Jevtana

Generic Name: Cabazitaxel
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: (2α,5β,7β,10β,13α) - 4 - acetoxy - 13 - ({(2R,3S) - 3 - [(terbutoxycarbonyl) - 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)
Molecular Formula: C45H57NO14
CAS Number: 183133-96-2

Warning(s)

  • Fatal Neutropenia
  • Risk of neutropenia-related death.1 Do not administer to patients with neutrophil counts ≤1500/mm3.1 Obtain frequent blood cell counts to monitor for neutropenia.1 (See Neutropenia under Cautions.)

  • Severe Hypersensitivity Reactions
  • Severe hypersensitivity reactions (hypotension, bronchospasm, generalized rash/erythema) reported;1 if severe hypersensitivity reaction occurs, immediately discontinue infusion and administer appropriate supportive treatment.1 (See Sensitivity Reactions under Cautions.)

  • Contraindicated in patients with a history of severe hypersensitivity reactions to cabazitaxel or to drugs containing polysorbate 80.1

Introduction

Semisynthetic taxoid; an antineoplastic agent.1 13

Uses for Jevtana

Prostate Cancer

Used in combination with prednisone for the treatment of hormone-refractory metastatic prostate cancer in patients whose disease has progressed following prior treatment with docetaxel-based therapy.1 2 3 4 Regimen improved overall survival compared with mitoxantrone and prednisone.1 2

Slideshow: Flashback: FDA Drug Approvals 2013

Jevtana Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Premedication

  • Administer an IV antihistamine (diphenhydramine hydrochloride 25 mg or equivalent), IV histamine H2-receptor antagonist (ranitidine 50 mg or equivalent [except cimetidine]), and IV corticosteroid (dexamethasone 8 mg or equivalent) at least 30 minutes prior to each cabazitaxel infusion to minimize risk and/or severity of hypersensitivity reactions.1 2 5

  • Antiemetic prophylaxis (orally or IV as needed) is recommended.1

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Handle cautiously; use protective equipment (e.g., gloves) to minimize risk of dermal exposure.1 Immediately treat accidental contact by thoroughly washing skin with soap and water and thoroughly flushing mucous membranes with water.1

Cabazitaxel injection concentrate must be diluted prior to IV infusion.1

Diluted cabazitaxel solutions are supersaturated and may crystallize over time.1 Administer infusion solution through a 0.22-μm in-line filter.1

Solution should be at room temperature for administration.1

Do not use PVC containers or polyurethane administration sets during preparation or administration.1 5 7 Cabazitaxel injection concentrate contains polysorbate 80, which can cause leaching of diethylhexyl phthalate (DEHP) from PVC containers.1 7

Dilution

Cabazitaxel injection concentrate requires 2 dilutions prior to administration.1

First dilution step: Transfer entire contents of the diluent vial (approximately 5.7 mL of 13% [w/w] ethanol in water for injection) to a vial containing cabazitaxel 60 mg in 1.5 mL to produce a solution containing 10 mg/mL.1 Direct diluent toward wall of vial and inject slowly to minimize foaming.1

Mix injection concentrate and diluent by repeated inversions for ≥45 seconds; do not shake.1 Let solution stand for a few minutes to allow any foam to dissipate; all foam does not have to dissipate to continue preparation.1 Use initial diluted solution within 30 minutes of preparation.1

Second dilution step: Withdraw the appropriate dose and inject into a 250-mL non-PVC infusion bag or bottle containing 0.9% sodium chloride or 5% dextrose injection to produce a final cabazitaxel concentration of 0.1–0.26 mg/mL.1 If the required dose exceeds 65 mg, increase the volume of IV solution accordingly so that the concentration does not exceed 0.26 mg/mL.1 Mix thoroughly by gently inverting the bag or bottle.1

Use the final diluted solution within 8 hours (including 1 hour for administration) if stored at room temperature or within 24 hours (including 1 hour for administration) if stored under refrigeration.1

