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cabazitaxel
Cabazitaxel, a semi-synthetic taxane produced from yew needles, binds to tubulin, stabilizes microtubules, and inhibits mitosis. Cabazitaxel is active in docetaxel-sensitive as well as resistant tumours.
Pharmacokinetics are dose proportional between 10 and 30mg/m2
| Cross blood brain barrier? | yes |
| PPB | 89 to 92%;(albumin and lipoproteins) |
Cabazitaxel is extensively metabolized in the liver (≥95%), primarily by the CYP3A4 isoenzyme (80% to 90%)
| Active metabolites | yes |
| Inactive metabolites | yes |
The predominant route of cabazitaxel elimination is fecal excretion.
| Feces |
76%, as metabolites |
| Urine |
<4% (2% unchanged) |
| Half-life |
95 hours (terminal) |
- Prostate cancer
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
Extravasation Potential: Irritant
The following table contains adverse effects reported in patients treated with cabazitaxel 20 mg/m2 and prednisone in prostate cancer. It also includes severe or life-threatening adverse effects from both 20mg/m2 and 25mg/m2 treated groups.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (2%) (≥grade 3: 2%, including tachycardia, atrial/ventricular fibrillation, ↑ QTc) | I E | |||
| Cardiotoxicity (<1%) | E | ||||
| Hypotension (5%) (reported at 25 mg/m2) | I | ||||
| Venous thromboembolism (rare) | E | ||||
| Dermatological | Alopecia (3%) | E | |||
| Gastrointestinal | Abdominal pain (6%) | E | |||
| Anorexia, weight loss (13%) | E | ||||
| Constipation (18%) | E | ||||
| Diarrhea (31%) (1% severe) | E | ||||
| GI hemorrhage (rare) | E | ||||
| GI obstruction (rare) | E | ||||
| GI perforation (rare) | E | ||||
| Mucositis (5%) | E | ||||
| Nausea, vomiting (25%) | I | ||||
| General | Edema (7%) | E | |||
| Fatigue (25%) | E | ||||
| Hematological | Myelosuppression ± infection, bleeding (42%) (severe) (including anemia) | E | |||
| Hepatobiliary | ↑ LFTs (< 1% severe) | E | |||
| Hypersensitivity | Hypersensitivity (rare) | I E | |||
| Musculoskeletal | Musculoskeletal pain (11%) | E | |||
| Nervous System | Dizziness (4%) | E | |||
| Dysgeusia (7%) | E | ||||
| Headache (5%) | E | ||||
| Peripheral neuropathy (7%) | E | ||||
| Renal | Renal failure (2%) | E | |||
| Respiratory | Cough, dyspnea (6%) | E | |||
| Pneumonitis , ARDS (rare) | E D | ||||
| Urinary | Cystitis (rare; with previous radiation and docetaxel) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for cabazitaxel include myelosuppression, diarrhea, fatigue, nausea, vomiting, constipation, hematuria, musculoskeletal pain, anorexia, peripheral neuropathy and dysgeusia.
The major dose-limiting adverse effect of cabazitaxel is myelosuppression which may be severe and is dose-related (21% vs 6% severe neutropenia /febrile infective events for 25 vs 20mg/m2 respectively). In most patients, neutropenia first occurred within the first 2 cycles of treatment. Anemia has been observed as well and may be severe.
Severe hypersensitivity reactions characterized by hypotension, bronchospasm or generalized rash/erythema may occur within a few minutes of cabazitaxel infusions. Patients should be observed closely for these reactions, especially during the 1st and 2nd infusions. Because of the significant risk of hypersensitivity reactions, pre-medications are recommended prior to each treatment; emergency medications and resuscitation equipment must be readily available. Patients who experience severe hypersensitivity reactions should not be re-challenged.
Common gastrointestinal symptoms associated with cabazitaxel include diarrhea, nausea and/or vomiting. These symptoms may be treated with commonly used anti-diarrheal or anti-emetic medications and hydration as needed. If left untreated, renal failure may ensue.
Patients should be monitored closely for cardiovascular effects. Preclinical studies suggest a QTc effect; although no formal QT prolongation study has been conducted, cardiac arrhythmias have been reported in patients treated with cabazitaxel.
Interstitial pneumonitis/lung disease (ILD) and acute respiratory distress syndrome (ARDS) have been observed and may be fatal.
Cystitis due to radiation recall reaction has been observed in patients who previously received pelvic radiation and docetaxel-containing chemotherapy.
