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Avastin

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Avastin uses


WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

See full prescribing information for complete boxed warning.


Gastrointestinal Perforations

The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 3.2%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1) .]

Surgery and Wound Healing Complications

The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1) .]

Hemorrhage

Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occur up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.4), Adverse Reactions (6.1) .]

Indications and Usage (1.6) 12/2016

1 INDICATIONS AND USAGE

Avastin is a vascular endothelial growth factor-specific angiogenesis inhibitor indicated for the treatment of:


Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. (1.1)

1.1 Metastatic Colorectal Cancer (mCRC)

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2) .]

1.2 Non-Squamous Non–Small Cell Lung Cancer

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 Glioblastoma

Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies .]

1.4 Metastatic Renal Cell Carcinoma (mRCC)

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

1.5 Persistent, Recurrent, or Metastatic Carcinoma of the Cervix

Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix. [See Clinical Studies .]

1.6 Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Avastin in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens.

Avastin, either in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine, followed by Avastin as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

2 DOSAGE AND ADMINISTRATION


Metastatic colorectal cancer (2.2)


Non–squamous non–small cell lung cancer (2.2)


Glioblastoma (2.2)


Metastatic renal cell carcinoma (mRCC) (2.2)


Persistent, recurrent, or metastatic carcinoma of the cervix (2.2)


Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (2.2)


Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (2.2)

2.1 Administration

Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV) infusion.

2.2 Recommended Doses and Schedules

Patients should continue treatment until disease progression or unacceptable toxicity.

Metastatic Colorectal Cancer

The recommended doses are 5 mg/kg or 10 mg/kg every 2 weeks when used in combination with intravenous 5-FU-based chemotherapy.


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

The recommended dose is 15 mg/kg every 3 weeks in combination with carboplatin and paclitaxel.

Glioblastoma

The recommended dose is 10 mg/kg every 2 weeks.

Metastatic Renal Cell Carcinoma (mRCC)

The recommended dose is 10 mg/kg every 2 weeks in combination with interferon alfa.

Cervical Cancer

The recommended dose of Avastin is 15 mg/kg every 3 weeks as an intravenous infusion administered in combination with one of the following chemotherapy regimens: paclitaxel and cisplatin, or paclitaxel and topotecan.

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

The recommended dose is 10mg/kg every 2 weeks in combination with one of the following intravenous chemotherapy regimens: paclitaxel, pegylated liposomal doxorubicin, or topotecan (weekly); or 15 mg/kg every 3 weeks in combination with topotecan (every 3 weeks).

Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

The recommended dose is 15 mg/kg every 3 weeks when administered in combination with carboplatin and paclitaxel for 6 cycles and up to 8 cycles, followed by continued use of Avastin 15 mg/kg every 3 weeks as a single agent until disease progression. Alternatively, 15 mg/kg every 3 weeks when administrated in combination with carboplatin and gemcitabine for 6 cycles and up to 10 cycles, followed by continued use of Avastin 15 mg/kg every 3 weeks as a single agent until disease progression.

2.3 Preparation for Administration

Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw necessary amount of Avastin and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as the product contains no preservatives.

DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION.

2.4 Dose Modifications

There are no recommended dose reductions.

Discontinue Avastin for:


Temporarily suspend Avastin for:

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

None.

None (4)

5 WARNINGS AND PRECAUTIONS

5.1 Gastrointestinal Perforations and Fistulae

Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 3.2% across clinical studies. [See Adverse Reactions (6.1) .] From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), gastrointestinal perforations were reported in 3.2% of Avastin treated patients, all of whom had a history of prior pelvic radiation. Fatal outcome was reported in <1% of Avastin-treated patients. In a platinum-resistant ovarian cancer trial (Study 10), the incidence of GI perforation was 1.7% (3/179). In this trial, patients with evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded.

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of cases occurred within the first 50 days of initiation of Avastin. Avoid use of Avastin in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Permanently discontinue Avastin in patients with gastrointestinal perforation.

In Avastin clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer. In a cervical cancer trial (Study 9), the incidence of gastrointestinal-vaginal fistulae was 8.3% in Avastin-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. Patients who develop GI vaginal fistulas may also have bowel obstructions and require surgical intervention as well as diverting ostomies. [See Boxed Warning, Dosage and Administration (2.4) .]

