ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described in greater detail in other sections of the labeling:oEmbyro-Fetal Toxicity [see Warnings and Precautions (5.1)]oLeft Ventricular dysfunction [see Warnings and Precautions (5.2)]oInfusion-Related Reactions [see Warnings and Precautions (5.3)]oDiarrhea [see Warnings and Precautions (5.4)]. oEmbyro-Fetal Toxicity [see Warnings and Precautions (5.1)]. oLeft Ventricular dysfunction [see Warnings and Precautions (5.2)]. oInfusion-Related Reactions [see Warnings and Precautions (5.3)]. oDiarrhea [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 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 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 months or longer, and 17% were exposed for greater than one year.Biliary Tract CancerThe 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 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%). 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 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-01Adverse ReactionZIIHERAN=80All Grades(%)Grades or 4(%)Gastrointestinal disordersDiarrheaa 5010Abdominal painb 291Nausea181Vomiting151Injury, poisoning and procedural complicationsInfusion-related reaction351General disorders and administration site conditionsFatiguec 244Skin and subcutaneous tissue disordersRashd 190Metabolism and nutrition disordersDecreased appetite160 Graded per CTCAE version 5.a Diarrhea includes diarrhea and enteritisb Abdominal pain includes abdominal pain and abdominal pain upperc Fatigue includes asthenia and fatigue Rash includes dermatitis, dermatitis acneiform, palmar-plantar erythrodysaesthesia syndrome, rash, rash maculo-papular, and rash pustularTable 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-01Laboratory AbnormalitiesZIIHERAAll Grades(%)Grades or 4(%)Hematology Hemoglobin decreased8814 Lymphocytes decreased448Chemistry Lactate dehydrogenase increased550 Albumin decreased530 Aspartate aminotransferase increased4710 Alanine aminotransferase increased468 Alkaline phosphatase increased415 Sodium decreased3510 Potassium decreased345The denominator used to calculate the rate varied from 78 to 80 based on the number of patients with baseline value and at least one post-treatment value.. Hemoglobin decreased. Lymphocytes decreased. Lactate dehydrogenase increased. Albumin decreased. Aspartate aminotransferase increased. Alanine aminotransferase increased. Alkaline phosphatase increased. Sodium decreased. Potassium decreased.

BOXED WARNING SECTION.

WARNING: EMBRYO-FETAL TOXICITY. Embryo-Fetal Toxicity: Exposure to ZIIHERA during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)].. WARNING: EMBRYO-FETAL TOXICITYSee full prescribing information for complete boxed warning.oExposure to ZIIHERA during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception. (5.1). oExposure to ZIIHERA during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception. (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been conducted to evaluate the carcinogenic or mutagenic potential of zanidatamab-hrii.Fertility studies with zanidatamab-hrii have not been conducted.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Zanidatamab-hrii is bispecific HER2-directed antibody that binds to two extracellular sites on HER2. Binding of zanidatamab-hrii with HER2 results in internalization leading to reduction of the receptor on the tumor cell surface. Zanidatamab-hrii induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumor growth inhibition and cell death in vitro and in vivo.. 12.2 Pharmacodynamics Zanidatamab-hrii exposure-response relationships and the time course of the pharmacodynamic response are unknown.Cardiac ElectrophysiologyA mean increase in the QTc interval 20 ms was not observed at the recommended approved dosage.. 12.3 Pharmacokinetics Zanidatamab-hrii PK parameters are presented as means (percent coefficient of variation) following administration of ZIIHERA 20 mg/kg every weeks after the 7th or later dose unless otherwise indicated.Zanidatamab-hrii maximum concentration (Cmax) is 600 (22.2) ug/mL, the lowest measured concentration (Ctrough) is 178 (29.6) ug/mL, and total systemic exposure (AUC0-336h) is 3,976 (22.5) daysug/mL following administration of ZIIHERA. The Cmax of zanidatamab-hrii is dose proportional and the total systemic exposure (AUC0-inf) of zanidatamab-hrii is greater than dose proportional with increasing doses. The mean Ctrough accumulation ratio of zanidatamab-hrii is approximately 2.4.DistributionThe volume of distribution of zanidatamab-hrii is approximately 7.5 (33) based on the population pharmacokinetic analysis.EliminationThe estimated half-life (t1/2) 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.MetabolismZanidatamab-hrii is expected to be metabolized into small peptides by catabolic pathways.Specific PopulationsNo 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 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 <= ULN and any AST) or severe (total bilirubin 3 ULN and any AST) hepatic impairment on the pharmacokinetics of zanidatamab-hrii is unknown.. 