ABRAXANE SIDE EFFECTS

SIDE EFFECTS

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

The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea.

The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue. The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%).

In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma, the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%).

Clinical Trials Experience

Metastatic Breast Cancer

Table 1 shows the frequency of important adverse reactions in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.

Table 1: Adverse Reactions in the Randomized Metastatic Breast Cancer Study on an Every-3-WeeksSchedule

	Percent of Patients
	ABRAXANE 260 mg/m² over 30 min (n=229)	Paclitaxel Injection 175 mg/m² over 3 ha (n=225)
Bone Marrow
Neutropenia
< 2.0 x 109/L	80	82
< 0.5 x 109/L	9	22
Thrombocytopenia
< 100 x 109/L	2	3
< 50 x 109/L	<1	<1
Anemia
< 11 g/dL	33	25
< 8 g/dL	1	<1
Infections	24	20
Febrile Neutropenia	2	1
Neutropenic Sepsis	<1	<1
Bleeding	2	2
Hypersensitivity Reactionb
All	4	12
Severec	0	2
Cardiovascular
Vital Sign Changes During Administration
Bradycardia	<1	<1
Hypotension	5	5
Severe Cardiovascular Eventsc	3	4
Abnormal ECG
All Patients	60	52
Patients with Normal Baseline	35	30
Respiratory
Cough	7	6
Dyspnea	12	9
Sensory Neuropathy
Any Symptoms	71	56
Severe Symptomsc	10	2
Myalgia / Arthralgia
Any Symptoms	44	49
Severe Symptomsc	8	4
Asthenia
Any Symptoms	47	39
Severe Symptomsc	8	3
Fluid Retention/Edema
Any Symptoms	10	8
Severe Symptomsc	0	<1
Gastrointestinal
Nausea
Any Symptoms	30	22
Severe Symptomsc	3	<1
Vomiting
Any Symptoms	18	10
Severe Symptomsc	4	1
Diarrhea
Any Symptoms	27	15
Severe Symptomsc	<1	1
Mucositis
Any Symptoms	7	6
Severe Symptomsc	<1	0
Alopecia	90	94
Hepatic (Patients with Normal Baseline)
Bilirubin Elevations	7	7
Alkaline Phosphatase Elevations	36	31
AST (SGOT) Elevations	39	32
Injection Site Reaction	<1	1
a Paclitaxel injection patients received premedication. b Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. c Severe events are defined as at least Grade 3 toxicity.

 

Other Adverse Reactions

Hematologic Disorders

Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm³ (Grade 4) in 9% of the patients treated with a dose of 260 mg/m² compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m². Pancytopenia has been observed in clinical trials.

Infections

Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.

Hypersensitivity Reactions (HSRs)

Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

Cardiovascular

Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation.

Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported.

Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia.

Respiratory

Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE.

Neurologic

The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy.

No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial.

Vision Disorders

Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m²). These effects generally have been reversible.

Arthralgia/Myalgia

The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days.

Hepatic

Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.

Renal

Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities.

Other Clinical Events

Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported.

Non-Small Cell Lung Cancer

Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m² on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m², following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion.

The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose-and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment.

The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatintreated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group).

Table 2 provides the frequency and severity of laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.

Table 2: Selected Hematologic Laboratory-Detected Abnormalities with a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups

	ABRAXANE (100 mg/m² weekly) plus carboplatin		Paclitaxel Injection (200 mg/m² every 3 weeks) plus carboplatin
	Grades 1-4 (%)	Grade 3-4 (%)	Grades 1-4 (%)	Grade 3-4 (%)
Anemia1,2	98	28	91	7
Neutropenia1,3	85	47	83	58
Thrombocytopenia1,3	68	18	55	9
1 508 patients assessed in ABRAXANE/carboplatin-treated group. 2 514 patients assessed in paclitaxel injection/carboplatin-treated group. 3 513 patients assessed in paclitaxel injection/carboplatin-treated group.

 

Table 3 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.

Table 3: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups

System Organ Class	Adverse Reaction	ABRAXANE (100 mg/m² weekly) + carboplatin (N=514)		Paclitaxel Injection (200 mg/m² every 3 weeks) + carboplatin (N=524)
		Grade 1-4 Toxicity (%)	Grade 3-4 Toxicity (%)	Grades 1-4 Toxicity (%)	Grade 3-4 Toxicity (%)
Nervous system disorders	Peripheral neuropathya	48	3	64	12
General disorders and administration site conditions	Edema peripheral	10	0	4	<1
Respiratory thoracic and mediastinal disorders	Epistaxis	7	0	2	0
	Arthralgia	13	<1	25	2
Musculoskeletal and connective tissue disorders	Myalgia	10	<1	19	2
a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).

 

For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE.

Adenocarcinoma Of The Pancreas

Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%.

Table 4 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 14 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients.

