Dosing and Dose Modification
Recommended dose1
The recommended dosage of IXEMPRA (ixabepilone) is 40 mg/m2 administered intravenously over 3 hours every 3 weeks. Doses for patients with body surface area (BSA) 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.
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 mg to 300 mg orally or equivalent)
Observe patients for hypersensitivity reactions (eg, flushing, rash, dyspnea,
and bronchospasm)
In cases of severe hypersensitivity reactions, infusion of IXEMPRA should be stopped
and aggressive supportive treatment (eg, epinephrine, corticosteroids) started
Patients who experienced a hypersensitivity reaction to IXEMPRA require premedication with corticosteroids
(eg, dexamethasone 20 mg IV, 30 minutes before infusion, or orally, 60 minutes before infusion), in addition
to pretreatment with H1 and H2 antagonists, and extension of the infusion time should be considered.
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Dose adjustments for certain toxicities1
For certain toxicities, an initial dose reduction of 20% is followed, on recurrence of toxicity, by an additional 20% dose reduction.¹
Patients should be evaluated during treatment by periodic clinical observation and laboratory tests, including complete blood cell counts. If toxicities are present, treatment should be delayed to allow recovery. General dosing adjustment guidelines for monotherapy and combination therapy are shown in the table below. Dose adjustment for specific toxicities are depicted below. If toxicities recur, an additional 20% dose reduction should be made.
If toxicities are present, treatment should be delayed to allow for recovery, or discontinued, based on the table above.
Capecitabine dose modifications for toxicities (when used in combination with IXEMPRA)
For nonhematologic toxicities, follow the capecitabine label
Hematologic toxicities:
- For platelets <25,000/mm3 or platelets <50,000/mm3 with bleeding, hold for concurrent diarrhea or stomatitis until platelet count >50,000/mm3, then continue at same dose
- For neutrophil count <500 cells/mm3 for ≥7 days or febrile neutropenia, hold for concurrent diarrhea or stomatitis until neutrophil count >1000 cells/mm3, then continue at same dose
Retreatment criteria
Dose adjustments at the start of a cycle should be based on nonhematologic toxicity or blood counts from the preceding cycle following the guidelines above
Patients should not begin a new cycle of treatment unless the neutrophil count is ≥1500 cells/mm3,
the platelet count is ≥100,000 cells/mm3, and nonhematologic toxicities have improved to grade 1 (mild) or resolved
Safety Information: Peripheral neuropathy
Peripheral neuropathy was common. Patients treated with IXEMPRA should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain
Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy occurred during the first 3 cycles. Patients experiencing new or worsening peripheral neuropathy may require changes in the dose or discontinuation of IXEMPRA
Neuropathy was the most frequent cause of treatment discontinuation due to drug toxicity. Caution should be used when treating patients with diabetes mellitus or preexisting peripheral neuropathy
Safety Information: Myelosuppression
Myelosuppression is dose-dependent and primarily manifested as neutropenia
Patients should be monitored for myelosuppression; frequent peripheral blood cell counts are recommended for all patients receiving IXEMPRA
Patients who experience severe neutropenia or thrombocytopenia should have their dose reduced. Neutropenia-related deaths occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. Neutropenia-related death occurred in 0.4% of 240 patients with IXEMPRA as monotherapy
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Hepatically impaired patients1
Assessment of hepatic function is recommended before initiation of IXEMPRA (ixabepilone) and periodically thereafter
Patients with baseline AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN experienced greater toxicity than patients with baseline AST or ALT ≤2.5 x ULN or bilirubin ≤1.5 x ULN when treated with IXEMPRA at 40 mg/m2 in combination with capecitabine or as monotherapy in breast cancer studies
Toxicity in hepatic impairment
For combination therapy
IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN
Patients receiving combination treatment who have AST and ALT ≤2.5 x ULN and bilirubin ≤1 x ULN may receive the standard dose of IXEMPRA (40 mg/m²)
In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was greater
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 not exceeding, 30 mg/m² if tolerated
Use in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not recommended
Limited data are available for patients with AST or ALT >5 x ULN. Caution should be used when treating these patients
With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reactions were more frequent
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Dose modifications for drugs that influence CYP3A4¹
CYP3A4 Inhibitors
The use of concomitant strong CYP3A4 inhibitors should be avoided (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, or voriconazole)
Grapefruit juice may also increase plasma concentrations of IXEMPRA (ixabepilone) 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 counts between cycles of IXEMPRA)
CYP3A4 Inducers
IXEMPRA is a CYP3A4 substrate. The use of concomitant strong CYP3A4 inducers should be avoided (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. 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. 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.
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, 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.