5.2 Non-Gastrointestinal Fistulae

Serious and sometimes fatal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. Uncommon reports of fistulae that involve areas of the body other than the gastrointestinal tract were observed in clinical trials across various indications and have also been reported in post-marketing experience. Most events occurred within the first 6 months of Avastin therapy.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), 1.8% of Avastin-treated patients and 1.4% of control patients were reported to have had non-gastrointestinal vaginal, vesical, or female genital tract fistulae.

Permanently discontinue Avastin in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4) .]

5.3 Surgery and Wound Healing Complications

Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2) .] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1) .]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4) .]

Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).]

5.4 Hemorrhage

Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 0.4 to 6.9 %. [See Adverse Reactions .]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4) .]

5.5 Arterial Thromboembolic Events

Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4) .]

5.6 Venous Thromboembolic Events

Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may be at increased risk of venous thromboembolic events.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade ≥ 3 VTE were reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. Permanently discontinue Avastin in patients with life-threatening (Grade 4) VTE, including pulmonary embolism. [See Dosage and Administration (2.4), Adverse Reactions (6.1) .]

5.7 Hypertension

The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4) .]

5.8 Posterior Reversible Encephalopathy Syndrome

PRES has been reported with an incidence of < 0.5% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of PRES.

Discontinue Avastin in patients developing PRES. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing PRES is not known. [See Dosage and Administration (2.4) .]

5.9 Proteinuria

The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions .] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See Dosage and Administration (2.4) .] Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5) .]

5.10 Infusion Reactions

Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon ( < 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4) .]

5.11 Embryo-fetal Toxicity

Avastin may cause fetal harm based on the drug's mechanism of action and findings from animal studies. Congenital malformations were observed with the administration of Avastin to pregnant rabbits during organogenesis every 3 days at a dose as low as a clinical dose of 10 mg/kg. Furthermore, animal models link angiogenesis and VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with and for 6 months after the last dose of Avastin. [See Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1).]

5.12 Ovarian Failure

The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.3) .]

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the label:


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 Some of the adverse reactions are commonly seen with chemotherapy; however, Avastin may exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine peripheral sensory neuropathy with paclitaxel or oxaliplatin, and nail disorders or alopecia with paclitaxel.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

Most common adverse reactions incidence ( > 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. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Genentech, Inc. at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 more than 5500 patients with CRC, non-squamous NSCLC, glioblastoma, mRCC, cervical cancer, platinum-resistant or platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, including controlled (Studies 1, 2, 4, 5, 8, 9, 10, 11, and 12) 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 (14) .] The population was aged 18-89 years (median 60 years), 42% male and 86% 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, 218 cervical cancer patients who received a median of 6 doses of Avastin, 179 platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer patients who received a median of 6 doses of Avastin, and 572 platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer patients who received a median of between 12 and 16 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 (2.4), Warnings and Precautions (5.3) .]

Hemorrhage

The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Avastin compared with patients receiving bolus-IFL plus placebo. 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 (2.4), Warnings and Precautions (5.4) .]

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 (2.4), Warnings and Precautions (5.6) .]

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%.

Proteinuria

Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5, 8 and 10. 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 (5.9) .]

Renal Injury

A retrospective analysis across clinical trials where 5805 patients had received Avastin and chemotherapy and 3713 had received chemotherapy alone has shown higher rates of elevated serum creatinine levels (ranging between 1.5 – 1.9 times baseline levels) in patients who had received Avastin. Creatinine levels did not return to baseline in approximately one-third of patients who received Avastin.

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.

Ovarian Failure

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 (5.12), Use in Specific Populations (8.3) .]

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.

Arm 1

IFL + Placebo

(n = 396)

 Arm 2

IFL + Avastin

(n = 392)
NCI-CTC Grade 3-4 Events 74% 87%
Body as a Whole
Asthenia 7% 10%
Abdominal Pain 5% 8%
Pain 5% 8%
Cardiovascular
Hypertension 2% 12%
Deep Vein Thrombosis 5% 9%
Intra-Abdominal Thrombosis 1% 3%
Syncope 1% 3%
Digestive
Diarrhea 25% 34%
Constipation 2% 4%
Hemic/Lymphatic
Leukopenia 31% 37%
NeutropeniaCentral 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. 14% 21%

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.

