Cabazitaxel - Uses, Mechanism of Action, Precautions, and Side Effects

Overview

Cabazitaxel is an antineoplastic (kills or slows down cancer) agent. It is applied in chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). This form of cancer is resistant to medical and surgical therapies aimed at reducing testosterone levels. Cabazitaxel treatment for prostate cancer is prescribed when previous therapies, including Docetaxel, do not produce favorable results. This medication inhibits the proliferation of cancer cells, ultimately leading to their death, while supporting the growth of normal cells. The drug received approval from the US FDA (United States Food and Drug Administration) on June 17, 2010, for treatment in patients with mCRPC.

Drug Group

Cabazitaxel belongs to the drug group known as antineoplastic agents or chemotherapeutic agents. Specifically, it is classified as a taxane derivative, a type of microtubule inhibitor.

Indications

Injection with Cabazitaxel along with Prednisone is prescribed in metastatic castration-resistant prostate cancer; metastatic indicates it is the kind of prostate cancer that has spread into other parts of the body. Moreover, such cancers keep progressing despite therapies, lowering the level of testosterone.

Dosage Forms and Available Strengths

Cabazitaxel Injection is available as a concentrated solution in the following strengths:

• 20 mg (milligrams) per 1 mL (milliliter) (single-dose vial).

• 60 mg/1.5 mL (single-dose vial).

Each vial requires dilution before administration.

For Patients

How Does Cabazitaxel Work in Metastatic Castration-Resistant Prostate Cancer?

Cabazitaxel works by binding to tubulin, a crucial protein involved in cell division. Microtubules cannot adequately break down when tubulin is blocked. This disrupts the division process of cancer cells. They are unable to proceed because they become trapped in the division stage. They eventually pass away. Cabazitaxel impacts both healthy and malignant cells. But it more successfully targets proliferating cancer cells. That is why doctors use it for metastatic castration-resistant prostate cancer, the aggressive kind that keeps spreading.

What Are the Clinical Uses of Cabazitaxel?

• Cabazitaxel primarily treats metastatic castration-resistant prostate cancer (mCRPC) in men who have already received treatment with Docetaxel.

• It is usually given along with Prednisone.

• It works for patients whose cancer kept progressing after previous treatments, including hormone therapy.

• It is mainly used for prostate cancer, though researchers are testing it for other cancers too.

What Is the Dosage of Cabazitaxel?

Recommended Dose:

• Standard: 20 mg/m² (milligrams per square meter) administered intravenously by one-hour infusion every three weeks. Oral Prednisone 10 mg daily.

• Alternative: For some patients, a dose of 25 mg/m² can be administered at the discretion of the healthcare provider.

How Is Cabazitaxel Administered?

• Premedication: Administer antihistamines, corticosteroids, and H2 antagonists at least 30 minutes prior to Cabazitaxel administration to prevent allergic reactions. Antiemetic medication may also be given if needed.

• Preparation: Dilute Cabazitaxel into a non-PVC (polyvinyl chloride) container with 0.9% sodium chloride or 5% dextrose injection under aseptic conditions. The final concentration should be 0.10 to 0.26 mg/mL (milligrams per milliliter). Do not mix with other drugs. Use the prepared solution at room temperature within eight hours or 72 hours if refrigerated.

• Administration: The solution is administered through an IV over a period of one hour at room temperature. A non-PVC filter (0.22 micrometers) must be used during infusion. Check that the solution is clear before use. If crystals or particles appear, throw them away.

• Dose Adjustments: Delay or adjust the dose if side effects like neutropenia (low levels of neutrophils), diarrhea, or neuropathy occur. For patients with liver problems, adjust the dose based on the severity of the impairment. Avoid strong CYP3A inhibitors. If unavoidable, reduce the Cabazitaxel dose by 25 %.

• Disposal: Handle as a hazardous drug; follow proper safety protocols. Discard any unused portions appropriately.

What Are the Side Effects of Cabazitaxel?

