MONITORING AND MANAGING SELECTED … AND MANAGING SELECTED ADVERSE EVENTS WHEN TREATING WITH...

MONITORING AND MANAGING SELECTED ADVERSE EVENTS WHEN TREATING WITH AVASTIN-BASED THERAPYThe following information should not be a substitute for your professional medical judgment and should be individualized for the patient.

IndicationsAvastin 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.

Latereffects

Earlyeffects

Anti-vascular effects

Anti-angiogenesis

ATTAINING VEGF INHIBITION CONTINUING VEGF INHIBITION

Proposed effects

Anti-vascular

Anti-angiogenesis

Potential effect on vessels

Regression of existing tumor vasculature8-13

Inhibition of new and recurrenttumor vessel growth9,14,16

Potential impact on tumor

Reduction of tumor size9,15

Inhibition of tumor growth17-19

2

Proposed mechanism of action as observed in preclinical models

VEGF=vascular endothelial growth factor.

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 activity7

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

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

As demonstrated in preclinical models:

Avastin may exert certain effects to inhibit tumor growth and development8-19

Angiogenesis is required for tumor growth4,5

Tumors need a blood supply to grow and to metastasize

Proposed early and later effects of Avastin8-13,15,17,19-22


Prop

osed

mech

anism

o

f action

VEGF A pro-angiogenic factor that is present throughout tumor progression1-3

• While expressed in normal tissues, VEGF is also present at physiologically relevant levels in tumors4,5

• A VEGF ligand binds to receptors on endothelial cells to help drive angiogenesis1,3,6

ANGIOGENESISEssential process in tumor development4

• Implicated in tumor growth4

AVASTINDirectly binds VEGF to inhibit angiogenesis7

• May regress existing tumor vasculature and inhibit new and recurrent tumor vessel growth8-14

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

4

FDA-approved Prescribing Information for the duration of Avastin treatment7:Patients should continue treatment until disease progression or unacceptable toxicity.

Do

sing

4


Dosing per pivotal Phase III trial protocolsAvastin dosing in approved indications7

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/kg7

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/kg7

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).7,23

‡ 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.7

¶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.7,24

# 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 continued use of Avastin 15 mg/kg q3w as a single agent 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 continued use of Avastin 15 mg/kg IV q3w as a single agent until disease progression or unacceptable toxicity.

Across all indications, study results were achieved with Avastin given at the approved dose until disease progression or unacceptable toxicity7,25

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 continued use of Avastin 15 mg/kg IV q3w as a single agent until disease

progression or

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

gemcitabine followed by continued use of Avastin 15 mg/kg IV q3w as a single agent until disease

progression

6

30 minutes

60 minutesSecond dose

90 minutesFirst dose

Subsequent doses

IF TOLERATED

IF TOLERATED

6


Preparation for administration7

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 times7

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

8

FDA-approved Prescribing Information for the duration of Avastin treatment7: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)†

8

Du

ration

* 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.27

† Cycle information was not collected for EPP (Expanded Participation Project) patients. Therefore, these patients were not included in this analysis.27

nsNSCLC=non-squamous non-small cell lung cancer.

Duration of Avastin therapy in pivotal trials

Treat MCRC with Avastin until second disease progression7,26

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 nsNSCLC7,27*

Across all indications, study results were achieved with Avastin given at the approved dose until disease progression or unacceptable toxicity7,25

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

DISEASE PROGRESSIONOR

UNACCEPTABLE TOXICITYPC alone

Avastin + PC Avastin + PC

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

10

First-lineStudy 2107Grade 3–4

Second-line Avastin-naive Study E3200

Grade 3–5†

MCRC*

Avastin + IFL

Placebo + IFL

12%

2%

9%

2%

Avastin + FOLFOX4

FOLFOX4 alone

First-lineStudy E4599Grade 3–5

NSCLCAvastin + PC

PC alone

8%

0.7%

10

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

The presence of VEGF is associated with the production of nitric oxide.28-33

Hypertension in VEGF inhibition

Why hypertension may occur

VEGF interacts with nitric oxide to regulate vascular tone The exact mechanism of Avastin-related hypertension is not fully understood

Some studies suggest that VEGF increases nitric oxide production, resulting in vasodilation28-32

Nitric oxide is a messenger molecule (a molecule that carries signals between cells) that can regulate various physiologic functions, including blood pressure (BP)28,29