Arm 1

IFL + Placebo

(n = 98)

 Arm 2

IFL + Avastin

(n = 102)

 Arm 3

5-FU/LV + Avastin

(n = 109)
Body as a Whole
Pain 55% 61% 62%
Abdominal Pain 55% 61% 50%
Headache 19% 26% 26%
Cardiovascular
Hypertension 14% 23% 34%
Hypotension 7% 15% 7%
Deep Vein Thrombosis 3% 9% 6%
Digestive
Vomiting 47% 52% 47%
Anorexia 30% 43% 35%
Constipation 29% 40% 29%
Stomatitis 18% 32% 30%
Dyspepsia 15% 24% 17%
GI Hemorrhage 6% 24% 19%
Weight Loss 10% 15% 16%
Dry Mouth 2% 7% 4%
Colitis 1% 6% 1%
Hemic/Lymphatic
Thrombocytopenia 0% 5% 5%
Nervous
Dizziness 20% 26% 19%
Respiratory
Upper Respiratory Infection 39% 47% 40%
Epistaxis 10% 35% 32%
Dyspnea 15% 26% 25%
Voice Alteration 2% 9% 6%
Skin/Appendages
Alopecia 26% 32% 6%
Skin Ulcer 1% 6% 6%
Special Senses
Taste Disorder 9% 14% 21%
Urogenital
Proteinuria 24% 36% 36%

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-hematologic and 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%).

Glioblastoma

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-α) plus Avastin compared to 304 patients receiving IFN-α 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, hemoptysis, 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-α plus placebo arm are presented in Table 3.

System Organ Class/Preferred termAdverse events were encoded using MedDRA, Version 10.1. IFN-α + Placebo

(n = 304)

 IFN-α + Avastin

(n = 337)
Gastrointestinal disorders
Diarrhea 16% 21%
General disorders and administration site conditions
Fatigue 27% 33%
Investigations
Weight decreased 15% 20%
Metabolism and nutrition disorders
Anorexia 31% 36%
Musculoskeletal and connective tissue disorders
Myalgia 14% 19%
Back pain 6% 12%
Nervous system disorders
Headache 16% 24%
Renal and urinary disorders
Proteinuria 3% 20%
Respiratory, thoracic and mediastinal disorders
Epistaxis 4% 27%
Dysphonia 0% 5%
Vascular disorders
Hypertension 9% 28%

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.

Grade 1-4 reactions Grade 3-4 reactions
Chemo Alone

(n=222)

 Chemo+Avastin

(n=218)

 Chemo Alone

(n=222)

 Chemo+Avastin

(n=218)
Metabolism and Nutrition Disorders
Decreased Appetite 26% 34%
Hyperglycemia 19% 26%
Hypomagnesemia 15% 24%
Hyponatremia 10% 19%
Hypoalbuminemia 11% 16%
General Disorders and Administration Site Conditions
Fatigue 75% 80%
Edema Peripheral 22% 15%
Investigations
Weight Decreased 7% 21%
Blood Creatinine Increased 10% 16%
Infections and Infestations
Urinary Tract Infection 14% 22%
Infection 5% 10%
Vascular Disorders
Hypertension 6% 29% 0.5% 11.5%
Thrombosis 3% 10% 2.7% 8.3%
Nervous System Disorders
Headache 13% 22%
Dysarthria 1% 8%
Gastrointestinal Disorders
Stomatitis 10% 15%
Proctalgia 1% 6%
Anal Fistula - 6%
Blood and Lymphatic System Disorders
Neutropenia 6% 12%
Lymphopenia 5% 12%
Psychiatric Disorders
Anxiety 10% 17%
Reproductive System and Breast Disorders
Pelvic Pain 8% 14%
Respiratory, Thoracic and Mediastinal Disorders
Epistaxis 1% 17%
Renal and Urinary Disorders
Proteinuria 3% 10%

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.

Platinum-Resistant Recurrent Epithelia Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Patients with evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded in this study.

Grade 2-4 adverse events occurring at a higher incidence ( ≥5%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone are presented in Table 5.

