Zanidatamab-hrii (Monograph)

Brand name: Ziihera
Drug class: Antineoplastic Agents

Warning

WARNING: EMBRYO-‘FETAL TOXICITY

See full prescribing information for complete boxed warning.

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

Introduction

Zanidatamab-hrii, a bispecific HER2-directed antibody, is an antineoplastic agent.

Uses for Zanidatamab-hrii

Zanidatamab-hrii has the following uses:

Zanidatamab-hrii 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).

Zanidatamab-hrii Dosage and Administration

General

Zanidatamab-hrii is available in the following dosage form(s) and strength(s):

For injection: 300 mg lyophilized powder in a single-dose vial for reconstitution and dilution.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

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.
Premedicate patients with acetaminophen, an antihistamine, and a corticosteroid 30-60 minutes prior to each administration of zanidatamab-hrii infusion to prevent potential infusion-related reactions (IRRs).
Administer as an IV infusion after reconstitution and dilution.
The recommended dosage of zanidatamab-hrii is 20 mg/kg given as an IV infusion once every 2 weeks until disease progression or unacceptable toxicity.
See Full Prescribing Information for additional information on preparation, administration, and dosage modifications for adverse reactions.

Cautions for Zanidatamab-hrii

Contraindications

None.

Warnings/Precautions

Embryo-fetal Toxicity

Based on the mechanism of action, zanidatamab-hrii can cause fetal harm when administered to a pregnant woman. There are no human or animal data on the use of zanidatamab-hrii 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 zanidatamab-hrii. 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. Advise females of reproductive potential to use effective contraception while receiving zanidatamab-hrii and for 4 months following the last dose of the drug.

Left Ventricular Dysfunction

Zanidatamab-hrii 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. Left ventricular dysfunction leading to permanent discontinuation of zanidatamab-hrii 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 zanidatamab-hrii and at regular intervals during treatment. Withhold dose or permanently discontinue zanidatamab-hrii based on severity of adverse reactions.

The safety of zanidatamab-hrii has not been established in patients with a baseline ejection fraction below 50%.

Infusion-related Reactions

Zanidatamab-hrii can cause infusion-related reactions (IRRs). An IRR was reported in 31% of 233 patients treated with zanidatamab-hrii as a single agent in clinical studies, including Grade 3 (0.4%), and Grade 2 (25%). IRRs leading to permanent discontinuation of zanidatamab-hrii 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 zanidatamab-hrii, administer premedications to prevent potential IRRs. Monitor patients for signs and symptoms of IRR during zanidatamab-hrii administration and as clinically indicated after completion of infusion. Medications and emergency equipment to treat IRRs should be 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 zanidatamab-hrii in patients with recurrent severe or life-threatening infusion-related reactions.

Diarrhea

Zanidatamab-hrii can cause severe diarrhea.

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 zanidatamab-hrii based on severity.

Specific Populations

Pregnancy

Based on mechanism of action, zanidatamab-hrii can cause fetal harm when administered to a pregnant woman. There are no human or animal data on the use of zanidatamab-hrii 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 zanidatamab-hrii is not recommended during pregnancy. 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.

Monitor women who received zanidatamab-hrii 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.

Lactation

There 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 mother’s clinical need for zanidatamab-hrii treatment and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. This consideration should also take into account the zanidatamab-hrii half-life of approximately 21 days and a washout period of 4 months.

Females and Males of Reproductive Potential

Zanidatamab-hrii can cause fetal harm when administered to a pregnant woman.

Verify the pregnancy status of females of reproductive potential prior to the initiation of zanidatamab-hrii.

Zanidatamab-hrii can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with zanidatamab-hrii and for 4 months following the last dose of the drug.

Pediatric Use

Safety and efficacy of zanidatamab-hrii have not been established in pediatric patients.

Geriatric Use

Of the 80 patients who received zanidatamab-hrii for unresectable or metastatic biliary tract cancer in the HERIZON-BTC-01 study, there were 39 (49%) patients 65 years of age and older. Thirty-seven (46%) were 65-74 years of age and 2 (3%) were 75 years of age or older.

No overall differences in safety or effectiveness were observed between these patients and younger adult patients.

Common Adverse Effects

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

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Zanidatamab-hrii is a bispecific HER2-directed antibody that binds to two extracellular sites on HER2. Binding of zanidatamab-hrii with HER2 results in internalization leading to a 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.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Patient Information).
Advise female patients of the potential risk to a fetus. Advise female patients to contact their healthcare provider with a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with zanidatamab-hrii and for 4 months following the last dose.
Advise patients that zanidatamab-hrii can cause cardiac dysfunction and to contact a healthcare provider immediately for signs and symptoms of cardiac dysfunction.
Advise patients of the risk of infusion-related reactions and to inform a healthcare provider immediately for symptoms of an infusion-related reaction.
Advise patients that zanidatamab-hrii 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.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

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.