AVASTIN · 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

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

Boxed WARNINGS Gastrointestinal (GI) perforation— Serious and sometimes fatal GI perforation occurs at a higher incidence (up to

3.2%) in Avastin-treated patients compared to controls. Discontinue Avastin for GI perforation

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 in patients with wound dehiscence. Discontinue at least 28 days

prior to elective surgery. 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

— Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed

Hemorrhage— Severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage,

epistaxis, and vaginal bleeding are increased in Avastin-treated patients. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis

Please see accompanying full Prescribing Information, including Boxed WARNINGS, and back cover for additional important safety information.

S:5”S:8.75”

T:5.25”T:9”

B:5.5”B:9.25”

Tumor Type Dose/Schedule

MCRC—IFL* (First-line Study 2107) 5 mg/kg IV q2w

MCRC—FOLFOX4† (Second-line Study E3200) 10 mg/kg IV q2w

MCRC—fluoropyrimidine-based chemotherapy in patients who had progressed on a first-line Avastin- containing regimen‡ (First- through second-line TML study§)

5 mg/kg IV q2w OR7.5 mg/kg IV q3w

NSCLC—PCII 15 mg/kg IV q3w

mRCC—IFN¶ 10 mg/kg IV q2w

Tumor Type Dose/Schedule

CC—cisplatin/paclitaxel or topotecan/paclitaxel# 15 mg/kg IV q3w

prOC**

10 mg/kg IV q2w if used in combination with weekly paclitaxel, PLD, or weekly topotecan

or 15 mg/kg IV q3w if used in combination with

topotecan q3w

psOC††

15 mg/kg IV q3w for 6 and up to 8 cycles if used in combination with carboplatin and

paclitaxel, followed by Avastin 15 mg/kg IV q3w as a single agent as maintenance until

disease progression or unacceptable toxicity or

15 mg/kg IV q3w for 6 and up to 10 cycles if used in combination with carboplatin and

gemcitabine, followed by Avastin 15 mg/kg IV q3w as a single agent as maintenance until

disease progression or unacceptable toxicity

Dosing per pivotal Phase III trial protocolsAvastin dosing in approved indications1

Avastin is administered as a solution for intravenous (IV) infusion at the following doses and schedules

Important treatment considerations—Women of childbearing potential 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

Counsel patients about the possible risks, including hazard to the fetus and/or loss of pregnancy, of both continued treatment and prolonged exposure following discontinuation, keeping in mind the approximate half-life of Avastin (20 days; range 11–50 days). Patients should also be counseled to continue adequate contraception for 6 months following the last dose of Avastin

Nursing mothers should be advised to discontinue nursing or Avastin, taking into account the half-life of the product and the importance of Avastin to the mother

In the majority of approved indications (NSCLC, second-line MCRC in combination with FOLFOX4 [Study E3200], mRCC, CC, and prOC), Avastin is consistently dosed at the weekly equivalent of 5 mg/kg1

In first-line MCRC in combination with IFL (Study 2107) and when Avastin is continued in patients who had progressed on a first-line Avastin-containing regimen in combination with fluoropyrimidine-based chemotherapy‡ (the TML study§), Avastin is dosed at the weekly equivalent of 2.5 mg/kg1

q2w=every 2 weeks; q3w=every 3 weeks.* 5 mg/kg IV dose evaluated in first-line metastatic colorectal cancer (MCRC) in combination with 5-fluorouracil (5-FU)/leucovorin (LV)/irinotecan (IFL).

†10 mg/kg IV dose evaluated in second-line, Avastin-naive MCRC patients in combination with 5-FU/LV/ oxaliplatin (FOLFOX4).1,2

‡5 mg/kg IV q2w and 7.5 mg/kg IV q3w doses evaluated, in combination with fluoropyrimidine and either irinotecan- or oxaliplatin-containing chemotherapy, in MCRC patients who had progressed on a first-line Avastin-containing regimen.

§TML=Treatment through Multiple Lines (first and second line).||15 mg/kg IV dose evaluated in first-line locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) in combination with paclitaxel/carboplatin (PC). Avastin plus PC was given for up to 6 cycles, after which Avastin was continued alone until disease progression or unacceptable toxicity.1

¶10 mg/kg IV dose evaluated in metastatic renal cell carcinoma (mRCC) in combination with interferon alfa (IFN). AVOREN protocol allowed for IFN dose escalation (attaining a dose of 9 million international units [MIU] within the first 2 weeks), reduction, or discontinuation. IFN was discontinued after 52 weeks or earlier.1,3

# 15 mg/kg IV dose evaluated in persistent, recurrent, or metastatic cervical cancer (CC) in combination with either cisplatin/paclitaxel or topotecan/paclitaxel. Treatment was given until disease progression or unacceptable toxicity.

** 10 mg/kg IV dose evaluated in platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (prOC) in combination with weekly paclitaxel, pegylated liposomal doxorubicin (PLD), or weekly topotecan; or 15 mg/kg IV dose evaluated in combination with topotecan administered every 3 weeks. Treatment was given until disease progression or unacceptable toxicity.

†† 15 mg/kg IV dose evaluated in platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (psOC) q3w when administered in combination with carboplatin and paclitaxel for 6 cycles and up to 8 cycles, followed by Avastin 15 mg/kg q3w as a single agent as maintenance until disease progression. Alternatively, Avastin can be administered as a 15 mg/kg dose q3w when given in combination with carboplatin and gemcitabine for 6 cycles and up to 10 cycles, followed by Avastin 15 mg/kg q3w as a single agent as maintenance until disease progression or unacceptable toxicity.