System Organ Class Preferred Term Chemo

(n=181)

 Chemo+Avastin

(n=179)
Blood And Lymphatic System Disorders
Neutropenia 25.4% 30.7%
General Disorders And Administration Site Conditions
Mucosal Inflammation 5.5% 12.8%
Infections And Infestations
Infection 4.4% 10.6%
Nervous System Disorders
Peripheral Sensory Neuropathy 7.2% 17.9%
Renal And Urinary Disorders
Proteinuria 0.6% 12.3%
Respiratory, Thoracic and Mediastinal Disorders
Epistaxis 0.0% 5.0%
Skin And Subcutaneous Tissue Disorders
Palmar–Plantar Erythrodysaesthesia Syndrome 5.0% 10.6%
Vascular Disorders
Hypertension 5.5% 19.0%

Grade 3–4 adverse events occurring at a higher incidence ( ≥ 2%) in 179 patients receiving Avastin plus chemotherapy compared to 181 patients receiving chemotherapy alone were hypertension (6.7% vs. 1.1%) and palmar-plantar erythrodysaesthesia syndrome (4.5% vs. 1.7%).

There were no Grade 5 events occurring at a higher incidence ( ≥ 2%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone.

Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with carboplatin and gemcitabine, followed by Avastin as a single agent

Adverse events occuring in a randomized, double-blinded study (Study 11) of chemotherapy compared to Avastin plus chemotherapy are presented in Table 6.

System Organ Class Preferred Term Carboplatin + Gemcitabine + Placebo

(n=233)

 Carboplatin + Gemcitabine + Avastin

(n=247)
Blood and Lymphatic System Disorders
Thrombocytopenia 51% 58%
Gastrointestinal Disorders
Diarrhea 29% 38%
Gingival Bleeding 0% 7%
Hemorrhoids 3% 8%
Nausea 66% 72%
Stomatitis 7% 15%
General Disorders and Administration Site Conditions
Fatigue 75% 82%
Mucosal Inflammation 10% 15%
Infections and Infestations
Sinusitis 9% 15%
Injury, Poisoning and Procedural Complications
Contusion 9% 17%
Musculoskeletal and Connective Tissue Disorders
Arthralgia 19% 28%
Back Pain 13% 21%
Nervous System Disorders
Dizziness 17% 23%
Headache 30% 49%
Psychiatric Disorders
Insomnia 15% 21%
Renal and Urinary Disorders
Proteinuria 3% 20%
Respiratory, Thoracic and Mediastinal Disorders
Cough 18% 26%
Dysphonia 3% 13%
Dyspnea 24% 30%
Epistaxis 14% 55%
Oropharyngeal Pain 10% 16%
Rhinorrhea 4% 10%
Sinus Congestion 2% 8%
Vascular Disorders
Hypertension 9% 42%

Grade 3 or 4 adverse events occurring at a higher incidence (≥ 2%) in 247 patients treated with Avastin plus chemotherapy compared to 233 patients treated with placebo plus chemotherapy were thrombocytopenia (40.1% vs. 33.9%), nausea (4.5% vs. 1.3%), fatigue (6.5% vs. 4.3%), headache (3.6% vs. 0.9%), proteinuria (9.7% vs. 0.4%), dyspnea (4.5% vs. 1.7%), epistaxis (4.9% vs. 0.4%), and hypertension (17.0% vs. 0.9%). Grade ≥ 3 Anemia (16.2% vs. 18.9%) and decreased white blood cell count (1.6% vs. 4.3%) occurred with a ≥ 2% higher frequency in the chemotherapy alone arm compared to the Avastin plus chemotherapy arm. There were no Grade 5 adverse events occurring at a higher incidence (≥ 2%) for the Avastin plus chemotherapy arm compared to the placebo plus chemotherapy arm.

Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with carboplatin and paclitaxel, followed by Avastin as a single agent

Adverse events occurring in a randomized, open-label study, Study 12, of chemotherapy compared to Avastin plus chemotherapy, are presented in Table 7.

