Ixabepilone (Monograph)

Brand name: Ixempra
Drug class: Antineoplastic Agents
- Epothilones
- Microtubule Inhibitors
VA class: AN900
Chemical name: (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[14.1.0] heptadecane-5,9-dione
Molecular formula: C₂₇H₄₂N₂O₅S
CAS number: 219989-84-1

Medically reviewed by Drugs.com on Jul 31, 2024. Written by ASHP.

Warning

Increased risk of toxicity and neutropenia-related death in patients with AST or ALT >2.5 times upper limit of normal (ULN) or bilirubin >1 times ULN in combination with oral capecitabine; concomitant use of ixabepilone and capecitabine not recommended in these patients. (See Hepatic Impairment and also see Contraindications under Cautions.)

Introduction

Antineoplastic agent; semisynthetic derivative of epothilone B; a microtubule inhibitor.

Uses for Ixabepilone

Breast Cancer

Treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

Used in combination with oral capecitabine for treatment of metastatic or locally advanced breast cancer in patients whose disease is resistant to treatment with an anthracycline and a taxane or in patients whose cancer is taxane-resistant and for whom further anthracycline therapy is contraindicated.

Under investigation for initial therapy of advanced breast cancer^{† [off-label]}.

Ixabepilone Dosage and Administration

General

To minimize risk of hypersensitivity reactions, premedicate with diphenhydramine 50 mg orally (or a similar antihistamine) and an H₂-receptor antagonist (e.g., ranitidine 150–300 mg orally) 1 hour before the infusion. (See Hypersensitivity Reactions under Cautions.)
In patients who experienced a prior hypersensitivity reaction to the drug, premedicate with corticosteroids (e.g., dexamethasone 20 mg either IV 30 minutes prior to infusion or orally 60 minutes prior to infusion) in addition to pretreatment with an antihistamine and an H₂-receptor antagonist.
Consult specialized references for procedures for proper handling and disposal of antineoplastics.

Administration

IV Administration

Administer by IV infusion.

Administer through an appropriate 0.2- to 1.2-µm inline filter. Use only diethylhexylphthalate (DEHP)-free infusion containers and administration sets.

Handle cautiously; use protective equipment (e.g., latex gloves) to minimize risk of dermal exposure.

Prior to administration, reconstitute powder for injection and dilute.

Reconstitution

Prior to reconstitution, remove kit from the refrigerator and allow to stand at room temperature for approximately 30 minutes. When first removed from the refrigerator, a white precipitate may be visible in diluent vial, but precipitate will dissolve to form a clear solution once the diluent warms to room temperature.

Reconstitute powder for injection by slowly adding 8 or 23.5 mL of the supplied diluent to the vial labeled as containing 15 or 45 mg, respectively, to provide a solution containing 2 mg/mL. Gently swirl the vial and invert until the powder completely dissolves. Use only the diluent provided by the manufacturer for reconstitution.

Following reconstitution, must be diluted further with an appropriate infusion solution as soon as possible; reconstituted solution may be stored in vial for ≤1 hour at room temperature and room light.

Dilution

Withdraw the appropriate dose and dilute in appropriate volume of lactated Ringer’s injection, 0.9% sodium chloride injection (pH adjusted with sodium bicarbonate), or Plasma-Lyte A injection pH 7.4 supplied in diethylhexylphthalate (DEHP)-free bags. Usually, a 250-mL bag of infusion solution is sufficient; however, verify the final infusion concentration of each dose based on the volume of infusion solution used; final infusion concentration must be between 0.2–0.6 mg/mL. Mix the infusion bag thoroughly by manual rotation.

If 0.9% sodium chloride injection is used as infusion solution, must adjust pH to 6–9 by adding 2 mEq sodium bicarbonate injection (i.e., 2 mL of 8.4% w/v or 4 mL of 4.2% w/v solution) prior to adding reconstituted dose.

Following dilution, solution is stable at room temperature and room light for ≤6 hours; complete administration of diluted ixabepilone must occur within this 6-hour period.

Rate of Administration

Administer over 3 hours. If dosage is increased to 60 mg/m² (such as in patients receiving a potent CYP3A4 inducer), administer over 4 hours. (See Interactions.)

Dosage

Adults

Breast Cancer

IV

40 mg/m² every 3 weeks.