AUC = area under the curve
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Use in special populations1
Geriatric Use
Clinical studies of IXEMPRA (ixabepilone) 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 grade 3/4 adverse reactions was higher in patients ≥65 years of age
versus those <65 years of age (82% versus 68%) including grade 3/4 stomatitis (9% versus 1%), diarrhea (9% versus 6%),
palmar-plantar erythrodysesthesia (hand-foot) syndrome (27% versus 20%), peripheral neuropathy (24% versus 22%),
febrile neutropenia (9% versus 3%), fatigue (16% versus 12%), and asthenia (11% versus 6%)
Toxicity-related deaths occurred in 2 (4.7%) of 43 patients ≥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 x ULN
In a population pharmacokinetic analysis of IXEMPRA as monotherapy, there was no meaningful effect of mild and moderate renal insufficiency (CrCL >30 mL/min) on the pharmacokinetics of IXEMPRA
Pregnant women and nursing mothers
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 if 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 into 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.
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How IXEMPRA is supplied
IMPORTANT SAFETY INFORMATION
WARNING: Toxicity in hepatic impairment
- IXEMPRA® (ixabepilone) in combination with capecitabine is
contraindicated in patients with
AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity
and neutropenia-related death
- In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions,
febrile neutropenia, serious
adverse reactions, and toxicity-related deaths was greater in patients with hepatic
impairment
- Caution should be used when using IXEMPRA as monotherapy in patients with AST or
ALT >5 x ULN. Use of
IXEMPRA in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN is not
recommended
- With monotherapy, grade 4 neutropenia, febrile neutropenia, and serious adverse
reactions were more frequent in
patients with hepatic impairment
Contraindications
- IXEMPRA is contraindicated in patients:
- with a known history of a severe (CTC grade 3/4) hypersensitivity reaction to agents
containing Cremophor® EL
or its derivatives such as polyoxyethylated castor oil
- who have a baseline neutrophil count <1500 cells/mm3 or a platelet
count <100,000 cells/mm3
Peripheral neuropathy
- Peripheral neuropathy was common. Patients treated with IXEMPRA should be monitored
for symptoms of
neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia,
discomfort, or neuropathic pain
- Neuropathy occurred early during treatment; ~75% of new onset or worsening neuropathy
occurred during the first
3 cycles. Patients experiencing new or worsening peripheral neuropathy may require
changes in the dose or
discontinuation of IXEMPRA
- Neuropathy was the most frequent cause of treatment discontinuation due to drug
toxicity. Caution should be used
when treating patients with diabetes mellitus or preexisting peripheral neuropathy
Myelosuppression
- Myelosuppression is dose-dependent and primarily manifested as neutropenia
- Patients should be monitored for myelosuppression; frequent peripheral blood cell
counts are recommended for all
patients receiving IXEMPRA
- Patients who experience severe neutropenia or thrombocytopenia should have their
dose reduced. Neutropenia-
related deaths occurred in 1.9% of 414 patients with normal hepatic function or
mild hepatic impairment treated
with IXEMPRA in combination with capecitabine. Neutropenia-related death occurred
in 0.4% of 240 patients with
IXEMPRA as monotherapy
Hypersensitivity reaction
- Premedicate with an H1 and an H2 antagonist approximately
1 hour before IXEMPRA infusion and observe for
hypersensitivity reactions (eg, flushing, rash, dyspnea, and bronchospasm)
- In case of severe hypersensitivity reactions, infusion of IXEMPRA should be stopped
and aggressive supportive
treatment (eg, epinephrine, corticosteroids) started
- Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must
be premedicated in
subsequent cycles with a corticosteroid in addition to the H1 and H2
antagonists, and extension of the infusion
time should be considered
Pregnancy
- Women should be advised not to become pregnant when taking IXEMPRA. If this drug
is used during pregnancy or
the patient becomes pregnant, the patient should be apprised of the potential hazard
to the fetus
Cardiac adverse reactions
- Caution should be exercised in patients with a history of cardiac disease. Discontinuation
of IXEMPRA should be
considered in patients who develop cardiac ischemia or impaired cardiac function
due to reports of cardiovascular
adverse reactions (eg, myocardial ischemia, supraventricular arrhythmia, and ventricular
dysfunction). The
frequency of cardiac adverse reactions (myocardial ischemia and ventricular dysfunction)
was higher in the
IXEMPRA in combination with capecitabine (1.9%) than in the capecitabine alone (0.3%)
treatment group
Potential for cognitive impairment from excipients
- IXEMPRA contains dehydrated alcohol USP. Consideration should be given to the possibility
of central nervous
system and other effects of alcohol
Adverse reactions
- The most common adverse reactions (≥20%) reported by patients receiving IXEMPRA
were peripheral sensory
neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis,
diarrhea, and
musculoskeletal pain. The following additional events occurred in ≥20% in combination
treatment: palmar-plantar
erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder,
and constipation.
Drug-associated hematologic abnormalities (>40%) include neutropenia, leukopenia,
anemia, and
thrombocytopenia
Cremophor is a registered trademark of BASF AG.
AST = aspartate aminotransferase; ALT = alanine aminotransferase;
ULN = upper limit of normal; CTC = common terminology criteria.
Please see Full US Prescribing Information,
including boxed WARNING regarding hepatic impairment.