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

5.1 Embryo-Fetal Toxicity

Based on the mechanism of action, ZIIHERA can cause fetal harm when administered to a pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.

Verify the pregnancy status of females of reproductive potential prior to the initiation of ZIIHERA. Advise pregnant women and females of reproductive potential that exposure to ZIIHERA during pregnancy or within 4 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception while receiving ZIIHERA and for 4 months following the last dose of ZIIHERA.

5.2 Left Ventricular Dysfunction

ZIIHERA can cause decreases in left ventricular ejection fraction (LVEF). LVEF declined by greater than 10% and decreased to less than 50% in 4.3% of 233 patients. LVD leading to permanent discontinuation of ZIIHERA was reported in 0.9% of patients. The median time to first occurrence of left ventricular dysfunction was 5.6 months (range: 1.6 to 18.7 months). Left ventricular dysfunction resolved in 70% of patients.

Assess LVEF prior to initiation of ZIIHERA and at regular intervals during treatment. Withhold dose or permanently discontinue ZIIHERA based on severity of adverse reactions [see Dosage and Administration (2.4)].

The safety of ZIIHERA has not been established in patients with a baseline ejection fraction that is below 50% [see Dosage and Administration (2.4)].

5.3 Infusion-Related Reactions

ZIIHERA can cause infusion-related reactions (IRRs). An IRR was reported in 31% of 233 patients treated with ZIIHERA as a single agent in clinical studies, including Grade 3 (0.4%), and Grade 2 (25%). IRRs leading to permanent discontinuation of ZIIHERA were reported in 0.4% of patients. IRRs occurred on the first day of dosing in 28% of patients; 97% of IRRs resolved within one day.

Prior to each dose of ZIIHERA, administer premedications to prevent potential IRRs [see Dosage and Administration (2.2)]. Monitor patients for signs and symptoms of IRR during ZIIHERA administration and as clinically indicated after completion of infusion. Have medications and emergency equipment to treat IRRs available for immediate use.

If an IRR occurs, slow, or stop the infusion, and administer appropriate medical management. Monitor patients until complete resolution of signs and symptoms before resuming. Permanently discontinue ZIIHERA in patients with recurrent severe or life-threatening infusion-related reactions [see Dosage and Administration (2.4)].

5.4 Diarrhea

ZIIHERA can cause severe diarrhea [see Adverse Reactions (6.1)].

Diarrhea was reported in 48% of 233 patients treated in clinical studies, including Grade 3 (6%) and Grade 2 (17%). If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Withhold or permanently discontinue ZIIHERA based on severity [see Dosage and Administration (2.4)].

The following clinically significant adverse reactions are described in greater detail in other sections of the labeling:

• Embyro-Fetal Toxicity [see Warnings and Precautions (5.1)]
• Left Ventricular dysfunction [see Warnings and Precautions (5.2)]
• Infusion-Related Reactions [see Warnings and Precautions (5.3)]
• Diarrhea [see Warnings and Precautions (5.4)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population of ZIIHERA described in WARNINGS AND PRECAUTIONS reflect exposure in 233 patients administered ZIIHERA 20 mg/kg intravenously as a single agent in two single-arm, open-label studies (ZWI‑ZW25‑101 and HERIZON‑BTC‑01), which enrolled 109 patients with biliary tract cancer, and 124 patients with other cancers. Among 233 patients who received ZIIHERA, 39% were exposed for 6 months or longer, and 17% were exposed for greater than one year.

Biliary Tract Cancer

The safety of ZIIHERA was evaluated in 80 patients with previously treated, unresectable or metastatic HER2-positive biliary tract cancer who received at least one prior gemcitabine-containing chemotherapy regimen in HERIZON‑BTC‑01 [See Clinical Studies (14)]. Patients received ZIIHERA 20 mg/kg by IV infusion once every 2 weeks until disease progression or unacceptable toxicity. The median duration of exposure to ZIIHERA was 5.6 months (range: 0.5 to 27.2 months).

