Cabazitaxel

FDA Drug Information • Also known as: Jevtana

Brand Names: Jevtana
Dosage Form: POWDER, FOR SUSPENSION
Product Type: BULK INGREDIENT

⚠ Boxed Warning (Black Box)

WARNING: NEUTROPENIA AND HYPERSENSITIVITY WARNING: NEUTROPENIA AND HYPERSENSITIVITY See full prescribing information for complete boxed warning. Neutropenic deaths have been reported. Obtain frequent blood counts to monitor for neutropenia. JEVTANA is contraindicated in patients with neutrophil counts of ≤1,500 cells/mm 3 . Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features. Consider primary prophylaxis with G-CSF in all patients receiving a dose of 25 mg/m 2 ( 4 , 5.1 , 5.2 ) Severe hypersensitivity can occur and may include generalized rash/erythema, hypotension and bronchospasm. Discontinue JEVTANA immediately if severe reactions occur and administer appropriate therapy. ( 2.1 , 5.2 ) Contraindicated if history of severe hypersensitivity reactions to cabazitaxel or to drugs formulated with polysorbate 80. ( 4 ) Neutropenia : Neutropenic deaths have been reported. Monitor for neutropenia with frequent blood cell counts. JEVTANA is contraindicated in patients with neutrophil counts of ≤1,500 cells/mm 3 . Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features. Consider primary prophylaxis with G-CSF in all patients receiving a dose of 25 mg/m 2 [see Contraindications (4) and Warnings and Precautions (5.1 , 5.2) ] . Severe hypersensitivity : Severe hypersensitivity reactions can occur and may include generalized rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of the JEVTANA infusion and administration of appropriate therapy. Patients should receive premedication. JEVTANA is contraindicated in patients who have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 [see Dosage and Administration (2.1) , Contraindications (4) , and Warnings and Precautions (5.3) ] .

Description

11 DESCRIPTION JEVTANA (cabazitaxel) injection is an antineoplastic agent belonging to the taxane class that is for intravenous use. It is prepared by semi-synthesis with a precursor extracted from yew needles. The chemical name of cabazitaxel is (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3-[(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate – propan-2-one (1:1). Cabazitaxel has the following structural formula: Cabazitaxel is a white to almost-white powder with a molecular formula of C 45 H 57 NO 14 C 3 H 6 O and a molecular weight of 894.01 (for the acetone solvate) / 835.93 (for the solvent free). It is lipophilic, practically insoluble in water and soluble in alcohol. JEVTANA (cabazitaxel) injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution and is available in single-dose vials containing 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 g polysorbate 80 (citric acid monohydrate is used to adjust the pH of the polysorbate 80 between 3.3 to 3.8). Each mL contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80. DILUENT for JEVTANA is a clear, colorless, sterile, and non-pyrogenic solution containing 13% (w/w) ethanol in water for injection, approximately 5.7 mL. JEVTANA requires two dilutions prior to intravenous infusion. JEVTANA injection should be diluted only with the supplied DILUENT for JEVTANA, followed by dilution in either 0.9% sodium chloride solution or 5% dextrose solution. Chemical Structure

What Is Cabazitaxel Used For?

