Ziihera (Zanidatamab)
Bispecific HER2-targeted antibody for biliary tract cancer
Ziihera (zanidatamab) is a bispecific HER2-targeted antibody used to treat adults with HER2-positive biliary tract cancer that cannot be surgically removed or has spread. It works by binding to two different sites on the HER2 protein on cancer cells, blocking their growth and triggering the immune system to destroy them. This medicine is given as an intravenous infusion every two weeks and has received conditional marketing authorization from the European Medicines Agency (EMA).
Quick Facts: Ziihera
Key Takeaways
- Ziihera is a bispecific antibody that targets two different sites on the HER2 protein, providing enhanced cancer cell killing compared to single-target antibodies.
- It is specifically approved for HER2-positive biliary tract cancer (cholangiocarcinoma and gallbladder cancer) that has progressed after prior chemotherapy.
- Heart function must be monitored before and during treatment, as Ziihera may cause decreased left ventricular ejection fraction.
- Infusion reactions are the most commonly reported serious side effect and require monitoring during and after each infusion.
- Effective contraception is required during treatment and for 4 months after the last dose, as Ziihera may harm an unborn baby.
What Is Ziihera and What Is It Used For?
Ziihera contains the active substance zanidatamab, which belongs to a class of medicines known as bispecific antibodies. Unlike conventional monoclonal antibodies that bind to a single target, zanidatamab is engineered to simultaneously bind to two distinct regions (epitopes) on the same protein — the human epidermal growth factor receptor 2 (HER2). HER2 is a protein found on the surface of certain cancer cells, where it promotes cell growth, division, and survival.
When zanidatamab binds to both HER2 epitopes (known as extracellular domain 2 and extracellular domain 4), it causes the HER2 receptors on the cancer cell surface to cluster together in a process called receptor crosslinking. This clustering has three important effects: it blocks the signaling pathways that tell cancer cells to grow and divide, it promotes the internalization and degradation of HER2 receptors (reducing the number available on the cell surface), and it triggers the immune system to recognize and destroy the cancer cells through mechanisms known as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).
The result of this multi-pronged attack is that Ziihera can slow down or stop the growth of HER2-positive cancer cells, and in many cases, lead to their death. This dual-targeting mechanism provides a potential advantage over therapies that target only one epitope on HER2, as it addresses cancer cell growth from multiple angles simultaneously.
Approved Indication
Ziihera is specifically approved for use in adults with biliary tract cancer (BTC), which is a collective term for cancers that arise in the bile ducts, gallbladder, or ampulla of Vater. These are relatively rare but aggressive cancers with limited treatment options, particularly after first-line chemotherapy has failed. To be eligible for Ziihera treatment, patients must meet the following criteria:
- HER2-positive status: The cancer must have high levels of HER2 protein on its surface, as determined by validated diagnostic testing (immunohistochemistry and/or in situ hybridization).
- Unresectable or advanced disease: The tumor cannot be completely removed by surgery, or has spread to nearby tissues (locally advanced) or to distant parts of the body (metastatic).
- Prior chemotherapy: The patient must have previously received at least one line of chemotherapy, and the disease has either returned (recurred) or worsened (progressed) during or after that treatment.
HER2 overexpression is found in approximately 15–20% of biliary tract cancers, making HER2 testing an essential step before initiating Ziihera therapy. Your oncologist will order appropriate tests to determine whether your cancer is HER2-positive and whether Ziihera is a suitable treatment option for you.
Ziihera has been granted conditional marketing authorization by the European Medicines Agency (EMA). This means that further evidence about this medicine is expected, and the EMA reviews new information at least annually to update the product information as needed.
What Should You Know Before Receiving Ziihera?
Contraindications
You must not receive Ziihera if you are allergic (hypersensitive) to zanidatamab or any of the other ingredients in this medicine (listed in the composition section). Allergic reactions to the medicine itself are different from infusion-related reactions, which are managed differently. If you are unsure whether you have an allergy to any of the components, speak with your doctor or nurse before receiving Ziihera.
Do not receive Ziihera if you have a known hypersensitivity to zanidatamab or to any of the excipients. If you experience signs of a severe allergic reaction (such as difficulty breathing, swelling of the face or throat, severe skin rash, or a sudden drop in blood pressure), seek emergency medical attention immediately.
