Avastin

Bevacizumab is used with chemotherapy to treat cancer of the colon (large intestine) or rectum that has spread to other parts of the body. Bevacizumab is also used with chemotherapy to treat certain types of lung cancer. Bevacizumab is also used to treat glioblastoma (a certain type of cancerous brain tumor) that has been already treated with other medications. Bevacizumab is also used in combination with another medication to treat renal cell cancer (RCC, a type of cancer that begins in the kidney) that has spread to other parts of the body. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumors. This may slow the growth and spread of tumors.

Avastin is the brand name of the drug bevacizumab, which is used to treat certain cancers of the colon, rectum, lung, brain, ovary, cervix, and kidney.

Avastin was once used as a breast cancer treatment, but the Food and Drug Administration (FDA) determined that the benefits of the medicine didn't outweigh the risks for most breast cancer patients.

The drug is in a class of medications known as antiangiogenic agents, which work by stopping the formation of blood vessels that feed tumors.

Avastin is typically given along with other chemotherapy treatments. It's often used as a second-line treatment or given when cancers have spread to other areas of the body.

The medicine was first approved by the FDA to treat advanced colon cancer in 2004.

Avastin is manufactured by Genentech/Roche.

Avastin and Lucentis

Avastin has also been used off-label to treat wet age-related macular degeneration (an eye disease).

"Off label" refers to a drug that is prescribed to treat a disease or condition for which is has not been approved by the FDA. Many drugs are used this way and are still safe and effective.

In 2007, the manufacturer decided to discontinue making the drug available to compounding pharmacies for this purpose. The manufacturer, Genentech, has another drug, ranibizumab ophthalmic (Lucentis), that's used to treat macular degenration.

However, after protests from healthcare professionals, this decision was reversed.

Ranibizumab is generally considered safer than Avastin in the treatment of macular degenration; however, it is also more expensive.

If you have macular degeneration, talk to your doctor about which drug is best for you.

Avastin Warnings

Avastin contains a black-box warning because it could put you at risk for developing a serious or life-threatening hole in the wall of your stomach or intestine.

Call your doctor right away if you experience any of the following symptoms while receiving Avastin:

• Stomach pain
• Nausea
• Vomiting
• Fever
• Constipation

The medicine also contains a black-box warning because it can slow the healing of wounds. It some cases, it can cause a wound that's closed to split open.

Call your doctor immediately if you experience any problems with wound healing.

Tell your physician if you've recently had a surgical procedure or plan to have one. This medicine shouldn't be used for 28 days before or after a surgery.

Avastin contains yet another black-box warning because of the risk for severe or life-threatening bleeding.

Tell your doctor if you've recently coughed up blood, or if you experience any of the following symptoms while receiving Avastin:

• Nosebleeds
• Bleeding from your gums
• Coughing up or vomiting blood
• Coughing up or vomiting material that looks like coffee grounds
• Unusual bruising or bleeding
• Increased menstrual flow
• Unusual vaginal bleeding
• Pink, red, or dark brown urine
• Red or tarry black bowel movements
• Headache
• Dizziness
• Weakness

Before taking Avastin, tell your doctor if you have or have ever had:

• High blood pressure
• Any condition that affects the heart or blood vessels
• A bleeding or blood-clotting disorder
• A history of stomach or intestinal bleeding
• Cancer that spread to your brain or spine

Also, tell your physician if you've ever received radiation therapy on the left side of your chest.

Some people who receive Avastin have a reaction to the infusion. Tell your healthcare provider if you experience the following during your injection:

• Dizziness
• Nausea
• Sweating
• Headache
• Chest pain
• Wheezing

Older adults may be more likely to suffer side effects of Avastin.

Your doctor will probably want to check your blood pressure and urine often while you're receiving Avastin.

Make sure to keep all appointments with your physician and laboratory while using this medicine.

Pregnancy and Avastin

It's not known whether Avastin will harm an unborn baby. The medicine did cause birth defects in animal studies.

Avastin may make it difficult for some women to become pregnant. Avastin may cause a woman's ovaries to stop working properly, which could affect fertility.

Talk to your doctor if you're pregnant or plan to become pregnant in the future.

If you stop receiving Avastin, you should keep using birth control methods for at least six months before trying to conceive.

It's not known whether this medicine passes into breast milk or could harm a breastfeeding baby. Breastfeeding while receiving Avastin isn't recommended.

