Bevacizumab

Tell your doctor about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs you're taking, especially:

• Anticoagulants (blood thinners) such as warfarin (Coumadin)
• Irinotecan (Camptosar)
• Sunitinib (Sutent)

Also, tell your doctor if you're taking or if you've ever taken an anthracycline such as:

• Daunorubicin (Cerubidine)
• Doxorubicin (Adriamycin, Rubex)
• Epirubicin (Ellence)
• Idarubicin (Idamycin)

Avastin and Other Interactions

Don't receive any immunizations without your doctor's approval while taking Avastin.

Use caution around sharp objects to avoid your chances of getting cut or bruised.

The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

If bevacizumab is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Gastrointestinal Perforations

Bevacizumab administration can result in the development of gastrointestinal perforation, in some instances resulting in fatality.

• Gastrointestinal perforation, sometimes associated with intra-abdominal abscess, occurred throughout treatment with bevacizumab (i.e., was not correlated to duration of exposure).
• The incidence of gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intra-abdominal abscess) in patients with colorectal cancer and in patients with non-small cell lung cancer (NSCLC) receiving bevacizumab was 2.4% and 0.9%, respectively. The typical presentation was reported as abdominal pain associated with symptoms such as constipation and vomiting.
• Gastrointestinal perforation should be included in the differential diagnosis of patients presenting with abdominal pain on bevacizumab.
• Bevacizumab therapy should be permanently discontinued in patients with gastrointestinal perforation.

Wound Healing Complications

• Bevacizumab administration can result in the development of wound dehiscence, in some instances resulting in fatality.
• Bevacizumab therapy should be permanently discontinued in patients with wound dehiscence requiring medical intervention.
• The appropriate interval between termination of bevacizumab and subsequent elective surgery required to avoid the risks of impaired wound healing/wound dehiscence has not been determined.

Hemorrhage

• Fatal pulmonary hemorrhage can occur in patients with non-small cell lung cancer treated with chemotherapy and bevacizumab.
• Incidence: The incidence of serious or fatal hemoptysis was 31% in patients with squamous histology and 2.3% in patients with NSCLS excluding predominant squamous histology.
• Patients with recent hemoptysis (at least one-half teaspoonful of red blood) should not receive bevacizumab.

Bevacizumab is injected into a vein through an IV. A healthcare provider will give you this injection.

Some people receiving a bevacizumab injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregivers if you feel dizzy, nauseated, light-headed, sweaty, or have a headache, shortness of breath, or chest pain during the injection.

Bevacizumab is usually given once every 2 or 3 weeks.

Your blood pressure will need to be checked often. Protein levels in your urine may also need to be tested.

Bevacizumab can cause problems with wound healing, which could result in bleeding or infection. If you need to have any type of surgery, you will need to stop receiving bevacizumab at least 28 days ahead of time. Do not start using bevacizumab for at least 28 days after surgery, or until your surgical incision heals.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Bevacizumab can make it easier for you to bleed. Call your doctor or seek emergency medical attention if you have:

• easy bruising, unusual bleeding (nose, mouth, vagina, rectum), or any bleeding that will not stop;

• signs of bleeding in your digestive tract--severe stomach pain, bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds; or

• signs of bleeding in the brain--sudden numbness or weakness (especially on one side of the body), sudden severe headache, problems with vision or balance.

Bevacizumab can cause a rare but serious neurologic disorder affecting the brain. Symptoms may occur within hours of your first dose, or they may not appear for up to a year after your treatment started. Call your doctor at once if you have extreme weakness or tiredness, headache, confusion, vision problems, fainting, or seizure (blackout or convulsions).

Some people receiving bevacizumab have developed a fistula (an abnormal passageway) within the throat, lungs, gallbladder, kidney, bladder, or vagina. Call your doctor if you have: chest pain and trouble breathing, stomach pain or swelling, urine leakage, or if you feel like you are choking and gagging when you eat or drink.

