ZIRABEV Adverse Reactions

(bevacizumab-bvzr)

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Gastrointestinal Perforations and Fistulae [see Warnings and Precautions (5.1)].
Surgery and Wound Healing Complications [see Warnings and Precautions (5.2)].
Hemorrhage [see Warnings and Precautions (5.3)].
Arterial Thromboembolic Events [see Warnings and Precautions (5.4)].
Venous Thromboembolic Events [see Warnings and Precautions (5.5)].
Hypertension [see Warnings and Precautions (5.6)].
Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.7)].
Renal Injury and Proteinuria [see Warnings and Precautions (5.8)].
Infusion-Related Reactions [see Warnings and Precautions (5.9)].
Ovarian Failure [see Warnings and Precautions (5.11)].
Congestive Heart Failure [see Warnings and Precautions (5.12)].

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety data in Warnings and Precautions and described below reflect exposure to bevacizumab in 4463 patients including those with mCRC (AVF2107g, E3200), non-squamous NSCLC (E4599), GBM (EORTC 26101), mRCC (BO17705), cervical cancer (GOG-0240), epithelial ovarian, fallopian tube, or primary peritoneal cancer (MO22224, AVF4095, GOG-0213, and GOG-0218) or another cancer at the recommended dose and schedule for a median of 6 to 23 doses. The most common adverse reactions observed in patients receiving bevacizumab as a single agent or in combination with other anti-cancer therapies at a rate >10% were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Across clinical studies, bevacizumab was discontinued in 8% to 22% of patients because of adverse reactions [see Clinical Studies (14)].

Metastatic Colorectal Cancer

In Combination with bolus IFL

The safety of bevacizumab was evaluated in 392 patients who received at least one dose of bevacizumab in a double-blind, active-controlled study (AVF2107g), which compared bevacizumab (5 mg/kg every 2 weeks) with bolus-IFL to placebo with bolus IFL in patients with mCRC [see Clinical Studies (14.1)]. Patients were randomized (1:1:1) to placebo with bolus IFL, bevacizumab with bolus IFL, or bevacizumab with fluorouracil and leucovorin. The demographics of the safety population were similar to the demographics of the efficacy population. All Grades 3–4 adverse reactions and selected Grades 1–2 adverse reactions (i.e., hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Adverse reactions are presented in Table 2.

Table 2: Grades 3–4 Adverse Reactions Occurring at Higher Incidence (≥2%) in Patients Receiving Bevacizumab vs. Placebo in Study AVF2107g
Adverse Reaction*Bevacizumab with IFL
(N=392)
Placebo with IFL
(N=396)
*
NCI-CTC version 3

Hematology

  Leukopenia

37%

31%

  Neutropenia

21%

14%

Gastrointestinal

  Diarrhea

34%

25%

  Abdominal pain

8%

5%

  Constipation

4%

2%

Vascular

  Hypertension

12%

2%

  Deep vein thrombosis

9%

5%

  Intra-abdominal thrombosis

3%

1%

  Syncope

3%

1%

General

  Asthenia

10%

7%

  Pain

8%

5%

In Combination with FOLFOX4

The safety of bevacizumab was evaluated in 521 patients in an open-label, active-controlled study (E3200) in patients who were previously treated with irinotecan and fluorouracil for initial therapy for mCRC. Patients were randomized (1:1:1) to FOLFOX4, bevacizumab (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1) with FOLFOX4, or bevacizumab alone (10 mg/kg every 2 weeks). Bevacizumab was continued until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population.

Selected Grades 3–5 non-hematologic and Grades 4–5 hematologic occurring at a higher incidence (≥2%) in patients receiving bevacizumab with FOLFOX4 compared to FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse reaction rates due to the reporting mechanisms.

First-Line Non-Squamous Non-Small Cell Lung Cancer

The safety of bevacizumab was evaluated as first-line treatment in 422 patients with unresectable NSCLC who received at least one dose of bevacizumab in an active-controlled, open-label, multicenter trial (E4599) [see Clinical Studies (14.3)]. Chemotherapy-naïve patients with locally advanced, metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel and carboplatin with or without bevacizumab (15 mg/kg every 3 weeks). After completion or upon discontinuation of chemotherapy, patients randomized to receive bevacizumab continued to receive bevacizumab alone until disease progression or until unacceptable toxicity. The trial excluded patients with predominant squamous histology (mixed cell type tumors only), CNS metastasis, gross hemoptysis (1/2 teaspoon or more of red blood), unstable angina, or receiving therapeutic anticoagulation. The demographics of the safety population were similar to the demographics of the efficacy population.

