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CABAZITAXEL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cabazitaxel, a microtubule inhibitor, belongs to the taxane class and is prepared by semi-synthesis, with a precursor extracted from yew needles.

Specific Substances

    1) C45H57NO14C3H6O
    2) XRP6258
    1.2.1) MOLECULAR FORMULA
    1) C(45)H(57)NO(14)C(3)H(6)O

Available Forms Sources

    A) FORMS
    1) Single use vial of 60 mg/1.5 mL along with a diluent (5.7 mL) (Prod Info JEVTANA(R) IV infusion, 2010).
    B) USES
    1) Cabazitaxel is used in combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer that were previously treated with docetaxel (Prod Info JEVTANA(R) IV infusion, 2010; Di Lorenzo et al, 2010).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Cabazitaxel is used in combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer.
    B) PHARMACOLOGY: Cabazitaxel, a microtubule inhibitor, binds to tubulin and promotes its assembly into microtubules while inhibiting disassembly. The stabilization that occurs produces inhibition of mitotic and interphase cellular functions.
    C) TOXICOLOGY: Cabazitaxel inhibits normal interphase and mitotic cellular function, causing cell death. Overdose effects are likely to occur in rapidly dividing cells (ie, bone marrow, gastrointestinal tract).
    D) EPIDEMIOLOGY: At the time of this review, no overdose events have been reported with cabazitaxel.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Neutropenia and leukopenia have been commonly reported with therapy. Several reports of death have been associated with neutropenia and febrile neutropenia. The most common grade 3 to 4 events include: neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia. Renal failure, including some fatalities, has been reported with cabazitaxel use. Other common (greater than 10%) less severe events may include: nausea, vomiting, constipation, abdominal pain, peripheral edema, peripheral neuropathy, fever, dyspnea, dysgeusia, musculoskeletal symptoms, and hematuria. Hypersensitivity reactions have developed and are more likely to occur during the first or second dose. INFREQUENT: Less common adverse events may include: intestinal mucosa inflammation, dysrhythmias, hypotension, edema, and dysuria.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Data are limited. Effects are anticipated to be similar to adverse effects reported during therapeutic use. Early symptoms may include nausea, vomiting, and diarrhea (which may be severe) with potential alterations in fluid and electrolyte balance. Hematuria may occur.
    2) SEVERE TOXICITY: Myelosuppression (neutropenia and leukopenia) is likely to develop and may be severe. Other potentially serious events include renal failure and severe diarrhea associated with electrolyte imbalance.
    0.2.5) CARDIOVASCULAR
    A) Hypotension and cardiac dysrhythmias have been reported infrequently with cabazitaxel therapy.
    0.2.7) NEUROLOGIC
    A) Peripheral neuropathy (motor and sensory) has been reported with therapeutic use; severe events are uncommon.
    0.2.8) GASTROINTESTINAL
    A) Diarrhea is likely to develop with therapeutic use and may be severe. Nausea, vomiting, and mucositis may occur with therapy.
    0.2.10) GENITOURINARY
    A) Renal failure, including some deaths, has been associated with cabazitaxel use.
    B) Urinary tract infection, hematuria, and dysuria have developed with therapeutic use.
    0.2.13) HEMATOLOGIC
    A) Leukopenia and neutropenia are commonly reported with therapy; the effects may be potentially severe in many patients. Neutropenia was the most common event that led to discontinuation of therapy. Several deaths associated with neutropenic complications (sepsis, septic shock) have occurred during clinical trials.
    B) Anemia and thrombocytopenia have been frequently reported with cabazitaxel use.
    0.2.19) IMMUNOLOGIC
    A) Hypersensitivity reactions, including anaphylaxis, have been reported during a single clinical trial.
    0.2.20) REPRODUCTIVE
    A) Cabazitaxel is classified as FDA pregnancy category D. In animal studies, cabazitaxel was embryotoxic and fetotoxic.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential.