Also call your doctor if you have:

• fever, chills, vomiting, and constipation;

• swollen gums, painful mouth sores, pain when swallowing, skin sores, cold or flu symptoms, cough;

• pain, swelling, warmth, or redness in one or both legs;

• chest tightness or heavy feeling, pain spreading to the jaw or shoulder, nausea, sweating, general ill feeling;

• missed menstrual periods;

• signs of any skin infection--sudden redness, warmth, swelling, or oozing, or any skin wound or surgical incision that will not heal; or

• dangerously high blood pressure--severe headache, blurred vision, pounding in your neck or ears, nosebleed, anxiety, confusion, severe chest pain, shortness of breath, irregular heartbeats.

Older adults may be more likely to have side effects from this medication.

Common side effects may include:

• nosebleed, rectal bleeding;

• increased blood pressure;

• mild or occasional headache;

• runny nose, sneezing;

• dry or watery eyes;

• dry or flaky skin;

• changes in your sense of taste; or

• back pain.

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.

Contraindications

• None.1 3

Warnings/Precautions

Warnings

Consider the usual cautions, precautions, and contraindications of any other antineoplastic agents included in the therapeutic regimen.3

Severe, sometimes fatal, GI perforation reported; generally manifested as abdominal pain, nausea, vomiting, constipation, and fever.1 Usually occurs within the first 50 days following initiation of bevacizumab.1

GI perforation sometimes associated with or complicated by fistula formation and/or intra-abdominal abscess.1 4

If GI perforation (GI perforation, fistula formation in GI tract, and/or intra-abdominal abscess) occurs, discontinue bevacizumab permanently.1

Wound healing and bleeding complications (including wound dehiscence), sometimes fatal, reported.1

Do not initiate bevacizumab therapy until ≥28 days following major surgery and after surgical incision has fully healed.1

Discontinue bevacizumab ≥28 days prior to elective surgery.1 Appropriate interval between discontinuance of bevacizumab and subsequent elective surgery not established, but consider long half-life of bevacizumab.1 (See Half-life under Pharmacokinetics.) Manufacturer recommends resuming therapy only after surgical incision has fully healed.1

Discontinue bevacizumab permanently if wound dehiscence and wound healing complications requiring medical intervention occur.1 (See Boxed Warning.)

Severe, sometimes fatal, hemorrhagic events (e.g., hemoptysis, GI bleeding, hematemesis, CNS hemorrhage, epistaxis, vaginal bleeding) reported.1 (See Boxed Warning.)

Risk of severe or fatal pulmonary hemorrhage in patients with non-small cell lung cancer.1 Serious or fatal pulmonary hemorrhage reported in 31% of patients with squamous cell histology and in 4% of patients with nonsquamous cell histology.1

Risk of CNS hemorrhage in patients with NSCLC and CNS metastases.1 Intracranial hemorrhage reported in patients with glioblastoma.1

Mild hemorrhagic events, most commonly grade 1 epistaxis, also reported.1

Do not administer to patients with recent hemoptysis (≥½ teaspoon of red blood).1 If severe hemorrhage (i.e., requiring medical intervention) occurs, discontinue bevacizumab permanently.1

Sensitivity Reactions

Infusion reactions (e.g., hypertension, hypertensive crisis associated with neurologic manifestations, wheezing, oxygen desaturation, grade 3 hypersensitivity, chest pain, headache, rigor, diaphoresis) reported.1

Infuse initial doses slowly, increasing rate of infusion as tolerated.1 (See Rate of Administration under Dosage and Administration.)

If severe infusion reactions occur, interrupt infusion and administer appropriate medical therapy.1 Adequate information on rechallenge not available.44

Other Warnings/Precautions

Severe, sometimes fatal, non-GI fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, and bladder sites reported; usually occurs within first 6 months of treatment.1 If non-GI fistula formation involving an internal organ occurs, discontinue bevacizumab permanently.1

Serious, sometimes fatal, arterial thromboembolic events (e.g., cerebral infarction, TIA, MI, angina) reported.1 7 8 16 17 Increased risk in patients with a history of arterial thromboembolism or patients >65 years of age.1 7 Weigh risks against benefits of therapy.17 Discontinue therapy permanently if severe arterial thromboembolic event occurs;1 7 safety of resuming therapy after resolution of an arterial thromboembolic event not studied.1