Do not admix with other drugs.1

Discard any unused portions.1

Rate of Administration

Administer over 1 hour.1

Dosage

Adults

Prostate Cancer
IV

25 mg/m2 every 3 weeks in combination with oral prednisone (10 mg daily).1 2

In clinical trial, treatment duration was limited to 10 cycles.2 3 5

Dosage Modification for Toxicity
Dosage Modification for Severe Prolonged Neutropenia

Monitor CBC weekly during the first cycle of therapy and prior to each treatment cycle thereafter.1

If severe prolonged neutropenia (grade 3 or greater neutropenia lasting >1 week) occurs despite appropriate use of a granulocyte colony-stimulating factor (G-CSF) (e.g., filgrastim, pegfilgrastim), interrupt cabazitaxel therapy until the neutrophil count is >1500/mm3; upon resumption of therapy, reduce dosage to 20 mg/m2 every 3 weeks.1

Manufacturer recommends secondary prophylaxis with G-CSF in patients who have experienced severe prolonged neutropenia.1

Discontinue cabazitaxel if severe prolonged neutropenia recurs following dosage reduction to 20 mg/m2 every 3 weeks.1

Dosage Modification for Febrile Neutropenia

Monitor CBC weekly during the first cycle of therapy and prior to each treatment cycle thereafter.1

If febrile neutropenia occurs, interrupt cabazitaxel therapy until improvement or resolution occurs and neutrophil count is >1500/mm3; upon resumption of therapy, reduce dosage to 20 mg/m2 every 3 weeks.1

Manufacturer recommends secondary prophylaxis with G-CSF in patients who have experienced an episode of febrile neutropenia.1

Discontinue cabazitaxel if febrile neutropenia recurs following dosage reduction to 20 mg/m2 every 3 weeks.1

Dosage Modification for Diarrhea

If severe diarrhea (grade 3 or greater) or persistent diarrhea occurs despite appropriate medical therapy (e.g., antidiarrheals, fluid and electrolyte replacement), interrupt cabazitaxel therapy until the diarrhea improves or resolves; upon resumption of therapy, reduce dosage to 20 mg/m2 every 3 weeks.1

Discontinue cabazitaxel if severe or persistent diarrhea recurs following dosage reduction to 20 mg/m2 every 3 weeks.1

Prescribing Limits

Adults

Prostate Cancer
IV

No data available to support use beyond 10 cycles.5

Special Populations

Hepatic Impairment

Should not be used in patients with hepatic impairment (serum ALT and/or AST ≥1.5 times ULN or total serum bilirubin at or above ULN).1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations.1 (See Renal Impairment under Cautions.)

Cautions for Jevtana

Contraindications

  • Known severe hypersensitivity reaction to cabazitaxel or other formulations containing polysorbate 80.1

  • Baseline neutrophil count ≤1500/mm3.1

Warnings/Precautions

Warnings

Neutropenia

Risk of severe, sometimes fatal, neutropenia.1

Monitor CBCs weekly during the first treatment cycle and prior to each treatment cycle thereafter.1 Administer recommended dose for initial cycle; adjust dosage for each subsequent cycle as needed based on hematologic recovery.1 (See Dosage Modification for Toxicity under Dosage and Administration.) Do not administer cabazitaxel until neutrophil count is >1500/mm3.1

Consider primary prophylaxis with G-CSF in patients with high-risk clinical features that could potentially increase risk of complications associated with prolonged neutropenia (e.g., age >65 years, poor performance status, prior episodes of febrile neutropenia, extensive prior radiation, poor nutritional status, other serious comorbidities).1 3

Consider therapeutic use of G-CSF and secondary prophylaxis in all patients at increased risk for neutropenic complications.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

If severe prolonged neutropenia occurs despite appropriate treatment (e.g., G-CSF) or if febrile neutropenia occurs, temporary interruption of cabazitaxel therapy followed by dosage reduction or discontinuance of cabazitaxel therapy may be required.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Sensitivity Reactions

Risk of severe hypersensitivity reactions (e.g., hypotension, bronchospasm, generalized rash/erythema).1

Premedicate all patients prior to each infusion to reduce the risk and/or severity of hypersensitivity reactions.1 (See Premedication under Dosage and Administration.)

