"The U.S. Food and Drug Administration announced today that the agency is recommending removing the breast cancer indication from the label for Avastin (bevacizumab) because the drug has not been shown to be safe and effective for that use."...
Avastin Side Effects Center
Medical Editor: John P. Cunha, DO, FACOEP
Avastin (bevacizumab) is used to treat a certain type of brain tumor as well as cancers of the kidney, colon, rectum, lung, or breast. It is usually given as part of a combination of cancer medicines. Avastin is in the antiangiogenic agent drug class. Common side effects include dry mouth, cough, voice changes, loss of appetite, diarrhea, vomiting, constipation, mouth sores, nausea, headache.
Dose of Avastin varies depending on the type of cancer being treated, and the patient's weight. There may be other drugs that can interact with Avastin. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Avastin should be used only when prescribed during pregnancy. Avastin may harm to a fetus. Women of child-bearing age should use an effective form of birth control while using this medication and for an extended period after stopping this drug. Based on information from related drugs, this medication may pass into breast milk. Breast-feeding while using this medication is not recommended. Do not breast-feed for extended periods after stopping this drug. Consult your doctor before breast-feeding.
Our Avastin (bevacizumab) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What is Patient Information in Detail?
Easy-to-read and understand detailed drug information and pill images for the patient or caregiver from Cerner Multum.
Avastin in Detail - Patient Information: Side Effects
Bevacizumab can cause a rare but serious neurologic disorder affecting the brain. Symptoms include headache, confusion, vision problems, feeling very weak or tired, fainting, and seizure (blackout or convulsions). These rare symptoms may occur within hours of your first dose of bevacizumab, or they may not appear for up to a year after your treatment started. Call your doctor at once if you have any of these side effects.
Some people receiving a bevacizumab injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, nauseated, light-headed, sweaty, or have a headache, wheezing, or chest pain during the injection.
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.
Call your doctor at once if you have a serious side effect such as:
- any wound that will not heal;
- severe stomach pain with fever, vomiting, and constipation;
- blood in your urine or stools, vomit that looks like blood or coffee grounds;
- easy bruising, unusual bleeding (nose, mouth, vagina, rectum), purple or red pinpoint spots under your skin, or any bleeding that will not stop;
- fever, chills, body aches, flu symptoms, sores in your mouth and throat;
- sudden numbness or weakness, severe headache, confusion, or problems with vision, speech, or balance;
- pain, swelling, warmth, or redness in one or both legs;
- chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;
- dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, confusion, shortness of breath, uneven heartbeats, seizure);
- puffy eyes, swelling in your stomach, arms, or legs;
- rapid weight gain, urinating less than usual or not at all;
- urine that looks foamy;
- pain or burning when you urinate, loss of bladder or bowel control;
- ongoing vaginal discharge, itching, or other irritation; or
- missed menstrual periods.
Less serious side effects may include:
- mild headache;
- back pain;
- diarrhea, loss of appetite;
- cold symptoms such as stuffy nose, sneezing, sore throat;
- dry or watery eyes;
- dry or flaky skin, hair loss;
- changes in your sense of taste; or
- jaw pain, swelling, numbness, loose teeth, gum infection.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Read the entire detailed patient monograph for Avastin (Bevacizumab) »
What is Patient Information Overview?
A concise overview of the drug for the patient or caregiver from First DataBank.
Avastin Overview - Patient Information: Side Effects
Dry mouth, cough, voice changes, loss of appetite, diarrhea, vomiting, constipation, mouth sores, nausea, headache may occur. If any of these effects persist or worsen, notify your doctor or pharmacist immediately.
Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.
Tell your doctor right away if you have any serious side effects, including: trouble breathing, swelling of ankles/feet, sudden weight gain, unusual tiredness, fast heartbeat, fainting, signs of infection (e.g., fever, persistent sore throat), calf pain/swelling, muscle cramps, muscle loss, yellowing eyes/skin, frothy/dark urine, difficulty urinating, decreased amount of urine.
Symptoms of a severe infusion reaction that may occur during bevacizumab treatment include difficulty breathing, flushing, severe dizziness, nausea/vomiting, shaking, or chest pain. Tell your healthcare professional if you have any of these symptoms during your treatment. Your doctor will monitor you closely and will temporarily stop your treatment if a reaction occurs.
Bevacizumab infrequently may cause blood clots to form, leading to serious medical conditions (heart attack/angina, stroke/TIA). Seek immediate medical attention if you develop chest pain/tightness, sudden vision changes, weakness on one side of the body, confusion, or slurred speech. If any of these conditions occur, you should not be given this medication again.
