AFLIBERCEPT: 26,891 Adverse Event Reports & Safety Profile

Aflibercept-boav is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration. Aflibercept-boav is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa. Aflibercept-boav is produced in recombinant Chinese hamster ovary (CHO) cells. EYDENZELT (aflibercept-boav) injection is a sterile, clear to slightly opalescent, and colorless to very pale brownish-yellow solution. EYDENZELT does not contain anti-microbial preservative and is supplied as a sterile, aqueous solution for intravitreal injection in a single-dose, pre-filled syringe or a single-dose glass vial designed to deliver 0.05 mL of solution containing 2 mg of aflibercept-boav in histidine (0.038 mg), L-histidine monohydrochloride monohydrate (0.033 mg), polysorbate 20 (0.015 mg), sodium chloride (0.038 mg), trehalose (5 mg) and water for injection with a pH of 6.2.

AND USAGE EYLEA is indicated for the treatment of: EYLEA is a vascular endothelial growth factor (VEGF) inhibitor indicated for the treatment of patients with: Neovascular (Wet) Age-Related Macular Degeneration (AMD) ( 1.1 )

Macular Edema Following Retinal Vein

Occlusion (RVO) ( 1.2 )

Diabetic Macular

Edema (DME) ( 1.3 )

Diabetic

Retinopathy (DR) ( 1.4 ) Retinopathy of Prematurity (ROP) ( 1.5 )

1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)

1.2 Macular Edema Following Retinal Vein Occlusion (RVO)

1.3 Diabetic Macular Edema (DME)

1.4 Diabetic Retinopathy (DR)

1.5 Retinopathy of Prematurity (ROP)

AND ADMINISTRATION Neovascular (Wet) Age-Related Macular Degeneration (AMD) The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 3 months, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). ( 2.5 ) Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). ( 2.5 ) Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy. Patients should be assessed regularly. ( 2.5 )

Macular Edema Following Retinal Vein

Occlusion (RVO) The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection once every 4 weeks (approximately every 25 days, monthly). ( 2.6 )

Diabetic Macular

Edema (DME) and Diabetic Retinopathy (DR) The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). ( 2.7 , 2.8 ) Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months). (2.7 , 2.8 ) Retinopathy of Prematurity (ROP) The recommended dose for EYLEA is 0.4 mg (0.01 mL or 10 microliters of 40 mg/mL solution) administered by intravitreal injection. Treatment may be given bilaterally on the same day. Injections may be repeated in each eye. The treatment interval between doses injected into the same eye should be at least 10 days. ( 2.9 )

2.1 Important Injection Instructions For ophthalmic intravitreal injection. EYLEA must only be administered by a qualified physician. Pre-filled Syringe: A 30-gauge × ½-inch sterile injection needle is needed but not provided. Vial: A 5-micron sterile filter needle (18-gauge × 1½-inch), a 1-mL Luer lock syringe and a 30-gauge × ½-inch sterile injection needle are needed. EYLEA is available packaged as follows: Pre-filled Syringe Vial Kit with Injection Components (filter needle, syringe, injection needle) <span class="opacity-50 text-xs">[see How Supplied/Storage and Handling (16) ]</span>.

2.2 Preparation for Administration – Pre-filled Syringe The EYLEA pre-filled glass syringe is sterile and for one-time use in one eye only. Do not use the EYLEA pre-filled syringe for the treatment of ROP. The pre-filled syringe should be inspected visually prior to administration. Do not use if particulates, cloudiness, or discoloration are visible, or if the package is open or damaged. The appearance of the syringe cap on the pre-filled syringe may vary (for example, color and design). Do not use if any part of the pre-filled syringe is damaged or if the syringe cap is detached from the Luer lock. The intravitreal injection should be performed with a 30-gauge × ½-inch injection needle (not provided). The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept (equivalent to 50 microliters). The excess volume must be discarded prior to the administration. PRE-FILLED SYRINGE DESCRIPTION – Figure 1: Use aseptic technique to carry out the following steps: 1.

Prepare

When ready to administer EYLEA, open the carton and remove sterilized blister pack. Carefully peel open the sterilized blister pack ensuring the sterility of its contents. Keep the syringe in the sterile tray until you are ready for assembly. 2.

Remove Syringe

Using aseptic technique, remove the syringe from the sterilized blister pack. 3.

