Dosage & Administration
Dose reduction is required in patients with elevated AST, ALT, or bilirubin.(
IXEMPRA is a hazardous drug. Follow aplicable special handling and disposal procedures.1
IXEMPRA
1. Prior to reconstituting, remove the IXEMPRA Kit from the refrigerator and allow it to stand at room temperature for approximately 30 minutes. When the vials are first removed from the refrigerator, a white precipitate may be observed in the DILUENT vial. This precipitate will dissolve to form a clear solution once the DILUENT warms to room temperature.
2. With a suitable syringe, aseptically withdraw the DILUENT and slowly inject it into the IXEMPRA for injection vial. The 15-mg IXEMPRA is reconstituted with 8 mL of DILUENT and the 45-mg IXEMPRA is reconstituted with 23.5 mL of DILUENT.
3. Gently swirl and invert the vial until the powder in IXEMPRA is completely dissolved.
4. After reconstituting with the DILUENT, the concentration of ixabepilone is 2 mg/mL.
5. After reconstituting IXEMPRA, dilute the reconstituted with infusion fluid as soon as possible. The reconstituted solution may be stored in the vial (not the syringe) for a maximum of 1 hour at room temperature and room light.
Before administration, the reconstituted solution must be further diluted with one of the specified infusion fluids listed below. Other infusion fluids should not be used with IXEMPRA.
The IXEMPRA infusion must be prepared in a DEHP [di-(2-ethylhexyl) phthalate] free bag.
The following infusion fluids have been qualified for use in the dilution of IXEMPRA:
Lactated Ringer’s Injection, USP
0.9% Sodium Chloride Injection, USP (pH adjusted with Sodium Bicarbonate Injection, USP)
When using a 250 mL or a 500 mL bag of 0.9% Sodium Chloride Injection to prepare the infusion, the pH must be adjusted to a pH between 6.0 and 9.0 by adding 2 mEq (ie, 2 mL of an 8.4% w/v solution or 4 mL of a 4.2% w/v solution) of Sodium Bicarbonate Injection, prior to the addition of the reconstituted IXEMPRA solution.
For most doses, a 250 mL bag of infusion fluid is sufficient. However, it is necessary to check the final IXEMPRA infusion concentration of each dose based on the volume of infusion fluid to be used.
The final concentration for infusion must be between 0.2 mg/mL and 0.6 mg/mL. To calculate the final infusion concentration, use the following formulas:
1. Aseptically, withdraw the appropriate volume of reconstituted solution containing 2 mg of ixabepilone per mL.
2. Aseptically, transfer to an intravenous bag containing an appropriate volume of infusion fluid to achieve the final desired concentration of IXEMPRA.
3. Thoroughly mix the infusion bag by manual rotation.
4. Once diluted with infusion fluid, the solution is stable at room temperature and room light for a maximum of 6 hours. Administration of diluted IXEMPRA must be completed within this 6-hour period.
The infusion solution must be administered through an appropriate in-line filter with a microporous membrane of 0.2 to 1.2 microns.
DEHP-free infusion containers and administration sets must be used.
Discard any remaining solution according to institutional procedures for hazardous drugs.
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Ixempra Prescribing Information
IXEMPRA is contraindicated in patients who have:
- a neutrophil count <1500 cells/mm3or a platelet count <100,000 cells/mm3[see Warnings and Precautions ].
- a history of severe hypersensitivity to agents containing Cremophor®EL or its derivatives (e.g., polyoxyethylated castor oil)[see Warnings and Precautions ].
IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN
- Baseline neutrophil count <1500 cells/mm3or a platelet count <100,000 cells/mm3.
- Hypersensitivity to drugs formulated with Cremophor®EL .
- IXEMPRA in combination with capecitabine is contraindicated for use in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN..
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/m2in combination with capecitabine or as single agent in breast cancer studies.