Serious adverse reactions occurred in 53% of patients who received ZIIHERA. Serious adverse reactions in >2% of patients included biliary obstruction (15%), biliary tract infection (8%), sepsis (8%), pneumonia (5%), diarrhea (3.8%), gastric obstruction (3.8%), and fatigue (2.5%). A fatal adverse reaction of hepatic failure occurred in one patient who received ZIIHERA.

Permanent discontinuation due to an adverse reaction occurred in 2.5% of patients who received ZIIHERA. Adverse reactions which resulted in permanent discontinuation in ≥1% of patients who received ZIIHERA included decreased ejection fraction and pneumonitis.

Dosage interruptions due to an adverse reaction, excluding temporary interruptions of ZIIHERA infusions due to infusion-related reactions, occurred in 41% of patients who received ZIIHERA. The most frequent adverse reactions (>2% of patients) that required dosage interruption were diarrhea, increased alanine aminotransferase, increased aspartate aminotransferase, decreased ejection fraction, pneumonia, cholangitis, fatigue, biliary obstruction, abdominal pain, increased blood creatinine, and decreased potassium.

Dosage reductions due to an adverse reaction occurred in 4% of patients who received ZIIHERA. Adverse reactions requiring dosage reductions in >1% of patients were diarrhea, nausea, and decreased weight.

The most common adverse reactions in patients receiving ZIIHERA (≥20%) were diarrhea, infusion-related reaction, abdominal pain, and fatigue.

Table 3 summarizes the adverse reactions that occurred in HERIZON‑BTC‑01.

Table 3. Adverse Reactions (≥15%) in Patients with Unresectable or Metastatic HER2-Positive BTC Receiving ZIIHERA in HERIZON-BTC-01:

^* Graded per CTCAE version 5.
^a Diarrhea includes diarrhea and enteritis
^b Abdominal pain includes abdominal pain and abdominal pain upper
^c Fatigue includes asthenia and fatigue
^d Rash includes dermatitis, dermatitis acneiform, palmar-plantar erythrodysaesthesia syndrome, rash, rash maculo-papular, and rash pustular

Table 4 summarizes the laboratory abnormalities in HERIZON‑BTC‑01.

Table 4. Laboratory Abnormalities (≥30%) that Worsened from Baseline in Patients with Unresectable or Metastatic HER2-Positive BTC Receiving ZIIHERA in HERIZON-BTC-01:

^* The denominator used to calculate the rate varied from 78 to 80 based on the number of patients with a baseline value and at least one post-treatment value.

Risk Summary

Based on mechanism of action, ZIIHERA can cause fetal harm when administered to a pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Use of ZIIHERA is not recommended during pregnancy (see CLINICAL CONSIDERATIONS). Advise patients of potential risks to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Monitor women who received ZIIHERA during pregnancy or within 4 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with local standard of care.

Risk Summary

There are no data on the presence of zanidatamab‑hrii in human milk, the effects on the breastfed child, or the effects on milk production. Published data suggest human IgG is present in human milk but does not enter neonatal or infant circulation in substantial amounts. Consider developmental and health benefits of breastfeeding along with the mother’s clinical need for ZIIHERA treatment and any potential adverse effects on the breastfed child from ZIIHERA or from the underlying maternal condition. This consideration should also take into account the ZIIHERA half-life of approximately 21 days and a washout period of 4 months [see Clinical Pharmacology (12.3)].

ZIIHERA can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to the initiation of ZIIHERA [see Use in Specific Populations (8.1)].

Contraception

Females

ZIIHERA can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with ZIIHERA and for 4 months following the last dose of ZIIHERA.

Safety and efficacy of ZIIHERA have not been established in pediatric patients.

Of the 80 patients who received ZIIHERA for unresectable or metastatic biliary tract cancer in HERIZON‑BTC‑01, there were 39 (49%) patients 65 years of age and older. Thirty‑seven (46%) were aged 65‑74 years old and 2 (3%) were aged 75 years or older [see Clinical Studies (14)].

No overall differences in safety or effectiveness were observed between these patients and younger adult patients.