Common Side Effects:

• Low blood counts (leading to anemia, neutropenia, and thrombocytopenia).

• Diarrhea.

• Fatigue.

• Nausea and vomiting.

• Constipation.

• Weakness.

• Abdominal pain.

• Blood in urine.

• Loss of appetite.

• Back pain.

• Nerve damage (peripheral neuropathy).

• Shortness of breath.

• Fever.

• Changes in taste.

• Joint aches.

• Cough.

• Hair loss (Cabazitaxel hair loss is a common side effect of the treatment).

• Heartburn.

Infusion-Related Side Effects:

• Allergic reactions may include rash, flushing, fever, and low blood pressure. These are rare and usually happen during the first or last infusion.

• Patients should be monitored continuously during infusion. If any signs of allergic reactions appear, stop the treatment immediately and continue to observe the patient.

Injection Site Effects:

• Darkening of the vein.

• Redness, swelling, or soreness near the injection site.

What Are the Things to Inform the Doctor Before Taking Cabazitaxel?

• Before receiving a Cabazitaxel injection, inform your doctor and pharmacist if you are allergic to Cabazitaxel, any other medications, polysorbate 80, or any of the injection's ingredients.

• Inform the doctor and pharmacist of any prescription or non-prescription medications, vitamins, and supplements you plan to take. Your doctor may need to adjust the dosage of the drugs or monitor you for side effects.

• Some over-the-counter or herbal products can interact with Cabazitaxel. These include Aspirin, NSAIDs like Ibuprofen and Naproxen, and St. John's wort. Inform the doctor and pharmacist about all medications you are taking before starting treatment. Do not start any new medications or supplements without asking a healthcare provider first.

• Notify your doctor if you have or have had liver disease, kidney disease, anemia, bleeding ulcers, or lung problems. Also, inform your doctor if you have received pelvic radiation therapy, as this may affect your treatment.

• Cabazitaxel injection is for use in men only. If your female partner could become pregnant, both of you must use birth control during treatment and for four months after your final dose. If your partner becomes pregnant during treatment, contact your doctor, as Cabazitaxel may harm the fetus.

• Cabazitaxel injections may reduce fertility in men.

• If you have surgery, including dental procedures, inform the doctor or dentist that you are receiving a Cabazitaxel injection.

Dietary Considerations

Consult your doctor before consuming grapefruit or drinking grapefruit juice while taking this medication.

Missed Dose

In the event of a missed dose, contact your healthcare provider.

Overdose

• There is no antidote for Cabazitaxel overdose. Overdoses can happen if the drug is not prepared correctly.

• An overdose can make side effects worse, especially bone marrow suppression and stomach problems. It can be fatal.

• If an overdose occurs, the patient needs to be in a specialized unit. Doctors should closely monitor vital signs, blood chemistry, and organ functions.

• Doctors should administer G-CSF (granulocyte colony-stimulating factor) immediately. Other supportive treatments may be needed depending on the situation.

Storage and Handling

Store at 20 to 25°C (68 to 77°F); temperature excursions are allowed between 15°C and 30°C (59°F to 86°F).

Disposal

Cabazitaxel injection is a dangerous cancer medicine. It should be handled and disposed of carefully by following FDA safety procedures to prevent harm.

For Doctors

Chemical Taxonomy

Cabazitaxel is an antineoplastic agent from the taxane class, derived semi-synthetically from yew needles. It is available as a sterile, preservative-free, light-yellow solution for intravenous use, containing 10 mg/mL of Cabazitaxel (non-solvate), citric acid, ethanol, polysorbate 80, and polyethylene glycol 400. Cabazitaxel 2-propanol solvate is a lipophilic, off-white powder, insoluble in water and soluble in alcohol, with a molecular weight of 896.03 for the solvate.

What Are the Pharmacological Actions of Cabazitaxel?