In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was increased oin patients with hepatic impairment. IXEMPRA 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
With IXEMPRA single agent therapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reatcitons were increased in patients with hepatic impairment
IXEMPRA is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting. Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting [see Clinical Studies (
In an open-label, multicenter, multinational, randomized trial of 752 patients with metastatic or locally advanced breast cancer, the efficacy and safety of IXEMPRA (40 mg/m2every 3 weeks) in combination with capecitabine (at 1000 mg/m2twice daily for 2 weeks followed by 1 week rest) were assessed in comparison with capecitabine as a single agent (at 1250 mg/m2twice daily for 2 weeks followed by 1 week rest). Patients were previously treated with anthracyclines and taxanes. Patients were required to have demonstrated tumor progression or resistance to taxanes and anthracyclines as follows:
- tumor progression within 3 months of the last anthracycline dose in the metastatic setting or recurrence within 6 months in the adjuvant or neoadjuvant setting, and
- tumor progression within 4 months of the last taxane dose in the metastatic setting or recurrence within 12 months in the adjuvant or neoadjuvant setting.
For anthracyclines, patients who received a minimum cumulative dose of 240 mg/m2of doxorubicin or 360 mg/m2of epirubicin were also eligible.
In this study, the median age of patients was 53 years, 67% were White, 23% were Asian, and 3% were Black; Karnofsky performance status was 70-100%, and 75% had received prior adjuvant or neo-adjuvant chemotherapy. Tumors were ER-positive in 47% of patients, ER-negative in 43%, HER2-positive in 15%, HER2-negative in 61%, and ER-negative, PR-negative, HER2-negative in 25%. The baseline disease characteristics and previous therapies for all patients (n=752) are shown in Table 6.
aFor IXEMPRA plus capecitabine versus capecitabine only, prior treatment in the metastatic setting included cyclophosphamide (25% vs. 23%), fluorouracil (22% vs. 16%), vinorelbine (11% vs. 12%), gemcitabine (9% each arm), carboplatin (9% vs. 7%), liposomal doxorubicin (3% each arm), and cisplatin (2% vs. 3%). | ||
bTumor progression within 3 months in the metastatic setting or recurrence within 6 months in the adjuvant or neoadjuvant setting. | ||
c24% and 21% of patients had received 2 or more taxane-containing regimens in the combination and single agent treatment groups, respectively. | ||
IXEMPRA with capecitabine n=375 | Capecitabine n=377 | |
Site of disease | ||
| Visceral disease (liver or lung) | 316(84%) | 315 (84%) |
| Liver | 245 (65%) | 228(61%) |
| Lung | 180(48%) | 174 (46%) |
| Lymph node | 250 (67%) | 249 (66%) |
| Bone | 168(45%) | 162 (43%) |
| Skin/soft tissue | 60(16%) | 62(16%) |
Number of prior chemotherapy regimens in metastatic setting a | ||
| 0 | 27 ( 7%) | 33 ( 9%) |
| 1 | 179(48%) | 184(49%) |
| 2 | 152(41%) | 138(37%) |
| ≥3 | 17 ( 5%) | 22 ( 6%) |
Anthracycline resistance b | 164(44%) | 165 (44%) |
Taxane Resistance c | ||
| Neoadjuvant/adjuvant setting | 40(11%) | 44(12%) |
| Metastatic setting | 327 (87%) | 319 (85%) |
The patients in the combination treatment group received a median of 5 cycles of treatment and patients in the capecitabine single-agent treatment group received a median of 4 cycles of treatment.
The major efficacy outcome measures of the study was progression-free survival (PFS) defined as time from randomization to radiologic progression as determined by Independent Radiologic Review (IRR), clinical progression of measurable skin lesions or death from any cause. Additional efficacy outcome measures included objective tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST), response duration, and overall survival.
