Ixempra Side Effects

Generic Name: ixabepilone

Please note - some side effects for Ixempra may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Ixempra - for the Consumer

Ixempra

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Ixempra:

Constipation; diarrhea; dizziness; fingernail or toenail changes; hair loss; headache; loss of appetite; mild fever; mild joint or muscle pain; mouth sores; nausea; stomach pain or upset; taste changes; tiredness or weakness; trouble sleeping; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Ixempra:

Severe allergic reactions (rash; hives; itching; flushing; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, throat, or tongue); chest pain or tightness; fainting; fast or irregular heartbeat; numbness, tingling, or burning of the hands or feet; pain, swelling, redness, or blistering at the injection site; redness, tenderness, or dryness of the palms of hands or soles of feet; severe or persistent dizziness; severe or persistent nausea, vomiting, or diarrhea; severe tiredness or weakness; shortness of breath; signs of an infection (eg, fever, chills, cough, sore throat, burning or painful urination); swelling of the arms, hands, legs, or feet; unusual bruising or bleeding; unusual weight gain.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Ixempra Side Effects - for the Professional

Ixempra

The following adverse reactions are discussed in greater detail in other sections.

• Peripheral neuropathy [see Warnings and Precautions (5.1)]
• Myelosuppression [see Warnings and Precautions (5.2)]
• Hypersensitivity reactions [see Warnings and Precautions (5.4)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

Unless otherwise specified, assessment of adverse reactions is based on one randomized study (Study 046) and one single-arm study (Study 081). In Study 046, 369 patients with metastatic breast cancer were treated with Ixempra 40 mg/m2 administered intravenously over 3 hours every 21 days, combined with capecitabine 1000 mg/m2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated with capecitabine as monotherapy (n=368) in this study received 1250 mg/m2 twice daily for 2 weeks every 21 days. In Study 081, 126 patients with metastatic or locally advanced breast cancer were treated with Ixempra 40 mg/m2 administered intravenously over 3 hours every 3 weeks.

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 reactions occurred in ≥20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. The most common hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia.

Table 4 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 5.

Table 4: Nonhematologic Drug-related Adverse Reactions Occurring in at Least 5% of Patients with Metastatic or Locally Advanced Breast Cancer Treated with Ixempra

	Study 046				Study 081
	Ixempra with capecitabine n=369		Capecitabine n=368		Ixempra monotherapy n=126
System Organ Classa/ Preferred Term	Total (%)	Grade 3/4 (%)	Total (%)	Grade 3/4 (%)	Total (%)	Grade 3/4 (%)
a System organ class presented as outlined in Guidelines for Preparing Core Clinical Safety Information on Drugs by the Council for International Organizations of Medical Sciences (CIOMS).
b A composite of multiple MedDRA Preferred Terms.
c NCI CTC grading for febrile neutropenia ranges from Grade 3 to 5. Three patients (1%) experienced Grade 5 (fatal) febrile neutropenia. Other neutropenia-related deaths (9) occurred in the absence of reported febrile neutropenia [see Warnings and Precautions (5.2)].
d No grade 4 reports.
e Peripheral sensory neuropathy (graded with the NCI CTC scale) was defined as the occurrence of any of the following: areflexia, burning sensation, dysesthesia, hyperesthesia, hypoesthesia, hyporeflexia, neuralgia, neuritis, neuropathy, neuropathy peripheral, neurotoxicity, painful response to normal stimuli, paresthesia, pallanesthesia, peripheral sensory neuropathy, polyneuropathy, polyneuropathy toxic and sensorimotor disorder. Peripheral motor neuropathy was defined as the occurrence of any of the following: multifocal motor neuropathy, neuromuscular toxicity, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.
f Palmar-plantar erythrodysesthesia (hand-foot syndrome) was graded on a 1-3 severity scale in Study 046.
Infections and Infestations
Upper respiratory tract infectionb	4	0	3	0	6	0
Blood and Lymphatic System Disorders
Febrile neutropenia	5	4c	1	1d	3	3d
Immune System Disorders
Hypersensitivityb	2	1d	0	0	5	1d
Metabolism and Nutrition Disorders
Anorexiab	34	3d	15	1d	19	2d
Dehydrationb	5	2	2	<1d	2	1d
Psychiatric Disorders
Insomniab	9	<1d	2	0	5	0
Nervous System Disorders
Peripheral neuropathy
Sensory neuropathyb,e	65	21	16	0	62	14
Motor neuropathyb	16	5d	<1	0	10	1d
Headache	8	<1d	3	0	11	0
Taste disorderb	12	0	4	0	6	0
Dizziness	8	1d	5	1d	7	0
Eye Disorders
Lacrimation increased	5	0	4	<1d	4	0
Vascular Disorders
Hot flushb	5	0	2	0	6	0
Respiratory, Thoracic, and Mediastinal Disorders
Dyspneab	7	1	4	1	9	1d
Coughb	6	0	2	0	2	0
Gastrointestinal Disorders
Nausea	53	3d	40	2d	42	2d
Vomitingb	39	4d	24	2	29	1d
Stomatitis/mucositisb	31	4	20	3d	29	6
Diarrheab	44	6d	39	9	22	1d
Constipation	22	0	6	<1d	16	2d
Abdominal painb	24	2d	14	1d	13	2d
Gastroesophageal reflux diseaseb	7	1d	8	0	6	0
Skin and Subcutaneous Tissue Disorders
Alopeciab	31	0	3	0	48	0
Skin rashb	17	1d	7	0	9	2d
Nail disorderb	24	2d	10	<1d	9	0
Palmar-plantar erythrodysesthesia syndromeb,f	64	18d	63	17d	8	2d
Pruritus	5	0	2	0	6	1d
Skin exfoliationb	5	<1d	3	0	2	0
Skin hyperpigmentationb	11	0	14	0	2	0
Musculoskeletal, Connective Tissue, and Bone Disorders
Myalgia/arthralgiab	39	8d	5	<1d	49	8d
Musculoskeletal painb	23	2d	5	0	20	3d
General Disorders and Administration Site Conditions
Fatigue/astheniab	60	16	29	4	56	13
Edemab	8	0	5	<1d	9	1d
Pyrexia	10	1d	4	0	8	1d
Painb	9	1d	2	0	8	3d
Chest painb	4	1d	<1	0	5	1d
Investigations
Weight decreased	11	0	3	0	6	0