Warnings and Precautions
Before and during your treatment with Ziihera, it is important to inform your doctor or nurse if you experience any of the following symptoms, as they may indicate a decrease in your heart’s pumping ability (decreased left ventricular ejection fraction, or LVEF):
- Shortness of breath, either at rest or during activity
- New or worsening cough
- Unusual tiredness or fatigue
- Swelling of the ankles, feet, or legs
- Irregular or rapid heartbeat (palpitations)
- Sudden or unexplained weight gain
- Dizziness or lightheadedness
- Loss of consciousness (fainting)
Your doctor will check your heart function using an echocardiogram or a MUGA (multigated acquisition) scan before starting Ziihera treatment and will continue to monitor it at regular intervals throughout your therapy. If significant changes in heart function are detected, your doctor may temporarily pause treatment, reduce the dose, or discontinue Ziihera permanently, depending on the severity of the cardiac findings.
Cardiac monitoring is particularly important because HER2-targeted therapies as a class are associated with a known risk of cardiotoxicity. While Ziihera uses a different mechanism of action compared to some other HER2-targeted agents, the potential for cardiac effects must still be carefully managed.
Infusion-Related Reactions
Since Ziihera is administered as an intravenous infusion, reactions to the infusion can occur. These reactions can range from mild to severe and may happen during the infusion or in the hours following it. Your healthcare team will monitor you during and after each infusion, particularly during the first few treatments when the risk of infusion reactions tends to be highest.
To help prevent or reduce the severity of infusion reactions, your doctor may prescribe pre-medications including antihistamines (to reduce allergic-type reactions), corticosteroids (to reduce inflammation), and antipyretics (to prevent fever). These are typically given 30 to 60 minutes before each infusion. If a serious infusion reaction occurs, your doctor may slow down, temporarily stop, or permanently discontinue the infusion depending on the severity of the reaction.
Children and Adolescents
Ziihera is not recommended for use in children and adolescents (under 18 years of age). The safety and effectiveness of zanidatamab have not been established in this age group, and biliary tract cancer is extremely rare in pediatric populations.
Pregnancy and Breastfeeding
Before starting treatment, you must inform your doctor or nurse if you are pregnant, breastfeeding, think you may be pregnant, or are planning to have a baby. Ziihera may cause harm to an unborn child based on its mechanism of action and findings from animal studies with HER2-targeted therapies. Your doctor will discuss the risks and benefits of treatment if you are pregnant or planning to become pregnant.
If you are a woman of childbearing potential, you must use effective contraception during Ziihera treatment and for at least 4 months after your final dose. Discuss the most appropriate contraceptive method with your doctor. If you become pregnant during treatment or within 4 months of your last dose, inform your doctor immediately.
It is not known whether zanidatamab passes into breast milk. Because antibodies can be excreted in human milk and could potentially harm a nursing infant, breastfeeding should be avoided during Ziihera treatment and for 4 months after the last dose. Your doctor will weigh the benefits of breastfeeding for the child against the benefits of treatment for you.
Driving and Using Machines
Ziihera may cause fatigue, which could affect your ability to drive or operate machinery safely. If you feel tired after receiving your infusion, do not drive or use tools or machines until you feel well enough to do so. This is particularly relevant on infusion days and the day after treatment.
Ziihera contains less than 1 mmol (23 mg) of sodium per dose unit, meaning it is essentially sodium-free. This is relevant for patients on a sodium-restricted diet.
How Does Ziihera Interact with Other Drugs?
Unlike many small-molecule drugs that are metabolized by liver enzymes (particularly the cytochrome P450 system), zanidatamab is a large protein molecule (antibody) that is broken down through normal protein catabolism rather than enzymatic metabolism. This means it is less likely to interact with other medicines through the traditional pharmacokinetic pathways that affect absorption, distribution, metabolism, or excretion of drugs.
However, this does not mean that interactions are impossible. It is important to tell your doctor, nurse, or pharmacist about all medicines you are currently taking, have recently taken, or might plan to take. This includes prescription medications, over-the-counter products, herbal supplements, and vitamins. Your healthcare team needs a complete picture of your medication use to ensure safe and effective treatment.