Grade 3 or 4 venous thromboembolic events (e.g., DVT, intra-abdominal venous thrombosis) reported.1 Increased risk of developing second thromboembolic event reported in patients with metastatic colorectal cancer receiving bevacizumab with chemotherapy despite use of full-dose warfarin therapy following an initial venous thromboembolic event.1

Severe hypertension (grade 3 or 4) reported.1

Monitor BP every 2–3 weeks during therapy.1 If hypertension occurs, initiate appropriate antihypertensive therapy and monitor BP regularly.1 Temporarily discontinue therapy in patients with severe hypertension not controlled with medical management.1 Discontinue therapy permanently if hypertensive crisis or hypertensive encephalopathy occurs.1 If therapy is discontinued because of hypertension, monitor BP at regular intervals thereafter.1

RPLS (a brain-capillary leak syndrome) reported.1 29 30 32 May manifest with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances; mild to severe hypertension also may occur.1 32 Manifestations occurred from 16 hours to 1 year after initiation of bevacizumab.1 32 Magnetic resonance imaging (MRI) is necessary to confirm diagnosis of RPLS.1 32

Closely monitor and maintain strict control of BP during and following bevacizumab infusion.30 If RPLS develops, discontinue bevacizumab and initiate treatment of hypertension as clinically indicated.1 31 32 Symptoms usually lessen or resolve within days of drug discontinuance, but some patients have experienced ongoing neurologic sequelae.1 32 Risk of reinitiating bevacizumab in patients previously experiencing RPLS not known.1 32

Increased incidence and severity of proteinuria reported.1 Severity ranges from clinically silent to nephrotic syndrome.6 Proteinuria with findings of thrombotic microangiopathy on renal biopsy reported in patients receiving bevacizumab alone or in combination with other antineoplastic agents for various cancers.1 37

Monitor patients for development or worsening of proteinuria with serial urinalysis.1 Further assessment (e.g., 24-hour urine collection) recommended if ≥2+ urine dipstick reading occurs.1 Interrupt bevacizumab therapy for moderate proteinuria (≥2 g per 24 hours); resume therapy when proteinuria is <2 g per 24 hours.1 Safety of continuing therapy in patients with moderate to severe proteinuria not known.1

Discontinue bevacizumab permanently in patients with nephrotic syndrome.1

Ovarian failure reported in premenopausal women receiving bevacizumab in combination with chemotherapy (i.e., modified FOLFOX6)† for adjuvant treatment of colorectal cancer.1 Recovery of ovarian function occurred in 22% of patients following discontinuance of bevacizumab.1 Long-term effects on fertility unknown.1

Inform women of childbearing potential of risk of ovarian failure prior to initiating bevacizumab.1

Severe (grade 3 or 4) neutropenia, febrile neutropenia, infection with severe neutropenia (sometimes fatal), and serious infections (e.g., pneumonia, catheter infections, wound infections) reported.1

CHF reported; higher risk in patients also receiving or who had previously received anthracyclines.1

Safety of continuation or resumption of bevacizumab in patients who develop cardiac dysfunction not studied.1

Microangiopathic hemolytic anemia reported in patients with solid tumors receiving bevacizumab and sunitinib†;35 36 cases were reversible within 3 weeks following discontinuance of both drugs without other interventions.35 36 Use of bevacizumab in combination with sunitinib is not recommended.35 36

Potential for immunogenicity.1 Incidence of antibody formation not established.1

Permanent loss of vision, endophthalmitis (infectious and sterile), intraocular inflammation, retinal detachment, increased IOP, hemorrhage (including conjunctival, vitreous, or retinal hemorrhage), vitreous floaters, ocular hyperemia, and ocular pain or discomfort reported in patients receiving intravitreal injection† of bevacizumab for treatment of various ocular disorders†.1

Specific Populations

Category C.1

Not known whether distributed into milk.1 Discontinue nursing or the drug, taking into account the long half-life (approximately 20 days) and the importance of the drug to the woman.1

Safety and efficacy not established in children <18 years of age.1 3

No difference in overall survival relative to younger adults observed in patients receiving bevacizumab and chemotherapy for metastatic colorectal cancer.1 However, possible increased risk of asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, MI, CHF, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, hyponatremia, nausea, vomiting, ileus, and fatigue.1

Increased incidence of arterial thromboembolic events in patients >66 years of age receiving bevacizumab with chemotherapy compared with younger adults.1 (See Thromboembolism under Cautions.)

