ZIIHERA Powder for solution for injection Ref.[113521] Active ingredients: Ζanidatamab

Source: FDA, National Drug Code (US) Revision Year: 2024

1. Indications and Usage

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 [see Dosage and Administration (2.1)].

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2. Dosage and Administration

2.1 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 [see Clinical Studies (14)].

Information on FDA-approved tests for HER2 protein expression in biliary tract cancers is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Premedications

Premedicate all patients 30 to 60 minutes prior to each dose of ZIIHERA to reduce the risk of infusion-related reactions [see Warnings and Precautions (5.3)]:

Administer acetaminophen, an antihistamine (such as diphenhydramine) and a corticosteroid (such as hydrocortisone).

2.3 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.

2.4 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.

Table 1. Dosage Modifications for Adverse Reactions:

Adverse Reaction	Severity	Treatment Modification
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	• Withhold ZIIHERA for at least 4 weeks. • Repeat LVEF assessment within 4 weeks. • Resume ZIIHERA treatment within 4 to 8 weeks if LVEF returns to normal limits and the absolute decrease is ≤ 15% points from baseline. • Permanently discontinue ZIIHERA if LVEF has not recovered to within 15% points from pre-treatment baseline.
	Confirmed symptomatic congestive heart failure	• Permanently discontinue ZIIHERA.
Infusion-Related Reactions[see Warnings and Precautions (5.3)]	Mild (Grade 1)	• Reduce ZIIHERA infusion rate by 50%. • For subsequent ZIIHERA infusions increase infusion rate gradually to the rate prior to the adverse reaction, as tolerated.
	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)	• No dose modification of ZIIHERA is required. • Initiate appropriate medical therapy and monitor as clinically indicated.
	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	• Permanently discontinue ZIIHERA.
Other Adverse Reactions (excluding LVD, IRR, Diarrhea, and Pneumonitis)[see Adverse Reactions (6.1)]	Mild/Moderate (Grades ½)	• No dosage modification is required for ZIIHERA. • Initiate appropriate medical therapy and monitor as clinically indicated.
	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.

2.5 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 (2.3)].
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:
- Intravenous (IV) Bag: Polyvinyl chloride (PVC), polyolefin (PO), ethyl vinyl acetate (EVA), polypropylene (PP) and ethylene-propylene copolymer.
- Infusion sets: Polyvinyl chloride/ bis (2-ethylhexyl) phthalate (PVC/DEHP). Polyurethane (PUR), polyethylene-lined (PE-lined) acrylonitrile-butadiene-styrene (ABS).
- Inline filters: Polyethersulfone solution filter (PES), polyvinylidene fluoride air filter (PVDF).
- 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.

Table 2. Recommended ZIIHERA Infusion Durations:

Dose	Infusion Duration
First and Second	120-150 minutes
Third and Fourth	90 minutes, if previous infusions were well-tolerated
Subsequent	60 minutes, if previous infusions were well-tolerated

16.2. Storage and Handling

Store in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) in the original carton until time of reconstitution. Do not freeze.

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