12.6 Immunogenicity There is insufficient information to characterize the anti-drug antibody response to zanidatamab-hrii and the effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of zanidatamab-hrii.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES HER2-positive (IHC 3+) Biliary Tract Cancer (BTC)The efficacy of ZIIHERA was evaluated in 62 patients with HER2-positive (IHC 3+ by central assessment) BTC in Cohort of HERIZON-BTC-01 (NCT04466891), an open-label, multicenter, single arm trial in patients with unresectable or metastatic disease. Patients were required to have received at least one prior gemcitabine-containing systemic chemotherapy regimen in the advanced disease setting and adequate cardiac function (defined as LVEF >= 50%).Patients received ZIIHERA 20 mg/kg intravenously every weeks. ZIIHERA was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) as determined by an independent central review (ICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.The median age was 64 years (range: 38 to 79 years), 47% of patients were age 65 or older; 55% were female; 61% were Asian, 31% were White, 2% were American Indian or Alaskan Native and for 6% race was unknown or not reported; 89% were Non-Hispanic or Latino, 8% Hispanic/Latino, and for 3% ethnicity was unknown or not reported. All patients had baseline Eastern Cooperative Oncology Group (ECOG) performance status of (32%) or (68%). Fifty-three percent of patients had gallbladder cancer, 27% had intrahepatic cholangiocarcinoma, and 19% had extrahepatic cholangiocarcinoma. All patients received at least prior line of gemcitabine-based therapy, 31% had prior lines of therapy, and 10% had or more prior lines of therapy for unresectable or metastatic disease.Efficacy results are summarized in Table 5.Table Efficacy Results in HERIZON-BTC-01Efficacy ParameterZIIHERA(N=62)Objective Response Rate (95% CI)52% (39, 65) Complete response, (%)2 (3.2) Partial response, (%)30 (48)Duration of Response (DOR)N=32 Median+, months (95% CI)14.9 (7.4, NE) DOR >= months, (%) (19 59) DOR >= 12 months, (%) 14 (44)Assessed by independent central review+ Based on Kaplan-Meier estimate Based on observed duration of responseNE not estimable. Complete response, (%). Partial response, (%). Median+, months (95% CI). DOR >= months, (%) DOR >= 12 months, (%).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS None.. oNone. (4). oNone. (4).

DESCRIPTION SECTION.

11 DESCRIPTION Zanidatamab-hrii is humanized, IgG-like, bispecific HER2-directed antibody. Zanidatamab-hrii is produced in Chinese hamster ovary cells via recombinant DNA technology and has molecular weight of 124.8 kDa.ZIIHERA (zanidatamab-hrii) for injection is supplied as sterile, preservative free, white lyophilized powder that requires reconstitution and dilution for intravenous use. Each single-dose vial of reconstituted product contains 300 mg of zanidatamab-hrii and the inactive ingredients: polysorbate 20 (0.63 mg), sodium succinate (4.3 mg), succinic acid (4.3 mg), and sucrose (567 mg). Following reconstitution with 5.7 mL Sterile Water for Injection, solution containing 50 mg/mL zanidatamab-hrii is produced with deliverable volume of mL, with pH of 4.6. The resulting solution is diluted and administered by intravenous infusion.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oPremedicate patients with acetaminophen, an antihistamine and corticosteroid, 30-60 minutes prior to each administration of ZIIHERA infusion to prevent potential infusion-related reactions (IRRs). (2.2)oThe recommended dosage of ZIIHERA is 20 mg/kg given as an intravenous infusion once every weeks. (2.3). oPremedicate patients with acetaminophen, an antihistamine and corticosteroid, 30-60 minutes prior to each administration of ZIIHERA infusion to prevent potential infusion-related reactions (IRRs). (2.2). oThe recommended dosage of ZIIHERA is 20 mg/kg given as an intravenous infusion once every 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)]:oAdminister acetaminophen, an antihistamine (such as diphenhydramine) and corticosteroid (such as hydrocortisone).. oAdminister acetaminophen, an antihistamine (such as diphenhydramine) and corticosteroid (such as hydrocortisone).. 2.3 Recommended Dosage Recommended Dosage and AdministrationThe recommended dosage of ZIIHERA is 20 mg/kg, administered as an intravenous infusion once every weeks until disease progression or unacceptable toxicity. Missed doseIf 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 2-week interval between doses.. 