Common Side Effects of Avastin

Tell your doctor if any of the following side effects become severe or don't go away:

• Loss of appetite
• Heartburn
• Change in taste
• Diarrhea
• Weight loss
• Dry mouth
• Voice changes
• High blood pressure
• Sores on the skin or in the mouth

Serious Side Effects of Avastin

Contact your doctor immediately if you experience any of the symptoms listed in the Warning section, or any of the following serious side effects:

• Gagging, coughing, or choking after drinking or eating
• Slow or difficult speech
• Dizziness or fainting
• Weakness or numbness of an arm or leg
• Pain in the arms, neck, or upper back
• Chest pain
• Shortness of breath
• Seizures
• Extreme fatigue
• Vision loss or changes in vision
• Confusion
• Signs of infection, which may include fever, chills, or sore throat
• Unexplained weight gain
• Swelling of the eyes, face, stomach, hands, feet, ankles, or lower legs
• Foamy urine
• Dry, hacking cough
• Itching, redness, or scaling of the skin
• Pain, swelling, redness, or warmth in one leg only

See also Warning section.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.

Mechanism Of Action

Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.

Pharmacokinetics

The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total serum bevacizumab concentrations (i.e., the assay did not distinguish between free bevacizumab and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of Avastin weekly, every 2 weeks, or every 3 weeks, the estimated half-life of bevacizumab was approximately 20 days (range 11-50 days). The predicted time to reach steady state was 100 days. The accumulation ratio following a dose of 10 mg/kg of bevacizumab every 2 weeks was 2.8.

The clearance of bevacizumab varied by body weight, gender, and tumor burden. After correcting for body weight, males had a higher bevacizumab clearance (0.262 L/day vs. 0.207 L/day) and a larger Vc (3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or above median value of tumor surface area) had a higher bevacizumab clearance (0.249 L/day vs. 0.199 L/day) than patients with tumor burdens below the median. In Study 1, there was no evidence of lesser efficacy (hazard ratio for overall survival) in males or patients with higher tumor burden treated with Avastin as compared to females and patients with low tumor burden. The relationship between bevacizumab exposure and clinical outcomes has not been explored.

Animal Toxicology And/Or Pharmacology

Rabbits dosed with bevacizumab exhibited reduced wound healing capacity. Using full-thickness skin incision and partial thickness circular dermal wound models, bevacizumab dosing resulted in reductions in wound tensile strength, decreased granulation and re-epithelialization, and delayed time to wound closure.

Clinical Studies

Metastatic Colorectal Cancer (mCRC)

Study 1

In this double-blind, active-controlled study, patients were randomized (1:1:1) to IV bolus-IFL (irinotecan 125 mg/m², 5-FU 500 mg/m², and leucovorin (LV) 20 mg/m² given once weekly for 4 weeks every 6 weeks) plus placebo (Arm 1), bolus-IFL plus Avastin (5 mg/kg every 2 weeks) (Arm 2), or 5-FU/LV plus Avastin (5 mg/kg every 2 weeks) (Arm 3). Enrollment in Arm 3 was discontinued, as pre-specified, when the toxicity of Avastin in combination with the bolus-IFL regimen was deemed acceptable. The main outcome measure was overall survival (OS).

Of the 813 patients randomized to Arms 1 and 2, the median age was 60, 40% were female, 79% were Caucasian, 57% had an ECOG performance status of 0, 21% had a rectal primary and 28% received prior adjuvant chemotherapy. In 56% of the patients, the dominant site of disease was extra-abdominal, while the liver was the dominant site in 38% of patients.

The addition of Avastin resulted in an improvement in survival across subgroups defined by age ( < 65 yrs, ≥ 65 yrs) and gender. Results are presented in Table 6 and Figure 1.

Table 6: Study 1 Efficacy Results

	IFL+Placebo	IFL+Avastin 5 mg/kg q 2 wks
Number of Patients	411	402
Overall Survivala
Median (months)	15.6	20.3
Hazard ratio		0.66
Proeression-free Survivala
Median (months)	6.2	10.6
Hazard ratio		0.54
Overall Response Rateb
Rate (percent)	35%	45%
Duration of Response
Median (months)	7.1	10.4
a p < 0.001 by stratified log rank test. b p < 0.01 by χ2 test.

Figure 1: Duration of Survival in Study 1

Among the 110 patients enrolled in Arm 3, median OS was 18.3 months, median progression-free survival (PFS) was 8.8 months, objective response rate (ORR) was 39%, and median duration of response was 8.5 months.

Study 2

Study 2 was a randomized, open-label, active-controlled trial in patients who were previously treated with irinotecan ± 5-FU for initial therapy for metastatic disease or as adjuvant therapy. Patients were randomized (1:1:1) to IV FOLFOX4 (Day 1: oxaliplatin 85 mg/m² and LV 200 mg/m² concurrently, then 5-FU 400 mg/m² bolus followed by 600 mg/m² continuously; Day 2: LV 200 mg/m² , then 5-FU 400 mg/m² bolus followed by 600 mg/m² continuously; repeated every 2 weeks), FOLFOX4 plus Avastin (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1), or Avastin monotherapy(10 mg/kg every 2 weeks). The main outcome measure was OS.

