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Avastin (Bevacizumab) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

The most serious adverse reactions in patients receiving AVASTIN were:

  • Gastrointestinal Perforations (see WARNINGS)
  • Non-Gastrointestinal Fistula Formation (see WARNINGS)
  • Wound Healing Complications (see WARNINGS)
  • Hemorrhage (see WARNINGS)
  • Arterial Thromboembolic Events (see WARNINGS)
  • Hypertensive Crises (see WARNINGS: Hypertension)
  • Reversible Posterior Leukoencephalopathy Syndrome (see WARNINGS)
  • Neutropenia and Infection (see WARNINGS)
  • Nephrotic Syndrome (see WARNINGS: Proteinuria)
  • Congestive Heart Failure (see WARNINGS)

The most common adverse events in patients receiving AVASTIN were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria.

Adverse Reactions in Clinical Trails

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 adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

The data described below reflect exposure to AVASTIN in 1529 patients, including 665 receiving AVASTIN for at least 6 months and 199 receiving AVASTIN for at least one year. AVASTIN was studied primarily in placebo- and active‑controlled trials (n = 501, and n = 1028, respectively).

Gastrointestinal Perforation

The incidence of gastrointestinal perforation across all studies ranged from 0–3.7%. The incidence of gastrointestinal perforation, in some cases fatal, in patients with mCRC receiving AVASTIN alone or in combination with chemotherapy was 2.4% compared to 0.3% in patients receiving only chemotherapy. The incidence of gastrointestinal perforation in NSCLC patients receiving AVASTIN was 0.9% compared to 0% in patients receiving only chemotherapy. (See WARNINGS: Gastrointestinal Perforations and DOSAGE AND ADMINISTRATION: Dose Modifications.)

Non-Gastrointestinal Fistula Formation

(See WARNINGS: Non‑Gastrointestinal Fistula Formation and DOSAGE AND ADMINISTRATION: Dose Modifications.)

Would Healing Complications

The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving AVASTIN as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus AVASTIN as compared to 4% (1/25) of patients who received bolus‑IFL alone. In the same study, the incidence of wound dehiscence was also higher in the AVASTIN‑treated patients (1% vs. 0.5%).

Hemorrhage

Severe or fatal hemorrhages, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in AVASTIN‑treated patients compared to patients treated with chemotherapy alone. NCI‑CTC Grade 3–5 hemorrhagic events occurred in 4.7% of NSCLC patients and 5.2% of mCRC patients receiving AVASTIN compared to 1.1% and 0.7% for the control groups respectively. (See WARNINGS: Hemorrhage.)

The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus AVASTIN compared with patients receiving bolus‑IFL plus placebo. These events were generally mild in severity (NCI‑CTC Grade 1) and resolved without medical intervention. Additional mild to moderate hemorrhagic events reported more frequently in patients receiving bolus‑IFL plus AVASTIN when compared to those receiving bolus‑IFL plus placebo included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). (See WARNINGS: Hemorrhage and DOSAGE AND ADMINISTRATION: Dose Modifications.)

Arterial Thromboembolic Events

The incidence of arterial thromboembolic events was increased in NSCLC patients receiving PC plus AVASTIN (3.0%) compared with patients receiving PC alone (1.4%). Five events were fatal in the PC plus AVASTIN arm, compared with 1 event in the PC alone arm. This increased risk is consistent with that observed in patients with mCRC. (See WARNINGS: Arterial Thromboembolic Events, DOSAGE AND ADMINISTRATION: Dose Modifications and PRECAUTIONS: Geriatric Use.)

Venous Thromboembolic Events

The incidence of NCI‑CTC grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving AVASTIN with chemotherapy as compared to those receiving chemotherapy alone. In addition, in patients with mCRC, the risk of developing a second subsequent thromboembolic event in patients receiving AVASTIN and chemotherapy is increased compared to patients receiving chemotherapy alone. In Study 1, 53 patients (14%) on the bolus‑IFL plus AVASTIN arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus AVASTIN and 3% (1/30) of patients receiving bolus‑IFL alone.

The overall incidence of NCI‑CTC Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus AVASTIN and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, the incidence of the following NCI‑CTC Grade 3 and 4 venous thromboembolic events was higher in patients receiving bolus‑IFL plus AVASTIN as compared to patients receiving bolus‑IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra‑abdominal venous thrombosis (10 vs. 5 patients).

