Ziihera Drug Information

    Generic name: ZANIDATAMAB-HRII

    Bispecific HER2-directed Antibody [EPC]

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    Uses of 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. 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). 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. 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).

    Dosage & Administration of Ziihera

    Left 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 baseline
    Confirmed symptomatic congestive heart failure
    • Permanently discontinue ZIIHERA.
    Infusion-Related Reactions[see Warnings and Precautions (5.3)]Mild (Grade 1)
    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)
    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.
      • Resume ZIIHERA treatment at a reduced dose of 15 mg/kg after severity improves to ≤ Grade 1.
      • Permanently discontinue ZIIHERA for recurrent Grade 3 symptoms that last > 3 days despite optimized medical management.
    Life threatening (Grade 4)
    • Permanently discontinue ZIIHERA
    Pneumonitis[see Adverse Reactions (6.1)]Confirmed Grade ≥ 2
    Other Adverse Reactions (excluding LVD, IRR, Diarrhea, and Pneumonitis)[see Adverse Reactions (6.1)]Mild/Moderate (Grades 1/2)
    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.

    Side Effects of Ziihera

    • 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.

    Warnings & Cautions for Ziihera

    • Left Ventricular Dysfunction: Assess left ventricular ejection fraction (LVEF) prior to initiation of ZIIHERA and at regular intervals during treatment. Withhold or permanently discontinue ZIIHERA based on severity. ( 2.4 , 5.2 )
    • Infusion-Related Reactions (IRRs): Premedicate before each infusion of ZIIHERA. Interrupt the infusion, decrease the infusion rate, and/or permanently discontinue ZIIHERA based on severity. ( 2.4 , 5.3 )
    • Diarrhea: 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 a pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Verify the pregnancy status of females of reproductive potential prior to the initiation of ZIIHERA. Advise pregnant women and females of reproductive potential that exposure to ZIIHERA during pregnancy or within 4 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception while receiving ZIIHERA and for 4 months following the last dose of ZIIHERA. 5.2 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 a 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 a single agent in clinical studies, including Grade 3 (0.4%), and Grade 2 (25%). IRRs leading to permanent discontinuation of ZIIHERA were reported in 0.4% of patients. 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 3 (6%) and Grade 2 (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 )] .

    Pregnancy Safety for Ziihera

    Pregnancy Risk Summary Based on mechanism of action, ZIIHERA can cause fetal harm when administered to a pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.

    Use of ZIIHERA is not recommended during pregnancy (see CLINICAL CONSIDERATIONS). Advise patients of potential risks to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

    In the U.S. general population, background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received ZIIHERA during pregnancy or within 4 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with local standard of care.

    Pediatric Use of Ziihera

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

    Clinical Studies of Ziihera

    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 1 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 2 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 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. All patients received at least 1 prior line of gemcitabine-based therapy, 31% had 2 prior lines of therapy, and 10% had 3 or more prior lines of therapy for unresectable or metastatic disease.

    Efficacy results are summarized in Table 5. Table 5 Efficacy Results in HERIZON-BTC-01 Efficacy Parameter* ZIIHERA (N=62) Objective Response Rate (95% CI) 52% Complete response, n (%) 2 Partial response, n (%) 30 Duration of Response (DOR) N=32 Median †, months (95% CI) 14.9 (7.4, NE) DOR ≥ 6 months, n (%) ‡ DOR ≥ 12 months, n (%) ‡ 14 * Assessed by independent central review † Based on Kaplan-Meier estimate ‡ Based on observed duration of response NE = not estimable

    Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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