4.1. Therapeutic indications

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).

4.2. Posology and method of administration

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.

Patient selection

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.

Posology

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.

Premedications

Premedication should be administered 30 to 60 minutes prior to each infusion to prevent potential infusion related reactions. Premedication is recommended to include a corticosteroid, antihistamine, and antipyretic (see section 4.4).

Dose modifications for left ventricular dysfunction

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

Dose modifications for infusion related reactions

Management of infusion related reactions (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.

Dose modifications for pneumonitis

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.

Missed dose

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.

Special populations

Renal impairment

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).

Hepatic impairment

Dose adjustments are not required for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (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).

Elderly population

No dose adjustment is required in patients aged 65 years and over (see section 5.2).

Paediatric population

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.

Method of administration

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

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Embryo-foetal toxicity, pregnancy and contraception

Based on the mechanism of action, zanidatamab may cause foetal harm when administered to a pregnant woman. In post-marketing reports of other HER2-directed antibodies, use during pregnancy resulted in cases of oligohydramnios manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death (see section 4.6).

Patients should be advised to avoid becoming pregnant while receiving Ziihera. A pregnancy test should be performed before initiating treatment to exclude pregnancy.

Female patients of childbearing potential should use an effective method of contraception while receiving Ziihera and for 4 months following the last dose (see section 4.6).

Left ventricular dysfunction

Decreases in LVEF have been reported with medicinal products that block HER2 activity, including zanidatamab. LVEF should be assessed prior to initiation of Ziihera by echocardiogram or multigated acquisition (MUGA) scan and at regular intervals during treatment to ensure that LVEF is within normal limits. If the LVEF declines and has not improved, or has declined further at the subsequent assessment, Ziihera should be discontinued as recommended in Table 1 (see section 4.2).

Zanidatamab has not been studied in patients with a pre-treatment LVEF value of < 50%; history of myocardial infarction or unstable angina within 6 months; troponin levels consistent with myocardial infarction, or clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, uncontrolled hypertension, or any history of symptomatic congestive heart failure (CHF).

Infusion related reactions

Ziihera can cause infusion related reactions (IRRs) (see section 4.8). Premedications should be administered prior to each dose, to reduce the risk of IRRs (see section 4.2).

Patients should be monitored for signs and symptoms of IRRs during administration and as clinically indicated after completion of infusion. Appropriate emergency medicine and equipment to treat IRRs should be available for immediate use, and IRRs should be managed as recommended in Table 2 (see section 4.2).

Pneumonitis

Pneumonitis has been reported with medicinal products that block HER2 activity, including Ziihera. Pneumonitis has been reported in 0.4% of 233 patients treated with Ziihera 20 mg/kg intravenously as a single agent in clinical studies. Patients should be monitored for signs and symptoms of pneumonitis. In the event of confirmed Grade ≥ 2 pneumonitis, treatment should be permanently discontinued (see section 4.2).

Excipients with known effect

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

Polysorbate 20

This medicinal product contains 0.63 mg of polysorbate 20 in each vial, which is equivalent 0.105 mg/mL. Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

No dedicated clinical studies evaluating the drug interaction potential of zanidatamab have been conducted. Zanidatamab is an antibody that is not expected to impact the cytochrome P450 enzymes. Also, zanidatamab is not known to target mechanisms related to proinflammatory cytokines or any mechanism related to proinflammatory cytokines that may impact the pharmacokinetics (PK) of concomitant medicines.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in females

To exclude pregnancy, women of childbearing potential should undergo pregnancy testing before initiation of Ziihera.

Based on the mechanism of action, zanidatamab may cause embryo-foetal harm when administered during pregnancy. Female patients should use effective contraception during treatment with Ziihera and for 4 months following the last dose.

Pregnancy

Based on the mechanism of action, zanidatamab may cause foetal harm when administered to a pregnant woman. There are no human or animal data on the use of zanidatamab in pregnancy. In post‑marketing reports of other HER2-directed antibodies, use during pregnancy resulted in cases of oligohydramnios manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Ziihera is not recommended for use during pregnancy or in women of childbearing potential not using contraception. Patients should be advised on potential risks to the foetus.

Women who received Ziihera during pregnancy or within 4 months prior to conception should be monitored for oligohydramnios. If oligohydramnios occurs, foetal testing that is appropriate for gestational age and consistent with local standard of care should be performed.

Breast-feeding

It is not known whether zanidatamab is excreted in human milk, or what effect it has on a breast-fed child or milk production.

A decision should be made whether to discontinue breast-feeding or to discontinue treatment, taking into account the benefit of breast-feeding for the child and the benefit of Ziihera therapy for the woman. This consideration should also take into account the washout period of 4 months (see section 5.2).

Fertility

Fertility studies have not been performed with zanidatamab.

4.7. Effects on ability to drive and use machines

Zanidatamab has minor influence on the ability to drive and use machines. Fatigue has been reported with the use of Ziihera. Therefore, patients should be advised to use caution when driving or operating machines.