Do

sing

2


Across all indications, study results were achieved with Avastin given at the approved dose until disease progression or unacceptable toxicity1,3-8

FDA-approved Prescribing Information for the duration of Avastin treatment1

“Patients should continue treatment until disease progression or unacceptable toxicity.”

Num

ber o

f Pat

ient

s (n

)

0

100

200

300

400

500

≥6 Cycles≥4 Cycles≥3 Cycles ≥5 Cycles≥2 Cycles≥1 Cycle

n=422

98% 99% 90% 91% 79% 73% 73% 65% 66% 52% 60% 44%

n=437

n=387 n=402

n=338n=323 n=314

n=286 n=284

n=230n=258

n=194

Avastin + PC (n=429)‡

PC alone (n=440)‡

4


Duration of Avastin therapy in pivotal trialsIn pivotal Phase III MCRC trials, Avastin has demonstrated survival benefits in the first line and when continued beyond first progression1,4

TML study* results were achieved with Avastin given at the approved dose until second disease progression or unacceptable toxicity

IndicationsAvastin 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.

Important treatment considerations—Dose modifications There are no recommended dose reductions

Discontinue Avastin in patients with— Gastrointestinal (GI) perforations (GI perforations, fistula formation

in the GI tract, intra-abdominal abscess)— Fistula formation involving an internal organ— Wound dehiscence and wound healing complications requiring

medical intervention— Serious hemorrhage (ie, requiring medical intervention)— Severe arterial thromboembolic event (ATE)— Life-threatening (grade 4) venous thromboembolic events, including

pulmonary embolism— Hypertensive crisis or hypertensive encephalopathy— Posterior reversible encephalopathy syndrome (PRES)— Nephrotic syndrome

Temporarily suspend Avastin for: at least 4 weeks prior to elective surgery, severe hypertension not controlled with medical management, moderate to severe proteinuria, and severe infusion reactions

The safety of resumption of Avastin therapy in patients that experienced PRES or ATE is unknown

First-line advanced nsNSCLC1,9†

Recurrent ovarian cancer

nsNSCLC=non-squamous non-small cell lung cancer.† Per protocol, patients had to be progression free and without unacceptable toxicity to receive each cycle of treatment, based on investigator assessment (not independently verified), and patients progression free after 6 cycles of Avastin plus PC were eligible to receive Avastin alone.9

‡ Cycle information was not collected for EPP (Expanded Participation Project) patients. Therefore, these patients were not included in this analysis.9

Chemotherapies included carboplatin and gemcitabine, carboplatin and paclitaxel, paclitaxel, PLD, and topotecan.

Du

ration

Patients start with Avastin and chemotherapy Administer as indicated Monitor and manage adverse events Continue Avastin until either - Disease progression - Unacceptable toxicity For patients with platinum-sensitive ovarian cancer, Avastin monotherapy may be continued after completion of combination therapy treatment cycles

Disease progression

or

unacceptable toxicity:

Discontinue Avastin

DISEASE PROGRESSIONOR

UNACCEPTABLE TOXICITYPC alone

Avastin + PC Avastin + PC

*TML=Treatment through Multiple Lines (first and second line).

Patient starts with Avastin Administer as indicated Monitor and manage adverse events Continue Avastin until

- Cancer grows or spreads - Unacceptable adverse events

Second disease

progression or

unacceptable toxicity

To realize the clinical benefit of Avastin, patients in clinical trials were treated until disease progression or unacceptable toxicity

Patient continues with Avastin Administer Avastin Monitor and manage Continue Avastin

Avastin treatment may be continued when chemotherapy is switched

Disease progression

Across all indications, study results were achieved with Avastin given at the approved dose until disease progression or unacceptable toxicity1,3-8

FDA-approved Prescribing Information for the duration of Avastin treatment1

“Patients should continue treatment until disease progression or unacceptable toxicity.”

30 minutes

60 minutesSecond dose

90 minutesFirst dose

Subsequent doses

IF TOLERATED

IF TOLERATED

6


Preparation for administration1

Avastin should be diluted for infusion using aseptic technique

Withdraw the necessary amount of Avastin to obtain the required dose and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP

Inspect visually for particulate matter and discoloration prior to administration. Discard any unused portion left in a vial, as the product contains no preservatives

Diluted Avastin solutions for infusion may be stored at 2°C–8°C (36°F–46°F) for up to 8 hours

Avastin infusions should not be administered or mixed with dextrose solution

Additional serious adverse events Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included— GI fistulae (up to 2% in metastatic colorectal cancer and ovarian cancer patients)— Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical

cancer trial)— Arterial thromboembolic events (grade ≥3, 2.6%)— Proteinuria (nephrotic syndrome, <1%)

Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included— GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial— Venous thromboembolism (grade 3–4, up to 10.6%) in patients with

persistent, recurrent, or metastatic cervical cancer treated with Avastin— Hypertension (grade 3–4, 5%–18%)— Posterior reversible encephalopathy syndrome (PRES) (<0.5%)

Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Avoid use 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

Administration and infusion times1

DO NOT ADMINISTER AS AN IV PUSH OR BOLUS

DO NOT INITIATE AVASTIN UNTIL AT LEAST 28 DAYS FOLLOWING SURGERY AND UNTIL THE SURGICAL WOUND IS FULLY HEALED

In clinical studies, infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

Infusion reactions in clinical trials and in postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, NCI-CTC grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy

NCI-CTC=National Cancer Institute Common Toxicity Criteria.

