Cabazitaxel is a potent microtubule stabilizer used for the treatment of metastatic hormone-refractory prostate cancer. It is a semi-synthetic taxane prepared with a precursor extracted from yew needles. Cabazitaxel carries a black box warning for neutropenia and hypersensitivity reactions; it is contraindicated in patients with neutrophil counts less than or equal to 1,500 cells/mm3, patients with severe hepatic impairment, and in patients with a history of severe hypersensitivity reaction to cabazitaxel or other drugs formulated with polysorbate 80. Unlike other taxanes, cabazitaxel is a poor substrate for the multidrug resistance P-glycoprotein efflux pump and may be useful for treating multidrug-resistant tumors.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
-If the first or second (final) dilution comes into contact with mucosa, immediately and thoroughly wash with soap and water.
Emetic Risk
-Low
-Administer routine antiemetic prophylaxis prior to treatment.
Route-Specific Administration
Injectable Administration
-Administer as an intravenous infusion.
-Prior to administration, patients should have absolute neutrophil counts greater than 1,500 cells/mm3.
-Do not use PVC infusion containers and polyurethane infusion sets for preparation and administration of cabazitaxel.
-To prevent hypersensitivity reactions, all patients should be premedicated intravenously at least 30 minutes before cabazitaxel with an antihistamine (dexchlorpheniramine 5 mg, diphenhydramine 25 mg, or equivalent), a corticosteroid (dexamethasone 8 mg or equivalent), and an H2-antagonist. Antiemetic prophylaxis is also recommended.
-Primary prophylaxis of neutropenia with G-CSF is recommended for high risk patients (e.g., older patients and those with poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities); also consider primary prophylaxis for all patients treated with a cabazitaxel dose of 25 mg/m2.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. If properly stored, undiluted cabazitaxel is a clear, yellow to brownish viscous solution.
-If cabazitaxel is not clear or appears to have precipitation, discard the solution.
-The cabazitaxel injection and diluent vials contain overfill to compensate for liquid loss during preparation. The concentration of cabazitaxel after the first dilution with the entire contents of the accompanying diluent is 10 mg/mL.
Intravenous Administration
NOTE: The cabazitaxel kit contains one vial with cabazitaxel injection (60 mg/1.5 mL) and another vial with a special diluent of 13% (w/w) ethanol in water; two dilutions are required prior to administration.
First dilution:
-Mix each vial of cabazitaxel injection (60 mg/1.5 mL) with the entire contents of the supplied diluent. After reconstitution, the resultant solution will have a cabazitaxel concentration of 10 mg/mL.
-When transferring the diluent, direct the needle onto the inside wall of the vial and inject slowly to limit foaming. Remove the syringe and needle and gently mix by repeated inversions for at least 45 seconds to ensure complete mixing. Do not shake.
-Let the solution stand for a few minutes to allow any foam to dissipate. Check that the solution is homogenous. It is not required that all foam dissipate prior to continuing the preparation process.
-The resulting cabazitaxel solution (10 mg/mL) requires further dilution before administration. The second dilution should be done immediately (within 30 minutes) to obtain the final infusion.
Second dilution:
-Withdraw the recommended dose from the vial containing the cabazitaxel solution after the initial dilution (10 mg/mL). Further dilute the withdrawn volume into a sterile 250 mL PVC-free container of either 0.9% Sodium Chloride injection or 5% Dextrose solution injection. If a cabazitaxel dose of 65 mg or greater is required, use a larger volume of the infusion vehicle, so the concentration of the final infusion solution does not exceed 0.26 mg/mL.
-The concentration of the final infusion solution should be 0.1 to 0.26 mg/mL.
-Remove the syringe and needle and thoroughly mix the final infusion solution by gently inverting the bag or bottle.
-Do not mix cabazitaxel with any other drugs.
-The final solution is supersaturated and may crystallize over time. Discard the solution if this occurs.
-Storage of diluted solution: The final infusion solution should be used within 8 hours (including the one-hour infusion) if stored at room temperature or within 24 hours (including the one-hour infusion) if stored under refrigeration.
Intravenous Infusion:
-Using a 0.2 or 0.22 micrometer in-line filter, administer cabazitaxel as an intravenous infusion over 1 hour at room temperature.
Anemia occurred with a similar incidence in patients treated with cabazitaxel 25 mg/m2 compared to 20 mg/m2 in data from 3 randomized clinical trials (98% to 99.7% vs. 99.8%; grade 3 or 4, 11% to 14% vs. 10%).
Infection occurred more often in patients treated with cabazitaxel 25 mg/m2 compared with 20 mg/m2 in a randomized clinical trial comparing the 2 doses (38% vs. 28%; grade 3 or 4, 20% vs. 10%; grade 5, 3% vs. 1%); primary prophylaxis with G-CSF was not allowed in this trial. The incidence of infection (including bacteremia, urinary tract infection, cellulitis, furuncle, influenza, respiratory tract infection, and viral infection) was lower in a randomized clinical trial where patients received cabazitaxel 25 mg/m2 and primary prophylaxis with G-SCF (19%; grade 3 or 4, 4%). Neutropenic infection occurred in 0.8% of patients who received cabazitaxel 25 mg/m2 with primary G-CSF prophylaxis, in 7% of patients who received 25 mg/m2 without primary G-CSF prophylaxis (grade 3 or 4, 6%), and in 3% of patients who received 20 mg/m2 with primary G-CSF prophylaxis at investigator discretion. Urinary tract infection (UTI) occurred in 8% to 11% (grade 3 or 4, 2%) of patients treated with cabazitaxel 20 mg/m2 or 25 mg/m2 in 2 randomized clinical trials; UTI was more common in patients 65 years of age or older compared to younger patients (10% vs. 3%). Pneumonia occurred in 6% of patients who received cabazitaxel in one clinical trial (grade 3 or 4, 1.6%).