Table 5: Hematologic Abnormalities in Patients with Metastatic or Locally Advanced Breast Cancer Treated with Ixempra

	Study 046				Study 081
	Ixempra with capecitabine n=369		Capecitabine n=368		Ixempra monotherapy n=126
Hematology Parameter	Grade 3 (%)	Grade 4 (%)	Grade 3 (%)	Grade 4 (%)	Grade 3 (%)	Grade 4 (%)
a G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte macrophage colony stimulating factor) was used in 20% and 17% of patients who received Ixempra in Study 046 and Study 081, respectively.
Neutropeniaa	32	36	9	2	31	23
Leukopenia (WBC)	41	16	5	1	36	13
Anemia (Hgb)	8	2	4	1	6	2
Thrombocytopenia	5	3	2	2	5	2

The following serious adverse reactions were also reported in 1323 patients treated with Ixempra as monotherapy or in combination with other therapies in Phase 2 and 3 studies.

Infections and Infestations: sepsis, pneumonia, infection, neutropenic infection, urinary tract infection, bacterial infection, enterocolitis, laryngitis, lower respiratory tract infection

Blood and Lymphatic System Disorders: coagulopathy, lymphopenia

Metabolism and Nutrition Disorders: hyponatremia, metabolic acidosis, hypokalemia, hypovolemia

Nervous System Disorders: cognitive disorder, syncope, cerebral hemorrhage, abnormal coordination, lethargy

Cardiac Disorders: myocardial infarction, supraventricular arrhythmia, left ventricular dysfunction, angina pectoris, atrial flutter, cardiomyopathy, myocardial ischemia

Vascular Disorders: hypotension, thrombosis, embolism, hemorrhage, hypovolemic shock, vasculitis

Respiratory, Thoracic, and Mediastinal Disorders: pneumonitis, hypoxia, respiratory failure, acute pulmonary edema, dysphonia, pharyngolaryngeal pain

Gastrointestinal Disorders: ileus, colitis, impaired gastric emptying, esophagitis, dysphagia, gastritis, gastrointestinal hemorrhage

Hepatobiliary Disorders: acute hepatic failure, jaundice

Skin and Subcutaneous Tissue Disorders: erythema multiforme

Musculoskeletal, Connective Tissue, and Bone Disorders: muscular weakness, muscle spasms, trismus

Renal and Urinary Disorders: nephrolithiasis, renal failure

General Disorders and Administration Site Conditions: chills

Investigations: increased transaminases, increased blood alkaline phosphatase, increased gamma-glutamyltransferase

Postmarketing Experience

Radiation recall has been reported during postmarketing use of Ixempra. Because this reaction was reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

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Side Effects by Body System - for Healthcare Professionals

Hematologic

Myelosuppression manifesting primarily as neutropenia can occur. It is generally dose-dependent and can result in infection or death. In clinical studies, grade 4 neutropenia (less than 500 cells/mm3) occurred in 36% of patients treated with ixabepilone in combination with capecitabine and 23% of patients treated with ixabepilone monotherapy. Patients should be monitored for myelosuppression with frequent peripheral blood cell counts. Dosage reduction should be instituted in patients who experience severe neutropenia or thrombocytopenia.