Ad

min

istration

% of Patients

NCI-CTC grade 3–4 events

Asthenia

Abdominal pain

Pain

Hypertension

Deep vein thrombosis

Intra-abdominal thrombosis

Syncope

Diarrhea

Constipation

Leukopenia

Neutropenia†

Avastin + IFL(n=392)

Placebo + IFL (n=396)

10

8

8

12

9

3

3

34

4

37

21

7

5

5

2

5

1

1

25

2

31

14

Perc

enta

ge S

urvi

ving

OS (Months)

0

20

40

60

80

100

6 12 18 24 30

Avastin + IFL (n=402)Placebo + IFL (n=411)

8


Study 2107*: Phase III trial of Avastin plus IFL in first-line MCRC The only biologic with an FDA-approved label that includes prospectively demonstrated OS in a Phase III first-line MCRC trial1,5,9

At 1 year, 74% of Avastin-treated patients were alive vs 63% of those receiving placebo plus IFL5

At 2 years, 45% of Avastin-treated patients were alive vs 30% of those receiving placebo plus IFL9

Avastin plus IFL: First-line Study 2107 Grade 3–4 adverse events (≥2% higher incidence in the Avastin arm)1

† Central laboratories were collected on days 1 and 21 of each cycle. Neutrophil counts were available in 303 patients receiving placebo plus IFL and 276 patients receiving Avastin plus IFL.

MC

RC

first-lin

e data

Median OS:

20.3 vs 15.6 months(HR=0.66 [95% CI, 0.54–0.81],

P<0.001)

Avastin + IFL(n=402)

Placebo + IFL(n=411)

HRP

value

PFS, months1,5 10.6 (median) 6.2 (median)0.54

(95% CI, 0.45–0.66)9 <0.001

ORR (RECIST criteria, %)1,5 45 35 NR <0.01

OS=overall survival; HR=hazard ratio; CI=confidence interval; PFS=progression-free survival; ORR=overall response rate; RECIST=Response Evaluation Criteria in Solid Tumors; NR=not reported.

* Study 2107 was a randomized, double-blind, active-controlled trial evaluating Avastin 5 mg/kg IV q2w plus IFL until disease progression or unacceptable toxicity vs placebo plus IFL as first-line treatment of MCRC (N=813).1,5

Avastin + �uoropyrimidine-based chemotherapy (n=409)Fluoropyrimidine-based chemotherapy alone (n=411)

Perc

enta

ge S

urvi

ving

OS (Months)12 24 4836

0

20

40

60

80

100

10


The TML study*†: Phase III trial of Avastin plus fluoropyrimidine- based chemotherapy‡ in second-line MCRC patients who had progressed on a first-line Avastin-containing regimen The only biologic to demonstrate significant OS when continued after a first-line Avastin-containing regimen in MCRC1

* TML=Treatment through Multiple Lines (first and second line).† The TML study was a prospective, randomized, open-label, multinational, controlled, Phase III study evaluating Avastin 5 mg/kg IV q2w or Avastin 7.5 mg/kg IV q3w plus fluoropyrimidine-based chemotherapy‡ vs fluoropyrimidine-based chemotherapy‡ alone as second-line treatment of MCRC in patients treated with first-line Avastin-containing chemotherapy (N=820).1

‡ Chemotherapy combinations included either an irinotecan- or oxaliplatin-containing regimen. After first progression, chemotherapy was switched: oxaliplatin irinotecan or irinotecan oxaliplatin.1,4

There was no significant difference in response rate1

Avastin plus fluoropyrimidine-based chemotherapy‡: The TML study

No new safety signals were observed in the TML study (ML18147) 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.1

MC

RC

data th

rou

gh

first an

d seco

nd

lines

Avastin plus fluoropyrimidine-based

chemotherapy‡

Fluoropyrimidine-based chemotherapy‡

aloneHR P value

PFS, months1 5.7 (median) 4.0 (median)0.68

(95% CI, 0.59–0.78)

<0.0001

Median OS:

11.2 vs 9.8 months(HR=0.81 [95% CI, 0.69–0.94],

P=0.0057)

Avastin + FOLFOX4 (n=286)FOLFOX4 alone (n=291)

Perc

enta

ge S

urvi

ving

OS (Months)

0

20

40

60

80

100

6 12 18 24 3630

12


Study E3200*: Phase III trial of Avastin plus FOLFOX4 in second-line, Avastin-naive MCRC patients Avastin is the first FDA-approved biologic with an OS benefit in second-line MCRC1,2,9

* Study E3200 was an open-label, randomized, controlled trial evaluating Avastin 10 mg/kg IV q2w plus FOLFOX4 vs FOLFOX4 alone as second-line treatment of MCRC in Avastin-naive patients (N=829).1,2

†Avastin + FOLFOX4: n=280; FOLFOX4 alone: n=279.2

‡Avastin + FOLFOX4: n=286; FOLFOX4 alone: n=291.2

At 1 year, 56% of Avastin-treated patients were alive vs 43% of those receiving FOLFOX4 alone2

At 2 years, 22% of Avastin-treated patients were alive vs 14% of those receiving FOLFOX4 alone9

Avastin plus FOLFOX4: Second-line Study E3200 Grade 3–5 adverse events (≥2% higher incidence in the Avastin arm)1§

§ These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study.