Hypertension

Fatal CNS hemorrhage complicating AVASTIN induced hypertension can occur.

In Study 1 the incidences of hypertension and of severe hypertension were increased in patients with mCRC receiving AVASTIN compared to those receiving chemotherapy alone (see Table 3).

Table 3: Incidence of Hypertension and Severe Hypertension in Study 1
Arm 1 IFL + Placebo
(n = 394)
Arm 2 IFL + AVASTIN
(n = 392)
Arm 3 5‑FU/LV + AVASTIN
(n = 109)
Hypertension 1 (>150/100 mmHg) 43%60%67%
Severe Hypertension (>200/110 mmHg) 2%7%10%

1 This includes patients with either a systolic or diastolic reading greater than the cutoff value on one or more occasions.

Among patients with severe hypertension in the AVASTIN arms, slightly over half the patients (51%) had a diastolic reading greater than 110 mmHg associated with a systolic reading less than 200 mmHg.

Similar results were seen in patients receiving AVASTIN alone or in combination with FOLFOX4 or carboplatin and paclitaxel. (See WARNINGS: Hypertension and DOSAGE AND ADMINISTRATION: Dose Modifications.)

Neutropenia and Infection

An increased incidence of neutropenia has been reported in patients receiving AVASTIN and chemotherapy compared to chemotherapy alone. In Study 1, the incidence of NCI‑CTC Grade 3 or 4 neutropenia was increased in patients with mCRC receiving IFL+AVASTIN (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of NCI‑CTC Grade 4 neutropenia was increased in patients with NSCLC receiving PC plus AVASTIN (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus AVASTIN vs. 1.8% for PC alone). There were 19 (4.5%) infections with NCI‑CTC Grade 3 or 4 neutropenia in the PC plus AVASTIN arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus AVASTIN arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

Proteinuria

(See WARNINGS: Proteinuria, DOSAGE AND ADMINISTRATION: Dose Modifications, and PRECAUTIONS: Geriatric Use.)

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving AVASTIN has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with AVASTIN, primarily in combination with chemotherapy. High titer human anti‑AVASTIN antibodies were not detected.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to AVASTIN with the incidence of antibodies to other products may be misleading.

Metastatic Carcinoma of the Colon and Rectum

The data in Tables 4 and 5 were obtained in Study 1. All NCI‑CTC Grade 3 and 4 adverse events and selected NCI‑CTC Grade 1 and 2 adverse events (hypertension, proteinuria, thromboembolic events) were reported for the overall study population. The median age was 60, 60% were male, 79% were Caucasian, 78% had a colon primary lesion, 56% had extra‑abdominal disease, 29% had prior adjuvant or neoadjuvant chemotherapy, and 57% had ECOG performance status of 0. The median duration of exposure to AVASTIN was 8 months in Arm 2 and 7 months in Arm 3. Severe and life threatening (NCI‑CTC Grade 3 and 4) adverse events, which occurred at a higher incidence (≥2%) in patients receiving bolus‑IFL plus AVASTIN as compared to bolus‑IFL plus placebo, are presented in Table 4.

Table 4: NCI‑CTC Grade 3 and 4 Adverse Events in Study 1 (Occurring at Higher Incidence (≥2%) in AVASTIN vs. Control)
Arm 1 IFL + Placebo (n = 396) Arm 2 IFL + AVASTIN (n = 392)
NCI‑CTC Grade 3–4 Events295  (74%)340  (87%)
Body as a Whole
 Asthenia28 (7%)38 (10%)
 Abdominal Pain20 (5%)32 (8%)
 Pain21 (5%)30 (8%)
Cardiovascular
 Hypertension10 (2%)46 (12%)
 Deep Vein Thrombosis19 (5%)34 (9%)
 Intra‑Abdominal Thrombosis5 (1%)13 (3%)
 Syncope4 (1%)11 (3%)
Digestive
 Diarrhea99 (25%)133 (34%)
 Constipation9 (2%)14 (4%)
Hemic/Lymphatic
 Leukopenia122 (31%)145 (37%)
Neutropenia Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.41 (14%)58 (21%)

NCI‑CTC Grade 1–4 adverse events which occurred at a higher incidence (≥5%) in patients receiving bolus‑IFL plus AVASTIN as compared to the bolus‑IFL plus placebo arm, are presented in Table 5.

