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When to Use Ixempra

When to use non-taxane therapy for metastatic breast cancer

Think IXEMPRA® (ixabepilone) when resistance emerges in mBC1

IXEMPRA® (ixabepilone), in combination with capecitabine, is the only FDA-approved, non-taxane microtubule-targeting agent indicated as first-line therapy for the treatment of patients with metastatic or locally advanced breast cancer resistant to an anthracycline and a taxane 1L, first-line; 2L, second-line; mBC, metastatic breast cancer.
* Reflects approved indications for IXEMPRA.

When resistance emerges in the adjuvant setting1

  • Consider IXEMPRA + capecitabine in patients resistant to an anthracycline (progressing while on therapy or within 6 months) and a taxane (progressing while on therapy or within 12 months)

When resistance emerges in the metastatic setting1

  • Consider IXEMPRA + capecitabine in patients who are resistant to an anthracycline (progressing within 3 months) or in whom further anthracycline use is contraindicated and who progress within 4 months of taxane therapy
  • Consider IXEMPRA as monotherapy in patients resistant or refractory to an anthracycline, a taxane, and capecitabine

IXEMPRA, in combination with capecitabine, is the only FDA-approved, non-taxane microtubule-targeting agent indicated as first-line therapy for the treatment of patients with metastatic or locally advanced breast cancer resistant to an anthracycline and a taxane1,2

Resistance in mBC

Treatment resistance to current therapies remains an issue for patients with metastatic breast cancer (mBC)3-5

When the interval between treatment and recurrence is brief, treatment resistance is the likely cause3

  • Due to the use of anthracyclines and taxanes in the adjuvant setting, the emergence of resistance may limit their use in the metastatic setting3,5,6

Some common causes of resistance to taxanes and other chemotherapies5

Resistance to taxanes and other chemotherapies can be caused by the mutation of beta-tubulin, overexpression of beta-III tubulin, or efflux drug transporters

Defined resistance criteria used in IXEMPRA® (ixabepilone) registrational studies1

Defined resistance criteria used in IXEMPRA® (ixabepilone) registrational studies in the neoadjuvant/adjuvant setting
Defined resistance criteria used in IXEMPRA® (ixabepilone) registrational studies in the metastatic setting
HER2, human epidermal growth factor receptor 2.
* For anthracyclines, patients who received a minimum cumulative dose of 240 mg/m2 of doxorubicin or 360 mg/m2 of epirubicin were also eligible.

Mechanism Of Action

IXEMPRA® (ixabepilone) is a non-taxane microtubule-targeting agent1

In preclinical studies, IXEMPRA, a semisynthetic analog of epothilone B, had low susceptibility to multiple mechanisms of resistance1,7-9,*

  • IXEMPRA binds directly to beta-tubulin subunits and suppresses their dynamic instability, blocking the mitotic phase of the cell division cycle and inducing cell death1
  • IXEMPRA has antitumor activity in vivo against multiple human tumor xenografts, including drug-resistant types that1:
    • Harbor tubulin mutations
    • Overexpress efflux transporters such as P-gp and MRP1
    • Overexpress beta-III tubulin isoforms
  • IXEMPRA is also active in xenografts resistant to multiple agents, including taxanes, anthracyclines, and vinca alkaloids1
  • IXEMPRA works synergistically with capecitabine and possesses anti-angiogenic activity1
* The clinical significance of this has not been determined.

IXEMPRA mechanism of action1,7

The IXEMPRA® (ixabepilone) mechanism of action

Dosing and Administration

IXEMPRA® (ixabepilone) dosing1

The recommended dosage of IXEMPRA is 40 mg/m2 administered intravenously over 3 hours every 3 weeks

  • Doses for patients with body surface area greater than 2.2 m2 should be calculated based on 2.2 m2
  • The dose of IXEMPRA is the same for monotherapy and for combination therapy with capecitabine
  • For certain toxicities, an initial 20% dose reduction should be made, followed by an additional 20% dose reduction if toxicities recur
The recommended dosage of IXEMPRA® (ixabepilone) is 40 mg/m2 administered intravenously over 3 hours every 3 weeks The recommended dosage of IXEMPRA® (ixabepilone) is 40 mg/m2 administered intravenously over 3 hours every 3 weeks

For certain toxicities, an initial dose reduction of 20% should be made, followed by an additional 20% dose reduction if toxicities recur

  • Patients should be evaluated during treatment by periodic clinical observation and laboratory tests, including complete blood cell counts
  • Depending on the type and severity of the toxicity, patients may require treatment discontinuation or no dose adjustment; if toxicities are present, treatment should be delayed to allow recovery
  • Dosing adjustment guidelines for monotherapy and combination therapy are shown in the table below

Dose adjustment for toxicities*

The recommended dose adjustment guidelines for IXEMPRA® (ixabepilone) * Toxicities graded in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0.