IXEMPRA in combination with capecitabine resulted in a statistically significant improvement in PFS compared to capecitabine. The results of the study are presented in Table 7and Figure 1.
aStratified by visceral metastasis in liver/lung, prior chemotherapy in metastatic setting, and anthracycline resistance. | ||
bCochran-Mantel-Haenszel test | ||
Efficacy Parameter | IXEMPRA with capecitabine n=375 | Capecitabine n=377 |
| PFS | ||
| Number of events | 242 | 256 |
| Median | 5.7 months | 4.1 months |
| (95% Cl) | (4.8 - 6.7) | (3.1 - 4.3) |
| Hazard Ratio (95% Cl) | 0.69 (0.58 - 0.83) | |
| p-valuea(Log rank) | <0.0001 | |
| Objective Tumor Response Rate | 34.7% | 14.3% |
| (95% Cl) | (29.9 - 39.7) | (10.9 -18.3) |
| p-valuea,b(CMH) | <0.0001 | |
| Duration of Response, Median | 6.4 months | 5.6 months |
| (95% Cl) | (5.6 - 7.1) | (4.2 - 7.5) |
There was no statistically significant difference in overall survival between treatment arms in this study, as well as in a second similar study. In the study described above, the median overall survivals were 12.9 months (95% Cl: 11.5, 14.2) in the combination therapy arm and 11.1 months (95% Cl: 10.0,12.5) in the capecitabine alone arm [Hazard Ratio 90 (95% Cl: 0.77,1.05), p-value=0.19j.
In the second trial, comparing IXEMPRA in combination with capecitabine versus capecitabine alone, conducted in 1221 patients pretreated with an anthracycline and a taxane, the median overall survival was 16.4 months (95% Cl: 15.0,17.9) in the combination therapy arm and 15.6 months (95% Cl: 13.9,17.0), in the capecitabine alone arm [Hazard Ratio 0.90 (95% Cl: 0.78,1.03), p-value=0.12.
IXEMPRA was evaluated as a single agent in a multicenter single-arm study in 126 women with metastatic or locally advanced breast cancer. The study enrolled patients whose tumors had recurred or had progressed following two or more chemotherapy regimens including an anthracycline, a taxane, and capecitabine. Patients who had received a minimum cumulative dose of 240 mg/m2of doxorubicin or 360 mg/m2of epirubicin were also eligible. Tumor progression or recurrence were prospectively defined as follows:
- Disease progression while on therapy in the metastatic setting (defined as progression while on treatment or within 8 weeks of last dose),
- Recurrence within 6 months of the last dose in the adjuvant or neoadjuvant setting (only for anthracycline and taxane),
- HER2-positive patients must also have progressed during or after discontinuation of trastuzumab.
In this study, the median age was 51 years (range, 30-78), and 79% were White, 5% Black, and 2% Asian, Kamofsky performance status was 70-100%, 88% had received two or more prior chemotherapy regimens for metastatic disease, and 86% had liver and/or lung metastases. Tumors were ER-positive in 48% of patients, ER-negative in 44%, HER2-positive in 7%, HER2-negative in 72%, and ER-negative, PR-negative, HER2-negative in 33%.
IXEMPRA was administered at a dose of 40 mg/m2intravenously over 3 hours every 3 weeks. Patients received a median of 4 cycles (range 1 to 18) of IXEMPRA therapy.
Objective tumor response was determined by independent radiologic and investigator review using RECIST. Efficacy results are presented in Table 8.
aAll responses were partial. | |
bAs assessed by IRR. | |
Endpoint | Result |
| Objective tumor response rate (95% Cl) | |
| 12.4% (6.9 -19.9) 18.3% (11.9-26.1) |
| Time to responseb(n=14) | |
| 6.1 (5 - 54.4) |
| Duration of responseb(n=14) | |
| 6.0 (5.0 - 7.6) |
IXEMPRA is indicated as a single agent for the treatment of patients with metastatic or locally advanced breast cancer whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine [see Clinical Studies (
In an open-label, multicenter, multinational, randomized trial of 752 patients with metastatic or locally advanced breast cancer, the efficacy and safety of IXEMPRA (40 mg/m2every 3 weeks) in combination with capecitabine (at 1000 mg/m2twice daily for 2 weeks followed by 1 week rest) were assessed in comparison with capecitabine as a single agent (at 1250 mg/m2twice daily for 2 weeks followed by 1 week rest). Patients were previously treated with anthracyclines and taxanes. Patients were required to have demonstrated tumor progression or resistance to taxanes and anthracyclines as follows:
- tumor progression within 3 months of the last anthracycline dose in the metastatic setting or recurrence within 6 months in the adjuvant or neoadjuvant setting, and
- tumor progression within 4 months of the last taxane dose in the metastatic setting or recurrence within 12 months in the adjuvant or neoadjuvant setting.