Nausea and vomiting have occurred in patients treated with cabazitaxel; antiemetic prophylaxis is recommended with treatment. Nausea was reported in 25% of patients treated with cabazitaxel 20 mg/m2 (grade 3 or 4, 0.7%) and vomiting in 15% (grade 3 or 4, 1.2%) of these patients in a randomized clinical trial. In this trial and one other, where primary prophylaxis with G-CSF was either prohibited or at investigators discretion, nausea was reported in 32% to 34% of patients treated with cabazitaxel 25 mg/m2 (grade 3 or 4, 1% to 2%); vomiting occurred in 18% to 22% of patients (grade 3 or 4, 1% to 2%). In a third randomized clinical trial where all patients received primary prophylaxis with G-CSF, nausea was reported in 23% of those who received cabazitaxel 25 mg/m2 and vomiting in 13% of these patients.
Dehydration occurred in 5% of patients treated with cabazitaxel 25 mg/m2 in a randomized clinical trial (grade 3 or 4, 2%); it was more common in patients age 65 and older compared to younger patients (7% vs. 2%).
Renal failure (unspecified) of any grade occurred in 4% of patients treated with cabazitaxel 25 mg/m2 in a randomized clinical trial; 4 cases were fatal and most were associated with sepsis, dehydration, or obstructive uropathy. Deaths due to renal failure were reported, some without a clear etiology. Acute kidney injury including increased serum creatinine, renal failure, and renal impairment occurred in 5% of cabazitaxel-treated patients in another clinical trial (grade 3 or 4, 2.4%). Take appropriate measures to identify causes of renal failure and treat aggressively.
Hematuria (including hemorrhagic cystitis) occurred in 14% to 21% of patients treated with cabazitaxel 20 mg/m2 or 25 mg/m2 in 3 randomized clinical trials (grade 3 or 4, 0.8% to 4%). One of these trials reported that most cases of hematuria were grade 1 (11%; grade 2 or higher, 6%); other factors associated with hematuria did not account for the increased incidence in cabazitaxel-treated patients. The incidence of hematuria was higher in patients who received prior radiation compared to those who did not receive prior radiation (19.4% vs. 14.4%). Dysuria was reported in 4% to 7% of patients who received cabazitaxel in 2 of these trials (grade 3 or 4, 0.3% or less); lower urinary tract symptoms including dysuria as well as urinary urgency, nocturia, pollakiuria, urinary incontinence, and urinary retention were reported in 10% of patients in the third trial. In one clinical trial, cystitis and radiation cystitis were reported in 1.2% and 1.5% of patients who received prior pelvic radiation, respectively. Radiation recall hemorrhagic cystitis has been reported in postmarketing experience with cabazitaxel; cystitis from radiation recall may occur late in treatment.
Dizziness (0.8% to 8%) and headache (4% to 8%; grade 3 or 4, 0.2% or less) have been reported in patients treated with cabazitaxel 20 mg/m2 and 25 mg/m2 in clinical trials. In one trial, the incidence of dizziness was higher in patients age 65 years or older compared to younger patients (10% vs. 5%).
Musculoskeletal pain including arthralgia, back pain, bone pain, musculoskeletal chest pain, myalgia, and neck pain occurred in 27% of patients treated with cabazitaxel in a randomized clinical trial (grade 3 or 4, 1.6%). Back pain was specifically reported in 11% to 16% (grade 3 or 4, 0.9% to 4%) and arthralgia in 7% to 11% (grade 3 or 4, 0.5% to 1%) of patients who received cabazitaxel in 2 other clinical trials. Additional pain syndromes reported with cabazitaxel treatment have included bone pain (8%; grade 3 or 4, 2%), cancer pain (8%; grade 3 or 4, 1.6%), muscle cramps/muscle spasms (7%), pain in extremities (4.8% to 7%; grade 3 or 4, 0.5% or less), and generalized pain (5% to 6%; grade 3 or 4, 1% or less).
Arrhythmias including atrial fibrillation, atrial flutter, atrial tachycardia, AV block, bradycardia, palpitations, supraventricular tachycardia (SVT) occurred in 5% of patients treated with cabazitaxel in a randomized clinical trial (grade 3 or 4, 1%). In another clinical trial, cardiac disorders including arrhythmias, aortic valve incompetence, aortic valve stenosis, heart failure, acute coronary syndrome, angina, and ventricular fibrillation occurred in 6% of cabazitaxel-treated patients (grade 3 or 4, 0.8%).
Dyspnea was reported in 5% to 12% of patients treated with cabazitaxel across 3 randomized clinical trials (grade 3 or 4, 1% or less); in one of these trials, dyspnea was more common in patients age 65 or older compared to younger patients (10% vs. 3%). Cough has been reported in 6% to 11% of cabazitaxel-treated patients. Interstitial pneumonia/pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS) have been reported in postmarketing experience with cabazitaxel.
Fatigue (25% to 37%; grade 3 or 4, 3% to 5%) and asthenia (15% to 20%; grade 3 or 4, 2% to 5%) were reported in patients treated with cabazitaxel in 2 randomized clinical trials. Fatigue as a composite term including asthenia, lethargy, and malaise was also reported in cabazitaxel-treated patients in a third clinical trial (53%; grade 3 or 4, 4%). Across these trials, fatigue (31% vs. 23%) and asthenia (30% vs. 19%) were more common in patients age 65 or older compared to younger patients.
