ZIIHERA

1 INDICATIONS AND USAGE ZIIHERA is a bispecific HER2-directed antibody indicated for: Gastroesophageal Adenocarcinoma (GEA) • in combination with fluoropyrimidine- and platinum-containing chemotherapy, and tislelizumab-jsgr, as first-line treatment of adult patients with HER2-positive (IHC 3+ or IHC 2+/ISH+) unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma, as detected by an FDA-authorized test. ( 1.1 ) • in combination with fluoropyrimidine- and platinum-containing chemotherapy, as first-line treatment of adult patients with HER2-positive (IHC 3+) unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma, as detected by an FDA-authorized test. ( 1.1 ) Biliary Tract Cancer (BTC) • for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) BTC, as detected by an FDA-authorized test.* ( 1.2 ) *This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 ) 1.1 Gastroesophageal Adenocarcinoma (GEA) • ZIIHERA, in combination with fluoropyrimidine- and platinum-containing chemotherapy and tislelizumab-jsgr, is indicated for the first-line treatment of adult patients with HER2-positive (IHC 3+ or IHC 2+/ISH+) unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma, as detected by an FDA-authorized test [see Dosage and Administration ( 2.1 )] . • ZIIHERA, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with HER2-positive (IHC 3+) unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma, as detected by an FDA-authorized test [see Dosage and Administration ( 2.1 )] . 1.2 Biliary Tract Cancer (BTC) ZIIHERA, as a single agent, is indicated for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC), as detected by an FDA-authorized test [see Dosage and Administration ( 2.1 )] . This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14.2 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION • Premedicate all patients to reduce the risk of infusion-related reactions (IRRs). ( 2.2 ) • Administer loperamide during the first cycle to patients receiving ZIIHERA in combination with fluoropyrimidine- and platinum-containing chemotherapy for diarrhea prophylaxis. ( 2.2 ) Gastroesophageal Adenocarcinoma (GEA): • Patients weighing less than 70 kg: ZIIHERA 1,800 mg intravenously every 3 weeks or 1,200 mg every 2 weeks infusion in combination with fluoropyrimidine- and platinum-containing chemotherapy, with or without tislelizumab-jsgr. ( 2.3 ) • Patients weighing 70 kg or greater: ZIIHERA 2,400 mg intravenously every 3 weeks or 1,600 mg every 2 weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy, with or without tislelizumab-jsgr. ( 2.3 ) Biliary Tract Cancer: ZIIHERA 20 mg/kg intravenously every 2 weeks. ( 2.3 ) 2.1 Patient Selection HER2-Positive Gastroesophageal Adenocarcinoma (GEA) Select patients for treatment of unresectable locally advanced or metastatic GEA based on HER2-positive status (IHC 3+ or IHC 2+/ISH+), as detected by FDA-authorized tests [see Clinical Studies ( 14.1 )] . Information on FDA-authorized tests for HER2 protein expression and gene amplification in gastric, gastroesophageal junction, or esophageal adenocarcinoma is available at: http://www.fda.gov/CompanionDiagnostics . Biliary Tract Cancer (BTC) Select patients for treatment of unresectable or metastatic biliary tract cancer based on HER2-positive (IHC 3+) tumor specimens, as detected by an FDA-authorized test [see Clinical Studies ( 14.2 )] . Information on FDA-authorized tests for HER2 protein expression in biliary tract cancers is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Premedications and Important Administration Information Premedicate all patients 30 to 60 minutes prior to each dose of ZIIHERA to reduce the risk of infusion-related reactions [see Warnings and Precautions ( 5.4) ] : • Administer acetaminophen, an antihistamine (such as diphenhydramine) and a corticosteroid (such as hydrocortisone). ZIIHERA in combination with fluoropyrimidine- and platinum-containing chemotherapy with or without tislelizumab-jsgr Antidiarrheal prophylaxis: • Administer loperamide 4 mg twice daily beginning on Day 1 and continue for at least 7 days during the first cycle of treatment. • If patients experience Grade 1 or higher diarrhea during the first cycle, continue prophylaxis with loperamide 4 mg twice daily for at least the first 7 days of each subsequent cycle [see Warnings and Precautions ( 5.1 )]. Fluorouracil-containing regimens: • When ZIIHERA is administered in combination with fluorouracil-containing regimens, administer fluorouracil as an intravenous infusion. Do