The Avastin monotherapy arm was closed to accrual after enrollment of 244 of the planned 290 patients following a planned interim analysis by the data monitoring committee based on evidence of decreased survival compared to FOLFOX4 alone.

Of the 829 patients randomized to the three arms, the median age was 61 years, 40% were female, 87% were Caucasian, 49% had an ECOG performance status of 0, 26% received prior radiation therapy, and 80% received prior adjuvant chemotherapy, 99% received prior irinotecan, with or without 5-FU as therapy for metastatic disease, and 1% received prior irinotecan and 5-FU as adjuvant therapy.

The addition of Avastin to FOLFOX4 resulted in significantly longer survival as compared to FOLFOX4 alone (median OS 13.0 months vs. 10.8 months; hazard ratio 0.75 [95% CI 0.63, 0.89], p =0.001 stratified log rank test) with clinical benefit seen in subgroups defined by age ( < 65 yrs, ≥ 65 yrs) and gender. PFS and ORR based on investigator assessment were higher in the Avastin plus FOLFOX4 arm.

Study 3

The activity of Avastin in combination with bolus or infusional 5-FU/LV was evaluated in a single arm study enrolling 339 patients with mCRC with disease progression following both irinotecan- and oxaliplatin-containing chemotherapy regimens. Seventy-three percent of patients received concurrent bolus 5-FU/LV. One objective partial response was verified in the first 100 evaluable patients for an overall response rate of 1% (95% CI 0-5.5%).

Study 4

Study 4 was a prospective, randomized, open-label, multinational, controlled trial in patients with histologically confirmed metastatic colorectal cancer who had progressed on a first-line Avastin containing regimen. Patients were excluded if they progressed within 3 months of initiating firstline chemotherapy and if they received Avastin for less than 3 consecutive months in the first-line setting.

Patients were randomized (1:1) within 3 months after discontinuation of Avastin as first-line therapy to receive fluoropyrimidine/oxaliplatin- or fluoropyrimidine/irinotecan-based chemotherapy with or without Avastin administered at 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks. The choice of second line therapy was contingent upon first-line chemotherapy treatment. Second-line treatment was administered until progressive disease or unacceptable toxicity. The main outcome measure was OS defined as the time from randomization until death from any cause.

Of the 820 patients randomized, the majority of patients were male (64%) and the median age was 63.0 years (range 21 to 84 years). At baseline, 52% of patients were ECOG performance status (PS) 1, 44% were ECOG PS 0, 58% received irinotecan-based therapy as first-line treatment, 55% progressed on first-line treatment within 9 months, and 77% received their last dose of Avastin as first-line treatment within 42 days of being randomized. Second-line chemotherapy regimens were generally balanced between each treatment arm.

The addition of Avastin to fluoropyrimidine-based chemotherapy resulted in a statistically significant prolongation of survival and PFS; there was no significant difference in overall response rate, a key secondary outcome measure. Results are presented in Table 7 and Figure 2.

Table 7 : Study 4 Efficacy Results

	Chemotherapy	Avastin + Chemotherapy
Number of Patients	411	409
Overall Survivala
Median (months)	9.8	11.2
Hazard ratio (95% CI)	0.81 (0.69, 0.94)
Progression-Free Survivalb
Median (months)	4.0	5.7
Hazard ratio (95% CI)	0.68 (0.59, 0.78)
a p = 0.0057 by unstratified log rank test. b p-value < 0.0001 by unstratified log rank test.

Figure 2: Duration of Survival in Study 4

Lack Of Efficacy In Adjuvant Treatment Of Colon Cancer

Lack of efficacy of Avastin as an adjunct to standard chemotherapy for the adjuvant treatment of colon cancer was determined in two randomized, open-label, multicenter clinical trials.

