Cabazitaxel – Uses, Dosage, Side Effects, Interaction

Cabazitaxel is a taxane and antineoplastic agent which is currently used in the therapy of castration-resistant metastatic prostate cancer after the failure of docetaxel. Therapy with cabazitaxel has been associated with a low rate of serum enzyme elevations but has not been linked to cases of clinically apparent acute liver injury, although it can cause severe hypersensitivity infusion reactions which in some instances can be associated with acute liver injury. Cabazitaxel is prepared by semi-synthesis with a precursor extracted from yew needles (10-deacetylbaccatin III). It was approved by the U.S. Food and Drug Administration (FDA) on June 17, 2010.

Use in Cancer

Cabazitaxel is approved to be used with prednisone to treat:

• Prostate cancer that has metastasized (spread to other parts of the body) in men whose cancer is castrate-resistant (has not responded to treatments that lower testosterone levels) and who have already been treated with chemotherapy that included docetaxel.

Cabazitaxel is also being studied in the treatment of other types of cancer.

Contraindication

• Neutrophil counts of ≤1,500/mm3
• History of severe hypersensitivity to or polysorbate 80
• a bad infection
• caloric undernutrition
• dehydration
• anemia
• decreased blood platelets
• low levels of a type of white blood cell called neutrophils
• liver problems
• severe liver disease
• acute kidney failure
• inflammation of the bladder with hemorrhage
• vomiting
• excessive diarrhea
• pregnancy
• lung tissue problem
• Child-Pugh class A liver impairment
• Child-Pugh class B liver impairment
• Child-Pugh class C liver impairment

Dosage

Strengths: 60 mg/1.5 mL

Prostate Cancer

• 20 mg/m2 IV over one-hour every three weeks
• Some patients may receive a dose of 25 mg/m2 every three weeks
• In selected patients, the dose may be increased to 25 mg/m2; primary prophylaxis with G-CSF is recommended in these patients.
• Use in combination with oral prednisone 10 mg once a day.
• The dose is based on the calculation of the Body Surface Area (BSA).
• Give a premedication regimen at least 30 minutes prior to each administration, including antiemetics prophylaxis as needed.
• Ensure adequate hydration throughout treatment.

Renal Dose Adjustments

• CrCl 15 mL/min to less than 90 mL/min not requiring hemodialysis: No adjustment necessary
• End-stage renal dysfunction (CrCl less than 15 mL/min): Use with caution and monitor carefully during treatment.

Liver Dose Adjustments

• Mild hepatic dysfunction (total bilirubin greater than 1 to 1.5 times upper limit of normal [x ULN] or AST greater than 1.5 x ULN): Maximum dose 20 mg/m2
• Moderate hepatic dysfunction (total bilirubin greater than 1.5 to 3 x ULN and any AST): Maximum tolerated dose 15 mg/m2; however, the efficacy of this dose is unknown
• Severe hepatic dysfunction (total bilirubin greater than 3 x ULN): Contraindicated

Dose Adjustments

Dose modifications:

• Patients at a 20 mg/m2 dose who require dose reduction should decrease their dosage to 15 mg/m2
• Patients at a 25 mg/m2 dose who require dose reduction should decrease their dosage to 20 mg/m2
• One additional dose reduction to 15 mg/m2 may be considered

Adjust dosage for the following adverse events:

• Prolonged (more than 1 week) Grade 3 or higher neutropenia despite appropriate medication including G-CSF: Delay treatment until the neutrophil count is greater than 1,500 cells/mm3, then reduce dose by one dose level. Use G-CSF for secondary prophylaxis.
• Febrile neutropenia or neutropenic infection: Delay treatment until improvement or resolution, and the neutrophil count is greater than 1,500 cells/mm3, then reduce dose by one dose level.
• Grade 3 or higher, or persisting diarrhea despite appropriate medication, fluid, and electrolytes replacement: Delay treatment until improvement or resolution, then reduce dose by one dose level.
• Grade 2 peripheral neuropathy: Delay treatment until improvement or resolution, then reduce dose by one dose level.
• Grade 3 or higher peripheral neuropathy: Discontinue treatment.