Anorexia was reported in 13% to 19% (grade 3 or 4, 1% or less) and dysgeusia in 7% to 11% of patients treated with cabazitaxel 20 mg/m2 or 25 mg/m2 in 3 randomized clinical trials; decreased appetite was more common in patients age 65 or older compared to younger patients in 1 of these trials (16% vs. 7%). Weight loss occurred in 4% to 9% (grade 3 or 4, 0.2% or less) of cabazitaxel-treated patients in these trials.
Alopecia occurred in 3% to 10% of patients treated with cabazitaxel in 3 randomized clinical trials.
Fever occurred in 5% to 12% of patients treated with cabazitaxel across 3 randomized clinical trials (grade 3 or 4, 0.2% to 1%). In one of these trials, fever was more common in patients age 65 or older compared to younger patients (15% vs. 8%).
Peripheral edema (including lymphedema) occurred in 7% to 11% of patients treated with cabazitaxel in 3 randomized clinical trials (grade 3 or 4, less than 1%). In one of these trials, peripheral edema was more common in patients age 65 or older compared to younger patients (11% vs. 0%).
Severe infusion-related reactions and serious hypersensitivity reactions or anaphylaxis have been reported with cabazitaxel use; cabazitaxel is contraindicated in patients with a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80. Reactions may occur within the first few minutes of initiation of infusion. Observe patients closely for signs and symptoms of hypersensitivity reactions, especially during the first and second infusions. Reactions may include rash (unspecified), erythema, hypotension, and bronchospasm. To decrease the risk and/or severity of hypersensitivity reactions, all patients should be premedicated with a corticosteroid, antihistamine, and H2 antagonist prior to each dose of cabazitaxel. Severe hypersensitivity reactions require immediate discontinuation of the cabazitaxel infusion and institution of appropriate therapy. Facilities, equipment, and personnel for the treatment of hypotension and bronchospasm should be available. Do not re-challenge patients who develop severe hypersensitivity reactions to cabazitaxel.
Elevated hepatic enzymes including increased AST and ALT levels (grade 3 or 4, less than or equal to 1%) and hyperbilirubinemia (grade 3 or 4, less than or equal to 1%) occurred in men with metastatic hormone-refractory prostate cancer who received cabazitaxel plus prednisone (n = 371) in a randomized, comparative trial.
Fatal ischemic stroke and cerebral hemorrhage have occurred in patients treated with cabazitaxel.
Fatal disseminated intravascular coagulation (DIC) occurred in patients treated with cabazitaxel in one randomized clinical trial.
Fatal acute pulmonary edema occurred in patients treated with cabazitaxel in one randomized clinical trial.
Bone marrow suppression including neutropenia and pancytopenia may occur with cabazitaxel treatment; neutropenic deaths have been reported. In 2 clinical trials, the incidence of leukopenia (95% to 96% vs. 80%; grade 3 or 4, 60% to 69% vs. 29%) and neutropenia (89% to 94% vs. 67%; grade 3 or 4, 73% to 82% vs. 42%) were higher in patients treated with cabazitaxel 25 mg/m2 compared to 20 mg/m2. Primary prophylaxis with G-CSF was not allowed in one trial, with the option to use after development of neutropenia at investigators discretion; G-CSF was allowed at investigators discretion in the other trial. Febrile neutropenia occurred in 7% to 9.2% of patients treated with cabazitaxel 25 mg/m2 and in 2.1% of those who received 20 mg/m2 in these trials. Neutropenic infection/sepsis occurred in 6.4% of patients who received cabazitaxel 25 mg/m2 (grade 5, 1.3%) compared with 2.1% of those treated with 20 mg/m2; 4 of the 5 deaths in patients who received 25 mg/m2 died in the first 30 days of treatment. Grade 3 or 4 neutropenia (97% vs. 89%) and febrile neutropenia (11% vs. 5%) were more common in patients who were age 65 years or older compared to younger patients. In a clinical trial where cabazitaxel 25 mg/m2 was administered with primary prophylaxis of G-CSF, lymphopenia occurred in 72% (grade 3 or 4, 27%), neutropenia in 66% (grade 3 or 4, 45%) and febrile neutropenia in 3.2% of patients; only one patient (0.8%) died from sepsis in the first 30 days of treatment. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features that predispose them to increased complications from prolonged neutropenia; consider primary prophylaxis in all patients receiving cabazitaxel at a dose of 25 mg/m2.
Thrombocytopenia occurred more often in patients treated with cabazitaxel 25 mg/m2 compared to 20 mg/m2 in data from 3 randomized clinical trials (41% to 48% vs. 35%; grade 3 or 4, 3.2% to 4% vs. 3%).
Severe diarrhea including enterocolitis and neutropenic enterocolitis has been reported in patients treated with cabazitaxel; deaths related to diarrhea and electrolyte imbalance occurred in clinical trials. In a randomized clinical trial, diarrhea was reported in 31% (grade 3 or 4, 1%) of patients treated with cabazitaxel 20 mg/m2; the incidence was higher across 3 randomized clinical trials where patients received cabazitaxel at a dose of 25 mg/m2 (40% to 47%; grade 3 or 4, 4% to 6%) and included colitis, gastroenteritis, and hemorrhagic diarrhea. In one of these trials, the incidence of diarrhea was higher in patients who had received prior radiation therapy compared to those who had not (41% vs. 27%), and in patients 65 years or older compared to younger patients (43% vs. 33%). Treatment with rehydration or antidiarrheal medications may be necessary; an interruption of therapy or dose reduction may be required for patients with severe diarrhea.
