Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical
Trials Experience
(Additions and/or revisions underlined)
Esophageal Squamous Cell
Carcinoma
The safety of OPDIVO was
evaluated in ATTRACTION-3, a randomized, active-controlled, open-label,
multicenter trial in 209 patients with unresectable advanced, recurrent or
metastatic ESCC refractory or intolerant to at least one fluoropyrimidine- and
platinum-based chemotherapy. The
trial excluded patients who were refractory or intolerant to taxane therapy,
had brain metastases that were symptomatic or required treatment, had
autoimmune disease, used systemic corticosteroids or immunosuppressants, had
apparent tumor invasion of organs adjacent to the esophageal tumor or had
stents in the esophagus or respiratory tract. Patients received OPDIVO 240 mg
by intravenous infusion over 30 minutes every 2 weeks (n=209) or investigator’s choice: docetaxel 75 mg/m2
intravenously every 3 weeks (n=65) or paclitaxel 100 mg/m2 intravenously once a week for 6 weeks followed
by 1 week off (n=143).
Patients were treated
until disease progression or unacceptable toxicity. The median duration of
exposure was 2.6 months (range: 0 to 29.2 months) in OPDIVO-treated patients
and 2.6 months (range: 0 to 21.4 months)
in docetaxel- or paclitaxel-treated patients.
Among patients who received
OPDIVO, 26% were exposed for >6 months and 10% were exposed for >1 year.
Serious adverse
reactions occurred in 38% of patients receiving OPDIVO. Serious adverse reactions reported in greater than or equal to 2% of patients who received OPDIVO
were pneumonia, esophageal fistula, interstitial lung disease
and pyrexia. The following fatal adverse reactions
occurred in patients
who received OPDIVO: interstitial lung disease or pneumonitis (1.4%),
pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%),
gastrointestinal hemorrhage (0.5%), pulmonary
embolism (0.5%), and sudden death (0.5%).
OPDIVO was discontinued
in 13% of patients and was delayed in 27% of patients for an adverse reaction.
Tables 30 and 31
summarize the adverse reactions and laboratory abnormalities, respectively, in
ATTRACTION-3.
8
Use in Specific Populations
8.5 Geriatric
Use
(Additions
and/or revisions underlined)
Of the 1359 patients randomized to single-agent OPDIVO
in CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, and
CHECKMATE-067, 39%were 65 years or older and 9% were 75 years or older. No
overall differences in safety or effectiveness were reported between elderly
patients and younger patients.
In CHECKMATE-275 (urothelial cancer), 55% of patients
were 65 years or older and 14% were 75 years or older. No overall differences
in safety or effectiveness were reported between elderly patients and younger
patients.
In CHECKMATE-238 (adjuvant treatment of melanoma), 26%
of patients were 65 years or older and 3% were 75 years or older. No overall
differences in safety or effectiveness were reported between elderly patients
and younger patients.
In ATTRACTION-3 (esophageal squamous cell carcinoma),
53% of patients were 65 years or older and 10% were 75 years or older. No
overall differences in safety or effectiveness were reported between elderly
patients and younger patients.
Approved Drug Label (PDF)
5
Warnings and Precautions
Immune-Mediated Pneumonitis
(Newly added information)
In NSCLC, immune-mediated pneumonitis occurred in 9% (50/576) of patients receiving OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks, including
Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. The median duration was 1.5 months (range:
5 days to 25+ months).
Immune-mediated pneumonitis led to permanent discontinuation of OPDIVO
with ipilimumab in 5%
of patients and withholding of OPDIVO with ipilimumab in 3.6% of patients.
Systemic
corticosteroids were required in 100% of patients with pneumonitis followed by a corticosteroid taper. Pneumonitis resolved in 72% of the patients. Approximately 13% (2/16) of patients had recurrence of pneumonitis after re-initiation of
OPDIVO with ipilimumab.
6
Adverse Reactions
Clinical Trials Experience
(Extensive changes; please refer to
label)
Immunogenicity
(Additions and/or
revisions underlined)
Of the patients with melanoma, advanced
renal cell carcinoma, metastatic colorectal cancer, and metastatic or recurrent
non-small cell lung cancer who were treated
with OPDIVO and ipilimumab and evaluable
for the presence
of anti-nivolumab antibodies, the incidence
of anti-nivolumab antibodies was 26% (132/516) with OPDIVO 3 mg/kg followed
by ipilimumab 1 mg/kg every 3 weeks, 36.7%
(180/491) with OPDIVO 3 mg/kg every 2 weeks and ipilimumab 1 mg every 6 weeks,
and 38% (149/394) with OPDIVO 1 mg/kg followed
by ipilimumab 3 mg/kg every
3 weeks. The incidence
of neutralizing antibodies against nivolumab was 0.8% (4/516) with OPDIVO 3 mg/kg followed
by ipilimumab 1 mg/kg every 3 weeks, 1.4% (7/491)
with OPDIVO 3 mg/kg every 2 weeks and ipilimumab 1 mg every 6 weeks, and 4.6% (18/394)
with OPDIVO 1 mg/kg followed
by ipilimumab 3 mg/kg every 3 weeks.
8
Use in Specific Populations
Geriatric Use
(Newly added information)
Of the 576 patients
randomized to OPDIVO
3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks in CHECKMATE-227 (NSCLC), 48% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported
between older patients and younger
patients; however, there was a higher
discontinuation rate due to adverse reactions in patients
aged 75 years or older (29%) relative
to all patients
who received OPDIVO with ipilimumab (18%).
Of the 396 patients in the primary
efficacy population (PD-L1 ?1%) randomized to OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks in CHECKMATE-227, the hazard ratio for overall
survival was 0.70 (95% CI: 0.55, 0.89) in the 199 patients younger
than 65 years compared to 0.91 (95% CI: 0.72, 1.15) in the 197 patients 65 years or older [see Clinical Studies
(14.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide
(Additions and/or
revisions underlined)
• OPDIVO may be used in combination with ipilimumab as your
first treatment for NSCLC:
o when your lung cancer has spread to other parts of your
body (metastatic), and
o your tumors are positive for PD-L1, but do not have an
abnormal EGFR or ALK gene.
How will I receive OPDIVO?
• Your healthcare provider will give you OPDIVO into your
vein through an intravenous (IV) line over 30 minutes.
• When OPDIVO is used alone, it is usually
given every 2 weeks or 4 weeks depending on the dose you are
receiving.
• When OPDIVO is used in combination with ipilimumab,
OPDIVO is usually given every 3 weeks, for a total of
4 doses. Ipilimumab will be given on the same day. After
that, OPDIVO will be given alone every 2 weeks or 4
weeks depending on the dose you are receiving.
• For NSCLC that has spread, OPDIVO is given every 2
weeks and ipilimumab is given every 6 weeks for up to 2
years.
The most common side effects of OPDIVO when used alone
include:
• stomach-area (abdominal) pain
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1
Immune-Mediated Pneumonitis
Additions
and/or revisions underlined:
OPDIVO with Ipilimumab
OPDIVO
1 mg/kg with Ipilimumab 3 mg/kg
Immune-mediated pneumonitis occurred in 6%
(25/407) of patients with melanoma and 10% (5/49) of patients with HCC who
received OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks. Median time to onset
was 1.6 months (range: 24 days to 10.1 months) in patients with melanoma and
8.3 months (range: 1.2 to 17.5 months) in patients with HCC.
Immune-mediated pneumonitis led to permanent
discontinuation of OPDIVO with ipilimumab in 2.9% of patients with melanoma or HCC
(n=456) and withholding of OPDIVO with ipilimumab in 3.9%. All patients with pneumonitis
required systemic corticosteroids, including 90% who received high-dose corticosteroids
(at least 40 mg prednisone equivalents per day) for a median duration of 1 month
(5 days to 25 months). Complete resolution occurred in 81% of patients. Of the 18
patients in whom OPDIVO or ipilimumab was withheld for pneumonitis, 11 reinitiated
treatment after symptom improvement; of these, 18% (2/11) had recurrence of pneumonitis.