Laboratory Monitoring

    A) Obtain CBC with differential and platelets daily to evaluate for bone marrow suppression (primarily neutropenia). Serial counts should be monitored until patient recovery.
    B) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    C) Closely monitor liver enzymes, renal function, fluid status and electrolytes. Ensure adequate hydration, and correct electrolyte abnormalities as needed.
    D) Monitor vital signs, including temperature.
    E) Obtain an ECG. Continuous cardiac monitoring is indicated in patients with evidence of conduction abnormalities.
    F) Clinically evaluate patients for the development of mucositis and/or peripheral neuropathy.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is primarily symptomatic and supportive, there is no antidote. Early signs of toxicity may include nausea/vomiting and diarrhea, that can be severe. Treat with IV fluids, antidiarrheals (eg, high-dose loperamide, diphenoxylate) and antiemetics. It may be necessary to treat with multiple, concomitant agents, from different drug classes, in patients with persistent vomiting. BONE MARROW SUPPRESSION: Neutropenia should be anticipated. Colony stimulating factor (filgrastim or sargramostim) should be initiated as soon as possible after exposure. Consider protective isolation. PERIPHERAL NEUROPATHY: May develop in overdose. Monitor and treat symptoms. MYALGIAS: Initially treat with NSAIDs.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) NEUTROPENIA: Bone marrow suppression (ie, neutropenia) may be severe. Neutropenia is the dose-dependent and the dose-limiting toxicity in therapy. Colony stimulating factor (filgrastim or sargramostim) should be initiated as soon as possible. Patients with severe neutropenia should be in protective isolation. Platelet and red cell transfusions may be necessary. DIARRHEA: For severe or uncontrolled diarrhea treat with octreotide 100 mcg to 150 mcg IV (25 to 50 mcg/hr), IV fluids, antibiotics and electrolyte replacement as needed. EMESIS: Aggressively treat with antiemetics and fluid and electrolyte replacement. Closely monitor patients for hypotension, bradycardia and other cardiac dysrhythmias. Monitor liver enzymes and renal function.
    C) DECONTAMINATION
    1) PREHOSPITAL: Not indicated since overdose is unlikely because cabazitaxel is administered by the intravenous route.
    2) HOSPITAL: Activated charcoal and/or gastric lavage are not indicated since overdose most often occurs by the intravenous route.
    D) AIRWAY MANAGEMENT
    1) Consider orotracheal intubation in patients with significant CNS depression or respiratory failure.
    E) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    F) ANTIDOTE
    1) There is no known antidote for cabazitaxel.
    G) MYELOSUPPRESSION
    1) Severe neutropenia should be anticipated following a significant exposure. Place patients in protective isolation. Give colony stimulating factor as soon as possible. Closely monitor CBC with differential daily until patient recovery. Filgrastim: 5 mcg/kg/day IV or subQ (preferred route). Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily.
    H) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    I) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during the neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    J) NAUSEA AND VOMITING
    1) If nausea and vomiting develops, treat with high-dose dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, promethazine or prochlorperazine), 5-HT3 serotonin antagonists (eg, ondansetron, dolasetron, or granisetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and/or antipsychotics (eg, haloperidol). Diphenhydramine may be required to prevent dystonic reactions from dopamine antagonists, phenothiazines, or antipsychotics. Replace fluid and electrolytes as needed. Monitor liver enzymes and renal function closely.
    K) MUCOSITIS/STOMATITIS
    1) Mucosal inflammation has occurred with other taxanes and may develop with cabazitaxel. Ice chips (ie, cryotherapy) may help minimize symptoms. Palifermin, a keratinocyte growth factor, is indicated for the prevention of chemotherapy-induced oral mucositis. Treat mild symptoms of pain or xerostomia with bland rinses (ie, normal saline or sodium bicarbonate). Treat salivary gland dysfunction or xerostomia with sugarless candy/mints, pilocarpine/cevimeline, bethanechol, topical fluorides or remineralizing agents. Treat moderate pain symptoms with topical anesthetics (ie, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin) and mucosal coating agents (benzydamine) as needed. Moderate to severe symptoms may require systemic analgesics. Prophylactic treatment to prevent infection is suggested; topical or systemic treatment may be indicated. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In patients with severe carbazitaxel overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    L) PERIPHERAL NEUROPATHY
    1) Peripheral neurotoxicity may develop in overdose. Cabazitaxel-induced neurotoxicity can produce peripheral neuropathy (sensory and motor). Monitor and treat symptoms as indicated. Pain is sometimes present.
    M) INTRATHECAL INJECTION
    1) No clinical reports available, information derived from experience with other antineoplastics. Keep the patient upright if possible. Immediately drain at least 20 mL cerebrospinal fluid (CSF); drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative-free normal saline or Lactated Ringer's). For large overdoses, consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free NS or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes are 80 to 150 mL/hr for 18 to 24 hours). Add albumin 5% or fresh frozen plasma (25 mL FFP/L NS or LR) to the perfusion solution to increase removal as cabazitaxel is highly protein bound. Give dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.
    N) ENHANCED ELIMINATION
    1) Hemodialysis, hemoperfusion and plasmapheresis are unlikely to be useful as cabazitaxel is highly protein-bound with a large volume of distribution.
    O) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management. Patients with a cabazitaxel overdose need to be admitted.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), daily monitoring of CBC with differential until bone marrow suppression is resolved, along with monitoring of serum electrolytes, renal function and hepatic enzymes.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with a cabazitaxel overdose.
    4) TRANSFER CRITERIA: Patients with severe overdose or profound neutropenia may benefit from a transfer to a bone marrow transplant or cancer treatment center.
    P) PITFALLS
    1) Symptoms in patients may be delayed (particularly myelosuppression), so reliable follow-up is imperative. Patients taking these medications may have severe comorbidities and access to other drugs with significant toxicity.
    Q) PHARMACOKINETICS
    1) Cabazitaxel is highly protein-bound (89% to 92%). The volume of distribution is high (4864 L (2643 L/m(2) for a patient with a median body surface area of 1.84 m(2)) at steady state. It is extensively metabolized in the liver (greater than 95%) primarily by the CYP3A4/5 isoenzyme (80% to 90%) and to a lesser extent by CYP2C8. It is mainly excreted in the feces as numerous metabolites (76%) with renal excretion accounting for 3.7% of a dose. Based on a one hour IV infusion of 25mg/m(2), approximately 80% of the dose was eliminated in 2 weeks. In in vitro studies, cabazitaxel protein binding was not saturable up to 50,000 ng/mL (the maximum concentration used in clinical trials).
    R) DIFFERENTIAL DIAGNOSIS
    1) Differential diagnosis includes other chemotherapeutic agents.