Constipation occurred in 15% to 20% (grade 3 or 4, 1% or less) of patients treated with cabazitaxel 20 mg/m2 or 25 mg/m2 in 3 randomized clinical trials. In 2 of these trials, constipation was more common in patients 65 years of age or older compared to younger patients (18% to 20% vs. 7% to 13%). Abdominal pain was also reported in 6% to 17% of patients treated with cabazitaxel (grade 3 or 4, 0.5% to 2%). GI obstruction was reported in postmarketing experience with cabazitaxel; GI perforation and ileus have also been reported, including fatal outcome.
Dyspepsia including gastroesophageal reflux disease (GERD) and reflux gastritis was reported in 4.8% to 10% of patients treated with cabazitaxel 25 mg/m2 in 2 randomized clinical trials. Gastritis was also reported in postmarketing experience with cabazitaxel.
Stomatitis occurred in 5% to 8% of patients treated with cabazitaxel 20 mg/m2 to 25 mg/m2 in 2 randomized clinical trials (grade 3 or 4, 0.3%); mucosal inflammation occurred in 6% of cabazitaxel-treated patients in another clinical trial (grade 3 or 4, less than 1%). In one of these trials, stomatitis was more common in patients age 65 and older compared to younger patients (10% vs. 3%).
GI bleeding has been reported in patients treated with cabazitaxel in clinical trials, including fatal outcome.
Peripheral neuropathy occurred in 7% to 18% of patients treated with cabazitaxel 20 mg/m2 or 25 mg/m2 in 3 randomized clinical trials (grade 3 or 4, 1.6% or less). Polyneuropathy and paresthesias were each reported in 6% of patients treated with cabazitaxel 25 mg/m2 in one of these trials; grade 3 or 4 polyneuropathy was reported in 1.6% of these patients.
Bone fractures (e.g., femoral neck fracture, pathological fracture, rib fracture, spinal compression fracture, sternal fracture, thoracic vertebral fracture) were reported in 3.2% of patients treated with cabazitaxel in one randomized clinical trial (grade 3 or 4, 1.6%); falls occurred in 4.8% of cabazitaxel-treated patients in this trial.
Hypotension was reported in 5% of patients treated with cabazitaxel in one randomized clinical trial compared with 2% of those who received mitoxantrone (grade 3 or 4, less than 1% vs. less than 1%). Hypertension (including hypertensive crisis) occurred in 4% of cabazitaxel-treated patients in another randomized clinical trial, compared with 8% of those who received abiraterone or enzalutamide (grade 3 or 4, 2.4% vs. 2.4%); hypertension was more common in patients age 65 or older compared to younger patients (5% vs. 0%).
Insomnia occurred in 3.2% of patients treated with cabazitaxel in a randomized clinical trial.
Hypokalemia occurred in 3.2% of patients treated with cabazitaxel in a randomized clinical trial.
Pulmonary embolism occurred in 1.6% of patients treated with cabazitaxel in a randomized clinical trial.
Spinal cord compression occurred in 3.2% of patients with metastatic castration-resistant prostate cancer who progressed after receiving prior docetaxel-containing regimens and abiraterone or enzalutamide in a randomized clinical trial.
Cabazitaxel is contraindicated in patients with previous severe hypersensitivity reactions to cabazitaxel (taxane hypersensitivity) or other drugs formulated with polysorbate 80 (polysorbate 80 hypersensitivity). Premedicate all patients with an IV antihistamine, IV H2 antagonist, and IV corticosteroid prior to the initiation of each infusion of cabazitaxel; observe closely for hypersensitivity reactions, especially during the first and second infusions. If severe reactions occur, discontinue cabazitaxel and institute appropriate therapy. There is a risk of serious hypersensitivity reactions or anaphylaxis with cabazitaxel, which can occur within minutes of beginning a cabazitaxel infusion, and may include rash, erythema, hypotension, and bronchospasm; facilities and equipment for the treatment of hypotension and bronchospasm should be available. Do not rechallenge patients who have had a severe hypersensitivity reaction to cabazitaxel.
Cabazitaxel is contraindicated for use in patients with severe neutropenia (an absolute neutrophil count (ANC) 1,500 cells/mm3 or less); administer with caution to patients with a hemoglobin less than 10 g/dL. Monitor complete blood counts weekly during the first cycle and prior to each cycle thereafter; an interruption of therapy or dose reduction may be necessary. Bone marrow suppression, including severe neutropenia with some fatalities, anemia, and thrombocytopenia have been reported with cabazitaxel treatment. Primary prophylaxis of neutropenia is recommended in patients with high-risk features (older patients, poor performance status, poor nutritional status, previous febrile neutropenia, extensive prior radiation ports, or other serious comorbidities); consider primary prophylaxis with G-CSF in all patients receiving a cabazitaxel dose of 25 mg/m2.
Cabazitaxel is contraindicated in patients with severe hepatic impairment (total bilirubin greater than 3 times the ULN). Closely monitor patients with moderate hepatic impairment for toxicity; a dosage adjustment is necessary in these patients. Cabazitaxel is extensively metabolized in the liver; hepatic disease increases the risk of severe or life-threatening toxicities in patients receiving drugs in the same class as cabazitaxel and may cause a similar increase in risk for patients treated with cabazitaxel. In a dedicated study of 43 cancer patients, severe hepatic impairment resulted in delayed clearance of cabazitaxel; the maximum tolerated dose was not established.