Increased risk of proteinuria in patients ≥65 years of age receiving bevacizumab in combination with paclitaxel and carboplatin, compared with younger adults.1 (See Proteinuria under Cautions.)

Possible increased incidence of dyspepsia, GI hemorrhage, edema, epistaxis, increased cough, and voice alteration compared with younger adults.1

Common Adverse Effects

Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis.1

Specific Drugs

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about bevacizumab, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about bevacizumab. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using bevacizumab.

Review Date: October 4, 2017

Cervical cancer, persistent/recurrent/metastatic: IV: 15 mg/kg every 3 weeks (in combination with paclitaxel and either cisplatin or topotecan) until disease progression or unacceptable toxicity (Tewari 2014)

Colorectal cancer, metastatic, in combination with fluorouracil-based chemotherapy: IV: 5 mg/kg every 2 weeks (in combination with bolus-IFL) or 10 mg/kg every 2 weeks (in combination with FOLFOX4)

Colorectal cancer, metastatic, following first-line therapy containing bevacizumab: IV: 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks (in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based regimen)

Glioblastoma: IV: 10 mg/kg every 2 weeks as monotherapy or (off-label dosing) 10 mg/kg every 2 weeks (in combination with irinotecan) (Vredenburgh 2007)

Non–small cell lung cancer (nonsquamous cell histology): IV: 15 mg/kg every 3 weeks (in combination with carboplatin and paclitaxel) for 6 cycles followed by maintenance treatment (off-label use) of bevacizumab 15 mg/kg every 3 weeks as monotherapy until disease progression or unacceptable toxicity (Sandler 2006)

Ovarian (epithelial), fallopian tube, or primary peritoneal cancer (platinum-resistant recurrent): IV: 10 mg/kg every 2 weeks (in combination with weekly paclitaxel, every 4 week doxorubicin [liposomal], or days 1, 8, and 15 topotecan) or 15 mg/kg every 3 weeks (in combination with every 3 week topotecan) (Pujade-Lauraine 2014)

Ovarian (epithelial), fallopian tube, or primary peritoneal cancer (platinum-sensitive recurrent): IV: 15 mg/kg every 3 weeks (in combination with carboplatin and gemcitabine for 6 to 10 cycles or with carboplatin and paclitaxel for 6 to 8 cycles) then continue with bevacizumab (monotherapy) until disease progression or unacceptable toxicity (Aghajanian 2012; Aghajanian 2015; Coleman 2015).

Renal cell cancer, metastatic: IV: 10 mg/kg every 2 weeks (in combination with interferon alfa) or (off-label dosing) 10 mg/kg every 2 weeks as monotherapy (Yang 2003)

Age-related macular degeneration (off-label use/route): Intravitreal: 1.25 mg (0.05 mL) monthly for 3 months, then may be given scheduled (monthly) or as needed based on monthly ophthalmologic assessment (Chakravarthy 2013; Martin 2012)

Breast cancer, metastatic (off-label use): IV: 10 mg/kg every 2 weeks (in combination with paclitaxel) (Miller 2007)

Endometrial cancer, recurrent or persistent (off-label use): IV: 15 mg/kg every 3 weeks (as monotherapy) until disease progression or unacceptable toxicity (Aghajanian 2011)

Hereditary hemorrhagic telangiectasia (off-label use): IV: 5 mg/kg every 2 weeks for 6 doses (Dupuis-Girod 2012). Additional data may be necessary to further define the role of bevacizumab in this condition.