Considerations with Other HER2-Targeted Therapies
If you have previously received other HER2-targeted therapies (such as trastuzumab, pertuzumab, or trastuzumab emtansine), your doctor will take this history into account. Prior treatment with HER2-targeted agents may affect your baseline cardiac function, which is relevant given that Ziihera also carries a risk of cardiotoxicity. There are no specific contraindications regarding sequential use, but cumulative cardiac effects should be monitored.
Considerations with Cardiotoxic Medications
Because Ziihera has the potential to cause decreased left ventricular ejection fraction, particular caution should be exercised when it is used alongside other medications known to affect heart function. These may include certain chemotherapy agents (such as anthracyclines), some antihypertensive drugs, or other cardiac-active medications. Your oncologist will consider the overall cardiac risk profile when planning your treatment regimen.
| Drug Category | Interaction Type | Clinical Recommendation |
|---|---|---|
| Anthracyclines (e.g., doxorubicin) | Additive cardiotoxicity risk | Enhanced cardiac monitoring; avoid concurrent use if possible |
| Other HER2-targeted therapies | Cumulative cardiac risk | Baseline LVEF assessment; consider washout period |
| Vaccines (live) | Potential reduced efficacy | Avoid live vaccines during treatment; inactivated vaccines acceptable |
| Antihistamines (pre-medication) | Intended co-administration | Given as pre-medication 30–60 min before infusion |
| Corticosteroids (pre-medication) | Intended co-administration | Given as pre-medication to prevent infusion reactions |
What Is the Correct Dosage of Ziihera?
Ziihera is always administered by a qualified healthcare professional in a hospital or clinical setting. You will not be expected to prepare or administer this medicine yourself. The treatment protocol involves several key aspects that are managed by your oncology team.
Adults
The dose of Ziihera is calculated based on your body weight by your treating oncologist. The medicine is given as an intravenous (IV) infusion — a drip directly into a vein — once every two weeks (every 14 days). The duration of each infusion may vary between your first dose and subsequent doses, depending on how well you tolerate the treatment.
For the first infusion, the drip is typically administered more slowly to allow your healthcare team to monitor you closely for any adverse reactions. If the first infusion is well tolerated, subsequent infusions may be given over a shorter period. Your doctor will determine the appropriate infusion rate based on your individual response.
Standard Dosing Protocol
- Route: Intravenous (IV) infusion
- Frequency: Once every 2 weeks
- Dose calculation: Based on body weight (mg/kg), determined by your oncologist
- First infusion: Administered at a slower rate with close monitoring
- Subsequent infusions: May be given over a shorter period if well tolerated
Pre-Medication
Before each infusion, your doctor or nurse may give you medicines to help prevent infusion-related reactions. These pre-medications are typically administered 30 to 60 minutes before the Ziihera infusion and may include:
- Antihistamines: To reduce allergic-type reactions (e.g., diphenhydramine or cetirizine)
- Corticosteroids: To reduce inflammation and prevent immune-mediated reactions (e.g., dexamethasone)
- Antipyretics: To prevent fever (e.g., acetaminophen/paracetamol)
Children and Adolescents
Ziihera has not been studied in children and adolescents under 18 years of age. It is not recommended for use in this population. Biliary tract cancer is extremely rare in pediatric patients, and no dosing recommendations can be made for this age group.
Duration of Treatment
The number of infusions you receive depends on how your disease responds to the treatment and how well you tolerate it. Treatment typically continues for as long as there is clinical benefit (the cancer is responding or stable) and side effects remain manageable. Your oncologist will regularly assess your response through imaging studies and clinical evaluations to determine whether treatment should continue.
Missed Dose
If you forget or miss an appointment for your Ziihera infusion, contact your doctor or nurse as soon as possible to reschedule. It is important to maintain the regular two-week dosing interval as closely as possible to ensure optimal treatment efficacy. Your healthcare team will advise you on when to schedule your next infusion if a dose is missed.
Stopping Treatment
Do not stop your Ziihera treatment without first discussing it with your doctor. Discontinuing treatment prematurely may allow the cancer to progress. If you are considering stopping treatment due to side effects or other concerns, speak with your oncology team about available management strategies or alternative options.
