Zanidatamab-hrii, a humanized, immunoglobulin G (IgG)-like, bispecific anti-human epidermal growth factor receptor 2 (anti- HER2 ) antibody, is an antineoplastic agent.1
Zanidatamab-hrii is used for the treatment of adult patients with previously treated, unresectable or metastatic HER2 -positive (immunohistochemistry [IHC] 3+) biliary tract cancer (BTC), as detected by an FDA-approved test.1 Information on FDA-approved tests for HER2 protein expression in biliary tract cancers is available at: [Web].1
The accelerated approval of zanidatamab-hrii for this indication is based on overall response rate and duration of response.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1
Zanidatamab-hrii has been designated an orphan drug by FDA for use in the treatment of biliary tract cancer.2
The safety and efficacy of zanidatamab-hrii for the treatment of unresectable or metastatic HER2 -positive (IHC 3+) BTC were principally established in a phase 2b, open-label, multicenter, single-arm trial (HERIZON-BTC-01).1, 2, 8 Adults with pathologically confirmed, unresectable, locally advanced or metastatic, HER2 -amplified ( HER2 to chromosome 17 ratio of ≥2.0) gallbladder cancer, intrahepatic cholangiocarcinoma, or extrahepatic cholangiocarcinoma were included if they were also previously treated with ≥1 gemcitabine-containing systemic chemotherapy regimen in the advanced disease setting, and had ≥1 measurable target lesion per Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1), adequate cardiac function (left ventricular ejection fraction [LVEF] ≥50%), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.1, 3 HER2 -amplification and IHC were confirmed via central laboratory testing.3 Patients were excluded if they were previously treated with anti- HER2 therapy, or if they had symptomatic CNS metastases or leptomeningeal disease.1, 3 Zanidatamab-hrii was administered as a 20 mg/kg IV infusion every 2 weeks (Days 1 and 15) in 28-day cycles until disease progression or unacceptable toxicity.1, 3 Tumors were assessed by CT scan or MRI at baseline and approximately every 8 weeks during the trial.3 The primary efficacy endpoint was objective response rate (ORR), defined as the proportion of patients who received zanidatamab-hrii and had a confirmed best overall response of complete response or partial response, as assessed by independent central review (ICR) per RECIST 1.1.1, 3 Duration of response (DOR), as assessed by ICR per RECIST 1.1, was a key secondary outcome.1, 3
A total of 87 patients with unresectable, locally advanced or metastatic, HER2 -amplified BTC were enrolled to receive zanidatamab-hrii.1, 3, 8 Efficacy was evaluated in a modified intention-to-treat population, including 62 patients from Cohort 1 with IHC 3+ disease.1, 3, 8 The median age of patients was 64 years (38-79 years); the majority were female (55%) and Asian (61%).1, 8 The majority of patients had gallbladder cancer (53%), while 27% had intrahepatic cholangiocarcinoma and 19% had extrahepatic cholangiocarcinoma.1, 8 All patients received ≥1 prior line of gemcitabine-based therapy; 31% received 2 prior lines of therapy, and 10% received ≥3 prior lines of therapy.1 Approximately 26% received prior anti-programmed death (PD) receptor (ligand [L])-1 treatment.1, 8
The ORR, as assessed by ICR, was 52% (32/62 patients).1, 8 Complete response was achieved in 2 patients (3.2%), and a partial response was achieved in 30 patients (48%).1, 8 The median DOR was 14.9 months; 14 patients (44%) had sustained responses at ≥12 months.1, 8
Biliary tract cancer is a collective term encompassing gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma.26 Biliary tract cancers account for <1% of adult cancers; they are often identified in advanced stages and associated with a poor prognosis.26 In appropriate patients, the preferred, and potentially curative, treatment option is complete resection of the tumor.26 Recommendations for the treatment of advanced and metastatic disease are available from international experts.26, 27 For advanced or metastatic biliary tract cancer, cisplatin-gemcitabine combined with either durvalumab or pembrolizumab is recommended as first-line therapy.27 For second and later-line therapy, zanidatamab is recommended in patients with previously treated HER2-positive disease.27
Dispensing and Administration Precautions
