Ixabepilone

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Ixempra Kit: 15 mg (1 ea); 45 mg (1 ea) [contains alcohol, usp, cremophor el]

Pharmacology

Mechanism of Action

Ixabepilone is an epothilone B analog, which binds to the beta-tubulin subunit of the microtubule, stabilizing microtubular promoting tubulin polymerization and stabilizing microtubular function, thus arresting the cell cycle (at the G2/M phase) and inducing apoptosis. Activity in taxane-resistant cells has been demonstrated.

Pharmacokinetics/Pharmacodynamics

Distribution

>1,000 L

Metabolism

Extensively hepatic, via CYP3A4; >30 metabolites (inactive) formed

Excretion

Feces (65%; ~2% of the total dose as unchanged drug); urine (21%; ~6% of the total dose as unchanged drug)

Time to Peak

At the end of the 3-hour infusion

Half-Life Elimination

~52 hours

Protein Binding

67% to 77%

Use: Labeled Indications

Breast cancer (metastatic or locally advanced): Treatment (in combination with capecitabine) of metastatic or locally advanced breast cancer that is resistant to an anthracycline and a taxane, or that is taxane-resistant and when further anthracycline therapy is contraindicated; treatment (as a single agent) of metastatic or locally advanced breast cancer that is resistant or refractory to anthracyclines, taxanes, and capecitabine.

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

Contraindications

History of severe (grade 3 or 4) hypersensitivity to polyoxyethylated castor oil (Cremophor EL) or its derivatives; neutrophil count <1,500/mm³ or platelet count <100,000/mm³; combination therapy with ixabepilone and capecitabine in patients with AST or ALT >2.5 times ULN or bilirubin >1 times ULN

Dosage and Administration

Dosing: Adult

Note: Premedicate with an H₁-antagonist (diphenhydramine 50 mg orally or equivalent) and H₂-antagonist (ranitidine 150 to 300 mg orally or equivalent) ~1 hour prior to infusion. Patients with a history of hypersensitivity should also be premedicated with corticosteroids (dexamethasone 20 mg orally 1 hour before or IV 30 minutes before infusion). For dose calculation, body surface area (BSA) is capped at a maximum of 2.2 m².

Breast cancer (metastatic or locally advanced): IV: 40 mg/m² once every 3 weeks (maximum dose: 88 mg) either as monotherapy or in combination with capecitabine; continue until disease progression or unacceptable toxicity (Pérez 2007; Thomas 2007).

Dosage adjustment with concomitant strong CYP3A4 inhibitors/inducers:

CYP3A4 inhibitors: Avoid concomitant administration with strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, nefazodone, atazanavir, delavirdine, indinavir, nelfinavir, ritonavir, saquinavir); if concomitant administration with a strong CYP3A4 inhibitor cannot be avoided, consider a dose reduction to 20 mg/m². When a strong CYP3A4 inhibitor is discontinued, allow ~1 week to elapse prior to adjusting ixabepilone dose upward to the indicated dose.

CYP3A4 inducers: Avoid concomitant administration with strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital); if concomitant administration with a strong CYP3A4 inducer cannot be avoided and after maintenance on the strong CYP3A4 inducer is established, consider adjusting the ixabepilone dose gradually up to 60 mg/m² (as a 4-hour infusion), with careful monitoring. If the strong CYP3A4 enzyme inducer is discontinued, reduce ixabepilone dose to the dose used prior to initiation of the CYP3A4 inducer.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Hematologic:

Neutrophils <500/mm³ for ≥7 days: Reduce ixabepilone dose by 20%.

Neutropenic fever: Reduce ixabepilone dose by 20%.

Platelets <25,000/mm³ (or <50,000/mm³ with bleeding): Reduce ixabepilone dose by 20%.

Nonhematologic:

Neuropathy:

Grade 2 (moderate) lasting ≥7 days: Reduce ixabepilone dose by 20%.

Grade 3 (severe) lasting <7 days: Reduce ixabepilone dose by 20%.

Grade 3 (severe or disabling) lasting ≥7 days or disabling neuropathy: Discontinue ixabepilone treatment.

Grade 3 toxicity (severe; other than neuropathy): Reduce ixabepilone dose by 20%.

Grade 3 arthralgia/myalgia or fatigue (transient): Continue ixabepilone at current dose.

Grade 3 hand-foot syndrome: Continue ixabepilone at current dose.

Grade 4 toxicity (disabling): Discontinue ixabepilone treatment.

Cardiac ischemia or dysfunction: Consider discontinuing ixabepilone.

Note: Dosage adjustments at the start of a cycle are based on toxicities (hematologic and nonhematologic) from the previous cycle; delay new cycles until neutrophils have recovered to ≥1,500/mm³, platelets have recovered to ≥100,000/mm³ and nonhematologic toxicities have resolved or improved to at least grade 1. If toxicities recur, reduce dose an additional 20%.