Body surface area >2.2 m²: Calculate dosage based on 2.2 m².

Adjustments necessary when used in conjunction with potent inhibitors or potent inducers of CYP3A4. (See Interactions.)

Dosage Modification for Toxicity

If toxicities are present, delay treatment to allow recovery. A new treatment cycle should not begin unless the neutrophil count is >1500/mm³, platelet count is >100,000/mm³, or nonhematologic toxicities have improved to grade 1 (mild) or resolved.

Adjust dosage for monotherapy or combination therapy with ixabepilone according to toxicity. (See Table 1 and also see Table 2.) If toxicities recur, an additional 20% ixabepilone dosage reduction recommended.

Dosage adjustments at the start of a course of therapy should be based on nonhematologic toxicity from previous cycle.

NCIC Common Toxicity Criteria.

Table 1. Recommended Dosage Modifications for Nonhematologic Toxicity with Ixabepilone Monotherapy or Combination Therapy
Nonhematologic Toxicity	Ixabepilone Dosage Adjustment
Grade 2 neuropathy (moderate) lasting ≥7 days	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%
Grade 3 neuropathy (severe) lasting <7 days	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%
Grade 3 neuropathy (severe) lasting ≥7 days or disabling neuropathy	Discontinue therapy
Any grade 3 toxicity (severe) other than neuropathy	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%
Transient grade 3 arthralgia/myalgia or fatigue	No change in ixabepilone dosage
Grade 3 hand-foot syndrome (palmar-plantar erythrodysesthesia)	No change in ixabepilone dosage
Any grade 4 toxicity (disabling)	Discontinue therapy

Dosage adjustments at the start of a course of therapy should be based on blood cell counts from previous cycle.

Table 2. Recommended Dosage Modifications for Hematologic Toxicity with Ixabepilone Monotherapy or Combination Therapy
Hematologic Measurements	Ixabepilone Dosage Adjustment	Comments
ANC <500/mm³ for ≥7 days	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%	When used in combination with capecitabine, withhold capecitabine if concurrent diarrhea or stomatitis until ANC >1000/mm³, then resume same capecitabine dosage
Febrile neutropenia	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%	When used in combination with capecitabine, withhold capecitabine if concurrent diarrhea or stomatitis until ANC >1000/mm³, then resume same capecitabine dosage
Platelets <25,000/mm³	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%	When used in combination with capecitabine, withhold capecitabine if concurrent diarrhea or stomatitis until platelet count >50,000/mm³, then resume same capecitabine dosage
Platelets <50,000/mm³ with bleeding	Decrease dosage by 20%; if toxicity recurs, reduce dosage an additional 20%	When used in combination with capecitabine, withhold capecitabine if concurrent diarrhea or stomatitis until platelet count >50,000/mm³, then resume same capecitabine dosage

Special Populations

Hepatic Impairment

Prior to initiation and periodically thereafter assess hepatic function; dosage adjustment recommended based on hepatic function. (See Table 3.)

Breast Cancer

Monotherapy

Use not recommended in patients with AST or ALT >10 times ULN or bilirubin >3 times ULN. Use with caution in patients with AST or ALT >5 times ULN.

Adjust dosage based on degree of hepatic impairment (i.e., transaminase and bilirubin concentrations). (See Table 3.)

Excludes patients whose total bilirubin is elevated due to Gilbert’s disease.

Dosage recommendations are for first course of therapy; further dosage decreases in subsequent courses should be made based on individual tolerance.

Table 3. Dosage Adjustments for Ixabepilone Monotherapy in Patients with Hepatic Impairment120
Severity	Transaminase Concentrations	Bilirubin Concentrations	Dosage
Mild	AST and ALT ≤2.5 times ULN	≤1 times ULN	40 mg/m² every 3 weeks
	AST and ALT ≤10 times ULN	≤1.5 times ULN	32 mg/m² every 3 weeks
Moderate	AST and ALT ≤10 times ULN	>1.5 times ULN to ≤3 times ULN	Initially, 20 mg/m² every 3 weeks; subsequently, dosage may be increased to a maximum 30 mg/m², if tolerated

Combination Therapy with Capecitabine

Contraindicated in patients with serum AST or ALT >2.5 times ULN or serum bilirubin >1 times ULN.