5.2
Immune- Mediated Colitis
Additions
and/or revisions underlined:
OPDIVO with Ipilimumab
OPDIVO
1 mg/kg with Ipilimumab 3 mg/kg
Immune-mediated colitis occurred in 26% (107/407)
of patients with melanoma and 10% (5/49) of patients with HCC who received
OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including three fatal cases.
Median time to onset was 1.6 months (range: 3 days to 15.2 months) in patients
with melanoma and 2 months (range: 1.1 to 19 months) in patients with HCC.
Immune-mediated colitis led to permanent discontinuation
of OPDIVO with ipilimumab in 14% of patients with melanoma or HCC (n=456) and
withholding of OPDIVO with ipilimumab in 7%. All patients with colitis required
systemic corticosteroids, including 92% who received high-dose corticosteroids
(at least 40 mg prednisone equivalents per day) for a median duration of 1 month
(1 day to 30 months). Complete resolution occurred in 77% of patients.
Of the 33 patients in whom OPDIVO or ipilimumab was withheld for colitis,
20 reinitiated treatment after symptom improvement; of these, 40% (8/20) had
recurrence of colitis.
5.3
Immune-Mediated Hepatitis
Additions
and/or revisions underlined:
OPDIVO with Ipilimumab
OPDIVO
1 mg/kg with Ipilimumab 3 mg/kg
Immune-mediated hepatitis occurred in 13% (51/407)
of patients with melanoma and 20% (10/49) of patients with HCC who received
OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks. Median time to onset was 2.1
months (range: 15 days to 11 months) in patients with melanoma and 1.3 months
(range: 22 days to 4.1 months) in patients with HCC. Immune-mediated hepatitis
led to permanent discontinuation of OPDIVO with ipilimumab in 8% of patients
with melanoma or HCC (n=456) and withholding of OPDIVO with ipilimumab in 7%.
All patients with hepatitis required systemic corticosteroids, including
90% who received high- dose corticosteroids (at least 40 mg prednisone equivalents
per day) for a median duration of 1 month (1 day to 34 months). Complete resolution
occurred in 77% of patients. Of the 30 patients in whom OPDIVO or ipilimumab
was withheld for hepatitis, 13 reinitiated treatment after symptom improvement;
of these, 8% (1/13) had recurrence of hepatitis.
5.4 Immune-Mediated
Endocrinopathies
Additions
and/or revisions underlined:
Hypophysitis
OPDIVO
with Ipilimumab
OPDIVO
1 mg/kg with Ipilimumab 3 mg/kg
Hypophysitis occurred in 9% (36/407) of patients
with melanoma and 4% (2/49) of patients with HCC who received OPDIVO 1 mg/kg
with ipilimumab 3 mg/kg every 3 weeks. Median time to onset was 2.7 months (range:
27 days to 5.5 months) in patients with melanoma and 3.7 months (range: 3 to
4.3 months) in patients with HCL. Hypophysitis led to permanent discontinuation
of OPDIVO with ipilimumab in 4 patients with melanoma or HCC (n=456) and withholding
of OPDIVO with ipilimumab in 20 patients. Twenty- three patients received
high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a
median duration of 17 days (1 day to 2 months). Complete resolution occurred
in 16 patients.
Adrenal Insufficiency
OPDIVO
with Ipilimumab
OPDIVO
1 mg/kg with Ipilimumab 3 mg/kg
Adrenal insufficiency occurred in 5% (21/407)
of patients with melanoma and 18% (9/49) of patients with HCC who received
OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks. Median time to onset was 3.0
months (range: 21 days to 9.4 months) in patients with melanoma and 2.8 months
(range: 1.4 to 8 months) in patients with HCC.
Adrenal insufficiency led to permanent discontinuation
of OPDIVO with ipilimumab in 2 patients with melanoma or HCC (n=456) and withholding
of OPDIVO with ipilimumab in 9 patients. Ten patients received high-dose
corticosteroids (at least 40 mg prednisone equivalents per day) for a median
duration of 8.5 days (1 day to 3 months). Complete resolution occurred
in 13 patients.
Hypothyroidism and Hyperthyroidism
OPDIVO
with Ipilimumab
OPDIVO
1 mg/kg with Ipilimumab 3 mg/kg
Hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 22% (89/407) of patients with melanoma and 22% (11/49)
of patients with HCC who received OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every
3 weeks. Median time to onset was 2.1 months (range: 1 day to 10.1 months) in
patients with melanoma and 3.3 months (range: 1.4 to 16.2 months) in patients
with HCC.
Hypothyroidism or thyroiditis resulting in
hypothyroidism led to permanent discontinuation of OPDIVO with ipilimumab in 6 patients
with melanoma or HCC (n=456) and withholding of OPDIVO with ipilimumab in 14 patients.
Six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents
per day) for a median duration of 27 days (19 days to 1.6 months). Complete resolution
occurred in 50 patients.
Hyperthyroidism occurred in 8% (34/407) of
patients with melanoma and 10% (5/49) of patients with HCC who received OPDIVO
1 mg/kg with ipilimumab 3 mg/kg every 3 weeks. Median time to onset
was 23 days (range: 3 days to 3.7 months) in patients with melanoma and
1.4 months (range: 1.4 to 2.8 months) in patients with HCC.
Hyperthyroidism led to withholding of OPDIVO
with ipilimumab in 14 patients with melanoma or HCC (n=456). Five patients received high-dose
corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration
of 23 days (5 to 29 days). Complete resolution occurred in 38 patients.
5.6
Immune-Mediated Skin Adverse Reactions
Additions
and/or revisions underlined:
OPDIVO with Ipilimumab
OPDIVO
1 mg/kg with Ipilimumab 3 mg/kg
Immune-mediated rash occurred in 22.6% (92/407)
of patients with melanoma and 35% (17/49) of patients with HCC who received
OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks. Median time to onset was
18 days (range: 1 day to 9.7 months) in patients with melanoma and 15 days (range:
6 days to 3.1 months) in patients with HCC.
Immune-mediated rash led to permanent
discontinuation of OPDIVO with ipilimumab in 0.4% of patients with melanoma or
HCC (n=456) and withholding of OPDIVO with ipilimumab in 4.4%. All patients
with rash required systemic corticosteroids, including 18% who received high-dose
corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration
of 12 days (1 day to 5.3 months). Complete resolution occurred
in 52% of patients. Of the 20 patients in whom OPDIVO or ipilimumab was
withheld for rash, 12 reinitiated treatment after symptom improvement;
of these, 17% (2/12) had recurrence of rash.
5.9
Infusion-Related Reactions
Additions
and/or revisions underlined:
OPDIVO with Ipilimumab
OPDIVO
1 mg/kg with Ipilimumab 3 mg/kg
Infusion-related reactions occurred in 2.5%
(10/407) of patients with melanoma and in 8% (4/49) of patients with HCC who
received OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks.
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions
and/or revisions underlined:
… CHECKMATE-039 or a single-arm trial in NSCLC
(n=117); OPDIVO 1 mg/kg with ipilimumab 3 mg/kg in patients enrolled in CHECKMATE-067
(n=313), CHECKMATE-040 (n=49), or another randomized trial (n=94); and OPDIVO
3 mg/kg administered with ipilimumab 1 mg/kg (n=666) in patients enrolled in CHECKMATE-214
or CHECKMATE-142.
Following
Table 21: additions and/or revisions underlined:
MSI-H or dMMR Metastatic Colorectal Cancer
… In the OPDIVO with ipilimumab cohort,
serious adverse reactions occurred in 47% of patients …
Following
Table 23: additions and/or revisions underlined:
Hepatocellular Carcinoma
The safety of OPDIVO 3 mg/kg every 2 weeks
as a single agent was evaluated in a 154-patient subgroup of patients with HCC
and Child-Pugh Class A cirrhosis who progressed on or were intolerant to
sorafenib. These patients enrolled in Cohorts 1 and 2 of CHECKMATE-040,
a multicenter, multiple cohort, open-label trial [see Clinical Studies (14.10)]. Patients were required to have an AST
and ALT ?5 x ULN and total bilirubin <3 mg/dL. The median duration of exposure
to OPDIVO was 5 months (range: 0 to 22+ months). Serious adverse reactions occurred
in 49% of patients. The most frequent serious adverse reactions reported in at least
2% of patients were pyrexia, ascites, back pain, general physical health deterioration,
abdominal pain, pneumonia, and anemia.