MC

RC

secon

d-lin

e data

Median OS:

13.0 vs 10.8 months(HR=0.75 [95% CI, 0.63–0.89],

P=0.001)

Avastin + FOLFOX4

FOLFOX4alone

HR P value

PFS, months2† 7.3 (median) 4.7 (median) 0.61 <0.0001

ORR, %2‡ 23 9 NR <0.0001

% of PatientsNCI-CTC grade 3–5 (nonhematologic) and grade 4–5 (hematologic) events

Avastin + FOLFOX4(n=287)

FOLFOX4 alone (n=285)

Diarrhea 18 13

Nausea 12 5

Vomiting 11 4

Dehydration 10 5

Ileus 4 1

Neuropathy—sensory 17 9

Neurologic—other 5 3

Fatigue 19 13

Abdominal pain 8 5

Headache 3 0

Hypertension 9 2

Hemorrhage 5 1

OS (Months)

10 20 30 50400

20

40

60

80

100

Perc

enta

ge S

urvi

ving

Avastin + PC (n=434)PC alone (n=444)

More than half of Avastin-treated patients were alive at 1 year in Study E4599.6

14


Study E4599*: Phase III trial of Avastin plus PC in first-line advanced nsNSCLCIn Study E4599, median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68–0.94], P=0.013)1

Avastin plus PC demonstrated a median PFS of 6.2 months (vs 4.5 months with PC alone, HR=0.66 [95% CI, 0.57–0.77], P<0.001) in Study E4599, based on investigator assessment (not independently verified)1,6

Avastin plus PC had a response rate of 35% vs 15% with PC alone (P<0.001), based on investigator assessment (not independently verified)6

Study E4599 is the first and only prospective Phase III randomized clinical trial of an FDA-approved biologic in first-line metastatic NSCLC to demonstrate statistically significant improvement in OS (>12 months), its primary endpoint, in an intent-to-treat population1,6

— Study E4599 also improved PFS and objective response rate, its secondary endpoints, in an intent-to-treat population, based on investigator assessment (not independently verified)1,6

The intent-to-treat population included all patients randomized before start of treatment. The results of Study E4599 included both progressors and non-progressors.1,6

* Study E4599 was a large, multicenter, randomized trial of Avastin 15 mg/kg IV q3w plus PC vs PC alone (N=878). Avastin plus PC was given for up to 6 cycles, after which Avastin was continued alone until disease progression or unacceptable toxicity.

nsN

SCLC

data

1-year survival:51% vs 44%6

2-year survival:23% vs 15%6

As shown in Study E4599, Avastin plus PC has a well-documented safety profile1

Most common grade 3–5 adverse events in first-line advanced nsNSCLC patients (≥2% higher incidence in the Avastin arm)1

CNS=central nervous system.

% of PatientsNCI-CTC grade 3–5 events (nonhematologic) and grade 4–5 (hematologic) events

Avastin + PC(n=427)

PC alone (n=441)

Neutropenia 27 17

Fatigue 16 13

Hypertension 8 0.7

Infection without neutropenia 7 3

Venous thrombus/embolism 5 3

Febrile neutropenia 5 2

Pneumonitis/pulmonary infiltrates 5 3

Infection with grade 3 or 4 neutropenia 4 2

Hyponatremia 4 1

Headache 3 1

Proteinuria 3 0

The WARNINGS AND PRECAUTIONS section of the Avastin full Prescribing Information states:

In clinical studies in NSCLC 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 1 of 83 Avastin-treated patients (rate 1.2%, 95% CI, 0.06%–5.93%).1

42 8 12 24166 10 14 18 20 220.0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n Pr

ogre

ssio

n Fr

ee

PFS (Months)

Avastin + IFN (n=327)Placebo + IFN (n=322)

Median PFS:10.2 vs 5.4 months(HR=0.60 [95% CI, 0.49–0.72],

P<0.0001)

16


AVOREN*: Phase III trial of Avastin plus IFN in mRCC Avastin plus IFN improved median PFS by 89% over placebo plus IFN (10.2 months vs 5.4 months, HR=0.60 [95% CI, 0.49–0.72], P<0.0001)1

PFS was statistically significantly prolonged among patients receiving Avastin plus IFN compared to those receiving placebo plus IFN3

There was no improvement in OS based on the final analysis, with a median OS of 23 months in the Avastin plus IFN arm and 21 months in the placebo plus IFN arm (HR=0.86 [95% CI, 0.72–1.04])1

PFS and objective response rate were investigator assessed in AVOREN.1,11

* AVOREN was a large, multicenter, randomized, double-blind trial of Avastin 10 mg/kg IV q2w until disease progression or unacceptable toxicity plus IFN vs placebo plus IFN (N=649).3

Grade 3–5 adverse events in AVOREN (occurring at higher incidence [≥2%] in Avastin plus IFN vs placebo plus IFN)1

mR

CC

data

Avastin + IFN(n=306)

Placebo + IFN(n=289)

P value

Objective response rate, % 30 12 <0.0001

Adverse eventAvastin + IFN

(n=337)Placebo + IFN

(n=304)

Fatigue 13% 8%

Asthenia 10% 7%

Proteinuria 7% 0%

Hypertension 6% 1%

Hemorrhage 3% 0.3%

0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n Su

rviv

ing

Months

6 120 18 36 4224 30

Avastin + chemotherapy (n=227)Chemotherapy alone (n=225)

18


Study GOG 240*: Phase III trial of Avastin plus chemotherapy in CC1,7

The first biologic regimen with OS benefit in CC vs chemotherapy alone1

Avastin plus chemotherapy demonstrated a statistically significant 30% increase in median OS vs chemotherapy alone (vs 12.9 months, respectively)1

Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel.

Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel.* Study GOG 240 was a randomized, active-controlled, multicenter trial comparing Avastin 15 mg/kg IV q3w plus chemotherapy versus chemotherapy alone (N=452).

Avastin plus chemotherapy in CC: Study GOG 240grade 1–4 and 3–4 adverse events (with incidence difference of ≥5% between treatment arms)1

Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel.