NOT administer fluorouracil as an intravenous bolus due to the potential increase in diarrhea [see Warnings and Precautions ( 5.1 )] . Missed dose ZIIHERA in combination with fluoropyrimidine- and platinum-containing chemotherapy with or without tislelizumab-jsgr If a planned dose of ZIIHERA is delayed or missed, administer the dose as soon as possible if 7 days or fewer have passed since the scheduled time. If more than 7 days have passed since the planned dose, withhold ZIIHERA and resume on day 1 of the next cycle. ZIIHERA as a single agent If a planned dose of ZIIHERA is delayed or missed, administer the dose as soon as possible; do not wait until the next planned dose. Adjust the administration schedule to maintain a 2-week interval between doses. 2.3 Recommended Dosage Gastroesophageal Adenocarcinoma (GEA) Administer ZIIHERA as an intravenous infusion until disease progression or unacceptable toxicity at the recommended dosages presented in Table 1: Table 1: Dosage recommendations for patients with GEA Patient body weight Dosage < 70 kg: • 1,800 mg every 3 weeks or • 1,200 mg every 2 weeks ≥ 70 kg: • 2,400 mg every 3 weeks or • 1,600 mg every 2 weeks Refer to the Prescribing Information of each of the individual therapeutic agents used in combination with ZIIHERA for additional dosing information. If chemotherapy is discontinued for reasons other than disease progression, treatment with ZIIHERA, and/or tislelizumab-jsgr can continue until disease progression. Biliary Tract Cancer The recommended dosage of ZIIHERA is 20 mg/kg, administered as an intravenous infusion once every 2 weeks until disease progression or unacceptable toxicity. 2.4 Dosage Modifications for Adverse Reactions The recommended dosage reduction of ZIIHERA for adverse reactions is described in Table 2. Permanently discontinue ZIIHERA in patients who cannot tolerate an initial dose reduction. Table 2: Recommended Dosage Reductions for Adverse Reactions Indication Recommended dosage Dosage Modification Gastroesophageal Adenocarcinoma (GEA) Patient body weight < 70 kg: 1,800 mg every 3 weeks or 1,200 mg every 2 weeks 1,400 mg every 3 weeks or 900 mg every 2 weeks Patient body weight ≥ 70 kg: 2,400 mg every 3 weeks or 1,600 mg every 2 weeks 1,800 mg every 3 weeks or 1,200 mg every 2 weeks Biliary Tract Cancer (BTC) 20 mg/kg every 2 weeks 15 mg/kg every 2 weeks The recommended dosage modifications and management for adverse reactions for ZIIHERA are described in Table 3. Table 3: Dosage Modifications for Adverse Reactions Adverse Reaction Severity Treatment Modification Diarrhea [see Warnings and Precautions ( 5.1 )] Mild/Moderate (Grade 1 or 2) • No dosage modification of ZIIHERA is required. • Initiate appropriate medical therapy and monitor as clinically indicated. Severe (Grade 3) • Withhold ZIIHERA treatment until severity improves to ≤ Grade 1. • Initiate or intensify appropriate medical therapy and monitor as clinically indicated. • Administer subsequent ZIIHERA treatment at the same dose level or consider a dose reduction. • For recurrent Grade 3 symptoms, withhold ZIIHERA treatment and ensure medical management has been optimized. o Resume ZIIHERA treatment at a reduced dose after severity improves to ≤ Grade 1 • Permanently discontinue ZIIHERA for recurrent Grade 3 symptoms that last > 3 days despite optimized medical management. Life threatening (Grade 4) • Permanently discontinue ZIIHERA. Left Ventricular Dysfunction (LVD) [see Warnings and Precautions ( 5.3 )] Absolute decrease of ≥ 16% points in LVEF from pre-treatment baseline or LVEF < 50% and absolute decrease of ≥ 10% points below pre-treatment baseline • Withhold ZIIHERA for at least 4 weeks. • Repeat LVEF assessment within 4 weeks. • Resume ZIIHERA treatment within 4 to 8 weeks if LVEF returns to normal limits and the absolute decrease is ≤ 15% points from baseline. • Permanently discontinue ZIIHERA if LVEF has not recovered to within 15% points from pre-treatment baseline. Confirmed symptomatic congestive heart failure • Permanently discontinue ZIIHERA. Infusion-Related Reactions [see Warnings and Precautions ( 5.4 )] Mild (Grade 1) • Reduce ZIIHERA infusion rate by 50%. • For subsequent ZIIHERA infusions increase infusion rate gradually to the rate prior to the adverse reaction, as tolerated. Moderate (Grade 2) • Stop ZIIHERA infusion immediately. • Treat with appropriate therapy. • Resume ZIIHERA infusion at 50% of previous infusion rate once symptoms resolve. • For subsequent ZIIHERA infusions, increase infusion rate