Administer zanidatamab-hrii via IV infusion in a dedicated line with a low protein-binding 0.2-micron in-line filter.1 Do not administer via rapid IV bolus injection.1
Zanidatamab-hrii is available as a 300-mg single-dose vial of preservative-free lyophilized powder that must be reconstituted and diluted prior to IV infusion.1
Do not administer in the same IV line with other medications.1
Store vials of zanidatamab-hrii refrigerated at 2-8°C in original carton.1 Do not freeze.1
Zanidatamab-hrii is compatible with 0.9% sodium chloride injection and 5% dextrose injection.1
Determine the number of zanidatamab-hrii vials needed to obtain the appropriate dose according to the patient's body weight.1 Remove the vials from the refrigerator and allow them to reach room temperature prior to reconstitution.1
Reconstitute each 300 mg vial with 5.7 mL of sterile water for injection.1 The concentration of each reconstituted vial should be 50 mg/mL in an extractable volume of 6 mL.1 Swirl the vial gently until completely dissolved; do not shake or vigorously swirl.1 Allow the reconstituted vial to settle to allow bubbles to dissipate.1
Inspect the reconstituted solution for particulate matter and discoloration.1 The reconstituted product should be a colorless to light yellow, clear to slightly opalescent solution with no visible particles.1 Discard if any particulate matter or discoloration is observed.1
The reconstituted solution should be used immediately, or stored at room temperature (18-24°C) or in the refrigerator (2-8°C) for ≤4 hours.1
Following reconstitution, withdraw the necessary volume for the calculated dose from each vial.1 Slowly add the necessary zanidatamab-hrii dose volume to a polyvinyl chloride (PVC), polyolefin (PO), ethyl vinyl acetate (EVA), polypropylene (PP) or ethylene-propylene copolymer infusion bag containing 0.9% sodium chloride injection or 5% dextrose injection.1 The final concentration of the diluted solution should be between 0.4-6 mg/mL.1 Discard any unused reconstituted solution remaining in vials.1
Gently invert the infusion bag to mix.1 Do not shake.1
The infusion solution must be a clear, colorless solution with no visible particles.1 Do not use if the solution is discolored or particles are observed.1
Store the prepared zanidatamab-hrii solution at room temperature (18-24°C) for ≤12 hours or in the refrigerator (2-8°C) for ≤24 hours, including time from reconstitution to completion of IV infusion.1 If these specified times are exceeded, discontinue the current zanidatamab-hrii infusion bag and prepare a new bag that contains the remaining dosage to be infused.1
Administer the first 2 doses via IV infusion over 120-150 minutes.1 Administer doses 3 and 4 over 90 minutes, if previous infusions were well-tolerated.1 Administer subsequent doses (dose 5 and thereafter) over 60 minutes, if previous infusions were well-tolerated.1
Temporary interruption or infusion rate reduction may be necessary for patients who experience infusion-related reactions.1
For the treatment of previously treated, unresectable or metastatic HER2 -positive (IHC 3+) biliary tract cancer, the recommended adult dosage of zanidatamab-hrii is 20 mg/kg every 2 weeks (Days 1 and 15) in 28-day cycles.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
If a dose of zanidatamab-hrii is delayed or missed, administer the dose as soon as possible; do not wait until the next planned dose.1 Adjust the administration schedule to maintain a 2-week interval between doses.1
Dosage Modification for Toxicity
If adverse events occur during zanidatamab-hrii therapy, temporary interruption of therapy, dosage reduction, and/or discontinuance of the drug may be necessary.1 In general, if dosage reduction is necessary, the recommended dosage is 15 mg/kg.1 If a dosage of 15 mg/kg is not tolerated, zanidatamab-hrii should be permanently discontinued.1
If left ventricular dysfunction (absolute decrease of ≥16% points in LVEF from pre-treatment baseline, or LVEF ≤50% and absolute decrease of ≥10% points below pre-treatment baseline) occurs, withhold zanidatamab-hrii for ≥4 weeks.1 Repeat LVEF assessment within 4 weeks.1 If LVEF returns to normal limits within 4-8 weeks and the absolute decrease is ≤15% points from pre-treatment baseline, resume zanidatamab-hrii treatment.1 If LVEF has not recovered to within 15% points from pre-treatment baseline, permanently discontinue zanidatamab-hrii.1
If confirmed symptomatic congestive heart failure occurs, permanently discontinue zanidatamab-hrii.1
Infusion-Related Reactions (IRRs)
If Grade 1 (mild) IRR occurs, reduce the infusion rate by 50%.1 For subsequent zanidatamab-hrii infusions, increase infusion rate gradually to the rate prior to the adverse reaction, as tolerated.1
If Grade 2 (moderate) IRR occurs, stop the zanidatamab-hrii infusion immediately.1 Treat with appropriate therapy.1 Once symptoms resolve, resume the infusion at 50% of previous infusion rate.1 For subsequent infusions, increase the infusion rate gradually to the rate prior to the adverse reaction, as tolerated.1
If Grade 3 (severe) IRR occurs, stop the zanidatamab-hrii infusion immediately.1 Promptly treat with appropriate therapy.1 Infusion should not be restarted during the same cycle, even if signs and symptoms completely resolve.1 For subsequent infusions, administer zanidatamab-hrii at 50% of the previous infusion rate.1 For recurrent Grade 3 IRR, permanently discontinue zanidatamab-hrii.1
If Grade 4 (life-threatening) IRR occurs, stop the zanidatamab-hrii infusion immediately.1 Promptly treat with appropriate therapy.1 Permanently discontinue zanidatamab-hrii.1
If Grade 1 or 2 (mild-moderate) diarrhea occurs, no dosage modification of zanidatamab-hrii is required.1 Initiate appropriate medical therapy and monitor as clinically indicated.1
If Grade 3 (severe) diarrhea occurs, withhold zanidatamab-hrii until severity improves to Grade ≤1.1 Initiate or intensify appropriate medical therapy and monitor as clinically indicated.1 For subsequent doses, zanidatamab-hrii may be resumed at the same dosage or dosage reduction to 15 mg/kg may be considered.1 For recurrent Grade 3 diarrhea, withhold zanidatamab-hrii and ensure medical management has been optimized.1 If severity improves to Grade ≤1, resume zanidatamab-hrii at a reduced dosage of 15 mg/kg.1 If Grade 3 symptoms last >3 days despite optimized medical management, permanently discontinue zanidatamab-hrii.1
If Grade 4 (life-threatening) diarrhea occurs, permanently discontinue zanidatamab-hrii.1
If confirmed Grade ≥2 pneumonitis occurs, permanently discontinue zanidatamab-hrii.1
Electrolyte Imbalances or Laboratory Abnormalities
If Grade 4 (life-threatening) electrolyte imbalances or laboratory abnormalities occur, if corrected within 3 days of onset, zanidatamab-hrii may be resumed at the same dosage once symptoms improve to Grade ≤1.1 For recurrent Grade 4 electrolyte imbalances or laboratory abnormalities, permanently discontinue zanidatamab-hrii.1
If Grade 1-2 (mild-moderate) adverse reactions occur, no dosage modification is required for zanidatamab-hrii.1 Initiate appropriate medical therapy and monitor as clinically indicated.1
If Grade 3 (severe) adverse reactions occur, withhold zanidatamab-hrii treatment until severity improves to Grade ≤1.1 Initiate appropriate medical therapy and monitor as clinically indicated.1 Administer subsequent zanidatamab-hrii doses at the same dose.1 For recurrent Grade 3 symptoms, consider dosage reduction to 15 mg/kg.1
For Grade 4 (life-threatening) adverse reactions, permanently discontinue zanidatamab-hrii.1 Initiate appropriate medical therapy and monitor as clinically indicated.1
The manufacturer makes no specific recommendations for patients with hepatic impairment.1
The manufacturer makes no specific recommendations for patients with renal impairment.1
The manufacturer makes no specific recommendations for geriatric patients.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action, zanidatamab-hrii can cause fetal harm when administered to a pregnant woman.1 A boxed warning about this risk is included in the prescribing information for zanidatamab-hrii.1 There are no human or animal data available to inform the risk of embryo-fetal toxicity; however, oligohydramnios, fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported in women receiving an anti- HER2 antibody during pregnancy in postmarketing experience.1
Verify the pregnancy status of females of reproductive potential prior to the initiation of zanidatamab-hrii.1 Advise pregnant women and females of reproductive potential that exposure to zanidatamab-hrii during pregnancy or within 4 months prior to conception can result in fetal harm.1 Advise females of reproductive potential to use effective contraception while receiving zanidatamab-hrii and for 4 months following the last dose of zanidatamab-hrii.1