Only Grades 3–5 non-hematologic and Grades 4–5 hematologic adverse reactions were collected. Grades 3–5 non-hematologic and Grades 4–5 hematologic adverse reactions occurring at a higher incidence (≥2%) in patients receiving bevacizumab with paclitaxel and carboplatin compared with patients receiving chemotherapy alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thromboembolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Recurrent Glioblastoma

The safety of bevacizumab was evaluated in a multicenter, randomized, open-label study (EORTC 26101) in patients with recurrent GBM following radiotherapy and temozolomide of whom 278 patients received at least one dose of bevacizumab and are considered safety evaluable [see Clinical Studies (14.4)]. Patients were randomized (2:1) to receive bevacizumab (10 mg/kg every 2 weeks) with lomustine or lomustine alone until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. In the bevacizumab with lomustine arm, 22% of patients discontinued treatment due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving bevacizumab with lomustine, the adverse reaction profile was similar to that observed in other approved indications.

Metastatic Renal Cell Carcinoma

The safety of bevacizumab was evaluated in 337 patients who received at least one dose of bevacizumab in a multicenter, double-blind study (BO17705) in patients with mRCC. Patients who had undergone a nephrectomy were randomized (1:1) to receive either bevacizumab (10 mg/kg every 2 weeks) or placebo with interferon alfa [see Clinical Studies (14.5)]. Patients were treated until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–5 adverse reactions occurring at a higher incidence (>2%) were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Adverse reactions are presented in Table 3.

Table 3: Grades 1–5 Adverse Reactions Occurring at Higher Incidence (≥5%) of Patients Receiving Bevacizumab vs. Placebo with Interferon Alfa in Study BO17705
Adverse Reaction*Bevacizumab with Interferon Alfa
(N=337)
Placebo with Interferon Alfa
(N=304)
*
NCI-CTC version 3

Metabolism and nutrition

  Decreased appetite

36%

31%

  Weight loss

20%

15%

General

  Fatigue

33%

27%

Vascular

  Hypertension

28%

9%

Respiratory, thoracic and mediastinal

  Epistaxis

27%

4%

  Dysphonia

5%

0%

Nervous system

  Headache

24%

16%

Gastrointestinal

  Diarrhea

21%

16%

Renal and urinary

  Proteinuria

20%

3%

Musculoskeletal and connective tissue

  Myalgia

19%

14%

  Back pain

12%

6%

The following adverse reactions were reported at a 5-fold greater incidence in patients receiving bevacizumab with interferon-alfa compared to patients receiving placebo with interferon-alfa and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs. 0); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs. 1); tinnitus (7 vs. 1); tooth abscess (7 vs. 0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

Persistent, Recurrent, or Metastatic Cervical Cancer

The safety of bevacizumab was evaluated in 218 patients who received at least one dose of bevacizumab in a multicenter study (GOG-0240) in patients with persistent, recurrent, or metastatic cervical cancer [see Clinical Studies (14.6)]. Patients were randomized (1:1:1:1) to receive paclitaxel and cisplatin with or without bevacizumab (15 mg/kg every 3 weeks), or paclitaxel and topotecan with or without bevacizumab (15 mg/kg every 3 weeks). The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–4 adverse reactions occurring at a higher incidence (≥2%) in 218 patients receiving bevacizumab with chemotherapy compared to 222 patients receiving chemotherapy alone were abdominal pain (12% vs. 10%), hypertension (11% vs. 0.5%), thrombosis (8% vs. 3%), diarrhea (6% vs. 3%), anal fistula (4% vs. 0%), proctalgia (3% vs. 0%), urinary tract infection (8% vs. 6%), cellulitis (3% vs. 0.5%), fatigue (14% vs. 10%), hypokalemia (7% vs. 4%), hyponatremia (4% vs. 1%), dehydration (4% vs. 0.5%), neutropenia (8% vs. 4%), lymphopenia (6% vs. 3%), back pain (6% vs. 3%), and pelvic pain (6% vs. 1%). Adverse reactions are presented in Table 4.

Table 4: Grades 1–4 Adverse Reactions Occurring at Higher Incidence (≥5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study GOG-0240
Adverse Reaction*Bevacizumab with Chemotherapy
(N=218)
Chemotherapy
(N=222)
*
NCI-CTC version 3

General

  Fatigue

80%

75%

  Peripheral edema

15%

22%

Metabolism and nutrition

  Decreased appetite

34%

26%

  Hyperglycemia

26%

19%

  Hypomagnesemia

24%

15%

  Weight loss

21%

7%

  Hyponatremia

19%

10%

  Hypoalbuminemia

16%

11%

Vascular

  Hypertension

29%

6%

  Thrombosis

10%

3%

Infections

  Urinary tract infection

22%

14%

  Infection

10%

5%

Nervous system

  Headache

22%

13%

  Dysarthria

8%

1%

Psychiatric

  Anxiety

17%

10%

Respiratory, thoracic and mediastinal

  Epistaxis

17%

1%

Renal and urinary

  Increased blood creatinine

16%

10%

  Proteinuria

10%

3%

Gastrointestinal

  Stomatitis

15%

10%

  Proctalgia

6%

1%

  Anal fistula

6%

0%

Reproductive system and breast

  Pelvic pain

14%

8%

Hematology

  Neutropenia

12%

6%

  Lymphopenia

12%

5%

Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Stage III or IV Following Initial Surgical Resection