For anthracyclines, patients who received a minimum cumulative dose of 240 mg/m2of doxorubicin or 360 mg/m2of epirubicin were also eligible.
In this study, the median age of patients was 53 years, 67% were White, 23% were Asian, and 3% were Black; Karnofsky performance status was 70-100%, and 75% had received prior adjuvant or neo-adjuvant chemotherapy. Tumors were ER-positive in 47% of patients, ER-negative in 43%, HER2-positive in 15%, HER2-negative in 61%, and ER-negative, PR-negative, HER2-negative in 25%. The baseline disease characteristics and previous therapies for all patients (n=752) are shown in Table 6.
aFor IXEMPRA plus capecitabine versus capecitabine only, prior treatment in the metastatic setting included cyclophosphamide (25% vs. 23%), fluorouracil (22% vs. 16%), vinorelbine (11% vs. 12%), gemcitabine (9% each arm), carboplatin (9% vs. 7%), liposomal doxorubicin (3% each arm), and cisplatin (2% vs. 3%). | ||
bTumor progression within 3 months in the metastatic setting or recurrence within 6 months in the adjuvant or neoadjuvant setting. | ||
c24% and 21% of patients had received 2 or more taxane-containing regimens in the combination and single agent treatment groups, respectively. | ||
IXEMPRA with capecitabine n=375 | Capecitabine n=377 | |
Site of disease | ||
| Visceral disease (liver or lung) | 316(84%) | 315 (84%) |
| Liver | 245 (65%) | 228(61%) |
| Lung | 180(48%) | 174 (46%) |
| Lymph node | 250 (67%) | 249 (66%) |
| Bone | 168(45%) | 162 (43%) |
| Skin/soft tissue | 60(16%) | 62(16%) |
Number of prior chemotherapy regimens in metastatic setting a | ||
| 0 | 27 ( 7%) | 33 ( 9%) |
| 1 | 179(48%) | 184(49%) |
| 2 | 152(41%) | 138(37%) |
| ≥3 | 17 ( 5%) | 22 ( 6%) |
Anthracycline resistance b | 164(44%) | 165 (44%) |
Taxane Resistance c | ||
| Neoadjuvant/adjuvant setting | 40(11%) | 44(12%) |
| Metastatic setting | 327 (87%) | 319 (85%) |
The patients in the combination treatment group received a median of 5 cycles of treatment and patients in the capecitabine single-agent treatment group received a median of 4 cycles of treatment.
The major efficacy outcome measures of the study was progression-free survival (PFS) defined as time from randomization to radiologic progression as determined by Independent Radiologic Review (IRR), clinical progression of measurable skin lesions or death from any cause. Additional efficacy outcome measures included objective tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST), response duration, and overall survival.
IXEMPRA in combination with capecitabine resulted in a statistically significant improvement in PFS compared to capecitabine. The results of the study are presented in Table 7and Figure 1.