Capecitabine dosage adjustments for combination therapy with ixabepilone: Refer to Capecitabine monograph.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: In general, utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012). Note: According to the manufacturer, patients with a body surface area (BSA) >2.2 m² should be dosed based upon a maximum BSA of 2.2 m².

Reconstitution

Allow to stand at room temperature for ~30 minutes prior to reconstitution. Diluent vial may contain a white precipitate which should dissolve upon reaching room temperature. Reconstitute only with the provided diluent. Dilute the 15 mg vial with 8 mL and the 45 mg vial with 23.5 mL (using provided diluent) to a concentration of 2 mg/mL (contains overfill). Gently swirl and invert vial until dissolved completely. Prior to administration, further dilute using a non-DEHP container (eg, glass, polypropylene or polyolefin), to a final concentration of 0.2 to 0.6 mg/mL in ~250 mL LR, adjusted NS (pH adjusted prior to ixabepilone addition with 2 mEq sodium bicarbonate per 250 to 500 mL sodium chloride) or PLASMA-LYTE A Injection pH 7.4. Mix thoroughly.

Administration

IV: Infuse over 3 hours. Use non-DEHP administration set (eg, polyethylene); filter with a 0.2 to 1.2 micron inline filter. Administration should be completed within 6 hours of preparation. If the dose is increased (above 40 mg/m²) due to concomitant CYP3A4 inducer use, infuse over 4 hours.

Ixabepilone is an irritant (Pérez Fidalgo 2012).

Dietary Considerations

Avoid grapefruit juice (may increase plasma concentrations of ixabepilone).

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); protect from light. Reconstituted solution (in the vial) is stable for up to 1 hour at room temperature and room light; infusion solution diluted in appropriate solution for infusion is stable for 6 hours at room temperature and room light if a pH range of 6 to 9 is maintained (infusion must be completed within 6 hours).

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ixabepilone. Management: Avoid this combination whenever possible. If this combination must be used, a gradual increase in ixabepilone dose from 40 mg/m² to 60 mg/m² (given as a 4-hour infusion), as tolerated, should be considered. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ixabepilone. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

DexAMETHasone (Systemic): May decrease the serum concentration of Ixabepilone. Management: Avoid this combination whenever possible. If this combination must be used, a gradual increase in ixabepilone dose from 40 mg/m² to 60 mg/m² (given as a 4-hour infusion), as tolerated, should be considered. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Grapefruit Juice: May increase the serum concentration of Ixabepilone. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

St John's Wort: May decrease the serum concentration of Ixabepilone. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

Percentages reported with monotherapy.

>10%:

Central nervous system: Peripheral neuropathy (63%; grades 3/4: 14%; grade 3/4 median onset: Cycle 4), peripheral sensory neuropathy (62%; grades 3/4: 14%), headache (11%)

Dermatologic: Alopecia (48%)

Gastrointestinal: Nausea (42%), vomiting (29%), mucositis (≤29%), stomatitis (≤29%), diarrhea (22%), anorexia (19%), constipation (16%), abdominal pain (13%)

Hematologic & oncologic: Leukopenia (grade 3: 36%; grade 4: 13%), neutropenia (grade 3: 31%; grade 4: 23%)

Neuromuscular & skeletal: Weakness (56%), arthralgia (≤49%), myalgia (≤49%), musculoskeletal pain (20%)

1% to 10%:

Cardiovascular: Edema (9%), chest pain (5%)

Central nervous system: Peripheral motor neuropathy (10%; grade 3: 1%), pain (8%), dizziness (7%), insomnia (5%)

Dermatologic: Nail disease (9%), skin rash (9%), palmar-plantar erythrodysesthesia (8%), pruritus (6%), desquamation (2%), hyperpigmentation (2%)

Endocrine & metabolic: Hot flash (6%), weight loss (6%), dehydration (2%)

Gastrointestinal: Dysgeusia (6%), gastroesophageal reflux (6%)

Hematologic & oncologic: Anemia (grade 3: 6%; grade 4: 2%), febrile neutropenia (3%; grade 3: 3%), thrombocytopenia (grade 3: 5%; grade 4: 2%)

Hypersensitivity: Hypersensitivity (5%; grade 3: 1%)

Infection: Infection (5%)

Ophthalmic: Increased lacrimation (4%)

Respiratory: Dyspnea (9%), upper respiratory tract infection (6%), cough (2%)

Miscellaneous: Fever (8%)

