Table 4: Laboratory Abnormalities (≥ 30%) that Worsened from Baseline in Patients with Unresectable or Metastatic HER2-Positive BTC Receiving ZIIHERA 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
*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.
*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.
|useInPregnancyFDA=====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.
|administration=*Patient Selection
|administration=*Patient Selection
**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 .
**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 .
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Overview
Zanidatamab-hrii is a bispecific HER2-directed antibody that is FDA approved for the treatment of ZIIHERA is a bispecific HER2-directed antibody that is FDA approved 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.. Common adverse reactions include *diarrhea,
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).
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zanidatamab-hrii in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zanidatamab-hrii in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Zanidatamab-hrii FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zanidatamab-hrii in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zanidatamab-hrii in pediatric patients.
Contraindications
None.
Warnings
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.
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 .
The safety of ZIIHERA has not been established in patients with a baseline ejection fraction that is below 50%.
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 . 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 .
Diarrhea
ZIIHERA 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 ZIIHERA based on severity.
Adverse Reactions
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.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.
summarizes the laboratory abnormalities in HERIZON BTC 01
Table 3: Adverse Reactions (≥ 15%) in Patients with Unresectable or Metastatic HER2-Positive BTC Receiving ZIIHERA in HERIZON-BTC-01
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.
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
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.
Postmarketing Experience
There is limited information regarding Zanidatamab-hrii Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Zanidatamab-hrii Drug Interactions in the drug label.
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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zanidatamab-hrii in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Zanidatamab-hrii during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Zanidatamab-hrii in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Zanidatamab-hrii in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Zanidatamab-hrii in geriatric settings.
Gender
There is no FDA guidance on the use of Zanidatamab-hrii with respect to specific gender populations.
Race
There is no FDA guidance on the use of Zanidatamab-hrii with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Zanidatamab-hrii in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Zanidatamab-hrii in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Zanidatamab-hrii in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Zanidatamab-hrii in patients who are immunocompromised.
Administration and Monitoring
Administration
Patient Selection
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 .
Information on FDA-approved tests for HER2 protein expression in biliary tract cancers is available.
Premedications.
Premedicate all patients 30 to 60 minutes prior to each dose of ZIIHERA to reduce the risk of infusion-related reactions.
**Administer acetaminophen, an antihistamine (such as diphenhydramine) and a corticosteroid (such as hydrocortisone).
Recommended Dosage
Recommended Dosage and Administration
The recommended dosage of ZIIHERA is 20 mg/kg, administered as an intravenous infusion once every 2 weeks until disease progression or unacceptable toxicity.
Missed dose
If a planned dose of ZIIHERA is delayed or missed, administer the dose as soon as possible; do not wait until the next planned dose. Adjust the administration schedule to maintain a 2-week interval between doses.
Dosage Modifications for Adverse Reactions
The recommended dosage reduction of ZIIHERA for adverse reactions is 15 mg/kg as described in TABLE 1.
Permanently discontinue ZIIHERA in patients who cannot tolerate 15 mg/kg.
Preparation and Administration Instructions.Administer only as an intravenous infusion after ZIIHERA is reconstituted and diluted.
Reconstitution
Calculate the recommended dose based on the patient’s weight to determine the number of vials needed.
Remove the vial(s) from the refrigerator and allow the vial(s) to reach room temperature.
Reconstitute each 300 mg vial of ZIIHERA with 5.7 mL of Sterile Water for Injection by slowly directing the stream toward the inside of the wall of the vial, to obtain a final concentration of 50 mg/mL in an extractable volume of 6 mL.
Swirl the vial gently until completely dissolved. Do not shake or vigorously swirl.
Allow the reconstituted vial to settle to allow bubbles to dissipate.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted product should be a colorless to light yellow, clear to slightly opalescent solution with no visible particles. Discard the reconstituted vial if any discoloration or particulate matter is observed.
The product does not contain a preservative. Use the reconstituted ZIIHERA solution immediately or store the reconstituted ZIIHERA solution for up to 4 hours, either at room temperature (18°C to 24°C [64°F to 75°F]) or in a refrigerator (2°C to 8ºC [36°F to 46ºF]).
Dilution.
Withdraw the necessary volume for the calculated dose from each vial [see Dosage and Administration.
Slowly add the necessary dose volume to an infusion bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection to prepare an infusion solution with a final concentration of the diluted solution between 0.4 mg/mL and 6 mg/mL.
Gently invert the infusion bag to mix. Do not shake.
The infusion solution must be a clear, colorless solution with no visible particles. Do not use if visible particles are observed or if the solution is discolored.
Discard any unused portion left in the vial(s).
Use the infusion solution immediately upon dilution or store the infusion solution at room temperature (18°C to 24°C [64°F to 75°F]) for up to 12 hours or in the refrigerator (2ºC to 8ºC [36ºF to 46ºF]) for up to 24 hours.
These time limits include the beginning of reconstitution through the duration of infusion.
If these specified times are exceeded, discontinue the current infusion bag and prepare a new bag which contains the remaining dosage of ZIIHERA to be infused.
Compatibility with intravenous administration materials and the infusion solution has been demonstrated in the following materials:
Closed System Transfer devices: acrylonitrile-butadiene-styrene (ABS), acrylic c-polymer, polycarbonate (PC), polyisoprene (PI), polyester, polypropylene (PP) polytetrafluoroethylene (PTFE), silicone and stainless steel (SS).
Administration
Administer ZIIHERA as an intravenous infusion with a 0.2 or 0.22 micron filter.
Do not administer as an intravenous push or bolus.
Do not co-administer ZIIHERA and other intravenous drugs through the same intravenous line. File:ZIHT.png Recommended ZIIHERA Infusion Durations.
For injection: 300 mg white lyophilized powder in a single-dose vial.
Monitoring
There is limited information regarding Zanidatamab-hrii Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Zanidatamab-hrii and IV administrations.
Overdosage
There is limited information regarding Zanidatamab-hrii overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Zanidatamab-hrii Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Zanidatamab-hrii Mechanism of Action in the drug label.
Structure
There is limited information regarding Zanidatamab-hrii Structure in the drug label.
Pharmacodynamics
There is limited information regarding Zanidatamab-hrii Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Zanidatamab-hrii Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Zanidatamab-hrii Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Zanidatamab-hrii Clinical Studies in the drug label.
How Supplied
There is limited information regarding Zanidatamab-hrii How Supplied in the drug label.
Storage
There is limited information regarding Zanidatamab-hrii Storage in the drug label.
Images
Drug Images
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