Ovarian Cancer: Avastin Safety Profile

Stage III or IV ovarian cancer (OC) after primary surgery
Avastin, in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, is indicated for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection.

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

Avastin, in combination with carboplatin and paclitaxel, or 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.

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Discontinue for gastrointestinal perforation
  • Surgery and wound healing complications
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage have occurred
    • Do not administer Avastin to patients with serious hemorrhage or recent history of hemoptysis
    • Discontinue for Grade 3-4 hemorrhage

Avastin has a well-documented safety profile

Grade 1–5 adverse reactions occurring at a higher incidence (≥5%) in patients receiving Avastin with chemotherapy followed by single-agent Avastin vs chemotherapy alone in the GOG-0218 study[1]

Adverse reaction*
CP+Avastin→Avastin
(n=608)
CP+Avastin→PBO
(n=607)
CP+PBO→PBO
(n=602)
Gastrointestinal disorders
 
Diarrhea
38%
40%
34%
Nausea
58%
53%
51%
Stomatitis
25%
19%
14%
General disorders and administration site conditions
 
Fatigue
80%
72%
73%
Musculoskeletal and connective tissue disorders
 
Arthralgia
41%
33%
35%
Muscular weakness
15%
13%
9%
Pain in extremity
25%
19%
17%
Nervous system disorders
 
Dysarthria
12%
10% 2%
Headache
34%
26%
21%
Respiratory, thoracic, and mediastinal disorders
 
Dyspnea
26%
28%
20%
Epistaxis
31%
30%
9%
Nasal mucosal disorder
10%
7%
4%
Vascular disorders
 
Hypertension
32%
24%
14%

GOG=Gynecologic Oncology Group; CP=carboplatin + paclitaxel; PBO=placebo; AUC=area under the curve; q3w=every 3 weeks.
The demographics of the safety population were similar to the demographics of the efficacy population.

CP+Avastin→Avastin=carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles, with concurrent Avastin started at cycle 2, followed by single-agent Avastin q3w for a total of up to 22 cycles of therapy.
CP+Avastin→PBO=carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles, with concurrent Avastin started at cycle 2, followed by placebo alone q3w for a total of up to 22 cycles of therapy. 

CP+PBO→PBO=carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles, with concurrent placebo started at cycle 2, followed by placebo alone q3w for a total of up to 22 cycles of therapy.
*National Cancer Institute Common Terminology Criteria version 3.

  • Grade 3–4 adverse reactions occurring at a higher incidence (≥2%) in either of the Avastin arms vs the chemotherapy only arm were fatigue (CP+Avastin→Avastin, 9%; CP+Avastin→PBO, 6%; CP+PBO→PBO, 6%), hypertension (CP+Avastin→Avastin, 10%; CP+Avastin→PBO, 6%; CP+PBO→PBO, 2%), platelet count decreased (CP+Avastin→Avastin, 21%; CP+Avastin→PBO, 20%; CP+PBO→PBO, 15%), and white blood cell count decreased (CP+Avastin→Avastin, 51%; CP+Avastin→PBO, 53%; CP+PBO→PBO, 50%)[1]
  • No grade 5 adverse events occurred at a higher incidence of ≥3% in the CP+Avastin→Avastin and CP+Avastin→PBO arms vs the CP+PBO→PBO arm[54]

Safety profile of Avastin in psOC was evaluated in the OCEANS study: Avastin plus chemotherapy vs placebo plus chemotherapy[1]

Grade 1−5 adverse events in OCEANS
(occurring at higher incidence (≥5%) in Avastin plus chemo vs placebo + chemo)

Adverse events Avastin + Carboplatin and Gemcitabine
(n=247) (%)
Placebo + Carboplatin and Gemcitabine
(n=233) (%)
Adverse events Avastin + Carboplatin and Gemcitabine
(n=247) (%)
Placebo + Carboplatin and Gemcitabine
(n=233) (%)
Blood and lymphatic system disorders   Psychiatric disorders  
Thrombocytopenia 58 51 Insomnia 21 15
Gastrointestinal disorders   Renal and urinary disorders  
Nausea 72 66 Proteinuria 20 3
Diarrhea 38 29 Respiratory, thoracic, and mediastinal disorders  
Epistaxis 55 14
Stomatitis 15 7 Dyspnea 30 24
Hemorrhoids 8 3 Cough 26 18
Gingival bleeding 7 0 Oropharyngeal pain 16 10
General disorders and administration site conditions   Dysphonia 13 3
Fatigue 82 75
Mucosal inflammation 15 10 Rhinorrhea 10 4
Infections and infestations   Sinus congestion 8 2
Sinusitis 15 9
Injury, poisoning, and procedural complications   Vascular disorders  
Contusion 17 9 Hypertension 42 9
Musculoskeletal and connective tissue disorders        
Arthralgia 28 19      
Back pain 21 13      
Nervous system disorders        
Headache 49 30      
Dizziness 23 17      

psOC=platinum-sensitive ovarian cancer.

