2.1 Recommended Dose and Schedule

The recommended dosage of ZALTRAP is 4 mg per kg of actual body weight as an intravenous infusion over 1 hour every two weeks in combination with FOLFIRI until disease progression or unacceptable toxicity. Administer ZALTRAP prior to any component of the FOLFIRI regimen on the day of treatment.

Refer to prescribing information for irinotecan, fluorouracil, and leucovorin for the recommended dosage and dosage modifications for these drugs.

2.2 Dosage Modifications for Adverse Reactions

Discontinue ZALTRAP for:

• Severe hemorrhage [see Warnings and Precautions (5.1)]
• Gastrointestinal perforation [see Warnings and Precautions (5.2)]
• Impaired wound healing [see Warnings and Precautions (5.3)]
• Fistula formation [see Warnings and Precautions (5.4)]
• Hypertensive crisis or hypertensive encephalopathy [see Warnings and Precautions (5.5)]
• Arterial thromboembolic events (ATE) [see Warnings and Precautions (5.6)]
• Nephrotic syndrome or thrombotic microangiopathy (TMA) [see Warnings and Precautions (5.7)]
• Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.10)]

Temporarily suspend ZALTRAP:

• At least 4 weeks prior to elective surgery [see Warnings and Precautions (5.3)].
• For uncontrolled hypertension until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.5)].
• For proteinuria of 2 grams per 24 hours or more. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.7)].

2.3 Preparation and Administration

5.1 Hemorrhage

Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/hemorrhage (all grades) was reported in 38% of patients treated with ZALTRAP/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3–4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and post-procedural hemorrhage, were reported in 3% of patients receiving ZALTRAP/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving ZALTRAP.

Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage [see Dosage and Administration (2.2)].

5.2 Gastrointestinal Perforation

Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Across three placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3–4 GI perforation occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo.

Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2)].

5.3 Impaired Wound Healing

Grade 3 impaired wound healing was reported in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI regimen.

Withhold ZALTRAP for at least 4 weeks prior to elective surgery. Do not administer ZALTRAP for at least 4 weeks after major surgery and until wounds have adequately healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Discontinue ZALTRAP in patients with impaired wound healing. The safety of resumption of ZALTRAP after resolution of wound healing complications has not been established [see Dosage and Administration (2.2)].

5.4 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 patient treated with placebo (0.2%).

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

5.5 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 antihypertensive 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 antihypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend ZALTRAP in patients with uncontrolled hypertension until controlled and permanently reduce the 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)].

5.6 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)].

5.7 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 compared 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.

Monitor proteinuria by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria during ZALTRAP therapy. Patients with a dipstick of ≥2+ for protein or a UPCR greater than 1 should undergo a 24-hour urine collection.

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)].

5.8 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.

5.9 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 Use in Specific Populations (8.5)]. Monitor elderly patients closely for diarrhea.

5.10 Reversible Posterior Leukoencephalopathy Syndrome

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 magnetic resonance imaging (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)].

5.11 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, ZALTRAP can cause fetal harm when administered to pregnant women. Administration of ziv-aflibercept during the period of organogenesis was embryotoxic and teratogenic in rabbits at exposure levels approximately 0.3 times the human exposure at the 4 mg per kg dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZALTRAP and for 1 month following the last dose [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

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

The safety of ZALTRAP in combination with FOLFIRI was evaluated in VELOUR (EFC102621) [see Clinical Studies (14)]. Patients received ZALTRAP 4 mg per kg (N=611) or placebo (N=605) intravenously every two weeks (one cycle) in combination with FOLFIRI. Patients received a median of 9 cycles of ZALTRAP/FOLFIRI.

The most common Grade 3–4 adverse reactions (≥5%) in the ZALTRAP/FOLFIRI arm were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.

The most frequent adverse reactions leading to permanent discontinuation in ≥1% of patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.

The ZALTRAP dose was reduced and/or omitted in 17% of patients. Cycle delays >7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI.

The most common adverse reactions (≥20%) in the ZALTRAP/FOLFIRI arm were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache.