Table 4: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm

	ABRAXANE (125 mg/m²)/ Gemcitabined		Gemcitabine
	Grades 1-4 (%)	Grade 3-4 (%)	Grades 1-4 (%)	Grade 3-4 (%)
Neutropeniaa,b	73	38	58	27
Thrombocytopeniab,c	74	13	70	9
a 405 patients assessed in ABRAXANE/gemcitabine-treated group. b 388 patients assessed in gemcitabine-treated group. c 404 patients assessed in ABRAXANE/gemcitabine-treated group. d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group.

 

Table 5 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group.

Table 5: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm

System Organ Class	Adverse Reaction	ABRAXANE (125 mg/m²) and gemcitabine (N=421)		Gemcitabine (N=402)
		All Grades	Grade 3 or Higher	All Grades	Grade 3 or Higher
General disorders and administration site conditions	Fatigue	248 (59%)	77 (18%)	183 (46%)	37 (9%)
	Peripheral edema	194 (46%)	13 (3%)	122 (30%)	12 (3%)
	Pyrexia	171 (41%)	12 (3%)	114 (28%)	4 (1%)
	Asthenia	79 (19%)	29 (7%)	54 (13%)	17 (4%)
	Mucositis	42 (10%)	6 (1%)	16 (4%)	1 (<1%)
Gastrointestinal disorders	Nausea	228 (54%)	27 (6%)	192 (48%)	14 (3%)
	Diarrhea	184 (44%)	26 (6%)	95 (24%)	6 (1%)
	Vomiting	151 (36%)	25 (6%)	113 (28%)	15 (4%)
	Alopecia	212 (50%)	6 (1%)	21 (5%)	0
Skin and subcutaneous tissue disorders	Rash	128 (30%)	8 (2%)	45 (11%)	2 (<1%)
Nervous system disorders	Peripheral neuropathya	227 (54%)	70 (17%)	51 (13%)	3 (1%)
	Dysgeusia	68 (16%)	0	33 (8%)	0
	Headache	60 (14%)	1 (<1%)	38 (9%)	1 (<1%)
Metabolism and nutrition disorders	Decreased appetite	152 (36%)	23 (5%)	104 (26%)	8 (2%)
	Dehydration	87 (21%)	31 (7%)	45 (11%)	10 (2%)
	Hypokalemia	52 (12%)	18 (4%)	28 (7%)	6 (1%)
Respiratory, thoracic and mediastinal disorders	Cough	72 (17%)	0	30 (7%)	0
	Epistaxis	64 (15%)	1 (<1%)	14 (3%)	1 (<1%)
Infections and infestations	Urinary tract infections b	47 (11%)	10 (2%)	20 (5%)	1 (<1%)
Musculoskeletal and connective tissue disorders	Pain in extremity	48 (11%)	3 (1%)	24 (6%)	3 (1%)
	Arthralgia	47 (11%)	3 (1%)	13 (3%)	1 (<1%)
	Myalgia	44 (10%)	4 (1%)	15 (4%)	0
Psychiatric disorders	Depression	51 (12%)	1 (<1%)	24 (6%)	0
a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococcal.

 

Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included:

Infections & infestations: oral candidiasis, pneumonia

Vascular disorders: hypertension

Cardiac disorders: tachycardia, congestive cardiac failure

Eye disorders: cystoid macular edema

Peripheral Neuropathy

Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine only; no patients developed Grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.

Sepsis

Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent.

Pneumonitis

Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ABRAXANE or with paclitaxel injection and may be expected to occur with ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity Reactions

Severe and sometimes fatal hypersensitivity reactions. Cross-hypersensitivity between ABRAXANE and other taxanes has been reported.

Cardiovascular

Congestive heart failure, left ventricular dysfunction, and atrioventricular block. Most patients were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory

Pneumonitis, interstitial pneumonia, and pulmonary embolism

Radiation pneumonitis in patients receiving concurrent radiotherapy. Lung fibrosis has been reported with paclitaxel injection.

Neurologic

Cranial nerve palsies and vocal cord paresis, as well as autonomic neuropathy resulting in paralytic ileus.

Vision Disorders

Reduced visual acuity due to cystoid macular edema (CME). After cessation of treatment, CME may improve, and visual acuity may return to baseline. Abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage.

Hepatic

Hepatic necrosis and hepatic encephalopathy leading to death in patients treated with paclitaxel injection.

Gastrointestinal (GI)

Intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis. In patients treated with paclitaxel injection, neutropenic enterocolitis (typhlitis) despite the coadministration of G-CSF, alone and in combination with other chemotherapeutic agents.

Injection Site Reaction

Extravasation. Closely monitor the ABRAXANE infusion site for possible infiltration during drug administration.

Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported with paclitaxel injection. In some cases, the onset of the injection site reaction occurred during a prolonged infusion or was delayed up to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site has been reported.

Metabolic and Nutritional Disorders

Tumor lysis syndrome

Other Clinical Events

Skin reactions including generalized or maculopapular rash, erythema, and pruritus

Photosensitivity reactions, radiation recall phenomenon, scleroderma, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

Conjunctivitis, cellulitis, and increased lacrimation have been reported with paclitaxel injection.

Accidental Exposure

Upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.

Following topical exposure, tingling, burning, and redness have been reported.