2.4 Dosage Modifications for Adverse Reactions oThe recommended dosage reduction of ZIIHERA for adverse reactions is 15 mg/kg as described in Table 1.oPermanently discontinue ZIIHERA in patients who cannot tolerate 15 mg/kg.Table Dosage Modifications for Adverse ReactionsAdverse ReactionSeverityTreatment ModificationLeft Ventricular Dysfunction (LVD)[see Warnings and Precautions (5.2)]Absolute decrease of >= 16% points in LVEF from pre-treatment baselineorLVEF <= 50% and absolute decrease of >= 10% points below pre-treatment baselineoWithhold ZIIHERA for at least weeks.oRepeat LVEF assessment within weeks.oResume ZIIHERA treatment within to weeks if LVEF returns to normal limits and the absolute decrease is <= 15% points from baseline.oPermanently discontinue ZIIHERA if LVEF has not recovered to within 15% points from pre-treatment baseline.Confirmed symptomatic congestive heart failureoPermanently discontinue ZIIHERA.Infusion-Related Reactions[see Warnings and Precautions (5.3)]Mild (Grade 1)oReduce ZIIHERA infusion rate by 50%.oFor subsequent ZIIHERA infusions increase infusion rate gradually to the rate prior to the adverse reaction, as tolerated.Moderate (Grade 2)oStop ZIIHERA infusion immediately.oTreat with appropriate therapy.oResume ZIIHERA infusion at 50% of previous infusion rate once symptoms resolve.oFor subsequent ZIIHERA infusions increase infusion rate gradually to the rate prior to the adverse reaction, as tolerated. Severe (Grade 3)oStop ZIIHERA infusion immediately.oPromptly treat with appropriate therapy; infusion should not be restarted during the same cycle even if signs and symptoms completely resolve.oSubsequent ZIIHERA infusions should be administered at 50% of previous infusion rate.oPermanently discontinue ZIIHERA for recurrent Grade reaction.Life threatening (Grade 4)oStop ZIIHERA infusion immediately and permanently discontinue.oPromptly treat with appropriate therapy.Diarrhea[see Warnings and Precautions (5.4)]Mild/Moderate (Grade or 2)oNo dose modification of ZIIHERA is required.oInitiate appropriate medical therapy and monitor as clinically indicated.Severe (Grade 3)oWithhold ZIIHERA treatment until severity improves to <= Grade 1.oInitiate or intensify appropriate medical therapy and monitor as clinically indicated.oAdminister subsequent ZIIHERA treatment at the same dose level or consider dose reduction to 15 mg/kg.oFor recurrent Grade symptoms, withhold ZIIHERA treatment and ensure medical management has been optimized.oResume ZIIHERA treatment at reduced dose of 15 mg/kg after severity improves to <= Grade 1.oPermanently discontinue ZIIHERA for recurrent Grade symptoms that last 3 days despite optimized medical management. Life threatening (Grade 4)oPermanently discontinue ZIIHERAPneumonitis[see Adverse Reactions (6.1)]Confirmed Grade >= 2oPermanently discontinue ZIIHERA.Other Adverse Reactions (excluding LVD, IRR, Diarrhea, and Pneumonitis)[see Adverse Reactions (6.1)]Mild/Moderate (Grades 1/2)oNo dosage modification is required for ZIIHERA.oInitiate appropriate medical therapy and monitor as clinically indicated.Severe (Grade 3)oWithhold ZIIHERA treatment until severity improves to <= Grade 1.oInitiate appropriate medical therapy and monitor as clinically indicated.oAdminister subsequent ZIIHERA treatment at the same dose; consider dose reduction to 15 mg/kg if Grade symptoms recur.Life Threatening (Grade 4)oPermanently discontinue ZIIHERA, except as noted below.oInitiate appropriate medical therapy and monitor as clinically indicated.oZIIHERA treatment may be resumed at the same dose level for Grade electrolyte imbalances or laboratory abnormalities that are corrected within days of onset; do not resume until symptoms improve to <= Grade 1.oPermanently discontinue ZIIHERA for recurrent Grade electrolyte imbalances or laboratory abnormalities.. oThe recommended dosage reduction of ZIIHERA for adverse reactions is 15 mg/kg as described in Table 1.. oPermanently discontinue ZIIHERA in patients who cannot tolerate 15 mg/kg.. oWithhold ZIIHERA for at least weeks.. oRepeat LVEF assessment within weeks.. oResume ZIIHERA treatment within to weeks if LVEF returns to normal limits and the absolute decrease is <= 15% points from baseline.. oPermanently discontinue ZIIHERA if LVEF has not recovered to within 15% points from pre-treatment baseline.. oPermanently discontinue ZIIHERA.. oReduce ZIIHERA infusion rate by 50%.. oFor subsequent ZIIHERA infusions increase infusion rate gradually to the rate prior to the adverse reaction, as tolerated.. oStop ZIIHERA infusion immediately.. oTreat with appropriate therapy.. oResume ZIIHERA infusion at 50% of previous infusion rate once symptoms resolve.. oFor subsequent ZIIHERA infusions increase infusion rate gradually to the rate prior to the adverse reaction, as tolerated. oStop ZIIHERA infusion immediately.. oPromptly treat with appropriate therapy; infusion should not be restarted during the same cycle even if signs and symptoms completely resolve.. oSubsequent ZIIHERA infusions should be administered at 50% of previous infusion rate.. oPermanently discontinue ZIIHERA for recurrent Grade reaction.. oStop ZIIHERA infusion immediately and permanently discontinue.. oPromptly treat with appropriate therapy.. oNo dose modification of ZIIHERA is required.. oInitiate appropriate medical therapy and monitor as clinically indicated.. oWithhold ZIIHERA treatment until severity improves to <= Grade 1.. oInitiate or intensify