1 INDICATIONS AND USAGE JEVTANA ® is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. JEVTANA is a microtubule inhibitor indicated in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Recommended Dose: JEVTANA 20 mg/m 2 administered every three weeks as a one-hour intravenous infusion in combination with oral prednisone 10 mg administered daily throughout JEVTANA treatment. ( 2.1 ) A dose of 25 mg/m 2 can be used in select patients at the discretion of the treating healthcare provider. ( 2.1 , 5.1 , 5.2 , 6.1 , 14 ) JEVTANA requires two dilutions prior to administration. ( 2.5 ) Use the entire contents of the accompanying diluent to achieve a concentration of 10 mg/mL JEVTANA. ( 2.5 ) PVC equipment should not be used. ( 2.5 ) Premedication Regimen: Administer intravenously 30 minutes before each dose of JEVTANA: Antihistamine (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent antihistamine) Corticosteroid (dexamethasone 8 mg or equivalent steroid) H 2 antagonist ( 2.1 ) Antiemetic prophylaxis (oral or intravenous) is recommended as needed. ( 2.1 ) Dosage Modifications: See full prescribing information ( 2.2 , 2.3 , 2.4 ) 2.1 Dosing Information The recommended dose of JEVTANA is based on calculation of the Body Surface Area (BSA), and is 20 mg/m 2 administered as a one-hour intravenous infusion every three weeks in combination with oral prednisone 10 mg administered daily throughout JEVTANA treatment. A dose of 25 mg/m 2 can be used in select patients at the discretion of the treating healthcare provider [see Warnings and Precautions (5.1 , 5.2) , Adverse Reactions (6.1) , and Clinical Studies (14) ] . Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features. Consider primary prophylaxis with G-CSF in all patients receiving a dose of 25 mg/m 2 [see Contraindications (4) and Warnings and Precautions (5.1 , 5.2) ] . Premedicate at least 30 minutes prior to each dose of JEVTANA with the following intravenous medications to reduce the risk and/or severity of hypersensitivity [see Warnings and Precautions (5.3) ] : antihistamine (dexchlorpheniramine 5 mg, or diphenhydramine 25 mg or equivalent antihistamine), corticosteroid (dexamethasone 8 mg or equivalent steroid), H 2 antagonist. Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed [see Warnings and Precautions (5.3) ] . JEVTANA injection single-dose vial requires two dilutions prior to administration [see Dosage and Administration (2.5) ] . 2.2 Dose Modifications for Adverse Reactions Reduce or discontinue JEVTANA dosing for adverse reactions as described in Table 1. Table 1: Recommended Dosage Modifications for Adverse Reactions in Patients Treated with JEVTANA Toxicity Dosage Modification Prolonged grade ≥3 neutropenia (greater than 1 week) despite appropriate medication including granulocyte-colony stimulating factor (G-CSF) Delay treatment until neutrophil count is >1,500 cells/mm 3 , then reduce dosage of JEVTANA by one dose level. Use G-CSF for secondary prophylaxis. Febrile neutropenia or neutropenic infection Delay treatment until improvement or resolution,...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: Bone Marrow Suppression [see Warnings and Precautions (5.1) ] Increased Toxicities in Elderly Patients [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.4) ] Renal Failure [see Warnings and Precautions (5.5) ] Urinary Disorders Including Cystitis [see Warnings and Precautions (5.6) ] Respiratory Disorders [see Warnings and Precautions (5.7) ] Use in Patients with Hepatic Impairment [see Warnings and Precautions (5.8) ] Most common all grades adverse reactions and laboratory abnormalities (≥10%) with JEVTANA 20 mg/m 2 or 25 mg/m 2 are neutropenia, anemia, diarrhea, nausea, fatigue, asthenia, vomiting, hematuria, constipation, decreased appetite, back pain, and abdominal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. TROPIC Trial (JEVTANA 25 mg/m 2 compared to mitoxantrone) The safety of JEVTANA in combination with prednisone was evaluated in 371 patients with metastatic castration-resistant prostate cancer treated in the randomized TROPIC trial, compared to mitoxantrone plus prednisone. Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (5%) JEVTANA-treated patients and 3 (<1%) mitoxantrone-treated patients. The most common fatal adverse reactions in JEVTANA-treated patients were infections (n=5) and renal failure (n=4). The majority (4 of 5 patients) of fatal infection-related adverse reactions occurred after a single dose of JEVTANA. Other fatal adverse reactions in JEVTANA-treated patients included ventricular fibrillation, cerebral hemorrhage, and dyspnea. The most common (≥10%) grade 1–4 adverse reactions were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, and alopecia. The most common (≥5%) grade 3–4 adverse reactions in patients who received JEVTANA were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia. Treatment discontinuations due to adverse reactions occurred in 18% of patients who received JEVTANA and 8% of patients who received mitoxantrone. The most common adverse reactions leading to treatment discontinuation in the JEVTANA group were neutropenia and renal failure. Dose reductions were reported in 12% of JEVTANA-treated patients and 4% of mitoxantrone-treated patients. Dose delays were reported in 28% of JEVTANA-treated patients and 15% of mitoxantrone-treated patients. Table 2: Adverse Reactions Graded using NCI CTCAE version 3. and Hematologic Abnormalities in ≥5% of Patients in TROPIC Adverse Reactions JEVTANA 25 mg/m 2 every 3 weeks with prednisone 10 mg daily n=371 Mitoxantrone 12 mg/m 2 every 3 weeks with prednisone 10 mg daily n=371 Grade 1–4 % Grade 3–4 % Grade 1–4 % Grade 3–4 % Blood and Lymphatic System Disorders Anemia Based on laboratory values, JEVTANA: n=369, mitoxantrone: n=370. 98 11 82 5 Leukopenia 96 69 93 42 Neutropenia 94 82 87 58 Thrombocytopenia 48 4 43 2 Febrile Neutropenia 7 7 1 1 Gastrointestinal Disorders Diarrhea 47 6 11 <1 Nausea 34 2 23 <1 Vomiting 22 2 10 0 Constipation 20 1 15 <1 Abdominal Pain Includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and GI pain. 17 2 6 0 Dyspepsia Includes gastroesophageal reflux disease and reflux gastritis. 10 0 2 0 General Disorders and...