If used during pregnancy or within 4 months prior to conception, monitor for oligohydramnios.1 If oligohydramnios occurs, perform fetal testing appropriate for gestational age and according to standard of care.1
Other Warnings and Precautions
Zanidatamab-hrii can cause decreases in left ventricular ejection fraction (LVEF).1 In a pooled safety analysis, LVEF declined by >10% and decreased to <50% in 4.3% of 233 patients.1 Left ventricular dysfunction (LVD) leading to permanent discontinuation of zanidatamab-hrii was reported in 0.9% of patients.1 The median time to first occurrence of LVD was 5.6 months; LVD resolved in 70% of patients.1
Assess LVEF prior to initiation of zanidatamab-hrii and at regular intervals during treatment.1 Withhold dose or permanently discontinue zanidatamab-hrii based on severity.1
The safety of zanidatamab-hrii has not been established in patients with a baseline ejection fraction <50%.1
Zanidatamab-hrii can cause infusion-related reactions (IRRs).1 In a pooled safety analysis, IRRs were reported in 31% of 233 patients treated with zanidatamab-hrii as a single agent, including Grade 3 (0.4%) and Grade 2 (25%).1 IRRs leading to permanent discontinuation of zanidatamab-hrii were reported in 0.4% of patients.1 IRRs occurred on the first day of dosing in 28% of patients; 97% of IRRs resolved within 1 day.1
Prior to each dose of zanidatamab-hrii, administer premedications to prevent potential IRRs.1 Monitor patients for signs and symptoms of IRR during administration and as clinically indicated after completion of infusion.1 Medications and emergency equipment to treat IRRs should be available for immediate use.1
If an IRR occurs, slow or stop the infusion, and administer appropriate medical management.1 Monitor patients until complete resolution of signs and symptoms before resuming therapy.1 Permanently discontinue zanidatamab-hrii in patients with recurrent severe or life-threatening IRRs.1
Zanidatamab-hrii can cause severe diarrhea.1 In a pooled safety analysis, diarrhea was reported in 48% of 233 patients treated with zanidatamab-hrii, including Grade 3 (6%) and Grade 2 (17%).1
If diarrhea occurs, administer antidiarrheal treatment, and perform diagnostic tests to exclude other causes of diarrhea as clinically indicated.1 Withhold or permanently discontinue zanidatamab-hrii based on severity.1
There are no human or animal data on zanidatamab-hrii use in pregnant women.1 However, based on its mechanism of action, zanidatamab-hrii can cause fetal harm when administered to a pregnant woman.1 Oligohydramnios, fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported in women receiving an anti- HER2 antibody during pregnancy in postmarketing experience.1
Verify the pregnancy status of females of reproductive potential prior to the initiation of zanidatamab-hrii.1 Advise pregnant women and females of reproductive potential that exposure to zanidatamab-hrii during pregnancy or within 4 months prior to conception can result in fetal harm.1 Advise females of reproductive potential to use effective contraception while receiving zanidatamab-hrii and for 4 months following the last dose of zanidatamab-hrii.1
In women who received zanidatamab during pregnancy or within 4 months prior to conception, monitor for oligohydramnios.1 If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with local standard of care.1
It is not known whether zanidatamab-hrii is distributed into human milk.1 Effects of the drug on breastfed infants or milk production are also not known.1 However, published data suggest that human IgG is present in human milk but does not enter neonatal or infant circulation in substantial amounts.1 Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for zanidatamab-hrii treatment and any potential adverse effects on the breastfed child from zanidatamab-hrii or the underlying maternal condition.1 The half-life of zanidatamab-hrii of approximately 21 days, and the washout period of 4 months should also be taken into consideration.1
Females and Males of Reproductive Potential
Based on its mechanism of action, zanidatamab-hrii can cause embryo-fetal harm when administered to a pregnant woman.1
Verify pregnancy status prior to initiating treatment with zanidatamab-hrii.1
Females of reproductive potential should use effective contraception during treatment with zanidatamab-hrii for 4 months after the last dose.1