aStratified by visceral metastasis in liver/lung, prior chemotherapy in metastatic setting, and anthracycline resistance. | ||
bCochran-Mantel-Haenszel test | ||
Efficacy Parameter | IXEMPRA with capecitabine n=375 | Capecitabine n=377 |
| PFS | ||
| Number of events | 242 | 256 |
| Median | 5.7 months | 4.1 months |
| (95% Cl) | (4.8 - 6.7) | (3.1 - 4.3) |
| Hazard Ratio (95% Cl) | 0.69 (0.58 - 0.83) | |
| p-valuea(Log rank) | <0.0001 | |
| Objective Tumor Response Rate | 34.7% | 14.3% |
| (95% Cl) | (29.9 - 39.7) | (10.9 -18.3) |
| p-valuea,b(CMH) | <0.0001 | |
| Duration of Response, Median | 6.4 months | 5.6 months |
| (95% Cl) | (5.6 - 7.1) | (4.2 - 7.5) |
There was no statistically significant difference in overall survival between treatment arms in this study, as well as in a second similar study. In the study described above, the median overall survivals were 12.9 months (95% Cl: 11.5, 14.2) in the combination therapy arm and 11.1 months (95% Cl: 10.0,12.5) in the capecitabine alone arm [Hazard Ratio 90 (95% Cl: 0.77,1.05), p-value=0.19j.
In the second trial, comparing IXEMPRA in combination with capecitabine versus capecitabine alone, conducted in 1221 patients pretreated with an anthracycline and a taxane, the median overall survival was 16.4 months (95% Cl: 15.0,17.9) in the combination therapy arm and 15.6 months (95% Cl: 13.9,17.0), in the capecitabine alone arm [Hazard Ratio 0.90 (95% Cl: 0.78,1.03), p-value=0.12.
IXEMPRA was evaluated as a single agent in a multicenter single-arm study in 126 women with metastatic or locally advanced breast cancer. The study enrolled patients whose tumors had recurred or had progressed following two or more chemotherapy regimens including an anthracycline, a taxane, and capecitabine. Patients who had received a minimum cumulative dose of 240 mg/m2of doxorubicin or 360 mg/m2of epirubicin were also eligible. Tumor progression or recurrence were prospectively defined as follows:
- Disease progression while on therapy in the metastatic setting (defined as progression while on treatment or within 8 weeks of last dose),
- Recurrence within 6 months of the last dose in the adjuvant or neoadjuvant setting (only for anthracycline and taxane),
- HER2-positive patients must also have progressed during or after discontinuation of trastuzumab.
In this study, the median age was 51 years (range, 30-78), and 79% were White, 5% Black, and 2% Asian, Kamofsky performance status was 70-100%, 88% had received two or more prior chemotherapy regimens for metastatic disease, and 86% had liver and/or lung metastases. Tumors were ER-positive in 48% of patients, ER-negative in 44%, HER2-positive in 7%, HER2-negative in 72%, and ER-negative, PR-negative, HER2-negative in 33%.
IXEMPRA was administered at a dose of 40 mg/m2intravenously over 3 hours every 3 weeks. Patients received a median of 4 cycles (range 1 to 18) of IXEMPRA therapy.
Objective tumor response was determined by independent radiologic and investigator review using RECIST. Efficacy results are presented in Table 8.
aAll responses were partial. | |
bAs assessed by IRR. | |
Endpoint | Result |
| Objective tumor response rate (95% Cl) | |
| 12.4% (6.9 -19.9) 18.3% (11.9-26.1) |
| Time to responseb(n=14) | |
| 6.1 (5 - 54.4) |
| Duration of responseb(n=14) | |
| 6.0 (5.0 - 7.6) |
- The recommended dosage of IXEMPRA is 40 mg/m
2 administered as a 3-hour intravenous infusion once every 3 weeks ().2.2 Recommended DosageThe recommended dosage of IXEMPRA is 40 mg/m2administered intravenously over 3 hours every 3 weeks. Calculate doses for patients with body surface area (BSA) greater than 2.2 m2should be calculated based on 2.2 m2.
Dose reduction is required in patients with elevated AST, ALT, or bilirubin.(
IXEMPRA is a hazardous drug. Follow aplicable special handling and disposal procedures.1
IXEMPRA
1. Prior to reconstituting, remove the IXEMPRA Kit from the refrigerator and allow it to stand at room temperature for approximately 30 minutes. When the vials are first removed from the refrigerator, a white precipitate may be observed in the DILUENT vial. This precipitate will dissolve to form a clear solution once the DILUENT warms to room temperature.