Severe gastrointestinal symptoms such as GI bleeding, GI perforation, ileus, and neutropenic enterocolitis, including some fatalities, have been reported during treatment with cabazitaxel; abdominal pain/tenderness, fever, persistent constipation, and diarrhea should be evaluated and treated promptly. The risk for serious GI events is increased with neutropenia, age, corticosteroid therapy, patients with a history of pelvic radiotherapy, adhesions, ulceration, or GI bleeding, and concomitant use of non-steroidal anti-inflammatory agents (NSAIDs), anti-platelet therapy, or anticoagulant therapy. Severe diarrhea, nausea, and vomiting may also occur; deaths due to diarrhea and electrolyte imbalance were reported in clinical trials. Antiemetic prophylaxis is recommended; patients who develop severe diarrhea should receive rehydration and treatment with anti-diarrheal medications as needed. An interruption of therapy or dose reduction may be necessary. Cabazitaxel is a poor substrate for the P-glycoprotein (P-gp) efflux pump, which may allow it to accumulate in enterocytes that express P-gp. This characteristic may explain the relative differences in GI toxicities between cabazitaxel and other taxane compounds that are better P-gp substrates.
Patients who have received prior radiation therapy (e.g., pelvic radiation) are at an increased risk of gastrointestinal adverse reactions including nausea, vomiting, and severe diarrhea, as well as cystitis and hematuria. Antiemetic prophylaxis is recommended. Treat patients with rehydration, antidiarrheal medications, or antiemetic medications as needed. Monitor patients who have previously received pelvic radiation for signs and symptoms of cystitis during treatment with cabazitaxel. Interrupt or discontinue cabazitaxel in patients experiencing grade 3 or higher diarrhea or severe hemorrhagic cystitis. Medical and/or surgical supportive treatment may be required to treat severe hemorrhagic cystitis.
Cases of renal failure have been reported in patients receiving cabazitaxel, including 4 with a fatal outcome in the clinical trial. Most cases of renal failure were associated with sepsis, dehydration, or obstructive uropathy. The etiology of some deaths due to renal failure in the clinical trial was not clear. Identify and treat the causes of renal failure aggressively in patients receiving cabazitaxel. No differences in cabazitaxel clearance have been observed in patients with mild or moderate renal impairment. Use caution in patients with severe renal impairment or end-stage renal disease.
Use caution if cabazitaxel is used in patients with underlying or chronic lung disease (CLD), as they may be at higher risk for adverse pulmonary reactions. Interstitial pneumonia/pneumonitis, interstitial lung disease, and acute respiratory distress syndrome have been reported with cabazitaxel treatment and may have fatal outcomes. Monitor patients for new or progressive, unexplained pulmonary symptoms or respiratory insufficiency such as dyspnea, cough, and fever. If symptoms develop, interrupt cabazitaxel therapy (consider discontinuation) and evaluate; initiate treatment as appropriate. The benefit of resuming therapy must be carefully evaluated.
In one clinical trial (TROPIC trial), geriatric patients (65 years and older) treated with cabazitaxel 25 mg/m2 were more likely to die of causes other than disease progression within 30 days of the last cabazitaxel dose compared with younger patients (6% vs. 2%); neutropenia (87% vs. 74%) and febrile neutropenia (8% vs. 6%) occurred more often in older patients compared with younger patients in this trial. In another randomized clinical trial (PROSELICA trial) which included all patients older than 60 years of age, deaths due to infection within 30 days of starting therapy with cabazitaxel occurred in 0.7% of patients receiving cabazitaxel 20 mg/m2 compared with 1.3% of patients treated with cabazitaxel 25 mg/m2. In the 20 mg/m2 arm of this trial, 2% of patients 65 years of age or older died due to causes other than disease progression within 30 days of the last cabazitaxel dose, compared with 3% of patients younger than 65 years. In the 25 mg/m2 arm, 5% of patients 65 years of age or older died due to causes other than disease progression within 30 days of the last cabazitaxel dose, compared with 2% of patients younger than 65 years. No overall differences in efficacy were observed between patients greater than or equal to 65 years of age and younger patients. Advanced age may also increase the risk of GI hemorrhage or perforation, ileus, and neutropenic enterocolitis, which have been associated with fatalities.
The safety and efficacy of cabazitaxel has not been established in children or adolescents. The maximum tolerated dose (MTD) of cabazitaxel based on the dose-limiting toxicity (DLT) of febrile neutropenia was 30 mg/m2 IV over 1 hour every 21 days in pediatric patients (ages 3 to 18 years) with solid tumors receiving prophylactic G-CSF (n = 39). No objective responses were observed in 11 patients with refractory high grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG); one patient had a partial response among the 9 patients with ependymoma. Infusion-related/hypersensitivity reactions were seen in 10 patients (26%); 3 experienced anaphylactic reactions. The incidence of infusion related/hypersensitivity reactions decreased with steroid premedication. The most frequent treatment-emergent adverse events were similar to those reported in adults.
The safety and efficacy of cabazitaxel have not been established in females. Although there are no adequate and well-controlled studies in pregnant women, cabazitaxel can cause fetal harm and potential loss of pregnancy based on animal studies. Maternal and embyrofetal toxicity including increased post-implantation loss, embryolethality, and fetal deaths occurred when cabazitaxel was administered to female rats during organogenesis at 0.02 to 0.06 times the Cmax at the recommended human dose; decreased mean fetal birth weight associated with delays in skeletal ossification occurred at doses approximately 0.02 times the maximum recommended human dose. Administration of cabazitaxel did not result in fetal abnormalities in rats or rabbits. 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 cabazitaxel.