Hematologic side effects have included neutropenia, leukopenia, anemia, and thrombocytopenia in more than 40% of patients. Coagulopathy and lymphopenia have also been reported.

Hypersensitivity

Hypersensitivity reactions have been reported during ixabepilone use. Patients with a history of severe hypersensitivity reactions to agents containing polyoxyethylated castor oil should not be treated with ixabepilone. All patients should be premedicated with an H1 and an H2 antagonist approximately one hour before ixabepilone infusion and be observed for hypersensitivity reactions (e.g., flushing, rash, dyspnea and bronchospasm). If a severe hypersensitivity reaction occurs, ixabepilone infusion should be stopped and aggressive supportive treatment (e.g., epinephrine, corticosteroids) started. Patients experiencing a hypersensitivity reaction in one cycle of ixabepilone treatment must be premedicated in subsequent cycles with a corticosteroid in addition to the H1 and H2 antagonists. Extension of the infusion time should also be considered.

Of the 1323 patients treated with ixabepilone in clinical studies, nine patients (1%) experienced severe hypersensitivity reactions including anaphylaxis, and three of the 9 were able to be retreated.

Nervous system

Peripheral neuropathy is a commonly reported side effect associated with ixabepilone, often occurring early during treatment. Patients should be monitored for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. A reduction or delay in the dose of ixabepilone may be required in patients experiencing new or worsening symptoms. Extra caution should be used when treating patients with diabetes mellitus or existing moderate to severe neuropathy.

Nervous system side effects have included peripheral neuropathy, fatigue, and asthenia in more than 20% of patients. Insomnia, headache, dizziness, cognitive disorder, syncope, cerebral hemorrhage, abnormal coordination, lethargy, and hot flush have also been reported.

Cardiovascular

Cardiovascular side effects including myocardial ischemia, ventricular dysfunction, and supraventricular arrhythmias have been associated with ixabepilone use. Chest pain (5%), myocardial infarction, left ventricular dysfunction, angina pectoris, atrial flutter, cardiomyopathy, thrombosis, embolism, hemorrhage, hypovolemic shock, vasculitis and hypotension have also been reported.

The frequency of myocardial ischemia and ventricular dysfunction was higher when ixabepilone was used in combination with capecitabine (1.9%) than with capecitabine monotherapy (0.3%). Supraventricular arrhythmias were observed in the combination arm (0.5%) and not in the capecitabine monotherapy arm. Caution is recommended in patients with a history of cardiac disease, and discontinuation of ixabepilone should be considered in patients who develop cardiac ischemia or impaired cardiac function.

Musculoskeletal

Musculoskeletal side effects occurring in more than 20% of patients have included myalgia, arthralgia, musculoskeletal pain, and palmar-plantar erythrodysesthesia (hand-foot) syndrome. Muscular weakness, muscle spasms, and trismus have also been reported.

Gastrointestinal

Gastrointestinal side effects have included nausea, vomiting, stomatitis/mucositis, diarrhea, anorexia, abdominal pain, and constipation in more than 20% of patients. Gastroesophageal reflux (6%), taste disorder (6%), ileus, colitis, impaired gastric emptying, esophagitis, dysphagia, gastritis, enterocolitis, and gastrointestinal hemorrhage have also been reported.

Dermatologic

Dermatologic side effects have included alopecia (48%), skin rash (9%), and nail disorder (9%). Pruritus (6%), skin exfoliation, skin hyperpigmentation, and erythema multiforme have also been reported. Radiation recall has been reported during postmarketing use but frequency or causal relationship to drug exposure cannot be established.

Respiratory

Respiratory side effects have included dyspnea (9%), upper respiratory tract infection (6%), and cough. Laryngitis, lower respiratory tract infection, pneumonia, pneumonitis, hypoxia, respiratory failure, acute pulmonary edema, dysphonia, and pharyngolaryngeal pain have also been reported.

Hepatic

Hepatic side effects have included acute hepatic failure, jaundice, increased transaminases, increased blood alkaline phosphatase, and increased gamma-glutamyltransferase.

Renal

Renal side effects have included nephrolithiasis, urinary tract infection, and renal failure.

Metabolic

Metabolic side effects have included hyponatremia, metabolic acidosis, hypokalemia, and hypovolemia.

Ocular

Ocular side effects including increased lacrimation (4%) have been reported.

Other

Other side effects have included edema (9%), pyrexia (8%), pain (8%), decreased weight (6%), sepsis, infection, bacterial infection, neutropenic infection, neutropenic fever, and chills.

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