Gastrointestinal-vaginal fistulae reported in the GOG 240 study1

CC

data

Grade 1–4 reactions Grade 3–4 reactions

Avastin + chemotherapy

(n=218)

Chemotherapy alone

(n=222)

Avastin + chemotherapy

(n=218)

Chemotherapy alone

(n=222)

Metabolism and nutrition disordersDecreased appetite 34% 26%Hyperglycemia 26% 19%Hypomagnesemia 24% 15%Hyponatremia 19% 10%Hypoalbuminemia 16% 11%

General disorders and administration site conditions

Fatigue 80% 75%Edema peripheral 15% 22%

InvestigationsWeight decreased 21% 7%Blood creatinine increased 16% 10%

Infections and infestationsUrinary tract infection 22% 14%Infection 10% 5%

Vascular disordersHypertension 29% 6% 11.5% 0.5%Thrombosis 10% 3% 8.3% 2.7%

Nervous system disorderHeadache 22% 13%Dysarthria 8% 1%

Gastrointestinal disordersStomatitis 15% 10%Proctalgia 6% 1%Anal fistula 6% –

Blood and lymphatic system disorders

Neutropenia 12% 6%Lymphopenia 12% 5%

Psychiatric disordersAnxiety 17% 10%

Reproductive system and breast disorders

Pelvic pain 14% 8%Respiratory, thoracic, and mediastinal disorders

Epistaxis 17% 1%

Renal and urinary disordersProteinuria 10% 3%

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 fistulae may also have bowel obstructions and require surgical intervention, as well as diverting ostomies

Avastin + chemotherapy Chemotherapy alone

ORR, %45

(95% CI, 39–52)34

(95% CI, 28–40)

3.9-month increasein median OS

(HR=0.74 [95% CI, 0.58–0.94], P=0.0132)

Prop

ortio

n Pr

ogre

ssio

n Fr

ee

0

0.2

0.4

0.6

0.8

1.0

3 60 9 18 21 2412 15

PFS (Months)

182 92 35 18 9 1 1 0179 144 91 51 19 6 4 1

00Avastin + chemo

Chemo alone

Number at Risk

Prop

ortio

n Pr

ogre

ssio

n Fr

ee

0

0.2

0.4

0.6

0.8

1.0

3 60 9 18 21 2412 15

PFS (Months)

182 92 35 18 9 1 1 0179 144 91 51 19 6 4 1

00Avastin + chemo

Chemo alone

Number at Risk

3.4-month increase in median PFS(HR=0.38 [95% CI, 0.30–0.49], P<0.0001)

20


AURELIA study*: Phase III trial of Avastin plus chemotherapy in prOC1,8

The first biologic regimen with statistically significant PFS benefit in prOC vs chemotherapy alone1

Avastin plus chemotherapy doubled the median PFS vs chemotherapy alone (6.8 vs 3.4 months, respectively)1

Statistically significant improvement in investigator-assessed PFS was supported by a retrospective independent review analysis Avastin plus chemotherapy demonstrated

— A 62% reduction in the risk of progression vs chemotherapy alone— Doubled median PFS vs chemotherapy alone (6.8 vs 3.4 months)

Chemotherapy included paclitaxel, PLD, or topotecan.* AURELIA study was a multicenter, open-label, randomized trial comparing Avastin 10 mg/kg IV q2w or 15 mg/kg IV q3w plus chemotherapy vs chemotherapy alone in patients with prOC that recurred within <6 months from the most recent platinum-based therapy (N=361).

PFS data are based on investigator assessment.

Important safety information—AURELIA study 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

Avastin plus chemotherapy in prOC: AURELIA Studygrade 3–4 adverse events (with ≥2% higher incidence in the Avastin plus chemotherapy arm)1

There were no grade 5 events occurring at a higher incidence (≥2%) in patients receiving Avastin plus chemotherapy vs chemotherapy alone1

Grade 2–4 adverse events occurring at a higher incidence (≥5%) in patients receiving Avastin plus chemotherapy compared with patients receiving chemotherapy alone included neutropenia (31% vs 25%), mucosal inflammation (13% vs 6%), infection (11% vs 4%), peripheral sensory neuropathy (18% vs 7%), proteinuria (12% vs 1%), epistaxis (5% vs 0%), palmar-plantar erythrodysaesthesia syndrome (11% vs 5%), and hypertension (19% vs 6%).1

prO

C d

ata

Avastin + chemotherapy Chemotherapy alone HR

Number of patients 179 182

OS16.6 months (median)(95% CI, 13.7–19.0)

13.3 months (median)(95% CI, 11.9–16.4)

0.89 (95% CI, 0.69–1.14)

ORR28% (n=142)

(95% CI, 21–36)13% (n=144)

(95% CI, 7–18)

Median of response duration

9.4 months 5.4 months

Adverse events Avastin + chemotherapy (n=179) (%)

Chemotherapy alone (n=181) (%)

Hypertension 6.7 1.1

Palmar-plantar erythrodysaesthesia syndrome

4.5 1.7

Chemotherapy included paclitaxel, PLD, or topotecan.