gradually to the rate prior to the adverse reaction, as tolerated. Severe (Grade 3) • Stop ZIIHERA infusion immediately. • Promptly treat with appropriate therapy; infusion should not be restarted during the same cycle even if signs and symptoms completely resolve. • Subsequent ZIIHERA infusions should be administered at 50% of previous infusion rate. • Permanently discontinue ZIIHERA for recurrent Grade 3 reaction. Life threatening (Grade 4) • Stop ZIIHERA infusion immediately and permanently discontinue. • Promptly treat with appropriate therapy. Other Adverse Reactions (excluding LVD, IRR and Diarrhea) [see Adverse Reactions ( 6.1 )] Mild/Moderate (Grades 1/2) • No dosage modification is required for ZIIHERA. • Initiate appropriate medical therapy and monitor as clinically indicated. Severe (Grade 3) • Withhold ZIIHERA treatment until severity improves to ≤ Grade 1. • Initiate appropriate medical therapy and monitor as clinically indicated. • Administer subsequent ZIIHERA treatment at the same dose; consider dose reduction if Grade 3 symptoms recur. Life threatening (Grade 4) • Permanently discontinue ZIIHERA, except as noted below. • Initiate appropriate medical therapy and monitor as clinically indicated. • ZIIHERA treatment may be resumed at the same dose level for Grade 4 electrolyte imbalances or laboratory abnormalities that are corrected within 3 days of onset; do not resume until symptoms improve to ≤ Grade 1. • Permanently discontinue ZIIHERA for recurrent Grade 4 electrolyte imbalances or laboratory abnormalities. 2.5 Preparation and Administration Instructions Administer as an intravenous infusion after ZIIHERA is reconstituted and diluted. Reconstitution • Calculate the recommended dose based on the patient’s weight to determine the number of vials needed. • Remove the vial(s) from the refrigerator and allow the vial(s) to reach room temperature. • Reconstitute each 300 mg vial of ZIIHERA with 5.7 mL of Sterile Water for Injection by slowly directing the stream toward the inside of the wall of the vial, to obtain a concentration of 50 mg/mL in an extractable volume of 6 mL. • Swirl the vial gently until completely dissolved. Do not shake or vigorously swirl. • Allow the reconstituted vial to settle to allow bubbles to dissipate. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted product should be a colorless to light yellow, clear to slightly opalescent solution with no visible particles. Discard the reconstituted vial if any discoloration or particulate matter is observed. • The product does not contain a preservative. Use the reconstituted ZIIHERA solution immediately or store the reconstituted ZIIHERA solution for up to 4 hours, either at room temperature (18°C to 24°C [64°F to 75°F]) or in a refrigerator (2°C to 8°C [36°F to 46°F]). Dilution • Withdraw the necessary volume for the calculated dose from each vial [see Dosage and Administration ( 2.3 )] . • Slowly add the necessary dose volume to an infusion bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection to prepare an infusion solution with a final concentration between 4 mg/mL and 20 mg/mL. Use the least possible volume of diluent necessary, do not exceed a maximum volume of 500 mL. • Gently invert the infusion bag to mix. Do not shake. • The infusion solution must be a clear, colorless solution with no visible particles. Do not use if visible particles are observed or if the solution is discolored. • Discard any unused portion left in the vial(s). • Use the infusion solution immediately upon dilution or store the infusion solution at room temperature (18°C to 24°C [64°F to 75°F]) for up to 12 hours or in the refrigerator (2°C to 8°C [36°F to 46°F]) for up to 24 hours. o These time limits include the beginning of reconstitution through the duration of infusion. o If these specified times are exceeded, discontinue the current infusion bag and prepare a new bag which contains the remaining dosage of ZIIHERA to be infused. • Compatibility with intravenous administration materials and the infusion solution has been demonstrated in the following materials: o Intravenous (IV) Bag: Polyvinyl chloride (PVC), polyolefin (PO), ethyl vinyl acetate (EVA), polypropylene (PP), and ethylene-propylene copolymer. o Infusion sets: Polyvinyl chloride/ bis (2-ethylhexyl) phthalate (PVC/DEHP), Polyurethane (PUR), polyethylene-lined (PE-lined), acrylonitrile-butadiene-styrene (ABS). o Inline filters: Polyethersulfone solution filter (PES), polyvinylidene fluoride air filter (PVDF). o Closed System