Zanidatamab-hrii (Ziihera)

Number: 1075

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses zanidatamab-hrii (Ziihera) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of zanidatamab-hrii (Ziihera) is required of all Aetna participating providers and members in applicable plan designs. For precertification of zanidatamab-hrii (Ziihera), call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification. 

  1. Criteria for Initial Approval

    Biliary Tract Cancer

    Aetna considers zanidatamab-hrii (Ziihera) medically necessary for subsequent treatment of unresectable or resected gross residual (R2) disease or metastatic HER2-positive (IHC 3+) biliary tract cancer (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer) when used as a single agent.

    Aetna considers all other indications as experimental, investigational, or unproven.

  2. Continuation of Therapy

    Aetna considers continuation of zanidatamab-hrii (Ziihera) therapy medically necessary in members requesting reauthorization for an indication listed in section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Zanidatamab-hrii is supplied as Ziihera 300 mg lyophilized powder in a single-dose vial for injection for intravenous use.

  • Premedicate persons with acetaminophen, an antihistamine and a corticosteroid, 30-60 minutes prior to each administration of Ziihera infusion to prevent potential infusion-related reactions (IRRs).
  • The recommended dosage of Ziihera is 20 mg/kg given as an intravenous infusion once every 2 weeks.

Source: Jazz Pharmaceuticals, 2025

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Other CPT codes related to the CPB:
96413 Chemotherapy administration, IV infusion technique; up to 1 hour, single or initial substance/drug
96415      each additional hour (list in addition to code for primary procedure)

HCPCS codes covered if selection criteria are met:
J9276 Injection, zanidatamab-hrii, 2 mg

Other HCPCS codes related to the CPB:
J0131 Injection, acetaminophen, not otherwise specified,10 mg
J0134 Injection, acetaminophen (fresenius kabi), not therapeutically equivalent to j0131, 10 mg
J0136 Injection, acetaminophen (b braun), not therapeutically equivalent to j0131, 10 mg
J0137 Injection, acetaminophen (hikma), not therapeutically equivalent to j0131, 10 mg
J0138 Injection, acetaminophen 10 mg and ibuprofen 3 mg
J1201 Injection, cetirizine hydrochloride, 0.5 mg
J1200 Injection, diphenhydramine hcl, up to 50 mg
J2550 Injection, promethazine hcl, up to 50 mg
J3410 Injection, hydroxyzine hcl, up to 25 mg
J0702 Injection, betamethasone acetate 3mg and betamethasone sodium phosphate 3mg
J1020 Injection, methylprednisolone acetate, 20 mg
J1030 Injection, methylprednisolone acetate, 40 mg
J1040 Injection, methylprednisolone acetate, 80 mg
J1094 Injection, dexamethasone acetate, 1 mg
J1100 Injection, dexamethasone sodium phosphate, 1mg
J1700 Injection, hydrocortisone acetate, up to 25 mg
J1710 Injection, hydrocortisone sodium phosphate, up to 50 mg
J1720 Injection, hydrocortisone sodium succinate, up to 100 mg
J2357 Injection, omalizumab, 5 mg
J2650 Injection, prednisolone acetate, up to 1 ml
J2786 Injection, reslizumab, 1 mg
J2920 Injection, methylprednisolone sodium succinate, up to 40 mg
J2930 Injection, methylprednisolone sodium succinate, up to 125 mg
J7509 Methylprednisolone oral, per 4 mg
J7510 Prednisolone oral, per 5 mg
J7512 Prednisone, immediate release or delayed release, oral, 1 mg
J8540 Dexamethasone, oral, 0.25 mg

ICD-10 codes covered if selection criteria are met:
C22.1 Intrahepatic bile duct carcinoma [unresectable or resected gross residual (R2) disease or metastatic HER2-positive (IHC 3+)]
C23 Malignant neoplasm of gallbladder [unresectable or resected gross residual (R2) disease or metastatic HER2-positive (IHC 3+)]
C24.0 Malignant neoplasm of extrahepatic bile duct [unresectable or resected gross residual (R2) disease or metastatic HER2-positive (IHC 3+)]
C24.8 Malignant neoplasm of overlapping sites of biliary tract [unresectable or resected gross residual (R2) disease or metastatic HER2-positive (IHC 3+)]
C24.9 Malignant neoplasm of biliary tract, unspecified [unresectable or resected gross residual (R2) disease or metastatic HER2-positive (IHC 3+)]

Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

  • HER2-positive Biliary Tract Cancer

    Ziihera is indicated for the treatment of adults with previously treated, unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive immunohistochemistry (IHC 3+) biliary tract cancer (BTC), as detected by an FDA-approved test.

