Fistula Formation
Fistula formation involving gastrointestinal and non-gastrointestinal sites occurs at a higher incidence in patients treated with Zaltrap. In patients with mCRC, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with Zaltrap/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with Zaltrap (0.3%) and in 1 placebo-treated patient (0.2%).

Discontinue Zaltrap therapy in patients who develop fistula [see Dosage and Administration (2.2)].

Hypertension
Zaltrap increases the risk of Grade 3–4 hypertension. There is no clinical trial experience administering Zaltrap to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% of patients treated with Zaltrap/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with Zaltrap/FOLFIRI. Among those patients treated with Zaltrap/FOLFIRI developing Grade 3–4 hypertension, 54% had onset during the first two cycles of treatment.

Monitor blood pressure every two weeks or more frequently as clinically indicated during treatment with Zaltrap. Treat with appropriate anti-hypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend Zaltrap in patients with uncontrolled hypertension until controlled, and permanently reduce Zaltrap dose to 2 mg per kg for subsequent cycles. Discontinue Zaltrap in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.2)].

Arterial Thromboembolic Events
Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received Zaltrap. In patients with mCRC, ATE was reported in 2.6% of patients treated with Zaltrap/FOLFIRI and 1.7% of patients treated with placebo/FOLFIRI. Grade 3–4 events occurred in 11 patients (1.8%) treated with Zaltrap/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI.

Discontinue Zaltrap in patients who experience an ATE [see Dosage and Administration (2.2)].

Proteinuria
Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with Zaltrap. In patients with mCRC, proteinuria was reported in 62% patients treated with Zaltrap/FOLFIRI compared to 41% patients treated with placebo/FOLFIRI. Grade 3–4 proteinuria occurred in 8% of patients treated with Zaltrap/FOLFIRI to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Nephrotic syndrome occurred in 2 patients (0.5%) treated with Zaltrap/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies.