Monitor proteinuria by urine dipstick analysis and urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria during Zaltrap therapy. Obtain a 24-hour urine collection in patients with a UPCR greater than 1.

Suspend Zaltrap administration for proteinuria 2 grams per 24 hours or more, and resume when proteinuria is less than 2 grams per 24 hours. If recurrent, suspend until proteinuria is less than 2 grams per 24 hours and then permanently reduce the Zaltrap dose to 2 mg per kg. Discontinue Zaltrap in patients who develop nephrotic syndrome or TMA [see Dosage and Administration (2.2)].

Neutropenia and Neutropenic Complications
A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving Zaltrap. In patients with mCRC, Grade 3–4 neutropenia occurred in 37% of patients treated with Zaltrap/FOLFIRI compared to 30% patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Grade 3–4 febrile neutropenia occurred in 4% of patients treated with Zaltrap/FOLFIRI compared to 2% of patients treated with placebo/FOLFIRI. Grade 3–4 neutropenic infection/sepsis occurred in 1.5% of patients treated with Zaltrap/FOLFIRI and 1.2% of patients treated with placebo/FOLFIRI.

Monitor CBC with differential count at baseline and prior to initiation of each cycle of Zaltrap. Delay Zaltrap/FOLFIRI until neutrophil count is at or above 1.5 × 109/L.

Diarrhea and Dehydration
The incidence of severe diarrhea is increased in patients treated with Zaltrap/FOLFIRI. In patients with mCRC, Grade 3–4 diarrhea was reported in 19% of patients treated with Zaltrap/FOLFIRI compared to 8% of patients treated with placebo/FOLFIRI. Grade 3–4 dehydration was reported in 4% of patients treated with Zaltrap/FOLFIRI compared to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. The incidence of diarrhea is increased in patients who are age 65 years or older as compared to patients younger than 65 years of age [see Geriatric Use (8.5)]. Monitor elderly patients closely for diarrhea.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with Zaltrap monotherapy or in combination with chemotherapy.

Confirm the diagnosis of RPLS with MRI and discontinue Zaltrap in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death [see Dosage and Administration (2.2)].

Adverse Reactions
The following serious adverse reactions are discussed elsewhere in the labeling:

•Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)]
•Gastrointestinal Perforation [see Boxed Warning, Warnings and Precautions (5.2)]
•Compromised Wound Healing [see Boxed Warning, Warnings and Precautions (5.3)]
•Fistula Formation [see Warnings and Precautions (5.4)]
•Hypertension [see Warnings and Precautions (5.5)]
•Arterial Thromboembolic Events [see Warnings and Precautions (5.6)]
•Proteinuria [see Warnings and Precautions (5.7)]
•Neutropenia and Neutropenic Complications [see Warnings and Precautions (5.8)]
•Diarrhea and Dehydration [see Warnings and Precautions (5.9)]
•Reversible P