appropriate medical therapy and monitor as clinically indicated.. oAdminister subsequent ZIIHERA treatment at the same dose level or consider dose reduction to 15 mg/kg.. oFor recurrent Grade symptoms, withhold ZIIHERA treatment and ensure medical management has been optimized.oResume ZIIHERA treatment at reduced dose of 15 mg/kg after severity improves to <= Grade 1.oPermanently discontinue ZIIHERA for recurrent Grade symptoms that last 3 days despite optimized medical management. oResume ZIIHERA treatment at reduced dose of 15 mg/kg after severity improves to <= Grade 1.. oPermanently discontinue ZIIHERA for recurrent Grade symptoms that last 3 days despite optimized medical management.. oPermanently discontinue ZIIHERA. oPermanently discontinue ZIIHERA.. oNo dosage modification is required for ZIIHERA.. oInitiate appropriate medical therapy and monitor as clinically indicated.. oWithhold ZIIHERA treatment until severity improves to <= Grade 1.. oInitiate appropriate medical therapy and monitor as clinically indicated.. oAdminister subsequent ZIIHERA treatment at the same dose; consider dose reduction to 15 mg/kg if Grade symptoms recur.. oPermanently discontinue ZIIHERA, except as noted below.. oInitiate appropriate medical therapy and monitor as clinically indicated.. oZIIHERA treatment may be resumed at the same dose level for Grade electrolyte imbalances or laboratory abnormalities that are corrected within days of onset; do not resume until symptoms improve to <= Grade 1.. oPermanently discontinue ZIIHERA for recurrent Grade electrolyte imbalances or laboratory abnormalities.. 2.5 Preparation and Administration Instructions Administer only as an intravenous infusion after ZIIHERA is reconstituted and diluted.ReconstitutionoCalculate the recommended dose based on the patients weight to determine the number of vials needed.oRemove the vial(s) from the refrigerator and allow the vial(s) to reach room temperature.oReconstitute 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 final concentration of 50 mg/mL in an extractable volume of mL.oSwirl the vial gently until completely dissolved. Do not shake or vigorously swirl.oAllow the reconstituted vial to settle to allow bubbles to dissipate.oParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted product should be 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.oThe product does not contain preservative. Use the reconstituted ZIIHERA solution immediately or store the reconstituted ZIIHERA solution for up to hours, either at room temperature (18C to 24C [64F to 75F]) or in refrigerator (2C to 8oC [36F to 46oF]).DilutionoWithdraw the necessary volume for the calculated dose from each vial [see Dosage and Administration (2.3)].oSlowly 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 final concentration of the diluted solution between 0.4 mg/mL and mg/mL.oGently invert the infusion bag to mix. Do not shake.oThe infusion solution must be clear, colorless solution with no visible particles. Do not use if visible particles are observed or if the solution is discolored.oDiscard any unused portion left in the vial(s).oUse the infusion solution immediately upon dilution or store the infusion solution at room temperature (18C to 24C [64F to 75F]) for up to 12 hours or in the refrigerator (2oC to 8oC [36oF to 46oF]) for up to 24 hours.oThese time limits include the beginning of reconstitution through the duration of infusion.oIf these specified times are exceeded, discontinue the current infusion bag and prepare new bag which contains the remaining dosage of ZIIHERA to be infused. oCompatibility with intravenous administration materials and the infusion solution has been demonstrated in the following materials: oIntravenous (IV) Bag: Polyvinyl chloride (PVC), polyolefin (PO), ethyl vinyl acetate (EVA), polypropylene (PP) and ethylene-propylene copolymer.oInfusion sets: Polyvinyl chloride/ bis (2-ethylhexyl) phthalate (PVC/DEHP). Polyurethane (PUR), polyethylene-lined (PE-lined) acrylonitrile-butadiene-styrene (ABS).oInline filters: Polyethersulfone solution filter (PES), polyvinylidene fluoride air filter (PVDF).oClosed System Transfer devices: acrylonitrile-butadiene-styrene (ABS), acrylic c-polymer, polycarbonate (PC), polyisoprene (PI), polyester, polypropylene (PP) polytetrafluoroethylene (PTFE), silicone and stainless steel (SS).AdministrationoAdminister ZIIHERA as an intravenous infusion with 0.2 or 0.22 micron filter.oDo not administer as an intravenous push or bolus.oDo not co-administer ZIIHERA and other intravenous drugs through the same intravenous line.Table 2: Recommended ZIIHERA Infusion DurationsDoseInfusion DurationFirst and Second120-150 minutesThird and Fourth90 minutes, if previous infusions were well-toleratedSubsequent60 minutes, if previous infusions were well-tolerated. oCalculate the recommended dose based on the patients weight to determine the number of vials needed.. oRemove the vial(s) from the refrigerator and allow the vial(s) to reach room temperature.. oReconstitute 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 final concentration of 50 mg/mL in an extractable volume of mL.. oSwirl the vial gently until completely dissolved. Do not shake or vigorously swirl.. oAllow the reconstituted vial to settle to allow bubbles to dissipate.. oParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted product should be 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.. oThe product does not contain preservative. Use the reconstituted ZIIHERA solution immediately or store the reconstituted ZIIHERA solution for up to hours, either at room temperature (18C to 24C [64F to 75F]) or in refrigerator (2C to 8oC [36F to 46oF]).. oWithdraw the necessary volume for the calculated dose from each vial [see Dosage and Administration (2.3)].. oSlowly 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 final concentration of the diluted solution between 0.4 mg/mL and mg/mL.. oGently invert the infusion bag to mix. Do not shake.. oThe infusion solution must be clear, colorless solution with no visible particles. Do not use if visible particles are observed or if the solution is discolored.. oDiscard any unused portion left in the vial(s).. oUse the infusion solution immediately upon dilution or store the infusion solution at room temperature (18C to 24C [64F to 75F]) for up to 12 hours or in the refrigerator (2oC to 8oC [36oF to 46oF]) for up to 24 hours.oThese time limits include the beginning of reconstitution through the duration of infusion.oIf these specified times are exceeded, discontinue the current infusion bag and prepare new bag which contains the remaining dosage of ZIIHERA to be infused. oThese time limits include the beginning of reconstitution through the duration of infusion.. oIf these specified times are exceeded, discontinue the current infusion bag and prepare new bag which contains the remaining dosage of ZIIHERA to be infused.. oCompatibility with intravenous administration materials and the infusion solution has been demonstrated in the following materials: oIntravenous (IV) Bag: Polyvinyl chloride (PVC), polyolefin (PO), ethyl vinyl acetate (EVA), polypropylene (PP) and ethylene-propylene copolymer.oInfusion sets: Polyvinyl chloride/ bis (2-ethylhexyl) phthalate (PVC/DEHP). Polyurethane (PUR), polyethylene-lined (PE-lined) acrylonitrile-butadiene-styrene (ABS).oInline filters: Polyethersulfone solution filter (PES), polyvinylidene fluoride air filter (PVDF).oClosed System Transfer devices: acrylonitrile-butadiene-styrene (ABS), acrylic c-polymer, polycarbonate (PC), polyisoprene (PI), polyester, polypropylene (PP) polytetrafluoroethylene (PTFE), silicone and stainless steel (SS).. oIntravenous (IV) Bag: Polyvinyl chloride (PVC), polyolefin (PO), ethyl vinyl acetate (EVA), polypropylene (PP) and ethylene-propylene copolymer.. oInfusion sets: Polyvinyl chloride/ bis (2-ethylhexyl) phthalate (PVC/DEHP). Polyurethane (PUR), polyethylene-lined (PE-lined) acrylonitrile-butadiene-styrene (ABS).. oInline filters: Polyethersulfone solution filter (PES), polyvinylidene fluoride air filter (PVDF).. oClosed System Transfer devices: acrylonitrile-butadiene-styrene (ABS), acrylic c-polymer, polycarbonate (PC), polyisoprene (PI), polyester, polypropylene (PP) polytetrafluoroethylene (PTFE), silicone and stainless steel (SS).. oAdminister ZIIHERA as an intravenous infusion with 0.2 or 0.22 micron filter.. oDo not administer as an intravenous push or bolus.. oDo not co-administer ZIIHERA and other intravenous drugs through the same intravenous line.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS For injection: 300 mg white lyophilized powder in single-dose vial.. For injection: 300 mg lyophilized powder in single-dose vial. (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential ZIIHERA can cause fetal harm when administered to pregnant woman [see Warnings and Precautions 5.1), Use in Specific Populations (8.1)].Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to the initiation of ZIIHERA [see Use in Specific Populations (8.1)].ContraceptionFemalesZIIHERA can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with ZIIHERA and for months following the last dose of ZIIHERA.

GERIATRIC USE SECTION.

8.5 Geriatric Use Of the 80 patients who received ZIIHERA for unresectable or metastatic biliary tract cancer in HERIZON-BTC-01, there were 39 (49%) patients 65 years of age and older. Thirty-seven (46%) were aged 65-74 years old and (3%) were aged 75 years or older [see Clinical Studies (14)].No overall differences in safety or effectiveness were observed between these patients and younger adult patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING ZIIHERA is supplied as sterile, preservative free, white lyophilized powder in single-dose vial. Each single-dose vial (NDC 68727-950-01) contains 300 mg zanidatamab-hrii. Each carton of ZIIHERA (NDC 68727-950-02) contains single-dose vials.Store in refrigerator at 2oC to 8oC (36oF to 46oF) in the original carton until time of reconstitution. Do not freeze.

INDICATIONS & USAGE SECTION.

