Dosing and uses of Jevtana (cabazitaxel)
Adult dosage forms and strengths
injectable solution
- 60mg/1.5mL
Prostate Cancer
Indicated in combination with prednisone for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen
25 mg/sq.meter IV q3Weeks; infuse IV over 1 hr
Give with prednisone 10 mg PO qDay (ie, administer prednisone every day throughout course of treatment with cabazitaxel)
Dose modification
- Reduce dose to 20 mg/m² with following reactions
- Febrile neutropenia or prolonged (>1 week) neutropenia grade 3 or greater: Delay until neutrophil count is >1500/mm³, and then reinitiate at reduced dose; consider G-CSF for secondary prophylaxis
- Persistent diarrhea or diarrhea grade 3 or greater: Delay until improvement, and then reinitiate at reduced dose of 20 mg/m²
- Grade 2 peripheral neuropathy: Delay treatment until improvement or resolution; then reduce dose to 20 mg/m²
- Grade 3 peripheral neuropathy: Discontinue therapy
- Discontinue if reactions persist despite reduced dose
Hepatic Impairment
Mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 x upper limit of normal (ULN) or AST >1.5 x ULN): Reduce dose to 20 mg/m²
Moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3 x ULN and AST = any): 15 mg/m²
Severe hepatic impairment (total bilirubine >3 x ULN): Contraindicated
Administration
Vial contents require 2 dilutions prior to administration
Use entire contents of accompanying diluent to achieve a concentration of 10 mg/mL
Antiemetic prophylaxis recommended as needed
Premedication regimen
- Initiate premedication 30 minutes before each dose Antihistamine (eg, diphenhydramine 25 mg IV) Corticosteroid (dexamethasone 8 mg IV or equivalent) H2-antagonist (eg, ranitidine 50 mg IV)
Other Information
Use cytotoxic precautions for handling, administration, and disposaL
Pediatric dosage forms and strengths
Safety and efficacy not established
Jevtana (cabazitaxel) adverse (side) effects
>10%
Anemia (11-98%)
Leukopenia (69-96%)
Neutropenia (82-94%)
Thrombocytopenia (4-48%)
Diarrhea (6-47%)
Fatigue (5-37%)
Nausea (2-34%)
Vomiting (2-22%)
Asthenia (5-20%)
Constipation (1-20%)
Abdominal pain (2-17%)
Hematuria (2-17%)
Anorexia (1-16%)
Back pain/arthralgia (11-16%)
Peripheral neuropathy (1-13%)
Pyrexia (1-12%)
Dyspnea (1-12%)
Cough (11%)
Dysgeusia (11%)
1-10%
Dyspepsia (10%)
Alopecia (10%)
Peripheral edema (1-9%)
Weight loss (9%)
Dizziness (8%)
Headache (8%)
UTI (2-8%)
Dysuria (7%)
Febrile neutropenia (1-7%)
Mucosal inflammation (1-6%)
Hypotension (5%)
Arrhythmia (1-5%)
Postmarketing Reports
Gastrointestinal: Gastritis, intestinal obstruction
Interstitial pneumonia/pneumonitis
Interstitial lung disease
Acute respiratory distress syndrome
Warnings
Black box warnings
Neutropenic deaths have been reported; frequent blood cell counts should be performed
Do not give if neutrophils 1,500 cells/mm³ or less
Severe hypersensitivity reactions can occur and may include generalized rash/erythema, hypotension, and bronchospasm; immediately discontinue and initiate treatment as indicated
Contraindications
Neutrophil count 1500/mm³ or less
Hypersensitivity to cabazitaxel or drugs formulated with polysorbate 80
Severe hepatic impairment (total bilirubin > 3 x ULN)
Cautions
Extensively metabolized in liver, hepatic impairment likely to increase serum concentrations
Bone marrow suppression manifested as neutropenia, anemia, thrombocytopenia and/or pancytopenia may occur; neutropenia and febrile neutropenia, including neutropenic deaths, have been reported; monitor blood counts frequently to determine if initiation of G-CSF and/or dosage modification is needed; G-CSF may be administered to reduce the risks of neutropenia complications in patients with high risk clinical features; therapeutic use of G-CSF and secondary prophylaxis should be considered in all patients considered to be at increased risk for neutropenia complications
Gastrointestinal symptoms (nausea, vomiting, diarrhea), including mortality related to diarrhea, has been reported; rehydrate and treat with antiemetics and antidiarrheals as needed
