IXEMPRA: Package Insert and Label Information (Page 4 of 5)

13.2 Animal Toxicology and/or Pharmacology

Overdosage

In rats, single intravenous doses of ixabepilone from 60 to 180 mg/m 2 (mean AUC values ≥8156ng·h/mL) were associated with mortality occurring between 5 and 14 days after dosing, and toxicity was principally manifested in the gastrointestinal, hematopoietic (bone-marrow), lymphatic, peripheral-nervous, and male-reproductive systems. In dogs, a single intravenous dose of 100 mg/m 2 (mean AUC value of 6925 ng·h/mL) was markedly toxic, inducing severe gastrointestinal toxicity and death 3 days after dosing.

14 CLINICAL STUDIES

Combination Therapy

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/m 2 every 3 weeks) in combination with capecitabine (at 1000 mg/m 2 twice daily for 2 weeks followed by 1 week rest) were assessed in comparison with capecitabine as a single agent (at 1250 mg/m 2 twice 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/m 2 of doxorubicin or 360 mg/m 2 of 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.

Table 6: Baseline Disease Characteristics and Previous Therapies

a For 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%).

b Tumor progression within 3 months in the metastatic setting or recurrence within 6 months in the adjuvant or neoadjuvant setting.

c 24% 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%)
Liver245 (65%)228(61%)
Lung180(48%)174 (46%)
Lymph node250 (67%)249 (66%)
Bone168(45%)162 (43%)
Skin/soft tissue60(16%)62(16%)
Number of prior chemotherapy regimens in metastatic setting a
027 ( 7%)33 ( 9%)
1179(48%)184(49%)
2152(41%)138(37%)
≥317 ( 5%)22 ( 6%)
Anthracycline resistance b 164(44%)165 (44%)
Taxane Resistance c
Neoadjuvant/adjuvant setting40(11%)44(12%)
Metastatic setting327 (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 7 and Figure 1.

Table 7: Efficacy of IXEMPRA in Combination with Capecitabine vs Capecitabine Alone — Intent-to-Treat Analysis

a Stratified by visceral metastasis in liver/lung, prior chemotherapy in metastatic setting, and anthracycline resistance.

b Cochran-Mantel-Haenszel test

Efficacy Parameter IXEMPRA with capecitabine n=375 Capecitabine n=377
PFS
Number of events242256
Median5.7 months4.1 months
(95% Cl)(4.8 — 6.7)(3.1 — 4.3)
Hazard Ratio (95% Cl)0.69 (0.58 — 0.83)
p-value a (Log rank) <0.0001
Objective Tumor Response Rate34.7%14.3%
(95% Cl)(29.9 — 39.7)(10.9 -18.3)
p-value a,b (CMH) <0.0001
Duration of Response, Median6.4 months5.6 months
(95% Cl)(5.6 — 7.1)(4.2 — 7.5)

Figure 1: Progression-free Survival Kaplan Meier Curves

Figure 1
(click image for full-size original)

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 as a Single Agent

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/m 2 of doxorubicin or 360 mg/m 2 of 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/m 2 intravenously 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.

Table 8: Efficacy of IXEMPRA in Metastatic and Locally Advanced Breast Cancer

a All responses were partial.

b As assessed by IRR.

Endpoint Result
Objective tumor response rate (95% Cl)
  • IRR Assessment a (n=113)
  • Investigator Assessment (n=126)
12.4% (6.9 -19.9) 18.3% (11.9-26.1)
Time to response b (n=14)
  • Median, weeks (min — max)
6.1 (5 — 54.4)
Duration of response b (n=14)
  • Median, months (95% Cl)
6.0 (5.0 — 7.6)

15 REFERENCES

  1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html OSHA

16 HOW SUPPLIED/STORAGE AND HANDLING

IXEMPRA is supplied as a Kit containing one single-dose vial of IXEMPRA ® (ixabepilone) for injection and one vial of DILUENT for IXEMPRA.

NDC 70020-1910-1 IXEMPRA ® Kit containing one single-dose vial of IXEMPRA ® (ixabepilone) for injection, 15 mg and one vial of DILUENT for IXEMPRA, 8 mL
NDC 70020-1911 -1 IXEMPRA ® Kit containing one single-dose vial of IXEMPRA ® (ixabepilone) for injection, 45 mg and one vial of DILUENT for IXEMPRA, 23.5 mL

IXEMPRA Kit must be stored in a refrigerator at 2° C to 8° C (36° F to 46° F). Retain in original package until time of use to protect from light.

IXEMPRA is a hazardous drug. Follow applicable special handling and disposal procedures. 1

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling

17.1 Peripheral Neuropathy

Advice patients to report any numbness and tingling of the hands or feet to their healthcare provider [see Warnings and Precautions ( 5.1)].

17.2 Fever/Neutropenia

Instruct patients to immediately contact their healthcare provider if a fever of 100.5° F or greater or other evidence of potential infection such as chills, cough, or burning or pain on urination occur [see Warnings and Precautions ( 5.2)].

17.3 Hypersensitivity Reactions

Advise patients to immediately contact their healthcare provider if they experience urticaria, pruritus, rash, flushing, swelling, dyspnea, chest tightness, or other hypersensitivity-related symptoms following an infusion of IXEMPRA [see Warnings and Precautions ( 5.4)].

17.4 Cardiac Adverse Reactions

Advise patients to immediately contact call their healthcare provider if they experience chest pain, difficulty breathing, palpitations, or unusual weight gain [see Warnings and Precautions ( 5.5)].

17.5 Embryo-Fetal Toxicity

Advise females of reproductive potential and pregnant women of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective contraception during treatment with IXEMPRA and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IXEMPRA and for 4 months after the last dose [see Warnings and Precautions ( 5.6) and Use in Specific Populations ( 8.1, 8.3)].

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2023. All Rights Reserved.