Range Of Toxicity

    A) TOXICITY: A minimum lethal dose has not been established.
    B) THERAPEUTIC DOSE: ADULT: Administer 25 mg/m(2) every 3 weeks as a 1 hour intravenous infusion in combination with oral prednisone. PEDIATRIC: The safety and efficacy of cabazitaxel have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Cabazitaxel is used in combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer.
    B) PHARMACOLOGY: Cabazitaxel, a microtubule inhibitor, binds to tubulin and promotes its assembly into microtubules while inhibiting disassembly. The stabilization that occurs produces inhibition of mitotic and interphase cellular functions.
    C) TOXICOLOGY: Cabazitaxel inhibits normal interphase and mitotic cellular function, causing cell death. Overdose effects are likely to occur in rapidly dividing cells (ie, bone marrow, gastrointestinal tract).
    D) EPIDEMIOLOGY: At the time of this review, no overdose events have been reported with cabazitaxel.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Neutropenia and leukopenia have been commonly reported with therapy. Several reports of death have been associated with neutropenia and febrile neutropenia. The most common grade 3 to 4 events include: neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia. Renal failure, including some fatalities, has been reported with cabazitaxel use. Other common (greater than 10%) less severe events may include: nausea, vomiting, constipation, abdominal pain, peripheral edema, peripheral neuropathy, fever, dyspnea, dysgeusia, musculoskeletal symptoms, and hematuria. Hypersensitivity reactions have developed and are more likely to occur during the first or second dose. INFREQUENT: Less common adverse events may include: intestinal mucosa inflammation, dysrhythmias, hypotension, edema, and dysuria.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Data are limited. Effects are anticipated to be similar to adverse effects reported during therapeutic use. Early symptoms may include nausea, vomiting, and diarrhea (which may be severe) with potential alterations in fluid and electrolyte balance. Hematuria may occur.
    2) SEVERE TOXICITY: Myelosuppression (neutropenia and leukopenia) is likely to develop and may be severe. Other potentially serious events include renal failure and severe diarrhea associated with electrolyte imbalance.