Table 5: NCI‑CTC Grade 1–4 Adverse Events in Study 1 (Occurring at Higher Incidence (≥5%) in IFL + AVASTIN vs. IFL)
Arm 1
IFL + Placebo
(n = 98)
Arm 2
IFL + AVASTIN
(n = 102)
Arm 3
5‑FU/LV + AVASTIN
(n = 109)
Body as a Whole
 Pain54 (55%)62 (61%)67 (62%)
 Abdominal Pain54 (55%)62 (61%)55 (50%)
 Headache19 (19%)27 (26%)30 (26%)
Cardiovascular
 Hypertension14 (14%)23 (23%)37 (34%)
 Hypotension7 (7%)15 (15%)8 (7%)
 Deep Vein Thrombosis3 (3%)9 (9%)6 (6%)
Digestive
 Vomiting46 (47%)53 (52%)51 (47%)
 Anorexia29 (30%)44 (43%)38 (35%)
 Constipation28 (29%)41 (40%)32 (29%)
 Stomatitis18 (18%)33 (32%)33 (30%)
 Dyspepsia15 (15%)25 (24%)19 (17%)
 GI Hemorrhage6 (6%)25 (24%)21 (19%)
 Weight Loss10 (10%)15 (15%)18 (16%)
 Dry Mouth2 (2%)7 (7%)4 (4%)
 Colitis1 (1%)6 (6%)1 (1%)
Hemic/Lymphatic
 Thrombocytopenia5 (5%)5 (5%)
Nervous
 Dizziness20 (20%)27 (26%)21 (19%)
Respiratory
 Upper Respiratory Infection38 (39%)48 (47%)44 (40%)
 Epistaxis10 (10%)36 (35%)35 (32%)
 Dyspnea15 (15%)26 (26%)27 (25%)
 Voice Alteration2 (2%)9 (9%)6 (6%)
Skin/Appendages
 Alopecia25 (26%)33 (32%)6 (6%)
 Skin Ulcer1 (1%)6 (6%)7 (6%)
Special Senses
 Taste Disorder9 (9%)14 (14%)23 (21%)
Urogenital
 Proteinuria24 (24%)37 (36%)39 (36%)

The data in Table 6 were obtained in Study 3. Only NCI‑CTC Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were reported. The median age was 61 years, 40% were female, 87% were Caucasian, 99% received prior chemotherapy for metastatic colorectal cancer, 26% had received prior radiation therapy, and the 49% had an ECOG performance status of 0. Selected NCI‑CTC Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events which occurred at a higher incidence in patients receiving FOLFOX4 plus AVASTIN as compared to those who received FOLFOX4 alone, are presented in Table 6. These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 3.

Table 6: NCI‑CTC Grade 3–5 Non‑Hematologic and Grade 4–5 Hematologic Adverse Events in Study 3 (Occurring at Higher Incidence (≥2%) with AVASTIN + FOLFOX4 vs. FOLFOX4)
FOLFOX4
(n = 285)
FOLFOX4 + AVASTIN
(n = 287)
AVASTIN
(n = 234)
Patients with at least one event171 (60%)219 (76%)87 (37%)
Gastrointestinal
 Diarrhea36 (13%)51 (18%)5 (2%)
 Nausea13 (5%)35 (12%)14 (6%)
 Vomiting11 (4%)32 (11%)15 (6%)
 Dehydration14 (5%)29 (10%)15 (6%)
 Ileus4 (1%)10 (4%)11 (5%)
Neurology
 Neuropathy–sensory26 (9%)48 (17%)2 (1%)
 Neurologic–other8 (3%)15 (5%)3 (1%)
Constitutional symptoms
 Fatigue37 (13%)56 (19%)12 (5%)
Pain
 Abdominal pain13 (5%)24 (8%)19 (8%)
 Headache0 (0%)8 (3%)4 (2%)
Cardiovascular (general)
 Hypertension5 (2%)26 (9%)19 (8%)
Hemorrhage
 Hemorrhage2 (1%)15 (5%)9 (4%)

Non‑Squamous, Non‑Small Cell Lung Cancer

The data in Table 7 were obtained in Study 5. Only NCI‑CTC Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events were reported. The median age was 63, 46% were female, no patients had received prior chemotherapy, 76% had Stage IV disease, 12% had Stage IIIB disease with malignant pleural effusion, 11% had recurrent disease, and 40% had an ECOG performance status of 0. The median duration of exposure to AVASTIN was 4.9 months.

