(ix ab EP i lone)
- Azaepothilone B
- Epothilone B Lactam
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]
Brand Names: U.S.
- Ixempra Kit
- Antineoplastic Agent, Antimicrotubular
- Antineoplastic Agent, Epothilone B Analog
Epothilone B analog; 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.
Extensively hepatic, via CYP3A4; >30 metabolites (inactive) formed
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 infusion (3 hours)
67% to 77%
Use: Labeled Indications
Breast cancer: Treatment of metastatic or locally-advanced breast cancer resistant to treatment with an anthracycline and a taxane, or if taxane-resistant and further anthracycline therapy is contraindicated (in combination with capecitabine) or as monotherapy in tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.
Anthracycline resistance is defined as progression during treatment or within 3 months in the metastatic setting (within 6 months in the adjuvant setting). Taxane resistance is defined as progression during treatment within 4 months in the metastatic setting (within 12 months in the adjuvant setting).
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
Note: Premedicate with an H1-antagonist (eg, oral diphenhydramine 50 mg) and H2-antagonist (eg, oral ranitidine 150 to 300 mg) ~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/dose over 3 hours every 3 weeks (maximum dose: 88 mg) either as monotherapy or in combination with capecitabine
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, 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.
Refer to adult dosing.
Dosing: Renal Impairment
There are no dosage adjustments provided in the manufacturer’s labeling, however, renal excretion is minimal. Pharmacokinetics (monotherapy) are not affected in patients with mild-to-moderate renal insufficiency (CrCl >30 mL/minute); monotherapy has not been studied in patients with serum creatinine >1.5 times ULN. Combination therapy with capecitabine has not been studied in patients with CrCl <50 mL/minute.
Dosing: Hepatic Impairment
Ixabepilone monotherapy (initial cycle; adjust doses for subsequent cycles based on toxicity):
AST and ALT ≤2.5 times ULN and bilirubin ≤1 times ULN: No dosage adjustment necessary
AST and ALT >2.5 to ≤10 times ULN and bilirubin >1 to ≤1.5 times ULN: Reduce dose to 32 mg/m2
AST and ALT ≤10 times ULN and bilirubin >1.5 to ≤3 times ULN: Reduce dose to 20 to 30 mg/m2 (initiate treatment at 20 mg/m2, may escalate up to a maximum of 30 mg/m2 in subsequent cycles if tolerated)
AST or ALT >10 times ULN or bilirubin >3 times ULN: Use is not recommended
Combination therapy of ixabepilone with capecitabine:
AST and ALT ≤2.5 times ULN and bilirubin ≤1 times ULN: No dosage adjustment necessary
AST or ALT >2.5 times ULN or bilirubin >1 times ULN: Use is contraindicated
Dosing: Adjustment for Toxicity
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%
Grade 2 (moderate) for ≥7 days: Reduce ixabepilone dose by 20%
Grade 3 (severe) for <7 days: Reduce ixabepilone dose by 20%
Grade 3 (severe or disabling) for ≥7 days: 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
Note: Adjust dosage 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 persist despite initial dose reduction, reduce dose an additional 20%.
Capecitabine dosage adjustments for combination therapy with ixabepilone: Refer to Capecitabine monograph.
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
Allow to reach 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 lactated Ringer’s, adjusted sodium chloride 0.9% (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.
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.
Avoid grapefruit juice (may increase plasma concentrations of ixabepilone).
Store intact vials under refrigeration 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; infusion solution diluted in appropriate solution for infusion is stable for 6 hours at room temperature if a pH range of 6 to 9 is maintained (infusion must be completed within 6 hours).
Aprepitant: May increase the serum concentration of CYP3A4 Substrates. 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. 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. Avoid combination
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. 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. Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ixabepilone. Consider therapy modification
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination
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
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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
Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination
Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification
MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. 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. 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. Monitor therapy
Palbociclib: May increase the serum concentration of CYP3A4 Substrates. 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. Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
St John's Wort: May decrease the serum concentration of Ixabepilone. Avoid combination
Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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. Monitor therapy
Percentages reported with monotherapy.
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% (Limited to important or life-threatening): 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
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 use. The risk for neutropenia is increased with hepatic dysfunction, especially when used in combination with capecitabine. 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 with an H1- and H2-antagonist 1 hour prior to infusion; patients who experience hypersensitivity (eg, bronchospasm, dyspnea, flushing, rash) should also be premedicated with a corticosteroid for all subsequent cycles if treatment is continued.
• Peripheral neuropathy: Peripheral (sensory and motor) neuropathy occurs commonly; may require dose reductions, treatment delays or discontinuation. Usually occurs during the first 3 cycles. Use with caution in patients with pre-existing neuropathy.
• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease. The incidence of MI, 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: [U.S. 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. In mono- and combination therapy, toxicities and serious adverse reactions are increased with hepatic dysfunction; 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.
• Elderly: Use with caution in the elderly; toxicities or serious adverse events with combination therapy may be increased.
CBC with differential; hepatic function (ALT, AST, bilirubin); monitor for hypersensitivity, signs/symptoms of neuropathy
Pregnancy Risk Factor
Adverse events were observed in animal reproduction studies. Women of childbearing potential should be advised to use effective contraception during treatment.
• 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, insomnia, 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, angina, tachycardia, 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.
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- Drug class: mitotic inhibitors
Other brands: Ixempra