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 confirmatory trial(s).. ZIIHERA is 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 confirmatory trial(s). (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).Embryo-Fetal ToxicityAdvise female patients of the potential risk to fetus. Advise female patients to contact their healthcare provider with known or suspected pregnancy [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during treatment with ZIIHERA and for months following the last dose [see Warnings and Precautions (5.1), Use in Specific Populations (8.3)]. Left Ventricular DysfunctionAdvise patients that ZIIHERA can cause cardiac dysfunction and to contact healthcare provider immediately for signs and symptoms of cardiac dysfunction [see Warnings and Precautions (5.2)].Infusion-Related ReactionsAdvise patients of the risk of infusion-related reactions and to inform healthcare provider immediately for symptoms of an infusion-related reaction [see Warnings and Precautions (5.3)].DiarrheaAdvise patients that ZIIHERA can cause diarrhea, which may be severe. Instruct patients how to manage diarrhea, and to contact their healthcare provider for sustained diarrhea that does not respond to supportive care [see Dosage and Administration (2.4), Warnings and Precautions (5.4)].Distributed by:Jazz Pharmaceuticals, Inc.Palo Alto, CA 94306Manufactured by:Jazz Pharmaceuticals Ireland LimitedFifth Floor, Waterloo ExchangeWaterloo Road, Dublin 4Dublin, IrelandD04 E5W7U.S. License No. 2167.

LACTATION SECTION.

8.2 Lactation Risk SummaryThere are no data on the presence of zanidatamab-hrii in human milk, the effects on the breastfed child, or the effects on milk production. Published data suggest human IgG is present in human milk but does not enter neonatal or infant circulation in substantial amounts. Consider developmental and health benefits of breastfeeding along with the mothers clinical need for ZIIHERA treatment and any potential adverse effects on the breastfed child from ZIIHERA or from the underlying maternal condition. This consideration should also take into account the ZIIHERA half-life of approximately 21 days and washout period of months [see Clinical Pharmacology (12.3)].

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Zanidatamab-hrii is bispecific HER2-directed antibody that binds to two extracellular sites on HER2. Binding of zanidatamab-hrii with HER2 results in internalization leading to reduction of the receptor on the tumor cell surface. Zanidatamab-hrii induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumor growth inhibition and cell death in vitro and in vivo.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been conducted to evaluate the carcinogenic or mutagenic potential of zanidatamab-hrii.Fertility studies with zanidatamab-hrii have not been conducted.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel. ZIIHERA Vial Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Safety and efficacy of ZIIHERA have not been established in pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Zanidatamab-hrii exposure-response relationships and the time course of the pharmacodynamic response are unknown.Cardiac ElectrophysiologyA mean increase in the QTc interval 20 ms was not observed at the recommended approved dosage.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Zanidatamab-hrii PK parameters are presented as means (percent coefficient of variation) following administration of ZIIHERA 20 mg/kg every weeks after the 7th or later dose unless otherwise indicated.Zanidatamab-hrii maximum concentration (Cmax) is 600 (22.2) ug/mL, the lowest measured concentration (Ctrough) is 178 (29.6) ug/mL, and total systemic exposure (AUC0-336h) is 3,976 (22.5) daysug/mL following administration of ZIIHERA. The Cmax of zanidatamab-hrii is dose proportional and the total systemic exposure (AUC0-inf) of zanidatamab-hrii is greater than dose proportional with increasing doses. The mean Ctrough accumulation ratio of zanidatamab-hrii is approximately 2.4.DistributionThe volume of distribution of zanidatamab-hrii is approximately 7.5 (33) based on the population pharmacokinetic analysis.EliminationThe estimated half-life (t1/2) 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.MetabolismZanidatamab-hrii is expected to be metabolized into small peptides by catabolic pathways.Specific PopulationsNo 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 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 <= ULN and any AST) or severe (total bilirubin 3 ULN and any AST) hepatic impairment on the pharmacokinetics of zanidatamab-hrii is unknown.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryBased on mechanism of action, ZIIHERA can cause fetal harm when administered to pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. In literature reports, use of 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.Clinical ConsiderationsFetal/Neonatal Adverse ReactionsMonitor women who received ZIIHERA during pregnancy or within 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.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONZIIHERA (zye HAYR rah)(zanidatamab-hrii)for injection, for intravenous useWhat is the most important information should know about ZIIHERAZIIHERA can cause serious side effects, including:oharm to your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ZIIHERA.oIf you are able to become pregnant, your healthcare provider should do pregnancy test before you start treatment with ZIIHERA.oFemales who are able to become pregnant should use birth control (contraception) during treatment with ZIIHERA and for months after the last dose. See What are the possible side effects of ZIIHERA for more information about side effects.What is ZIIHERAZIIHERA is prescription medicine used to treat adults who have type of bile duct (cholangiocarcinoma) or gallbladder cancer called biliary tract cancer (BTC), that is human epidermal growth factor receptor (HER2)-positive (IHC 3+). ZIIHERA may be used when your BTC: owas previously treated;ocannot be removed by surgery or has spread to other parts of your body (metastatic).Your healthcare provider will perform test to make sure ZIIHERA is right for you.It is not known if ZIIHERA is safe and effective in children.Before receiving ZIIHERA, tell your healthcare provider about all of your medical conditions, including if you:ohave or have had any heart problemsoare breastfeeding or plan to breastfeed. It is not known if ZIIHERA passes into your breastmilk. Talk to your healthcare provider about the best way to feed your baby if you receive treatment with ZIIHERA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should