NCI CTC Grade 3, 4, and 5 adverse events that occurred at a ≥2% higher incidence in patients receiving PC plus AVASTIN as compared with PC alone are presented in Table 7.

Table 7: NCI‑CTC Grade 3–5 Non‑Hematologic and Grade 4 and 5 Hematologic Adverse Events in Study  5 (Occurring at a ≥2% Higher Incidence in AVASTIN‑Treated Patients Compared with Control)
NCI‑CTC Category TermEvents were reported and graded according to NCI-CTC, Version 2.0. Per protocol, investigators were required to report NCI-CTC Grade 3–5 non‑hematologic and Grade 4 and 5 hematologic events.No.(%) of NSCLC Patients
PC (n=441)PC + AVASTIN (n=427)
Any event286 (65%)334 (78%)
Blood/bone marrow
 Neutropenia76 (17%)113 (27%)
Constitutional Symptoms
 Fatigue57 (13%)67 (16%)
Cardiovascular (general)
 Hypertension3 (0.7%)33 (8%)
Vascular
 Venous thrombus/embolism14 (3%)23 (5%)
Infection/febrile neutropenia
 Infection without neutropenia12 (3%)30 (7%)
 Infection with NCI‑CTC Grade 3 or 4 neutropenia9 (2%)19 (4%)
 Febrile neutropenia8 (2%)23 (5%)
Pulmonary/upper respiratory
 Pneumonitis/pulmonary infiltrates11 (3%)21 (5%)
Metabolic/laboratory
 Hyponatremia5 (1%)16 (4%)
Pain
 Headache2 (0.5%)13 (3%)
Renal/genitourinary
 Proteinuria0 (0%)13 (3%)

Other Serious Adverse Events

The following additional serious adverse events occurred in at least one subject treated with AVASTIN in clinical studies or post‑marketing experience.

Body as a Whole: polyserositis

Digestive: intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration

Hemic and lymphatic: pancytopenia

Respiratory: nasal septum perforation



REPORTS OF SUSPECTED AVASTIN SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Avastin. The information is not vetted and should not be considered as verified clinical evidence.

Possible Avastin side effects / adverse reactions in 49 year old female

Reported by a health professional (non-physician/pharmacist) from United Kingdom on 2011-10-03

Patient: 49 year old female weighing 75.0 kg (165.0 pounds)

Reactions: Palmar-Plantar Erythrodysaesthesia Syndrome

Adverse event resulted in: death, disablity

Suspect drug(s):
Docetaxel
    Dosage: 180.00-mg-1.00 times per-3.0weeks/intravenous (not otherwise specified)
    Indication: Breast Cancer Metastatic
    Start date: 2010-02-16
    End date: 2011-02-11

Avastin
    Dosage: 1000.00-mg-1.00 times/intravenous (not otherwise specified)
    Indication: Breast Cancer Metastatic
    Start date: 2011-01-06
    End date: 2011-02-11

Capecitabine
    Dosage: 2300.00-mg/oral
    Administration route: Oral
    Indication: Breast Cancer Metastatic
    Start date: 2010-03-17
    End date: 2011-04-28

Other drugs received by patient: Lansoprazole; Dexamethasone



Possible Avastin side effects / adverse reactions in 62 year old female

Reported by a health professional (non-physician/pharmacist) from Spain on 2011-10-03

Patient: 62 year old female

Reactions: Female Genital Tract Fistula

Suspect drug(s):
Fluorouracil
    Dosage: frequency: 2 x per 14 day
    Indication: Colorectal Cancer Metastatic
    Start date: 2011-06-13

Oxaliplatin
    Indication: Colorectal Cancer Metastatic
    Start date: 2011-06-13
    End date: 2011-08-01

Avastin
    Indication: Colorectal Cancer Metastatic
    Start date: 2011-06-27
    End date: 2011-06-27

Leucovorin Calcium
    Indication: Colorectal Cancer Metastatic
    Start date: 2011-06-13



Possible Avastin side effects / adverse reactions in 58 year old male

Reported by a health professional (non-physician/pharmacist) from United States on 2011-10-04

Patient: 58 year old male

Reactions: Endophthalmitis

Suspect drug(s):
Avastin



See index of all Avastin side effect reports >>

Drug label data at the top of this Page last updated: 2007-09-20

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