The toxicity profile observed in these patients
with advanced HCC … Immune-mediated hepatitis requiring systemic corticosteroids
occurred in 8 (5%) patients.
The safety of OPDIVO 1 mg/kg in combination
with ipilimumab 3 mg/kg was evaluated in a subgroup comprising 49 patients with
HCC and Child-Pugh Class A cirrhosis enrolled in Cohort 4 of the CHECKMATE-040 trial
who progressed on or were intolerant to sorafenib. OPDIVO and ipilimumab were administered
every 3 weeks for 4 doses, followed by single-agent OPDIVO 240 mg every 2 weeks
until disease progression or unacceptable toxicity. During the OPDIVO and ipilimumab
combination period, 33 of 49 (67%) patients received all 4 planned doses of OPDIVO
and ipilimumab. During the entire treatment period, the median duration of
exposure to OPDIVO was 5.1 months (range: 0 to 35+ months) and to ipilimumab was
2.1 months (range: 0 to 4.5 months). Forty-seven percent of patients were exposed
to treatment for >6 months, and 35% of patients were exposed to treatment for
>1 year. Serious adverse reactions occurred in 59% of patients. Treatment was
discontinued in 29% of patients and delayed in 65% of patients for an adverse
reaction.
The most frequent serious adverse reactions
(reported in greater than or equal to 4% of patients) were pyrexia, diarrhea, anemia,
increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia,
increased blood bilirubin, and pneumonitis.
Tables 24 and 25 summarize the adverse reactions
and laboratory abnormalities, respectively, in CHECKMATE-040. Based on the design
of the study, the data below cannot be used to identify statistically significant
differences between the cohorts summarized below for any adverse reaction.
Table
24 newly added; please refer to label for complete information.
Clinically important adverse reactions reported
in <10% of patients who received OPDIVO with ipilimumab were hyperglycemia (8%),
colitis (4%), and increased blood creatine phosphokinase (2%).
Table
25 newly added; please refer to label for complete information.
In patients who received OPDIVO with ipilimumab,
virologic breakthrough occurred in 4 of 28 (14%) patients and 2 of 4 (50%) patients
with active HBV or HCV at baseline, respectively. In patients who received single-agent
OPDIVO, virologic breakthrough occurred in 5 of 47 (11%) patients and 1 of 32 (3%)
patients with active HBV or HCV at baseline, respectively. HBV virologic breakthrough
was defined as at least a 1 log increase in HBV DNA for those patients with detectable
HBV DNA at baseline. HCV virologic breakthrough was defined as a 1 log increase
in HCV RNA from baseline.
6.2 Immunogenicity
Additions
and/or revisions underlined:
… Of the patients with melanoma, advanced renal
cell carcinoma, and metastatic colorectal cancer who were treated with OPDIVO and
ipilimumab and evaluable for the presence of anti-nivolumab antibodies, the incidence
of anti-nivolumab antibodies was 26% (132/516) with OPDIVO 3 mg/kg followed by ipilimumab
1 mg/kg every 3 weeks and 38% (149/394) with OPDIVO 1 mg/kg followed by ipilimumab
3 mg/kg every 3 weeks … with OPDIVO 1 mg/kg followed by ipilimumab 3 mg/kg every
3 weeks.
Of the patients with hepatocellular carcinoma
who were treated with OPDIVO and ipilimumab every 3 weeks for 4 doses followed by
OPDIVO every 3 weeks and were evaluable for the presence of anti-nivolumab antibodies,
the incidence of anti-nivolumab antibodies was 45% (20/44) with OPDIVO 3 mg/kg followed
by ipilimumab 1 mg/kg and 56% (27/48) with OPDIVO 1 mg/kg followed by ipilimumab
3 mg/kg; the corresponding incidence of neutralizing antibodies against nivolumab
was 14% (6/44) and 23% (11/48), respectively.
8
Use in Specific Populations
8.5 Geriatric Use
Newly
added information to the bottom of the subsection:
Of the 49 patients who received OPDIVO 1 mg/kg
in combination with ipilimumab 3 mg/kg in CHECKMATE-040 (hepatocellular carcinoma),
29% were between 65 years and 74 years of age and 8% were 75 years or older. Clinical
studies of OPDIVO in combination with ipilimumab did not include sufficient numbers
of patients with hepatocellular carcinoma aged 65 and over to determine whether
they respond differently from younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions
and/or revisions underlined:
What is OPDIVO?
OPDIVO is a prescription medicine used to
treat:
The
most common side effects of OPDIVO when used in combination with ipilimumab
include:
Addition
of the following:
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Immune-Mediated Pneumonitis
(additions
underlined)
…
OPDIVO
with Ipilimumab
![]()
OPDIVO
1 mg/kg with Ipilimumab 3 mg/kg
In patients receiving OPDIVO 1 mg/kg with ipilimumab
3 mg/kg every 3 weeks, immune- mediated pneumonitis occurred in 6%
(25/407) of patients. The median time to onset of immune- mediated pneumonitis
was 1.6 months (range: 24 days to 10.1 months). Immune-mediated pneumonitis led
to permanent discontinuation or withholding of OPDIVO with ipilimumab in 2.2% and
3.7% of patients, respectively. Approximately 84% of patients with pneumonitis
received high-dose corticosteroids (at least
40 mg prednisone equivalents per day) for a median duration of 30 days (range:
5 days to 11.8 months). Complete resolution occurred in 68% of patients. Approximately
13% of patients had recurrence of pneumonitis after re-initiation of OPDIVO with
ipilimumab.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg
In patients receiving OPDIVO 3 mg/kg with
ipilimumab 1 mg/kg every 3 weeks, immune- mediated pneumonitis occurred in 4.4%
(24/547) of patients. The median time to onset of immune- mediated pneumonitis
was 2.6 months (range: 8 days to 9.2 months). Immune-mediated pneumonitis led
to permanent discontinuation or withholding of OPDIVO with ipilimumab in 2.0%
and 1.6% of patients, respectively. Approximately 92% of patients with
pneumonitis received high-dose corticosteroids (at least 40 mg prednisone
equivalents per day) for a median duration of 19 days (range: 4 days to 3.2
months). Approximately 8% of patients required addition of infliximab to
high-dose corticosteroids. Complete resolution occurred in 79% of patients
without recurrence of pneumonitis after re-initiation of OPDIVO with
ipilimumab.
5.2 Immune-Mediated Colitis
(additions underlined)
…
OPDIVO with
Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg
![]()
In patients receiving OPDIVO 1 mg/kg with
ipilimumab 3 mg/kg every 3 weeks, immune- mediated colitis occurred in
26% (107/407) of patients including three fatal cases. The median time to onset
of immune-mediated colitis was 1.6 months (range: 3 days to 15.2 months).
Immune- mediated colitis led to permanent discontinuation or withholding of
OPDIVO with ipilimumab in 16% and 7% of patients, respectively. Approximately
96% of patients with colitis received high- dose corticosteroids (at least 40
mg prednisone equivalents per day) for a median duration of 1.1 month (range: 1
day to 12 months). Approximately 23% of patients required addition of
infliximab to high-dose corticosteroids. Complete resolution occurred in 75% of
patients. Approximately 28% of patients had recurrence of colitis after
re-initiation of OPDIVO with ipilimumab.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg
In patients receiving OPDIVO 3 mg/kg with ipilimumab
1 mg/kg every 3 weeks, immune- mediated colitis occurred in 10% (52/547) of
patients. The median time to onset of immune- mediated colitis was 1.7 months
(range: 2 days to 19.2 months). Immune-mediated colitis led to permanent
discontinuation or withholding of OPDIVO with ipilimumab in 3.5% and 4.2% of
patients, respectively. Approximately 83% of patients with colitis received
high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a
median duration of 21 days (range: 1 day to 27 months). Approximately 23% of
patients required addition of infliximab to high-dose corticosteroids. Complete
resolution occurred in 89% of patients. Two patients had recurrence of colitis after re-initiation of OPDIVO with
ipilimumab.