Malignant pleural mesothelioma, unresectable (off-label use): IV: 15 mg/kg every 3 weeks (in combination with pemetrexed and cisplatin) for up to 6 cycles, followed by bevacizumab maintenance therapy at 15 mg/kg once every 3 weeks until disease progression or unacceptable toxicity (Zalcman 2016)

Soft tissue sarcoma, angiosarcoma, metastatic or locally advanced (off-label use): IV: 15 mg/kg every 3 weeks until disease progression or unacceptable toxicity (Agulnik 2013). Additional data may be necessary to further define the role of bevacizumab in this condition.

Concerns related to adverse effects:

• Fistula/abscess formation: Gastrointestinal (GI) fistula (including enterocutaneous, esophageal, duodenal, and rectal fistulas), and intra-abdominal abscess have been reported in patients receiving bevacizumab for colorectal cancer, ovarian cancer, and other cancers (not related to treatment duration). Non-GI fistula formation (including tracheoesophageal, bronchopleural, biliary, vaginal, vesical, renal, bladder, and female tract fistulas) has been observed (rarely fatal), most commonly within the first 6 months of treatment. GI-vaginal fistulas have been reported in cervical cancer patients, all of whom had received prior pelvic radiation; patients may also have bowel obstructions requiring surgical intervention and diverting ostomies. Permanently discontinue in patients who develop internal organ fistulas, tracheoesophageal (TE) fistula, or any grade 4 fistula.

• Gastrointestinal perforation: [US Boxed Warning]: GI perforation, (sometimes fatal) has occurred in 0.3% to 3.2% of clinical study patients receiving bevacizumab; discontinue (permanently) if GI perforation occurs. All cervical cancer patients with GI perforation had a history of prior pelvic radiation. GI perforation was observed in patients with platinum-resistant ovarian cancer, although patients with evidence of recto-sigmoid involvement (by pelvic exam), bowel involvement (on CT scan), or clinical symptoms of bowel obstruction were excluded from the study; avoid bevacizumab use in these ovarian cancer patient populations. Most cases occur within 50 days of treatment initiation; monitor patients for signs/symptoms (eg, fever, abdominal pain with constipation and/or nausea/vomiting).

• Heart failure: Among approved and nonapproved uses evaluated thus far, the incidence of heart failure (HF) and/or left ventricular dysfunction (including LVEF decline) is higher in patients receiving bevacizumab plus chemotherapy when compared to chemotherapy alone. Use with caution in patients with cardiovascular disease. The safety of therapy resumption or continuation in patients with cardiac dysfunction has not been studied. In studies of patients with metastatic breast cancer (an off-label use), the incidence of grades 3 or 4 HF was increased in patients receiving bevacizumab plus paclitaxel when compared to the control arm. Patients with metastatic breast cancer who received prior anthracycline therapy had a higher rate of HF compared to those receiving paclitaxel alone (3.8% vs 0.6% respectively). A meta-analysis of 5 studies which enrolled patients with metastatic breast cancer who received bevacizumab suggested an association with an increased risk of heart failure; all trials included in the analysis enrolled patients who either received prior or were receiving concurrent anthracycline therapy (Choueiri 2011). In a scientific statement from the American Heart Association, bevacizumab has been determined to be an agent that may either cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate/major) (AHA [Page 2016]).

• Hemorrhage: [US Boxed Warning]: Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous system hemorrhage, epistaxis, and vaginal bleeding have been reported (up to 5 times more frequently if receiving bevacizumab). Avoid use in patients with serious hemorrhage or recent hemoptysis (≥2.5 mL blood). Serious or fatal pulmonary hemorrhage has been reported in patients receiving bevacizumab (primarily in patients with non–small cell lung cancer with squamous cell histology [not an FDA-approved indication]). Intracranial hemorrhage, including cases of grade 3 or 4 hemorrhage, has occurred in patients with previously treated glioblastoma. Treatment discontinuation is recommended in all patients with intracranial bleeding or other serious hemorrhage. Use with caution in patients at risk for thrombocytopenia.

• Hypertension: May cause and/or worsen hypertension; the incidence of severe hypertension in increased with bevacizumab. Use caution in patients with preexisting hypertension and monitor BP closely (every 2 to 3 weeks during treatment; regularly after discontinuation if bevacizumab-induced hypertension occurs or worsens). Permanent discontinuation is recommended in patients who experience a hypertensive crisis or hypertensive encephalopathy. Temporarily discontinue in patients who develop uncontrolled hypertension.

