Zanidatamab-Hrii

1 INDICATIONS AND USAGE ZIIHERA 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-approved 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 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ZIIHERA is a bispecific HER2-directed antibody 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-approved test. ( 1 ) 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 )

2 DOSAGE AND ADMINISTRATION • Premedicate patients with acetaminophen, an antihistamine and a corticosteroid, 30‑60 minutes prior to each administration of ZIIHERA infusion to prevent potential infusion-related reactions (IRRs). ( 2.2 ) • The recommended dosage of ZIIHERA is 20 mg/kg given as an intravenous infusion once every 2 weeks. ( 2.3 ) 2.1 Patient Selection Select patients for treatment of unresectable or metastatic biliary tract cancer based on HER2-positive (IHC 3+) tumor specimens, as detected by an FDA-approved test [see Clinical Studies ( 14 )] . Information on FDA-approved tests for HER2 protein expression in biliary tract cancers is available at: http://www.fda.gov/CompanionDiagnostics . 2.2 Premedications 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 ( 5.3 )] : • Administer acetaminophen, an antihistamine (such as diphenhydramine) and a corticosteroid (such as hydrocortisone). 2.3 Recommended Dosage Recommended Dosage and Administration The recommended dosage of ZIIHERA is 20 mg/kg, administered as an intravenous infusion once every 2 weeks until disease progression or unacceptable toxicity. Missed dose 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. 2.4 Dosage Modifications for Adverse Reactions • The recommended dosage reduction of ZIIHERA for adverse reactions is 15 mg/kg as described in Table 1 . • Permanently discontinue ZIIHERA in patients who cannot tolerate 15 mg/kg. Table 1 Dosage Modifications for Adverse Reactions Adverse Reaction Severity Treatment Modification Left Ventricular Dysfunction (LVD) [see Warnings and Precautions ( 5.2 )] 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 ( 5.3 )] 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. Diarrhea [see Warnings and Precautions ( 5.4 )] Mild/Moderate (Grade 1 or 2) • No dose 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 dose reduction to 15 mg/kg. • For recurrent Grade 3 symptoms, withhold ZIIHERA treatment and ensure medical management has been optimized. o Resume ZIIHERA treatment at a reduced dose of 15 mg/kg after severity improves to ≤ Grade 1. o Permanently discontinue ZIIHERA for recurrent Grade 3 symptoms that last > 3 days despite optimized medical management. Life threatening (Grade 4) • Permanently discontinue ZIIHERA Pneumonitis [see Adverse Reactions ( 6.1 )] Confirmed Grade ≥ 2 • Permanently discontinue ZIIHERA. Other Adverse Reactions (excluding LVD, IRR, Diarrhea, and Pneumonitis) [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 to 15 mg/kg 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 only 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 final 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 8ºC [36°F to 46ºF]). 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 of the diluted solution between 0.4 mg/mL and 6 mg/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 (2ºC to 8ºC [36ºF to 46ºF]) 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 c-polymer, 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. • Do not administer as an intravenous push or bolus. • Do not co-administer ZIIHERA and other intravenous drugs through the same intravenous line. Table 2: Recommended ZIIHERA Infusion Durations Dose Infusion Duration First and Second 120-150 minutes Third and Fourth 90 minutes, if previous infusions were well-tolerated Subsequent 60 minutes, if previous infusions were well-tolerated

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in other sections of the labeling: • Embyro-Fetal Toxicity [see Warnings and Precautions ( 5.1 )] • Left Ventricular dysfunction [see Warnings and Precautions ( 5.2 )] • Infusion-Related Reactions [see Warnings and Precautions ( 5.3 )] • Diarrhea [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (≥ 20%) are diarrhea, infusion-related reaction, 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. The pooled safety population of ZIIHERA described in WARNINGS AND PRECAUTIONS reflect exposure in 233 patients administered ZIIHERA 20 mg/kg intravenously as a single agent in two single-arm, open-label studies (ZWI‑ZW25‑101 and HERIZON‑BTC‑01), which enrolled 109 patients with biliary tract cancer, and 124 patients with other cancers. Among 233 patients who received ZIIHERA, 39% were exposed for 6 months or longer, and 17% were exposed for greater than one year. Biliary Tract Cancer 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 )]. 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 53% 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 an adverse reaction, 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 3 summarizes the adverse reactions that occurred in HERIZON‑BTC‑01. Table 3: Adverse Reactions (≥ 15%) in Patients with Unresectable or Metastatic HER2-Positive BTC Receiving ZIIHERA 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 erythrodysaesthesia syndrome, rash, rash maculo-papular, and rash pustular Table 4 summarizes the laboratory abnormalities in HERIZON‑BTC‑01. Table 4: 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.

12.3 Pharmacokinetics Zanidatamab‑hrii PK parameters are presented as means (percent coefficient of variation) following administration of ZIIHERA 20 mg/kg every 2 weeks after the 7 th or later dose unless otherwise indicated. Zanidatamab‑hrii maximum concentration (C max ) is 600 (22.2) µg/mL, the lowest measured concentration (C trough ) is 178 (29.6) µg/mL, and total systemic exposure (AUC 0-336h ) is 3,976 (22.5) days*µg/mL following administration of ZIIHERA. The C max of zanidatamab‑hrii is dose proportional and the total systemic exposure (AUC 0-inf ) of zanidatamab‑hrii is greater than dose proportional with increasing doses. The mean C trough accumulation ratio of zanidatamab‑hrii is approximately 2.4. Distribution The volume of distribution of zanidatamab‑hrii is approximately 7.5 (33) L based on the population pharmacokinetic analysis. Elimination The estimated half-life (t 1/2 ) of zanidatamab‑hrii is approximately 21 days with an associated clearance (CL) of 0.012 L/h (27.9) based on the population pharmacokinetic analysis. Metabolism Zanidatamab‑hrii is expected to be metabolized into small peptides by catabolic pathways. Specific Populations No clinically significant differences in the pharmacokinetics of zanidatamab-hrii were observed based on age (24 to 88 years), sex, race (White and Asian), mild and moderate renal impairment (eGFR 30 to 89 mL/min estimated using the CKD‑EPI), mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin between 1 and 1.5 times ULN and any AST), or body weight (35 kg to 128 kg). The effect of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR < 15 mL/min) with or without hemodialysis, and moderate (total bilirubin > 1.5 to ≤ 3 ULN and any AST) or severe (total bilirubin > 3 ULN and any AST) hepatic impairment on the pharmacokinetics of zanidatamab‑hrii is unknown.