Transfer devices: acrylonitrile-butadiene-styrene (ABS), acrylic copolymer, polycarbonate (PC), polyisoprene (PI), polyester, polypropylene (PP) polytetrafluoroethylene (PTFE), silicone, and stainless steel (SS). Administration • Administer ZIIHERA as an intravenous infusion with a 0.2 or 0.22 micron filter per the recommended infusion durations listed in Table 4. • Do not administer as an intravenous push or bolus. • Do not co-administer ZIIHERA and other intravenous drugs through the same intravenous line. • Administer ZIIHERA first, followed by tislelizumab-jsgr (if included in the regimen), and then chemotherapy when ZIIHERA is given in combination regimens for the treatment of GEA . Table 4: Recommended ZIIHERA Infusion Durations Dose Infusion Duration First 120 minutes Second 90 minutes, if previous infusions were well-tolerated Subsequent 60 minutes, if previous infusions were well-tolerated

4 CONTRAINDICATIONS None. • None. ( 4 )

5 WARNINGS AND PRECAUTIONS • Left Ventricular Dysfunction: Assess left ventricular ejection fraction (LVEF) prior to initiation of ZIIHERA and at regular intervals during treatment. Withhold or permanently discontinue ZIIHERA based on severity. ( 2.4 , 5.3 ) • Infusion-Related Reactions (IRRs): Premedicate before each infusion of ZIIHERA. Interrupt the infusion, decrease the infusion rate, and/or permanently discontinue ZIIHERA based on severity. ( 2.2 , 2.4 , 5.4 ) 5.1 Diarrhea ZIIHERA can cause severe diarrhea. When ZIIHERA is used in combination with fluoropyrimidine- and platinum-containing chemotherapy with or without tislelizumab-jsgr, severe, life threatening, and fatal cases of diarrhea can occur despite loperamide prophylaxis [see Adverse Reactions ( 6.1 ), Use in Specific Populations ( 8.5 )] . The risk of severe and life threatening diarrhea is higher when ZIIHERA is administered with chemotherapy and tislelizumab-jsgr, with a higher risk in patients aged 65 years or older compared to younger patients [see Geriatric Use ( 8.5 )] . Advise patients to increase oral fluids, begin antidiarrheals, and notify their healthcare provider immediately if diarrhea occurs [see Patient Counseling Information ( 17 )] . Administer antidiarrheal prophylaxis with loperamide in cycle 1 for all patients receiving ZIIHERA in combination with fluoropyrimidine- and platinum-containing chemotherapy with or without tislelizumab-jsgr. Begin loperamide at the first loose stool when ZIIHERA is administered in combination with chemotherapy or as a single agent. Administer fluids, electrolytes, and additional antidiarrheal agents as necessary. When ZIIHERA was used in combination with chemotherapy with or without tislelizumab-jsgr, 9% of patients had a dose reduction of ZIIHERA due to diarrhea and concomitant agents were dose reduced in 22% of patients. Before modifying the dose of ZIIHERA, evaluate, modify or discontinue drug(s) contributing to diarrhea in accordance with their respective prescribing information. Withhold, reduce the dose, or permanently discontinue ZIIHERA based on severity [see Dosage and Administration ( 2.2 , 2.4 )] . In a Phase 2 study evaluating ZIIHERA in combination with FOLFOX in patients with GEA, 57% of patients who received a fluorouracil bolus without loperamide prophylaxis (N=14), experienced Grade 3 diarrhea, while 30% of patients who did not receive a fluorouracil bolus but received loperamide prophylaxis (N=10) experienced Grade 3 diarrhea. If treating patients with ZIIHERA in combination with FOLFOX, do not administer the fluorouracil bolus. Gastroesophageal Adenocarcinoma (GEA) In Combination with fluoropyrimidine- and platinum-containing chemotherapy and tislelizumab: When ZIIHERA was used in combination with fluoropyrimidine- and platinum-containing chemotherapy and tislelizumab-jsgr, diarrhea was reported in 85% of 330 patients treated in clinical studies, including Grade 4 (2.1%), Grade 3 (24%), and Grade 2 (31%) events. Fatal outcomes resulting from diarrhea occurred in 1.5% of patients. Diarrhea leading to dose reduction of ZIIHERA occurred in 10% of patients, and permanent discontinuation of ZIIHERA occurred in 3.9% of patients. In cycle 1, diarrhea at Grade 4 severity occurred in 1.5% and Grade 3 severity occurred in 15% of patients despite use of loperamide prophylaxis. The median time to onset for cycle 1 diarrhea was 6 days and median time to resolution was 18 days. In Combination with fluoropyrimidine- and platinum-containing chemotherapy: When ZIIHERA was used in combination with fluoropyrimidine- and