Vital Signs

    3.3.3) TEMPERATURE
    A) Fever may occur with therapeutic use (Prod Info JEVTANA(R) IV infusion, 2010).

Cardiovascular

    3.5.1) SUMMARY
    A) Hypotension and cardiac dysrhythmias have been reported infrequently with cabazitaxel therapy.
    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Severe dysrhythmias have been reported infrequently with cabazitaxel therapy (Prod Info TAXOTERE(R) injection concentrate IV infusion, 2010).
    b) In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, all grade dysrhythmias were reported in 5% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 2% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371). Grade 3 or 4 dysrhythmias were reported in 1% or less of patients in the cabazitaxel and mitoxantrone groups, respectively (Prod Info JEVTANA(R) IV infusion, 2010).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has been reported infrequently with cabazitaxel therapy (Prod Info JEVTANA(R) IV infusion, 2010).
    b) In a single, randomized clinical trial, all grade hypotension was reported in 5% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 2% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371). Grade 3 or 4 hypotension was reported in less than 1% of patients in both the cabazitaxel group and in the mitoxantrone group (Prod Info JEVTANA(R) IV infusion, 2010).
    C) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) In a single, randomized clinical trial, all grade peripheral edema was reported in 9% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 9% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371). Grade 3 or 4 peripheral edema was reported in less than 1% of patients in both the cabazitaxel group and in the mitoxantrone group (Prod Info JEVTANA(R) IV infusion, 2010).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea and cough have been reported with cabazitaxel therapy (Prod Info JEVTANA(R) IV infusion, 2010).

Neurologic

    3.7.1) SUMMARY
    A) Peripheral neuropathy (motor and sensory) has been reported with therapeutic use; severe events are uncommon.
    3.7.2) CLINICAL EFFECTS
    A) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM
    1) WITH THERAPEUTIC USE
    a) Peripheral neuropathy (motor and sensory neuropathy) has been reported with cabazitaxel use (Prod Info JEVTANA(R) IV infusion, 2010).
    b) In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, all grade peripheral neuropathy (including peripheral motor and sensory neuropathy) was reported in 13% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 3.2% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371). Grade 3 or 4 peripheral neuropathy was reported in less than 1% of patients in both the cabazitaxel group and in the mitoxantrone group (Prod Info JEVTANA(R) IV infusion, 2010).
    B) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia has been reported with cabazitaxel therapy (Prod Info JEVTANA(R) IV infusion, 2010).
    b) In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, all grade asthenia was reported in 20% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 12% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371). Grade 3 or 4 asthenia was reported in 5% and 2% of patients in the cabazitaxel and mitoxantrone groups, respectively. A higher incidence of asthenia was seen in patients 65 years and older compared with younger patients (24% vs 15%) (Prod Info JEVTANA(R) IV infusion, 2010).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache may develop with therapy (Prod Info JEVTANA(R) IV infusion, 2010).
    b) In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, all grade headache was reported in 8% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 5% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) (Prod Info JEVTANA(R) IV infusion, 2010).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness may develop with therapy (Prod Info JEVTANA(R) IV infusion, 2010).
    b) In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, all grade dizziness was reported in 8% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 6% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371). A higher incidence of dizziness was seen in patients 65 years and older compared with younger patients (10% vs 5%) (Prod Info JEVTANA(R) IV infusion, 2010).