The safety of bevacizumab was evaluated in GOG-0218, a multicenter, randomized, double-blind, placebo-controlled, three arm study, which evaluated the addition of bevacizumab to carboplatin and paclitaxel for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection [see Clinical Studies (14.7)]. Patients were randomized (1:1:1) to carboplatin and paclitaxel without bevacizumab (CPP), carboplatin and paclitaxel with bevacizumab for up to six cycles (CPB15), or carboplatin and paclitaxel with bevacizumab for six cycles followed by bevacizumab as a single agent for up to 16 additional doses (CPB15+). Bevacizumab was given at 15 mg/kg every three weeks. On this trial, 1215 patients received at least one dose of bevacizumab. The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–4 adverse reactions occurring at a higher incidence (≥2%) in either of the bevacizumab arms versus the control arm were fatigue (CPB15+ - 9%, CPB15 - 6%, CPP - 6%), hypertension (CPB15+ - 10%, CPB15 - 6%, CPP - 2%), thrombocytopenia (CPB15+ - 21%, CPB15 - 20%, CPP - 15%) and leukopenia (CPB15+ - 51%, CPB15 - 53%, CPP - 50%). Adverse reactions are presented in Table 5.

Table 5: Grades 1–5 Adverse Reactions Occurring at Higher Incidence (≥5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study GOG-0218
Adverse Reaction*Bevacizumab with Carboplatin and Paclitaxel followed by Bevacizumab Alone
(N=608)
Bevacizumab with Carboplatin and Paclitaxel
(N=607)
Carboplatin and Paclitaxel§
(N=602)
*
NCI-CTC version 3,
CPB15+,
CPB15,
§
CPP

General

  Fatigue

80%

72%

73%

Gastrointestinal

  Nausea

58%

53%

51%

  Diarrhea

38%

40%

34%

  Stomatitis

25%

19%

14%

Musculoskeletal and connective tissue

  Arthralgia

41%

33%

35%

  Pain in extremity

25%

19%

17%

  Muscular weakness

15%

13%

9%

Nervous system

  Headache

34%

26%

21%

  Dysarthria

12%

10%

2%

Vascular

  Hypertension

32%

24%

14%

Respiratory, thoracic and mediastinal

  Epistaxis

31%

30%

9%

  Dyspnea

26%

28%

20%

  Nasal mucosal disorder

10%

7%

4%

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

The safety of bevacizumab was evaluated in 179 patients who received at least one dose of bevacizumab in a multicenter, open-label study (MO22224) in which patients were randomized (1:1) to bevacizumab with chemotherapy or chemotherapy alone in patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within <6 months from the most recent platinum based therapy [see Clinical Studies (14.8)]. Patients were randomized to receive bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks. Patients had received no more than 2 prior chemotherapy regimens. The trial excluded patients with evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Patients were treated until disease progression or unacceptable toxicity. Forty percent of patients on the chemotherapy alone arm received bevacizumab alone upon progression. The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–4 adverse reactions occurring at a higher incidence (≥2%) in 179 patients receiving bevacizumab with 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%). Adverse reactions are presented in Table 6.

Table 6: Grades 2–4 Adverse Reactions Occurring at Higher Incidence (≥5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study MO22224
Adverse Reaction*Bevacizumab with Chemotherapy
(N=179)
Chemotherapy
(N=181)
*
NCI-CTC version 3

Hematology

  Neutropenia

31%

25%

Vascular

  Hypertension

19%

6%

Nervous system

  Peripheral sensory neuropathy

18%

7%

General

  Mucosal inflammation

13%

6%

Renal and urinary

  Proteinuria

12%

0.6%

Skin and subcutaneous tissue

  Palmar-plantar erythrodysaesthesia

11%

5%

Infections

  Infection

11%

4%

Respiratory, thoracic and mediastinal

  Epistaxis

5%

0%

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

Study AVF4095g

The safety of bevacizumab was evaluated in 247 patients who received at least one dose of bevacizumab in a double-blind study (AVF4095g) in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer [see Clinical Studies (14.9)]. Patients were randomized (1:1) to receive bevacizumab (15 mg/kg) or placebo every 3 weeks with carboplatin and gemcitabine for 6 to 10 cycles followed by bevacizumab or placebo alone until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–4 adverse reactions occurring at a higher incidence (≥2%) in patients receiving bevacizumab with chemotherapy compared to placebo with 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%). Adverse reactions are presented in Table 7.