Drug Interactions

7 DRUG INTERACTIONS Avoid coadministration of JEVTANA with strong CYP3A inhibitors. If patients require coadministration of a strong CYP3A inhibitor, consider a 25% JEVTANA dose reduction. ( 2.4 , 7.1 , 12.3 ) 7.1 CYP3A Inhibitors Cabazitaxel is primarily metabolized through CYP3A [see Clinical Pharmacology (12.3) ] . Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations of cabazitaxel. Avoid the coadministration of JEVTANA with strong CYP3A inhibitors. If patients require coadministration of a strong CYP3A inhibitor, consider a 25% JEVTANA dose reduction [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ].

Contraindications

4 CONTRAINDICATIONS JEVTANA is contraindicated in patients with: neutrophil counts of ≤1,500/mm 3 [see Warnings and Precautions (5.1) ] history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 [see Warnings and Precautions (5.3) ] severe hepatic impairment (total bilirubin >3 × ULN) [see Warnings and Precautions (5.8) ] Neutrophil counts of ≤1,500/mm 3 ( 2.2 , 4 ) History of severe hypersensitivity to JEVTANA or polysorbate 80 ( 4 ) Severe hepatic impairment (Total Bilirubin >3 × ULN) ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary The safety and efficacy of JEVTANA have not been established in females. There are no human data on the use of JEVTANA in pregnant women to inform the drug-associated risk. In animal reproduction studies, intravenous administration of cabazitaxel in pregnant rats during organogenesis caused embryonic and fetal death at doses lower than the maximum recommended human dose [see Data ] . Data Animal data In an early embryonic developmental toxicity study in rats, cabazitaxel was administered intravenously for 15 days prior to mating through day 6 of pregnancy, which resulted in an increase in pre-implantation loss at 0.2 mg/kg/day and an increase in early resorptions at ≥0.1 mg/kg/day (approximately 0.06 and 0.02 times the C max in patients at the recommended human dose, respectively). In an embryo-fetal developmental toxicity study in rats, cabazitaxel caused maternal and embryo-fetal toxicity consisting of increased postimplantation loss, embryolethality, and fetal deaths when administered intravenously at a dose of 0.16 mg/kg/day (approximately 0.06 times the C max in patients at the recommended human dose). Decreased mean fetal birthweight associated with delays in skeletal ossification was observed at doses ≥0.08 mg/kg. Cabazitaxel crossed the placenta barrier within 24 hours of a single intravenous administration of 0.08 mg/kg to pregnant rats at gestational day 17. A dose of 0.08 mg/kg in rats resulted in a C max approximately 0.02 times that observed in patients at the recommended human dose. Administration of cabazitaxel did not result in fetal abnormalities in rats or rabbits at exposure levels significantly lower than the expected human exposures.

Overdosage

10 OVERDOSAGE There is no known antidote for JEVTANA overdose. Overdose has resulted from improper preparation [see Dosage and Administration (2.5) ] . Read the entire section Dosage and Administration (2) carefully before mixing or diluting. Complications of overdose include exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders. Overdose has led to fatal outcome. In case of overdose, the patient should be kept in a specialized unit where vital signs, chemistry and particular functions can be closely monitored. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied JEVTANA is supplied as a kit, NDC 0024-5824-11, that contains the following: One single-dose vial of JEVTANA (cabazitaxel) injection: a clear yellow to brownish-yellow viscous solution of 60 mg/1.5 mL in a clear glass vial with a grey rubber closure, aluminum cap, and light green plastic flip-off cap (JEVTANA vial NDC 0024-5823-15). One single-dose vial of Diluent for JEVTANA: a clear colorless solution of 13% (w/w) ethanol in water for injection in a clear glass vial with a grey rubber closure, gold-color aluminum cap, and colorless plastic flip-off cap (diluent vial NDC 0024-5822-01). 16.2 Storage JEVTANA injection and Diluent for JEVTANA: Store at 25°C (77°F); excursions permitted between 15°C–30°C (59°F–86°F). Do not refrigerate. 16.3 Handling and Disposal JEVTANA is a hazardous anticancer drug. Follow applicable special handling and disposable procedures [see References (15) ].

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.