Ziihera 300 mg Powder for concentrate for solution for infusion

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.

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

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

Dose modifications for pneumonitis

Management of pneumonitis may require treatment discontinuation as described in Table 3.

Table 3. Dose modifications for pneumonitis

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

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

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 pharmacokinetics (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, 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)

^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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

Pharmacotherapeutic group: Antineoplastic agents, HER2 (Human Epidermal Growth Factor Receptor 2) inhibitors, ATC code: L01FD07.

Mechanism of action

Zanidatamab is a dual HER2-targeted bispecific antibody that simultaneously binds extracellular domains 2 and 4 on separate HER2 monomers (binding in trans). Binding of zanidatamab with HER2 results in internalization leading to a reduction of the receptor on the cell surface. Zanidatamab induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumour growth inhibition and tumour cell death.

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the studies described below with incidence of ADA in other studies.

ADA were rarely detected. Zanidatamab is categorised as a low-risk molecule to elicit an immune response on the basis of assessment of the immunogenicity risk factors and the low incidence of ADAs observed to date across the clinical studies (1.6% [3 of 183 evaluable participants] and 1.2% [1 of 85 evaluable participants] in Study 101 and Study 203, respectively). No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited.

Cardiac electrophysiology

The relationship between time-matched zanidatamab serum concentrations and ΔQTcF measurements was evaluated based on data obtained during treatment with zanidatamab from participants in Study 101. The C-QT analysis dataset included measurements of QTcF from 179 out of the 192 participants enrolled in Study 101. Zanidatamab has no effect on QTc interval and there was no relationship between zanidatamab exposure and change in QTc interval.

Clinical efficacy and safety

The efficacy of Ziihera was evaluated in Cohort 1 (N=62) of ZWI-ZW25-203 (Study 203), a multicentre open-label single arm trial of patients with locally advanced unresectable or metastatic biliary tract cancer who received at least one prior gemcitabine-containing systemic chemotherapy regimen for advanced disease, and experienced disease progression after or developed intolerance to the most recent prior therapy, and whose tumour tested HER2-positive (IHC3+).

Patients received Ziihera every 2 weeks at a dose of 20 mg/kg intravenously. It was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were confirmed objective response rate (cORR) and duration of response (DoR) as determined by an independent central review (ICR) according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.

The median age was 64 years (range: 38 to 79 years), 47% of patients were age 65 or older; 55% were female; 61% were Asian, 31% were White. All patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (32%) or 1 (68%).

Fifty-three percent of patients had gallbladder cancer, 27% had intrahepatic cholangiocarcinoma, and 19% had extrahepatic cholangiocarcinoma. Forty percent of patients had received more than one prior line of therapy for metastatic or locally advanced disease. The most commonly received prior treatments, other than gemcitabine, included: cisplatin (76%), oxaliplatin (16%), 5-fluoruracil (39%), and PD-1 or PD-L1 inhibitor (26%). The median overall survival (OS) in the IHC3+ population was 18.1 months (95% CI: 12.2, 22.9). The median duration of study follow-up in the IHC3+ population was 34.0 months.

Efficacy results are summarised in Table 6.

Table 6. Efficacy results in Study 203

^*Assessed by independent central review.

^†Based on Kaplan-Meier estimate.

LPLV = Last patient last visit 11 July 2024.

Paediatric population

The Medicines and Healthcare products Regulatory Agency has waived the obligation to submit the results of studies with Ziihera in all subsets of the paediatric population in biliary tract cancer (see section 4.2 for information on paediatric use).

Conditional marketing authorisation

This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The Medicines and Healthcare products Regulatory Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

Zanidatamab PK exhibited non-linear kinetics with more rapid clearance (CL) at low doses ranging from 5 to 30 mg/kg. Following the first dose, the geometric mean zanidatamab C_max was dose proportional with increasing doses, while total systemic exposure (AUC_0-∞) was greater than dose proportional with increasing doses. The geometric mean accumulation indices based on C_trough at steady state was approximately 2.7 for the 20 mg/kg once every 2 weeks zanidatamab dose level. The observed zanidatamab exposure and PK parameters following the first administration in the first cycle and steady state, based on the available sampling scheme, are described in Table 7.

The pharmacokinetics of zanidatamab following intravenous infusion in participants with HER2 expressing cancers was evaluated in a population pharmacokinetic model analysis from 279 participants. From the PopPK analysis, participants with BTC were predicted to have a typical CL of 0.0115 L/h, a typical Vc of 3.51 L, a typical Vp of 3.95 L, and an estimated t_1/2 of approximately 21 days. Based on the estimated t_1/2, it would take approximately 3.5 months (i.e., 5 half-lives) to reach steady state following multiple dose administration of zanidatamab.

Table 7. Study 203: Pharmacokinetic parameters (geometric mean [percent coefficient of variation]) of zanidatamab following the first administration of zanidatamab at 20 mg/kg Q2W in cycle 1 and steady-state in BTC patients

Abbreviations: AUC_0-tau = area under the curve during the dosing interval; C_max = maximum concentration;

C_trough = trough concentration; Q2W = once every 2 weeks.

Note: Cycle 1 and Cycle 4 are referred to as “first dose” and “steady-state”, respectively; these terms are interchangeable.