Ziihera should only be administered by healthcare professionals experienced in the treatment of cancer patients. Dose adjustments, interruptions, or discontinuation decisions should be made by your treating oncologist based on your individual clinical situation.
What Are the Side Effects of Ziihera?
Like all medicines, Ziihera can cause side effects, although not everyone experiences them. The type and severity of side effects can vary between patients and may depend on your overall health, the stage of your disease, and other treatments you may be receiving concurrently. It is important to report any side effects to your doctor or nurse, including those not listed here.
Serious Side Effects
Some side effects of Ziihera can be serious and require immediate medical attention. Contact your doctor or nurse right away if you notice any of the following:
Infusion-related reactions (very common): Symptoms may include nausea, fever, chills, fatigue, headache, decreased appetite, joint and muscle pain, and hot flashes. Reactions can range from mild to severe.
Decreased ejection fraction (common): Your heart may have difficulty pumping blood effectively. Symptoms include shortness of breath, cough, fatigue, swollen ankles and legs, irregular heartbeat, sudden weight gain, dizziness, or loss of consciousness.
Side Effects by Frequency
Very Common
- Infusion-related reactions (nausea, fever, chills, fatigue, headache, decreased appetite, joint and muscle pain, hot flashes)
- Diarrhea
- Abdominal pain (stomach pain)
- Nausea
- Vomiting
- Fatigue (feeling tired)
- Decreased appetite
- Skin rash
- Anemia (low red blood cells, shown in blood tests)
- Abnormal liver function (shown in blood tests)
Common
- Decreased ejection fraction (reduced heart pumping ability) — requires cardiac monitoring
Uncommon
- Pneumonitis (inflammation of the lungs) — symptoms include dry cough and shortness of breath
Managing Side Effects
Many side effects of Ziihera can be managed with supportive care. Your oncology team will provide guidance on how to handle common side effects such as diarrhea (with anti-diarrheal medications and hydration), nausea (with anti-nausea medications), and fatigue (with rest and activity management). For serious side effects, your doctor may need to adjust your dose, delay treatment, or discontinue Ziihera altogether.
Regular blood tests will be performed throughout your treatment to monitor your blood counts, liver function, and other laboratory values. These tests help your doctor detect potential problems early and take appropriate action before they become severe.
Cardiac monitoring (echocardiograms or MUGA scans) will be performed at regular intervals throughout treatment to assess your heart function. If a clinically significant decline in LVEF is detected, your doctor will determine the appropriate course of action, which may include temporary treatment interruption, dose modification, or permanent discontinuation.
Reporting suspected side effects after a medicine has been authorized is important, as it allows continued monitoring of the medicine’s benefit-risk balance. Healthcare professionals and patients are encouraged to report any suspected adverse reactions through their national reporting system.
How Should Ziihera Be Stored?
As a hospital-administered medicine, you will not need to store Ziihera at home. The healthcare staff at your treatment center are responsible for proper storage and handling. However, the following storage information is provided for reference and transparency:
- Storage temperature: Store in a refrigerator at 2°C to 8°C (36°F to 46°F).
- Do not freeze: Freezing may damage the medicine and compromise its effectiveness.
- Keep out of reach of children: Store in a secure location within the pharmacy or clinic.
- Expiry date: Do not use after the expiry date printed on the carton and vial label (marked as EXP). The expiry date refers to the last day of the stated month.
- After reconstitution: The diluted solution should be used immediately after preparation to ensure sterility and stability.
Unused medicine should not be disposed of via wastewater or household waste. Healthcare facilities follow established protocols for the safe disposal of pharmaceutical waste to protect the environment.
What Does Ziihera Contain?
Active Substance
The active substance is zanidatamab. Each vial contains 300 mg of zanidatamab as a lyophilized (freeze-dried) powder. After reconstitution with the appropriate volume of water for injections, each 6 mL vial contains zanidatamab at a concentration of 50 mg/mL.
Inactive Ingredients (Excipients)
The other ingredients in Ziihera are:
- Polysorbate 20 (E432): A surfactant that helps stabilize the protein and prevent aggregation. Each vial contains 0.63 mg of polysorbate 20 (equivalent to 0.105 mg/mL). Polysorbates can cause allergic reactions in some individuals. Inform your doctor if you have any known allergies to polysorbates.
- Disodium succinate: A buffering agent that helps maintain the pH of the solution.