  • There were no grade 5 events occurring at a higher incidence (≥3%) in patients receiving Avastin plus chemotherapy vs placebo plus chemotherapy [47,50]
  • Grade 3 or 4 adverse reactions occurring at a higher incidence (≥2%) in 247 patients receiving Avastin plus carboplatin and gemcitabine (chemotherapy), compared to 233 patients receiving placebo plus chemotherapy, were thrombocytopenia (40% vs 34%), nausea (4% vs 1.3%), fatigue (6% vs 4%), headache (4% vs 0.9%), proteinuria (10% vs 0.4%), dyspnea (4% vs 1.7%), epistaxis (5% vs 0.4%), and hypertension (17% vs 0.9%)[1]

Safety profile of Avastin in psOC was evaluated in the GOG-0213 study: Avastin plus chemotherapy vs chemotherapy alone[1]

Grade 1–5 adverse events in GOG-0213
(occurring at higher incidence (≥5%) in Avastin plus chemo vs chemo alone)

Adverse events Avastin + Carboplatin and Paclitaxel
(n=325) (%)
Carboplatin and Paclitaxel alone
(n=332) (%)
Adverse events Avastin + Carboplatin and Paclitaxel
(n=325) (%)
Carboplatin and Paclitaxel alone 
(n=332) (%)
Gastrointestinal disorders   Nervous system disorders  
Diarrhea 39 32 Headache 38 20
Abdominal pain 33 28 Dysarthria 14 2
Vomiting 33 25 Dizziness 13 8
Stomatitis 33 16 Investigations  
Aspartate aminotransferase increased 15 9
Metabolism and nutrition disorders   Weight decreased 15 4
Decreased appetite 35 25
Hyperglycemia 31 24 Blood creatinine
increased
13 5
Hypomagnesemia 27 17 Skin and subcutaneous tissue disorders  
Exfoliative rash 23 16
Hyponatremia 17 6 Nail disorder 10 2
Hypocalcemia 12 5 Dry skin 7 2
Hypoalbuminemia 11 6 Vascular disorders  
Hypertension 42 3
Hyperkalemia 9 3 Renal and urinary disorders  
Proteinuria 17 1
Musculoskeletal and connective tissue disorders   General disorders and administration site conditions  
Arthralgia 45 30 Chest pain 8 2
Myalgia 29 18 Infections and infestations  
Sinusitis 7 2
Pain in extremity 25 14      
Back pain 17 10      
Muscular weakness 13 8      
Neck pain 9 0      
Respiratory, thoracic, and mediastinal disorders        
Epistaxis 33 2
Dyspnea 30 25      
Cough 30 17      
Rhinitis allergic 17 4      
Nasal mucosal
disorder
14 3      
  • There were no grade 5 events occurring at a higher incidence (≥3%) in patients receiving Avastin plus chemotherapy vs chemotherapy alone[3,51] 
  • Grade 3 or 4 adverse events occurring at a higher incidence (≥2%) in 325 patients receiving Avastin plus carboplatin and paclitaxel (chemotherapy), compared to 332 patients receiving chemotherapy alone, were hypertension (11% vs 0.6%), fatigue (8% vs 3%), febrile neutropenia (6% vs 3%), proteinuria (8% vs 0%), abdominal pain (6% vs 0.9%), hyponatremia (4% vs 0.9%), headache (3% vs 0.9%), and pain in extremity (3.4% vs 0%)[1]

Safety profile of Avastin in prOC was evaluated in the AURELIA study: Avastin plus chemotherapy vs chemotherapy alone

Grade 3–4 adverse events observed in the AURELIA study (with ≥2% higher incidence in the Avastin plus chemotherapy* arm)[1]

Adverse events

Avastin + chemotherapy
(n=179) (%)

Chemotherapy alone
(n=181) (%)

Hyper­tension

6.7

1.1

Palmar-plantar erythrody­saesthesia syndrome

4.5

1.7

prOC=platinum-resistant ovarian cancer.