2. With a suitable syringe, aseptically withdraw the DILUENT and slowly inject it into the IXEMPRA for injection vial. The 15-mg IXEMPRA is reconstituted with 8 mL of DILUENT and the 45-mg IXEMPRA is reconstituted with 23.5 mL of DILUENT.
3. Gently swirl and invert the vial until the powder in IXEMPRA is completely dissolved.
4. After reconstituting with the DILUENT, the concentration of ixabepilone is 2 mg/mL.
5. After reconstituting IXEMPRA, dilute the reconstituted with infusion fluid as soon as possible. The reconstituted solution may be stored in the vial (not the syringe) for a maximum of 1 hour at room temperature and room light.
Before administration, the reconstituted solution must be further diluted with one of the specified infusion fluids listed below. Other infusion fluids should not be used with IXEMPRA.
The IXEMPRA infusion must be prepared in a DEHP [di-(2-ethylhexyl) phthalate] free bag.
The following infusion fluids have been qualified for use in the dilution of IXEMPRA:
Lactated Ringer’s Injection, USP
0.9% Sodium Chloride Injection, USP (pH adjusted with Sodium Bicarbonate Injection, USP)
When using a 250 mL or a 500 mL bag of 0.9% Sodium Chloride Injection to prepare the infusion, the pH must be adjusted to a pH between 6.0 and 9.0 by adding 2 mEq (ie, 2 mL of an 8.4% w/v solution or 4 mL of a 4.2% w/v solution) of Sodium Bicarbonate Injection, prior to the addition of the reconstituted IXEMPRA solution.
- PLASMA-LYTE A Injection pH 7.4®
For most doses, a 250 mL bag of infusion fluid is sufficient. However, it is necessary to check the final IXEMPRA infusion concentration of each dose based on the volume of infusion fluid to be used.
The final concentration for infusion must be between 0.2 mg/mL and 0.6 mg/mL. To calculate the final infusion concentration, use the following formulas:
1. Aseptically, withdraw the appropriate volume of reconstituted solution containing 2 mg of ixabepilone per mL.
2. Aseptically, transfer to an intravenous bag containing an appropriate volume of infusion fluid to achieve the final desired concentration of IXEMPRA.
3. Thoroughly mix the infusion bag by manual rotation.
4. Once diluted with infusion fluid, the solution is stable at room temperature and room light for a maximum of 6 hours. Administration of diluted IXEMPRA must be completed within this 6-hour period.
The infusion solution must be administered through an appropriate in-line filter with a microporous membrane of 0.2 to 1.2 microns.
DEHP-free infusion containers and administration sets must be used.
Discard any remaining solution according to institutional procedures for hazardous drugs.
- IXEMPRA must be reconstituted with the supplied DILUENT and further diluted to a concentration of 0.2 mg/mL to 0.6 mg/mL prior to administration ( ).
2.6 Preparation and AdministrationIXEMPRA is a hazardous drug. Follow aplicable special handling and disposal procedures.1
IXEMPRA
Kitcontains two vials, a vial labeled IXEMPRA (ixabepilone) for injection which contains ixabepilone powder and a vial containing DILUENT for IXEMPRA. Use only the supplied DILUENT to reconstitute IXEMPRA (ixabepilone) for injection.Reconstituation1. Prior to reconstituting, remove the IXEMPRA Kit from the refrigerator and allow it to stand at room temperature for approximately 30 minutes. When the vials are first removed from the refrigerator, a white precipitate may be observed in the DILUENT vial. This precipitate will dissolve to form a clear solution once the DILUENT warms to room temperature.
2. With a suitable syringe, aseptically withdraw the DILUENT and slowly inject it into the IXEMPRA for injection vial. The 15-mg IXEMPRA is reconstituted with 8 mL of DILUENT and the 45-mg IXEMPRA is reconstituted with 23.5 mL of DILUENT.