Reducing nitric oxide production results in vasoconstriction; it has been hypothesized that this process could play a role in hypertension28-33

Monitoring BP7

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

Patients with Avastin-induced or -exacerbated hypertension who discontinue Avastin should continue to have their BP monitored at regular intervals

Managing hypertension in patients receiving Avastin In clinical trials, appropriate antihypertensives were used to help manage hypertension23,26,34

Avastin should be temporarily suspended in patients with severe hypertension that is not controlled with medical management7

If appropriate, restart Avastin after hypertension is well controlled and within normal range7

Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy7

Hypertension monitoring and management with Avastin7

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

Nitric oxide

VEGF

Incidence of hypertension in select Avastin clinical trials7,23

* When continued beyond first progression in MCRC, 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.7

† These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study.7


Hyp

ertensio

n

12

Grade 3 0.8%

First-lineStudy 2107

Second-line Avastin-naive Study E3200†

MCRC*Grade 30.7%

Grade 40%

First-lineStudy E4599

NSCLC Grade 3–53%

12

Monitor urine protein (urine dipstick)

<2+ urine dipstick

Continue to monitor

≥2+ urine dipstick Nephrotic syndrome

Discontinue Avastin

Continue to monitor nephrotic syndrome as

appropriate

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

monitor regularly

Undergo further assessment with 24-hour urine collection

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

MonitoringMethod

Observations

Actions

Kidney glomerulus

The kidneys are made up of about 2.5 million glomeruli. Glomeruli are made up of a basement membrane, epithelial cells, and endothelial cells. Healthy glomerular endothelial cells help filter the plasma. Blood passes through the glomeruli, which filter out water and small solutes as waste.39,40

Nephrotic syndrome occurred in <1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome7

Discontinue Avastin in patients with nephrotic syndrome

Background information Nephrotic syndrome involves protein levels in the urine of more than 3.5 g/24 hours, low blood protein levels, high cholesterol levels, high triglyceride levels, and edema41

A urine dipstick is generally reported as negative (<10 mg/dL), trace (10–20 mg/dL), 1+ (30 mg/dL), 2+ (100 mg/dL), 3+ (300 mg/dL), or 4+ (1000 mg/dL)42

* When continued beyond first progression in MCRC, 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.7

† These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study.7

Diagnosing and monitoring proteinuria7

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

Data from a postmarketing safety study showed poor correlation between urine protein/creatinine ratio and 24-hour urine protein

Managing proteinuria in patients receiving Avastin7

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 g/24 hours

Avastin should be temporarily suspended in patients with moderate to severe proteinuria

Patients with moderate to severe proteinuria based on 24-hour collections should be monitored regularly until improvement and/or resolution is observed

Discontinue Avastin in patients with nephrotic syndrome

Proteinuria monitoring and management with Avastin7

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

Proteinuria in VEGF inhibition

Why proteinuria may occur Proteinuria, or an excess of protein in the urine, can occur with cancer and some cancer therapies7,35,36

The exact mechanism of Avastin-related proteinuria is not fully understood

In the clinical setting, impairment of the glomeruli that make up the kidneys may be a pathologic cause of persistent proteinuria37

In the preclinical setting, inhibition of VEGF, a key endothelial growth factor, has been shown to impair glomerular endothelial cells38

Incidence of proteinuria in select Avastin clinical trials7,23,25


Protein

uria

1414

*Hold Avastin for ≥28 days and until incision is fully healed.7

Gastrointestinal (GI) perforation and fistulae: Incidence and management of Avastin7

Incidence of GI perforation in Avastin-treated patientsSerious, and sometimes fatal, GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation, some fatal, in Avastin-treated patients range from 0.3% to 3.2% across clinical trials.

What to look for during treatment with AvastinThe typical presentation may include

Abdominal pain

Nausea

Emesis

Constipation

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.

ManagementDiscontinue Avastin in patients with GI perforations (GI perforation, fistula formation in the GI tract, intra-abdominal abscess).


Non-GI fistulae: Incidence and management of Avastin7

Incidence of non-GI fistulae in Avastin-treated patientsSerious 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 (<1%) 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 postmarketing 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, 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.

ManagementPermanently discontinue Avastin in patients with tracheo-esophageal (TE) fistula or any grade 4 fistula. Discontinue Avastin in patients with fistula formation involving an internal organ.