System Organ Class Preferred Term Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Avastin
(n=332) (n=325)
Gastrointestinal disorders
Diarrhea 32% 39%
Abdominal pain 28% 33%
Vomiting 25% 33%
Stomatitis 16% 33%
Metabolism and nutrition disorders
Decreased appetite 25% 35%
Hyperglycemia 24% 31%
Hypomagnesemia 17% 27%
Hyponatremia 6% 17%
Hypoalbuminaemia 6% 11%
Hypocalcemia 5% 12%
Hyperkalemia 3% 9%
Musculoskeletal and connective tissue disorders
Arthralgia 30% 45%
Myalgia 18% 29%
Pain in extremity 14% 25%
Back pain 10% 17%
Muscular weakness 8% 13%
Neck pain 0% 9%
Respiratory, thoracic and Mediastinal disorders
Dyspnea 25% 30%
Cough 17% 30%
Epistaxis 2% 33%
Rhinitis allergic 4% 17%
Nasal mucosal disorder 3% 14%
Nervous system disorders
Headache 20% 38%
Dizziness 8% 13%
Dysarthria 2% 14%
Investigations
Aspartate aminotransferase increased 9% 15%
Weight decreased 4% 15%
Blood creatinine increased 5% 13%
Skin and subcutaneous tissue Disorders
Exfoliative rash 16% 23%
Nail disorder 2% 10%
Dry skin 2% 7%
Vascular disorders
Hypertension 3% 42%
Renal and urinary disorders
Proteinuria 1% 17%
General disorders and administration Site conditions
Chest pain 2% 8%
Infections and infestations
Sinusitis 2% 7%

Grade 3 or 4 adverse events occurring at a higher incidence (≥ 2%) in 325 patients treated with Avastin plus chemotherapy compared to 332 patients treated with chemotherapy alone were hypertension (11.1% vs. 0.6%), fatigue (7.7% vs. 2.7%), febrile neutropenia (6.2% vs. 2.7%), proteinuria (8% vs. 0%), abdominal pain (5.8% vs. 0.9%), hyponatremia (3.7% vs. 0.9%), headache (3.1% vs. 0.9%), and pain in extremity (3.4% vs. 0%). No Grade ≥ 3 adverse events occurred with a ≥ 2% higher frequency in the chemotherapy alone arm compared to the Avastin plus chemotherapy arm. There were no Grade 5 adverse events occurring at a higher incidence (≥ 2%) in the Avastin plus chemotherapy arm compared to the chemotherapy alone arm.

6.2 Immunogenicity

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 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 Avastin using an enzyme-linked immunosorbent assay (ELISA). The clinical significance of these anti-product antibody responses to Avastin 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.

6.3 Postmarketing Experience

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

Cardiovascular: Pulmonary hypertension, PRES, Mesenteric venous occlusion

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

Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation

Musculoskeletal and Connective Tissue Disorders: Osteonecrosis of the jaw; Non-mandibular osteonecrosis (cases have been observed in pediatric patients who have received Avastin)

Neurological: Posterior Reversible Encephalopathy Syndrome (PRES)

Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria)

Respiratory: Nasal septum perforation, dysphonia

Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

7 DRUG INTERACTIONS

A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of Avastin on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Avastin may cause fetal harm based on findings from animal studies and the drug's mechanism of action. [See Clinical Pharmacology (12.1).] Limited postmarketing reports describe cases of fetal malformations with use of Avastin in pregnancy; however, these reports are insufficient to determine drug associated risks. In animal reproduction studies, intravenous administration of Avastin to pregnant rabbits every 3 days during organogenesis at doses approximately 1 to 10 times the clinical dose of 10 mg/kg produced fetal resorptions, decreased maternal and fetal weight gain and multiple congenital malformations including corneal opacities and abnormal ossification of the skull and skeleton including limb and phalangeal defects [see Data ]. Furthermore, animal models link angiogenesis and VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Pregnant rabbits dosed with 10 to 100 mg/kg Avastin (approximately 1 to 10 times the clinical dose of 10 mg/kg) every three days during the period of organogenesis (gestation day 6–18) exhibited decreases in maternal and fetal body weights and increased number of fetal resorptions. There were dose-related increases in the number of litters containing fetuses with any type of malformation (42.1% for the 0 mg/kg dose, 76.5% for the 30 mg/kg dose, and 95% for the 100 mg/kg dose ) or fetal alterations (9.1% for the 0 mg/kg dose, 14.8% for the 30 mg/kg dose, and 61.2% for the 100 mg/kg dose ). Skeletal deformities were observed at all dose levels, with some abnormalities including meningocele observed only at the 100 mg/kg dose level. Teratogenic effects included: reduced or irregular ossification in the skull, jaw, spine, ribs, tibia and bones of the paws; fontanel, rib and hindlimb deformities; corneal opacity; and absent hindlimb phalanges.