Patients with AST and ALT ≤2.5 times ULN and bilirubin ≤1 times ULN: 40 mg/m².

Renal Impairment

No specific dosage recommendations for patients with renal impairment.

Cautions for Ixabepilone

Contraindications

History of severe (grade 3 or 4) hypersensitivity reaction to agents containing polyoxyl 35 castor oil (Cremophor EL, polyoxyethylated castor oil).
Neutrophil count <1500/mm³ or platelet count <100,000/mm³.
Use in combination with capecitabine contraindicated in patients with serum AST or ALT >2.5 times ULN or serum bilirubin elevated above ULN (i.e., >1 times ULN).

Warnings/Precautions

Warnings

Peripheral Neuropathy

Peripheral neuropathy occurs commonly; usually develops early during treatment (e.g., during the first 3 cycles).

Monitor patients for symptoms of neuropathy (e.g., burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain). Dosage reduction or delay in therapy may be required in patients experiencing new or worsening symptoms. (See Dosage Modification for Toxicity under Dosage and Administration.)

Increased risk of severe neuropathy in patients with diabetes mellitus or preexisting peripheral neuropathy; use with caution.

Hematologic Effects

Risk of dose-limiting, potentially fatal myelosuppression, manifested primarily as neutropenia. Leukopenia, anemia, and thrombocytopenia also reported.

Monitor peripheral blood cell counts frequently during therapy.

Dosage reduction recommended in patients experiencing severe neutropenia or thrombocytopenia. (See Dosage Modification for Toxicity under Dosage and Administration.)

Contraindicated in patients with a neutrophil count <1500/mm³ or platelet count <100,000/mm³. (See Contraindications.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Avoid pregnancy during therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Cardiovascular Effects

Increased risk of adverse cardiac reactions (myocardial ischemia, ventricular dysfunction, supraventricular arrhythmias) with ixabepilone in combination with capecitabine compared with capecitabine alone.

Use with caution in patients with a history of cardiac disease. Consider discontinuance of therapy in patients who develop cardiac ischemia or impaired cardiac function.

CNS Effects

Diluent in the commercially available Ixempra kit contains dehydrated alcohol; consider possibility of adverse CNS effects (e.g., cognitive impairment and other effects of alcohol). (See Advice to Patients.)

Radiation Recall

Radiation recall reported.

Sensitivity Reactions

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, reported.

Premedicate patients with an antihistamine and an H₂-receptor antagonist approximately 1 hour before beginning the infusion; observe for hypersensitivity reactions (e.g., flushing, rash, dyspnea, bronchospasm).

If severe hypersensitivity reaction occurs, discontinue immediately and institute aggressive supportive treatment (e.g., epinephrine, corticosteroids). Premedicate patients who experienced a hypersensitivity reaction during a previous cycle with a corticosteroid (in addition to an antihistamine and an H₂-receptor antagonist) and consider increasing infusion time.

Contraindicated in patients with a history of severe hypersensitivity reaction to agents containing polyoxyl 35 castor oil (Cremophor EL, polyoxyethylated castor oil), such as paclitaxel. (See Contraindications.)

Other Warnings/Precautions

Adequate Patient Evaluation and Monitoring

Evaluate patients during therapy by periodic clinical observation and laboratory tests, including CBCs and hepatic function. Patients must have recovered from acute toxicities (e.g., neutrophils ≥1500/mm³, platelets ≥100,000/mm³, nonhematologic toxicities improved to grade 1) before each cycle. (See Dosage Modification for Toxicity under Dosage and Administration.)

Specific Populations

Pregnancy

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

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.

In combination with capecitabine, increased incidence of grade 3 or 4 adverse reactions in patients ≥65 years of age compared with younger adults. When used as monotherapy, no overall differences in safety observed in patients ≥65 years of age compared with younger adults.

Hepatic Impairment

Increased risk of serious toxicity in patients with baseline AST or ALT >2.5 times ULN or bilirubin >1.5 times ULN. Monitor hepatic function prior to initiation of therapy and periodically thereafter.

Use in combination with capecitabine contraindicated in patients with serum AST or ALT >2.5 times ULN or serum bilirubin >1 times ULN.