Compendial Uses 

  • HER2-positive biliary tract cancer

Zanidatamab-hrii is available as Ziihera (Jazz Pharmaceuticals, Inc.), a humanized, IgG-like, bispecific HER2-directed antibody. Ziihera is produced in Chinese hamster ovary cells by recombinant DNA technolgy. The drug binds to two extracellular sites on HER2 which results in internalization causing a reduction of the receptor on the tumor cell surface. Ziihera stimulates complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) which all result in tumor growth inhibition and cell death in vitro and in vivo (Jazz Pharmaceuticals, 2025).

The prescribing information notes that Ziihera carries the following boxed warning:

  • Exposure to Ziihera during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception.

Additionally, Ziihera carrries the following warnings and precautions and adverse reactions:

  • Warnings and precautions

    • Left ventricular dysfunction: Assess left ventricular ejection fraction (LVEF) prior to initiation of Ziihera and at regular intevals during treatment. Withhold or permanently discontinue Ziihera based on severity.
    • Infusion-related reactions (IRRs): Premedicate before each infusion of Ziihera. Interrupt the infusion, decrease the infusion rate, and/or permanently discontinue Ziihera based on severity.
    • Diarrhea: Ziihera can cause severe diarrhea. Administer antidiarrheal treatment as clinically indicated. Withhold or permanently discontinue Ziihera based on severity.

  • Adverse reactions: Most common adverse reactions (≥ 20%) are diarrhea, infusion-related reaction, abdominal pain, and fatigue.

On November 20, 2024, the U.S. Food and Drug Administration (FDA) granted accelerated approval to zanidatamab-hrii (Ziihera), a bispecific HER2-directed antibody, for previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC), as detected by an FDA-approved test. The FDA approval was based on supporting data from the HERIZON-BTC-01 study (FDA, 2024).

In the HERIZON-BTC-01 study, an open-label, multicenter, single arm trial, investigators evaluated the efficacy of Ziihera in 62 patients with unresectable or metastatic HER2-positive (IHC 3+ by central assessment) BTC in Cohort 1. Patients were to have received at least one prior gemcitabine-containing systemic chemotherapy regimen in the advanced disease setting and have adequate cardiac function (defined as left ventricular ejection fraction [LVEF] ≥ 50%). The median age was 64 years (range: 38 to 79 years), 47% of patients were age 65 or older. All patients had a baseline Eastern Cooperative
Oncology Group (ECOG) performance status of 0 (32%) or 1 (68%). Fifty-three percent of patients had gallbladder cancer, 27% had intrahepatic cholangiocarcinoma, and 19% had extrahepatic cholangiocarcinoma (FDA, 2024; Jazz Pharmaceuticals, 2025).

Patients received Ziihera 20 mg/kg intravenously every 2 weeks 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 ORR was 52% (95% confidence interval [CI]: 39, 65) and median DOR was 14.9 months (95% CI: 7.4, not estimable) (FDA, 2024; Jazz Pharmaceuticals, 2025).

References

The above policy is based on the following references:

  1. Jazz Pharmaceuticals, Inc. Ziihera (zanidatamab-hrii) for injection, for intravenous use. Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals; revised July 2025.
  2. National Comprehensive Cancer Network (NCCN). Zanidatamab-hrii. NCCN Drugs & Biologics Compendium. Plymouth Meeting, PA: NCCN; July 2025.
  3. U.S. Food and Drug Administration (FDA). FDA grants accelerated approval to zanidatamab-hrii for previously treated unresectable or metastatic HER2-positive biliary tract cancer. Drugs. Silver Spring, MD: FDA; November 21, 2024.