There were no grade 5 events occurring at a higher incidence (≥3%) in patients receiving Avastin plus chemotherapy vs chemotherapy alone[52]

Grade 2–4 adverse events observed in the AURELIA study (with ≥5% higher incidence in the Avastin plus chemotherapy arm)[1,50]

Adverse events

Avastin + chemotherapy (n=179) (%)

Chemotherapy alone (n=181) (%)

Blood and lymphatic system disorders

 

Neutropenia

30.7

25.4

General disorders and administration site conditions

 

Mucosal inflammation

12.8

5.5

Infections and infestations

 

Infection

10.6

4.4

Nervous system disorders

 

Peripheral sensory neuropathy

17.9

7.2

Renal and urinary disorders

 

Proteinuria

12.3

0.6

Respiratory, thoracic, and mediastinal disorders

 

Epistaxis

5.0

0

Skin and subcutaneous tissue disorders

 

Palmar−plantar erythrodysaesthesia syndrome

10.6

5.0

Vascular disorders

 

Hypertension

19.0

5.5

Chemotherapy included paclitaxel, pegylated liposomal doxorubicin, or topotecan. 

Indications

Stage III or IV ovarian cancer (OC) after primary surgery
Avastin, in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, is indicated for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection.

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

Avastin, in combination with carboplatin and paclitaxel, or 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.

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to patients treated with chemotherapy
    • The incidence of GI perforation ranged from 0.3% to 3% 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
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue 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. In clinical studies, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 7%
    • Do not administer Avastin to patients with serious hemorrhage or a recent history of hemoptysis (≥1/2 tsp of red blood)
    • Discontinue Avastin in patients who develop grade 3-4 hemorrhage

Additional serious adverse events

  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer)
    • Arterial thromboembolic events (grade ≥3, 5%, highest in patients with GBM)
    • Renal injury and proteinuria
      • Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
      • Nephrotic syndrome (<1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Venous thromboembolism (grade ≥3, 11% seen in GOG-0240)
    • Hypertension (grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
    • Congestive heart failure (CHF) (1%)
  • Infusion reactions with the first dose of Avastin occurred in <3% of patients, and severe reactions occurred in 0.2% of patients
  • 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
  • Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with Avastin

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 and for 6 months following their last dose of treatment
  • Avastin may impair fertility

Most common adverse events

  • Across studies, the most common adverse reactions observed in Avastin patients at a rate >10% were:

— Epistaxis
— Headache
— Hypertension
— Rhinitis

— Proteinuria
— Taste alteration
— Dry skin
— Rectal hemorrhage

— Lacrimation disorder
— Back pain
— Exfoliative dermatitis

  • Across all studies, Avastin was discontinued in 8% to 22% of patients because of adverse reactions

Indication-specific adverse events

  • In Stage III or IV OC after primary surgery, 608 patients received CP+Avastin→Avastin, 607 patients received CP+Avastin→PBO, and 602 patients received CP+PBO→PBO. Grade 3–4 adverse reactions occurring at a higher incidence (≥2%) in either of the Avastin arms vs the chemotherapy only arm were fatigue (CP+Avastin→Avastin, 9%; CP+Avastin→PBO, 6%; CP+PBO→PBO, 6%), hypertension (CP+Avastin→Avastin, 10%; CP+Avastin→PBO, 6%; CP+PBO→PBO, 2%), platelet count decreased (CP+Avastin→Avastin, 21%; CP+Avastin→PBO, 20%; CP+PBO→PBO, 15%), and white blood cell count decreased (CP+Avastin→Avastin, 51%; CP+Avastin→PBO, 53%; CP+PBO→PBO, 50%)
  • In psOC, grade 3 or 4 adverse reactions in the OCEANS study occurring at a higher incidence (≥2%) in 247 patients receiving Avastin plus carboplatin and gemcitabine (chemotherapy), compared to 233 patients receiving placebo plus chemotherapy, were thrombocytopenia (40% vs 34%), nausea (4% vs 1.3%), fatigue (6% vs 4%), headache (4% vs 0.9%), proteinuria (10% vs 0.4%), dyspnea (4% vs 1.7%), epistaxis (5% vs 0.4%), and hypertension (17% vs 0.9%)
  • In psOC, grade 3 or 4 adverse reactions in the GOG-0213 study occurring at a higher incidence (≥2%) in 325 patients receiving Avastin plus carboplatin and paclitaxel (chemotherapy), compared to 332 patients receiving chemotherapy alone, were hypertension (11% vs 0.6%), fatigue (8% vs 3%), febrile neutropenia (6% vs 3%), proteinuria (8% vs 0%), abdominal pain (6% vs 0.9%), hyponatremia (4% vs 0.9%), headache (3% vs 0.9%), and pain in extremity (3.4% vs 0%)
  • In prOC, grade 3–4 adverse reactions in AURELIA 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%)

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 full Prescribing Information, including Boxed WARNINGS, for additional important safety information.