Re-treatment criteria1

  • Dose adjustments at the start of a cycle should be based on nonhematologic toxicity or blood cell counts from the preceding cycle following the guidelines in the “Dose adjustment for toxicities” table above
  • Patients should not begin a new cycle of treatment unless the neutrophil count is ≥1,500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and nonhematologic toxicities have improved to grade 1 (mild) or resolved

Dose modification for patients with hepatic impairment1

  • Assessment of hepatic function is recommended before initiation of IXEMPRA and periodically thereafter
  • Patients with baseline AST or ALT >2.5 × ULN or bilirubin >1.5 × ULN experienced greater toxicity than patients with baseline AST or ALT ≤2.5 × ULN or bilirubin ≤1.5 × ULN when treated with IXEMPRA at 40 mg/m2 in combination with capecitabine or as monotherapy in breast cancer studies

For combination therapy

  • IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 × ULN or bilirubin >1 × ULN
  • Patients receiving combination treatment who have AST and ALT ≤2.5 × ULN and bilirubin ≤1 × ULN may receive the standard dose of IXEMPRA (40 mg/m2)

For monotherapy

  • Patients with hepatic impairment should be dosed with IXEMPRA based on the table below
  • Patients with moderate hepatic impairment should be started at 20 mg/m2; the dosage in subsequent cycles may be escalated up to, but should not exceed, 30 mg/m2 if tolerated
  • Use in patients with AST or ALT >10 × ULN or bilirubin >3 × ULN is not recommended
  • Limited data are available for patients with AST or ALT >5 × ULN; caution should be used when treating these patients

Dose adjustments for IXEMPRA monotherapy in patients with hepatic impairment

Dose adjustments for IXEMPRA® (ixabepilone) monotherapy in patients with hepatic impairment ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.
* Excluding patients whose total bilirubin is elevated due to Gilbert syndrome.
Dosage recommendations are for first course of therapy; further decreases in subsequent courses should be based on individual tolerance.

Dose modification: inhibitors and inducers of CYP3A41

CYP3A4 inhibitors

  • Avoid the use of concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, or voriconazole)
  • Grapefruit juice may also increase plasma concentrations of IXEMPRA and should be avoided
  • Based on pharmacokinetic studies, if a strong CYP3A4 inhibitor must be coadministered, a dose reduction to 20 mg/m2 is predicted to adjust the IXEMPRA AUC to the range observed without inhibitors and should be considered
  • If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the IXEMPRA dose is adjusted upward to the indicated dose
  • Patients receiving CYP3A4 inhibitors during treatment with IXEMPRA should be monitored closely for acute toxicities (eg, frequent monitoring of peripheral blood cell counts between cycles of IXEMPRA)

CYP3A4 inducers

  • IXEMPRA is a CYP3A4 substrate; avoid the use of concomitant strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, and phenobarbital)
  • Selection of an alternative concomitant medication with no or minimal enzyme induction potential should be considered
  • The following guidance may be considered for dosing in patients requiring coadministration of a strong CYP3A4 inducer if no alternatives are feasible
    • Once patients have been maintained on a strong CYP3A4 inducer, the dose of IXEMPRA may be gradually increased from 40 mg/m2 to 60 mg/m2, depending on tolerance
    • If the dose is increased, IXEMPRA should be given as a 4-hour intravenous infusion
    • There are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers; however, it is predicted to adjust the AUC to the range observed without inducers
    • Patients whose dose is increased above 40 mg/m2 should be monitored carefully for toxicities associated with IXEMPRA
    • If the strong inducer is discontinued, the IXEMPRA dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer
  • St. John’s wort may decrease ixabepilone plasma concentrations unpredictably and should be avoided
AUC, area under the curve.