5.3 Immune-Mediated Hepatitis
(additions
underlined)
…
OPDIVO
with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg
![]()
In patients receiving OPDIVO 1 mg/kg with ipilimumab
3 mg/kg every 3 weeks, immune- mediated hepatitis occurred in 13% (51/407) of
patients; the median time to onset was 2.1 months (range: 15 days to 11
months). Immune-mediated hepatitis led to permanent discontinuation or
withholding of OPDIVO with ipilimumab in 6% and 5% of patients, respectively.
Approximately 92% of patients with hepatitis received high-dose corticosteroids
(at least 40 mg prednisone equivalents per day) for a median duration of 1.1
month (range: 1 day to 13.2 months). Complete resolution occurred in 75% of
patients. Approximately 11% of patients had recurrence of hepatitis after
re-initiation of OPDIVO with ipilimumab.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg
In patients receiving OPDIVO 3 mg/kg with ipilimumab
1 mg/kg every 3 weeks, immune- mediated hepatitis occurred in 7% (38/547) of
patients; the median time to onset was 2 months (range: 14 days to 26.8
months). Immune-mediated hepatitis led to permanent discontinuation or ![]()
withholding of OPDIVO with ipilimumab in 3.7% and
3.1% of patients, respectively. Approximately 92% of patients with hepatitis
received high-dose corticosteroids (at least 40 mg prednisone equivalents per
day) for a median duration of 1.0 month (range: 1 day to 4.0 months). Complete
resolution occurred in 87% of patients without recurrence of hepatitis after
re-initiation of OPDIVO with ipilimumab.
5.4 Immune-Mediated Endocrinopathies Hypophysitis
(additions underlined)
…
OPDIVO
as a Single Agent
In patients receiving OPDIVO as a single agent, hypophysitis
occurred in 0.6% (12/1994) of patients; the median time to onset was 4.9 months
(range: 1.4 to 11 months). Hypophysitis led to permanent discontinuation of OPDIVO
in 0.1% and withholding of OPDIVO in 0.2% of patients. Approximately 67% of
patients with hypophysitis received hormone replacement therapy and 33% received
high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a
median duration of 14 days (range: 5 to 26 days).
OPDIVO
with Ipilimumab
![]()
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg
In patients receiving OPDIVO 1 mg/kg with ipilimumab
3 mg/kg every 3 weeks, hypophysitis occurred in 9% (36/407) of patients;
the median time to onset was 2.7 months (range: 27 days to
5.5 months). Hypophysitis led to permanent
discontinuation or withholding of OPDIVO with ipilimumab in 1.0% and 3.9% of patients,
respectively. Approximately 75% of patients with hypophysitis received hormone replacement
therapy and 56% received high-dose corticosteroids (at least 40 mg prednisone
equivalents per day) for a median duration of 19 days (range: 1 day to
2.0 months).
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg
In patients receiving OPDIVO 3 mg/kg with ipilimumab
1 mg/kg every 3 weeks, hypophysitis occurred in 4.6% (25/547) of patients; the
median time to onset was 2.8 months (range: 1.3 months to 7.3 months).
Hypophysitis led to permanent discontinuation or withholding of OPDIVO with
ipilimumab in 1.3% and 2.6% of patients, respectively. Approximately 72% of
patients with hypophysitis received hormone replacement therapy and 60%
received high-dose corticosteroids (at least 40 mg prednisone equivalents per
day) for a median duration of 10 days (range: 1 day to 1.6 months).
Adrenal
Insufficiency
…
OPDIVO as a Single Agent
In
patients receiving OPDIVO as a single agent, adrenal insufficiency occurred in 1%
(20/1994) of patients and the median time to onset was 4.3 months (range: 15 days
to 21 months). Adrenal insufficiency led to permanent discontinuation of OPDIVO
in 0.1% and withholding of OPDIVO in 0.5% of patients. Approximately 85% of
patients with adrenal insufficiency received hormone replacement therapy and 25%
received high-dose corticosteroids (at least 40 mg prednisone equivalents per day)
for a median duration of 11 days (range: 1 day to 1 month).
![]()
OPDIVO with
Ipilimumab
OPDIVO
1 mg/kg with Ipilimumab 3 mg/kg
In
patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3
weeks, adrenal insufficiency occurred in 5% (21/407) of patients and the median
time to onset was 3.0 months (range: 21 days to 9.4 months). Adrenal insufficiency
led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 0.5%
and 1.7% of patients, respectively. Approximately 57% of patients with adrenal
insufficiency received hormone replacement therapy and 33% received high-dose corticosteroids
(at least 40 mg prednisone equivalents per day) for a median duration of 9 days
(range: 1 day to 2.7 months).
OPDIVO
3 mg/kg with Ipilimumab 1 mg/kg
In
patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks,
adrenal insufficiency occurred in 7% (41/547) of patients and the median time
to onset was 3.4 months (range: 2.0 months to 22.3 months). Adrenal
insufficiency led to permanent discontinuation or withholding of OPDIVO with
ipilimumab in 1.3% and 2.0% of patients, respectively Approximately 93% of
patients with adrenal insufficiency received hormone replacement therapy and
18% received high-dose corticosteroids (at least 40 mg prednisone equivalents
per day) for a median duration of 12 days (range: 1 day to 5.6 months).
Hypothyroidism and
Hyperthyroidism
…
OPDIVO as a Single Agent
In
patients receiving OPDIVO as a single agent, hypothyroidism or thyroiditis resulting
in hypothyroidism occurred in 9% (171/1994) of patients; the median time to onset
was 2.9 months (range: 1 day to 16.6 months). Approximately 79% of patients with
hypothyroidism received levothyroxine and 4% also required corticosteroids. Resolution
occurred in 35% of patients.
Hyperthyroidism
occurred in 2.7% (54/1994) of patients receiving OPDIVO as a single agent; the median
time to onset was 1.5 months (range: 1 day to 14.2 months). Approximately 26% of
patients with hyperthyroidism received methimazole, 9% received carbimazole, 4%
received propylthiouracil, and 9% received corticosteroids. Resolution occurred
in 76% of patients.
![]()
OPDIVO with
Ipilimumab
OPDIVO
1 mg/kg with Ipilimumab 3 mg/kg
In
patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3
weeks, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in
22% (89/407) of patients; the median time to onset was 2.1 months (range: 1 day
to 10.1 months). Approximately 73% of patients with hypothyroidism or thyroiditis
received levothyroxine. Resolution occurred in 45% of patients.
Hyperthyroidism
occurred in 8% (34/407) of patients receiving OPDIVO with ipilimumab: the median
time to onset was 23 days (range: 3 days to 3.7 months). Approximately 29% of patients
with hyperthyroidism received methimazole and 24% received carbimazole.
Resolution occurred in 94% of patients.
OPDIVO
3 mg/kg with Ipilimumab 1 mg/kg
In
patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks,
hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22%
(119/547) of patients; the median time to onset was 2.2 months (range: 1 day to
21.4 months). Approximately 76% of patients with hypothyroidism or thyroiditis
received levothyroxine. Resolution occurred in 31% of patients.
Hyperthyroidism
occurred in 12% (66/547) of patients receiving OPDIVO with ipilimumab: the
median time to onset was 1.4 months (range: 6 days to 14.2 months).
Approximately 14% of patients with hyperthyroidism received methimazole and 3%
received carbimazole. Resolution occurred in 85% of patients.
Type 1 Diabetes Mellitus
…
OPDIVO as a Single Agent
In
patients receiving OPDIVO as a single agent, diabetes occurred in 0.9% (17/1994)
of patients including two cases of diabetic ketoacidosis. The median time to onset
was 4.4 months (range: 15 days to 22 months).
