Cabazitaxel

Generic name: Cabazitaxel

Trade name: Jevtana

Full names: Cabazitaxel, Cabazitaxel, Jevtana

Indications:

Indicated for combined treatment with prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-containing regimens.

Usage and Dosage:

Dosing Method:

Cabazitaxel requires a two-step dilution process before administration. The entire contents of the diluent vial must be added to the concentrate during reconstitution to ensure it reaches the proper concentration/dose.

Use a 0.22 micron in-line filter to infuse for more than 1 hour. Do not use polyurethane-containing infusion sets for administration. Allow to reach room temperature before infusion. Premedicate with antihistamines, corticosteroids, and H2 antagonists at least 30 minutes before infusion. Observe closely during infusion (for allergies).

Recommended dosage:

Metastatic prostate cancer: IV: 20 mg/m2 every 3 weeks (in combination with prednisone); 25 mg/m2 every 3 weeks (in combination with prednisone). Both regimens may be used at the prescriber's discretion.

Dose adjustment of medications:

Strong CYP3A inhibitors: Concomitant use with strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, protease inhibitors, nefazodone, telithromycin, voriconazole) may increase cabazitaxel plasma concentrations; avoid concurrent use. If use of this drug cannot be avoided, consider a 25% reduction in cabazitaxel dose.

Kidney impairment: CrCl ≥ 15mL/minute: No dosage adjustment is required. CrCl <15 mL/minute and end-stage renal disease: Use with caution; monitor closely.

Hepatic Impairment: Mild Impairment (total bilirubin >1 to ≤1.5 times ULN or AST ≥1.5 times ULN): Administer 20 mg/m2; use with caution and monitor closely. Moderate impairment (total bilirubin >1.5 to ≤3 times ULN and any AST): Reduce dose to 15 mg/m2 (based on tolerability; efficacy of this dose is unknown); use with caution and close monitoring. Severe impairment (total bilirubin exceeds 3 times ULN): Contraindicated.

Obesity: ASCO (American Society of Clinical Oncology) gives appropriate medication guidelines for the dosing of chemotherapy in obese adults with cancer: Use the patient's actual body weight (whole weight) to calculate body surface area or body weight as a basis for determining dosage, especially when the intent of treatment is curative; Manage associated toxicities in the same manner and regimen as in non-obese patients; If the dose is reduced due to toxicity, consider resuming full weight-based dosing in subsequent cycles, especially if the issues causing the toxicity (e.g., hepatic or renal impairment) are resolved.

Adjustment for Toxicity:

Note: If receiving cabazitaxel 20 mg/m2 and a dose reduction is necessary, reduce the dose to 15 mg/m2. If cabazitaxel 25 mg/m2 is received, the dose should be reduced to 20 mg/m2; additional dose reductions to 15 mg/m2 may be considered.

Hematological toxicity: Neutropenia ≥ grade 3 >1 week despite WBC growth factors. Delay treatment until ANC >1,500/mm3, then reduce dose by one dose level and continue WBC growth factor secondary prevention. Neutropenic fever or neutropenic infection occurs: Delay treatment until improvement/resolution and ANC >1,500/mm3, then reduce dose by one dose level and continue WBC growth factor secondary prophylaxis.

Persistent hematologic toxicity (despite dose reduction): Discontinue treatment.

Severe hypersensitivity reaction: Discontinue medication immediately. Diarrhea ≥Grade 3 or persistent diarrhea despite appropriate medications, fluids, and electrolyte replacements: Delay treatment until improvement or resolution, then reduce dose by one dose level.

Persistent diarrhea (despite dose reduction): Discontinue treatment.

Peripheral Neuropathy (Grade 2): Delay treatment until improvement or resolution, then reduce dose by one dose level.

Peripheral neuropathy ≥ Grade 3: Stop treatment.

Pulmonary symptoms (new or worsening): Interrupt cabazitaxel treatment, monitor closely and promptly investigate and manage symptoms. Treatment may need to be discontinued (with careful evaluation of the potential benefits of resuming treatment).