8.2 Lactation

No data are available regarding the presence of Avastin in human milk, the effects on the breast fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential for serious adverse reactions in breastfed infants from Avastin, advise a nursing woman that breastfeeding is not recommended during treatment with Avastin.

8.3 Females and Males of Reproductive Potential

Contraception

Females

Avastin may cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use effective contraception during treatment with Avastin and for 6 months following the last dose of Avastin. [See Use in Specific Populations.]

Infertility

Females

Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin-treated patients. [See Warnings and Precautions (5.12), Adverse Reactions (6.1) .]

8.4 Pediatric Use

The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years who have received Avastin. Avastin is not approved for use in patients under the age of 18 years.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with Avastin and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Animal Data

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.

8.5 Geriatric Use

In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 5, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.9) .]

Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5) .]

10 OVERDOSAGE

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.

11 DESCRIPTION

Avastin (bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and in vivo assay systems. Avastin contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF. Avastin has an approximate molecular weight of 149 kD. Avastin is produced in a mammalian cell (Chinese Hamster Ovary) expression system in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product.

Avastin is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for intravenous infusion. Avastin is supplied in 100 mg and 400 mg preservative-free, single-use vials to deliver 4 mL or 16 mL of Avastin (25 mg/mL). The 100 mg product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 400 mg product is formulated in 960 mg α,α-trehalose dihydrate, 92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Avastin binds VEGF and prevents the interaction of VEGF to its receptors 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 Avastin to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.

12.3 Pharmacokinetics

The pharmacokinetic profile of Avastin was assessed using an assay that measures total serum Avastin concentrations (i.e., the assay did not distinguish between free Avastin and Avastin 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 Avastin 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 Avastin every 2 weeks was 2.8.

The clearance of Avastin varied by body weight, gender, and tumor burden. After correcting for body weight, males had a higher Avastin 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 Avastin 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 Avastin exposure and clinical outcomes has not been explored.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or mutagenicity studies of Avastin have been conducted.

Avastin may impair fertility. Female cynomolgus monkeys treated with 0.4 to 20 times the recommended human dose of Avastin exhibited arrested follicular development or absent corpora lutea as well as dose-related decreases in ovarian and uterine weights, endometrial proliferation, and the number of menstrual cycles. Following a 4- or 12-week recovery period, there was a trend suggestive of reversibility. After the 12-week recovery period, follicular maturation arrest was no longer observed, but ovarian weights were still moderately decreased. Reduced endometrial proliferation was no longer observed at the 12-week recovery time point; however, decreased uterine weight, absent corpora lutea, and reduced number of menstrual cycles remained evident.

13.2 Animal Toxicology and/or Pharmacology

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

14 CLINICAL STUDIES

14.1 Metastatic Colorectal Cancer

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 8 and Figure 1.

IFL + Placebo IFL + Avastin

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

Figure 1

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 first-line 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 9 and Figure 2.

Chemotherapy Avastin + Chemotherapy
Number of Patients 411 409
Overall Survivalp = 0.0057 by unstratified log rank test.
Median (months) 9.8 11.2
Hazard ratio (95% CI) 0.81 (0.69, 0.94)
Progression-Free Survivalp-value < 0.0001 by unstratified log rank test.
Median (months) 4.0 5.7
Hazard ratio (95% CI) 0.68 (0.59, 0.78)
Figure 2

Duration of Survival in Study 4
Figure 2

14.2 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 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].

14.3 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-naïve 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].

Figure 3

14.4 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 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).

14.5 Metastatic Renal Cell Carcinoma (mRCC)

Study 8

Patients with treatment-naïve mRCC were evaluated in a multicenter, randomized, double-blind, international study comparing Avastin plus interferon alfa 2a (IFN-α2a) 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-α2a (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-α2a compared to those receiving IFN-α2a 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-α2a arm and 21 months in the IFN-α2a plus placebo arm [HR 0.86, (95% CI 0.72, 1.04)].

Figure 4

Progression-Free Survival in Study 8
Figure 4

14.6 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:


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 10 and Figure 5.