Renal disorders reported were associated with sepsis, severe dehydration due to diarrhea, vomiting and obstructive uropathy, and may be fatal.
Refer to protocol by which patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Patients on LHRH agonists should continue on the agents.
Use with caution in patents with hemoglobin < 10 g/dL. Hemoglobin and hematocrit should be checked prior to treatment.
Pre-medications (prophylaxis for infusion reaction):
At least 30 minutes prior to each administration of cabazitaxel:
- A corticosteroid IV/PO (e.g. Dexamethasone 8 mg)
- An H1-receptor antagonist IV/PO (e.g. Diphenhydramine 25 mg)
- An H2-receptor antagonist IV/PO (e.g. Ranitidine 50 mg)
Other Supportive Care:
- The product monograph recommends that primary G-CSF prophylaxis be considered in patients at higher risk of complications from prolonged neutropenia (e.g. age > 65 years, poor performance or nutritional status, previous occurrence of febrile neutropenia, extensive prior radiation ports, or other serious comorbidities).
- Also refer to CCO GCSF recommendations.
Q3weeks: cabazitaxel 20 mg/m2 on day 1, as 1 hour IV infusion, with
prednisone 10 mg po daily on days 1-21
(Cabazitaxel 25 mg/m2 may be used in select patients at the physician’s discretion)
Do not treat until ANC > 1.5 x 109/L and platelets are ≥ 100 x 109/L.
| Dose (mg/m2) | Dose (mg/m2) | |
| Starting dose | 25 | 20 |
| First reduction | 20 | 15 |
| Second reduction | 15 | Discontinue |
|
Adverse reactions / Counts (x 109/L) |
Action |
Dose for Next Cycle* |
|
Neutropenia grade ≥3 for ≥ 7 days (despite supportive care) |
Hold until ANC >1.5 and platelets ≥ 100, then |
↓ 1 dose level |
|
Febrile neutropenia or thrombocytopenic bleeding |
Hold until ANC >1.5 and platelets ≥ 100, then |
↓ 1 dose level |
|
Diarrhea grade 2 persisting despite adequate supportive care |
Hold until recovery to grade ≤1 |
↓ 1 dose level |
|
Diarrhea or other organ/ non- hematologic toxicity grade 3 |
Hold until recovery to ≤ grade 2 |
↓ 1 dose level |
|
Grade 3 peripheral neuropathy |
Hold until recovery to ≤ grade 2 |
↓ 1 dose level |
|
Grade 3 GI perforation/hemorrhage |
Hold |
↓ 1 dose level |
|
Grade 4 organ, other non-hematologic toxicity |
Discontinue |
Not applicable |
|
≥ grade 3 renal failure |
Discontinue |
Not applicable |
| New or worsening respiratory symptoms | Hold and investigate | Discontinue if confirmed pneumonitis/ILD or ARDS |
| Signs & symptoms suggesting cystitis | Hold and investigate | Consider discontinuing if confirmed cystitis |
|
*Do not retreat until neutrophils > 1.5 x 109/L, platelets ≥ 100 x 109/L and other toxicity ≤ grade 2 (grade 1 for persistent diarrhea) **Discontinue if toxicity continues at reduced dose |
||
Management of Infusion-related reactions:
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
| Grade | Management | Re-challenge |
| 1 or 2 |
Restart:
|
|
| 3 or 4 |
|
|
|
Total Bilirubin |
|
AST/ALT |
Dose (mg/m2) |
|
< ULN |
and |
<1.5 x ULN |
No change |
|
>1 to ≤ 1.5 x ULN |
or |
>1.5 x ULN |
20 (monitor carefully) |
|
>1.5 to ≤ 3 x ULN |
and |
any |
Maximum 15 (unknown efficacy; monitor carefully) |
|
>3 x ULN |
and |
any |
Contraindicated |
No dosage adjustment is needed in patients with renal impairment not requiring hemodialysis.
|
Creatinine Clearance (ml/min)
|
Dosage modification
|
|
50 - 80
|
No adjustment.
|
|
15 - 50
|
No adjustment.
|
|
<15; end stage renal disease
|
Limited clinical data. Treat with caution and monitor patient carefully.
|
No specific dose adjustment recommended in elderly patients, but they are more at risk for severe toxicity, including myelosuppression, infection and cardiac effects.
Safety and efficacy in children have not been established.
- Use non-PVC equipment for preparation and administration, as cabazitaxel contains polysorbate 80 that increases the rate of di-(2-ethylhexyl) phtalate extraction (DEHP) from polyvinyl chloride (PVC). Also do not use polyurethane equipment.