3. Gently swirl and invert the vial until the powder in IXEMPRA is completely dissolved.
4. After reconstituting with the DILUENT, the concentration of ixabepilone is 2 mg/mL.
5. After reconstituting IXEMPRA, dilute the reconstituted with infusion fluid as soon as possible. The reconstituted solution may be stored in the vial (not the syringe) for a maximum of 1 hour at room temperature and room light.
DilutionBefore administration, the reconstituted solution must be further diluted with one of the specified infusion fluids listed below. Other infusion fluids should not be used with IXEMPRA.
The IXEMPRA infusion must be prepared in a DEHP [di-(2-ethylhexyl) phthalate] free bag.
The following infusion fluids have been qualified for use in the dilution of IXEMPRA:
Lactated Ringer’s Injection, USP
0.9% Sodium Chloride Injection, USP (pH adjusted with Sodium Bicarbonate Injection, USP)
When using a 250 mL or a 500 mL bag of 0.9% Sodium Chloride Injection to prepare the infusion, the pH must be adjusted to a pH between 6.0 and 9.0 by adding 2 mEq (ie, 2 mL of an 8.4% w/v solution or 4 mL of a 4.2% w/v solution) of Sodium Bicarbonate Injection, prior to the addition of the reconstituted IXEMPRA solution.
- PLASMA-LYTE A Injection pH 7.4®
For most doses, a 250 mL bag of infusion fluid is sufficient. However, it is necessary to check the final IXEMPRA infusion concentration of each dose based on the volume of infusion fluid to be used.
The final concentration for infusion must be between 0.2 mg/mL and 0.6 mg/mL. To calculate the final infusion concentration, use the following formulas:
Total Infusion Volume= mL of Reconstituted Solution + mL of infusion fluidFinal Infusion Concentration= Dose of IXEMPRA (mg)/Total Infusion Volume (mL)1. Aseptically, withdraw the appropriate volume of reconstituted solution containing 2 mg of ixabepilone per mL.
2. Aseptically, transfer to an intravenous bag containing an appropriate volume of infusion fluid to achieve the final desired concentration of IXEMPRA.
3. Thoroughly mix the infusion bag by manual rotation.
4. Once diluted with infusion fluid, the solution is stable at room temperature and room light for a maximum of 6 hours. Administration of diluted IXEMPRA must be completed within this 6-hour period.
AdministrationThe infusion solution must be administered through an appropriate in-line filter with a microporous membrane of 0.2 to 1.2 microns.
DEHP-free infusion containers and administration sets must be used.
Discard any remaining solution according to institutional procedures for hazardous drugs.
IXEMPRA for injection, 15 mg single-dose vial supplied with DILUENT for IXEMPRA, 8 mL.
IXEMPRA for injection, 45 mg single-dose vial supplied with DILUENT for IXEMPRA, 23.5 mL.
- Lactation: Advise not to breastfeed ().
8.2 LactationRisk SummaryThere is no data on the presence of IXEMPRA in human milk, the effects on the breastfed child, or the effects on milk production. Ixabepilone and/or its metabolites were present in milk of lactating rats (see Data). Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with IXEMPRA and for 2 weeks after the last dose.
DataAnimal dataFollowing intravenous administration of radiolabeled ixabepilone to rats on days 7 to 9 postpartum, concentrations of radioactivity in milk were comparable with those in plasma and declined in parallel with the plasma concentrations.
- Hepatic Impairment: Reduce the dosage in patients with elevated AST, ALT, or bilirubin (,
2.4 Dosage Modifications in Patients with Hepatic ImpairmentDosage Modifications in Patients with Hepatic ImpairmentCombination TherapyIXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN
[see Contraindications (4)].Single AgentReduce the dose of IXEMPRA for patients with hepaptic impairment as recommended in Table 2.