Figure 5

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

(n=225)

 Chemotherapy + Avastin

(n=227)
Overall Survival
Median (months)Kaplan-Meier estimates. 12.9 16.8
Hazard ratio [95% CI] 0.74 [0.58;0.94]

(p-valuelog-rank test (stratified). = 0.0132)

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)].

Topotecan + Paclitaxel +/- Avastin

(n=223)

 Cisplatin + Paclitaxel +/- Avastin

(n=229)
Overall Survival
Median (months)Kaplan-Meier estimates. 13.3 15.5
Hazard ratio [95% CI] 1.15 [0.91, 1.46]

p-value=0.23

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).

Figure 5

14.7 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; AURELIA) 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 × 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 12 and Figure 6. Results for the separate chemotherapy cohorts are presented in Table 13.

Efficacy Parameter CTchemotherapy

(N=182)

 CT+Avastin

(N=179)
PFS per Investigator
Median (95% CI), in months 3.4 (2.1, 3.8) 6.8 (5.6, 7.8)
HR (95% CI)per stratified Cox proportional hazards model 0.38 (0.30, 0.49)
p-value per stratified logrank test <0.0001
Overall Survival
Median (95% CI), in months 13.3 (11.9, 16.4) 16.6 (13.7, 19.0)
HR (95% CI) 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
Figure 6

Investigator-Assessed Progression-Free Survival in Study 10 ITT Population



Efficacy Parameter Paclitaxel Topotecan PLD
CTchemotherapy

(N=55)

 CT+Avastin

(N=60)

 CT

(N=63)

 CT+Avastin

(N=57)

 CT

(N=64)

 CT+Avastin

(N=62)
NE= Not Estimable
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)per stratified Cox proportional hazards model 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) 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 Measurable Disease at Baseline 43 45 50 46 51 51
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
Figure 6

14.8 Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Study 11

Study 11 was a randomized, double-blind, placebo-controlled trial (AVF4095g; OCEANS) studying Avastin plus chemotherapy versus chemotherapy alone in the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have not received prior chemotherapy in the recurrent setting or prior Avastin treatment (n=484). Patients were randomized (1:1) to receive carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2 on Days 1 and 8) and concurrent placebo every 3 weeks for 6 to 10 cycles followed by placebo alone until disease progression or unacceptable toxicity (n=242) or carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2 on Days 1 and 8) and concurrent Avastin (15 mg/kg Day 1) every 3 weeks for 6 to 10 cycles followed by Avastin (15 mg/kg every 3 weeks) as a single agent until disease progression or unacceptable toxicity (n=242).

The main efficacy outcome measures was investigator-assessed PFS. Secondary outcome measures were ORR and OS.

The median age was 61 years (range 28–87 years) and 37% of patients were ≥ age 65. All patients had measurable disease at baseline, 74% had baseline CA-125 levels greater than the ULN (35 U/mL). The platinum-free interval (PFI) was 6–12 months in 42 % of patients and > 12 months in 58% of patients. The ECOG performance status was 0 or 1 for 99.8% of patients.

A statistically signficant prolongation in PFS was demonstrated among Avastin plus chemotherapy-treated patients compared to those receiving placebo plus chemotherapy (Table 14 and Figure 7). Independent radiology review of PFS was consistent with investigator assessment (HR=0.45, 95% CI=[0.35, 0.58]). Overall survival was not significantly improved with the addition of Avastin to chemotherapy [HR=0.95, 95% CI (0.77, 1.17)].

Crb + Gem + Placebo

(n=242)

 Crb + Gem + Bev

(n=242)
Progression Free Survival
Median PFS (months) 8.4 12.4
Hazard ratio

(95% CI)

 0.46

(0.37, 0.58)
p –value < 0.0001
Objective Response Rate
% patients with objective response 57% 78%
p –value < 0.0001
Figure 7

Progression-Free Survival Based on Investigator Assessment for Study 11

Figure 7

Study 12

Study 12 was a randomized, controlled, open-label trial (GOG-0213) studying Avastin plus chemotherapy versus chemotherapy alone in the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have not received more than one previous regimen of chemotherapy (n=673). Patients were randomized (1:1) to receive carboplatin (AUC5) and paclitaxel (175 mg/m2 IV over 3 hours) every 3 weeks for 6 to 8 cycles (n=336) or carboplatin (AUC5) and paclitaxel (175 mg/m2 IV over 3 hours) and concurrent Avastin (15 mg/kg) every 3 weeks for 6 to 8 cycles followed by Avastin (15 mg/kg every 3 weeks) as a single agent until disease progression or unacceptable toxicity (n=337).