platinum-containing chemotherapy , diarrhea was reported in 81% of 395 patients treated in clinical studies, including Grade 4 (1.3%), Grade 3 (20%) and Grade 2 (33%). Diarrhea leading to dose reduction of ZIIHERA occurred in 10% of patients, and permanent discontinuation of ZIIHERA occurred in 1.8% of patients. In cycle 1, diarrhea at Grade 4 severity occurred in 0.8% and Grade 3 severity occurred in 14% of patients despite use of loperamide prophylaxis. The median time to onset for cycle 1 diarrhea was 6 days and median time to resolution was 18 days. Biliary Tract Cancer (BTC) When ZIIHERA was used as a single agent, diarrhea was reported in 49% of 233 patients treated in clinical studies, including Grade 3 (6%) and Grade 2 (17%). Grade 3 diarrhea occurred in 2.6% of patients during cycle 1 of treatment. Of all diarrhea events occurring during the first cycle of treatment, median time to onset was 4 days and median time to resolution was 21 days. 5.2 Embryo-Fetal Toxicity Based on the mechanism of action, ZIIHERA can cause fetal harm when administered to a pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Verify the pregnancy status of females of reproductive potential prior to the initiation of ZIIHERA. Advise pregnant women and females of reproductive potential that exposure to ZIIHERA during pregnancy or within 4 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception while receiving ZIIHERA and for 4 months following the last dose of ZIIHERA. 5.3 Left Ventricular Dysfunction (LVD) ZIIHERA can cause decreases in left ventricular ejection fraction (LVEF). Assess LVEF prior to initiation of ZIIHERA and at regular intervals during treatment. Withhold dose or permanently discontinue ZIIHERA based on severity of adverse reactions [see Dosage and Administration ( 2.4 )] . The safety of ZIIHERA has not been established in patients with a baseline ejection fraction that is below 50% [see Dosage and Administration ( 2.4 )] . Gastroesophageal Adenocarcinoma (GEA) In patients who received ZIIHERA in combination with chemotherapy and tislelizumab-jsgr, LVEF decrease (an absolute decline in LVEF of more than 10%, resulting in a final value below 50%) was observed in 9% of 330 patients. LVD leading to permanent discontinuation of ZIIHERA was reported in 3% of patients. Fatal outcomes due to LVD occurred in one patient (0.3%). The median time to first occurrence of LVD was 6.9 months (range: 1.2 to 29.1 months). Left ventricular dysfunction resolved in 78% of patients. In patients who received ZIIHERA in combination with chemotherapy, LVEF decrease was observed in 5% of 395 patients. LVD leading to permanent discontinuation of ZIIHERA was reported in 1.0% of patients. The median time to first occurrence of left ventricular dysfunction was 6.0 months (range: 1.4 to 15.0 months). Left ventricular dysfunction resolved in 70% of patients. Biliary Tract Cancer (BTC) In patients who received ZIIHERA as a single agent, LVEF decrease was observed in 4.3% of 233 patients. LVD leading to permanent discontinuation of ZIIHERA was reported in 0.9% of patients. The median time to first occurrence of left ventricular dysfunction was 5.6 months (range: 1.6 to 18.7 months). LVD resolved in 70% of patients. 5.4 Infusion-Related Reactions ZIIHERA can cause infusion-related reactions (IRRs). Prior to each dose of ZIIHERA, administer premedication to prevent potential IRRs [see Dosage and Administration ( 2.2 )] . Monitor patients for signs and symptoms of IRR during ZIIHERA administration and as clinically indicated after completion of infusion. Have medications and emergency equipment to treat IRRs available for immediate use. If an IRR occurs, slow or stop the infusion, and administer appropriate medical management. Monitor patients until complete resolution of signs and symptoms before resuming. Permanently discontinue ZIIHERA in patients with recurrent severe or life-threatening IRRs [see Dosage and Administration ( 2.4 )] . Gastroesophageal Adenocarcinoma (GEA) An IRR was reported in 22% of 330 patients treated with ZIIHERA and chemotherapy with tislelizumab-jsgr in clinical studies, including Grade 4 (0.3%), Grade 3 (1.2%), and Grade 2 (16%) despite use of prophylaxis. IRRs leading to permanent discontinuation of ZIIHERA were reported in 0.3% of patients. IRRs occurred on the first day of dosing in 17% of patients. Of all patients who experienced IRRs, 60% of reactions resolved within the first day. An IRR was reported in 24% of 395 patients treated with ZIIHERA and