Wound healing and/or surgical complications: Incidence and management of Avastin7

Incidence of wound healing and/or surgical complications in Avastin-treated patientsThe incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. 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%; in patients who did not receive Avastin, the incidence was 4%.

Necrotizing fasciitis, including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, GI perforation, or fistula formulation.

ManagementIn clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. Do not administer Avastin until the 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 (range 11–50 days). Suspend Avastin for at least 28 days prior to elective surgery.

Discontinue Avastin in patients who develop necrotizing fasciitis.

GI p

erforatio

n/N

on

-GI fi

stulae/

Wo

un

d h

ealing

Avastin plus IV 5-FU–based

chemotherapy

Hold Avastin

≥28 days

before surgery

SURG

ERY

Hold Avastin

≥28 days after

surgery*

Continue Avastin plus IV 5-FU–based

chemotherapy

1616

Arterial thromboembolic events (ATEs): Incidence and management of Avastin7

Incidence of ATEs in Avastin-treated patientsSerious, and sometimes fatal, ATEs occurred at a higher incidence in patients receiving Avastin compared with those in the control arm.

Across indications, the incidence of grade ≥3 ATEs (including cerebral infarction, transient ischemic attacks, myocardial infarction, and angina) in Avastin-treated patients was 2.6% compared with 0.8% in the control arms.

Among patients receiving Avastin in combination with chemotherapy, the risk of developing an ATE during therapy was increased in patients with a history of ATEs or diabetes, or age greater than 65 years.

ManagementPermanently discontinue Avastin in patients who experience a severe ATE. The safety of resumption of Avastin therapy after resolution of an ATE has not been studied.

Venous thromboembolic events (VTEs): Incidence and management of Avastin7

Incidence of VTEs in Avastin-treated patientsPatients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may be at increased risk of VTEs.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer, grade ≥3 VTEs were reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone.

ManagementPermanently discontinue Avastin in patients who experience a life-threatening (grade 4) VTE, including pulmonary embolism.

Hemorrhage: Incidence and management of Avastin

Incidence of hemorrhage in Avastin-treated patients7

Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to 5-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%.

Serious or fatal pulmonary hemorrhage occurred in 4 of 13 (31%) patients with squamous cell histology and 2 of 53 (4%) patients with non-squamous NSCLC receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

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% confidence interval, 0.06%−5.93%).

What to look for during treatment with Avastin7,43

Avastin can cause 2 different types of bleeding:

Minor bleeding: Episodes lasting less than 10 minutes not requiring medical intervention; most commonly mild nosebleeds

Serious and potentially fatal bleeding: Including coughing up blood, GI bleeding, vomiting blood, bleeding in the brain, nosebleeds, and vaginal bleeding— These events occurred up to 5 times more often in people who received

Avastin compared with people who received chemotherapy alone

Management7

Patients who have recently coughed up blood (greater than or equal to a half-teaspoon of red blood) or with serious bleeding should not receive Avastin. Avastin should be permanently discontinued if severe bleeding occurs.


Hem

orrh

age/ATEs/V

TEs

1818

Posterior reversible encephalopathy syndrome (PRES): Incidence and management of Avastin7

Incidence of PRES in Avastin-treated patientsPRES has been reported with an incidence of <0.5% in clinical studies.

What to look for during treatment with AvastinPRES is a neurologic disorder that may present with

Headache

Seizure

Lethargy

Confusion

Blindness

Other visual and neurologic disturbances

Mild to severe hypertension

The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin.

ManagementMagnetic resonance imaging 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.

Infusion reactions: Incidence and management of Avastin7

Incidence of infusion reactions in Avastin- treated patientsAvastin is a humanized monoclonal antibody.

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

What to look for during treatment with AvastinInfusion reactions reported in the clinical trials and postmarketing experience include

Hypertension

Hypertensive crises associated with neurologic signs and symptoms

Wheezing

Oxygen desaturation

Grade 3 hypersensitivity

Chest pain

Headaches

Rigors

Diaphoresis

ManagementAvastin infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered.