![]()
OPDIVO with
Ipilimumab
OPDIVO
1 mg/kg with Ipilimumab 3 mg/kg
In
patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3
weeks, diabetes occurred in 1.5% (6/407) of patients; the median time to onset
was 2.5 months (range: 1.3 to 4.4 months). OPDIVO with ipilimumab was withheld in
a patient and permanently discontinued in a second patient who developed
diabetes.
OPDIVO
3 mg/kg with Ipilimumab 1 mg/kg
In
patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks,
diabetes occurred in 2.7% (15/547) of patients; the median time to onset was
3.2 months (range: 19 days to 16.8 months). OPDIVO with ipilimumab was withheld
in 33% of patients and permanently discontinued in 20% of patients who
developed diabetes.
5.5 Immune-Mediated Nephritis and Renal Dysfunction
(additions
underlined)
…
OPDIVO with Ipilimumab
OPDIVO
1 mg/kg with Ipilimumab 3 mg/kg
In
patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, immune-
mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients; the
median time to onset was 2.7 months (range: 9 days to 7.9 months).
Immune-mediated nephritis and renal dysfunction led to permanent discontinuation
or withholding of OPDIVO with ipilimumab in 0.7%![]()
and 0.5% of patients, respectively. Approximately
67% of patients received high-dose corticosteroids (at least 40 mg prednisone
equivalents per day) for a median duration of 13.5 days (range: 1 day to 1.1 months).
Complete resolution occurred in all patients. Two patients resumed OPDIVO with ipilimumab
without recurrence of nephritis or renal dysfunction.
OPDIVO
3 mg/kg with Ipilimumab 1 mg/kg
In
patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks,
immune- mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of
patients; the median time to onset was 2.5 months (range: 1 day to 13.2
months). Immune-mediated nephritis and renal dysfunction led to permanent
discontinuation or withholding of OPDIVO with ipilimumab in 1.1% and 2.7% of
patients, respectively. Approximately 76% of patients received high-dose
corticosteroids (at least 40 mg prednisone equivalents per day) for a median
duration of 15 days (range: 1 day to 5.9 months). Complete resolution occurred
in 64% of patients. One patient had recurrence of nephritis or renal
dysfunction after re-initiation of OPDIVO with ipilimumab.
5.6 Immune-Mediated Skin Adverse Reactions
(additions underlined)
…
OPDIVO with
Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg
![]()
In patients receiving OPDIVO 1 mg/kg with ipilimumab
3 mg/kg every 3 weeks, immune- mediated rash occurred in 22.6% (92/407) of
patients; the median time to onset was 18 days (range: 1 day to 9.7 months).
Immune-mediated rash led to permanent discontinuation or withholding of OPDIVO with
ipilimumab in 0.5% and 3.9% of patients, respectively. Approximately 17% of
patients with rash received high-dose corticosteroids (at least 40 mg prednisone
equivalents per
![]()
day) for a median duration of 14 days (range: 2 days
to 4.7 months). Complete resolution occurred in 47% of patients. Approximately 6%
of patients who resumed OPDIVO and ipilimumab after resolution had recurrence
of rash.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg
In patients receiving OPDIVO 3 mg/kg with ipilimumab
1 mg/kg every 3 weeks, immune- mediated rash occurred in 16.6% (91/547) of
patients; the median time to onset was 1.5 months (range: 1 day to 20.9
months). Immune-mediated rash led to permanent discontinuation or withholding
of OPDIVO with ipilimumab in 0.5% and 2.9% of patients, respectively.
Approximately 19% of patients with rash received high-dose corticosteroids (at
least 40 mg prednisone equivalents per day) for a median duration of 25 days
(range: 1 day to 23.1 months). Complete resolution occurred in 64% of patients.
Approximately 3.6% of patients who resumed OPDIVO and ipilimumab after
resolution had recurrence of rash.
5.7 Immune-Mediated Encephalitis
(additions underlined)
…
![]()
OPDIVO with
Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg
Encephalitis occurred in one patient (0.2%) receiving
OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks after 1.7 months
of exposure.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg
Encephalitis occurred in one patient receiving
OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks (0.2%) after approximately
4 months of exposure.
5.8 Other Immune-Mediated Adverse Reactions
(additions underlined)
…
![]()
Across clinical trials of OPDIVO administered as a single
agent or in combination with ipilimumab, the following clinically significant immune-mediated
adverse reactions, some with fatal outcome, occurred in less than 1.0% of
patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis,
pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica,
autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory
response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis
(Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia,
pericarditis, and myasthenic syndrome.
…
5.9 Infusion Reactions
(additions underlined)
…
OPDIVO with
Ipilimumab
![]()
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg
In patients receiving OPDIVO 1 mg/kg with ipilimumab
3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407)
of patients.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg
![]()
In patients receiving OPDIVO 3 mg/kg with ipilimumab
1 mg/kg every 3 weeks, infusion-related reactions occurred in 5.1% (28/547) of
patients.
6
Adverse Reactions
6.1 Clinical Trials Experience
(extensive additions, please refer to
label)
6.3 Immunogenicity
(additions underlined)
…
Of the patients who were treated with OPDIVO and
ipilimumab and evaluable for the presence of anti-nivolumab antibodies, the
incidence of anti-nivolumab antibodies was 26.0% with nivolumab 3 mg/kg
followed by ipilimumab 1 mg/kg every 3 weeks and 37.8% with nivolumab 1
mg/kg followed by ipilimumab 3 mg/kg every 3 weeks. The incidence of neutralizing
antibodies against nivolumab was 0.5% with nivolumab 3 mg/kg followed by
ipilimumab 1 mg/kg every 3 weeks and 4.6% with nivolumab 1 mg/kg followed by
ipilimumab 3 mg/kg every 3 weeks. Of patients evaluable for the presence of
anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies ranged
from 6.3 to 8.4% and neutralizing antibodies against ipilimumab ranged
from 0 to 0.3%.
Overall, there was no evidence of increased
incidence of infusion reactions or effects on efficacy with anti-nivolumab
antibody development.
…
8
Use in Specific Populations
8.5 Geriatric Use
…
Of the 550 patients randomized to ipilimumab 1 mg/kg
administered with nivolumab 3 mg/kg in CHECKMATE-214 (Renal Cell Carcinoma),
38% were 65 years or older and 8% were 75 years or older. No overall difference
in safety was reported between elderly patients and younger patients. In
elderly patients with intermediate or poor risk, no overall difference in
effectiveness was reported.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(additions underlined)
…
Call or see your healthcare provider right
away if you develop any symptoms of the following problems or these symptoms
get worse:
Liver problems (hepatitis). Signs and symptoms of hepatitis may include:
yellowing of your
skin or the whites of your eyes
dark urine (tea
colored)
severe nausea or vomiting
bleeding or
bruising more easily than normal
pain on the right
side of your stomach area
feeling less hungry
than usual (abdomen)
decreased
energy
drowsiness
...
Problems
in other organs. Signs of these
problems may include:
…
What
is OPDIVO?
OPDIVO is a prescription medicine used to treat:
…
…
The
most common side effects of OPDIVO when used in combination with ipilimumab
include:
…
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions are underlined)
…Also described below are single-agent OPDIVO data from CHECKMATE-238,
a randomized trial for the adjuvant treatment of patients with completely
resected Stage IIIB/C and IV melanoma, CHECKMATE-017 and CHECKMATE-057,
which are randomized trials in patients with metastatic NSCLC, CHECKMATE-025,
which is a randomized trial in patients with advanced RCC, CHECKMATE-205 and CHECKMATE-039,
which are open-label, multiple-cohort trials
in patients with cHL, CHECKMATE-141, a randomized trial in patients with
recurrent or metastatic SCCHN, CHECKMATE-275, which is a single-arm trial in
patients with urothelial carcinoma, and CHECKMATE-040, which is an open- label,
multiple-cohort trial in patients with HCC.