The first study conducted in 3451 patients with high risk stage II and III colon cancer, who had undergone surgery for colon cancer with curative intent, was a 3-arm study of Avastin administered at a dose equivalent to 2.5 mg/kg/week on either a 2-weekly schedule in combination with FOLFOX4, or on a 3-weekly schedule in combination with XELOX and FOLFOX4 alone. Patients were randomized as follows: 1151 patients to FOLFOX4 arm, 1155 to FOLFOX4 plus Avastin arm, and 1145 to XELOX plus Avastin arm. The median age was 58 years, 54% were male, 84% were Caucasian and 29% were ≥ age 65. Eighty-three percent had stage III disease. The main efficacy outcome of the study was disease free survival (DFS) in patients with stage III colon cancer. Addition of Avastin to chemotherapy did not improve DFS. As compared to the control arm, the proportion of stage III patients with disease recurrence or with death due to disease progression were numerically higher in the FOLFOX4 plus Avastin and in the XELOX plus Avastin arms. The hazard ratios for DFS were 1.17 (95% CI: 0.98-1.39) for the FOLFOX4 plus Avastin versus FOLFOX4 and 1.07 (95% CI: 0.90-1.28) for the XELOX plus Avastin versus FOLFOX4. The hazard ratios for overall survival were 1.31 (95% CI=1.03, 1.67) and 1.27 (95% CI=1.00, 1.62) for the comparison of Avastin plus FOLFOX4 versus FOLFOX4 and Avastin plus XELOX versus FOLFOX4, respectively. Similar lack of efficacy for DFS were observed in the Avastin-containing arms compared to control in the high-risk stage II cohort.

In a second study, 2710 patients with stage II and III colon cancer who had undergone surgery with curative intent, were randomized to receive either Avastin administered at a dose equivalent to 2.5 mg/kg/week in combination with mFOLFOX6 (N=1354) or mFOLFOX6 alone (N=1356). The median age was 57 years, 50% were male and 87% Caucasian. Seventy-five percent had stage III disease. The main efficacy outcome was DFS among stage III patients. The hazard ratio for DFS was 0.92 (95% CI: 0.77, 1.10). Overall survival, an additional efficacy outcome, was not significantly improved with the addition of Avastin to mFOLFOX6 (HR=0.96, 95% CI=[0.75,1.22].

Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

Study 5

The safety and efficacy of Avastin as first-line treatment of patients with locally advanced, metastatic, or recurrent non-squamous NSCLC was studied in a single, large, randomized, active-controlled, open-label, multicenter study.

Chemotherapy-naive patients with locally advanced, metastatic or recurrent non-squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel 200 mg/m² and carboplatin AUC = 6.0, by IV on day 1 (PC) or PC in combination with Avastin 15 mg/kg by IV on day 1 (PC plus Avastin). After completion or upon discontinuation of chemotherapy, patients in the PC plus Avastin arm continued to receive Avastin alone until disease progression or until unacceptable toxicity. Patients with predominant squamous histology (mixed cell type tumors only), central nervous system (CNS) metastasis, gross hemoptysis ( ≥ 1/2 tsp of red blood), unstable angina, or receiving therapeutic anticoagulation were excluded. The main outcome measure was duration of survival.

Of the 878 patients randomized, the median age was 63, 46% were female, 43% were ≥ age 65, and 28% had ≥ 5% weight loss at study entry. Eleven percent had recurrent disease and of the 89% with newly diagnosed NSCLC, 12% had Stage IIIB with malignant pleural effusion and 76% had Stage IV disease.

The results are presented in Figure 3. OS was statistically significantly higher among patients receiving PC plus Avastin compared with those receiving PC alone; median OS was 12.3 months vs. 10.3 months [hazard ratio 0.80 (repeated 95% CI 0.68, 0.94), final p- value 0.013, stratified log-rank test]. Based on investigator assessment which was not independently verified, patients were reported to have longer PFS with Avastin in combination with PC compared to PC alone.

Figure 3: Duration of Survival in Study 5

In an exploratory analyses across patient subgroups, the impact of Avastin on OS was less robust in the following: women [HR = 0.99 (95% CI: 0.79, 1.25)], age ≥ 65 years [HR=0.91 (95% CI: 0.72, 1.14)] and patients with ≥ 5% weight loss at study entry [HR=0.96 (95% CI: 0.73, 1.26)].

The safety and efficacy of Avastin in patients with locally advanced, metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy was studied in another randomized, double-blind, placebo controlled, three-arm study of Avastin in combination with cisplatin and gemcitabine (CG) versus placebo and CG. A total of 1043 patients were randomized 1:1:1 to receive placebo plus CG, Avastin 7.5 mg/kg plus CG or Avastin 15.0 mg/kg plus CG. The median age was 58 years, 36% were female, and 29% were ≥ age 65. Eight percent had recurrent disease and 77% had Stage IV disease. Progression-free survival, the main efficacy outcome measure, was significantly higher in both Avastin containing arms compared to the placebo arm [HR 0.75 (95% CI 0.62, 0.91), p = 0.0026 for the Avastin 7.5 mg/kg plus CG arm and HR 0.82 (95% CI 0.68; 0.98), p = 0.0301 for the Avastin 15.0 mg/kg plus CG arm]. The addition of Avastin to CG chemotherapy failed to demonstrate an improvement in the duration of overall survival, an additional efficacy outcome measure, [HR 0.93 (95% CI 0.78; 1.11), p = 0.4203 for the Avastin 7.5 mg/kg plus CG arm and HR 1.03 (95% CI 0.86; 1.23), p = 0.7613 for the Avastin 15.0 mg/kg plus CG arm].