This medication can cause bleeding. Some episodes may be minor including nosebleeds, minor gum bleeding, and vaginal bleeding. If these persist or worsen, notify your doctor or pharmacist promptly. Other episodes may be more serious including stomach bleeding or bleeding in the lungs (see also Warning section).
This medication may cause high blood pressure. This reaction can be severe enough to require blood pressure treatment. Learn to check your blood pressure regularly and share the results with your doctor.
Rarely, bevacizumab may cause a condition called RPLS (reversible posterior leukoencephalopathy syndrome). Get medical help right away if you develop persistent headache, seizures, sudden vision changes, mental/mood changes (e.g., confusion).
This medication may affect the ovaries, possibly reducing fertility and causing hormone changes. Talk to your doctor for more details.
A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, severe trouble breathing.
This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.
In the US -
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.
Read the entire patient information overview for Avastin (Bevacizumab)»
What is Prescribing information?
The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.
Avastin FDA Prescribing Information: Side Effects
The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Gastrointestinal Perforations and Fistulae[See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
- Non-Gastrointestinal Fistulae [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
- Surgery and Wound Healing Complications [See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
- Hemorrhage [See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
- Arterial Thromboembolic Events [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
- Venous Thromboembolic Events [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
- Hypertensive Crisis [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
- Posterior Reversible Encephalopathy Syndrome [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
- Proteinuria [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
- Infusion Reactions [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
- Ovarian Failure [See WARNINGS AND PRECAUTIONS, Use in Specific Populations]
The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.
Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.
Clinical Trial Experience
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 data below reflect exposure to Avastin in 4817 patients with CRC, non-squamous NSCLC, glioblastoma, mRCC, or cervical cancer, including controlled (Studies 1, 2, 4, 5, 8 and 9) or uncontrolled, single arm trials (Study 6) treated at the recommended dose and schedule for a median of 6 to 23 doses of Avastin. [See Clinical Studies] The population was aged 18-89 years (median 59 years), 44% male and 85% White. The population included 2184 first- and second-line mCRC patients who received a median of 10 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, 337 mRCC patients who received a median of 16 doses of Avastin, and 218 cervical cancer patients who received a median of 6 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 1338 adjuvant CRC patients, including 669 female patients, who received a median of 23 doses of Avastin, and 403 previously untreated patients with diffuse large B-cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL.
Surgery and Wound 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 Study 6, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
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. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Avastin when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
Venous Thromboembolic Events
The overall incidence of 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, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra-abdominal venous thrombosis (10 vs. 5 patients).
The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. 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 (VTE). 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.
In a second, randomized, 4-arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%).
From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade 3 or 4 VTE have been reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. There were no patients with Grade 5 VTE. [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
Neutropenia and Infection
The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (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 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%)].
In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.
Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8).
In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re-initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re-initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See WARNINGS AND PRECAUTIONS]
Congestive Heart Failure (CHF)
The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3-4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.
In previously untreated patients with diffuse large B-cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left-ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R-CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R-CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R-CHOP arm compared to 5.0% in the R-CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R-CHOP arm (10.4%) compared to the R-CHOP alone arm (5.0%). Time to onset of left-ventricular dysfunction or CHF was 1-6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.
The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% (7/32) of the Avastin-treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or a FSH level < 30 mIU/mL during the post-treatment period. Long term effects of Avastin exposure on fertility are unknown. [See WARNINGS AND PRECAUTIONS, Use in Specific Populations]
Post-Treatment Vascular Events
In an open-label, randomized, controlled trial of Avastin in adjuvant colorectal cancer, an indication for which Avastin is not approved, the overall incidence rate of post-treatment Grade ≥ 3 vascular events was 3.1% (41 of 1338) among patients receiving mFOLFOX6 plus Avastin, compared to 1.6% (21 of 1349) among patients receiving mFOLFOX6 alone. Post-treatment vascular events included arterial and venous thromboembolic events, ischemic events, and vascular aneurysms.
Metastatic Colorectal Cancer (mCRC)
The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.
All Grade 3-4 adverse events and selected Grade 1-2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3-4) 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 1.
Table 1 : NCI-CTC Grade 3-4 Adverse Events in Study 1 (Occurring
at Higher Incidence [ ≥ 2%] Avastin vs. Control)
|Arm 1 IFL + Placebo
(n = 396)
|Arm 2 IFL + Avastin
(n = 392)
|NCI-CTC Grade 3-4 Events||74%||87%|
|Body as a Whole|
|Deep Vein Thrombosis||5%||9%|
|a 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.|
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 2. Grade 1-4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued.