PRES/In

fusio

n reactio

ns

20

When to Interrupt Avastin When to Discontinue Avastin

Temporarily suspend Avastin for: At least 4 weeks prior to elective surgery Severe hypertension not controlled with medical management Moderate to severe proteinuria Severe infusion reactions

Avastin should be discontinued if patients experience any of the following: 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

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

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Embryo-fetal toxicity: Incidence and management of Avastin7

Incidence of embryo-fetal toxicity in Avastin- treated patientsAvastin may cause fetal harm based on the drug’s mechanism of action and findings from animal studies. Limited postmarketing reports describe cases of fetal malformations with use of Avastin in pregnancy; however, these reports are insufficient to determine drug associated risks.

Congenital malformations were observed with the administration of bevacizumab 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 (VEGFR2) to critical aspects of female reproduction, embryo-fetal development, and postnatal development.

ManagementAdvise 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.

Ovarian failure: Incidence and management of Avastin7

Incidence of ovarian failure in Avastin-treated patientsAvastin increases the risk of ovarian failure and may impair fertility.

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 as adjuvant treatment for colorectal cancer, a use for which Avastin is not approved.

ManagementInform 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.mFOLFOX=modified FOLFOX.

When to discontinue or suspend Avastin7

Some conditions may prohibit the use of Avastin therapyAlthough there are no recommended dose reductions for Avastin, some situations may require discontinuation or temporary suspension.


Because of the potential for serious adverse reactions in breastfed infants from bevacizumab, advise a nursing woman that breastfeeding is not recommended during treatment with Avastin.

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Most common adverse events (AEs)7

Incidence of AEs during treatment with Avastin Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

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

Headache

Hypertension

Rhinitis

Proteinuria

Taste alteration

Dry skin

Rectal hemorrhage

Lacrimation disorder

Back pain

Exfoliative dermatitis

References: 1. Hanrahan V, Currie MJ, Gunningham SP, et al. J Pathol. 2003;200:183-194. 2. Fontanini G, Vignati S, Boldrini L, et al. Clin Cancer Res. 1997;3:861-865. 3. Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043. 4. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23: 1011-1027. 5. Bergers G, Benjamin LE. Nat Rev Cancer. 2003;3:401-410. 6. 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. 7. Avastin Prescribing Information. Genentech, Inc. December 2016. 8. O’Connor JPB, Carano RAD, Clamp AR, et al. Clin Cancer Res. 2009;15:6674-6682. 9. Tobelem G. Targ Oncol. 2007;2: 153-164. 10. Yuan F, Chen Y, Dellian M, et al. Proc Natl Acad Sci U S A. 1996;93:14765-14770. 11. Willett CG, Boucher Y, di Tomaso E, et al. Nat Med. 2004;10:145-147. 12. Lee CG, Heijn M, di Tomaso E, et al. Cancer Res. 2000;60:5565-5570. 13. Gerber HP, Ferrara N. Cancer Res. 2005;65:671-680. 14. Borgström P, Hillan KJ, Sriramarao P, et al. Cancer Res. 1996;56:4032-4039. 15. Yanagisawa M, Yorozu K, Kurasawa M, et al. Anticancer Drugs. 2010;21:687-694. 16. Borgström P, Bourdon MA, Hillan KJ, et al. Prostate. 1998;35:1-10. 17. Bagri A, Berry L, Gunter B, et al. Clin Cancer Res. 2010;16:3887-3900 [and supplemental appendix]. 18. Warren RS, Yuan H, Matli MR, et al. J Clin Invest. 1995;95:1789-1797. 19. Mabuchi S, Terai Y, Morishige K, et al. Clin Cancer Res. 2008;14:7781-7789. 20. Galizia G, Lieto E, Ferraraccio F, et al. Clin Cancer Res. 2004;10:3490-3499. 21. Vosseler S, Mirancea N, Bohlen P, et al. Cancer Res. 2005;65:1294-1305. 22. Nagy JA, Dvorak AM, Dvorak HF. Annu Rev Pathol. 2007;2:251-275. 23. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544. 24. Escudier B, Pluzanska A, Koralewski P, et al. Lancet. 2007;370:2103-2111. 25. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 26. Bennouna J, Sastre J, Arnold D, et al. Lancet Oncol. 2013;14:29-37. 27. Data on File. Genentech, Inc. 28. Wu HM, Huang Q, Yuan Y, et al. Am J Physiol. 1996;271:H2735-H2739. 29. Hood JD, Meininger CJ, Ziche M, et al. Am J Physiol. 1998;274:H1054-H1058. 30. Hariawala MD, Horowitz JR, Esakof D, et al. J Surg Res. 1996;63:77-82. 31. Shen BQ, Lee DY, Zioncheck TF. J Biol Chem. 1999;274:33057-33063. 32. Yang R, Thomas GR, Bunting S, et al. J Cardiovasc Pharmacol. 1996;27:838-844. 33. Kimura H, Esumi H. Acta Biochim Pol. 2003;50:49-59. 34. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550. 35. Rudman D, Chawla RK, Nixon DW. Trans Assoc Am Physicians. 1978;91:229-241. 36. Ferrari S, Pieretti F, Verri E, et al. Anticancer Drugs. 2005;16:733-738. 37. Oberbauer R, Haas M, Regele H, et al. J Clin Invest. 1995;96:22-29. 38. Ostendorf T, Kunter U, Eitner F, et al. J Clin Invest. 1999;104:913-923. 39. Sugimoto H, Hamano Y, Charytan D, et al. J Biol Chem. 2003;278:12605-12608. 40. Holechek MJ. Nephrol Nurs J. 2003;30:285-290. 41. Nephrotic syndrome. MedlinePlus Web site. http://www.nlm.nih.gov/medlineplus/ency/article/000490.htm. Updated September 20, 2011. Accessed February 1, 2017. 42. Carroll MF, Temte JL. Am Fam Physician. 2000;62:1333-1340. 43. Nosebleed. MedlinePlus Web site. http://www.nlm.nih.gov/medlineplus/ency/article/003106.htm. Updated January 24, 2012. Accessed February 1, 2017. 44. National Cancer Institute. Common terminology criteria for adverse events, version 4.03. June 14, 2010. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed February 1, 2017.