• Infusion reactions and hypersensitivity: Infusion reactions (eg, hypertension, hypertensive crisis, wheezing, oxygen desaturation, hypersensitivity [including anaphylactic/anaphylactoid reactions], chest pain, rigors, headache, diaphoresis) may occur with the first infusion (uncommon). Interrupt therapy in patients experiencing severe infusion reactions and administer appropriate therapy; there are no data to address routine premedication use or reinstitution of therapy in patients who experience severe infusion reactions.

• Mortality: Bevacizumab, in combination with chemotherapy (or biologic therapy), is associated with an increased risk of treatment-related mortality; a higher risk of fatal adverse events was identified in a meta-analysis of 16 trials in which bevacizumab was used for the treatment of various cancers (breast cancer, colorectal cancer, non–small cell lung cancer, pancreatic cancer, prostate cancer, and renal cell cancer) and compared to chemotherapy alone (Ranpura 2011).

• Necrotizing fasciitis: Cases of necrotizing fasciitis, including fatalities, have been reported (rarely); usually secondary to wound healing complications, GI perforation or fistula formation. Discontinue in patients who develop necrotizing fasciitis.

• Ocular adverse events: Serious eye infections and vision loss due to endophthalmitis have been reported from intravitreal administration (off-label use/route).

• Osteonecrosis of the jaw (ONJ): According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), medication-related osteonecrosis of the jaw (MRONJ) has been associated with bisphosphonates and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy. Antiangiogenic agents, when given concomitantly with antiresorptive agents, are associated with an increased risk of ONJ. Other risk factors for MRONJ include dentoalveolar surgery (eg, tooth extraction, dental implants), pre-existing inflammatory dental disease, and concomitant corticosteroid use. The AAOMS suggests that if medically permissible, initiation of antiangiogenic agents for cancer therapy should be delayed until optimal dental health is attained (if extractions are required, antiangiogenesis therapy should delayed until the extraction site has mucosalized or until after adequate osseous healing). Once antiangiogenic therapy for oncologic disease is initiated, procedures that involve direct osseous injury and placement of dental implants should be avoided. Patients developing ONJ during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]). Cases of non-mandibular ONJ has also been reported in pediatric patients who have received bevacizumab (bevacizumab is not approved for use in pediatric patients).

• Ovarian failure: In premenopausal women receiving bevacizumab in combination with mFOLFOX (fluorouracil/oxaliplatin based chemotherapy) the incidence of ovarian failure (amenorrhea ≥3 months) was higher (34%) compared to women who received mFOLFOX alone (2%). Ovarian function recovered in some patients after treatment was discontinued. Premenopausal women should be informed of the potential risk of ovarian failure.

• Posterior reversible encephalopathy syndrome: Cases of posterior reversible encephalopathy syndrome (PRES) have been reported. Symptoms (which include headache, seizure, confusion, lethargy, blindness and/or other vision, or neurologic disturbances) may occur from 16 hours to 1 year after treatment initiation. Resolution of symptoms usually occurs within days after discontinuation; however, neurologic sequelae may remain. PRES may be associated with hypertension; discontinue therapy and begin management of hypertension, if present. The safety of treatment reinitiation after PRES is not known.

• Proteinuria/nephrotic syndrome: Proteinuria and/or nephrotic syndrome have been associated with use; risks may be increased in patients with history of hypertension. Thrombotic microangiopathy has been associated with bevacizumab-induced proteinuria. Withhold treatment for ≥2 g proteinuria/24 hours and resume when proteinuria is <2 g/24 hours; discontinue in patients with nephrotic syndrome.

