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Ixabepilone

Pronunciation

(ix ab EP i lone)

Index Terms

  • Azaepothilone B
  • BMS-247550
  • Epothilone B Lactam

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]

Brand Names: U.S.

  • Ixempra Kit

Pharmacologic Category

  • Antineoplastic Agent, Antimicrotubular
  • Antineoplastic Agent, Epothilone B Analog

Pharmacology

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.

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 infusion (3 hours)

Half-Life Elimination

~52 hours

Protein Binding

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).

Use: Unlabeled

Treatment (second-line) of endometrial cancer

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

Dosing: Adult

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.

Dosing: Geriatric

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

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) 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.

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

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). 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.

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.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Dietary Considerations

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

Compatibility

Stable in lactated Ringer’s injection, adjusted sodium chloride 0.9% (pH adjusted with sodium bicarbonate); PLASMA-LYTE A Injection pH 7.4.

Storage

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).

Drug Interactions

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

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase 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

Adverse Reactions

Percentages reported with monotherapy:

>10%:

Central nervous system: Headache (11%)

Dermatologic: Alopecia (48%)

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

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

Neuromuscular & skeletal: Peripheral neuropathy (63%; grades 3/4: 14%; grade 3/4 median onset: cycle 4), sensory neuropathy (62%; grades 3/4: 14%), weakness (56%), myalgia/arthralgia (49%), musculoskeletal pain (20%)

1% to 10%:

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

Central nervous system: Fever (8%), pain (8%), dizziness (7%), insomnia (5%)

Dermatologic: Nail disorder (9%), rash (9%), palmar-plantar erythrodysesthesia/hand-and-foot syndrome (8%), pruritus (6%), skin exfoliation (2%), hyperpigmentation (2%)

Endocrine & metabolic: Hot flush (6%), dehydration (2%)

Gastrointestinal: Gastroesophageal reflux disease (6%), taste perversion (6%), weight loss (6%)

Hematologic: Anemia (grade 3: 6%; grade 4: 2%), neutropenic fever (3%; grade 3: 3%), thrombocytopenia (grade 3: 5%; grade 4: 2%)

Neuromuscular & skeletal: Motor neuropathy (10%; grade 3: 1%)

Ocular: Lacrimation increased (4%)

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

Miscellaneous: Hypersensitivity (5%; grade 3: 1%), infection (5%)

Mono- and combination therapy: <1% (Limited to important or life-threatening): Alkaline phosphatase increased, angina, atrial flutter, autonomic neuropathy, cardiomyopathy, cerebral hemorrhage, coagulopathy, colitis, dysphagia, dysphonia, embolism, enterocolitis, erythema multiforme, gastrointestinal hemorrhage, gastroparesis, GGT increased, hemorrhage, hepatic failure (acute), hypokalemia, hyponatremia, hypotension, hypovolemia, hypovolemic shock, hypoxia, ileus, interstitial pneumonia, jaundice, left ventricular dysfunction, metabolic acidosis, MI, nephrolithiasis, neutropenic infection, orthostatic hypotension, pneumonia, pneumonitis, pulmonary edema (acute), radiation recall, renal failure, respiratory failure, sepsis, septic shock, supraventricular arrhythmia, syncope, thrombosis, transaminases increased, trismus, urinary tract infection, vasculitis

ALERT: U.S. Boxed Warning

Hepatic impairment:

Ixabepilone in combination with capecitabine is contraindicated in patients with AST or ALT greater than 2.5 times the upper limit of normal (ULN) or bilirubin greater than 1 times ULN due to an increased risk of toxicity and neutropenia-related death.

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 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.

Disease-related concerns:

• 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.

Special populations:

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

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Monitoring Parameters

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

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Women of childbearing 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 alopecia, headache, constipation, abdominal pain, mouth sores, lack of appetite, 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, angina, tachycardia, arrhythmia, severe nausea, vomiting, severe diarrhea, bruising, bleeding, loss of strength and energy, severe dizziness, passing out, severe joint pain, severe muscle pain, redness or irritation on palms or soles of feet, or severe injection site 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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