…
Adjuvant Treatment of Melanoma
The safety of OPDIVO as a single agent was evaluated in
CHECKMATE-238, a randomized (1:1), double-blind trial in which 905 patients
with completely resected Stage IIIB/C or Stage IV melanoma received OPDIVO 3
mg/kg administered as an intravenous infusion every 2 weeks (n=452) or
ipilimumab 10 mg/kg (n=453), administered as an intravenous infusion every 3
weeks for 4 doses then every 12 weeks beginning at Week 24 for up to a 1 year.
The median duration of exposure was 11.5 months in OPDIVO-treated patients and
was 2.7 months in ipilimumab-treated patients. In this ongoing trial, 74% of
patients received OPDIVO for greater than 6 months.
Study therapy was discontinued for adverse reactions in 9% of
OPDIVO-treated patients and 42% of ipilimumab-treated patients. Twenty-eight
percent of OPDIVO-treated patients had at least one omitted dose for an adverse
reaction. Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated
patients. The most frequent Grade 3 and 4 adverse reactions reported in at
least 2% of OPDIVO-treated patients were diarrhea and increased lipase and
amylase. Serious adverse reactions occurred in 18% of OPDIVO-treated patients.
The most common adverse reactions (reported in at least 20% of
OPDIVO-treated patients) were fatigue, diarrhea, rash, musculoskeletal pain,
pruritus, headache, nausea, upper respiratory infection, and abdominal pain.
The most common immune-mediated adverse reactions were rash (16%),
diarrhea/colitis (6%), and hepatitis (3%).
Table 8 summarizes the adverse reactions that occurred in at least
10% of OPDIVO-treated patients in CHECKMATE-238.
Table 8: Adverse Reactions Occurring in Greater than or Equal to
10% of OPDIVO-Treated Patients (CHECKMATE-238) (Table has been added; please
refer to label)
Table 9: Laboratory Abnormalities Worsening from Baseline
Occurring in Greater than or
Equal to 10% of OPDIVO-Treated Patients
(CHECKMATE-238) (Table has been added; please refer to
label)
8
Use in Specific Populations
8.4 Pediatric Use
(Additions and/or revisions are underlined)
…The safety and effectiveness of OPDIVO have not been
established (1) in pediatric patients less than 12 years old with MSI-H or dMMR
mCRC or (2) in pediatric patients less than 18 years old for the other
approved indications.
8.5 Geriatric Use
(Additions and/or revisions are underlined)
…
In CHECKMATE-238 (Adjuvant Treatment of Melanoma), 26% of patients
were 65 years or older and 3% were 75 years or older. No overall differences in
safety or effectiveness were reported between elderly patients and younger
patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(Additions and/or revisions are underlined)
What is OPDIVO?
OPDIVO is a prescription medicine used to treat:
people
with a type of skin cancer called melanoma:
that
has spread or cannot be removed by surgery (advanced melanoma). You may receive
OPDIVO alone or in combination with ipilimumab, or
to
help prevent melanoma from coming back after it and lymph nodes that contain
cancer have been removed by surgery.
…
OPDIVO
may be used when your colon or rectal cancer:
has
spread to other parts of the body (metastatic),
is
mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H), and
you
have tried chemotherapy with a fluoropyrimidine, oxaliplatin, and
irinotecan, and it did not work or is no longer working.
It is not known if OPDIVO is safe and effective :
in children less than 12 years of age with
MSI-H or dMMR metastatic colorectal cancer, or
in children less than 18 years of age for the
treatment of any other cancers.
What are the possible side effects
of OPDIVO?
The most common side effects of
OPDIVO when used alone include:
…
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
… Also
described below are single-agent OPDIVO data from Trials 2 and 3, which are
randomized trials in patients with metastatic NSCLC, Trial 5, which is a
randomized trial in patients with advanced RCC, Trials 7 and 8, which are
open-label, multiple-cohort trials in patients with cHL, and Trial 9, a
randomized trial in patients with recurrent or metastatic SCCHN.
Trial 4
The
trial population
characteristics in the OPDIVO group
and dacarbazine group…
Trial
6
The trial population characteristics were: 65% male, median age 61 years…
Following
Table 13 – addition of the following:
Recurrent or Metastatic Squamous Cell
Carcinoma of the Head and Neck
The safety of OPDIVO was evaluated in
Trial 9, a randomized, active-controlled, open-label, multicenter trial in patients
with recurrent or metastatic SCCHN with progression during or within 6 months
of receiving prior platinum-based therapy [see
Clinical Studies (14.5)]. Patients received 3 mg/kg of OPDIVO (n=236)
administered intravenously (IV) over 60 minutes every 2 weeks or investigator’s
choice of either:
-
cetuximab
(n=13), 400 mg/m2 loading dose IV followed by 250 mg/m2 weekly
-
or
methotrexate (n=46) 40 to 60 mg/m2 IV weekly, or
-
docetaxel
(n=52) 30 to 40 mg/m2 IV weekly.
The median duration of exposure to nivolumab
was 1.9 months (range 1 day to 16.1+ months) in OPDIVO-treated patients. In
this trial, 18% of patients received OPDIVO for greater than 6 months and 2.5%
of patients received OPDIVO for greater than 1 year.
Trial 9 excluded patients with active
autoimmune disease, medical conditions requiring systemic immunosuppression, or
recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma
of unknown primary histology, salivary gland or non-squamous histologies (e.g.,
mucosal melanoma).
The median age of all randomized patients
was 60 years (range: 28 to 83); 28% of patients in the OPDIVO
group were 65 years of age and 37% in the comparator group were 65 years of
age, 83%
were male and 83% were White, 12% were Asian, and 4% were Black. Baseline ECOG
performance status was 0 (20%) or 1 (78%), 45% of patients received only one
prior line of systemic therapy, the remaining 55% of patients had two or more
prior lines of therapy, and 90% had prior radiation therapy.
OPDIVO was discontinued in 14% of patients
and was delayed in 24% of patients for an adverse reaction. Serious adverse
reactions occurred in 49% of patients receiving OPDIVO. The most frequent
serious adverse reactions reported in at least 2% of patients receiving OPDIVO
were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and
sepsis. Adverse reactions and laboratory abnormalities occurring in patients
with SCCHN were generally similar to those occurring in
patients with melanoma
and NSCLC. The
most common adverse
reactions occurring in >10% of OPDIVO-treated patients and at
a higher incidence than investigator’s choice were cough and dyspnea.
The most common laboratory abnormalities
occurring in ?10% of OPDIVO-treated patients and at a higher incidence than
investigator’s choice were increased alkaline phosphatase, increased amylase,
hypercalcemia, hyperkalemia, and increased TSH.
8
Use in Specific Populations
8.5 Geriatric Use
Of
the 1359 patients randomized to single-agent OPDIVO in Trials 2
through 6, 39% were 65 years or older and
9% were 75 years or older. No overall differences in safety or effectiveness
were reported between elderly patients and younger patients.
In Trials 1, 7, 8, and 9
did not include sufficient numbers of patients aged 65 years and older to determine
whether they respond differently from younger patients.
Of the 314 patients randomized to OPDIVO administered
with ipilimumab in Trial 6, 41% were 65
years or older
and 11% were
75 years or
older. No overall
differences in safety
or effectiveness were reported between
elderly patients and younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
What
is the most important information I should know about OPDIVO?
OPDIVO
is a medicine that may treat your melanoma, lung cancer, kidney cancer, blood cancer,
or head and neck cancer by working with your immune system.
What
is OPDIVO?
OPDIVO
is a prescription medicine used to treat:
head and neck cancer
OPDIVO
may be used when your head and neck cancer:
o has come back or spread, and
o you have tried chemotherapy that
contains platinum and it did not work or is no longer working.
The
most common side effects of OPDIVO when used alone include:
Addition of weakness
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Immune-Mediated Pneumonitis
OPDIVO can cause immune-mediated
pneumonitis, defined as requiring use of corticosteroids
and no clear alternate etiology. Fatal cases have been reported.
Monitor patients for signs with radiographic imaging and for
symptoms of pneumonitis.