Avastin + chemotherapy (n=179)

Chemotherapy alone (n=182)

22


OCEANS Study: Phase III trial of Avastin plus chemotherapy in platinum-sensitive ovarian cancer1

Avastin plus chemotherapy in psOC: OCEANS Study grade 3–4 adverse events (with incidence difference of ≥2% between treatment arms)1

Main efficacy outcome measure: Significant increase in PFS—median PFS of 12.4 months with Avastin plus chemotherapy vs 8.4 months with placebo plus chemotherapy (HR=0.46 [95% CI, 0.37–0.58], P<0.0001); independent radiology review of PFS was consistent with investigator assessment (HR=0.45 [95% CI, 0.35–0.58])1

Secondary outcome measure: Significantly improved ORR—78% with Avastin plus chemotherapy vs 57% with placebo plus chemotherapy (P<0.0001)1

OS was not significantly improved with the addition of Avastin to chemotherapy (HR=0.95 [95% CI, 0.77–1.17])1

In OCEANS, grade 1–5 adverse events occurring at a higher incidence (≥5%) in the Avastin plus chemotherapy arm vs placebo plus chemotherapy arm included thrombocytopenia (58% vs 51%), diarrhea (38% vs 29%), gingival bleeding (7% vs 0%), hemorrhoids (8% vs 3%), nausea (72% vs 66%), stomatitis (15% vs 7%), fatigue (82% vs 75%), mucosal inflammation (15% vs 10%), sinusitis (15% vs 9%), contusion (17% vs 9%), arthralgia (28% vs 19%), back pain (21% vs 13%), dizziness (23% vs 17%), headache (49% vs 30%), insomnia (21% vs 15%), proteinuria (20% vs 3%), cough (26% vs 18%), dysphonia (13% vs 3%), dyspnea (30% vs 24%), epistaxis (55% vs 14%), oropharyngeal pain (16% vs 10%), rhinorrhea (10% vs 4%), sinus congestion (8% vs 2%), and hypertension (42% vs 9%)1

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 arm1

PFS data are based on investigator assessment.

Grade 3–4 adverse events observed in the OCEANS study (with ≥2% higher incidence in the Avastin + chemotherapy arm)1

Adverse eventsAvastin + chemotherapy

(n=247) (%)Placebo + chemotherapy

(n=233) (%)

Thrombocytopenia 40.1 33.9

Nausea 4.5 1.3

Fatigue 6.5 4.3

Headache 3.6 0.9

Proteinuria 9.7 0.4

Dyspnea 4.5 1.7

Epistaxis 4.9 0.4


Prop

ortio

n Pr

ogre

ssio

n Fr

ee

0

0.2

0.4

0.6

0.8

1.0

60 18 24 3012

200242 33 1192176242 11 344

PFS (Months)

Avastin + chemoChemo alone

Number at Risk

Avastin + chemotherapy (n=242) Placebo + chemotherapy (n=242)

4-month increase in median PFS(HR=0.46 [95% CI, 0.37–0.58], P<0.0001)

psO

C O

CEA

NS d

ata

0.00.10.20.30.40.50.60.70.80.91.0

0 12 24 36 48 60 72 84OS (Months)

Prop

ortio

n Su

rviv

ing

336 305 235 155 70 22 2 0337 306 254 187 79 33 6 0Avastin + chemo

Chemo alone

Number at Risk

0.00.10.20.30.40.50.60.70.80.91.0

0 12 24 36 48 60 72 84OS (Months)

Prop

ortio

n Su

rviv

ing

336 305 235 155 70 22 2 0337 306 254 187 79 33 6 0Avastin + chemo

Chemo alone

Number at Risk

Avastin + chemotherapy (n=337)Chemotherapy alone (n=336)

5.3-month increase in median OS(HR=0.84 [95% CI, 0.69–1.01] [IVRS]*) (HR=0.82 [95% CI, 0.68–0.996] [eCRF]†)

24


GOG 213 Study: Phase III trial of Avastin plus chemotherapy in platinum-sensitive ovarian cancer1

* 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.

† 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.1

Avastin plus chemotherapy in psOC: Study GOG 213 grade 3–4 adverse events (with incidence difference of ≥2% between treatment arms)1

Main efficacy outcome measure: OS—median OS of 42.6 months with Avastin plus chemotherapy vs 37.3 months with chemotherapy alone (HR=0.84 [95% CI, 0.69–1.01] [IVRS]*; HR=0.82 [95% CI, 0.68–0.996] [eCRF]†)1

Objective response rate (ORR) is defined as the proportion of patients who achieve a complete response (disappearance of all target tumors) or a partial response (>30% decrease in the sum of the longest diameters of target tumors) based on modified Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. 12,13

No grade ≥3 adverse events occurred with a ≥2% higher frequency in the chemotherapy alone arm compared to the Avastin plus chemotherapy arm1

In GOG 213, grade 1–5 adverse events occurring at a higher incidence (≥5%) in the Avastin plus chemotherapy arm vs chemotherapy alone arm included diarrhea (39% vs 32%), abdominal pain (33% vs 28%), vomiting (33% vs 25%), stomatitis (33% vs 16%), decreased appetite (35% vs 25%), hyperglycemia (31% vs 24%), hypomagnesemia (27% vs 17%), hyponatremia (17% vs 6%), hypoalbuminemia (11% vs 6%), hypocalcemia (12% vs 5%), hyperkalemia (9% vs 3%), arthralgia (45% vs 30%), myalgia (29% vs 18%), pain in extremity (25% vs 14%), back pain (17% vs 10%), muscular weakness (13% vs 8%), neck pain (9% vs 0%), dyspnea (30% vs 25%), cough (30% vs 17%), epistaxis (33% vs 2%), rhinitis allergic (17% vs 4%), nasal mucosal disorder (14% vs 3%), headache (38% vs 20%), dizziness (13% vs 8%), dysarthria (14% vs 2%), aspartate aminotransferase increased (15% vs 9%), weight decreased (15% vs 4%), blood creatinine increased (13% vs 5%), exfoliative rash (23% vs 16%), nail disorder (10% vs 2%), dry skin (7% vs 2%), hypertension (42% vs 3%), proteinuria (17% vs 1%), chest pain (8% vs 2%), and sinusitis (7% vs 2%)1

psO

C G

OG

213 data

Avastin + chemotherapy (n=337)