Premedication1

  • To minimize the chance of occurrence of a hypersensitivity reaction, all patients must be premedicated approximately 1 hour before the infusion of IXEMPRA with:
    • An H1 antagonist (eg, diphenhydramine 50 mg orally or equivalent), and
    • An H2 antagonist (eg, ranitidine 150-300 mg orally or equivalent)
  • Patients who experienced a hypersensitivity reaction to IXEMPRA require premedication with corticosteroids (eg, dexamethasone 20 mg intravenously 30 minutes before infusion or orally 60 minutes before infusion) in addition to pretreatment with H1 and H2 antagonists

Overdosage1

  • Experience with overdose of IXEMPRA is limited to isolated cases; the adverse reactions reported in these cases included peripheral neuropathy, fatigue, musculoskeletal pain/myalgia, and gastrointestinal symptoms (nausea, anorexia, diarrhea, abdominal pain, and stomatitis)
  • The highest dose mistakenly received was 100 mg/m2 (total dose, 185 mg)
  • There is no known antidote for overdosage of IXEMPRA; in case of overdosage, the patient should be closely monitored, and supportive treatment should be administered
  • Management of overdose should include supportive medical interventions to treat the presenting clinical manifestations

Use in specific populations1

Hepatic impairment

  • IXEMPRA in combination with capecitabine must not be given to patients with AST or ALT >2.5 × ULN or bilirubin >1 × ULN
  • Dose reduction is recommended when administering IXEMPRA as monotherapy to patients with hepatic impairment
  • Because there is a need for dosage adjustment based upon hepatic function, assessment of hepatic function is recommended before initiation of IXEMPRA and periodically thereafter

Geriatric use

  • Clinical studies of IXEMPRA did not include sufficient numbers of subjects ≥65 years of age to determine whether they respond differently than younger subjects
  • Forty-five of 431 patients treated with IXEMPRA in combination with capecitabine were ≥65 years of age, and 3 patients were ≥75 years of age
    • Overall, the incidence of grades 3/4 adverse reactions was higher in patients ≥65 years of age versus those <65 years of age (82% vs 68%), including grades 3/4 stomatitis (9% vs 1%), diarrhea (9% vs 6%), palmar-plantar erythrodysesthesia (hand-foot) syndrome (27% vs 20%), peripheral neuropathy (24% vs 22%), febrile neutropenia (9% vs 3%), fatigue (16% vs 12%), and asthenia (11% vs 6%)
    • Toxicity-related deaths occurred in 2 of 43 patients (4.7%) ≥65 years of age with normal baseline hepatic function or mild impairment
  • Thirty-two of 240 breast cancer patients treated with IXEMPRA as monotherapy were ≥65 years of age, and 6 patients were ≥75 years of age; no overall differences in safety were observed in these patients compared to those <65 years of age

Renal impairment

  • IXEMPRA is minimally excreted via the kidney
  • No controlled pharmacokinetic studies were conducted with IXEMPRA in patients with renal impairment
  • IXEMPRA in combination with capecitabine has not been evaluated in patients with calculated creatinine clearance of <50 mL/min
  • IXEMPRA as monotherapy has not been evaluated in patients with creatinine >1.5 × ULN
  • In a population pharmacokinetic analysis of IXEMPRA as monotherapy, there was no meaningful effect of mild or moderate renal insufficiency (CrCl >30 mL/min) on the pharmacokinetics of IXEMPRA

Pregnant women and nursing mothers

  • Pregnancy Category D: IXEMPRA may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies with IXEMPRA in pregnant women. Women should be advised not to become pregnant when taking IXEMPRA. If this drug is used during pregnancy or the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus
  • It is not known whether IXEMPRA is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IXEMPRA, a decision must be made whether to discontinue nursing or to discontinue IXEMPRA, taking into account the importance of the drug to the mother

Pediatric use

  • The safety and effectiveness of IXEMPRA in pediatric patients have not been established
CrCl, creatinine clearance.

Resources

Professional information materials

Nurse's guide to IXEMPRA therapy

This practical guide includes dosing calculations for preparing IXEMPRA® (ixabepilone) for infusion, a review of indications/contraindications, and tables that summarize dose modifications for toxicities and special populations.

Nurse's guide to IXEMPRA therapy

Dosing and administration guide

Use this brochure as a quick guide for dosing and administration of IXEMPRA monotherapy and combination therapy with capecitabine.

Dosing and administration guide

Pharmacy fact sheet

For a reference for how IXEMPRA is supplied (the 15-mg and 45-mg IXEMPRA Kits), use this pharmacy fact sheet, which includes recommended dosing, premedication, and dose modifications for toxicities and special populations.

Pharmacy fact sheet

Study 046: Combination therapy

Ixabepilone Plus Capecitabine for Metastatic Breast Cancer Progressing After Anthracycline and Taxane Treatment. Portions of this journal article may contain information not included in the approved IXEMPRA labeling.

