Cabazitaxel

Pronunciation: ka-BAZ-i-TAX-el
Class: Taxoid

Trade Names

Jevtana
- Injection, solution, concentrate 40 mg/mL

Pharmacology

Inhibits mitosis by disrupting microtubular network essential for mitotic and interphase cellular functions. Cabazitaxel binds to free tubulin and promotes assembly of tubulin into stable microtubules, while simultaneously inhibiting disassembly.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

C max is 226 ng/mL and is reached at the end of a 1-h infusion.

Distribution

Approximately 89% to 92% protein bound. Steady-state Vd is 4,864 L.

Metabolism

Metabolized mainly by CYP3A4/5 and, to a lesser extent, by CYP2C8. There are multiple metabolites, including 3 active metabolites issued from O-demethylation.

Elimination

The half-life is 4 min (alpha phase), 2 h (beta phase), and 95 h (gamma phase). Cl is 48.5 L/h. Approximately 4% excreted in urine (2.3% as unchanged drug); approximately 76% excreted in feces.

Special Populations

Renal Function Impairment

Mild and moderate renal impairment did not have meaningful effects on the pharmacokinetics of cabazitaxel. No data are available for patients with severe renal impairment or ESRD.

Hepatic Function Impairment

No formal pharmacokinetic trials have been conducted. Hepatic impairment is likely to increase cabazitaxel concentrations.

Elderly

No significant difference was observed in the pharmacokinetics of cabazitaxel between patients younger than 65 y of age and those 65 y of age and older.

Indications and Usage

In combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.

Contraindications

History of severe hypersensitivity reactions to cabazitaxel or other drugs formulated with polysorbate 80; neutrophil count of 1,500 cells/mm 3 or less.

Dosage and Administration

Premedication regimen

Premedicate at least 30 min prior to each dose of cabazitaxel with an IV antihistamine (dexchlorpheniramine 5 mg, diphenhydramine 25 mg, or equivalent), an IV corticosteroid (dexamethasone 8 mg or equivalent), and an IV H 2 antagonist (ranitidine 50 mg or equivalent).

Prostate Cancer
Adults

IV 25 mg/m 2 IV as a 1-h infusion every 3 wk in combination with oral prednisone 10 mg daily throughout cabazitaxel treatment.

Dosage Modifications
Prolonged grade 3 or greater neutropenia (longer than 1 wk) despite appropriate medication, including granulocyte colony-stimulating factor

Delay treatment until neutrophil count is more than 1,500 cells/mm 3 , and then reduce dose of cabazitaxel to 20 mg/m 2 . Use granulocyte colony-stimulating factor (G-CSF) for secondary prophylaxis. Discontinue cabazitaxel if patient continues to experience this reaction at 20 mg/m 2 .

Febrile neutropenia

Delay treatment until improvement or resolution and until neutrophil count is more than 1,500 cells/mm 3 , and then reduce dose of cabazitaxel to 20 mg/m 2 . Use G-CSF for secondary prophylaxis. Discontinue cabazitaxel if patient continues to experience this reaction at 20 mg/m 2 .

Grade 3 or higher diarrhea or persisting diarrhea despite appropriate medication, fluid, and electrolyte replacement

Delay treatment until improvement or resolution, and then reduce dose of cabazitaxel to 20 mg/m 2 . Discontinue cabazitaxel if patient continues to experience this reaction at 20 mg/m 2 .

General Advice

  • All patients should be premedicated prior to the initiation of infusion of cabazitaxel. Observe patients closely for hypersensitivity reactions, especially during the first and second infusions.
  • Antiemetic prophylaxis is recommended and can be given orally or IV.
  • For IV infusion only. Not for intradermal, subcutaneous, IM, IV bolus, or intraarterial administration.
  • Concentrate must be diluted twice before administration.
  • Do not use PVC infusion containers or polyurethane infusion sets for preparation and administration of cabazitaxel.
  • Follow institutional and National Institutes of Health procedures for handling, administration, and disposal of cancer drugs. Wear appropriate protective equipment when preparing and administering cabazitaxel.
  • If cabazitaxel comes in contact with skin, wash skin immediately with soap and water. If contact with a mucous membrane occurs, flush thoroughly with water.
  • Withdraw entire contents of supplied diluent and transfer to vial of cabazitaxel concentrate to produce a final concentration of cabazitaxel 10 mg/mL. Mix initial diluted solution by repeated inversion for at least 45 sec. Do not shake.
  • Some foaming at top of solution is normal; allow solution to stand for a few minutes to allow foam to dissipate.
  • Prepare final dilution for infusion by withdrawing required amount of initial diluted cabazitaxel and injecting it into 250 mL infusion bag or bottle of sodium chloride 0.9% solution or dextrose 5% injection to produce a final concentration of cabazitaxel 0.1 to 0.26 mg/mL. If required cabazitaxel dose is more than 200 mg, use a larger volume of infusion vehicle so concentration does not exceed 0.26 mg/mL. Thoroughly mix infusion by manual rotation.
  • Do not use initial diluted solution or final dilution for infusion if solution is discolored, cloudy, or contains particulate matter.
  • Administer final diluted infusion solution IV over 1 h. Use an inline filter of 0.22 micrometer nominal pore size during administration.
  • Do not mix cabazitaxel with any other drugs.