receive ZIIHERAoZIIHERA is given through vein by an intravenous (IV) infusion over 120 to 150 minutes for your first and second infusions. If you tolerate the first and second infusions well, your third and fourth infusions may be given to you over 90 minutes. Each additional infusion may be given to you over 60 minutes.oZIIHERA is given every weeks.oYour healthcare provider:owill give you medicines 30 to 60 minutes before each treatment to help prevent infusion-related reactions or make them less severeomay slow down, temporarily stop, or permanently stop your treatment with ZIIHERA if you have certain side effectsomay do certain tests to check you for some side effectsowill decide how many treatments you needoIf you miss dose, call your healthcare provider as soon as possible to reschedule your appointment.What are the possible side effects of ZIIHERAZIIHERA can cause serious side effects, including:oSee What is the most important information should know about ZIIHERAoHeart problems that may affect how well your heart pumps blood. Your healthcare provider will check your heart function before and during treatment with ZIIHERA. Call your healthcare provider right away if you get any of the following signs and symptoms of heart problem:onew or worsening shortness of breathofeeling more tired than usualoswelling of your ankles or feetoloss of consciousnessoirregular heartbeatosudden weight gainodizziness or feeling light-headed oInfusion-related reactions, common side effect that can happen during treatment with ZIIHERA. Your healthcare provider will check for side effects during your infusions. Tell your healthcare provider right away if you get any of the following symptoms during or after your infusions of ZIIHERA:oshortness of breath or trouble breathingofeverochillsorashoflushingonausea or vomitingodizziness or feeling lightheadedochest discomfort oDiarrhea, common side effect during treatment with ZIIHERA that may be severe. Your healthcare provider may prescribe an antidiarrheal medicine or other treatment, as needed.Other common side effects of ZIIHERA include stomach pain and feeling tired.Tell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all of the possible side effects of ZIIHERA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of ZIIHERA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about ZIIHERA that is written for health professionals.What are the ingredients in ZIIHERAActive ingredient: zanidatamab-hrii Inactive ingredients: polysorbate 20, sodium succinate, succinic acid, and sucrose Distributed by:Jazz Pharmaceuticals, Inc.Palo Alto, CA 94306 Manufactured by:Jazz Pharmaceuticals Ireland LimitedFifth Floor, Waterloo ExchangeWaterloo Road, Dublin 4Dublin, IrelandD04 E5W7 U.S. License No. 2167 For more information, go to www.ZIIHERA.com or call 1-800-520-5568.This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 7/2025. oharm to your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ZIIHERA.oIf you are able to become pregnant, your healthcare provider should do pregnancy test before you start treatment with ZIIHERA.oFemales who are able to become pregnant should use birth control (contraception) during treatment with ZIIHERA and for months after the last dose. oIf you are able to become pregnant, your healthcare provider should do pregnancy test before you start treatment with ZIIHERA.. oFemales who are able to become pregnant should use birth control (contraception) during treatment with ZIIHERA and for months after the last dose.. owas previously treated;ocannot be removed by surgery or has spread to other parts of your body (metastatic).. owas previously treated;. ocannot be removed by surgery or has spread to other parts of your body (metastatic).. ohave or have had any heart problems. oare breastfeeding or plan to breastfeed. It is not known if ZIIHERA passes into your breastmilk. Talk to your healthcare provider about the best way to feed your baby if you receive treatment with ZIIHERA.. oZIIHERA is given through vein by an intravenous (IV) infusion over 120 to 150 minutes for your first and second infusions. If you tolerate the first and second infusions well, your third and fourth infusions may be given to you over 90 minutes. Each additional infusion may be given to you over 60 minutes.. oZIIHERA is given every weeks.. oYour healthcare provider:owill give you medicines 30 to 60 minutes before each treatment to help prevent infusion-related reactions or make them less severeomay slow down, temporarily stop, or permanently stop your treatment with ZIIHERA if you have certain side effectsomay do certain tests to check you for some side effectsowill decide how many treatments you need. owill give you medicines 30 to 60 minutes before each treatment to help prevent infusion-related reactions or make them less severe. omay slow down, temporarily stop, or permanently stop your treatment with ZIIHERA if you have certain side effects. omay do certain tests to check you for some side effects. owill decide how many treatments you need. oIf you miss dose, call your healthcare provider as soon as possible to reschedule your appointment.. oSee What is the most important information should know about ZIIHERA. oHeart problems that may affect how well your heart pumps blood. Your healthcare provider will check your heart function before and during treatment with ZIIHERA. Call your healthcare provider right away if you get any of the following signs and symptoms of heart problem:onew or worsening shortness of breathofeeling more tired than usualoswelling of your ankles or feetoloss of consciousnessoirregular heartbeatosudden weight gainodizziness or feeling light-headed onew or worsening shortness of breath. ofeeling more tired than usual. oswelling of your ankles or feet. oloss of consciousness. oirregular heartbeat. osudden weight gain. odizziness or feeling light-headed. oInfusion-related reactions, common side effect that can happen during treatment with ZIIHERA. Your healthcare provider will check for side effects during your infusions. Tell your healthcare provider right away if you get any of the following symptoms during or after your infusions of ZIIHERA:oshortness of breath or trouble breathingofeverochillsorashoflushingonausea or vomitingodizziness or feeling lightheadedochest discomfort oshortness of breath or trouble breathing. ofever. ochills. orash. oflushing. onausea or vomiting. odizziness or feeling lightheaded. ochest discomfort. oDiarrhea, common side effect during treatment with ZIIHERA that may be severe. Your healthcare provider may prescribe an antidiarrheal medicine or other treatment, as needed.