Specification:

60mg/1.5 mL

Adverse reactions:

Adverse reactions reported in combination with prednisone

>10% of reactions:

Gastrointestinal Tract: Diarrhea (31% to 47%), nausea (25% to 34%), vomiting (15% to 22%), constipation (18% to 20%), decreased appetite (13% to 19%), abdominal pain (6% to 17%) , anorexia (16%)

Genitourinary system: hematuria (14% to 21%), urinary tract infection (7% to 11%)

Hematology and oncology: anemia (98% to 100%; Grade 3/4: 10% to 14%)

Leukopenia: (80% to 96%; Grade 3/4: 29% to 69%)

Neutropenia (3% to 94%; Grade 3/4: 2% to 87%)

Thrombocytopenia: (35% to 48%; 3/4: 3% to 4%)

Neuromuscular and skeletal: weakness (15% to 20%), back pain (11% to 16%), joint pain (7% to 11%)

Respiratory: dyspnea (5% to 12%), cough (6% to 11%)

Others: Fever (5% to 12%)

Adverse reactions 1% to 10%:

Cardiovascular: peripheral edema (7% to 9%), arrhythmia (5%), hypotension (5% )

Central nervous system: dizziness (4% to 8%), headache (4% to 8%), pain (5%)

Dermatology: alopecia (3% to 10%)

Endocrinology and metabolism: weight loss (4% to 9%) ), dehydration (5%) gastrointestinal dyspepsia (10%), mucosal inflammation (6%), stomatitis (5%) Genitourinary system: frequent urination (4% to 7%)

Hematology and oncology: febrile neutropenia (2% to 9%; Grade 3/4: 2% to 9%), neutropenic infection (3% to 7%; Grade 3/4: 2% to 6%)

Liver: elevated serum ALT, elevated serum AST, elevated serum bilirubin Infection: Infection (28% to 38%)

Neuromuscular and skeletal: bone pain (8%), muscle spasm (7%), limb pain (5% to 7%)

Kidney: renal failure (4%)

Electrolyte disorders <1%: adult respiratory distress syndrome, enterocolitis, gastritis, gastrointestinal bleeding, gastrointestinal perforation, hypersensitivity reactions (including bronchospasm, erythema, hypotension, rash), interstitial pneumonia, interstitial lung disease, intestinal obstruction, neutropenic enterocolitis, sepsis, septic shock.

Contraindications:

Severe hypersensitivity reaction to cabazitaxel or any component of this formulation or to other drugs formulated with polysorbate 80;

Neutrophil count ≤1,500/mm3;

Severe liver damage (total bilirubin >3 times ULN);

Pregnancy;

Vaccine concurrently with yellow fever vaccine.

Notes:

Myelosuppression [US Label Warning]: Blood counts should be monitored frequently due to reports of death due to neutropenia. Cabazitaxel is contraindicated in patients with neutrophil counts ≤1,500/mm3. For patients with high-risk clinical features, fildagliptin is recommended for primary prophylaxis. Neutropenia, anemia, thrombocytopenia, and/or pancytopenia may occur; grade 3 and 4 neutropenia are present in more than 80% of patients treated with cabazitaxel in thyroid cancer. Deaths due to neutropenia, neutropenic fever, or infection have been reported in clinical trials, and some deaths have occurred within the first 30 days of treatment; the incidence of fatal neutropenic events was lower at the 20 mg/m2 dose. Optional treatment delays and dose reductions are recommended after the development of neutropenic fever or prolonged neutropenia. (WBC) Administration of white blood cell growth factors can reduce the risk of complications due to neutropenia. Although the effectiveness of primary prophylaxis with WBC growth factors has not been studied, their use is recommended in high-risk patients (e.g., older age, poor performance, history of neutropenic fever, radiation, poor nutritional status, other severe comorbidities); secondary prophylaxis and therapeutic WBC growth factors should be considered in all patients at increased risk for neutropenic complications.