Gastrointestinal

    3.8.1) SUMMARY
    A) Diarrhea is likely to develop with therapeutic use and may be severe. Nausea, vomiting, and mucositis may occur with therapy.
    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has commonly occurred with cabazitaxel therapy. Deaths have been associated with diarrhea and electrolyte imbalance during therapeutic use (Prod Info JEVTANA(R) IV infusion, 2010).
    b) In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, all grade diarrhea was reported in 47% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 11% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371). Grade 3 or 4 diarrhea was reported in 6% and less than 1% of patients in the cabazitaxel and mitoxantrone groups, respectively (Prod Info JEVTANA(R) IV infusion, 2010).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting may develop with therapeutic use (Prod Info JEVTANA(R) IV infusion, 2010).
    b) In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, all grade nausea was reported in 34% and all grade vomiting was reported in 22% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) (Prod Info JEVTANA(R) IV infusion, 2010).
    C) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Mucositis has been reported with therapeutic use (Prod Info JEVTANA(R) IV infusion, 2010).
    b) In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, all grade mucosal inflammation was reported in 6% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 3% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371). Grade 3 or 4 mucosal inflammation was reported in less than 1% of patients in both the cabazitaxel group and in the mitoxantrone group (Prod Info JEVTANA(R) IV infusion, 2010).
    D) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Abdominal pain, indigestion and loss of appetite have been reported with cabazitaxel therapy (Prod Info JEVTANA(R) IV infusion, 2010).

Genitourinary

    3.10.1) SUMMARY
    A) Renal failure, including some deaths, has been associated with cabazitaxel use.
    B) Urinary tract infection, hematuria, and dysuria have developed with therapeutic use.
    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) During a clinical trial, renal failure was reported with cabazitaxel therapy. Four fatalities due to renal failure were associated with sepsis, dehydration, or obstructive uropathy; however, some deaths caused by renal failure did not have a confirmed etiology (Prod Info JEVTANA(R) IV infusion, 2010).
    B) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) Hematuria can develop with cabazitaxel use (Prod Info JEVTANA(R) IV infusion, 2010).
    b) In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, all grade hematuria was reported in 17% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 4% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371). More patients in the cabazitaxel group had a grade 2 or higher hematuria compared with the mitoxantrone group (6% vs 2%). Grade 3 or 4 hematuria was reported in 2% and less than 1% of patients in the cabazitaxel and mitoxantrone groups, respectively (Prod Info JEVTANA(R) IV infusion, 2010).
    C) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) Urinary tract infection and dysuria have been reported with cabazitaxel therapy (Prod Info JEVTANA(R) IV infusion, 2010).

