Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Jazz Pharmaceuticals Ireland Ltd, 5 th Floor, Waterloo Exchange, Waterloo Road, Dublin 4, D04 E5W7, Ireland
Ziihera as monotherapy is indicated for the treatment of adults with unresectable locally advanced or metastatic HER2-positive (IHC3+) biliary tract cancer (BTC) previously treated with at least one prior line of systemic therapy (for biomarker-based patient selection, see section 4.2).
Ziihera must be initiated by a physician experienced in the diagnosis and treatment of patients with biliary tract cancer.It must be administered by a qualified healthcare professional, with appropriate resuscitation equipment available.
Patients treated with Ziihera for BTC should have documented HER2-positive tumour status, defined as a score of 3+ by immunohistochemistry (IHC) assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose. If a CE-marked IVD is not available, an alternate validated test should be used.
The recommended dose of Ziihera is 20 mg/kg, administered as an intravenous infusion every 2 weeks (every 14 days) until disease progression or unacceptable toxicity. For duration of infusion, see Table 4.
Premedication should be administered 30 to 60 minutes prior to each infusion to prevent potential infusion related reaction. Premedication is recommended to include a corticosteroid, antihistamine, and antipyretic (see section 4.4).
Left ventricular function must be assessed at baseline and at regular intervals during treatment. The recommendations on dose modifications in the event of left ventricular ejection fraction (LVEF) decrease are indicated in Table 1.
Table 1. Dose modifications for left ventricular dysfunction:
| Left ventricular dysfunction (see section 4.4) | Severity | Treatment modification |
| Absolute decrease of ≥ 16% points in LVEF from pre- treatment baseline | • Withhold treatment for at least 4 weeks. • Repeat LVEF assessment within 4 weeks. • Resume treatment within 4 to 8 weeks, if LVEF returns to normal limits and the absolute decrease is ≤ 15% points from baseline. • If LVEF has not recovered to within 15% points from baseline, permanently discontinue. | |
| LVEF value below 50% and absolute decrease of ≥ 10% points below pre-treatment baseline |
Management of infusion related reaction (IRRs) may require reduced infusion rate, dose interruption, or treatment discontinuation as described in Table 2.
Table 2. Dose and infusion duration modifications for infusion-related reactions:
| Infusion related reactions (see sections 4.4 and 4.8) | Severity | Treatment modification |
| Mild (Grade 1) | • Reduce infusion rate by 50%. • Subsequent infusions should start at this reduced rate. • Infusion rate for subsequent infusions may be increased gradually to the rate prior to symptoms, as tolerated. | |
| Moderate (Grade 2) | • Hold infusion immediately. • Treat with appropriate therapy. • Resume infusion at 50% of previous infusion rate once symptoms resolve. • Infusion rate for subsequent infusions may be increased gradually to the rate prior to symptoms, as tolerated. | |
| Severe (Grade 3) | • Hold infusion immediately. • Promptly treat with appropriate therapy. • Resume infusion at the next scheduled dose at 50% of previous infusion rate once symptoms resolve. • Permanently discontinue for recurrent Grade 3 symptoms. | |
| Life threatening (Grade 4) | • Hold infusion immediately. • Promptly treat with appropriate therapy. • Permanently discontinue. |
Management of pneumonitis may require treatment discontinuation as described in Table 3.
Table 3. Dose modifications for pneumonitis:
| Pneumonitis (see section 4.4) | Severity | Treatment modification |
| Confirmed Grade ≥ 2 | • Permanently discontinue. |
If a patient misses a dose of Ziihera, the scheduled dose should be administered as soon as possible. The administration schedule should be adjusted to maintain a 2-week interval between doses.
Dose adjustments are not required for patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min estimated using the CKD-EPI). Zanidatamab has not been evaluated in patients with severe renal impairment and patients with end-stage renal disease with or without dialysis. However, due to minor involvement of renal processes in the clearance of zanidatamab, no dose adjustment is recommended for patients with renal impairment as no difference in exposure is expected (see section 5.2).
Dose adjustments are not required for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin between 1 and 1.5 times ULN and any AST). Zanidatamab has not been evaluated in patients with moderate (total bilirubin > 1.5 to ≤ 3 ULN and any AST) to severe (total bilirubin > 3 ULN and any AST) hepatic impairment. However, due to minor involvement of hepatic processes in the clearance of zanidatamab, no dose adjustment is recommended for patients with hepatic impairment as no difference in exposure is expected (see section 5.2).
No dose adjustment is required in patients aged 65 years and over (see section 5.2).
Children under the age of 18 were not included in the clinical trials. Hence, the safety, efficacy and pharmacokinetics of zanidatamab have not been established in this population.
Ziihera is administered by intravenous infusion. It must not be administered by intravenous push or as a rapid single bolus injection.
The diluted solution for infusion must have a final concentration of 0.4 to 6 mg/mL zanidatamab.
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
Table 4. Recommended 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 |
The maximum tolerated dose of zanidatamab has not been determined. In clinical studies, the maximum tested dose has been 30 mg/kg. In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment initiated if required.
Unopened vial:
2 years.
Reconstituted solution:
Chemical and physical in-use stability of reconstituted solution has been demonstrated for up to 6 hours at room temperature (18ºC to 24ºC) and up to 24 hours at 2ºC to 8ºC.
From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and should not exceed 4 hours at room temperature (18ºC to 24ºC) or in the refrigerator (2ºC to 8ºC).
Diluted solution:
Chemical and physical in-use stability of the diluted solution has been demonstrated for up to 24 hours at room temperature (18ºC to 24ºC) and at 2ºC to 8ºC.
From a microbial point of view, the product should be used immediately. If not used immediately, in-use storage time and conditions are the responsibility of the user and should not exceed 12 hours at room temperature (18ºC to 24ºC) or 24 hours in the refrigerator at 2ºC to 8ºC. These storage times start from the time of reconstitution.
Store in a refrigerator (2ºC–8ºC).
Do not freeze.
For storage conditions after reconstitution and dilution of the product, see section 6.3.
20 mL Type I glass vial with a chlorobutyl stopper and flip-off cap.
Each pack contains either 1 vial or 2 vials.
Not all pack sizes may be marketed.
Ziihera must be reconstituted with sterile water for injections and subsequently diluted with sodium chloride 9 mg/mL (0.9%) solution for injection or 5% glucose for infusion.
Aseptic technique must be used for reconstitution and dilution of Ziihera.
Reconstitution:
Dilution:
Administration:
Disposal:
Ziihera vials are for single dose use only.
Discard any portion of the reconstituted solution that remains unused.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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