Glioblastoma

Study 6

The efficacy and safety of Avastin was evaluated in Study 6, an open-label, multicenter, randomized, non-comparative study of patients with previously treated glioblastoma. Patients received Avastin (10 mg/kg IV) alone or Avastin plus irinotecan every 2 weeks until disease progression or until unacceptable toxicity. All patients received prior radiotherapy (completed at least 8 weeks prior to receiving Avastin) and temozolomide. Patients with active brain hemorrhage were excluded.

Of the 85 patients randomized to the Avastin arm, the median age was 54 years, 32% were female, 81% were in first relapse, Karnofsky performance status was 90-100 for 45% and 70-80 for 55%.

The efficacy of Avastin was demonstrated using response assessment based on both WHO radiographic criteria and by stable or decreasing corticosteroid use, which occurred in 25.9% (95% CI 17.0%, 36.1%) of the patients. Median duration of response was 4.2 months (95% CI 3.0, 5.7). Radiologic assessment was based on MRI imaging (using T1 and T2/FLAIR). MRI does not necessarily distinguish between tumor, edema, and radiation necrosis.

Study 7

Study 7, was a single-arm, single institution trial with 56 patients with glioblastoma. All patients had documented disease progression after receiving temozolomide and radiation therapy. Patients received Avastin 10 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity.

The median age was 54, 54% were male, 98% Caucasian, and 68% had a Karnofsky Performance Status of 90-100.

The efficacy of Avastin was supported by an objective response rate of 19.6% (95% CI 10.9%, 31.3%) using the same response criteria as in Study 6. Median duration of response was 3.9 months (95% CI 2.4, 17.4).

Metastatic Renal Cell Carcinoma (mRCC)

Study 8

Patients with treatment-naive mRCC were evaluated in a multicenter, randomized, double-blind, international study comparing Avastin plus interferon alfa 2a (IFN- α 2a) versus placebo plus IFN-α2a. A total of 649 patients who had undergone a nephrectomy were randomized (1:1) to receive either Avastin (10 mg/kg IV infusion every 2 weeks; n = 327) or placebo (IV every 2 weeks; n = 322) in combination with IFN- α 2a (9 MIU subcutaneously three times weekly, for a maximum of 52 weeks). Patients were treated until disease progression or unacceptable toxicity. The main outcome measure of the study was investigator-assessed PFS. Secondary outcome measures were ORR and OS.

The median age was 60 years (range 18-82), 96% were white, and 70% were male. The study population was characterized by Motzer scores as follows: 28% favorable (0), 56% intermediate (1-2), 8% poor (3-5), and 7% missing.

The results are presented in Figure 4. PFS was statistically significantly prolonged among patients receiving Avastin plus IFN- α 2a compared to those receiving IFN- α 2a alone; median PFS was 10.2 months vs. 5.4 months [HR 0.60 (95% CI 0.49, 0.72), p-value < 0.0001, stratified log-rank test]. Among the 595 patients with measurable disease, ORR was also significantly higher (30% vs. 12%, p < 0.0001, stratified CMH test). There was no improvement in OS based on the final analysis conducted after 444 deaths, with a median OS of 23 months in the Avastin plus IFN- α 2a arm and 21 months in the IFN- α 2a plus placebo arm [HR 0.86, (95% CI 0.72, 1.04)].

Figure 4: Progression-Free Survival in Study 8

Persistent, Recurrent, Or Metastatic Carcinoma Of The Cervix

Study 9

Patients with persistent, recurrent, or metastatic carcinoma of the cervix were evaluated in a randomized, four-arm, multi-center trial comparing Avastin plus chemotherapy versus chemotherapy alone. A total of 452 patients were randomized (1:1:1:1) to receive paclitaxel and Cisplatin with or without Avastin, or paclitaxel and topotecan with or without Avastin.

The dosing regimens for Avastin, Paclitaxel, Cisplatin and Topotecan were as follows:

• Day 1: Paclitaxel 135 mg/m² IV over 24 hours, Day 2: cisplatin 50 mg/m² IV plus Avastin; or Day 1: paclitaxel 175 mg/m² IV over 3 hours, Day 2: cisplatin 50 mg/m² IV plus Avastin ; or Day 1: paclitaxel 175 mg/m² IV over 3 hours plus cisplatin 50 mg/m² IV plus Avastin
• Day 1: Paclitaxel 175 mg/m² over 3 hours plus Avastin, Days 1-3: topotecan 0.75 mg/m² over 30 minutes

Patients were treated until disease progression or unacceptable adverse events precluded further therapy. The main outcome measure of the study was overall survival (OS). Response rate (ORR) was a secondary outcome measure.