Twist Off Syringe Cap

Twist off (do not snap off) the syringe cap by holding the syringe in one hand and the syringe cap with the thumb and forefinger of the other hand (see Figure 2 ). Note: To avoid compromising the sterility of the product, do not pull back on the plunger.

Figure

2: 4.

Attach Needle

Using aseptic technique, firmly twist a 30-gauge × ½-inch injection needle onto the Luer lock syringe tip (see Figure 3 ).

Figure

3: Note: When ready to administer EYLEA, remove the plastic needle shield from the needle. 5.

Dislodge Air Bubbles

Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top (see Figure 4 ).

Figure

4: 6.

Expel Air And Set The Dose

To eliminate all bubbles and to expel excess drug, slowly depress the plunger rod to align the plunger dome edge (see Figure 5a ) with the black dosing line on the syringe (equivalent to 50 microliters) (see Figure 5b ).

Figure

5a: Figure 5b: 7. The pre-filled syringe is for one-time use in one eye only. After injection any unused product must be discarded.

Figure

1 Figure 2 Figure 3 Figure 4 Figure 5a Figure 5b

2.3 Preparation for Administration - Vial EYLEA should be inspected visually prior to administration. If particulates, cloudiness, or discoloration are visible, the vial must not be used. The glass vial is for one-time use in one eye only. Use aseptic technique to carry out the following preparation steps: Prepare for intravitreal injection with the following medical devices for single use: a 5-micron sterile filter needle (18-gauge × 1½-inch) a 1-mL sterile Luer lock syringe with marking to measure 0.05 mL for adults or 0.01 mL for pre-term infants with ROP a sterile injection needle (30-gauge × ½-inch) Remove the protective plastic cap from the vial (see Figure 6 ).

Figure

6: Clean the top of the vial with an alcohol wipe (see Figure 7 ).

Figure

7: Remove the 18-gauge × 1½-inch, 5-micron, filter needle and the 1-mL syringe from their packaging. Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip (see Figure 8 ).

Figure

8: Push the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or bottom edge of the vial. Using aseptic technique withdraw all of the EYLEA vial contents into the syringe, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid (see Figure 9a and Figure 9b ).

Figure

9a: Figure 9b: Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle. Remove the filter needle from the syringe and properly dispose of the filter needle. Note : Filter needle is not to be used for intravitreal injection. Remove the 30-gauge × ½-inch injection needle from its packaging and attach the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip (see Figure 10 ).

Figure

10: When ready to administer EYLEA, remove the plastic needle shield from the needle. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top (see Figure 11 ).

Figure

11: Administration in Adults: To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger rod so that the plunger edge aligns with the line that marks 0.05 mL on the syringe (see Figure 12a and Figure 12b ).

Figure

6 Figure 7 Figure 8 Figure 9a Figure 9b Figure 10 Figure 11 Figure 12a and b

2.4 Injection Procedure for Adults The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a topical broad–spectrum microbicide should be given prior to the injection. Pre-filled syringe : Inject by pressing the plunger carefully and with constant pressure. Do not apply additional pressure once the plunger has reached the bottom of the syringe. A small residual volume may remain in the syringe after a full dose has been injected. This is normal. Do not administer any residual solution observed in the syringe. Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available. Following intravitreal injection, patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay <span class="opacity-50 text-xs">[see Patient Counseling Information (17) ]</span>. Each sterile, pre-filled syringe or vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new sterile, pre-filled syringe or vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before EYLEA is administered to the other eye. After injection, any unused product must be discarded.

2.5 Neovascular (Wet) Age-Related Macular Degeneration (AMD) The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> . Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy. Patients should be assessed regularly.

2.6 Macular Edema Following Retinal Vein Occlusion (RVO) The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection once every 4 weeks (approximately every 25 days, monthly) <span class="opacity-50 text-xs">[see Clinical Studies (14.2) , (14.3) ]</span>.

2.7 Diabetic Macular Edema (DME) The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks <span class="opacity-50 text-xs">[see Clinical Studies (14.4) ]</span>. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months).

2.8 Diabetic Retinopathy (DR) The recommended dose for EYLEA is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when EYLEA was dosed every 4 weeks compared to every 8 weeks <span class="opacity-50 text-xs">[see Clinical Studies (14.5) ]</span> . Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months).