Absorption

Ziihera is administered as an intravenous infusion.

Distribution

Following intravenous dosing, zanidatamab undergoes biphasic elimination from the circulation. Based on population pharmacokinetic analysis, participants with HER2 amplified BTC were predicted to have a typical Vc of 3.51 L and a typical Vp of 3.95 L.

Elimination

Based on population pharmacokinetic analysis, participants with BTC were predicted to have a typical CL of 0.0115 L/h and an estimated t_1/2 of approximately 21 days for zanidatamab administered at 20 mg/kg every 2 weeks at steady-state.

Specific populations

Based on population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of zanidatamab were observed based on age (24 to 88 years), sex, race (White, Black, Asian), and body weight (35.4 kg to 128 kg).

Renal impairment

Based on population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of zanidatamab were observed based on mild and moderate renal impairment (eGFR 30 to 89 mL/min estimated using the CKD-EPI). The pharmacokinetics of zanidatamab in patients with severe renal impairment and end-stage renal disease with or without haemodialysis is unknown. However, as IgG monoclonal antibodies are not primarily cleared via renal pathways, a change in renal function is not expected to influence zanidatamab exposure.

Hepatic impairment

Based on population pharmacokinetics analysis, no clinically significant differences in the pharmacokinetics of zanidatamab were observed based on 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). The pharmacokinetics of zanidatamab in patients with moderate (total bilirubin > 1.5 to ≤ 3 ULN and any AST) or severe hepatic impairment (total bilirubin > 3 ULN and any AST) is unknown. However, as IgG monoclonal antibodies are not primarily cleared via hepatic pathways, a change in hepatic function is not expected to influence zanidatamab exposure.

Carcinogenicity

Studies have not been conducted to evaluate the carcinogenic potential of zanidatamab.

Genotoxicity

Studies have not been conducted to evaluate the mutagenic potential of zanidatamab.

Repeat-dose toxicity

Zanidatamab was generally well tolerated in a 13-week repeat dose toxicity study in cynomolgus monkeys dosed once weekly (intravenous) at dose levels resulting in exposure margins up to at least 10 times the exposure in human patients. Non-severe, transient, non-dose dependent treatment-related soft or watery faeces was observed at clinically relevant exposure. In some, but not all animals, soft or watery faeces correlated with non-severe changes in blood urea nitrogen and blood albumin levels. From day 22, BUN was generally increased (up to 45%) and albumin levels tended to be decreased (up to 12%) throughout the dosing phase. However, these values were not dose-related and remained within historical control ranges.

Developmental and reproductive toxicity

Reproductive and developmental toxicity studies have not been conducted with zanidatamab. However, antibodies that bind to HER2 have been observed to cause severe embryo-foetal toxicity.

Fertility studies have not been performed with zanidatamab. In a 13-week repeat‑dose toxicity study in cynomolgus monkeys dosed once weekly (intravenous) at dose levels resulting in exposure margins up to at least 10-times the exposure in human patients, zanidatamab had no effect on male and female reproductive organs when evaluated by organ weights and histopathology.

Polysorbate 20 (E432)

Disodium succinate

Succinic acid (E363)

Sucrose

Water for injections

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

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 (18 °C to 24 °C) and up to 24 hours at 2 °C to 8 °C.

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 (18 ℃ to 24 ℃) or in the refrigerator (2 °C to 8 °C).

Diluted solution

Chemical and physical in-use stability of the diluted solution has been demonstrated for up to 24 hours at room temperature (18 °C to 24 °C) and at 2 °C to 8 °C.

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 (18 °C to 24 °C) or 24 hours in the refrigerator at 2 °C to 8 °C. These storage times start from the time of reconstitution.

Store in a refrigerator (2 °C – 8 °C).

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

• Calculate the recommended dose of Ziihera based on the patient's weight to determine the number of vials needed.

• Remove the vial(s) from the refrigerator and allow them to reach room temperature.

• Reconstitute each vial with 5.7 mL of sterile water for injections to obtain a concentration of 50 mg/mL in an extractable volume of 6 mL.

• Gently swirl the vial until complete dissolution. Do not shake. Reconstitution should take no more than 10 minutes.

• Allow the reconstituted vial to settle to allow bubbles to dissipate.

• Visually inspect the reconstituted solution for particulate matter and discoloration. The reconstituted product should be a colourless to light yellow, clear to slightly opalescent solution that is essentially free of particles. Discard the reconstituted vial if any discoloration or particulate matter is observed.

Dilution

• Withdraw the necessary volume for the calculated dose from each vial.

• Slowly add the necessary dose volume to an appropriate size infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection or 5% glucose for infusion. The final concentration of the diluted solution should be between 0.4 mg/mL and 6 mg/mL.

• Mix the diluted solution by gentle inversion. Do not shake.

• The solution for infusion must be a clear, colourless solution with no visible particles. If particulate matter or discoloration is identified, the solution must be discarded.

• Compatibility with intravenous administration materials and the diluted Ziihera solution has been demonstrated in the following materials:

Administration

• Administer Ziihera as an intravenous infusion with a 0.2 or 0.22 micron filter.

• Do not co-administer Ziihera and other intravenous medicinal products concurrently through the same intravenous line.

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.