Chemotherapy alone (n=336)

HR

Additional efficacy outcome measurePFS, months

13.8 (median) 10.4 (median) 0.61

Exploratory efficacy outcome measureORR, %

78 (n=274)

56(n=286)

Grade 3–4 adverse events observed in the GOG 213 study (with ≥2% higher incidence in the Avastin + chemotherapy arm)1

Adverse eventsAvastin + chemotherapy

(n=325) (%)Chemotherapy alone

(n=332) (%)


Fatigue 7.7 2.7

Febrile neutropenia 6.2 2.7

Proteinuria 8 0

Abdominal pain 5.8 0.9

Hyponatremia 3.7 0.9

Headache 3.1 0.9

Pain in extremity 3.4 0

Number of patients with measurable disease at baseline was 274 in the Avastin plus chemotherapy arm and 286 in the chemotherapy alone arm1

More patients had a complete response (86/274 [31%] vs 31/286 [11%]) or partial response (127/274 [46%] vs 128/286 [45%]) with Avastin plus chemotherapy vs chemotherapy alone9

26


Hypertension monitoring and management with AvastinMonitoring blood pressure (BP)1

The incidence of severe hypertension is increased in patients receiving Avastin BP monitoring should be conducted every 2 to 3 weeks during treatment with Avastin In clinical trials, appropriate antihypertensives were used to help manage hypertension2,5,6

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management If appropriate, restart Avastin after hypertension is well controlled and within normal range Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy Patients with Avastin-induced or -exacerbated hypertension who discontinue Avastin should continue to have their BP monitored at regular intervals

Hypertension monitoring and management with Avastin1

The following information should not be a substitute for your professional medical judgment and should be individualized for the patient.

Proteinuria monitoring and management with AvastinDiagnosing and monitoring proteinuria1

The incidence and severity of proteinuria are increased in patients receiving Avastin

Urine dipstick or urinalyses are performed to detect proteinuria in most cases

Patients should be monitored for the development or worsening of proteinuria with serial urinalyses

Proteinuria monitoring and management with Avastin1

The following information should not be a substitute for your professional medical judgment and should be individualized for the patient.

Pregnancy warning Based on the mechanism of action and animal studies, Avastin may cause fetal harm

Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy

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

Advise nursing women that breastfeeding is not recommended during treatment with Avastin

Avastin may impair fertility

Hyp

ertensio

n an

d

pro

teinu

ria

Measure BP every 2 to 3 weeks

Administer appropriate antihypertensive therapy

Continue to monitor BP regularly

Temporarily suspend Avastin with severe

hypertension not controlled with medical management

If appropriate, restart Avastin after hypertension

is well controlled and within normal range

Hypertensive crisis or hypertensive

encephalopathy

Discontinue Avastin

Continue to monitor BP regularly

MonitoringMethod

Observations

Actions

Hypertension

Monitor urine protein (urine dipstick)

<2+ urine dipstick

Continue to monitor

≥2+ urine dipstick

Undergo further assessment with 24-hour urine collection

Restart Avastin when protein level is <2 g/24 hours

Nephrotic syndrome

Discontinue Avastin

Continue to monitor nephrotic syndrome as

appropriate

MonitoringMethod

Observations

Actions

Suspend Avastin if ≥2 g of protein/24 hours and

monitor regularly

Latereffects

Earlyeffects

Anti-vascular effects

Anti-angiogenesis

ATTAINING VEGF INHIBITION CONTINUING VEGF INHIBITION

Somatic Small Tumor secretion of Rapid tumor Angiogenic inhibitors mutation avascular pro-angiogenic growth and may cause regression tumor factors stimulates metastasis of tumor vasculature (≤2 mm) angiogenesis

28


Proposed mechanism of action as observed in preclinical models

Avastin is designed to directly bind to VEGF extracellularly to prevent interaction with VEGF receptors on the surface of endothelial cells, and may thereby inhibit VEGF’s angiogenic activity1

The mechanism of action of Avastin has been elucidated in preclinical models. Its clinical significance is unknown.

VEGF A pro-angiogenic factor that is present throughout tumor progression14-16

• While expressed in normal tissues, VEGF is also present at physiologically relevant levels in tumors17,18

• A VEGF ligand binds to receptors on endothelial cells to help drive angiogenesis14,16,19

ANGIOGENESISEssential process in tumor development17

• Implicated in tumor growth17

AVASTINDirectly binds VEGF to inhibit angiogenesis1

• May regress existing tumor vasculature and inhibit new and recurrent tumor vessel growth18,20-26

VEGF=vascular endothelial growth factor.

Most common adverse events Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were

— Epistaxis — Proteinuria — Lacrimation disorder— Headache — Taste alteration — Back pain— Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage

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

Angiogenesis is required for tumor growth17,18

Tumors need a blood supply to grow and to metastasize

As demonstrated in preclinical models:

Avastin may exert certain effects to inhibit tumor growth and development20-31

Proposed early and later effects of Avastin20-25,27,29,31-34

Prop

osed

m

echan

ism o

f action

Proposed effects Potential effect on vessels Potential impact on tumor

Anti-vascularRegression of existing tumor

vasculature20-25 Reduction of tumor size21-26

Anti-angiogenesisInhibition of new and recurrent

tumor vessel growth21,26,28 Inhibition of tumor growth29-31

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We do all we can to ensure our medications are accessible for the patients who need them. We can help your patients and practice address the needs of each patient’s coverage scenario:

* Each patient assistance option has its own eligibility criteria that must be met for patients to receive assistance. † To be eligible for free medicine from GATCF, insured patients must have exhausted all other forms of patient assistance (including the Genentech BioOncology Co-pay Card and support from co-pay assistance foundations supporting the patient’s disease state) and meet additional financial and medical criteria.

