ZIIHERA Powder for concentrate for solution for infusion Ref.[115391] Active ingredients: Zanidatamab

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.

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 PK of concomitant medicines.

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.

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.

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, multicenter 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):

^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. 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 national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.