Hematologic

    3.13.1) SUMMARY
    A) Leukopenia and neutropenia are commonly reported with therapy; the effects may be potentially severe in many patients. Neutropenia was the most common event that led to discontinuation of therapy. Several deaths associated with neutropenic complications (sepsis, septic shock) have occurred during clinical trials.
    B) Anemia and thrombocytopenia have been frequently reported with cabazitaxel use.
    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been commonly reported during a clinical trial with cabazitaxel therapy. The incidence was 96% for all grades and 69% for grades 3 or 4 leukopenia (Prod Info JEVTANA(R) IV infusion, 2010).
    b) In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, all grade leukopenia was reported in 96% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 93% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) (Prod Info JEVTANA(R) IV infusion, 2010).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia has been commonly reported during a clinical trial with cabazitaxel therapy. The incidence was 94% for all grades and 82% for grade 3 or 4 neutropenia. Severe neutropenia was more likely to develop in older patients. Neutropenia (2%) was the most common adverse event leading to discontinuation of therapy (Prod Info JEVTANA(R) IV infusion, 2010).
    b) INFECTIOUS COMPLICATION: Of 5 patients developing fatal infectious complications (sepsis or septic shock), all had grade 4 neutropenia and one had febrile neutropenia (Prod Info JEVTANA(R) IV infusion, 2010).
    c) ALL GRADES: In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, all grade neutropenia was reported in 94% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 87% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371). A higher incidence of neutropenia was seen in patients 65 years and older compared with younger patients (97% vs 89%) (Prod Info JEVTANA(R) IV infusion, 2010).
    d) GRADE 3 or 4 NEUTROPENIA: In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, grade 3 or 4 neutropenia was reported in 82% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 58% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371). A higher incidence of grade 3 or 4 neutropenia was seen in patients 65 years and older compared with younger patients (87% vs 74%). Of 5 patients with fatal infectious adverse effects, all had grade 4 neutropenia and 1 had febrile neutropenia. Another patient's death was related to neutropenia without a documented infection (Prod Info JEVTANA(R) IV infusion, 2010).
    C) FEBRILE NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In a single, randomized clinical trial in patients with hormone-refractory prostate cancer, febrile neutropenia was reported in 7% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 1% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371). Grade 3 or 4 febrile neutropenia was reported in 7% and 1% of patients in the cabazitaxel and mitoxantrone groups, respectively. A higher incidence of grade 3 or 4 neutropenia was seen in patients 65 years and older compared with younger patients (8% vs 6%). Of 5 patients with fatal infectious adverse effects, 1 had febrile neutropenia (Prod Info JEVTANA(R) IV infusion, 2010).
    b) During a clinical trial, fatal adverse reactions were primarily associated with infectious complications (n=5) (Prod Info JEVTANA(R) IV infusion, 2010).
    D) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia has been commonly reported during a single clinical trial with cabazitaxel therapy. The incidence was 98% for all grades and 11% for grade 3 or 4 anemia (Prod Info JEVTANA(R) IV infusion, 2010).
    b) In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, all grade anemia was reported in 98% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 82% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) (Prod Info JEVTANA(R) IV infusion, 2010).
    E) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a clinical trial, patients treated with cabazitaxel (n=371) and prednisone had an overall incidence of thrombocytopenia of 48%. Of these patients, 4% developed severe grade 3 to 4 thrombocytopenia (Prod Info JEVTANA(R) IV infusion, 2010).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia occurs infrequently with cabazitaxel therapy (Prod Info JEVTANA(R) IV infusion, 2010).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Muscle pain and muscle spasm may develop with cabazitaxel therapy (Prod Info JEVTANA(R) IV infusion, 2010).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia may develop with cabazitaxel therapy (Prod Info JEVTANA(R) IV infusion, 2010).
    b) In a single, randomized, clinical trial in patients with hormone-refractory prostate cancer, all grade arthralgia was reported in 11% of patients receiving cabazitaxel 25 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371) compared with 8% of patients treated with mitoxantrone 12 mg/m(2) every 3 weeks in combination with prednisone 10 mg daily (n=371). Grade 3 or 4 arthralgia was reported in 1% of patients in both the cabazitaxel group and in the mitoxantrone group (Prod Info JEVTANA(R) IV infusion, 2010).

Immunologic

    3.19.1) SUMMARY
    A) Hypersensitivity reactions, including anaphylaxis, have been reported during a single clinical trial.
    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Severe hypersensitivity reactions, including generalized rash/erythema, hypotension, and bronchospasm, may occur in the first few minutes following the administration of cabazitaxel, especially during the first and second transfusion (Prod Info JEVTANA(R) IV infusion, 2010).