Table 7: Grades 1–5 Adverse Reactions Occurring at Higher Incidence (≥5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Placebo with Chemotherapy in Study AVF4095g
Adverse Reaction*Bevacizumab with Carboplatin and Gemcitabine
(N=247)
Placebo with Carboplatin and Gemcitabine
(N=233)
*
NCI-CTC version 3

General

  Fatigue

82%

75%

  Mucosal inflammation

15%

10%

Gastrointestinal

  Nausea

72%

66%

  Diarrhea

38%

29%

  Stomatitis

15%

7%

  Hemorrhoids

8%

3%

  Gingival bleeding

7%

0%

Hematology

  Thrombocytopenia

58%

51%

Respiratory, thoracic and mediastinal

  Epistaxis

55%

14%

  Dyspnea

30%

24%

  Cough

26%

18%

  Oropharyngeal pain

16%

10%

  Dysphonia

13%

3%

  Rhinorrhea

10%

4%

  Sinus congestion

8%

2%

Nervous system

  Headache

49%

30%

  Dizziness

23%

17%

Vascular

  Hypertension

42%

9%

Musculoskeletal and connective tissue

  Arthralgia

28%

19%

  Back pain

21%

13%

Psychiatric

  Insomnia

21%

15%

Renal and urinary

  Proteinuria

20%

3%

Injury and procedural

  Contusion

17%

9%

Infections

  Sinusitis

15%

9%

Study GOG-0213

The safety of bevacizumab was evaluated in an open-label, controlled study (GOG-0213) in 325 patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have not received more than one previous regimen of chemotherapy [see Clinical Studies (14.9)]. Patients were randomized (1:1) to receive carboplatin and paclitaxel for 6 to 8 cycles or bevacizumab (15 mg/kg every 3 weeks) with carboplatin and paclitaxel for 6 to 8 cycles followed by bevacizumab as a single agent until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–4 adverse reactions occurring at a higher incidence (≥2%) in patients receiving bevacizumab with chemotherapy compared to 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% vs. 0%). Adverse reactions are presented in Table 8.

Table 8: Grades 1–5 Adverse Reactions Occurring at Higher Incidence (≥5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study GOG-0213
Adverse Reaction*Bevacizumab with Carboplatin and Paclitaxel
(N=325)
Carboplatin and Paclitaxel
(N=332)
*
NCI-CTC version 3

Musculoskeletal and connective tissue

  Arthralgia

45%

30%

  Myalgia

29%

18%

  Pain in extremity

25%

14%

  Back pain

17%

10%

  Muscular weakness

13%

8%

  Neck pain

9%

0%

Vascular

  Hypertension

42%

3%

Gastrointestinal

  Diarrhea

39%

32%

  Abdominal pain

33%

28%

  Vomiting

33%

25%

  Stomatitis

33%

16%

Nervous system

  Headache

38%

20%

  Dysarthria

14%

2%

  Dizziness

13%

8%

Metabolism and nutrition

  Decreased appetite

35%

25%

  Hyperglycemia

31%

24%

  Hypomagnesemia

27%

17%

  Hyponatremia

17%

6%

  Weight loss

15%

4%

  Hypocalcemia

12%

5%

  Hypoalbuminemia

11%

6%

  Hyperkalemia

9%

3%

Respiratory, thoracic and mediastinal

  Epistaxis

33%

2%

  Dyspnea

30%

25%

  Cough

30%

17%

  Rhinitis allergic

17%

4%

  Nasal mucosal disorder

14%

3%

Skin and subcutaneous tissue

  Exfoliative rash

23%

16%

  Nail disorder

10%

2%

  Dry skin

7%

2%

Renal and urinary

  Proteinuria

17%

1%

  Increased blood creatinine

13%

5%

Hepatic

  Increased aspartate aminotransferase

15%

9%

General

  Chest pain

8%

2%

Infections

  Sinusitis

7%

2%

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other bevacizumab products may be misleading.

In clinical studies for adjuvant treatment of a solid tumor, 0.6% (14/2233) of patients tested positive for treatment-emergent anti-bevacizumab antibodies as detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linked immunosorbent assay (ELISA). The clinical significance of these anti-bevacizumab antibodies is not known.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of bevacizumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General: Polyserositis

Cardiovascular: Pulmonary hypertension, Mesenteric venous occlusion

Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration

Hemic and lymphatic: Pancytopenia

Hepatobiliary disorders: Gallbladder perforation

Musculoskeletal and Connective Tissue Disorders: Osteonecrosis of the jaw

Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria)