• Thromboembolism: Bevacizumab is associated with an increased risk for arterial thromboembolic events (ATE), including cerebral infarction, stroke, MI, TIA, angina, and other ATEs, when used in combination with chemotherapy. History of ATE, diabetes, or ≥65 years of age may present an even greater risk. Although patients with cancer are already at risk for venous thromboembolism (VTE), a meta-analysis of 15 controlled trials has demonstrated an increased risk for VTE in patients who received bevacizumab (Nalluri 2008). Cervical cancer patients receiving bevacizumab plus chemotherapy may be at increased risk of grade 3 or higher VTE compared to those patients who received chemotherapy alone. Permanently discontinue therapy in patients with severe ATE or life-threatening (grade 4) VTE, including pulmonary embolism; the safety of treatment reinitiation after ATE has not been studied.

• Wound dehiscence: [US Boxed Warning]: The incidence of wound healing and surgical complications, including serious and fatal events, is increased in patients who have received bevacizumab; discontinue with wound dehiscence. Although the appropriate interval between withholding bevacizumab and elective surgery has not been defined, bevacizumab should be discontinued at least 28 days prior to surgery and should not be reinitiated for at least 28 days after surgery and until wound is fully healed. In a retrospective review of central venous access device placements (a minor procedure), a greater risk of wound dehiscence was observed when port placement and bevacizumab administration were separated by <14 days (Erinjeri 2011). If possible, it may be more appropriate to wait until at least 6 to 8 weeks after bevacizumab discontinuation for major surgical procedures (Cortes 2012; Gordon 2009).

Disease-related concerns:

• CNS metastases: Use with caution in patients with CNS metastases; one case of CNS hemorrhage was observed in a study of NSCLC patients with CNS metastases.

• Renal impairment: An increase in diastolic and systolic blood pressures were noted in a retrospective review of patients with renal insufficiency (CrCl ≤60 mL/minute) who received bevacizumab for renal cell cancer (Gupta 2011).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Anthracyclines: May potentiate cardiotoxic effects of anthracyclines. HF is more common with prior anthracycline exposure and/or left chest wall irradiation.

• Myelosuppressive chemotherapy: When used in combination with myelosuppressive chemotherapy, increased rates of severe or febrile neutropenia and neutropenic infection were reported.

• Sorafenib: The incidence of hand-foot syndrome is increased in patients treated with bevacizumab plus sorafenib in comparison to those treated with sorafenib monotherapy.

• Sunitinib: Microangiopathic hemolytic anemia (MAHA) has been reported when bevacizumab has been used in combination with sunitinib. Concurrent therapy with sunitinib and bevacizumab is also associated with dose-limiting hypertension in patients with metastatic renal cell cancer.

Special populations:

• Elderly: Use with caution in patients ≥65 years of age; greater risk for adverse events, including arterial thrombotic events and proteinuria. Serious adverse events occurring more frequently in the elderly also include weakness, deep thrombophlebitis, sepsis, hyper-/hypotension, MI, CHF, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia.

Treatment with bevacizumab may cause you to have problems with wound healing, which could result in bleeding or infection. If you need to have any type of surgery, you will need to stop receiving bevacizumab at least 4 weeks ahead of time. Do not start using bevacizumab for at least 4 weeks after surgery, or until your surgical incision heals.

Before being treated with bevacizumab, tell your doctor if you have a bleeding or blood-clotting disorder, heart disease, congestive heart failure, high blood pressure, or a history of heart attack, stroke, blood clots, or stomach or intestinal bleeding (including perforation).

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, itchy, or have a fast heartbeat, chills, wheezing, or chest pain during the injection.

Call your doctor at once if you have: any unusual bleeding or bruising, blood in your urine or stools, coughing up blood, any bleeding that will not stop, severe stomach pain with fever and vomiting, sudden numbness or weakness, leg pain or swelling, chest pain, severe headache, problems with speech or balance, swelling or rapid weight gain, urinating less than usual, loss of bladder or bowel control, or missed menstrual periods.

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.

To be sure this medication is not causing harmful effects, your blood pressure will need to be checked often. Your urine may also need to be tested. Visit your doctor regularly.

Bevacizumab may cause a woman's ovaries to stop working correctly. Symptoms of ovarian failure include 3 or more missed menstrual periods in a row. This may affect your fertility (ability to have children). Talk to your doctor about your specific risks.

Your doctor or pharmacist can provide more information about bevacizumab.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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