GI hemorrhage and perforation, ileus, enterocolitis, neutropenic enterocolitis, including fatal outcome; risk may be increased with neutropenia, age, steroid use, concomitant use of NSAIDs, antiplatelets, or anticoagulants, and prior history of pelvic radiotherapy, adhesions, ulceration and GI bleeding
Renal failure, including cases with fatal outcomes, reported
Elderly patients (ie, aged 65 years or older) were more likely to experience fatal outcomes not related to disease progression and certain adverse reactions, including neutropenia and febrile neutropenia
Cabazitaxel is a CYP3A substrate; caution with CYP3A inhibitors or inducers that may alter drug serum levels
May cause fetal harm when administered to a pregnant woman
Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome, including fatal outcomes reported; delay or discontinue therapy and treat as indicated
Severe hypersensitivity reactions can occur; premedicate with corticosteroids and H2 antagonists; discontinue infusion immediately if hypersensitivity is observed and treat as indicated
Reduce dose to 20 mg/m² in patients with mild hepatic impairment and to 15 mg/m² in patients with moderate hepatic impairment
Pregnancy and lactation
Pregnancy category: d
Lactation: Unknown whether distributed in breast milk, decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Jevtana (cabazitaxel)
Mechanism of action
Microtubule inhibitor; binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly; this results in microtubule stabilization, which results in the inhibition of mitotic and interphase cellular functions
Absorption
Peak plasma time: 1 hr
Peak plasma concentration: 226 ng/mL
AUC: 991 ng•h/mL
Distribution
Vd: 4,864 L at steady state
Protein bound: 89-92%; mainly bound to albumin (82%)
Metabolism
CYP3A substrate (main), CYP2C8 (less), P-gp substrate; extensively metabolized in liver by CYP3A4/5; 7 metabolites (3 active) detected in plasma; 20 metabolites detected in feces/urine
Elimination
Excretion: Feces (76%), urine (3.7%)
Half-Life: 95 hr (terminal half-life)
Administration
IV Compatibilities
Solution: 0.9% NaCl or dextrose 5%
IV Preparation
Use aseptic technique
2-step dilution process
Do not mix with any other drugs
Step 1 (1st dilution)
- Mix cabazitaxel 60 mg/1.5 mL vial with entire contents of supplied diluent
- Once reconstituted, resultant solution contains 10 mg/mL
- Vial contains slight overfill (ie, entire vial contains about 65 mg)
- When transferring the diluent, direct the needle onto the inside wall of vial and inject slowly to limit foaming
- Remove 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 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
Step 2 (2nd dilution)
- Withdraw recommended dose from reconstituted vial containing 10 mg/mL (1st dilution)
- Further dilute into sterile 250 mL PVC-free container (glass, polyolefin) of either 0.9% NaCl or dextrose 5% solution for infusion
- Final concentration should range between 0.1-0.26 mg/mL
- Thoroughly mix final infusion solution by gently inverting the bag/bottle
IV Administration
Administer IV infusion via volumetric infusion pump
Administer over 1 hr
Use an in-line filter (0.22 micron pore size) during administration
Storage
Appearance is clear, yellow to brownish-yellow, viscous solution under proper storage conditions
Store drug and diluent at room temp 25 degrees C (77 degrees F); brief exposure permitted between 15-30 degrees C (59-86 degrees F)
Do not refrigerate undiluted vial or diluent
Stability
- Do not use PVC infusion containers or polyurethane infusions sets for preparation and administration
- 1st diluted solution in vial: Use immediately (within 30 min) and discard unused portion
- 2nd (final) dilution in infusion bag: Use within 8 hr (ambient temperature, including infusion time), or for a total of 24 hr refrigerated
- Both 1st diluted solution and 2nd (final) infusion solution are supersaturated and may crystallize over time; if crystals and/or particulates appear, solutions must not be used and should be discarded