Closely observe patient for hypersensitivity reactions, especially during the first and second infusions.1 3 Have appropriate facilities and equipment for the treatment of hypotension and bronchospasm readily available, since hypersensitivity reactions may occur within minutes following initiation of an infusion.1

If severe hypersensitivity reaction occurs, discontinue infusion immediately and institute appropriate supportive treatment.1

Cabazitaxel injection concentrate contains polysorbate 80; do not administer to patients with a history of severe hypersensitivity reactions to cabazitaxel or to other agents containing polysorbate 80.1

Other Warnings and Precautions

GI Effects

Risk of nausea and vomiting.1 4 Manufacturer recommends antiemetic prophylaxis (orally or IV as needed).1

Risk of severe diarrhea.1 Death related to diarrhea, dehydration, and electrolyte imbalance reported.1 2

Administer rehydration therapy and antidiarrheal and antiemetic agents as needed; intensive measures may be required for management of severe diarrhea and electrolyte imbalance.1 In patients with severe or persistent diarrhea, temporary interruption of therapy followed by dosage reduction, or discontinuance of cabazitaxel therapy, may be required.1 (See Dosage Modification for Diarrhea under Dosage and Administration.)

Renal Effects

Renal failure reported,1 2 generally in association with sepsis, dehydration, or obstructive uropathy; some deaths due to renal failure did not have a clear etiology.1 If renal failure develops, take appropriate measures to identify the cause and treat aggressively.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryotoxic, fetotoxic, and abortifacient in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Adequate Patient Evaluation and Monitoring

Administer under the supervision of a qualified clinician experienced in the use of cytotoxic agents.1 Have appropriate diagnostic and treatment facilities readily available for management of treatment-related complications.1

Monitor CBCs weekly during first treatment cycle and prior to each treatment cycle thereafter.1

Patients must have recovered from acute toxicities (i.e., neutrophils recovered to >1500/mm3, improvement or resolution of febrile neutropenia or diarrhea) before each cycle.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Cabazitaxel or its metabolites are distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

No overall differences in efficacy or pharmacokinetics in individuals ≥65 years of age compared with younger adults.1 However, patients ≥65 years of age had higher incidence of neutropenia, fatigue, asthenia, pyrexia, dizziness, urinary tract infection, and dehydration; also had higher rate of death within 30 days of the last cabazitaxel dose from a cause other than disease progression.1

Hepatic Impairment

Safety and efficacy not established.1 However, cabazitaxel is extensively metabolized, and hepatic impairment is likely to increase serum concentrations of the drug.1

Hepatic impairment increases the risk of severe or life-threatening complications of other taxanes (e.g., docetaxel).1 14 Manufacturer states that cabazitaxel should not be used in patients with hepatic impairment (serum ALT and/or AST ≥1.5 times ULN or total serum bilirubin at or above ULN).1

Renal Impairment

Safety and efficacy not studied specifically to date.1

Mild to moderate renal impairment (Clcr 30 to <80 mL/minute) does not substantially alter clearance.1

Not studied in patients with severe renal impairment (Clcr <30 mL/minute) or end-stage renal disease;1 use with caution in these patients.1

Common Adverse Effects

Myelosuppression1 2 (neutropenia,1 2 leukopenia,1 2 anemia,1 2 thrombocytopenia1 2 ), diarrhea,1 2 fatigue,1 2 nausea,1 2 vomiting,1 2 constipation,1 2 asthenia,1 2 abdominal pain,1 2 anorexia,1 back pain,1 2 hematuria,1 2 peripheral neuropathy,1 2 pyrexia,1 2 dyspnea,1 2 cough,1 dysgeusia,1 arthralgia,1 2 alopecia.1

Interactions for Jevtana

No formal drug interaction studies to date.1

Metabolized principally by CYP3A4/5 and to a lesser extent by CYP2C8.1 4

Cabazitaxel does not induce CYP isoenzymes in vitro.1 In vitro data indicate low potential for inhibition of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5.1