The main efficacy outcome measure was OS. Other additional efficacy outcomes were investigator-assessed PFS, and ORR.

The median age was 60 years (range 23–85 years) and 33% of patients were ≥ age 65. Eighty-three percent had measurable disease at baseline, 74% had abnormal CA-125 levels at baseline. There were 69 (10.3%) patients who had received prior Avastin. Twenty-six percent had a platinum-free interval (PFI) of 6–12 months and 74% had a PFI of >12 months. GOG Performance Status was 0 or 1 for 99% of the patients.

Study results are presented in Table 15 and Figure 8.

Carboplatin + Paclitaxel

(n=336)

 Carboplatin + Paclitaxel + Avastin

(n=337)
Overall Survival (OS)
Median OS (months) 37.3 42.6
Hazard ratio (95% CI) (IVRS)Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of treatment free-interval prior to enrolling onto this study per IVRS (interactive voice response system) and secondary surgical debulking status. 0.84 (0.69, 1.01)
Hazard ratio (95% CI) (eCRF)Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval prior to enrolling onto this study per eCRF (electronic case report form) and secondary surgical debulking status. 0.82 (0.68, 0.996)
Progression-free Survival (PFS)
Median PFS (months) 10.4 13.8
Hazard ratio (95% CI) (IVRS) 0.61 (0.51, 0.72)
Objective Response Rate
Number of patients with measurable disease at baseline 286 274
Rate, % 159 (56%) 213 (78%)
Figure 8

Overall Survival ITT Population of Study 12

Figure 8

16 HOW SUPPLIED/STORAGE AND HANDLING

Avastin vials [100 mg (NDC 50242-060-01) and 400 mg (NDC 50242-061-01)] are stable at 2–8°C (36–46°F). Avastin vials should be protected from light. Do not freeze or shake.

Diluted Avastin solutions may be stored at 2–8°C (36–46°F) for up to 8 hours. Store in the original carton until time of use. No incompatibilities between Avastin and polyvinylchloride or polyolefin bags have been observed.

17 PATIENT COUNSELING INFORMATION

Advise patients:


Embryo-fetal Toxicity


Lactation


Avastin® (bevacizumab)

Manufactured by:

Genentech, Inc.

A Member of the Roche Group

1 DNA Way

South San Francisco, CA 94080-4990

Avastin® is a registered trademark of Genentech, Inc.

©2016 Genentech, Inc.

Representative sample of labeling

Avastin pharmaceutical active ingredients containing related brand and generic drugs:


Avastin available forms, composition, doses:


Avastin destination | category:


Avastin Anatomical Therapeutic Chemical codes:


Avastin pharmaceutical companies:


References

  1. Dailymed."AVASTIN (BEVACIZUMAB) INJECTION, SOLUTION [GENENTECH, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Cancer.Net."Angiogenesis and Angiogenesis Inhibitors to Treat Cancer". http://www.cancer.net/navigating-ca... (accessed August 28, 2018).
  3. "Bevacizumab". https://pubchem.ncbi.nlm.nih.gov/su... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Avastin?

Depending on the reaction of the Avastin after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Avastin not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Avastin addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Avastin, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Avastin consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

One visitor reported price estimates

What is your opinion about drug cost? Did you feel the cost is apt, or did you feel it is expensive?
The report given by the sdrugs.com website users shows the following figures about several people who felt the medicine Avastin is expensive, and the medicine is not expensive. The results are mixed. The perception of the cost of the medicine to be expensive or not depends on the brand name of the medicine, country, and place where it is sold, and the affordability of the patient. You can choose a generic drug in the place of the branded drug to save the cost. The efficiency of the medicine will not vary if it is generic or a branded one.
Visitors%
Expensive1
100.0%

Visitor reported frequency of use

No survey data has been collected yet

Visitor reported doses

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One visitor reported age

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> 601
100.0%

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