2.9 Retinopathy of Prematurity (ROP)

Recommended Dosage

The recommended dose for EYLEA is 0.4 mg (0.01 mL or 10 microliters of 40 mg/mL solution) administered by intravitreal injection. Treatment is initiated with a single injection per eligible eye and may be given bilaterally on the same day. Injections may be repeated in each eye. The treatment interval between doses injected into the same eye should be at least 10 days [see Clinical Pharmacology (12.3) and Clinical Studies (14.6) ].

Administration

Instructions in Pre-Term Infants with ROP The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a topical broad–spectrum microbicide should be given prior to the injection. Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available. Following intravitreal injection, patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay [see Patient Counseling Information (17) ]. Each sterile vial should only be used for the treatment of a single eye. Do not use the EYLEA pre-filled syringe for the treatment of ROP. If the contralateral eye requires treatment, a new sterile vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before EYLEA is administered to the other eye. Follow steps 1-10 listed in

2.3 Preparation for Administration – Vial. 11 . To eliminate all of the bubbles and to expel excess drug, SLOWLY depress the plunger rod so that the plunger edge aligns with the line that marks 0.01 mL on the syringe (see Figure 13a and Figure 13b ). For the treatment of ROP, the injection needle should be inserted into the eye 1 mm from the limbus with the needle angled to avoid the lens and to avoid the retina. After injection, any unused product must be discarded.

Figure

13a and b

Ocular or periocular infection ( 4.1 ) Active intraocular inflammation ( 4.2 ) Hypersensitivity ( 4.3 )

4.1 Ocular or Periocular Infections EYDENZELT is contraindicated in patients with ocular or periocular infections.

4.2 Active Intraocular Inflammation EYDENZELT is contraindicated in patients with active intraocular inflammation.

4.3 Hypersensitivity EYDENZELT is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in EYDENZELT. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe anaphylactic/anaphylactoid reactions, or severe intraocular inflammation.

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: 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) ] 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 Posterior Leukoencephalopathy

Syndrome [see Warnings and Precautions (5.10) ] Most common adverse reactions (≥20% incidence) 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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) <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span>. 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 &gt;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 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 Compilation of clinical and laboratory data 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

AND PRECAUTIONS Hemorrhage : Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in patients who have received ZALTRAP. Do not administer ZALTRAP to patients with severe hemorrhage. ( 5.1 )

Gastrointestinal

Perforation : Discontinue ZALTRAP therapy in patients who experience GI perforation. ( 5.2 )

Impaired Wound

Healing : Withhold ZALTRAP for at least 4 weeks prior to elective surgery. Do not administer for at least 4 weeks following major surgery and until wounds have adequately 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. ( 5.3 )

Fistula

Formation : Discontinue ZALTRAP if fistula occurs. ( 2.2 , 5.4 ) Hypertension : Monitor blood pressure and treat hypertension. Temporarily suspend ZALTRAP if hypertension is not controlled. Discontinue ZALTRAP if hypertensive crisis develops. ( 2.2 , 5.5 )

Arterial Thromboembolic

Events (ATE) : Discontinue ZALTRAP if ATE develops. ( 5.6 ) Proteinuria : Monitor urine protein. Suspend ZALTRAP for proteinuria of 2 grams per 24 hours or more. Discontinue ZALTRAP if nephrotic syndrome or thrombotic microangiopathy (TMA) develops. ( 2.2 , 5.7 ) Neutropenia and Neutropenic Complications : Delay administration of ZALTRAP/FOLFIRI until neutrophil count is 1.5 × 10 9 /L or higher. ( 5.8 ) Diarrhea and Dehydration : Incidence of severe diarrhea and dehydration is increased. Monitor elderly patients more closely. ( 5.9 , 8.5 )

Reversible Posterior Leukoencephalopathy

Syndrome : Discontinue ZALTRAP. ( 5.10 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of potential risk to fetus and need for use of effective contraception. ( 5.11 , 8.1 , 8.3 )

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

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 × 10 9 /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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> .

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 3 months following the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span> .

INTERACTIONS No dedicated drug-drug interaction studies have been conducted for ZALTRAP. No clinically important pharmacokinetic interactions were found between ziv-aflibercept and irinotecan/SN-38 or fluorouracil [see Clinical Pharmacology (12.3) ] .