Adverse reactions and laboratory abnormalities that occurred in ≥5% (all grades) of patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥2% higher frequency in patients who received ZALTRAP/FOLFIRI compared to those who received placebo/FOLFIRI in VELOUR are shown in Table 1. VELOUR was not designed to demonstrate a statistically significant difference in adverse reaction rates for ZALTRAP/FOLFIRI as compared to placebo/FOLFIRI for any adverse reactions listed below.

Table 1: Selected Adverse Reactions and Laboratory Findings in VELOUR

Primary System Organ Class Preferred Term	ZALTRAP/ FOLFIRI (N=611)		Placebo/ FOLFIRI (N=605)
	All grades (%)	Grades 3–4 (%)	All grades (%)	Grades 3–4 (%)
Note: Adverse Reactions are reported using MedDRA version 13.1 and graded using NCI CTC version 3.0
* Compilation of clinical and laboratory data
Blood and lymphatic system disorders
Leukopenia	78	16	72	12
Neutropenia	67	37	57	30
Thrombocytopenia	48	3	35	2
Gastrointestinal disorders
Diarrhea	69	19	57	8
Stomatitis	50	13	33	5
Abdominal Pain	27	4	24	2
Abdominal Pain Upper	11	1	8	1
Hemorrhoids	6	0	2	0
Rectal Hemorrhage	5	0.7	2	0.5
Proctalgia	5	0.3	2	0.3
Investigations
AST increased	62	3	54	2
ALT increased	50	3	39	2
Weight decreased	32	3	14	0.8
Renal and urinary disorders
Proteinuria*	62	8	41	1
Serum creatinine increased	23	0	19	0.5
General disorders and administration site conditions
Fatigue	48	13	39	8
Asthenia	18	5	13	3
Vascular disorders
Hypertension	41	19	11	1.5
Metabolism and nutrition disorders
Decreased Appetite	32	3	24	2
Dehydration	9	4	3	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	28	0.2	7	0
Dysphonia	25	0.5	3	0
Dyspnea	12	0.8	9	0.8
Oropharyngeal Pain	8	0.2	3	0
Rhinorrhea	6	0	2	0
Nervous system disorders
Headache	22	2	9	0.3
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysesthesia Syndrome	11	3	4	0.5
Skin Hyperpigmentation	8	0	3	0
Infections
Urinary Tract Infection	9	0.8	6	0.8

Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.

In patients with mCRC, severe hypersensitivity reactions have been reported with ZALTRAP/FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%).

In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3–4 VTE occurred in 8% of patients treated with ZALTRAP/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with ZALTRAP/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI.

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 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 products may be misleading.

In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for antiproduct antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo.

The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ZALTRAP. 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.

Musculoskeletal and connective tissue disorders: Osteonecrosis of the jaw

Cardiac disorders: Cardiac failure, ejection fraction decreased

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

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness in pediatric patients have not been established. Safety and efficacy were assessed, but not established in a dose-escalation, safety, and tolerability study (NCT00622414) in 21 patients with solid tumors 2 to 21 years of age (median age 12.9). The mean elimination half-life of free ziv-aflibercept determined after the first dose in 8 pediatric patients aged 5 to 17 years was within the range of values previously observed in adults. The maximum tolerated dose based on body weight in these pediatric patients was lower than the dose known to be safe and effective in adults with mCRC.

8.5 Geriatric Use

Of the 611 patients with mCRC, patients treated with ZALTRAP/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydration [see Warnings and Precautions (5.9)].

The effect of ZALTRAP on overall survival was similar in patients <65 years old and ≥65 years old who received ZALTRAP/FOLFIRI.

8.6 Renal Impairment

No dosage modification is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dosage modification is recommended for patients with mild (total bilirubin >1 to 1.5 times upper limit normal [ULN] and any aspartate transaminase [AST]) and moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment [see Clinical Pharmacology (12.3)]. ZALTRAP has not been studied in patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).

12.1 Mechanism of Action

Ziv-aflibercept acts as a soluble receptor that binds to human VEGF-A (equilibrium dissociation constant KD of 0.5 pM for VEGF-A165 and 0.36 pM for VEGF-A121), to human VEGF-B (KD of 1.92 pM), and to human PlGF (KD of 39 pM for PlGF-2). By binding to these endogenous ligands, ziv-aflibercept can inhibit the binding and activation of their cognate receptors. This inhibition can result in decreased neovascularization and decreased vascular permeability.