Respiratory: Nasal septum perforation

Vascular: Arterial (including aortic) aneurysms, dissections, and rupture

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Adverse Reactions

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Gastrointestinal Perforations and Fistulae [see Warnings and Precautions (5.1)].
Surgery and Wound Healing Complications [see Warnings and Precautions (5.2)].
Hemorrhage [see Warnings and Precautions (5.3)].
Arterial Thromboembolic Events [see Warnings and Precautions (5.4)].
Venous Thromboembolic Events [see Warnings and Precautions (5.5)].
Hypertension [see Warnings and Precautions (5.6)].
Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.7)].
Renal Injury and Proteinuria [see Warnings and Precautions (5.8)].
Infusion-Related Reactions [see Warnings and Precautions (5.9)].
Ovarian Failure [see Warnings and Precautions (5.11)].
Congestive Heart Failure [see Warnings and Precautions (5.12)].

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety data in Warnings and Precautions and described below reflect exposure to bevacizumab in 4463 patients including those with mCRC (AVF2107g, E3200), non-squamous NSCLC (E4599), GBM (EORTC 26101), mRCC (BO17705), cervical cancer (GOG-0240), epithelial ovarian, fallopian tube, or primary peritoneal cancer (MO22224, AVF4095, GOG-0213, and GOG-0218) or another cancer at the recommended dose and schedule for a median of 6 to 23 doses. The most common adverse reactions observed in patients receiving bevacizumab as a single agent or in combination with other anti-cancer therapies at a rate >10% were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Across clinical studies, bevacizumab was discontinued in 8% to 22% of patients because of adverse reactions [see Clinical Studies (14)].

Metastatic Colorectal Cancer

In Combination with bolus IFL

The safety of bevacizumab was evaluated in 392 patients who received at least one dose of bevacizumab in a double-blind, active-controlled study (AVF2107g), which compared bevacizumab (5 mg/kg every 2 weeks) with bolus-IFL to placebo with bolus IFL in patients with mCRC [see Clinical Studies (14.1)]. Patients were randomized (1:1:1) to placebo with bolus IFL, bevacizumab with bolus IFL, or bevacizumab with fluorouracil and leucovorin. The demographics of the safety population were similar to the demographics of the efficacy population. All Grades 3–4 adverse reactions and selected Grades 1–2 adverse reactions (i.e., hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Adverse reactions are presented in Table 2.

Table 2: Grades 3–4 Adverse Reactions Occurring at Higher Incidence (≥2%) in Patients Receiving Bevacizumab vs. Placebo in Study AVF2107g
Adverse Reaction*Bevacizumab with IFL
(N=392)
Placebo with IFL
(N=396)
*
NCI-CTC version 3

Hematology

  Leukopenia

37%

31%

  Neutropenia

21%

14%

Gastrointestinal

  Diarrhea

34%

25%

  Abdominal pain

8%

5%

  Constipation

4%

2%

Vascular

  Hypertension

12%

2%

  Deep vein thrombosis

9%

5%

  Intra-abdominal thrombosis

3%

1%

  Syncope

3%

1%

General

  Asthenia

10%

7%

  Pain

8%

5%

In Combination with FOLFOX4

The safety of bevacizumab was evaluated in 521 patients in an open-label, active-controlled study (E3200) in patients who were previously treated with irinotecan and fluorouracil for initial therapy for mCRC. Patients were randomized (1:1:1) to FOLFOX4, bevacizumab (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1) with FOLFOX4, or bevacizumab alone (10 mg/kg every 2 weeks). Bevacizumab was continued until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population.

Selected Grades 3–5 non-hematologic and Grades 4–5 hematologic occurring at a higher incidence (≥2%) in patients receiving bevacizumab with FOLFOX4 compared to FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse reaction rates due to the reporting mechanisms.

First-Line Non-Squamous Non-Small Cell Lung Cancer

The safety of bevacizumab was evaluated as first-line treatment in 422 patients with unresectable NSCLC who received at least one dose of bevacizumab in an active-controlled, open-label, multicenter trial (E4599) [see Clinical Studies (14.3)]. Chemotherapy-naïve patients with locally advanced, metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel and carboplatin with or without bevacizumab (15 mg/kg every 3 weeks). After completion or upon discontinuation of chemotherapy, patients randomized to receive bevacizumab continued to receive bevacizumab alone until disease progression or until unacceptable toxicity. The trial excluded patients with predominant squamous histology (mixed cell type tumors only), CNS metastasis, gross hemoptysis (1/2 teaspoon or more of red blood), unstable angina, or receiving therapeutic anticoagulation. The demographics of the safety population were similar to the demographics of the efficacy population.