SPL UNCLASSIFIED SECTION.

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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oFemales and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of ZIIHERA. (8.3). oFemales and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of ZIIHERA. (8.3). 8.1 Pregnancy Risk SummaryBased on mechanism of action, ZIIHERA can cause fetal harm when administered to pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. In literature reports, use of 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.Clinical ConsiderationsFetal/Neonatal Adverse ReactionsMonitor women who received ZIIHERA during pregnancy or within 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.. 8.2 Lactation Risk SummaryThere are no data on the presence of zanidatamab-hrii in human milk, the effects on the breastfed child, or the effects on milk production. Published data suggest human IgG is present in human milk but does not enter neonatal or infant circulation in substantial amounts. Consider developmental and health benefits of breastfeeding along with the mothers clinical need for ZIIHERA treatment and any potential adverse effects on the breastfed child from ZIIHERA or from the underlying maternal condition. This consideration should also take into account the ZIIHERA half-life of approximately 21 days and washout period of months [see Clinical Pharmacology (12.3)].. 8.3 Females and Males of Reproductive Potential ZIIHERA can cause fetal harm when administered to pregnant woman [see Warnings and Precautions 5.1), Use in Specific Populations (8.1)].Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to the initiation of ZIIHERA [see Use in Specific Populations (8.1)].ContraceptionFemalesZIIHERA can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with ZIIHERA and for months following the last dose of ZIIHERA.. 8.4 Pediatric Use Safety and efficacy of ZIIHERA have not been established in pediatric patients.. 8.5 Geriatric Use Of the 80 patients who received ZIIHERA for unresectable or metastatic biliary tract cancer in HERIZON-BTC-01, there were 39 (49%) patients 65 years of age and older. Thirty-seven (46%) were aged 65-74 years old and (3%) were aged 75 years or older [see Clinical Studies (14)].No overall differences in safety or effectiveness were observed between these patients and younger adult patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oLeft 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, 5.2)oInfusion-Related Reactions (IRRs): Premedicate before each infusion of ZIIHERA. Interrupt the infusion, decrease the infusion rate, and/or permanently discontinue ZIIHERA based on severity. (2.4, 5.3)oDiarrhea: ZIIHERA can cause severe diarrhea. Administer antidiarrheal treatment as clinically indicated. Withhold or permanently discontinue ZIIHERA based on severity. (2.4, 5.4). oLeft 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, 5.2). oInfusion-Related Reactions (IRRs): Premedicate before each infusion of ZIIHERA. Interrupt the infusion, decrease the infusion rate, and/or permanently discontinue ZIIHERA based on severity. (2.4, 5.3). oDiarrhea: ZIIHERA can cause severe diarrhea. Administer antidiarrheal treatment as clinically indicated. Withhold or permanently discontinue ZIIHERA based on severity. (2.4, 5.4). 5.1 Embryo-Fetal Toxicity Based on the mechanism of action, ZIIHERA can cause fetal harm when administered to pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. In literature reports, use of 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 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception while receiving ZIIHERA and for months following the last dose of ZIIHERA.. 5.2 Left Ventricular Dysfunction ZIIHERA can cause decreases in left ventricular ejection fraction (LVEF). LVEF declined by greater than 10% and decreased to less than 50% 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). Left ventricular dysfunction resolved in 70% of patients.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 baseline ejection fraction that is below 50% [see Dosage and Administration (2.4)].. 5.3 Infusion-Related Reactions ZIIHERA can cause infusion-related reactions (IRRs). An IRR was reported in 31% of 233 patients treated with ZIIHERA as single agent in clinical studies, including Grade (0.4%), and Grade (25%). IRRs leading to permanent discontinuation of ZIIHERA were reported in 0.4% of patients. IRRs occurred on the first day of dosing in 28% of patients; 97% of IRRs resolved within one day.Prior to each dose of ZIIHERA, administer premedications 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 infusion-related reactions [see Dosage and Administration (2.4)].. 5.4 Diarrhea ZIIHERA can cause severe diarrhea [see Adverse Reactions (6.1)].Diarrhea was reported in 48% of 233 patients treated in clinical studies, including Grade (6%) and Grade (17%). If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Withhold or permanently discontinue ZIIHERA based on severity [see Dosage and Administration (2.4)].