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for moderate
(Grade 2) or more severe (Grade 3-4) pneumonitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for severe
(Grade 3)
or life-threatening (Grade 4) pneumonitis and withhold OPDIVO until resolution for moderate (Grade 2) pneumonitis.
OPDIVO as
a Single Agent
In
patients receiving OPDIVO as a single agent, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. The median time to onset of immune-mediated pneumonitis
was 3.5 months (range: 1 day
to 22.3
months). Immune-mediated pneumonitis
led
to
permanent discontinuation of OPDIVO in
1.1%, and withholding of OPDIVO
in 1.3% of patients. Approximately 89%
of patients with pneumonitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median
duration of 26 days (range: 1 day to 6 months).
Complete resolution of symptoms following
corticosteroid taper occurred in 67% of patients.
Approximately 8% of patients
had recurrence of pneumonitis after re-initiation of OPDIVO.
OPDIVO
with Ipilimumab
In
patients receiving OPDIVO with ipilimumab, immune-mediated pneumonitis
occurred in 6% (25/407) of patients. The median time to onset of
immune-mediated pneumonitis was 1.6 months (range: 24 days to 10.1 months).
Immune-mediated pneumonitis led to permanent
discontinuation or withholding of OPDIVO with ipilimumab in 2.2% and 3.7% of patients,
respectively. Approximately 84% of patients
with
pneumonitis received high-dose
corticosteroids (at least 40
mg prednisone equivalents per day) for a median duration of 30 days
(range: 5 days to 11.8 months). Complete
resolution occurred in 68%
of patients. Approximately 13% of patients had recurrence of pneumonitis after
re-initiation of
OPDIVO with ipilimumab.
5.2 Immune-Mediated Colitis
OPDIVO can cause immune-mediated
colitis, defined as requiring use of corticosteroids with no clear alternate
etiology.
Withhold OPDIVO for moderate
or severe (Grade 2 or 3) colitis. Permanently discontinue OPDIVO for life-threatening (Grade 4) or for recurrent
colitis upon re-initiation
of OPDIVO.
When administered
in combination with ipilimumab, withhold OPDIVO and ipilimumab for moderate colitis (Grade 2). Permanently discontinue OPDIVO and ipilimumab
for severe or life- threatening …
OPDIVO as
a Single Agent
In patients receiving OPDIVO as a single agent, immune-mediated colitis occurred
in 2.9% (58/1994) of patients; the median time to onset was
5.3 months (range: 2 days to 20.9 months). Immune-mediated
colitis led to permanent
discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 1% of patients.
Approximately 91% of
patients with colitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day)
for a median duration of 23 days (range: 1 day to 9.3 months).
Four patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 74% of patients. Approximately 16% of patients had recurrence of colitis after re-initiation of OPDIVO.
OPDIVO
with Ipilimumab
In patients
receiving OPDIVO with
ipilimumab, immune-mediated colitis occurred in 26% (107/407) of patients
including three fatal cases. The median time to onset of immune-mediated
colitis was 1.6 months (range: 3 days to 15.2 months). Immune-mediated colitis
led to permanent
discontinuation or withholding of OPDIVO
with ipilimumab in
16% and 7% of patients, respectively. Approximately 96% of
patients
with colitis received high-dose corticosteroids (at
least 40 mg prednisone equivalents per day) for a median duration of 1.1 month (range: 1 day to
12 months).
Approximately
23% of patients required addition
of infliximab to high-dose corticosteroids. Complete resolution occurred in
75% of patients.
Approximately
28% of patients had recurrence
of colitis
after re-initiation of OPDIVO with ipilimumab.
5.3 Immune-Mediated Hepatitis
OPDIVO can cause immune-mediated hepatitis, defined as requiring use of corticosteroids and no clear alternate
etiology. Monitor patients for abnormal liver tests
prior to and periodically during treatment.
Administer
corticosteroids
at a
dose
of
1 to
2 mg/kg/day prednisone equivalents followed
by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) transaminase elevations, with or without concomitant elevation
in total bilirubin. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents for moderate (Grade 2)
transaminase elevations. Withhold OPDIVO
for moderate (Grade 2) and permanently
discontinue OPDIVO for severe
(Grade 3) or life-threatening (Grade 4) immune-mediated
hepatitis.
OPDIVO as
a Single Agent
In patients receiving
OPDIVO as a single agent, immune-mediated hepatitis occurred in
1.8% (35/1994) of patients;
the median time to onset was
3.3 months (range: 6 days to 9 months). Immune-mediated hepatitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 1% of patients. All patients with hepatitis received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration
of 23 days (range: 1 day
to 2 months). Two patients required
the addition of mycophenolic acid to high-dose corticosteroids. Complete resolution occurred in 74% of patients. Approximately 29% of patients had recurrence of hepatitis after re-initiation of OPDIVO.
OPDIVO
with Ipilimumab
In patients receiving OPDIVO with ipilimumab, immune-mediated hepatitis occurred in 13% (51/407) of patients; the median time to onset
was 2.1 months (range: 15 days to 11 months).
Immune-mediated hepatitis led to permanent discontinuation or withholding of OPDIVO with
ipilimumab in 6% and 5 % of
patients, respectively.
Approximately 92% of patients with hepatitis received
high-dose corticosteroids
(at least 40 mg prednisone equivalents per day) for a
median duration of 1.1 month (range:
1 day to 13.2 months). Complete resolution occurred
in 75% of patients. Approximately 11% of patients had recurrence of hepatitis
after re-initiation of OPDIVO with ipilimumab.
5.4 Immune-Mediated Endocrinopathies Hypophysitis
OPDIVO can cause immune-mediated
hypophysitis. Monitor patients
for signs and symptoms of
hypophysitis. Administer hormone replacement as clinically indicated and corticosteroids at a dose of 1mg/kg/day
prednisone equivalents
followed by corticosteroid taper
for moderate
(Grade 2) or greater hypophysitis...
In patients receiving OPDIVO as a single agent,
hypophysitis occurred in 0. 6% (12/1994) of patients; the median time to onset was 4.9 months
(range: 1.4 to 11 months).
Hypophysitis led to permanent discontinuation of
OPDIVO in 0.1%
and withholding of
OPDIVO in 0.2%
of patients. Approximately 67% of patients with hypophysitis
received hormone replacement therapy and 33% received high-dose corticosteroids (at least 40
mg
prednisone equivalents per day) for a median duration of 14
days (range: 5 to 26 days).
In patients receiving OPDIVO with ipilimumab,
hypophysitis occurred in 9% … Hypophysitis led to permanent discontinuation or
withholding of OPDIVO with ipilimumab in 1.0% and 3.9%
of patients, respectively. Approximately 75% of patients
with hypophysitis received hormone replacement therapy
and 56% received high-dose corticosteroids (at
least 40 mg prednisone
equivalents per day) for a median
duration of 19 days (range: 1 day to
2.0 months).
Adrenal Insufficiency
OPDIVO can
cause immune-mediated adrenal insufficiency…
Administer
corticosteroids at a dose of 1 to 2 mg/kg/day
prednisone equivalents followed by a corticosteroid taper for severe (Grade 3) or life-threatening
(Grade 4) adrenal insufficiency…
In patients receiving OPDIVO as a single agent,
adrenal insufficiency occurred in 1% (20/1994) of patients and the median time to onset was 4.3
months (range: 15 days to 21 months).
Adrenal insufficiency led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO
in 0.5% of patients. Approximately 85% of patients with adrenal insufficiency received
hormone replacement therapy and 25% received high-dose
corticosteroids (at least 40 mg prednisone equivalents per day) for
a median duration of 11 days (range: 1 day to 1
month).
In patients receiving OPDIVO with ipilimumab, adrenal insufficiency occurred
in 5% (21/407) of patients and the median time to onset
was 3.0 months (range: 21 days to 9.4
months).
Adrenal insufficiency led to permanent discontinuation or withholding of OPDIVO with ipilimumab in
0.5% and 1.7% of patients, respectively.
Approximately 57% of patients with
adrenal insufficiency received hormone replacement therapy
and 33% received high-dose
corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 9 days (range: 1 day to
2.7 months).