Adjust dosage for use with strong CYP450 3A inhibitors:

• Avoid the coadministration of strong inhibitors of CYP450 3A drugs.
• If concomitant use of strong inhibitors of CYP450 3A drugs is inevitable, consider a cabazitaxel 25% dose reduction.

Side Effects

The Most Common

• heartburn
• change in ability to taste food
• loss of appetite
• weight loss
• swelling of the inside of the mouth
• headache
• joint or back pain
• numbness, burning, or tingling in the hands, arms, feet, or legs
• hair loss
• nausea
• diarrhea
• vomiting
• stomach pain
• constipation
• swelling of the face, arms, hands, feet, ankles, or lower legs
• decreased urination
• blood in the urine
• blood in stool
• changes in stool color
• dry mouth, dark urine, decreased sweating, dry skin, and other signs of dehydration
• irregular heartbeat
• shortness of breath
• pale skin
• tiredness or weakness
• unusual bruising or bleeding

More Common

• numbness, burning pain, or tingly feeling in your hands or feet;
• sudden chest pain or discomfort, wheezing, dry cough, feeling short of breath;
• stomach pain or tenderness, severe vomiting or diarrhea, ongoing constipation;
• blood in your urine, urinating more often, pain or burning when you urinate;
• low blood cell counts–fever, chills, muscle pain, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands and feet, feeling light-headed or short of breath;
• signs of stomach bleeding–bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds; or
• signs of a kidney problem–little or no urinating; painful or difficult urination; swelling in your hands or feet; feeling tired or short of breath.
• fever, low blood cell counts;
• numbness or tingling;
• nausea, vomiting, stomach pain, loss of appetite;
• constipation, diarrhea;
• weakness, tired feeling;
• blood in your urine;
• back pain, joint pain;
• cough, shortness of breath;
• altered sense of taste; or
• hair loss.

Rare

• skin redness,
• chest tightness,
• lightheadedness,
• numbness, burning pain, or tingly feeling in your hands or feet,
• sudden chest pain or discomfort,
• wheezing,
• dry cough,
• shortness of breath,
• stomach pain or tenderness,
• severe vomiting,
• diarrhea,
• ongoing constipation,
• blood in your urine,
• urinating more often,
• pain or burning when you urinate,
• fever,
• chills,
• muscle pain,
• mouth sores,
• skin sores,
• easy bruising,
• unusual bleeding,
• pale skin,
• cold hands and feet,
• bloody or tarry stools,
• coughing up blood,
• vomiting that looks like coffee grounds,
• little or no urination,
• painful or difficult urination,
• swelling in your hands or feet, and
• tiredness

Drug Interaction

Pregnancy and Lactation

Pregnancy category D

Pregnancy

JEVTANA can cause fetal harm when administered to a pregnant woman. In non-clinical studies in rats and rabbits, cabazitaxel was embryotoxic, fetotoxic, and abortifacient at exposures significantly lower than those expected at the recommended human dose level. There are no adequate and well-controlled studies in pregnant women using JEVTANA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with JEVTANA [see Use in
Specific Populations

Lactation

Cabazitaxel or cabazitaxel metabolites are excreted in the maternal milk of lactating rats. It is not known whether this drug is excreted in human milk. Within 2 hours of a single intravenous administration of cabazitaxel to lactating rats at a dose of 0.08 mg/kg (approximately 0.02 times the maximum recommended human dose), radioactivity related to cabazitaxel was detected in the stomachs of nursing pups. This was detectable for up to 24 hours post-dose. Approximately 1.5% of the dose delivered to the mother was calculated to be delivered in maternal milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from JEVTANA, a decision should be made on whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

References