Only Grades 3–5 non-hematologic and Grades 4–5 hematologic adverse reactions were collected. Grades 3–5 non-hematologic and Grades 4–5 hematologic adverse reactions occurring at a higher incidence (≥2%) in patients receiving bevacizumab with paclitaxel and carboplatin compared with patients receiving chemotherapy alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thromboembolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Recurrent Glioblastoma

The safety of bevacizumab was evaluated in a multicenter, randomized, open-label study (EORTC 26101) in patients with recurrent GBM following radiotherapy and temozolomide of whom 278 patients received at least one dose of bevacizumab and are considered safety evaluable [see Clinical Studies (14.4)]. Patients were randomized (2:1) to receive bevacizumab (10 mg/kg every 2 weeks) with lomustine or lomustine alone until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. In the bevacizumab with lomustine arm, 22% of patients discontinued treatment due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving bevacizumab with lomustine, the adverse reaction profile was similar to that observed in other approved indications.

Metastatic Renal Cell Carcinoma

The safety of bevacizumab was evaluated in 337 patients who received at least one dose of bevacizumab in a multicenter, double-blind study (BO17705) in patients with mRCC. Patients who had undergone a nephrectomy were randomized (1:1) to receive either bevacizumab (10 mg/kg every 2 weeks) or placebo with interferon alfa [see Clinical Studies (14.5)]. Patients were treated until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–5 adverse reactions occurring at a higher incidence (>2%) were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Adverse reactions are presented in Table 3.

Table 3: Grades 1–5 Adverse Reactions Occurring at Higher Incidence (≥5%) of Patients Receiving Bevacizumab vs. Placebo with Interferon Alfa in Study BO17705
Adverse Reaction*Bevacizumab with Interferon Alfa
(N=337)
Placebo with Interferon Alfa
(N=304)
*
NCI-CTC version 3

Metabolism and nutrition

  Decreased appetite

36%

31%

  Weight loss

20%

15%

General

  Fatigue

33%

27%

Vascular

  Hypertension

28%

9%

Respiratory, thoracic and mediastinal

  Epistaxis

27%

4%

  Dysphonia

5%

0%

Nervous system

  Headache

24%

16%

Gastrointestinal

  Diarrhea

21%

16%

Renal and urinary

  Proteinuria

20%

3%

Musculoskeletal and connective tissue

  Myalgia

19%

14%

  Back pain

12%

6%

The following adverse reactions were reported at a 5-fold greater incidence in patients receiving bevacizumab with interferon-alfa compared to patients receiving placebo with interferon-alfa and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs. 0); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs. 1); tinnitus (7 vs. 1); tooth abscess (7 vs. 0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

Persistent, Recurrent, or Metastatic Cervical Cancer

The safety of bevacizumab was evaluated in 218 patients who received at least one dose of bevacizumab in a multicenter study (GOG-0240) in patients with persistent, recurrent, or metastatic cervical cancer [see Clinical Studies (14.6)]. Patients were randomized (1:1:1:1) to receive paclitaxel and cisplatin with or without bevacizumab (15 mg/kg every 3 weeks), or paclitaxel and topotecan with or without bevacizumab (15 mg/kg every 3 weeks). The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–4 adverse reactions occurring at a higher incidence (≥2%) in 218 patients receiving bevacizumab with chemotherapy compared to 222 patients receiving chemotherapy alone were abdominal pain (12% vs. 10%), hypertension (11% vs. 0.5%), thrombosis (8% vs. 3%), diarrhea (6% vs. 3%), anal fistula (4% vs. 0%), proctalgia (3% vs. 0%), urinary tract infection (8% vs. 6%), cellulitis (3% vs. 0.5%), fatigue (14% vs. 10%), hypokalemia (7% vs. 4%), hyponatremia (4% vs. 1%), dehydration (4% vs. 0.5%), neutropenia (8% vs. 4%), lymphopenia (6% vs. 3%), back pain (6% vs. 3%), and pelvic pain (6% vs. 1%). Adverse reactions are presented in Table 4.

Table 4: Grades 1–4 Adverse Reactions Occurring at Higher Incidence (≥5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study GOG-0240
Adverse Reaction*Bevacizumab with Chemotherapy
(N=218)
Chemotherapy
(N=222)
*
NCI-CTC version 3

General

  Fatigue

80%

75%

  Peripheral edema

15%

22%

Metabolism and nutrition

  Decreased appetite

34%

26%

  Hyperglycemia

26%

19%

  Hypomagnesemia

24%

15%

  Weight loss

21%

7%

  Hyponatremia

19%

10%

  Hypoalbuminemia

16%

11%

Vascular

  Hypertension

29%

6%

  Thrombosis

10%

3%

Infections

  Urinary tract infection

22%

14%

  Infection

10%

5%

Nervous system

  Headache

22%

13%

  Dysarthria

8%

1%

Psychiatric

  Anxiety

17%

10%

Respiratory, thoracic and mediastinal

  Epistaxis

17%

1%

Renal and urinary

  Increased blood creatinine

16%

10%

  Proteinuria

10%

3%

Gastrointestinal

  Stomatitis

15%

10%

  Proctalgia

6%

1%

  Anal fistula

6%

0%

Reproductive system and breast

  Pelvic pain

14%

8%

Hematology

  Neutropenia

12%

6%

  Lymphopenia

12%

5%

Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Stage III or IV Following Initial Surgical Resection