Mechanism of Action

Cabazitaxel is a microtubule inhibitor that binds to tubulin, promoting its assembly into microtubules while inhibiting the disassembly of these structures. This stabilization of microtubules disrupts mitotic and interphase cellular functions.

Pharmacodynamics

Cardiac electrophysiology: A study of 94 participants found no significant alterations in the QTc interval following a 25 mg/m² intravenous dosage. Due to study design limitations, a slight increase in QTc (less than 10 ms) could not be ruled out.

Pharmacokinetics

• Absorption: After a 25 mg/m² intravenous dose, the peak plasma concentration (Cmax) is 226 ng/mL, reached at the end of the one-hour infusion.

• Distribution: The volume of distribution (Vss) is 4,864 L. Cabazitaxel binds 89 to 92 percent to human serum proteins, primarily human serum albumin, and lipoproteins.

• Metabolism: Cabazitaxel is primarily metabolized in the liver by CYP3A4/5, with little participation from CYP2C8. It is the main circulating form in plasma, and several metabolites have been detected.

• Elimination: About 80 percent of the dose is eliminated within 2 weeks, mainly through feces. The renal excretion of unchanged drugs is minimal (2.3 percent).

• Plasma clearance: The plasma clearance is 48.5 L/h in metastatic prostate cancer patients, with a half-life of four minutes (α), 2 hours (β), and 95 hours (γ).

• Hepatic impairment: Pharmacokinetics do not change considerably with mild to moderate hepatic impairment. Severe hepatic impairment may decrease clearance by 39 percent, requiring a dose reduction (15 mg/m²). Cabazitaxel is contraindicated in severe hepatic impairment.

• Renal impairment: Mild to moderate renal impairment has minimal impact on Cabazitaxel pharmacokinetics.

Drug Interactions

• CYP3A Inhibitors: Ketoconazole (a strong CYP3A inhibitor) increases Cabazitaxel exposure by 25 percent.

• CYP3A Inducers: Rifampin (a strong CYP3A inducer) decreases exposure by 17 percent.

• Other interactions: Prednisone or Prednisolone and Midazolam do not affect Cabazitaxel pharmacokinetics.

• Cabazitaxel is a substrate of P-gp but does not inhibit MRP1, MRP2, or OCT1 in vitro.

Non-clinical Toxicity

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed on the carcinogenic potential of Cabazitaxel. It was genotoxic in vivo and increased micronuclei in rats at doses of 0.5 mg/kg or higher. In vitro induced numerical aberrations in human lymphocytes, but was not mutagenic in the Ames test. All these effects are consistent with Cabazitaxel's mechanism of action as a tubulin depolymerization blocker. In fertility studies, Cabazitaxel did not impact mating behavior or the fertility of females and males in rats at doses of up to 0.2 mg/kg/day. However, uterine atrophy and necrosis of the corpora lutea were observed in females at higher doses, while testicular degeneration was reported in males at doses as low as 1 mg/kg.

Warnings and Precautions

• Bone marrow suppression: Cabazitaxel is not recommended for patients with neutrophil levels of less than 1,500/mm³. Patients with hemoglobin levels less than 10 g/dL (grams per deciliter) should be closely monitored. Bone marrow suppression, including neutropenia, anemia, thrombocytopenia, and pancytopenia, may occur, with some cases resulting in fatal neutropenia. In clinical trials, there were fatalities linked to neutropenic infection, especially in the first 30 days of treatment. Primary prophylaxis with G-CSF is recommended in patients with high-risk factors.

• Hypersensitivity reactions: Severe reactions, such as rash, hypotension, and bronchospasm, may occur. These require premedication and careful monitoring.

• Renal Failure: Renal failure, sometimes fatal, has occurred, often associated with sepsis or dehydration.

• Gastrointestinal adverse reactions: Severe nausea, vomiting, diarrhea, GI hemorrhage, and perforation have been reported. Electrolyte imbalances may occur, and supportive treatments may be needed.

• Urinary disorders: Cystitis and hematuria may occur in patients with prior pelvic radiation.