The safety and efficacy of cabazitaxel have not been established in females. Counsel patients about the reproductive risk and contraception requirements during cabazitaxel treatment. Cabazitaxel can cause fetal harm and potential fetal loss if taken by the mother during pregnancy. Males with female partners of reproductive potential should use effective contraception during treatment with cabazitaxel and for 4 months after the last dose. Women who become pregnant with a male partner receiving cabazitaxel should be apprised of the potential hazard to the fetus. Based on animal toxicology studies, cabazitaxel may cause male infertility. In male rats, degeneration of the seminal vesicle and atrophy of the seminiferous tubule in the testis was observed at approximately 0.2 the AUC of human doses; minimal testicular degeneration was observed in dogs at approximately 0.1 times expected human exposures. In addition, cabazitaxel caused an increase in pre-implantation loss, early resorption, uterine atrophy, and necrosis of the corpora lutea in female rats at exposures of approximately 0.02 times the expected human exposure at the recommended dose.
Cabazitaxel should not be used in women who are breast-feeding; the safety and efficacy of cabazitaxel have not been established in females. Cabazitaxel and cabazitaxel metabolites are excreted in the breast milk of lactating rats; it is not known whether cabazitaxel is excreted in human breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cabazitaxel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
For the treatment of prostate cancer:
-for the treatment of castration-resistant metastatic prostate cancer in patients who have previously been treated with a docetaxel-containing regimen, in combination with prednisone:
Intravenous dosage:
Adults: 20 mg/m2 IV over 1 hour on day 1 in combination with prednisone (10 mg PO once daily continuously); repeat cycles every 3 weeks. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. At least 30 minutes prior to each dose, premedicate with an IV antihistamine (dexchlorpheniramine 5 mg, diphenhydramine 25 mg, or equivalent), IV corticosteroid (dexamethasone 8 mg or equivalent), and IV H2 antagonist to reduce the risk of hypersensitivity; primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features (e.g., older patients or those with poor performance status, previous febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities). A cabazitaxel dose of 25 mg/m2 IV may be used in select patients at the discretion of the treating healthcare provider; consider primary prophylaxis with G-CSF in all patients receiving this dose as it is associated with a higher incidence of hematologic toxicities. In a randomized clinical trial (TROPIC), overall survival was significantly increased in patients with metastatic castration-resistant prostate cancer (CRPC) treated with cabazitaxel 25 mg/m2 plus prednisone compared with mitoxantrone plus prednisone (15.1 vs. 12.7 months). A cabazitaxel dose of 20 mg/m2 was found to be non-inferior in terms of overall survival when compared with cabazitaxel 25 mg/m2 (13.4 vs. 14.5 months) in a separate multicenter, randomized, open-label clinical trial (PROSELICA).
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Neutropenia
-Grade 3 or higher for longer than 1 week, despite appropriate medication including G-CSF: Hold cabazitaxel therapy. When absolute neutrophil count (ANC) is more than 1,500 cells/mm3, resume treatment at the next lower dose level (25 mg/m2 to 20 mg/m2; 20 mg/m2 to 15 mg/m2). Use G-CSF for secondary prophylaxis. If toxicity continues after the dose is reduced to 15 mg/m2, discontinue cabazitaxel.
Febrile neutropenia or neutropenic infection
-Hold cabazitaxel therapy. Upon improvement or resolution, and when ANC is greater than 1,500 cells/mm3, resume treatment at the next lower dose level (25 mg/m2 to 20 mg/m2; 20 mg/m2 to 15 mg/m2). Use G-CSF for secondary prophylaxis. If toxicity continues after the dose is reduced to 15 mg/m2, discontinue cabazitaxel.
Diarrhea
-Grade 3 or higher diarrhea, or persistent diarrhea despite appropriate medication, fluid, and electrolyte replacement: Hold cabazitaxel therapy. Upon improvement or resolution, resume treatment at the next lower dose level (25 mg/m2 to 20 mg/m2; 20 mg/m2 to 15 mg/m2). If toxicity continues after the dose is reduced to 15 mg/m2, discontinue cabazitaxel.
Peripheral neuropathy
-Grade 2: Hold cabazitaxel therapy. Upon improvement or resolution, resume treatment at the next lower dose level (25 mg/m2 to 20 mg/m2; 20 mg/m2 to 15 mg/m2). If toxicity continues after the dose is reduced to 15 mg/m2, discontinue cabazitaxel.
-Grade 3 or higher: Discontinue cabazitaxel treatment.
Pneumonitis/Respiratory
-New/progressive, unexplained pulmonary symptoms or respiratory insufficiency (e.g., dyspnea, cough, and fever): Hold cabazitaxel therapy and evaluate; initiate treatment for respiratory symptoms as appropriate. Consider discontinuation of cabazitaxel treatment; the benefit of resuming therapy must be carefully evaluated.
Maximum Dosage Limits:
-Adults
25 mg/m2 IV once every 3 weeks.
-Elderly
25 mg/m2 IV once every 3 weeks.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
-Mild hepatic impairment (total bilirubin 1.1 to 1.5 times the upper limit of normal (ULN) or AST greater than 1.5 times the ULN): Administer cabazitaxel 20 mg/m2 IV.
-Moderate hepatic impairment (total bilirubin 1.6 to 3 times the ULN and any AST): Reduce the starting dose of cabazitaxel to 15 mg/m2 based on tolerability data; the efficacy of this dose is unknown.