Study 046: Combination therapy

Study 081: Monotherapy

Efficacy and Safety of Ixabepilone (BMS-247550) in a Phase II Study of Patients With Advanced Breast Cancer Resistant to an Anthracycline, a Taxane, and Capecitabine. Portions of this journal article may contain information not included in the approved IXEMPRA labeling.

Study 081: Monotherapy

IXEMPRA combination speaker program deck

View this educational slide deck, which includes an overview of breast cancer and factors associated with poor prognosis, as well as the clinical data for IXEMPRA combination therapy.

IXEMPRA combination speaker program deck

IXEMPRA monotherapy speaker program deck

View this educational slide deck, which includes IXEMPRA indications and usage and the clinical data for its use as monotherapy.

IXEMPRA monotherapy speaker program deck

Resources for use with patients

Patient brochure

This brochure explains to patients what to expect while being treated with IXEMPRA. This resource lists the indications for IXEMPRA and describes the signs and symptoms of common side effects and the more serious adverse reactions, including peripheral neuropathy, neutropenia, and hypersensitivity.

Patient brochure

Patient Support

Enroll eligible patients and learn more about a range of access resources and support services

R-Pharm US Access + Support

For reimbursement support, contact R-Pharm US Access and Support in one of the following ways:

Phone

Call the Support Center at 1-855-991-7277, 8 AM to 8 PM ET, Monday through Friday

Fax

Fax the Support Center at 1-877-541-7813

Download and complete the forms as directed below:

R-Pharm US Access and Support enrollment form

Complete this form to enroll your patients in the R-Pharm US Access and Support program. Select from the program’s various services and assistance offerings, including benefits investigation, support with prior authorization, co-pay assistance, and more.

R-Pharm US Access and Support patient authorization form

Patients should complete this form to authorize services and assistance from the R-Pharm US Access and Support program. This form is to be used only when an R-Pharm US Access and Support enrollment form was previously submitted without a patient authorization and agreement signature.

The information provided is intended for use by individuals involved with reimbursement support.

The accurate completion of reimbursement or coverage-related documentation is the responsibility of the healthcare provider and patient. R-Pharm US and its agents make no guarantee regarding reimbursement for any service or item.

Indications and Important Safety Informationexpand

Indications

IXEMPRA® (ixabepilone) is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.

  • Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting
  • Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting

IXEMPRA is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

Important Safety Information
WARNING: Toxicity in hepatic impairment

Contraindications

Peripheral neuropathy

Myelosuppression

Hypersensitivity reaction

Pregnancy

Cardiac adverse reactions

Potential for cognitive impairment from excipients

Adverse reactions

Monotherapy

Combination with capecitabine

Cremophor is a registered trademark of BASF AG.

AST = aspartate aminotransferase; ALT = alanine aminotransferase; ULN = upper limit of normal; CTC = common terminology criteria.

Indications

IXEMPRA® (ixabepilone) is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.

  • Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting
  • Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting

IXEMPRA is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

Please see US Full Prescribing Information, including boxed WARNING regarding hepatic impairment.

References: 1. IXEMPRA (ixabepilone) Prescribing Information; January 2016. 2. Perez EA. Microtubule inhibitors: differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Mol Cancer Ther. 2009;8(8):2086-2095. 3. Yardley DA. Drug resistance and the role of combination chemotherapy in improving patient outcomes. Int J Breast Cancer. 2013;2013:137414. doi:10.1155/2013/137414. 4. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205(2):275-292. 5. Coley HM. Mechanisms and strategies to overcome chemotherapy resistance in metastatic breast cancer. Cancer Treat Rev. 2008;34(4):378-390. doi:10.1016/j.ctrv.2008.01.007. 6. Beslija S, Bonneterre J, Burstein HJ, et al; for Central European Cooperative Oncology Group. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol. 2009;20(11):1771-1785. 7. Vahdat L. Ixabepilone: a novel antineoplastic agent with low susceptibility to multiple tumor resistance mechanisms. Oncologist. 2008;13(3):214-221. 8. Shen H, Lee FY, Gan J. Ixabepilone, a novel microtubule-targeting agent for breast cancer, is a substrate for P-glycoprotein (P-gp/MDR1/ABCB1) but not breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther. 2011;337(2):423-432. 9. Dumontet C, Jordan MA, Lee FFY. Ixabepilone: targeting βIII-tubulin expression in taxane-resistant malignancies. Mol Cancer Ther. 2009;8(1):17-25.

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