- Succinic acid (E363): Another buffering agent used in combination with disodium succinate.
- Sucrose: A sugar used as a stabilizer to protect the protein during the freeze-drying process.
- Water for injections: Used for reconstitution of the powder.
Appearance and Packaging
Ziihera is a white lyophilized (freeze-dried) powder supplied in a glass vial with a stopper and snap-off cap. Each carton contains 1 or 2 vials. Not all pack sizes may be available in every market.
Frequently Asked Questions About Ziihera
Ziihera (zanidatamab) is used to treat adults with HER2-positive biliary tract cancer (cancer of the bile ducts and gallbladder). It is indicated for patients whose cancer cannot be surgically removed (unresectable), has spread locally or to other parts of the body (locally advanced or metastatic), and has returned or worsened after prior chemotherapy treatment. HER2-positive means the cancer cells have high levels of a protein called HER2 on their surface.
Ziihera is administered as an intravenous (IV) infusion — a drip directly into a vein — once every two weeks by trained healthcare professionals in a hospital or clinic setting. The dose is calculated based on your body weight. Before each infusion, you may receive pre-medications (antihistamines, corticosteroids, and fever-reducing medicines) 30–60 minutes beforehand to help prevent infusion reactions.
The most frequently reported side effects include infusion-related reactions (nausea, fever, chills, fatigue, headache), diarrhea, abdominal pain, nausea, vomiting, fatigue, decreased appetite, skin rash, anemia, and abnormal liver function tests. A significant but less common side effect is decreased heart function (reduced ejection fraction), which is why cardiac monitoring is required throughout treatment.
No, pregnancy should be avoided during Ziihera treatment. Ziihera may harm an unborn baby. Women of childbearing potential must use effective contraception during treatment and for at least 4 months after the last dose. If you become pregnant during treatment, inform your doctor immediately. Breastfeeding should also be avoided during treatment and for 4 months after the last dose.
Ziihera is unique because it is a bispecific antibody that binds to two different sites (epitopes) on the HER2 protein simultaneously. This dual binding causes enhanced receptor clustering, more complete signal blockade, and stronger immune-mediated killing of cancer cells compared to therapies targeting only one HER2 epitope. It is specifically approved for biliary tract cancer, an indication where few HER2-targeted options previously existed.
HER2-targeted therapies, including Ziihera, can affect the heart’s ability to pump blood effectively (a condition called decreased left ventricular ejection fraction, or decreased LVEF). Your doctor will perform heart function tests (such as echocardiograms or MUGA scans) before starting treatment and at regular intervals during treatment to ensure your heart is functioning well. If significant changes are detected, your treatment may be paused, adjusted, or discontinued.
References
This article is based on the following international, peer-reviewed sources and regulatory documents:
- European Medicines Agency (EMA). Ziihera (zanidatamab) — Summary of Product Characteristics. EMA/CHMP, 2025. Available at: www.ema.europa.eu
- European Medicines Agency (EMA). Ziihera — European Public Assessment Report (EPAR). EMA, 2025.
- Meric-Bernstam F, et al. Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing biliary tract cancers (HERIZON-BTC-01): a phase 2b study. Lancet Oncology. 2024;25(8):1039–1049.
- Harding JJ, et al. Treating HER2-amplified biliary tract cancer: seeing the forest for the trees. Nature Reviews Clinical Oncology. 2024;21:386–398.
- Javle M, et al. Biliary cancer: utility of next-generation sequencing for clinical management. Cancer. 2023;129(15):2281–2290.
- World Health Organization (WHO). WHO Model List of Essential Medicines — 23rd List. WHO, 2023.
- European Society for Medical Oncology (ESMO). Biliary tract cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2023;34(2):127–140.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines: Biliary Tract Cancers. Version 2.2024.
Editorial Team
This article has been written and reviewed by the iMedic Medical Editorial Team, comprising board-certified specialists in oncology, clinical pharmacology, and internal medicine.
Written by specialist physicians with expertise in oncology and targeted cancer therapies, following international medical guidelines (EMA, FDA, ESMO, NCCN).
Independently reviewed by the iMedic Medical Review Board to ensure clinical accuracy, completeness, and adherence to evidence-based standards (GRADE framework).
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