References: 1. Avastin Prescribing Information. Genentech, Inc. December 2016. 2. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544. 3. Escudier B, Pluzanska A, Koralewski P, et al. Lancet. 2007;370:2103-2111. 4. Bennouna J, Sastre J, Arnold D, et al. Lancet Oncol. 2013;14:29-37. 5. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 6. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550. 7. Tewari KS, Sill MW, Long HJ III, et al. N Engl J Med. 2014;370:734-743. 8. Pujade-Lauraine E, Hilpert F, Weber B, et al. J Clin Oncol. 2014;32:1302-1308. 9. Data on file. Genentech, Inc. 10. Sandler A, Leon L, Fages S, et al. Poster presented at: World Conference on Lung Cancer; July 3-7, 2011; Amsterdam, The Netherlands. 11. Escudier B, Bellmunt J, Negrier S, et al. Slides presented at: Annual Meeting of the American Society of Clinical Oncology; May 29-June 2, 2009; Orlando, FL. 12. Therasse P, Arbuck SG, Eisenhauer EA, et al. J Natl Cancer Inst. 2000 Feb 2;92(3):205-16. 13. RECIST Version 1.1 Update. http://www.irrecist.com/recist/recist-comparative/01.html. Accessed November 29, 2016. 14. Hanrahan V, Currie MJ, Gunningham SP, et al. J Pathol. 2003;200:183-194. 15. Fontanini G, Vignati S, Boldrini L, et al. Clin Cancer Res. 1997;3:861-865. 16. Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043. 17. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. 18. Bergers G, Benjamin LE. Nat Rev Cancer. 2003;3:401-410. 19. Folkman J. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:2865-2882. 20. O’Connor JPB, Carano RAD, Clamp AR, et al. Clin Cancer Res. 2009;15:6674-6682. 21. Tobelem G. Targ Oncol.2007;2:153-164. 22. Yuan F, Chen Y, Dellian M, et al. Proc Natl Acad Sci U S A. 1996;93:14765-14770. 23. Willett CG, Boucher Y, di Tomaso E, et al. Nat Med. 2004;10:145-147. 24. Lee CG, Heijn M, di Tomaso E, et al. Cancer Res. 2000;60:5565-5570. 25. Gerber HP, Ferrara N. Cancer Res. 2005;65:671-680. 26. Borgström P, Hillan KJ, Sriramarao P, et al. Cancer Res. 1996;56:4032-4039. 27. Yanagisawa M, Yorozu K, Kurasawa M, et al. Anticancer Drugs. 2010;21:687-694. 28. Borgström P, Bourdon MA, Hillan KJ, et al. Prostate. 1998;35:1-10. 29. Bagri A, Berry L, Gunter B, et al. Clin Cancer Res. 2010;16:3887-3900 [and supplemental appendix]. 30. Warren RS, Yuan H, Matli MR, et al. J Clin Invest. 1995;95:1789-1797. 31. Mabuchi S, Terai Y, Morishige K, et al. Clin Cancer Res. 2008;14:7781-7789. 32. Galizia G, Lieto E, Ferraraccio F, et al. Clin Cancer Res. 2004;10:3490-3499. 33. Vosseler S, Mirancea N, Bohlen P, et al. Cancer Res. 2005;65:1294-1305. 34. Nagy JA, Dvorak AM, Dvorak HF. Annu Rev Pathol. 2007;2:251-275.

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lutio

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©2017 Genentech USA, Inc. All rights reserved. AVP/111014/0015(4) Printed in USA. (04/17)

Boxed WARNINGS Gastrointestinal (GI) perforation— Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-

treated patients compared to controls— The incidences of GI perforation ranged from 0.3% to 3.2% across clinical studies— Discontinue Avastin in patients with GI perforation

Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal

complications, is increased in Avastin-treated patients— Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is

fully healed. 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 Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention

Hemorrhage— Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central

nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 6.9%

— Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood)

— Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention) Additional serious adverse events Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included— GI fistulae (up to 2% in metastatic colorectal cancer and ovarian cancer patients)— Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial)— Arterial thromboembolic events (grade ≥3, 2.6%)— Proteinuria (nephrotic syndrome, <1%)

Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included— GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial— Venous thromboembolism (grade 3–4, up to 10.6%) in patients with persistent, recurrent,

or metastatic cervical cancer treated with Avastin— Hypertension (grade 3–4, 5%–18%)— Posterior reversible encephalopathy syndrome (PRES) (<0.5%)

Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Avoid use 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

Pregnancy warning Based on the mechanism of action and animal studies, Avastin may cause fetal harm Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin

Advise nursing women that breastfeeding is not recommended during treatment with Avastin Avastin may impair fertility

Most common adverse events Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were— Epistaxis — Rhinitis — Dry skin — Back pain — Headache — Proteinuria — Rectal hemorrhage — Exfoliative dermatitis — Hypertension — Taste alteration — Lacrimation disorder

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

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.You may also report side effects to Genentech at (888) 835-2555.Please see accompanying full Prescribing Information, including Boxed WARNINGS, for additional important safety information.

S:5”S:8.75”

T:5.25”T:9”

B:5.5”B:9.25”

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AVASTIN · 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