-Severe hepatic impairment (total bilirubin greater than 3 times the ULN): Do not use cabazitaxel. Cabazitaxel treatment is contraindicated in patients with severe hepatic impairment.
Patients with Renal Impairment Dosing
No dose adjustment is necessary in patients with renal impairment not requiring hemodialysis. Carefully monitor patients with end-stage renal disease (ESRD; CrCL less than 15 mL/min/1.73 m2) during treatment.
*non-FDA-approved indication
Adagrasib: (Major) Avoid coadministration of cabazitaxel with adagrasib if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A and adagrasib is a strong CYP3A inhibitor. In a drug interaction study, coadministration with another strong CYP3A inhibitor increased cabazitaxel exposure by 25%.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of cabazitaxel with clarithromycin if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Atazanavir: (Major) Avoid coadministration of cabazitaxel with atazanavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and atazanavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Atazanavir; Cobicistat: (Major) Avoid coadministration of cabazitaxel with atazanavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and atazanavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%. (Major) Avoid coadministration of cabazitaxel with cobicistat if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Ceritinib: (Major) Avoid coadministration of cabazitaxel with ceritinib if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and ceritinib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Chloramphenicol: (Major) Avoid coadministration of cabazitaxel with chloramphenicol if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and chloramphenicol is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clarithromycin: (Major) Avoid coadministration of cabazitaxel with clarithromycin if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cobicistat: (Major) Avoid coadministration of cabazitaxel with cobicistat if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Darunavir: (Major) Avoid coadministration of cabazitaxel with darunavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Darunavir; Cobicistat: (Major) Avoid coadministration of cabazitaxel with cobicistat if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%. (Major) Avoid coadministration of cabazitaxel with darunavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of cabazitaxel with cobicistat if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%. (Major) Avoid coadministration of cabazitaxel with darunavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Delavirdine: (Major) Avoid coadministration of cabazitaxel with delavirdine if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and delavirdine is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of cabazitaxel with cobicistat if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of cabazitaxel with cobicistat if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Erlotinib: (Moderate) The use of taxane-based chemotherapy with erlotinib appears to be one of the risk factors for gastrointestinal (GI) perforation with erlotinib. Monitor for symptoms of GI perforation (e.g., severe abdominal pain, fever, nausea, and vomiting) if coadministration of erlotinib with a taxane chemotherapy agent is necessary.
Fosamprenavir: (Major) Avoid coadministration of cabazitaxel with fosamprenavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and fosamprenavir is a strong CYP3A4 inhibitor; data also suggest that fosamprenavir has the potential to induce CYP3A4. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%; concomitant use with a strong CYP3A4 inducer decreased cabazitaxel exposure by 17%.
Grapefruit juice: (Major) Avoid coadministration of cabazitaxel with grapefruit juice due to increased cabazitaxel exposure. Cabazitaxel is primarily metabolized by CYP3A4 and grapefruit juice is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Idelalisib: (Major) Avoid coadministration of cabazitaxel with idelalisib if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and idelalisib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Indinavir: (Major) Avoid coadministration of cabazitaxel with indinavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and indinavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Itraconazole: (Major) Avoid use of cabazitaxel during and for 2 weeks after discontinuation of itraconazole due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and itraconazole is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Ketoconazole: (Major) Avoid coadministration of cabazitaxel with ketoconazole if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ketoconazole increased cabazitaxel exposure by 25%.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of cabazitaxel with clarithromycin if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Letermovir: (Moderate) A clinically significant increase in cabazitaxel exposure is not expected when coadministered with letermovir; however, if the patient is also receiving cyclosporine, increased cabazitaxel concentrations are possible. Consider a 25% reduction in the dose of cabazitaxel in patients who are also receiving cyclosporine. Cabazitaxel is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration of cabazitaxel with a moderate CYP3A4 inhibitor did not modify cabazitaxel exposure; however, when given with a strong CYP3A4 inhibitor, the cabazitaxel exposure increased by 25%.
Levoketoconazole: (Major) Avoid coadministration of cabazitaxel with ketoconazole if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ketoconazole increased cabazitaxel exposure by 25%.
Lonafarnib: (Major) Avoid coadministration of cabazitaxel with lonafarnib if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and lonafarnib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Lopinavir; Ritonavir: (Major) Avoid coadministration of cabazitaxel with ritonavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Mifepristone: (Major) Avoid coadministration of cabazitaxel with mifepristone if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown. Cabazitaxel is primarily metabolized by CYP3A4 and mifepristone is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Nefazodone: (Major) Avoid coadministration of cabazitaxel with nefazodone if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and nefazodone is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Nelfinavir: (Major) Avoid coadministration of cabazitaxel with nelfinavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and nelfinavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of cabazitaxel with ritonavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Posaconazole: (Major) Avoid coadministration of cabazitaxel with posaconazole if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and posaconazole is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Ribociclib: (Major) Avoid coadministration of cabazitaxel with ribociclib if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and ribociclib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Ribociclib; Letrozole: (Major) Avoid coadministration of cabazitaxel with ribociclib if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and ribociclib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Ritonavir: (Major) Avoid coadministration of cabazitaxel with ritonavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Saquinavir: (Major) Avoid coadministration of cabazitaxel with saquinavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and saquinavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tipranavir: (Major) Avoid coadministration of cabazitaxel with tipranavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and tipranavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Tucatinib: (Major) Avoid coadministration of cabazitaxel with tucatinib if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and tucatinib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of cabazitaxel with clarithromycin if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Voriconazole: (Major) Avoid coadministration of cabazitaxel with voriconazole if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and voriconazole is a strong CYP3A4 inhibitor; however, the inhibitory potential is less with voriconazole than with ketoconazole and itraconazole. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cabazitaxel is a taxane derivative of the natural taxoid 10-deacetylbaccatin III prepared semi-synthetically with a precursor extracted from yew needles. Cabazitaxel binds to tubulin and promotes its assembly into microtubules. Simultaneously, cabazitaxel inhibits microtubule disassembly by stabilizing tubulin. This results in inhibition of microtubule depolymerization and cell division, cell cycle arrest (G2/M phase), and the inhibition of tumor cell proliferation. Unlike other taxanes, cabazitaxel is a poor substrate for the multidrug resistance P-glycoprotein efflux pump and may be useful for treating multidrug-resistant tumors. In addition, cabazitaxel penetrates the blood-brain barrier, where Pgp efflux pumps may serve as barriers.