Reproductive

    3.20.1) SUMMARY
    A) Cabazitaxel is classified as FDA pregnancy category D. In animal studies, cabazitaxel was embryotoxic and fetotoxic.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In animal studies, cabazitaxel was embryotoxic, fetotoxic, and an abortifacient at doses approximately 0.02 times the maximum recommended human dose (MRHD). At doses approximately 0.02 times the Cmax at the MRHD, decreases in mean fetal birth weight, causing delays in skeletal ossification, were seen (Prod Info JEVTANA(R) intravenous injection, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified cabazitaxel as FDA pregnancy category D (Prod Info JEVTANA(R) intravenous injection, 2015).
    2) Do not administer this drug to a pregnant woman (Prod Info JEVTANA(R) intravenous injection, 2015).
    B) ANIMAL STUDIES
    1) In animal studies, cabazitaxel was shown to cross the placental barrier within 24 hours of administration. Maternal and embryofetal toxicity was reported with cabazitaxel doses up to 0.06 times the Cmax in cancer patients at the MRHD. However, fetal abnormalities were not evident following in utero exposure to cabazitaxel at exposure levels that were significantly lower than expected human exposures (Prod Info JEVTANA(R) intravenous injection, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether cabazitaxel is excreted in human milk. Discontinue nursing or discontinue cabazitaxel taking into account the importance of the drug to the mother (Prod Info JEVTANA(R) intravenous injection, 2015).
    B) ANIMAL STUDIES
    1) In animal studies, radioactivity related to cabazitaxel was detected in the stomach of nursing offspring within 2 hours of administration of a single IV dose (approximately 0.02 times the maximum recommended human dose) and was present for up to 24 hours post-dose. It was estimated that approximately 1.5% of the maternal dose was present in the maternal milk (Prod Info JEVTANA(R) intravenous injection, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) During male animal reproduction studies, There were no effects on mating performance or fertility with cabazitaxel at doses up to 0.2 mg/kg/day. Degeneration of seminal vesicle and seminiferous tubule atrophy in the testis was reported with IV cabazitaxel at doses up to 0.35 times the AUC in cancer patients at the recommended human dose. Minimal testicular degeneration was observed with cabazitaxel doses approximately one-tenth of the AUC in cancer patients at the recommended human dose (Prod Info JEVTANA(R) intravenous injection, 2015).
    2) During female animal reproduction studies, an increase in pre-implantation loss and early resorptions were reported with cabazitaxel doses up to 0.06 times the human exposure. Necrosis of the corpora lutea was reported with doses approximately 0.2 times the AUC at the recommended human dose. Atrophy of the uterus was reported with doses approximately equal to the AUC in cancer patients at the recommended human dose. There were no adverse effects on mating behavior or the ability to become pregnant (Prod Info JEVTANA(R) intravenous injection, 2015).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential (Prod Info JEVTANA(R) IV infusion, 2010).
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) Long-term studies of the carcinogenic potential of cabazitaxel have not been conducted (Prod Info JEVTANA(R) IV infusion, 2010).

Genotoxicity

    A) There was evidence of clastogenicity in the in vivo micronucleus test which induced an increase of micronuclei in rats at doses of 0.5 mg/kg or greater. Numerical aberrations with or without metabolic activation were increased in an in vitro test in human lymphocytes, but no induction of structural aberrations was observed. There was no evidence of mutagenicity in the Ames test (Prod Info JEVTANA(R) IV infusion, 2010).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Obtain CBC with differential and platelets daily to evaluate for bone marrow suppression (primarily neutropenia). Serial counts should be monitored until patient recovery.
    B) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    C) Closely monitor liver enzymes, renal function, fluid status and electrolytes. Ensure adequate hydration, and correct electrolyte abnormalities as needed.
    D) Monitor vital signs, including temperature.
    E) Obtain an ECG. Continuous cardiac monitoring is indicated in patients with evidence of conduction abnormalities.
    F) Clinically evaluate patients for the development of mucositis and/or peripheral neuropathy.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Obtain CBC with differential and platelets daily to evaluate for bone marrow suppression (primarily neutropenia). Serial counts should be monitored until patient recovery.
    B) BLOOD/SERUM CHEMISTRY
    1) Closely monitor fluid status and electrolytes for signs of dehydration or electrolyte imbalance.
    2) Monitor renal function tests.
    a) Of the limited cases of fatal renal failure associated with cabazitaxel therapy, sepsis, dehydration or obstructive uropathy were often present (Prod Info JEVTANA(R) IV infusion, 2010).
    3) Monitor liver enzymes.
    a) Alterations in liver function are likely to produce increased concentrations of cabazitaxel (Prod Info JEVTANA(R) IV infusion, 2010).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Monitor ECG for possible cardiac dysrhythmias as indicated.
    2) NERVE CONDUCTION STUDIES
    a) Nerve conduction studies may be useful in evaluating patients with sensory or motor neuropathies.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), daily monitoring of CBC with differential until bone marrow suppression is resolved, and monitoring of serum electrolytes, renal function, and hepatic enzymes.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management. Patients with cabazitaxel overdose need to be admitted.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with a cabazitaxel overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdose or severe neutropenia might benefit from transfer to a bone marrow transplant or oncology treatment center.