Use as monotherapy in patients with AST or ALT >10 times ULN or bilirubin >3 times ULN not recommended. Limited data available for patients with AST or ALT >5 times ULN; use with caution in these patients.

Dosage reduction recommended if used as monotherapy in patients with hepatic impairment. (See Special Populations under Dosage and Administration.)

Renal Impairment

Pharmacokinetics not evaluated; however, when used as monotherapy, impact of mild to moderate renal impairment (Cl_cr >30 mL/min) should be minimal.

Common Adverse Effects

Ixabepilone monotherapy: Peripheral sensory neuropathy, myelosuppression, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, musculoskeletal pain.

Ixabepilone in combination with capecitabine: Peripheral sensory neuropathy, myelosuppression, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, musculoskeletal pain, palmar-plantar erythrodysesthesia (hand-foot syndrome), anorexia, abdominal pain, nail disorder, constipation.

Drug Interactions

Metabolized principally by CYP3A4. Pharmacokinetic interactions with inhibitors or inducers of CYP3A4 are likely.

Does not inhibit CYP isoenzymes 3A4, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 2D6; does not induce CYP isoenzymes 3A4, 1A2, 2B6, or 2C9. Pharmacokinetic interactions with drugs metabolized by these isoenzymes unlikely.

Substrate and weak inhibitor of P-glycoprotein (P-gp).

Substrates of CYP isoenzymes: Pharmacokinetic interaction unlikely when used in combination with substrates of these isoenzymes.

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma ixabepilone concentrations). Avoid concomitant use with potent CYP3A4 inhibitors; if concomitant therapy is necessary, monitor closely for toxicity and reduce ixabepilone dosage. (See Specific Drugs and Foods under Interactions.)

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma ixabepilone concentrations); if concomitant therapy necessary, consider alternative drugs with less enzyme induction potential. Avoid concomitant use with potent CYP3A4 inducers; if concomitant therapy is necessary, consider gradual increase in ixabepilone dosage from 40 mg/m² over 3 hours to 60 mg/m² over 4 hours, depending on patient tolerance, and monitor patients carefully for toxicity. (See Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Decreased plasma ixabepilone concentrations	Avoid concomitant use; consider alternative drugs with no or minimal enzyme induction potential; if concomitant use is necessary, consider gradual increase in ixabepilone dosage to 60 mg/m² administered over 4 hours, depending on patient tolerance
Antifungals, azoles (fluconazole, itraconazole, ketoconazole, voriconazole)	Increased plasma ixabepilone concentrations	Avoid concomitant use with itraconazole, ketoconazole, and voriconazole; if concomitant use is necessary, monitor closely for toxicity and reduce ixabepilone dosage to 20 mg/m²; if azole antifungal is discontinued, allow 1 week to elapse before increasing ixabepilone dosage to 40 mg/m² Fluconazole: Effects from concomitant use not studied; use concomitantly with caution; consider alternative agents and monitor closely for toxicity (e.g., peripheral blood counts between cycles)
Antimycobacterials (rifampin, rifabutin)	Decreased plasma ixabepilone concentrations	Avoid concomitant use; consider alternative drugs with no or minimal enzyme induction potential; if concomitant use is necessary, consider gradual increase in ixabepilone dosage to 60 mg/m² administered over 4 hours, depending on patient tolerance
Capecitabine	Decreased plasma ixabepilone and capecitabine concentrations	Interaction unlikely to be clinically important; effectiveness of combination therapy demonstrated in clinical trials
Delavirdine	Increased plasma ixabepilone concentrations	Avoid concomitant use; if concomitant use is necessary, monitor closely for toxicity and reduce ixabepilone dosage to 20 mg/m²; if delavirdine is discontinued, allow 1 week to elapse before increasing ixabepilone dosage to 40 mg/m²
Dexamethasone	Decreased plasma ixabepilone concentrations	Avoid concomitant use; consider alternative drugs with no or minimal enzyme induction potential; if concomitant use is necessary, consider gradual increase in ixabepilone dosage to 60 mg/m² administered over 4 hours, depending on patient tolerance
Grapefruit	Increased plasma ixabepilone concentrations	Avoid concomitant use of grapefruit juice
HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)	Increased plasma ixabepilone concentrations	Avoid concomitant use; if concomitant use is necessary, monitor closely for toxicity and reduce ixabepilone dosage to 20 mg/m²; if HIV protease inhibitor is discontinued, allow 1 week to elapse before increasing ixabepilone dosage to 40 mg/m²
Macrolides (e.g., clarithromycin, erythromycin, telithromycin)	Increased plasma ixabepilone concentrations	Avoid concomitant use with clarithromycin and telithromycin; if concomitant use is necessary, monitor closely for toxicity and reduce ixabepilone dosage to 20 mg/m²; if macrolide is discontinued, allow 1 week to elapse before increasing ixabepilone dosage to 40 mg/m² Erythromycin: Effects from concomitant use not studied; use concomitantly with caution; consider alternative agents and monitor closely for acute toxicity (e.g., peripheral blood counts between cycles)
Nefazodone	Increased plasma ixabepilone concentrations	Avoid concomitant use; if concomitant use is necessary, monitor closely for toxicity and reduce ixabepilone dosage to 20 mg/m²; if nefazodone is discontinued, allow 1 week to elapse before increasing ixabepilone dosage to 40 mg/m²
St. John’s wort (Hypericum perforatum)	Possible unpredictable decreased plasma ixabepilone concentrations	Avoid concomitant use
Verapamil	Possible increased plasma ixabepilone concentrations	Effects from concomitant use not studied; use concomitantly with caution; consider alternative agents and monitor closely for acute toxicity (e.g., peripheral blood counts between cycles)