Substrate of P-glycoprotein (P-gp), but not a substrate of multidrug resistance proteins MRP1 and MRP2 or breast cancer resistance protein (BCRP).1

Cabazitaxel 25 mg/m2 is unlikely to inhibit MRP1, MRP2, P-gp, or BCRP in vivo.1 Does not inhibit MRP1 or MRP2 in vitro; inhibition of P-gp transport and BCRP observed in vitro, but at concentrations at least 38 times those achieved clinically.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Potential pharmacokinetic interaction (increased plasma cabazitaxel concentrations).1 4 Avoid concomitant use.1

Moderate CYP3A inhibitors: Use concomitantly with caution.1

Potent CYP3A inducers: Potential pharmacokinetic interaction (decreased plasma cabazitaxel concentrations).1 4 Avoid concomitant use.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Unlikely to inhibit metabolism of drugs that are substrates of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5.1

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Probable decrease in plasma cabazitaxel concentrations1

Avoid concomitant use1

Antifungals (itraconazole, ketoconazole, voriconazole)

Probable increase in plasma cabazitaxel concentrations1

Avoid concomitant use1

Antimycobacterials (rifabutin, rifampin, rifapentine)

Probable decrease in plasma cabazitaxel concentrations1 4

Avoid concomitant use1

HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)

Probable increase in plasma cabazitaxel concentrations1 4

Avoid concomitant use1

Macrolides (clarithromycin, telithromycin)

Probable increase in plasma cabazitaxel concentrations1 4

Avoid concomitant use1

Nefazodone

Probable increase in plasma cabazitaxel concentrations1

Avoid concomitant use1

Prednisone, prednisolone

No effect on cabazitaxel pharmacokinetics at prednisone or prednisolone dosage of 10 mg daily1

St. John's wort (Hypericum perforatum)

Probable decrease in plasma cabazitaxel concentrations1

Avoid concomitant use1

Jevtana Pharmacokinetics

Distribution

Extent

Not known whether cabazitaxel is distributed into human milk.1 (See Lactation under Cautions.) Crosses placenta and distributes into milk in rats.1

Plasma Protein Binding

89–92% (mainly albumin and lipoproteins).1

Elimination

Metabolism

Extensively (>95%) metabolized in the liver, mainly by CYP3A4/5 and to a lesser extent by CYP2C8.1

Elimination Route

Eliminated in feces (76%) as metabolites and in urine (3.7%) as unchanged drug or metabolites; about 20 metabolites have been identified in urine or feces.1

Half-life

Terminal half-life: 95 hours.1

Special Populations

Hepatic impairment is expected to result in increased serum cabazitaxel concentrations.1 (See Hepatic Impairment under Cautions.)

Mild to moderate renal impairment (Clcr 30 to <80 mL/minute) does not substantially alter cabazitaxel pharmacokinetics.1 Not studied in severe renal impairment (Clcr <30 mL/minute) or end-stage renal disease.1

Stability

Storage

Parenteral

Injection Concentrate

25°C (may be exposed to 15–30°C); do not refrigerate.1

Diluted cabazitaxel solutions are supersaturated and may crystallize over time.1

Use initial diluted solution (10 mg/mL) within 30 minutes of preparation.1

Use final diluted solution (0.1–0.26 mg/mL) within 8 hours (including 1 hour for administration) if stored at room temperature or within 24 hours (including 1 hour for administration) if stored under refrigeration.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Dextrose 5% in water1

Sodium chloride 0.9%1

Actions

  • A semisynthetic taxoid derived from the major natural taxoid (10-deacetyl baccatin III) extracted from the needles of various species of yew trees (Taxus species).1 4 9 10 13 The 7,10-dimethoxy analog of docetaxel.5

  • Like other taxanes (e.g., docetaxel, paclitaxel), cabazitaxel binds to β-tubulin subunits on microtubules and stabilizes and suppresses microtubule activity, thereby resulting in mitotic arrest and cell death.1 3 4 9 10 11 12 13

  • Active against some cell lines and tumors that are resistant to various chemotherapeutic agents, including other taxanes (i.e., docetaxel, paclitaxel).1 2 3 9 10 11 13