4.8. Undesirable effects

Summary of the safety profile

The pooled safety population of Ziihera reflects exposure in 233 patients who were administered Ziihera 20 mg/kg intravenously as a single agent in two single-arm trials. Among 233 patients who received Ziihera, 39% were exposed for 6 months or longer, and 17% were exposed for greater than one year.

From the pooled data, serious adverse reactions were observed in 8.2% of patients. The most frequent serious adverse reactions were diarrhoea (1.7%) and fatigue (1.3%).

The most common adverse reactions observed in the pooled data were diarrhoea (48.5%), infusion related reaction (30.5%), fatigue (26.2%), anaemia (21.9%) and rash (21.5%).

The safety of Ziihera in adult patients with BTC (N=87) was evaluated in Study 203, an open-label, multi-cohort, multicentre trial.

In Study 203 (N=87), serious adverse reactions occurred in 16.1% of patients. The most frequent serious adverse reactions were diarrhoea (2.3%), fatigue (2.3%), and alanine aminotransferase increased (2.3%).

The most common adverse reactions in Study 203 (N=87) were diarrhoea (46%), infusion related reaction (33.3%), abdominal pain (26.4%), anaemia (25.3%) and fatigue (24.1%).

Tabulated list of adverse reactions

Unless otherwise stated, the frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 233 patients exposed to Ziihera at 20 mg/kg administered intravenously as a single agent in two single-arm trials.

Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 5. Adverse reactions in patients receiving Ziihera as monotherapy reported in the pooled safety population (N=233)

System organ class

Frequency

Adverse reactions

Blood and lymphatic system disorders

Very common

Anaemia*

Metabolism and nutrition disorders

Very common

Decreased appetite

Cardiac disorders

Common

Ejection fraction decreased*

Gastrointestinal disorders

Very common

Diarrhoea*

Abdominal paina

Nausea

Vomiting

Hepatobiliary disorders

Very common

Alanine aminotransferase increased (ALT)*

Aspartate aminotransferase increased (AST)*

Skin and subcutaneous tissue disorders

Very common

Rashb

General disorders and administration site conditions

Very common

Fatiguec

Injury, poisoning and procedural complications

Very common

Infusion related reaction*

Respiratory, thoracic and mediastinal disorders

Uncommon

Pneumonitis

a Abdominal pain includes abdominal pain and abdominal pain upper.

b Rash includes dermatitis acneiform, rash, rash maculo-papular, rash pruritic, and urticaria.

c Fatigue includes asthenia, fatigue, and malaise.

* See “Description of selected adverse reactions” below.

Description of selected adverse reactions in the pooled safety population (N=233)

Diarrhoea

Diarrhoea was reported in 48.5% of patients who received Ziihera. Grade 3 reported event incidence in patients was 5.2%, Grade 4 and Grade 5 events were not observed. Median time to first onset was 10 days and median time to resolution was 3 days. The dose of Ziihera was reduced due to diarrhoea in 1.3% of patients and was held or delayed in 2.6% of patients. There were no discontinuations of treatment due to diarrhoea.

Infusion related reactions

Infusion related reactions (IRRs) were reported in 30.5% of patients who received Ziihera. Grade 3 reported event incidence in patients was 0.4%, Grade 4 and Grade 5 events were not observed. Median time to first onset was 1 day and median time to resolution was 1 day. Ziihera infusion was interrupted in 25.3% of patients and discontinued in 0.4% of patients due to IRRs (see section 4.4).

Anaemia

Anaemia was reported in 21.9% of patients who received Ziihera. Grade 3 reported event incidence in patients was 9.9%, Grade 4 was 0.4% and no Grade 5 events were observed. Median time to first onset was 42 days and median time to resolution was 14 days. Ziihera infusion was held or delayed in 0.4% of patients and there were no other actions taken with Ziihera due to anaemia.

ALT increased

ALT increased was reported in 12.4% of patients who received Ziihera. Grade 3 reported event incidence in patients was 1.7%, Grade 4 was 0.4% and no Grade 5 events were observed. Median time to first onset was 78 days and median time to resolution was 16 days. Ziihera infusion was held or delayed in 7 patients (3%) and there were no other actions taken with Ziihera due to ALT increased.

AST increased

AST increased was reported in 11.6% of patients who received Ziihera. Grade 3 reported event incidence in patients was 1.3%, Grade 4 was 0.9% and no Grade 5 events were observed. Median time to first onset was 87 days and median time to resolution was 15 days. The dose of Ziihera was held or delayed in 6 patients (2.6%) and there were no other actions taken with Ziihera due to AST increased.

Left ventricular dysfunction

Decreases in LVEF have been reported with medicinal products that block HER2 activity, including Ziihera. Twelve events of LVEF decreased were observed in 10 patients (4.3%) and one of these events was considered serious. Grade 3 reported event incidence in patients was 1.3%, Grade 4 and Grade 5 events were not observed. Median time to first onset was 171 days and median time to resolution was 27 days. The dose of Ziihera was reduced in 1 patient (0.4%), was held or delayed in 5 patients (2.1%) and was discontinued in 2 patients (0.9%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.