Storage/Stability

Store vials between 59° and 86°F. Do not refrigerate. Use initial diluted solution immediately (within 30 min). Final diluted infusion solution is stable for 8 h (including the 1-h infusion) at ambient temperature, or for a total of 24 h (including the 1-h infusion) under refrigerated conditions. Discard unused portion.

Drug Interactions

CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort)

Coadministration of cabazitaxel and strong CYP3A4 inducers is expected to decrease cabazitaxel plasma concentrations; avoid coadministration.

CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)

Coadministration of cabazitaxel and strong CYP3A4 inhibitors is expected to increase cabazitaxel plasma concentrations; avoid coadministration. Administer cabazitaxel and moderate CYP3A4 inhibitors (eg, aprepitant, diltiazem, fluconazole, fosamprenavir, verapamil) with caution.

Adverse Reactions

The incidences stated for the following adverse reactions were reported with cabazitaxel 25 mg/m 2 in combination with prednisone 10 mg daily.

Cardiovascular

Arrhythmia, hypotension (5%).

CNS

Fatigue (37%); asthenia (20%); peripheral neuropathy (13%); dysgeusia (11%); dizziness, headache (8%).

GI

Diarrhea (47%); nausea (34%); vomiting (22%); constipation (20%); abdominal pain (17%); anorexia (16%); dyspepsia (10%).

Genitourinary

Hematuria (17%); UTI (8%); dysuria (7%).

Hematologic-Lymphatic

Anemia (98%); leukopenia (96%); neutropenia (94%); thrombocytopenia (48%); febrile neutropenia (7%).

Metabolic-Nutritional

Peripheral edema, weight decreased (9%); dehydration (5%).

Musculoskeletal

Back pain (16%); arthralgia (11%); muscle spasms (7%).

Respiratory

Dyspnea (12%); cough (11%).

Miscellaneous

Pyrexia (12%); alopecia (10%); mucosal inflammation (6%); pain (5%).

Precautions

Warnings

Hypersensitivity

Severe hypersensitivity reactions, characterized by hypotension, bronchospasm, and/or generalized rash/erythema, may occur within a few minutes following initiation of infusion. Hypersensitivity reactions require immediate discontinuation of cabazitaxel and administration of appropriate therapy. Severe reactions should not receive rechallenge. Do not administer to patients with prior severe hypersensitivity reactions to cabazitaxel or other drugs formulated with polysorbate 80.

Neutropenia

Neutropenic deaths have been reported. Frequent blood cell counts should be performed on all patients. Do not administer cabazitaxel to patients with neutrophil counts of 1,500 cells/mm 3 or less.


Monitor

Monitor CBCs on a weekly basis during cycle 1 and before each treatment cycle thereafter so that the dosage can be adjusted if needed.


Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Patients 65 y of age and older appear to experience adverse reactions more frequently than younger patients treated with the same regimen.

Renal Function

Use with caution in patients with severe renal impairment or ESRD.

Hepatic Function

Do not give to patients with impaired hepatic function (total bilirubin at least ULN, or AST and/or ALT at least 1.5 × ULN ).

Granulocyte colony-stimulating factor

May be administered to reduce the risks of neutropenia complications. Consider primary prophylaxis in patients with high-risk clinical features. Consider therapeutic use of G-CSF and secondary prophylaxis in all patients considered to be at increased risk for neutropenia complications.

GI effects

Nausea, vomiting, and severe diarrhea may occur. Death related to diarrhea and electrolyte imbalance occurred in the randomized clinical trial. Treat patients with rehydration and antidiarrheal or antiemetic medications as needed. Delay treatment or reduce dosage for grade 3 or higher diarrhea.

Renal effects

Renal failure, including cases with fatal outcomes, was reported in the randomized clinical trial. Most cases occurred in association with dehydration, obstructive uropathy, or sepsis. Some deaths due to renal failure did not have a clear etiology. Take appropriate measures to identify renal failure and treat aggressively.

Overdosage

Symptoms

Bone marrow suppression, GI disorders.

Patient Information

  • Educate patient about the risk of potential hypersensitivity associated with cabazitaxel. Confirm that patients do not have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80. Instruct patients to immediately report signs of a hypersensitivity reaction.
  • Advise patient or caregiver that medication will be prepared and administered by health care provider in a health care setting.
  • Explain the importance of routine CBCs. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever to the treating health care provider.
  • Advise patients that it is important to take the oral prednisone as prescribed. Instruct patients to report if they were not compliant with their oral prednisone regimen.
  • Educate patients that severe and fatal infections, dehydration, and renal failure have been associated with cabazitaxel exposure. Instruct patients to immediately report decreased urinary output, fever, hematuria, and significant vomiting or diarrhea to their health care provider.
  • Inform elderly patients that certain adverse effects may be more frequent or severe.

Copyright © 2009 Wolters Kluwer Health.

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