Safety and efficacy of zanidatamab-hrii have not been established in pediatric patients <18 years of age.1
In clinical studies, 49% of 80 patients were ≥65 years of a 3% were ≥75 years of age.1 No overall differences in safety or efficacy were observed between geriatric patients (≥65 years of age) and younger adults (<65 years of age).1
Mild hepatic impairment (total bilirubin ≤ the upper limit of normal [ULN] and AST > ULN, or total bilirubin between 1-1.5 times ULN and any AST) does not have a clinically important effect on the pharmacokinetics of zanidatamab-hrii; however, the effects of moderate (total bilirubin 1.5 to ≤3) or severe (total bilirubin >3 ULN and any AST) hepatic impairment have not been studied.1
Mild-moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-89 mL/minute estimated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) does not have a clinically important effect on the pharmacokinetics of zanidatamab-hrii; however, the effects of severe renal impairment (eGFR 15-29 mL/minute) or end-stage renal disease (eGFR <15 mL/minute) with or without hemodialysis have not been studied.1
The most common adverse reactions (incidence ≥20%) reported with zanidatamab-hrii in clinical studies were diarrhea, infusion-related reaction, abdominal pain, and fatigue.1
Zanidatamab-hrii, a humanized, IgG-like, bispecific, anti- HER2 antibody, is an antineoplastic agent.1 Zanidatamab-hrii is produced by recombinant DNA technology in a mammalian cell (Chinese hamster ovary) culture.1 Zanidatamab-hrii binds to 2 extracellular sites on HER2 (the dimerisation domain and the extracellular juxtamembrane domain), resulting in the formation of receptor-antibody clusters, receptor internalization, and subsequent downregulation of the HER2 receptor on the tumor cell surface.1 Zanidatamab-hrii induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), resulting in tumor growth inhibition and cell death in vitro and in vivo.1
Peak plasma concentrations of zanidatamab-hrii are dose proportional, and the total systemic exposure is greater than dose proportional with increasing doses.1 Zanidatamab-hrii is expected to be metabolized into small peptides by catabolic pathways.1 The mean plasma half-life of zanidatamab-hrii is approximately 21 days.1 Age (24-88 years), sex, race (White and Asian), mild and moderate renal impairment (eGFR 30-89 mL/minute estimated using the CKD-EPI), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin between 1-1.5 times the ULN and any AST) or body weight (35-128 kg) do not have clinically important effects on the pharmacokinetics of zanidatamab-hrii.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Zanidatamab-hrii is obtained through specialty pharmacy distributors.9 Contact manufacturer or consult the zanidatamab-hrii website ([Web]) for specific availability information.9
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion | 300 mg | Ziihera® | Jazz Pharmaceuticals |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions May 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Jazz Pharmaceuticals, Inc. ZIIHERA® (zanidatamab-hrii) injection prescribing information. Palo Alto, CA; 2025 Jul.
2. Food and Drug Administration. Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2026 Jan 7.
3. Harding JJ, Fan J, Oh DY, et al. Zanidatamab for HER2 -amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol. 2023;24(7):772-782. doi:10.1016/S1470-2045(23)00242-5.
5. Merck Sharp & Dohme LLC. KEYTRUDA® (pembrolizumab) injection prescribing information. Rahway, NJ; 2025 Nov.
6. AstraZeneca Pharmaceuticals. IMFINZI™ (durvalumab) injection prescribing information. Wilmington, DE; 2025 Nov.
7. Daiichi Sankyo, Inc. ENHERTU (fam-trastuzumab deruxtecan-nxki) injection prescribing information. Basking Ridge, NJ; 2025 Dec.
8. US Food and Drug Administration. Center for Drug Evaluation and Research. Application 761416Orig1s000. Multi-discipline review. date. From FDA website.
9. Access and Support with JazzCares. Accessed 25 January 2026. http://www.ziiherahcp.com/access-and-support.
26. Vogel A, Bridgewater J, Edeline J et al., on behalf of the ESMO Guidelines Committee. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(2):127-140.
27. Vogel A, Ducreux M on behalf of the ESMO Guidelines Committee. Electronic address: [email protected]. ESMO Clinical Practice Guideline interim update on the management of biliary tract cancer. ESMO Open. 2025;10(1):104003.