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  • CLASSES

    Taxanes

    DEA CLASS

    Rx

    DESCRIPTION

    Microtubule stabilizer; semi-synthetic taxane made from a precursor extracted from yew needles
    Used for the treatment of metastatic hormone-refractory prostate cancer previously treated with docetaxel
    Contraindicated in patients with severe hypersensitivity to cabazitaxel or other drugs formulated with polysorbate 80, ANC less than or equal to 1,500 cells/mm3, and severe hepatic impairment

    COMMON BRAND NAMES

    Jevtana

    HOW SUPPLIED

    Jevtana Intravenous Inj Sol: 1.5mL, 60mg

    DOSAGE & INDICATIONS

    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. A cabazitaxel dose of 25 mg/m2 IV can be used in select patients at the discretion of the treating healthcare provider; this dose is associated with a higher incidence of hematologic toxicities. 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 (ranitidine 50 mg or equivalent) to reduce the risk of hypersensitivity; primary prophylaxis with G-CSF is recommended in older patients or those with poor performance status, previous febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities. In a randomized clinical trial, overall survival was significantly increased in patients with metastatic castration-resistant prostate cancer (CRPC) treated with cabazitaxel 25 mg/m2 plus prednisone (n = 378) compared with mitoxantrone plus prednisone (n = 377) (15.1 vs. 12.7 months). A cabazitaxel dose of 20 mg/m2 (n = 598) was found to be non-inferior in terms of overall survival when compared with cabazitaxel 25 mg/m2 (n = 602) (13.4 vs. 14.5 months) in a separate multicenter, randomized, open-label clinical trial (PROSELICA).

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    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.

    ADMINISTRATION

     
    CAUTION: Observe and exercise usual precautions for handling, preparing, and administering solutions of cytotoxic drugs.

    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 (ranitidine 50 mg or equivalent). Antiemetic prophylaxis is also recommended.
    Primary prophylaxis of neutropenia with G-CSF is recommended for older patients and patients with poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities.
    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 the cabazitaxel first diluted or second diluted solution is not clear or appears to have precipitation, discard the solution.
    If the undiluted injection or the first or second diluted dilution comes into contact with mucosa, immediately and thoroughly wash with soap and water.

    Intravenous Administration

    Cabazitaxel requires two dilutions prior to administration.
    Both the cabazitaxel injection and the diluent vials contain an overfill to compensate for liquid loss during preparation; after dilution with the entire contents of the accompanying diluent, the initial diluted solution should have a concentration of 10 mg/mL.
    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.
    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.
    Administration:
    Administer cabazitaxel as an intravenous infusion over 1 hour at room temperature.
    Use an in-line filter of 0.22 micrometer nominal pore size (0.2 micrometer) during infusion.

    STORAGE

    Jevtana :
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not refrigerate
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Polysorbate 80 hypersensitivity, risk of serious hypersensitivity reactions or anaphylaxis, taxane hypersensitivity

    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.

    Anemia, bone marrow suppression, neutropenia, thrombocytopenia

    Cabazitaxel is contraindicated for use in patients with 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); therapeutic use of G-CSF and secondary prophylaxis should be considered in all patients at increased risk for complications of neutropenia.

    Hepatic disease

    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.

    Abdominal pain, anticoagulant therapy, constipation, corticosteroid therapy, diarrhea, GI bleeding, GI perforation, ileus, vomiting

    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.

    Radiation therapy

    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.

    Dehydration, renal failure, sepsis

    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.

    Chronic lung disease (CLD), pneumonitis, respiratory distress syndrome

    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.

    Geriatric

    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.

    Children

    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.

    Pregnancy

    Cabazitaxel is contraindicated in pregnancy; it is not indicated for use in female patients. 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.

    Contraception requirements, infertility, reproductive risk

    Cabazitaxel is contraindicated during pregnancy and is not indicated for use in female patients. 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 3 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.

    Breast-feeding

    Cabazitaxel is not indicated for use in female patients. Cabazitaxel should not be used in women who are breast-feeding. 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.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 42.0-82.0
    leukopenia / Delayed / 29.0-69.0
    infection / Delayed / 10.0-20.0
    anemia / Delayed / 10.0-14.0
    diarrhea / Early / 1.0-6.0
    asthenia / Delayed / 2.0-5.0
    fatigue / Early / 3.0-5.0
    thrombocytopenia / Delayed / 3.0-4.0
    renal failure (unspecified) / Delayed / 0-4.0
    hematuria / Delayed / 2.0-4.0
    back pain / Delayed / 0.9-4.0
    vomiting / Early / 1.0-2.0
    nausea / Early / 0.7-2.0
    abdominal pain / Early / 0.5-2.0
    dehydration / Delayed / 2.0-2.0
    bone pain / Delayed / 0-2.0
    anorexia / Delayed / 0-1.0
    stomatitis / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    arthralgia / Delayed / 0.5-1.0
    hypotension / Rapid / 0-1.0
    dyspnea / Early / 0.7-1.0
    fever / Early / 0.2-1.0
    peripheral edema / Delayed / 0.2-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    constipation / Delayed / 0.3-0.7
    dysuria / Early / 0-0.3
    headache / Early / 0-0.2
    weight loss / Delayed / 0-0.2
    pancytopenia / Delayed / Incidence not known
    enterocolitis / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    hemorrhagic cystitis / Delayed / Incidence not known
    AV block / Early / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    atrial fibrillation / Early / Incidence not known
    atrial tachycardia / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    atrial flutter / Early / Incidence not known
    palpitations / Early / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    stroke / Early / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known

    Moderate

    cystitis / Delayed / 1.2-1.5
    gastritis / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    infusion-related reactions / Rapid / Incidence not known
    erythema / Early / Incidence not known

    Mild

    dysgeusia / Early / 7.0-11.0
    cough / Delayed / 6.0-11.0
    dyspepsia / Early / 0-10.0
    dizziness / Early / 4.0-10.0
    alopecia / Delayed / 3.0-10.0
    gastroesophageal reflux / Delayed / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Amoxicillin; Clarithromycin; Lansoprazole: (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%.
    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%.
    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%.
    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%.
    Cobicistat; Elvitegravir; 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%.
    Cobicistat; Elvitegravir; 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%.
    Conivaptan: (Major) Avoid coadministration of cabazitaxel with conivaptan if possible due to increased cabazitaxel exposure; subsequent treatment with cabazitaxel may be initiated no sooner than 1 week after the infusion of conivaptan is completed. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and conivaptan is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
    Dalfopristin; Quinupristin: (Major) Avoid coadministration of cabazitaxel with dalfopristin; quinupristin 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 dalfopristin; quinupristin 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%.
    Dasabuvir; Ombitasvir; Paritaprevir; 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%.
    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%.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    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%.
    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%.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of cabazitaxel with lopinavir; 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 lopinavir; ritonavir 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 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, RU-486: (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%.
    Ombitasvir; Paritaprevir; 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%.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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%.
    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%.
    Streptogramins: (Major) Avoid coadministration of cabazitaxel with dalfopristin; quinupristin 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 dalfopristin; quinupristin is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
    Telithromycin: (Major) Avoid coadministration of cabazitaxel with telithromycin 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 telithromycin is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
    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.
    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%.

    PREGNANCY AND LACTATION

    Pregnancy

    Cabazitaxel is contraindicated in pregnancy; it is not indicated for use in female patients. 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.

    Cabazitaxel is not indicated for use in female patients. Cabazitaxel should not be used in women who are breast-feeding. 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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    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.