Mono- and combination therapy: <1%, postmarketing, and/or case reports: Acute hepatic failure, acute pulmonary edema, angina pectoris, atrial flutter, autonomic neuropathy, blood coagulation disorder, cardiomyopathy, cerebral hemorrhage, colitis, delayed gastric emptying, dysphagia, embolism, enterocolitis, erythema multiforme, gastrointestinal hemorrhage, hemorrhage, hypokalemia, hyponatremia, hypotension, hypovolemia, hypovolemic shock, hypoxia, increased gamma-glutamyl transferase, increased serum alkaline phosphatase, increased serum transaminases, interstitial pneumonitis, intestinal obstruction, jaundice, left ventricular dysfunction, metabolic acidosis, myocardial infarction, nephrolithiasis, neutropenic infection, orthostatic hypotension, pneumonia, pneumonitis, radiation recall phenomenon, renal failure, respiratory failure, sepsis, septic shock, supraventricular cardiac arrhythmia, syncope, thrombosis, trismus, urinary tract infection, vasculitis, voice disorder

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Dose-dependent myelosuppression, particularly neutropenia, may occur with mono- or combination therapy. Neutropenic fever and infection have been reported with ixabepilone. The risk for neutropenic complications is increased with hepatic dysfunction, especially when used in combination with capecitabine. Monitor blood counts frequently. Severe neutropenia and/or thrombocytopenia may require dosage adjustment and/or treatment delay.
• Cognitive impairment: Due to the ethanol content in the diluent, may cause cognitive impairment; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Hypersensitivity: Diluent contains polyoxyethylated castor oil (Cremophor EL), which is associated with hypersensitivity reactions; use is contraindicated in patients with a history of severe hypersensitivity to Cremophor EL or its derivatives. Medications for the treatment of reaction should be available for immediate use; reactions may also be managed by reducing infusion rate. Premedicate all patients with an H₁- and H₂-antagonist 1 hour prior to infusion; monitor for hypersensitivity reactions. Patients who experience hypersensitivity (eg, bronchospasm, dyspnea, flushing, rash) should also be premedicated with a corticosteroid for all subsequent cycles (and extend the infusion duration) if treatment is continued.
• Peripheral neuropathy: Peripheral (sensory and motor) neuropathy has been commonly reported. Neuropathy usually occurs early in treatment, with most cases of new-onset or worsening neuropathy occurring during the first 3 cycles. Monitor for signs/symptoms of neuropathy (eg, burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain). New or worsening neuropathy symptoms may require dose reduction, treatment delay, and/or discontinuation. A majority of patients with neuropathy experienced either improvement or no worsening following dose reduction. Patients with preexisting peripheral neuropathy or diabetes may be at increased risk of developing severe neuropathy; use with caution.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease. The incidence of myocardial infarction, ventricular dysfunction and supraventricular arrhythmias is higher when ixabepilone is used in combination with capecitabine (as compared to capecitabine alone). Consider discontinuing ixabepilone in patients who develop cardiac ischemia or impaired cardiac function.
• Diabetes: Use with caution; may have an increased risk for severe peripheral neuropathy.
• Hepatic impairment: [US Boxed Warning]: Due to increased risk of toxicity and neutropenia-related mortality, combination therapy with capecitabine is contraindicated in patients with AST or ALT >2.5 times ULN or bilirubin >1 times ULN. Use (as monotherapy) is not recommended if AST or ALT >10 times ULN or bilirubin >3 times ULN; use caution in patients with AST or ALT >5 times ULN; data is limited and dose reductions may be necessary. Patients with baseline AST or ALT >2.5 times ULN or bilirubin >1.5 times ULN experienced greater toxicity with ixabepilone (either in combination with capecitabine or as monotherapy), compared to patients with baseline AST, ALT, or bilirubin below those levels. Dosage reductions are necessary.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Polyoxyethylated castor oil: Diluent contains polyoxyethylated castor oil (Cremophor EL), which is associated with hypersensitivity reactions.

Special populations:

• Elderly: Use with caution in elderly patients; toxicities or serious adverse events with combination therapy may be increased.

Monitoring Parameters

CBC with differential; hepatic function (ALT, AST, bilirubin); monitor for hypersensitivity reactions and signs/symptoms of neuropathy.

Pregnancy

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. May cause fetal harm if administered during pregnancy. Females of reproductive potential should be advised to use effective contraception during treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience hair loss, headache, nausea, vomiting, diarrhea, constipation, abdominal pain, mouth sores, lack of appetite, muscle pain, joint pain, nail changes, change in taste, trouble sleeping, or weight loss. Have patient report immediately to prescriber signs of infection, burning or numbness feeling, shortness of breath, excessive weight gain, swelling of arms or legs, flushing, chest pain, fast heartbeat, abnormal heartbeat, bruising, bleeding, severe loss of strength and energy, dizziness, passing out, redness or irritation on palms or soles of feet, or severe injection site redness, burning, edema, pain, or irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.