaxel S.K. 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 Cabazitaxel S.K. 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 Cabazitaxel S.K..
Inspect the Cabazitaxel S.K. injection and supplied diluent vials. The Cabazitaxel S.K. injection is a clear yellow to brownish-yellow viscous solution.
Step 1 – first dilution
Each vial of Cabazitaxel S.K. (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 Cabazitaxel S.K..
When transferring the diluent, direct the needle onto the inside wall of Cabazitaxel S.K. 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 Cabazitaxel S.K. solution (cabazitaxel 10 mg/mL) requires further dilution before administration. The second dilution should be done immediately (within 1 hour) to obtain the final infusion as detailed in Step 2.
Step 2 – second (final) dilution
Withdraw the recommended dose from the Cabazitaxel S.K. 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 Cabazitaxel S.K. is required, use a larger volume of the infusion vehicle so that a concentration of 0.26 mg/mL Cabazitaxel S.K. is not exceeded. The concentration of the Cabazitaxel S.K. 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 Cabazitaxel S.K. 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 Cabazitaxel S.K. 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 Cabazitaxel S.K. infusion solution should be administered intravenously as a one- hour infusion at room temperature.