In animals, ziv-aflibercept was shown to inhibit the proliferation of endothelial cells, thereby inhibiting the growth of new blood vessels. Ziv-aflibercept inhibited the growth of xenotransplanted colon tumors in mice.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Plasma concentrations of free and VEGF-bound ziv-aflibercept were measured using specific enzyme-linked immunosorbent assays (ELISA). Free ziv-aflibercept concentrations appear to exhibit linear pharmacokinetics in the dose range of 2 mg per kg to 9 mg per kg. Steady state concentrations of free ziv-aflibercept were reached by the second dose. The accumulation ratio for free ziv-aflibercept was approximately 1.2 after administration of 4 mg per kg every two weeks.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted to evaluate carcinogenicity or mutagenicity of ziv-aflibercept.

Ziv-aflibercept impaired reproductive function and fertility in monkeys. In a 6-month repeat-dose toxicology study in sexually mature monkeys, ziv-aflibercept inhibited ovarian function and follicular development, as evidenced by: decreased ovary weight, decreased amount of luteal tissue, decreased number of maturing follicles, atrophy of uterine endometrium and myometrium, vaginal atrophy, abrogation of progesterone peaks and menstrual bleeding. Alterations in sperm morphology and decreased sperm motility were present in male monkeys. These effects were observed at all doses tested including the lowest dose tested, 3 mg per kg. Reversibility was observed within 18 weeks after cessation of treatment. Systemic exposure (AUC) with a 3 mg per kg per dose in monkeys was approximately 0.6 times the AUC in patients at the 4 mg per kg dose.

13.2 Animal Toxicology and/or Pharmacology

Repeated administration of ziv-aflibercept resulted in a delay in wound healing in rabbits. In full-thickness excisional and incisional skin wound models, ziv-aflibercept administration reduced fibrous response, neovascularization, epidermal hyperplasia/re-epithelialization, and tensile strength.

Store ZALTRAP vials in a refrigerator at 2°C to 8°C (36°F to 46°F). Keep the vials in the original outer carton to protect from light. Discard unused portion.

Hemorrhage

• Inform patients that ZALTRAP can cause severe bleeding and advise patients to contact their healthcare provider for bleeding or symptoms of bleeding, including lightheadedness [see Warnings and Precautions (5.1)].

Gastrointestinal Perforation and Fistula Formation

• Advise patients to immediately contact their healthcare provider for signs and symptoms of gastrointestinal perforation or fistula [see Warnings and Precautions (5.2, 5.4)].

Impaired Wound Healing

• Advise patients that ZALTRAP may impair wound healing. Instruct patients to discuss any planned surgical procedure (including tooth extractions) with all their healthcare providers [see Warnings and Precautions (5.3)].

Hypertension

• Inform patients that ZALTRAP can cause or exacerbate existing hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their healthcare provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms [see Warnings and Precautions (5.5)].

Arterial Thromboembolic Events

• Inform patients of an increased risk of ATE [see Warnings and Precautions (5.6)].

Proteinuria

• Advise patients that they will need to undergo regular laboratory tests to monitor protein in their urine [see Warnings and Precautions (5.7)].

Neutropenia and Neutropenic Complications

• Advise patients to notify their healthcare provider of fever or other signs of infection [see Warnings and Precautions (5.8)].

Diarrhea and Dehydration

• Advise patients to notify their healthcare provider of severe diarrhea, vomiting, or severe abdominal pain [see Warnings and Precautions (5.9)].

Posterior Reversible Leukoencephalopathy Syndrome

• Advise patients to immediately contact their healthcare provider for new onset or worsening neurological function [see Warnings and Precautions (5.10)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential:

• of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].
• to use effective contraception during treatment with ZALTRAP and for 1 month following the last dose [see Use in Specific Populations (8.3)].

Lactation

• Advise women not to breastfeed during treatment with ZALTRAP and for 1 month following the last dose [see Use in Specific Populations (8.2)].

Aneurysms and Artery Dissections

• Advise patients to notify their healthcare provider if they have or have had an aneurysm (swelling/enlargement and weakening of part of a blood vessel) or artery dissection (tear in a blood vessel wall) [see Adverse Reactions (6.3)].