The safety of bevacizumab was evaluated in GOG-0218, a multicenter, randomized, double-blind, placebo-controlled, three arm study, which evaluated the addition of bevacizumab to carboplatin and paclitaxel for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection [see Clinical Studies (14.7)]. Patients were randomized (1:1:1) to carboplatin and paclitaxel without bevacizumab (CPP), carboplatin and paclitaxel with bevacizumab for up to six cycles (CPB15), or carboplatin and paclitaxel with bevacizumab for six cycles followed by bevacizumab as a single agent for up to 16 additional doses (CPB15+). Bevacizumab was given at 15 mg/kg every three weeks. On this trial, 1215 patients received at least one dose of bevacizumab. The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–4 adverse reactions occurring at a higher incidence (≥2%) in either of the bevacizumab arms versus the control arm were fatigue (CPB15+ - 9%, CPB15 - 6%, CPP - 6%), hypertension (CPB15+ - 10%, CPB15 - 6%, CPP - 2%), thrombocytopenia (CPB15+ - 21%, CPB15 - 20%, CPP - 15%) and leukopenia (CPB15+ - 51%, CPB15 - 53%, CPP - 50%). Adverse reactions are presented in Table 5.

Table 5: Grades 1–5 Adverse Reactions Occurring at Higher Incidence (≥5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study GOG-0218
Adverse Reaction*Bevacizumab with Carboplatin and Paclitaxel followed by Bevacizumab Alone
(N=608)
Bevacizumab with Carboplatin and Paclitaxel
(N=607)
Carboplatin and Paclitaxel§
(N=602)
*
NCI-CTC version 3,
CPB15+,
CPB15,
§
CPP

General

  Fatigue

80%

72%

73%

Gastrointestinal

  Nausea

58%

53%

51%

  Diarrhea

38%

40%

34%

  Stomatitis

25%

19%

14%

Musculoskeletal and connective tissue

  Arthralgia

41%

33%

35%

  Pain in extremity

25%

19%

17%

  Muscular weakness

15%

13%

9%

Nervous system

  Headache

34%

26%

21%

  Dysarthria

12%

10%

2%

Vascular

  Hypertension

32%

24%

14%

Respiratory, thoracic and mediastinal

  Epistaxis

31%

30%

9%

  Dyspnea

26%

28%

20%

  Nasal mucosal disorder

10%

7%

4%

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

The safety of bevacizumab was evaluated in 179 patients who received at least one dose of bevacizumab in a multicenter, open-label study (MO22224) in which patients were randomized (1:1) to bevacizumab with chemotherapy or chemotherapy alone in patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within <6 months from the most recent platinum based therapy [see Clinical Studies (14.8)]. Patients were randomized to receive bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks. Patients had received no more than 2 prior chemotherapy regimens. The trial excluded patients with evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Patients were treated until disease progression or unacceptable toxicity. Forty percent of patients on the chemotherapy alone arm received bevacizumab alone upon progression. The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–4 adverse reactions occurring at a higher incidence (≥2%) in 179 patients receiving bevacizumab with 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%). Adverse reactions are presented in Table 6.

Table 6: Grades 2–4 Adverse Reactions Occurring at Higher Incidence (≥5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study MO22224
Adverse Reaction*Bevacizumab with Chemotherapy
(N=179)
Chemotherapy
(N=181)
*
NCI-CTC version 3

Hematology

  Neutropenia

31%

25%

Vascular

  Hypertension

19%

6%

Nervous system

  Peripheral sensory neuropathy

18%

7%

General

  Mucosal inflammation

13%

6%

Renal and urinary

  Proteinuria

12%

0.6%

Skin and subcutaneous tissue

  Palmar-plantar erythrodysaesthesia

11%

5%

Infections

  Infection

11%

4%

Respiratory, thoracic and mediastinal

  Epistaxis

5%

0%

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

Study AVF4095g

The safety of bevacizumab was evaluated in 247 patients who received at least one dose of bevacizumab in a double-blind study (AVF4095g) in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer [see Clinical Studies (14.9)]. Patients were randomized (1:1) to receive bevacizumab (15 mg/kg) or placebo every 3 weeks with carboplatin and gemcitabine for 6 to 10 cycles followed by bevacizumab or placebo alone until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–4 adverse reactions occurring at a higher incidence (≥2%) in patients receiving bevacizumab with chemotherapy compared to placebo with 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%). Adverse reactions are presented in Table 7.