Advice to Patients

  • Risk of hypersensitivity reactions.1 Importance of informing clinician immediately if manifestations of severe hypersensitivity (e.g., rash, itching, dizziness or faintness, difficulty breathing, chest or throat tightness, facial swelling) occur.1 Importance of informing clinician of any history of hypersensitivity to cabazitaxel or other agents containing polysorbate 80.1

  • Risk of infection, including severe or potentially fatal infection.1 Importance of patients monitoring their temperature frequently and immediately notifying clinician if fever or other manifestations of infection (e.g., cough, burning on urination, myalgia) occur.1

  • Risk of dehydration.1 Importance of informing clinician if substantial vomiting or diarrhea occurs.1

  • Risk of renal failure.1 Importance of informing clinician if decreased urine output occurs or if edema develops.1

  • Importance of routine monitoring of blood cell counts.1

  • Importance of taking the oral prednisone component of the cabazitaxel/prednisone regimen for prostate cancer as directed.1 Importance of informing clinician if not adherent to oral prednisone regimen.1

  • Importance of informing geriatric patients that certain adverse effects may be more frequent or severe in older patients.1 (See Geriatric Use under Cautions.)

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Apprise patient of potential hazard to the fetus if used during pregnancy; women of childbearing potential should avoid becoming pregnant.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Cabazitaxel

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection concentrate, for IV infusion only

40 mg/mL (60 mg)

Jevtana (with water for injection containing alcohol 13% w/w diluent)

Sanofi-Aventis

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 12, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Sanofi-Aventis. Jevtana (cabazitaxel) injection prescribing information. Bridgewater, NJ; 2010 Jun.

2. de Bono JS, Oudard S, Ozguroglu M et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010; 376:1147-54. [PubMed 20888992]

3. Pal SK, Twardowski P, Sartor O. Critical appraisal of cabazitaxel in the management of advanced prostate cancer. Clin Interv Aging. 2010; 5:395-402. [PubMed 21152241]

4. . New treatments for metastatic prostate cancer. Med Lett Drugs Ther. 2010; 52:69-70.

5. Sanofi-Aventis. Bridgewater, NJ: Personal Communication.

6. Froehner M, Wirth MP. Cabazitaxel for castration-resistant prostate cancer. Lancet. 2011; 377:121-2; author reply 122-3. [PubMed 21215875]

7. Pearson SD, Trissel LA. Leaching of diethylhexyl phthalate from polyvinyl chloride containers by selected drugs and formulation components. Am J Hosp Pharm. 1993; 50:1405-9. [PubMed 8362871]

8. Kullak-Ublick GA, Becker MB. Regulation of drug and bile salt transporters in liver and intestine. Drug Metab Rev. 2003; 35:305-17. [PubMed 14705863]

9. Kurata T, Shimada Y, Tamura T et al. Phase I and pharmacokinetic study of a new taxoid, RPR 109881A, given as a 1-hour intravenous infusion in patients with advanced solid tumors. J Clin Oncol. 2000; 18:3164-71. [PubMed 10963645]

10. Mita AC, Denis LJ, Rowinsky EK et al. Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009; 15:723-30. [PubMed 19147780]

11. Pivot X, Koralewski P, Hidalgo JL et al. A multicenter phase II study of XRP6258 administered as a 1-h i.v. infusion every 3 weeks in taxane-resistant metastatic breast cancer patients. Ann Oncol. 2008; 19:1547-52. [PubMed 18436520]

12. Cisternino S, Bourasset F, Archimbaud Y et al. Nonlinear accumulation in the brain of the new taxoid TXD258 following saturation of P-glycoprotein at the blood-brain barrier in mice and rats. Br J Pharmacol. 2003; 138:1367-75. [PubMed 12711638]

13. Bouchet BP, Galmarini CM. Cabazitaxel, a new taxane with favorable properties. Drugs Today (Barc). 2010; 46:735-42. [PubMed 21076710]

14. Sanofi-Aventis. Taxotere (docetaxel) injection concentrate prescribing information. Bridgewater, NJ; 2010 May.

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