- Use a 0.22 micron in-line filter.
- Cabazitaxel products have different dilution instructions; refer to the respective product monograph to ensure that the appropriate instructions are followed.
- The concentrate-diluent solution should be further diluted immediately with either 5% dextrose or 0.9% sodium chloride solution.
- The final concentration of the infusion solution should be 0.1mg/mL-0.26mg/mL. Infuse IV over 1 hour at room temperature.
- Gently rotate the IV bag prior to administering to ensure proper mixing.
- Do not mix with other drugs. Crystallized infusion solutions should not be used.
- Store the unopened vials at room temperature (15°C- 30°C). Do not refrigerate.
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
- Patients who have hypersensitivities to this drug or any of its components, including other drugs formulated with polysorbate 80
- Patients with neutrophil counts of ≤1.5 x 109/L
- Patients with severe hepatic impairment (total bilirubin > 3 x ULN)
- Concomitant use of yellow fever vaccines
- Avoid use of live vaccines in patients receiving cabazitaxel. Inactivated vaccines may be administered; however, response may be diminished.
- Exercise caution in patients with anemia and those most at risk of developing gastrointestinal complications: patients with neutropenia, with a prior history of pelvic radiotherapy, GI disease (e.g. ulceration, bleeding), the elderly, concomitant use of NSAIDs, anti-platelet therapy or anti-coagulants.
- Patients should exercise caution when driving or operating a vehicle or potentially dangerous machinery as fatigue and dizziness have been reported.
Other Drug Properties:
-
Carcinogenicity:
No information available
-
Mutagenicity:
No
-
Genotoxicity:
Yes
-
Crosses placental barrier:
Yes
-
Embryotoxicity:
Yes
-
Fetotoxicity:
Yes
-
Teratogenicity:
Unknown
-
Abortifacient effects:
Yes
-
Pregnancy:
Cabazitaxel is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners during treatment, and for 6 months after the last dose.
-
Excretion into breast milk:
Yes
Cabazitaxel and its metabolites were excreted in milk in animal studies.
-
Breastfeeding:
Breastfeeding is not recommended during treatment.
-
Fertility effects:
Probable
Documented in animal studies with male animals. Discuss fertility preservation with patients who can get others pregnant.
Cabazitaxel does not inhibit MRP, OCT1, P-gp, OATP1B3 and BCRP at clinically relevant doses. Interactions with food and herbals have not been established. Prednisone/prednisolone 10mg daily dosing did not affect cabazitaxel pharmacokinetics.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) | ↓ cabazitaxel concentration and/or efficacy (up to 17% ↓ AUC) | ↑ metabolism of cabazitaxel | Caution; co-administration with strong inducers should be avoided. |
| CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) | ↑ cabazitaxel concentration and/or toxicity (up to 25% ↑ AUC) | ↓ metabolism of cabazitaxel | Caution; co-administration with strong inhibitors should be avoided. (Note: aprepitant had no effect on cabazitaxel AUC) |
| OATP1B1 substrates (e.g. atorvastatin, glyburide, SN-38, rifampin, valsartan) | ↑ OATP1B1 substrates concentration and/or toxicity | Cabazitaxel may inhibit OATP1B1 at clinically relevant doses. Limited data suggest that interaction risk may be limited to during the infusion and for 20 minutes afterwards. | Avoid, or separate cabazitaxel infusion and OATP1B1 substrate administration |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline, weekly during cycle 1, before each cycle, and as clinically indicated (also in patients with symptoms of anemia) |
Liver function tests |
Baseline and before each cycle |
Renal function tests |
Baseline and before each cycle |
Clinical toxicity assessment for infusion reactions, GI effects, infection, hypersensitivity, bleeding, anemia, respiratory effects, peripheral neuropathy and thromboembolism |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
New Drug Funding Program (NDFP Website )
- Cabazitaxel - Metastatic Castration Resistant Prostate Cancer
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Internet]. U.S Food and Drug Administration; [updated 2011 July 28].
Prescribing Information: JevtanaTM (Cabazitaxel). Sanofi-aventis Inc (US), June 2010.
Product Monograph: JevtanaTM (Cabazitaxel). Sanofi-aventis Inc (Canada), July 29, 2022.
Villaneueva C, Bazan F, Kim S et al. Cabazitaxel: A novel microtubule inhibitor. Drugs. 2011; 71(10): 1251-8.
November 2024 Updated Pregnancy and Lactation section
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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