The median age was 48 years (range: 20-85). Of the 452 patients randomized at baseline, 78% of patients were Caucasian, 80% had received prior radiation, 74% had received prior chemotherapy concurrent with radiation, and 32% had a platinum-free interval of less than 6 months. Patients had a GOG Performance Status (PS) of 0 (58%) or 1 (42%). Demographic and disease characteristics were balanced across arms.

The study results for OS in patients who received chemotherapy plus Avastin as compared to chemotherapy alone are presented in Table 8 and Figure 5.

Figure 5: Study 9: Overall Survival for Chemotherapy vs. Chemotherapy plus Avastin

Table 8: Study 9 Efficacy Results: Chemotherapy versus Chemotherapy + Avastin

	Chemotherapy (n=225)	Chemotherapy + Avastin (n=227)
Overall Survival
Median (months)a	12.9	16.8
Hazard ratio [95% CI]	0.74 [0.58;0.94]
	(p-valueb = 0.0132)
a Kaplan-Meier estimates. b log-rank test (stratified).

The overall response rate was also higher in patients who received chemotherapy plus Avastin [45% (95% CI: 39, 52)] than in patients who received chemotherapy alone [34% (95% CI: 28,40)].

Table 9: Study 9 Efficacy Results: Platinum Doublet versus Nonplatinum Doublet

	Topotecan + Paclitaxel +/- Avastin (n=223)	Cisplatin + Paclitaxel +/- Avastin (n=229)
Overall Survival
Median (months)a	13.3	15.5
Hazard ratio [95% CI]	1.15 [0.91, 1.46]
	p-value=0.23
a Kaplan-Meier estimates.

The hazard ratio for OS with Cisplatin +Paclitaxel + Avastin as compared to Cisplatin +Paclitaxel alone was 0.72 (95% CI: 0.51,1.02). The hazard ratio for OS with Topotecan +Paclitaxel +Avastin as compared to Topotecan +Paclitaxel alone was 0.76 (95% CI: 0.55, 1.06).

Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, Or Primary Peritoneal Cancer

Study 10

Avastin was evaluated in a multicenter, open-label, randomized, two-arm study (Study 10) comparing Avastin plus chemotherapy versus chemotherapy alone in patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within < 6 months from the most recent platinum-based therapy (N=361). Patients had received no more than 2 prior chemotherapy regimens. Patients received one of the following intravenous chemotherapies at the discretion of the investigator: paclitaxel (80mg/m² on days 1, 8, 15 and 22 every 4 weeks; pegylated liposomal doxorubicin (PLD) 40mg/m² on day 1 every 4 weeks; or topotecan 4mg/m² on days 1, 8 and 15 every 4 weeks or 1.25mg/m² on days 1-5 every 3 weeks). Patients were treated until disease progression, unacceptable toxicity, or withdrawal. Forty percent of patients on the chemotherapy alone arm received Avastin monotherapy upon progression. The main outcome measure was investigator-assessed Progression-Free Survival (PFS). Secondary outcome measures were Objective Response Rate (ORR) and Overall Survival (OS).

The median age was 61 years (range 25-84 years) and 37% of patients were ≥ age 65. Seventy-nine percent had measurable disease at baseline, 87% had baseline CA-125 levels ≥ 2 x ULN and 31% had ascites at baseline. Seventy-three percent had a platinum-free interval (PFI) of 3-6 months and 27% had PFI of < 3 months. ECOG Performance Status was 0 for 59%, 1 for 34% and 2 for 7% of the patients.

The addition of Avastin to chemotherapy demonstrated a statistically significant improvement in investigator-assessed PFS, which was supported by a retrospective independent review analysis. Study results for the intent to treat (ITT) population are presented in Table 10 and Figure 6. Results for the separate chemotherapy cohorts are presented in Table 11.