Gastrointestinal Toxicity: Nausea, vomiting, and diarrhea may occur. Diarrhea can be severe and may lead to dehydration and electrolyte imbalance; fatalities have been reported. According to the manufacturer, antiemetic prophylaxis is recommended. Antidiarrheal medications and fluid and electrolyte replacements may be necessary. Diarrhea grade ≥3 may require delay in treatment and/or dose reduction. Gastrointestinal bleeding and perforation, enterocolitis, neutropenic enterocolitis, and intestinal obstruction (some fatal) have also been observed. Use with caution in patients at risk for gastrointestinal complications (e.g., elderly patients, patients with neutropenia, or patients with a history of pelvic radiation, adhesions, gastrointestinal ulceration, or bleeding, concomitant use of steroids, NSAIDs, antiplatelet drugs, or anticoagulants). If symptoms such as abdominal pain, tenderness, fever, persistent constipation, diarrhea (with or without neutropenia) occur, immediate evaluation should be performed. Treatment interruption and/or discontinuation may be necessary.

Hypersensitivity Reactions: [US Black Box Warning]: Serious hypersensitivity reactions, including generalized rash, erythema, hypotension, and bronchospasm, may occur. If the allergy is severe, the drug needs to be discontinued immediately; administer appropriate supportive medications.

Use intravenous antihistamines, corticosteroids, and H2 antagonists prior to infusion. It is contraindicated in patients with a history of severe hypersensitivity to cabazitaxel or other drugs formulated with polysorbate 80. Observe closely during the infusion, especially during the first and second infusion. The reaction may occur within minutes. Do not attempt use again after a severe hypersensitivity reaction.

Pulmonary Toxicity: Interstitial pneumonia/pneumonitis, interstitial lung disease, and acute respiratory distress syndrome have been observed; these may be fatal. People with underlying lung disease may be at higher risk. Acute respiratory distress syndrome may occur in the setting of infection. If new or worsening pulmonary symptoms develop, cabazitaxel therapy should be discontinued immediately and symptoms should be promptly investigated and managed with close monitoring. Medication may need to be discontinued (a decision made after careful evaluation of its potential benefit in resuming treatment).

Kidney failure: Clinical trials reported kidney failure (including rare death) generally associated with dehydration, sepsis, or obstructive urinary tract disease. Use with caution in patients with severely impaired renal function (CrCl<30mL/min) and patients with end-stage renal disease.

Liver damage: It is contraindicated in patients with severe liver damage (total bilirubin > 3 times ULN). Use with caution and close monitoring in patients with mild impairment (total bilirubin >1 to ≤1.5 times ULN or AST >1.5 times ULN) and moderate impairment (total bilirubin >1.5 to ≤3 times ULN and any AST); reduce initial dose in patients with moderate impairment. Due to extensive hepatic metabolism, cabazitaxel concentrations may be increased in patients with hepatic impairment.

Storage:

Keep at low temperature and away from light.

Mechanism of action:

The anti-cancer mechanism and characteristics of Cabazitaxel are similar to those of docetaxel, and it is an anti-microtubule drug. Cabazitaxel binds to tubulin and promotes its assembly into microtubules. At the same time, it prevents the disassembly of these assembled microtubules and stabilizes the microtubules, thereby inhibiting cell mitosis and interphase cell functions.

Safety and efficacy:

The FDA approved cabazitaxel based on the large phase III clinical trial data conducted by TROPIC. It is the first chemotherapy drug proven to prolong the survival of patients with CRPC (castrate-resistant prostate cancer) after docetaxel failure. Therefore, cabazitaxel is used as a second-line treatment drug for CRPC, which is an epoch-making milestone.

In the CARD study, cabazitaxel (cabazitaxel) significantly prolonged progression-free survival compared with abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with doxycycline and an androgen-targeted inhibitor.

The median time to worsening of the FACT-P total score was 14.8 months in the cabazitaxel group (95% confidence interval 6.3–NE) compared with 8.9 months in the abiraterone/enzalutamide group (HR 0.72, 95% CI 0.44-1.20, p=0.21). Judging from the change in the EQ-5D-5L utility index score at the baseline examination, cabazitaxel had a significant effect on the treatment compared with the abiraterone/enzalutamide group (p=0.030), but in the EQ-5D-5L visual analog scale, there was no difference in the change between the treatment group and the baseline examination (p=0.060).