Monitoring

    A) Obtain CBC with differential and platelets daily to evaluate for bone marrow suppression (primarily neutropenia). Serial counts should be monitored until patient recovery.
    B) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    C) Closely monitor liver enzymes, renal function, fluid status and electrolytes. Ensure adequate hydration, and correct electrolyte abnormalities as needed.
    D) Monitor vital signs, including temperature.
    E) Obtain an ECG. Continuous cardiac monitoring is indicated in patients with evidence of conduction abnormalities.
    F) Clinically evaluate patients for the development of mucositis and/or peripheral neuropathy.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Activated charcoal and gastric lavage are not indicated since overdose is unlikely because cabazitaxel is administered by the intravenous route.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Cabazitaxel is only available parenterally; oral exposure is unlikely. See the PARENTERAL EXPOSURE section for further information.

Enhanced Elimination

    A) LACK OF EFFICACY
    1) Hemodialysis, hemoperfusion and plasmapheresis are unlikely to be useful as cabazitaxel is highly protein-bound with a large volume of distribution.

Range Of Toxicity

Summary

    A) TOXICITY: A minimum lethal dose has not been established.
    B) THERAPEUTIC DOSE: ADULT: Administer 25 mg/m(2) every 3 weeks as a 1 hour intravenous infusion in combination with oral prednisone. PEDIATRIC: The safety and efficacy of cabazitaxel have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) PROSTATE CANCER, METASTATIC
    1) The recommended dose is 25 mg/m(2) IV over 1 hour every 3 weeks in combination with oral prednisone 10 mg/day administered throughout cabazitaxel treatment (Prod Info JEVTANA(R) intravenous injection, 2014).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of cabazitaxel have not been established in pediatric patients (Prod Info JEVTANA(R) intravenous injection, 2014).

Minimum Lethal Exposure

    A) At the time of this review, a minimum lethal dose has not been established.

Maximum Tolerated Exposure

    A) At the time of this review, a maximum tolerated dose has not been established.

Pharmacology Toxicology

Pharmacologic Mechanism

    A) ANTINEOPLASTIC ACTION: Cabazitaxel inhibits cell division by promoting microtubule stabilization and assembly, which can lead to inhibition of mitotic and interphase cellular function (Prod Info JEVTANA(R) IV infusion, 2010).
    1) Unlike other antimicrotubule agents that induce microtubule disassembly, cabazitaxel promotes the assembly of microtubules from tubulin dimers, and stabilize microtubules by preventing depolymerization (Prod Info JEVTANA(R) IV infusion, 2010).

Physicochemical

Physical Characteristics

    A) Cabazitaxel is a white to off-white powder that is lipophilic, soluble in alcohol, and practically insoluble in water (Prod Info JEVTANA(R) IV infusion, 2010).

Molecular Weight

    A) 894.01 (acetone solvate); 835.93 (solvent-free) (Prod Info JEVTANA(R) IV infusion, 2010)

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