Table 10: Efficacy Results in Study 10 ITT Population

Efficacy Parameter	CTc (N=182)	CTc+Avastin (N=179)
PFS per Investigator
Median (95% CI), in months HR (95% CI)a	3.4 (2.1, 3.8)	6.8 (5.6, 7.8)
p-value b	0.38	(0.30, 0.49) < 0.0001
Overall Survival
Median (95% CI), in months	13.3 (11.9, 16.4)	16.6 (13.7, 19.0)
HR (95% CI)a	0.89	(0.69, 1.14)
Objective Response Rate
Number of Patients with Measurable	144	142
Disease at Baseline Rate, % (95% CI)	13% (7%, 18%)	28% (21%, 36%)
Median of Response Duration
in months	5.4	9.4
aper stratified Cox proportional hazards model bper stratified logrank test c chemotherapy

Figure 6: Investigator-Assessed Progression-Free Survival in Study 10 ITT Population

Table 11 : Study 10 Efficacy Results in Chemotherapy Cohorts

Efficacy Parameter	Paclitaxel		Topotecan		PLD
	CTb (N=55)	CTb+Avastin (N=60)	CTb (N=63)	CTb+Avastin (N=57)	CTb (N=64)	CTb+Avastin (N=62)
PFS per Investigator
Median (months)	3.9	9.6	2.1	6.2	3.5	5.1
(95% CI)	(3.5, 5.5)	(7.8, 11.5)	(1.9, 2.3)	(5.3, 7.6)	(1.9, 3.9)	(3.9, 6.3)
HR (95% CI)a	0.47 (0.31, 0.72)		0.24 (0.15, 0.38)		0.47 (0.32, 0.71)
Overall Survival
Median (months)	13.2	22.4	13.3	13.8	14.1	13.7
(95% CI)	(8.2, 19.7)	(16.7, 26.7)	(10.4, 18.3)	(11.0, 18.3)	(9.9, 17.8)	(11.0, 18.3)
HR (95% CI)a	0.64 (0.41, 1.01)		1.12 (0.73, 1.73)		0.94 (0.63, 1.42)
Objective Response Rate
Number of Patients with	43	45	50	46	51	51
Measurable Disease at Baseline
Rate, % (95% CI)	30 (17, 44)	53 (39, 68)	2 (0, 6)	17 (6, 28)	8 (0, 15)	16 (6, 26)
Median of Response Duration (months)	6.8	11.6	NE	5.2	4.6	8.0
a per stratified Cox proportional hazards model b chemotherapy NE= Not Estimable

Avastin comes as a liquid to be injected intravenously (into a vein) by your doctor or healthcare provider in a medical setting (hospital or clinic). You will likely receive an injection every 2 or 3 weeks, depending upon the condition being treated.

• The first injection will last 90 minutes.
• If the first injection is received with no serious side effects, the second injection will be given over 60 minutes. 
• If the infusion over 60 minutes was tolerated, the next doses will be given over 30 minutes.

Depending on how your body responds, your doctor may delay or stop your Avastin treatments.

Gastrointestinal Perforations

Avastin 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 Avastin (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 Avastin 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 Avastin.
• Avastin therapy should be permanently discontinued in patients with gastrointestinal perforation.

Wound Healing Complications

• Avastin administration can result in the development of wound dehiscence, in some instances resulting in fatality.
• Avastin therapy should be permanently discontinued in patients with wound dehiscence requiring medical intervention.
• The appropriate interval between termination of Avastin 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 Avastin.
• 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 Avastin.

Black Box Warnings

Gastrointestinal perforations

• Gastrointestinal (GI) perforation, fistula formation, and/or intra-abdominal abscess unrelated to therapy duration reported in patients with colorectal cancer as well as other types of cancers
• Typical presentation reported as abdominal pain associated with symptoms such as constipation and vomiting
• Include GI perforation in the differential diagnosis of patients presenting with abdominal pain
• Discontinue therapy permanently in patients with GI perforation

Surgery and wound healing complications

• Administration may result in the development of fatal wound dehiscence
• Discontinue therapy in patients with wound dehiscence requiring medical intervention
• Discontinue at least 28 days prior to elective surgery
• Do not initiate bevacizumab for at least 28 days after surgery and until the surgical wound is fully healed

Hemorrhage

• Severe or fatal hemorrhage, hemoptysis, gastrointestinal bleeding, CNS hemorrhage, and vaginal bleeding are increased in bevacizumab-treated patients
• Do not administer the drug to patients with serious hemorrhage or recent hemoptysis

Contraindications

None

Cautions

Impairs wound healing; discontinue before elected surgeries and do not initiate following surgery (see Black Box Warnings)

Bevacizumab products can result in minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events (see Black Box Warnings)

Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE; discontinue bevacizumab for severe ATE

Increased risk of venous thromboembolic events (VTE) reported in patients treated with bevacizumab for cervical cancer; discontinue bevacizumab for life-threatening VTE

Monitor blood pressure and treat hypertension; increased risk for severe hypertension; temporarily suspend treatment; discontinue if hypertensive crisis or hypertensive encephalopathy

Increased relative risk for heart failure has been associated with therapy

Posterior reversible encephalopathy syndrome (PRES) reported (0.5%); discontinue if PRES develops

Proteinuria reported; temporarily suspend treatment for ≥2 g proteinuria/24 hr; discontinue if nephrotic syndrome occurs (incidence <1%)