24

Mild; asymptomaticor mild symptoms;clinical or diagnosticobservations only;intervention notindicated

Moderate; minimal,local or noninvasiveintervention indicated; limiting age-appropriateinstrumental ADL*

Severe or medicallysignificant but not immediately life threatening;hospitalization or prolongation of hospitalization indicated; disabling;limiting self-care ADL†

Life-threatening consequences; urgent intervention indicated

Grade 1 Grade 2 Grade 3 Grade 4

Prehypertension Systolic BP 120– 139 mm Hg or diastolic BP 80–89 mm Hg

Stage 1 hypertension Systolic BP 140– 159 mm Hg or diastolic BP 90– 99 mm Hg Medical intervention indicated Recurrent or persistent (≥24 hrs) Symptomatic increase by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously WNL Monotherapy indicated

Stage 2 hypertension Systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg) Medical intervention indicated >1 drug or more intensive therapy than previously used indicated

Life-threateningconsequences eg, malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis Urgent intervention indicated

Continue Avastintreatment


Discontinue Avastin treatment

Temporarily suspendAvastin treatment if not controlled with medicalmanagement

AE

Hypertension

Treatmentwith Avastin

1 2 3 4

Grade

1+ proteinuria; urinary protein <1.0 g/24 hrs

Adults: 2+ proteinuria;urinary protein 1.0–3.4 g/24 hrs

Adults: urinary protein ≥3.5 g/24 hrs


Suspend Avastintreatment

Discontinue Avastin treatment

AE

Proteinuria

Treatmentwith Avastin

1 2 3

Grade

Venous thrombosis (eg, superficial thrombosis)

Venous thrombosis (eg, uncomplicated deep vein thrombosis) Medical intervention indicated

Thrombosis (eg, uncomplicated pulmonary embolism [venous]; non- embolic cardiac mural [arterial] thrombus) Medical intervention indicated

Life threatening (eg, pulmonary embolism, cerebrovascular event, arterial insufficiency) Hemodynamic or neurologic instability; urgent intervention indicated


Continue Avastintreatment Discontinue Avastin treatment

AE

Thromboembolicevent

Treatment with Avastin: ATE




Permanently discontinue Avastin treatment

Treatment with Avastin: VTE

1 2 3 4

Grade

24

NCI-CTCAE V4.03 recommendations for adverse events management7,44

NCI-CTCAE definition of grade

Hypertension

Proteinuria

ATE/VTE


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

ADL=activities of daily living.*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.† Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not being bedridden.

WNL=within normal limits.

NC

I recom

men

datio

ns

26

Notes: Notes:


No

tes

©2017 Genentech USA, Inc. All rights reserved. AVP/111014/0014(3) Printed in USA. (03/17)

www.avastin-hcp.com

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 — 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

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.

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