• Respiratory disorders: Serious respiratory issues, including pneumonia and acute respiratory distress syndrome, have been reported, with some fatal outcomes.

• Hepatic impairment: Cabazitaxel should not be administered to people with severe hepatic impairment. Dosage modifications are required for mild to moderate impairment.

• Elderly patients: Older patients are susceptible to adverse drug reactions, specifically neutropenia.

• Embryo-fetal toxicity: Cabazitaxel can cause fetal harm. It is contraindicated in pregnant women and should not be used during pregnancy. Contraception is recommended for men and women during treatment and for some time afterward.

What Are the Contraindications of Cabazitaxel?

Contraindications for Cabazitaxel Injection

• Low neutrophil counts: Cabazitaxel Injection is contraindicated in patients with neutrophil counts of ≤1,500/mm³ due to the risk of severe neutropenia.

• Severe hypersensitivity responses: Patients who have previously had severe hypersensitivity reactions to cabazitaxel or any other medicine containing polysorbate 80 should not be treated with it.

• Hepatic impairment: Cabazitaxel injection is contraindicated in patients with severe hepatic impairment, defined as total bilirubin greater than three times the upper limit of normal.

What Are the Drug Interactions of Cabazitaxel?

• CYP3A mainly metabolizes Cabazitaxel. Strong CYP3A (cytochrome P450 3A) inhibitors, such as Ketoconazole, Itraconazole, Clarithromycin, Atazanavir, Indinavir, Nefazodone, Nelfinavir, Ritonavir, Saquinavir, Telithromycin, and Voriconazole, may increase Cabazitaxel plasma levels.

• It is recommended to avoid coadministering Cabazitaxel Injection with strong CYP3A inhibitors. If coadministration is necessary, a 25 percent dose reduction of Cabazitaxel injection should be considered.

Clinical Studies

PROSELICA Trial

The PROSELICA trial compared two doses of Cabazitaxel (20 mg/m2 vs. 25 mg/m2) in 1200 patients with metastatic castration-resistant prostate cancer. The study found no significant differences in overall survival between the two doses, with median survival times of 13.4 months for 20 mg/m² and 14.5 months for 25 mg/m² (hazard ratio, 1.024; p = 0.69).

CARD Trial

The CARD trial compared Cabazitaxel and Prednisone/Prednisolone with Abiraterone or Enzalutamide in individuals who had progressed after Docetaxel and one of the latter therapies. Cabazitaxel demonstrated superior efficacy, with a median radiographic progression-free survival (rPFS) of 8.0 months compared to 3.7 months for Abiraterone/Enzalutamide (hazard ratio, 0.54; p < 0.0001). Overall survival was also longer for Cabazitaxel (13.6 months vs. 11.0 months, hazard ratio 0.64, p = 0.0078). Cabazitaxel had a higher tumor response rate (36.5% vs. 11.5%, p = 0.004).

Use in Specific Populations

• Pregnancy: Cabazitaxel has not been studied in pregnant women, and animal studies show it can cause embryo-fetal death. It crosses the placenta and may harm a developing fetus.

• Lactation: There is no data on Cabazitaxel in human milk; however, animal studies indicate that it can be excreted in milk and may cause harm to nursing pups.

• Females and Males of Reproductive Potential: Male patients should use efficient contraception during the treatment and for 4 months after. Cabazitaxel may affect male fertility.

• Pediatric Use: The safety and effectiveness of this use in pediatric patients have not been established. Some pediatric patients have experienced adverse reactions, including febrile neutropenia and infusion-related reactions.

• Geriatric Use: Older patients may be more susceptible to side effects, including neutropenia, fatigue, and dehydration. However, there were no differences in effectiveness in older patients.

• Renal Impairment: No dose adjustment is required for mild renal impairment; however, patients with end-stage renal disease should be closely monitored.

• Hepatic Impairment: For mild liver impairment, the dose should be reduced. Cabazitaxel is contraindicated in severe liver impairment.