Table 7: Grades 1–5 Adverse Reactions Occurring at Higher Incidence (≥5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Placebo with Chemotherapy in Study AVF4095g
Adverse Reaction*Bevacizumab with Carboplatin and Gemcitabine
(N=247)
Placebo with Carboplatin and Gemcitabine
(N=233)
*
NCI-CTC version 3

General

  Fatigue

82%

75%

  Mucosal inflammation

15%

10%

Gastrointestinal

  Nausea

72%

66%

  Diarrhea

38%

29%

  Stomatitis

15%

7%

  Hemorrhoids

8%

3%

  Gingival bleeding

7%

0%

Hematology

  Thrombocytopenia

58%

51%

Respiratory, thoracic and mediastinal

  Epistaxis

55%

14%

  Dyspnea

30%

24%

  Cough

26%

18%

  Oropharyngeal pain

16%

10%

  Dysphonia

13%

3%

  Rhinorrhea

10%

4%

  Sinus congestion

8%

2%

Nervous system

  Headache

49%

30%

  Dizziness

23%

17%

Vascular

  Hypertension

42%

9%

Musculoskeletal and connective tissue

  Arthralgia

28%

19%

  Back pain

21%

13%

Psychiatric

  Insomnia

21%

15%

Renal and urinary

  Proteinuria

20%

3%

Injury and procedural

  Contusion

17%

9%

Infections

  Sinusitis

15%

9%

Study GOG-0213

The safety of bevacizumab was evaluated in an open-label, controlled study (GOG-0213) in 325 patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have not received more than one previous regimen of chemotherapy [see Clinical Studies (14.9)]. Patients were randomized (1:1) to receive carboplatin and paclitaxel for 6 to 8 cycles or bevacizumab (15 mg/kg every 3 weeks) with carboplatin and paclitaxel for 6 to 8 cycles followed by bevacizumab as a single agent until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population.

Grades 3–4 adverse reactions occurring at a higher incidence (≥2%) in patients receiving bevacizumab with chemotherapy compared to 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% vs. 0%). Adverse reactions are presented in Table 8.

Table 8: Grades 1–5 Adverse Reactions Occurring at Higher Incidence (≥5%) in Patients Receiving Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study GOG-0213
Adverse Reaction*Bevacizumab with Carboplatin and Paclitaxel
(N=325)
Carboplatin and Paclitaxel
(N=332)
*
NCI-CTC version 3

Musculoskeletal and connective tissue

  Arthralgia

45%

30%

  Myalgia

29%

18%

  Pain in extremity

25%

14%

  Back pain

17%

10%

  Muscular weakness

13%

8%

  Neck pain

9%

0%

Vascular

  Hypertension

42%

3%

Gastrointestinal

  Diarrhea

39%

32%

  Abdominal pain

33%

28%

  Vomiting

33%

25%

  Stomatitis

33%

16%

Nervous system

  Headache

38%

20%

  Dysarthria

14%

2%

  Dizziness

13%

8%

Metabolism and nutrition

  Decreased appetite

35%

25%

  Hyperglycemia

31%

24%

  Hypomagnesemia

27%

17%

  Hyponatremia

17%

6%

  Weight loss

15%

4%

  Hypocalcemia

12%

5%

  Hypoalbuminemia

11%

6%

  Hyperkalemia

9%

3%

Respiratory, thoracic and mediastinal

  Epistaxis

33%

2%

  Dyspnea

30%

25%

  Cough

30%

17%

  Rhinitis allergic

17%

4%

  Nasal mucosal disorder

14%

3%

Skin and subcutaneous tissue

  Exfoliative rash

23%

16%

  Nail disorder

10%

2%

  Dry skin

7%

2%

Renal and urinary

  Proteinuria

17%

1%

  Increased blood creatinine

13%

5%

Hepatic

  Increased aspartate aminotransferase

15%

9%

General

  Chest pain

8%

2%

Infections

  Sinusitis

7%

2%

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other bevacizumab products may be misleading.

In clinical studies for adjuvant treatment of a solid tumor, 0.6% (14/2233) of patients tested positive for treatment-emergent anti-bevacizumab antibodies as detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linked immunosorbent assay (ELISA). The clinical significance of these anti-bevacizumab antibodies is not known.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of bevacizumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General: Polyserositis

Cardiovascular: Pulmonary hypertension, Mesenteric venous occlusion

Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration

Hemic and lymphatic: Pancytopenia

Hepatobiliary disorders: Gallbladder perforation

Musculoskeletal and Connective Tissue Disorders: Osteonecrosis of the jaw

Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria)

Respiratory: Nasal septum perforation

Vascular: Arterial (including aortic) aneurysms, dissections, and rupture

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