Cabazitaxel

Approved Indications:

• Metastatic Castration-Resistant Prostate Cancer (mCRPC):
  Indicated in combination with prednisone for the treatment of patients with mCRPC previously treated with a docetaxel-containing regimen.

Clinically Accepted Off-Label Uses:

• Currently, Cabazitaxel is primarily used in advanced prostate cancer management. Off-label uses are rare due to its high toxicity profile and limited indication spectrum. Clinical trials are investigating its use in other taxane-sensitive tumors such as:
• Metastatic breast cancer
• Ovarian cancer
• Non-small cell lung cancer (NSCLC) (under research)

Adults (including Elderly):

• Recommended Dose: Cabazitaxel 25 mg/m² administered as a 1-hour intravenous infusion every 3 weeks in combination with oral prednisone 10 mg daily throughout treatment.
• Premedication (Mandatory):
• Antihistamine (e.g., diphenhydramine 25–50 mg IV)
• Corticosteroid (e.g., dexamethasone 8 mg IV)
• H2 antagonist (e.g., ranitidine 50 mg IV)
  Administered approximately 30 minutes before infusion to prevent hypersensitivity reactions.

Renal Impairment:

• No dose adjustment required in mild to moderate renal impairment.
• Use with caution in severe renal impairment; data are limited.

Hepatic Impairment:

• Mild (bilirubin ≤ ULN and AST > ULN, or bilirubin >1 to ≤1.5 × ULN): Use with caution.
• Moderate to severe (bilirubin >1.5 × ULN): Contraindicated due to increased risk of severe toxicity.

Pediatrics:

• Not approved for use in pediatric populations.

Administration Route:

• Intravenous (IV) infusion over 1 hour.
• Must be diluted in a specific diluent and then further diluted in 0.9% sodium chloride or 5% dextrose prior to administration.

Cabazitaxel is a second-generation semisynthetic taxane. It binds to and stabilizes tubulin, thereby promoting the assembly of microtubules and inhibiting their disassembly. This leads to disruption of mitotic and interphase cellular functions, ultimately triggering apoptosis. Cabazitaxel is designed to overcome resistance associated with other taxanes like docetaxel by having poor affinity for the multidrug resistance (MDR) P-glycoprotein efflux pump, enabling greater retention in resistant cancer cells.

• Absorption: Not orally bioavailable; administered IV.
• Distribution: High volume of distribution (~4,864 L), indicating extensive tissue penetration.
• Protein Binding: 89–92% bound to plasma proteins (mainly albumin and lipoproteins).
• Metabolism: Primarily hepatic via CYP3A4 metabolism; minor metabolism via CYP2C8.
• Active Metabolites: No known pharmacologically active metabolites.
• Elimination Half-Life: Terminal half-life ~95 hours.
• Excretion:
• Feces: ~76% (main route, mostly as metabolites)
• Urine: ~3.7% (minor route)

• Pregnancy:
  Cabazitaxel is classified as Pregnancy Category D. It may cause fetal harm based on its mechanism of action and animal data. Use is contraindicated during pregnancy. Women of childbearing potential should use effective contraception during treatment and for at least 4 months after the last dose.
• Lactation:
  Unknown whether Cabazitaxel is excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, breastfeeding is contraindicated during and for at least 2 weeks after therapy.

• Primary Class: Antineoplastic Agent
• Subclass: Taxane Derivative (Second-generation)
• Other Designation: Microtubule Inhibitor / Mitotic Inhibitor

• Known hypersensitivity to Cabazitaxel or polysorbate 80
• Severe hepatic impairment (bilirubin >1.5 × ULN)
• Neutrophil count <1,500/mm³ before treatment initiation
• Pregnancy and breastfeeding
• Coadministration with live vaccines (e.g., yellow fever)

• Neutropenia: High risk of febrile neutropenia and fatal infections; monitor CBC weekly during initial cycles.
• Hypersensitivity Reactions: May be severe; premedication required.
• Gastrointestinal Toxicity: Diarrhea and vomiting may lead to dehydration; antiemetics and antidiarrheals should be used proactively.
• Renal Toxicity: Monitor renal function in patients with severe diarrhea or dehydration.
• Hepatic Impairment: Increased risk of toxicity and fatal outcomes.
• CNS Effects: Risk of peripheral neuropathy and dizziness; monitor regularly.
• Elderly (>65 years): Increased incidence of neutropenia and associated complications; close monitoring recommended.

Common (≥10%):

• Hematologic: Neutropenia, anemia, thrombocytopenia, leukopenia
• GI: Diarrhea, nausea, vomiting, abdominal pain
• General: Fatigue, asthenia, fever
• Infection-related: Febrile neutropenia, urinary tract infection

Less Common (1–10%):

• Peripheral neuropathy
• Dysgeusia
• Edema
• Hypotension
• Dyspnea
• Back pain
• Cystitis

Serious/Rare:

• Severe hypersensitivity (anaphylaxis)
• Sepsis
• Interstitial pneumonia
• Renal failure secondary to dehydration
• Intestinal obstruction or perforation

• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): May increase plasma levels of Cabazitaxel; avoid or reduce dose.
• Strong CYP3A4 inducers (e.g., rifampin, phenytoin): May decrease Cabazitaxel exposure; use alternative agents if possible.
• Live Vaccines: Contraindicated due to immunosuppression risk.
• P-glycoprotein substrates: Minimal interaction due to low affinity for P-gp.

• FDA Label Update (Recent Years):
• Enhanced warnings related to early recognition and treatment of neutropenic complications.
• Updates regarding dose modification guidance in hepatic dysfunction.
• Clinical Guidelines (e.g., NCCN):
• Still endorsed as a second-line treatment in mCRPC after docetaxel failure.
• Ongoing trials evaluating sequencing with novel androgen receptor-targeted agents.

• Vial (Unopened):
• Store at 20°C to 25°C (68°F to 77°F).
• Excursions permitted to 15°C–30°C (59°F–86°F).
• Protect from light; keep in original packaging.
• After First Dilution (Premix Solution):
• Stable for up to 8 hours at room temperature.
• After Final Dilution:
• Stable for 24 hours at 2°C–8°C (refrigerated) or 8 hours at room temperature.
• Do not freeze.
• Discard unused portions.