5.1 Diarrhea
Newly added
subsection:
ZIIHERA can cause severe diarrhea.
When ZIIHERA is used in combination
with fluoropyrimidine- and platinum-containing chemotherapy with or without tislelizumab-jsgr, severe, life threatening, and fatal cases
of diarrhea can occur
despite loperamide prophylaxis [see
Adverse Reactions (6.1), Use in Specific Populations (8.5)]. The risk of
severe and life threatening diarrhea is higher when ZIIHERA is administered
with chemotherapy and tislelizumab-jsgr, with a higher risk in patients aged 65
years or older compared to younger patients [see
Geriatric Use (8.5)]. Advise patients to increase oral fluids, begin
antidiarrheals, and notify their healthcare provider immediately if diarrhea
occurs [see Patient Counseling
Information (17)].
Administer antidiarrheal prophylaxis with loperamide in cycle 1 for all patients receiving ZIIHERA in
combination with fluoropyrimidine- and platinum-containing chemotherapy with or
without tislelizumab-jsgr. Begin loperamide at the first loose stool when
ZIIHERA is administered in combination with chemotherapy or as a single agent.
Administer fluids, electrolytes, and additional antidiarrheal agents as necessary. When ZIIHERA was used in combination with chemotherapy with or without tislelizumab-jsgr, 9% of
patients had a dose reduction of ZIIHERA due to diarrhea and concomitant agents
were dose reduced in 22% of patients. Before modifying the dose of ZIIHERA,
evaluate, modify or discontinue drug(s) contributing to diarrhea in accordance
with their respective prescribing information. Withhold, reduce the dose, or
permanently discontinue ZIIHERA based on severity [see Dosage and Administration (2.2, 2.4)].
In
a Phase 2 study evaluating ZIIHERA in combination with FOLFOX in patients
with GEA, 57% of
patients who received a fluorouracil bolus without loperamide prophylaxis
(N=14), experienced Grade 3 diarrhea, while 30% of patients who did not receive
a fluorouracil bolus but received loperamide prophylaxis (N=10) experienced
Grade 3 diarrhea. If treating patients with ZIIHERA in combination with FOLFOX,
do not administer the fluorouracil bolus.
Gastroesophageal Adenocarcinoma (GEA)
In Combination with fluoropyrimidine- and platinum-containing chemotherapy and tislelizumab:
When ZIIHERA was used in combination with fluoropyrimidine- and
platinum-containing chemotherapy and tislelizumab-jsgr, diarrhea was reported
in 85% of 330 patients treated in clinical studies, including Grade 4 (2.1%),
Grade 3 (24%), and Grade 2 (31%) events. Fatal outcomes resulting from diarrhea
occurred in 1.5% of patients. Diarrhea leading to dose reduction of ZIIHERA
occurred in 10% of patients, and permanent discontinuation of ZIIHERA occurred
in 3.9% of patients.
In cycle 1, diarrhea at Grade 4 severity
occurred in 1.5% and Grade 3 severity occurred in 15% of patients
despite use of loperamide prophylaxis. The median time to
onset for cycle 1 diarrhea was 6 days and median time to
resolution was 18 days.
In Combination with fluoropyrimidine- and platinum-containing chemotherapy:
When ZIIHERA was used in combination
with fluoropyrimidine- and platinum-containing chemotherapy, diarrhea was
reported in 81% of 395 patients treated in clinical studies, including Grade 4
(1.3%), Grade 3 (20%) and Grade 2 (33%). Diarrhea leading to dose reduction of
ZIIHERA occurred in 10% of patients,
and permanent discontinuation of ZIIHERA occurred
in 1.8% of patients.
In cycle 1, diarrhea at Grade 4 severity occurred in 0.8% and Grade 3 severity occurred in 14% of patients despite
use of loperamide prophylaxis. The median time to
onset for cycle 1 diarrhea
was 6 days and median time to resolution was 18 days.
Biliary Tract Cancer (BTC)
When ZIIHERA was used as a single agent, diarrhea was reported
in 49% of 233 patients
treated in clinical studies,
including Grade 3 (6%) and Grade 2 (17%). Grade 3 diarrhea occurred in 2.6% of
patients during cycle 1 of treatment. Of all diarrhea events occurring during
the first cycle of treatment, median time to onset was 4 days and median time
to resolution was 21 days.
5.3 Left
Ventricular Dysfunction (LVD)
Additions and/or
revisions underlined:
ZIIHERA can cause decreases
in left ventricular ejection fraction
(LVEF).
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)].
Gastroesophageal Adenocarcinoma (GEA)
In patients who received ZIIHERA
in combination with chemotherapy and tislelizumab-jsgr, LVEF decrease (an
absolute decline in LVEF of more than 10%, resulting in a final value below
50%) was observed in 9% of 330 patients. LVD leading to permanent discontinuation
of ZIIHERA was reported in 3% of patients.
Fatal outcomes due to LVD occurred in one
patient (0.3%). The median time to first occurrence of LVD was 6.9 months
(range: 1.2 to 29.1 months). Left ventricular dysfunction resolved in 78% of
patients.
In patients who received ZIIHERA
in combination with chemotherapy, LVEF decrease was observed in 5% of 395 patients.
LVD leading to permanent discontinuation of ZIIHERA was reported
in 1.0% of patients. The
median time to first occurrence of left ventricular dysfunction was 6.0 months
(range: 1.4 to 15.0 months). Left ventricular dysfunction resolved in 70% of
patients.
Biliary Tract Cancer (BTC)
In patients who received
ZIIHERA as a single agent,
LVEF decrease was observed 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). LVD resolved in 70% of patients.
5.4 Infusion-Related Reactions
Additions and/or
revisions underlined:
ZIIHERA can cause infusion-related reactions (IRRs).Prior to each dose of
ZIIHERA, administer premedication 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 IRRs [see Dosage and
Administration (2.4)].
Gastroesophageal Adenocarcinoma (GEA)
An IRR was reported in 22%
of 330 patients treated with ZIIHERA and chemotherapy with
tislelizumab-jsgr in clinical studies, including Grade 4 (0.3%),
Grade 3 (1.2%), and Grade 2 (16%) despite use of prophylaxis. IRRs leading to permanent discontinuation of ZIIHERA were
reported in 0.3% of patients.
IRRs occurred on the first day of dosing in 17% of patients. Of all
patients who experienced IRRs, 60% of reactions resolved within the first day.
An IRR was reported in 24% of 395
patients treated with ZIIHERA and chemotherapy in clinical studies, including
Grade 4 (0.3%), Grade 3 (1.5%), and Grade 2 (18%)despite use of prophylaxis.
IRRs leading to permanent discontinuation of ZIIHERA were reported in 1.3% of
patients. IRRs occurred on the first day of dosing
in 22% of patients.
Of all patients who experienced IRRs, 83% of reactions resolved within the first
day.
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 despite use of prophylaxis. IRRs occurred on the first day
of dosing in 28% of patients. Of all patients who experienced IRRs, 97% of
reactions were resolved within the first day.
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