Table 2 : 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|
|Deep Vein Thrombosis||3%||9%||6%|
|Upper Respiratory Infection||39%||47%||40%|
Avastin in Combination with FOLFOX4 in Second-line mCRC
Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3-5 non-hematologicand Grade 4-5 hematologic adverse events) occurring at a higher incidence ( ≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2.
Avastin in Combination with Fluoropyrimidine-Irinotecan or Fluoropyrimidine-Oxaliplatin Based Chemotherapy in Second-line mCRC Patients who have Progressed on an Avastin Containing Regimen in First-line mCRC:
No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC.
Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 5. Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events (occurring at a higher incidence ( ≥ 2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).
All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.
In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.
In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin-related adverse events (Grade 1-4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and PRES (1%). The incidence of Grade 3-5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).
Metastatic Renal Cell Carcinoma (mRCC)
All grade adverse events were collected in Study 8. Grade 3-5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN-a) plus Avastin compared to 304 patients receiving IFN-a plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).
Grade 1-5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN-α plus Avastin compared to the IFN-a plus placebo arm are presented in Table 3.
Table 3 : NCI-CTC Grades 1-5 Adverse Events in Study 8
(Occurring at Higher Incidence [ ≥ 5%] in IFN-α+ Avastin vs. IFN-α
|System Organ Class/Preferred terma||IFN-α +Placebo
(n = 304)
|IFN-α + Avastin
(n = 337)
|General disorders and administration site conditions|
|Metabolism and nutrition disorders|
|Musculoskeletal and connective tissue disorders|
|Nervous system disorders|
|Renal and urinary disorders|
|Respiratory, thoracic and mediastinal disorders|
|aAdverse events were encoded using MedDRA, Version 10.1.|
The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Avastin arm compared to IFN-α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).
Persistent, Recurrent, or Metastatic Carcinoma of the Cervix
All grade adverse reactions were collected in Study 9.
Grade 1-4 adverse reactions occurring where the incidence difference is ≥ 5% in patients receiving Avastin plus chemotherapy compared to chemotherapy alone are presented in Table 4.
Table 4 : NCI-CTC Grades 1-4 and 3-4 Adverse Reactions
in Study 9 (Incidence Difference of ≥ 5% Between Treatment Arms in Chemo +
Avastin vs. Chemo Alone)
|Grade 1-4 reactions||Grade 3-4 reactions|
|Chemo + Avastin
|Chemo + Avastin
|Metabolism and NutritionDisorders|
|General Disorders andAdministration Site Conditions|
|Blood Creatinine Increased||10%||16%|
|Infections and Infestations|
|Urinary Tract Infection||14%||22%|
|Nervous System Disorders|
|Anal F istula||—||6%|
|Blood and Lymphatic System Disorders|
|Reproductive System and Breast Disorders|
|Respiratory, Thoracic and Mediastinal Disorders|
|Renal and Urinary Disorders|
Grade 3 or 4 adverse reactions occurring at a higher incidence ( ≥ 2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone were abdominal pain (11.9% vs. 9.9%), diarrhea (5.5% vs. 2.7%), anal fistula (3.7% vs. 0%), proctalgia (2.8% vs. 0%), urinary tract infection 8.3% vs. 6.3%), cellulitis (3.2% vs. 0.5%), fatigue (14.2% vs. 9.9%), hypokalemia (7.3% vs. 4.5%), hyponatremia (3.7% vs. 1.4%), dehydration (4.1% vs. 0.5%), neutropenia (7.8% vs. 4.1%), lymphopenia (6.0% vs. 3.2%), back pain (5.5% vs. 3.2%), and pelvic pain (5.5% vs. 1.4%).
There were no Grade 5 adverse reactions occurring at a higher incidence ( ≥ 2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone.
As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment-emergent anti-bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linked immunosorbent assay (ELISA). The clinical significance of these anti-product antibody responses to bevacizumab is unknown.
Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and 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.
The following adverse reactions have been identified during post-approval use of Avastin. 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.
Body as a Whole: Polyserositis
Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort
Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration
Hemic and lymphatic: Pancytopenia
Hepatobiliary disorders: Gallbladder perforation
Musculoskeletal: Osteonecrosis of the jaw
Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria)
Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage
Read the entire FDA prescribing information for Avastin (Bevacizumab) »
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