Ixabepilone Pharmacokinetics

Absorption

Bioavailability

Peak concentrations usually attained at end of 3-hour infusion.

Distribution

Extent

Not known if ixabepilone is distributed into human milk.

Plasma Protein Binding

67–77%.

Elimination

Metabolism

Extensively metabolized in the liver, principally by oxidative metabolism via CYP3A4.

Elimination Route

86% of an IV dose is excreted in feces (65%) and urine (21%) primarily as metabolites; unchanged drug accounted for <2 and 6% of the dose in feces and urine, respectively.

Half-life

Approximately 52 hours (range: 20–72 hours).

No accumulation in plasma expected when administered once every 3 weeks.

Special Populations

Gender, race, and age do not have meaningful effects on pharmacokinetics of ixabepilone.

Stability

Storage

Parenteral

Powder for Injection

2–8° C in original package; protect from light.

Reconstituted solutions may be stored at room temperature for ≤1 hour in room light.

Solutions diluted in appropriate injections are stable at room temperature and room light for ≤6 hours. (See Dilution under Dosage and Administration.)

Actions

A microtubule inhibitor; binds to β-tubulin subunits on microtubules; stabilizes and suppresses microtubule activity resulting in mitotic arrest and apoptosis.
Active in xenografts resistant to multiple antineoplastic agents, including taxanes, anthracyclines, and vinca alkaloids.
Synergistic antitumor activity demonstrated in combination with capecitabine in vivo.
Has antiangiogenic activity.

Advice to Patients

Importance of reading patient information provided by the manufacturer.
Risk of neuropathy. Importance of patients notifying clinicians if they develop any numbness, tingling, or burning of the hands or feet.
Importance of patients notifying clinicians if they develop a fever of ≥100.5°F or other signs and symptoms of potential infection (e.g., chills, cough, burning or pain upon urination).
Importance of patients notifying clinicians if they experience urticaria, pruritus, rash, flushing, swelling, dyspnea, chest tightness, and/or other hypersensitivity-related symptoms following IV infusion of ixabepilone.
Importance of patients notifying clinicians if they notice chest pain, difficulty breathing, palpitations, or unusual weight gain.
Importance of patients informing clinicians if they are allergic to a drug such as paclitaxel that contains polyoxyl 35 castor oil (Cremophor EL, polyethoxylated castor oil).
Importance of patients informing clinicians if they have hepatic impairment. Importance of undergoing blood tests to determine liver function before and during ixabepilone therapy. Importance of not taking ixabepilone in combination with capecitabine if hepatic impairment is present.
Importance of not drinking grapefruit juice while receiving ixabepilone therapy.
Importance of informing patients that Ixempra contains alcohol and may cause drowsiness or dizziness. Importance of avoiding certain activities (e.g., operating machinery, driving a motor vehicle) if patient feels drowsy or dizzy.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., diabetes mellitus, liver disease).
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.