Risk of ovarian failure reported especially in premenopausal women receiving bevacizumab in combination with mFOLFOX chemotherapy compared to mFOLFOX alone; inform females of reproductive potential of the risk of ovarian failure prior to starting treatment

Advise females of reproductive potential to use effective contraception during treatment with and for 6 months after the last dose (see Pregnancy)

Infusion reactions may occur and include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis; stop infusion if severe and administer appropriate therapy

GI perforation and fistula formation

• Serious and sometimes fatal GI perforation occurs at a higher incidence in bevacizumab treated patients compared to controls; incidence of perforation ranged from 0.3 to 3.2% across clinical studies
• In a cervical cancer trial, the incidence of GI-vaginal fistulae was 8.2% in bevacizumab-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation
• In a platinum-resistant ovarian cancer trial, the incidence of GI perforation was 1.7%
• Serious and sometimes fatal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in bevacizumab-treated patients compared to controls
• From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer, 1.8% of bevacizumab-treated patients and 1.4% of control patients were reported to have had nongastrointestinal vaginal, vesical, or female genital tract fistulae

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.

Antineoplastic agent; a recombinant humanized monoclonal antibody.1 2 3 4 5

Storage

Parenteral

Injection Concentrate

2–8°C.1 Do not freeze; protect from light.1

Store diluted solution at 2–8°C for up to 8 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

No incompatibilities with PVC or polyolefin bags.1

Solution Compatibility

Compatible
Sodium chloride 0.9%
Incompatible
Dextrose solutions

• Antineoplastic agent;1 3 5 a recombinant humanized monoclonal IgG1 antibody containing human framework regions and murine complementarity-determining regions.1 6

• Binds to human vascular endothelial growth factor (VEGF) and prevents interaction of VEGF with its receptors (Flt-1, KDR) on the surface of endothelial cells.1 This may result in inhibition of angiogenesis, thus reducing microvascular growth of tumors and inhibiting metastatic disease progression.1 2 3 5

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

• 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 Avastin, 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 Avastin. 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 Avastin (bevacizumab).

Review Date: October 4, 2017

Call your doctor for instructions if you miss an appointment for your bevacizumab injection.

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

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

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

Avastin 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.

Avastin 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 Avastin 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 Avastin 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.

Applies to bevacizumab: intravenous solution

Along with its needed effects, bevacizumab (the active ingredient contained in Avastin) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking bevacizumab:

More common

• Black, tarry stools
• bleeding gums
• body aches or pain
• burning, tingling, numbness, or pain in the hands, arms, feet, or legs
• chest pain or discomfort
• chills
• cloudy urine
• convulsions
• cough
• cracks in the skin
• decreased urine output
• difficult or labored breathing
• dilated neck veins
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• ear congestion
• extreme fatigue
• fever
• irregular breathing
• irregular heartbeat
• lack or loss of strength
• lightheadedness
• loss of appetite
• loss of heat from the body
• loss of voice
• mood changes
• nasal congestion
• nervousness
• pain
• pain, redness, or swelling in the arm or leg
• painful or difficult urination
• pinpoint red spots on the skin
• pounding in the ears
• rapid breathing
• redness
• runny nose
• sensation of pins and needles
• slow or fast heartbeat
• sore throat
• sores on the skin
• sores, ulcers, or white spots on the lips or in the mouth
• stabbing pain
• sunken eyes
• sweating
• swelling of the face, fingers, feet, or lower legs
• swelling or inflammation of the mouth
• swollen glands
• thirst
• tightness in the chest
• trouble breathing
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of blood or material that looks like coffee grounds
• watery or bloody diarrhea
• weight gain
• wrinkled skin
• yellow skin

Less common

• Abdominal or stomach pain or tenderness
• bone pain
• difficulty with swallowing
• fainting
• severe constipation
• severe vomiting

Rare

• Back pain
• blisters
• blurred vision
• coma
• confusion
• dizziness
• drowsiness
• headache
• increased thirst
• muscle pain or cramps
• open sores
• pale skin

Incidence not known

• Bloody mucus or unexplained nosebleeds
• hoarseness
• sudden weakness in the arms or legs
• sudden, severe chest pain
• voice changes

Some side effects of bevacizumab may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Acid or sour stomach
• belching
• bloody nose
• change in taste or bad unusual or unpleasant (after) taste
• change in walking and balance
• clumsiness or unsteadiness
• diarrhea
• dry mouth
• excess flow of tears
• hair loss
• heartburn
• indigestion
• stomach discomfort, upset, or pain
• thinning of the hair
• weight loss

LactMed Record Number

825

Last Revision Date

20150908

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.