Cabazitaxel is administered as an intravenous infusion. It is 89% to 92% protein bound, primarily to albumin (82%) and lipoproteins (HDL, 88%; LDL, 70%; VLDL, 56%); protein binding was not saturable at the maximum concentrations observed in clinical trials. In vitro blood-to-plasma concentrations indicate it is equally distributed between blood and plasma. The volume of distribution (Vd) at steady-state was 4,864 L (2,643 L/m2). Cabazitaxel is extensively metabolized in the liver (more than 95%), mainly by CYP3A4/5 (80% to 90%), and to a lesser extent by CYP2C8. Cabazitaxel is the main circulating moiety in human plasma. Seven metabolites were detected in plasma (including 3 active metabolites issued from O-demethylation), with the main one accounting for 5% of cabazitaxel exposure. Based on a population pharmacokinetic analysis, the plasma clearance of cabazitaxel is 48.5 L/hour (coefficient of variation (CV), 39%; 26.4 L/hour/m2). Approximately 80% of cabazitaxel is eliminated within 2 weeks of a 25 mg/m2 1-hour infusion. It is mainly (76%) eliminated in the feces as numerous metabolites, renal elimination accounts for 3.7% of a dose, with 2.3% as unchanged drug. Elimination is characterized by a 3-compartment pharmacokinetic model after a 1-hour infusion with alpha-, beta-, and gamma-half-lives of 4 minutes, 2 hours, and 95 hours, respectively.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4/5, CYP2C8, P-glycoprotein (P-gp)
Cabazitaxel is primarily metabolized by CYP3A, and to a lesser extent by CYP2C8; cabazitaxel is also a substrate of P-gp. Concomitant use with strong CYP3A inhibitors should be avoided if possible; if not possible, a 25% dose reduction of cabazitaxel should be considered. In a drug interaction study, coadministration with a strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%; however, concomitant use with a moderate CYP3A inhibitor did not affect cabazitaxel exposure. Coadministration with a strong CYP3A inducer decreased exposure by cabazitaxel by 17%. While cabazitaxel inhibits P-gp, BCRP, OATP1B1, and OATP1B3 in vitro, the in vivo risk is low at the recommended dose of 25 mg/m2; additionally, the risk of inhibition of CYP isoenzymes is low based on in vitro studies. Cabazitaxel did not affect exposure of midazolam, a probe substrate of CYP3A, in a drug interaction study.
-Route-Specific Pharmacokinetics
Intravenous Route
Based on a population pharmacokinetic analysis, the mean Cmax in patients with metastatic prostate cancer was 226 ng/mL (CV, 107%), reached at the end of a 1-hour infusion (Tmax) of cabazitaxel 25 mg/m2; the mean AUC was 991 mL*ng/hour (CV, 34%). In patients with advanced solid tumors, no major deviation from dose proportionality was observed from 10 to 30 mg/m2.
-Special Populations
Hepatic Impairment
The pharmacokinetics of cabazitaxel were not affected by mild or moderate hepatic impairment (total bilirubin 1.1 to 3 times ULN or AST greater than 1.5 times ULN) in a dedicated study in cancer patients (n = 43); the maximum tolerated dose (MTD) was 20 mg/m2 and 15 mg/m2, respectively. Cabazitaxel clearance was decreased by 39% in three patients with severe hepatic impairment (total bilirubin greater than 3 times ULN) compared to patients with mild hepatic impairment (total bilirubin 1.1 to 1.5 times ULN or AST greater than 1.5 times ULN) (ratio 0.61, 90% CI, 0.36 to 1.05); the MTD was not established in patients with severe hepatic impairment.
Renal Impairment
The pharmacokinetics of cabazitaxel were not affected by mild to moderate renal impairment (n = 73; CrCL 30 mL/min or higher) in a population pharmacokinetic analysis (n = 170); this was confirmed in a separate dedicated pharmacokinetic study in cancer patients (CrCL higher than 80 mL/min/1.73 m2, n = 8; CrCL 30 to 50 mL/min/1.73 m2, n = 8; CrCL less than 30 mL/min/1.73 m2, n = 9). Limited pharmacokinetic data are available in patients with end-stage renal disease (ESRD; CrCL less than 15 mL/min/1.73 m2; n = 2).
Pediatrics
Based on a population pharmacokinetic analysis, clearance by body surface area was comparable in pediatric cancer patients (3 to 18 years; n = 31) to adults.
Geriatric
Based on a population pharmacokinetic analysis, age (younger than 65 years, n = 100; older than 65 years, n = 70) did not significantly affect the pharmacokinetics of cabazitaxel.