chemotherapy in clinical studies, including Grade 4 (0.3%), Grade 3 (1.5%), and Grade 2 (18%) despite use of prophylaxis. IRRs leading to permanent discontinuation of ZIIHERA were reported in 1.3% of patients. IRRs occurred on the first day of dosing in 22% of patients. Of all patients who experienced IRRs, 83% of reactions resolved within the first day. Biliary Tract Cancer (BTC) An IRR was reported in 31% of 233 patients treated with ZIIHERA as a single agent in clinical studies, including Grade 3 (0.4%), and Grade 2 (25%). IRRs leading to permanent discontinuation of ZIIHERA were reported in 0.4% of patients despite use of prophylaxis. IRRs occurred on the first day of dosing in 28% of patients. Of all patients who experienced IRRs, 97% of reactions were resolved within the first day.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in other sections of the labeling: • Diarrhea [see Warnings and Precautions ( 5.1 )] • Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.2) ] • Left Ventricular Dysfunction [see Warnings and Precautions (5.3 )] • Infusion-Related Reactions [see Warnings and Precautions ( 5.4 )] • Most common adverse reactions (≥ 20%) with ZIIHERA in combination with chemotherapy and tislelizumab-jsgr were diarrhea, nausea, decreased appetite, vomiting, hypokalemia, fatigue, rash, peripheral neuropathy, and IRR. ( 6.1 ) • Most common adverse reactions (≥ 20%) with ZIIHERA in combination with chemotherapy were diarrhea, nausea, vomiting, decreased appetite, fatigue, hypokalemia, peripheral neuropathy, IRR, and rash. ( 6.1 ) • Most common adverse reactions (≥ 20%) with ZIIHERA as a single agent were diarrhea, IRR, abdominal pain, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1‑800‑520‑5568 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. Gastroesophageal Adenocarcinoma (GEA) The pooled safety population of ZIIHERA described in WARNINGS AND PRECAUTIONS, reflects exposure to ZIIHERA in combination with chemotherapy, with or without tislelizumab-jsgr, in 725 patients with GEA from four open-label studies, including HERIZON-GEA-01 (N=605), ZWI-ZW25-201 (N=46), ZWI-ZW25-101 (N=41), and BGB-A317-ZW25-101 (N=33) at doses of 1,800 mg every 3 weeks (< 70 kg), 2,400 mg every 3 weeks (≥ 70 kg), 1,200 mg every 2 weeks (< 70 kg), 1,600 mg every 2 weeks (≥ 70 kg), or other doses. Among the 330 patients who received ZIIHERA in combination with chemotherapy and tislelizumab-jsgr for GEA, 64% were exposed for 6 months or longer, and 41% were exposed for 1 year or more. Among the 395 patients who received ZIIHERA in combination with chemotherapy for GEA, 57% were exposed for 6 months or longer, and 34% were exposed for 1 year or more. Biliary Tract Cancer (BTC) The pooled safety population of ZIIHERA administered 20 mg/kg intravenously as a single agent, described in WARNINGS AND PRECAUTIONS reflects exposure in 233 patients in two single-arm, open-label studies (ZWI-ZW25-101 and HERIZON-BTC-01): 109 patients with biliary tract cancer, and 124 patients with other cancers. Among 233 patients who received ZIIHERA as a single agent, 39% were exposed for 6 months or longer, and 17% were exposed for greater than one year. Gastroesophageal Adenocarcinoma (GEA) (HERIZON-GEA-01) The safety of ZIIHERA administered in combination with chemotherapy, with or without tislelizumab-jsgr for the treatment of GEA was evaluated in 901 patients [see Clinical Studies ( 14.1 )] . Patients received ZIIHERA by IV infusion every 3 weeks at 1,800 mg (< 70 kg body weight) or 2,400 mg (≥ 70 kg), with or without tislelizumab-jsgr and an investigator choice of a fluoropyrimidine- and platinum-based chemotherapy (CAPOX or FP) or trastuzumab with CAPOX or FP [see Clinical Studies ( 14.1 )] . Treatment in each arm continued until disease progression or unacceptable toxicity. ZIIHERA in combination with tislelizumab-jsgr and chemotherapy Sixty-three percent (63%) of patients were exposed to ZIIHERA for 6 months or longer and 39% 1 year or longer). Serious adverse reactions occurred in 59% of patients who received ZIIHERA. Serious adverse reactions in > 2% of patients included diarrhea (17%), infusion-related reactions (5%), vomiting (4.8%), hypokalemia (4.4%), acute kidney injury (3.7%), pneumonia (3.7%), nausea (2.4%), decreased appetite (2.4%), and anemia (2.4%). Fatal adverse reactions occurred in 2.4% of patients who received ZIIHERA in combination with tislelizumab-jsgr and chemotherapy include acute kidney injury (N=2), cardiac failure, diarrhea, dehydration, hypovolemic shock