[see Warnings and Precautions and Use in Specific Populations ].Table 2: Dose Modifications for IXEMPRA as a Single Agent for Patients with Hepatic Impairment aExcluding patients whose total bilirubin is elevated due to Gilbert's disease.
bDosage recommendations are for first course of therapy; further decreases in subsequent courses should be based on individual tolerance.
cFor patients with AST and ALT ≤ 10x ULN and lilirubin >1.5 to 3x ULN, consider increasing the dose from 20mg/m2to 30mg/m2in subsequent cycles if a dose of 20 mg/m2is tolerated.
TransaminaseLevelsBilirubinLevelsaIXEMPRAb(mg/m2AST and ALT ≤2.5 x ULN and ≤1 x ULN No Modification AST and ALT ≤10x ULN and ≤1.5 x ULN 32 AST and ALT ≤10 x ULN and >1.5 to ≤3 x ULN 20-30c AST and ALT > 10 x ULN or >3 x ULN Avoid Use ).8.6 Hepatic ImpairmentMonitor hepatic function before initiation of IXEMPRA and periodically thereafter.
Dose reduction is recommended when administering IXEMPRA as a single agent to patients with hepatic impairment [see Dosage and Administration ].
IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Contraindications ].
The alcohol content of IXEMPRA should be taken into account when given to patients with hepatic impairment [see Warnings and Precautions ].
IXEMPRA is contraindicated in patients who have:
- a neutrophil count <1500 cells/mm
3 or a platelet count <100,000 cells/mm
3 [see Warnings and Precautions ()].5.2 MyelosuppressionSevere, life-threatening, or fatal myelosuppression can occur in patients treated with IXEMPRA. Myelosuppression is dose-dependent and primarily manifests as neutropenia. In clinical studies, grade 4 neutropenia (<500 cells/mm3) occurred in 36% of patients treated with IXEMPRA in combination with capecitabine and 23% of patients treated with single agent IXEMPRA monotherapy. Febrile neutropenia and infection with neutropenia were reported in 5% and 6% of patients treated with IXEMPRA in combination with capecitabine, respectively, and 3% and 5% of patients treated with IXEMPRA as a single agent, respectively. Neutropenia-related death occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. The rate of neutropenia-related deaths was higher (29%, 5 out of 17) in patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN
[see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.3)]. Neutropenia-related death occurred in 0.4% of 240 patients treated with IXEMPRA as a single agent. No neutropenia-related deaths were reported in 24 patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN treated with IXEMPRA as a single agent.IXEMPRA is contraindicated for use in patients with a neutrophil count of <1500 cells/mm3.
[see Contraindications (4)].Monitor patients receiving IXEMPRA for myelosuppression with frequent peripheral blood cell counts. Withhold, reduce, or discontinue IXEMPRA depending on the severity and persistence of myelosuppression
[see Dosage and Administration (2.3)]. - a history of severe hypersensitivity to agents containing Cremophor
® EL or its derivatives (e.g., polyoxyethylated castor oil)[see Warnings and Precautions ()].5.4 Hypersensitivity ReactionsIXEMPRA is contraindicated in patients with a history of a severe hypersensitivity reaction to agents containing Cremophor®EL or its derivatives (eg, polyoxyethylated castor oil) [
see Contraindications (4)].Of the 1323 patients treated with IXEMPRA in clinical studies, 9 patients (1 %) had experienced severe hypersensitivity reactions (including anaphylaxis). Three of the 9 patients were able to be retreated. Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H1and H2antagonists, and extension of the infusion time should be considered
[see Dosage and Administration and Contraindications ]Administer an H1and H2antagonist approximately 1 hour before IXEMPRA infusion and observe patients for hypersensitivity reaction occur, stop the infusion of IXEMPRA provide supportive treatment as clinically indicated (e.g.. epinephrine, corticosteriods).
IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN
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/m2in combination with capecitabine or as single agent in breast cancer studies.
In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was increased oin patients with hepatic impairment. IXEMPRA 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
With IXEMPRA single agent therapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reatcitons were increased in patients with hepatic impairment