and intestinal obstruction (all N=1). Permanent discontinuation of ZIIHERA occurred in 13% of patients. Adverse reactions that resulted in permanent discontinuation of ZIIHERA in ≥ 1% of patients included diarrhea (4.4%) and ejection fraction decreased (2.7%). Dosage interruptions of ZIIHERA, excluding temporary interruptions of ZIIHERA infusions due to infusion-related reactions, occurred in 65% of patients. Adverse reactions requiring a dose interruption of ZIIHERA in > 3% of patients, excluding infusion-related reactions, were diarrhea (14%), neutropenia (11%), platelet count decreased (9%), fatigue (7%), ejection fraction decreased (7%), anemia (6%), hypokalemia (4.8%), decreased appetite (4.4%), vomiting (3.4%), and rash (3.1%). Dosage reductions of ZIIHERA occurred in 14% of patients. The adverse reactions requiring dosage reduction of ZIIHERA in ≥ 1% of patients were diarrhea (10%) and hypokalemia (1.0%). The most common adverse reactions (≥ 20%) were diarrhea (83%), nausea (56%), decreased appetite (46%), vomiting (44%), hypokalemia (39%), fatigue (37%), rash (36%), peripheral neuropathy (27%), and infusion-related reaction (25%). ZIIHERA in combination with chemotherapy Fifty-seven percent (57%) of patients were exposed to ZIIHERA for 6 months or longer and 32% for 1 year or longer. Serious adverse reactions occurred in 49% of patients who received ZIIHERA. Serious adverse reactions in > 2% of patients included diarrhea (11%), vomiting (3.3%), decreased appetite (2.6%), pneumonia (2.6%), sepsis (2.6%), hypokalemia (2.3%), and nausea (2.3%). Permanent discontinuation of ZIIHERA occurred in 10% of patients. Adverse reactions that resulted in permanent discontinuation of ZIIHERA in ≥ 1% of patients included ejection fraction decreased (2.0%), infusion-related reaction (1.6%), and diarrhea (1.6%). Dosage interruptions of ZIIHERA, excluding temporary interruptions of ZIIHERA infusions due to infusion-related reactions, occurred in 56% of patients. Adverse reactions requiring a dose interruption of ZIIHERA, excluding infusion-related reactions, occurring in > 3% of patients were diarrhea (14%), neutropenia (10%), platelet count decreased (10%), anemia (6%), ejection fraction decreased (6%), fatigue (6%), and hypokalemia (3.9%). Dosage reductions of ZIIHERA occurred in 15% of patients who received ZIIHERA in combination with chemotherapy. Adverse reactions requiring dosage reductions of ZIIHERA in ≥ 1% of patients were diarrhea (11%), decreased appetite (1.0%), and ejection fraction decreased (1.0%). The most common adverse reactions in patients receiving ZIIHERA in combination with chemotherapy (≥ 20%) were diarrhea (79%), nausea (54%), vomiting (44%), decreased appetite (40%), fatigue (36%), hypokalemia (33%), peripheral neuropathy (32%), infusion-related reaction (25%), and rash (22%). Table 5 summarizes the adverse reactions in HERIZON-GEA-01. Table 5: Adverse Reactions (≥ 10%) With an Increased Incidence (≥ 5% Increase in All Grades) in a ZIIHERA-containing arm in HERIZON-GEA-01 Adverse Reaction* ZIIHERA with chemotherapy and tislelizumab-jsgr N = 294 ZIIHERA with chemotherapy N = 305 Trastuzumab with chemotherapy N = 302 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Diarrhea a 83 26 79 21 53 14 Nausea 56 8 54 4.3 48 3.0 Vomiting b 44 6 44 3.6 34 4.3 Metabolism and nutrition disorders Decreased appetite 46 8 40 7 36 6 General disorders and administration site conditions Fatigue c 37 7 36 7 30 6 Skin and subcutaneous tissue disorders Rash d 36 5 22 2.6 25 5 Pruritus 17 0.7 8 0.3 3.6 0 Injury, poisoning, and procedural complications Infusion-related reaction 25 1.7 25 2.3 13 0.7 Investigations Ejection fraction decreased e 12 3.1 9 2.3 7 1.3 * Graded per CTCAE version 5. a Diarrhea includes colitis, diarrhea, enteritis, enterocolitis and enterocolitis hemorrhagic. b Vomiting includes hematemesis and vomiting. c Fatigue includes asthenia and fatigue. d Rash includes dermatitis, dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash maculo-papular, rash pustular and urticaria. e Ejection fraction decreased includes cardiac failure, ejection fraction decreased, left ventricular dysfunction and right ventricular failure. Table 6 summarizes the laboratory abnormalities in HERIZON‑GEA‑01. Table 6: Laboratory Abnormalities (≥ 30%) with an Increased Incidence (at least 5% of all Grades or 2% Grade 3-4) in a ZIIHERA-containing arm in HERIZON-GEA-01 Laboratory Abnormalities ZIIHERA with chemotherapy and tislelizumab-jsgr N = 294 ZIIHERA with chemotherapy N = 305 Trastuzumab with chemotherapy N = 302 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Hemoglobin decreased 97 19 92 16 92 16 Chemistry Potassium decreased 61 27 56 23 38 12 Blood calcium decreased 62 1.7 52 1.6 56 1.7 Aspartate aminotransferase increased 51 4.8 46 2.3 53 0.7 Blood magnesium decreased 42 0.3 43 3 24 0 Alanine aminotransferase increased 41 3.4 38 1.6 37 0 Sodium decreased 43 2 35 2.3 35 1 Creatinine increased 34 4.1 23 2.6 21 2.3 Biliary Tract Cancer (HERIZON-BTC-01) The safety of ZIIHERA was evaluated in 80 patients with previously treated, unresectable or metastatic HER2-positive biliary tract cancer who received at least one prior gemcitabine-containing chemotherapy regimen in HERIZON-BTC-01 [see Clinical Studies ( 14.2 )] . Patients received ZIIHERA 20 mg/kg by IV infusion once every 2 weeks until disease progression or unacceptable toxicity. The median duration of exposure to ZIIHERA was 5.6 months (range: 0.5 to 27.2 months). Serious adverse reactions occurred in 54% of patients who received ZIIHERA. Serious adverse reactions in > 2% of patients included biliary obstruction (15%), biliary tract infection (8%), sepsis (8%), pneumonia (5%), diarrhea (3.8%), gastric obstruction (3.8%), and fatigue (2.5%). A fatal adverse reaction of hepatic failure occurred in one patient who received ZIIHERA. Permanent discontinuation due to an adverse reaction occurred in 2.5% of patients who received ZIIHERA. Adverse reactions which resulted in permanent discontinuation in ≥ 1% of patients who received ZIIHERA included decreased ejection fraction and pneumonitis. Dosage interruptions due to adverse reactions, excluding temporary interruptions of ZIIHERA infusions due to infusion-related reactions, occurred in 41% of patients who received ZIIHERA. The most frequent adverse reactions (> 2% of patients) that required dosage interruption were diarrhea, increased alanine aminotransferase, increased aspartate aminotransferase, decreased ejection fraction, pneumonia, cholangitis, fatigue, biliary obstruction, abdominal pain, increased blood creatinine, and decreased potassium. Dosage reductions due to an adverse reaction occurred in 4% of patients who received ZIIHERA. Adverse reactions requiring dosage reductions in > 1% of patients were diarrhea, nausea, and decreased weight. The most common adverse reactions in patients receiving ZIIHERA (≥ 20%) were diarrhea, infusion-related reaction, abdominal pain, and fatigue. Table 7 summarizes the adverse reactions that occurred in HERIZON-BTC-01. Table 7: Adverse Reactions (≥ 15%) in HERIZON-BTC-01 Adverse Reaction* ZIIHERA N=80 All Grades (%) Grades 3 or 4 (%) Gastrointestinal disorders Diarrhea a 50 10 Abdominal pain b 29 1 Nausea 18 1 Vomiting 15 1 Injury, poisoning, and procedural complications Infusion-related reaction 35 1 General disorders and administration site conditions Fatigue c 24 4 Skin and subcutaneous tissue disorders Rash d 19 0 Metabolism and nutrition disorders Decreased appetite 16 0 * Graded per CTCAE version 5. a Diarrhea includes diarrhea and enteritis b Abdominal pain includes abdominal pain and abdominal pain upper c Fatigue includes asthenia and fatigue d Rash includes dermatitis, dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, rash, rash maculo-papular, and rash pustular Table 8 summarizes the laboratory abnormalities in HERIZON-BTC-01. Table 8: Laboratory Abnormalities (≥ 30%) that Worsened from Baseline in Patients with Unresectable or Metastatic HER2-Positive BTC Receiving ZIIHERA in HERIZON-BTC-01 Laboratory Abnormalities ZIIHERA* All Grades (%) Grades 3 or 4 (%) Hematology Hemoglobin decreased 88 14 Lymphocytes decreased 44 8 Chemistry Lactate dehydrogenase increased 55 0 Albumin decreased 53 0 Aspartate aminotransferase increased 47 10 Alanine aminotransferase increased 46 8 Alkaline phosphatase increased 41 5 Sodium decreased 35 10 Potassium decreased 34 5 * The denominator used to calculate the rate varied from 78 to 80 based on the number of patients with a baseline value and at least one post-treatment value.

8.1 Pregnancy Risk Summary Based on mechanism of action, ZIIHERA can cause fetal harm when administered to a pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Use of ZIIHERA is not recommended during pregnancy (see CLINICAL CONSIDERATIONS). Advise patients of potential risks to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received ZIIHERA during pregnancy or within 4 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with local standard of care.