Hypothyroidism and Hyperthyroidism
OPDIVO can cause autoimmune thyroid disorders. Monitor thyroid function prior to and periodically
during OPDIVO treatment…
In
patients receiving OPDIVO as a single agent, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% ( 171/1994) of patients; the median time to onset was 2.9
months (range: 1 day to 16.6 months). Approximately 79% of patients with hypothyroidism
received levothyroxine and 4% also required
corticosteroids. Resolution occurred in 35% of patients.
Hyperthyroidism occurred
in 2.7% (54/1994) of patients receiving
OPDIVO as a single agent; the median time to onset was 1.5 months (range: 1day to 14.2
months). Approximately 26% of patients with hyperthyroidism
received methimazole, 9% received
carbimazole, 4% received propylthiouracil, and 9% received corticosteroids.
Resolution occurred in 76% of patients.
In
patients receiving OPDIVO with ipilimumab, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients; the median time to onset was 2.1 months
(range: 1 day to 10.1 months).
Approximately 73% of patients with hypothyroidism or thyroiditis
received levothyroxine. Resolution occurred in 45% of patients.
…the median time to onset was 23 days (range: 3 days to 3.7 months).
Approximately 29% of patients with hyperthyroidism received methimazole and 24% received carbimazole…
Type 1
Diabetes Mellitus
OPDIVO can cause Type 1 diabetes mellitus…
In patients receiving OPDIVO as a single agent,
diabetes occurred in 0. 9% (17/1994)
of patients including two cases of diabetic ketoacidosis. The median time to onset was
4.4 months (range: 15 days to 22 months).
In
patients receiving OPDIVO with ipilimumab, diabetes occurred in 1.5% ... OPDIVO
with ipilimumab was withheld in a patient
and permanently discontinued in a second patient who developed
diabetes.
5.5 Immune-Mediated Nephritis and Renal Dysfunction
OPDVIO can cause immune-mediated nephritis, defined
as renal dysfunction or greater than or equal to Grade 2
increased creatinine…Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid
taper for life-threatening (Grade 4) increased serum creatinine. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day
prednisone equivalents for moderate (Grade 2) or severe (Grade 3)
increased serum creatinine, if worsening or no improvement occurs, increase dose of
corticosteroids
to 1 to 2 mg/kg/day prednisone equivalents.
Withhold OPDIVO for moderate (Grade 2) or severe (Grade 3) increased serum creatinine. Permanently discontinue
OPDIVO for life-threatening (Grade 4) increased serum creatinine.
OPDIVO as
a Single Agent
In
patients receiving OPDIVO as a single agent, immune-mediated nephritis
and renal dysfunction occurred
in 1.2% (23/1994)
of patients; the median time to onset
was 4.6 months
(range: 23 days to 12.3 months).
Immune-mediated nephritis and
renal dysfunction led to permanent
discontinuation of OPDIVO
in 0.3% and
withholding of OPDIVO
in 0.8% of patients. All patients
received high-dose
corticosteroids (at least 40
mg
prednisone equivalents per
day) for a median duration of 21 days (range: 1 day to 15.4 months). Complete resolution occurred in 48% of patients. No
patients had recurrence of nephritis or renal dysfunction after re-initiation of OPDIVO.
OPDIVO
with Ipilimumab
In
patients receiving OPDIVO with ipilimumab, immune-mediated nephritis and renal
dysfunction occurred in 2.2% (9/407)
of patients; the median time to onset was 2.7 months (range: 9 days to
7.9 months). Immune-mediated nephritis
and renal dysfunction
led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 0.7% and 0.5% of
patients, respectively. Approximately 67% of patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration
of 13.5 days (range: 1 day to 1.1
months)…
5.6 Immune-Mediated Skin Adverse Reactions
OPDIVO can cause immune-mediated
rash, including Stevens-Johnson syndrome
(SJS) and toxic epidermal necrolysis (TEN), some cases with
fatal outcome. For symptoms or signs of SJS
or TEN, withhold OPDIVO and refer the
patient for specialized care for assessment
and treatment. If SJS or TEN is confirmed, permanently discontinue OPDIVO.
For immune-mediated
rash, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents
followed by a corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) rash...
OPDIVO as
a Single Agent
In patients receiving OPDIVO as a single agent, immune-mediated rash occurred in 9% (171/1994) of patients; the median time to onset was
2.8 months (range:
less than 1 day
to 25.8
months). Immune-mediated rash led to permanent discontinuation
of OPDIVO in 0.3% and withholding of OPDIVO in 0.8% of patients. Approximately 16%
of patients with
rash received high-dose corticosteroids (at least 40 mg prednisone
equivalents per day) for a median duration of 12
days (range: 1 days to 8.9 months) and 85% received
topical corticosteroids. Complete resolution occurred in 48% of patients. Recurrence of rash occurred in 1.4% of
patients who resumed
OPDIVO after resolution of rash.
OPDIVO
with Ipilimumab
In patients receiving OPDIVO with ipilimumab, immune-mediated rash occurred in 22.6%
(92/407) of patients; the median time to onset was 18 days (range: 1 day to 9.7 months).
Immune-mediated rash led to permanent
discontinuation or withholding of OPDIVO
with ipilimumab in 0.5% and 3.9% of patients, respectively. Approximately 17% of patients with rash received high-dose corticosteroids (at least 40 mg prednisone equivalents per day)
for a median duration of 14 days (range: 2 days
to 4.7 months).
Complete resolution occurred
in 47% of patients. Approximately 6%
of patients who resumed OPDIVO and ipilimumab…
5.7 Immune-Mediated Encephalitis
ODPIVO can cause immune-mediated encephalitis with no
clear alternate etiology. Evaluation
of patients with neurologic symptoms may
include, but not be limited to,
consultation with a neurologist, brain MRI, and lumbar puncture…
OPDIVO as
a Single Agent
In patients receiving OPDIVO as a single agent, encephalitis occurred
in 0.2% (3/1994). Fatal limbic encephalitis occurred in one patient after 7.2
months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. In the other two patients encephalitis occurred post-allogeneic HSCT.
OPDIVO with Ipilimumab
Encephalitis
occurred in one patient receiving OPDIVO with ipilimumab (0.2%)
after 1.7 months of
exposure.
5.8 Other Immune-Mediated Adverse Reactions
OPDIVO can cause other clinically significant
immune-mediated adverse reactions…
Across clinical trials of OPDIVO administered
as a
single agent or in combination with ipilimumab… gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis,
myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.
5.9 Infusion Reactions
OPDIVO can cause severe infusion reactions, which have been reported…
OPDIVO as
a Single Agent
In patients receiving OPDIVO as a
single agent, infusion-related reactions occurred in 6.4% (127/1994) of patients.
OPDIVO
with Ipilimumab
In patients receiving OPDIVO with ipilimumab, infusion-related reactions occurred in
2.5% (10/407) of patients.
6
Adverse Reactions
6.1 Clinical Trials Experience
The
data in the Warnings
and Precautions section
reflect exposure to OPDIVO, as a single agent,
for clinically significant adverse reactions
in 1994 patients enrolled
in Trials 1 through 8 or a single-arm trial in NSCLC (n=117) administering OPDIVO as a single agent.
In addition, clinically significant
adverse reactions of OPDIVO administered with ipilimumab were evaluated in 407
patients with melanoma enrolled in Trial 6 (n=313) or a Phase 2 randomized
study
(n=94), administering OPDIVO with
ipilimumab, supplemented by immune-mediated adverse reaction reports
in
ongoing
clinical
trials.
The data described below reflect
exposure to OPDIVO as a single agent in Trials 1, 4,
and 6, and to OPDIVO with ipilimumab in Trial 6,
which are randomized …Also described
below are single-agent OPDIVO data from Trials 2 and 3, which are randomized trials in patients with metastatic NSCLC, Trial 5, which is a randomized trial in patients with advanced RCC, and Trials 7 and 8, which are open-label,
multiple-cohort trials in patients
with cHL.
Table 2, Table 3, Table 4, Table 5
Greater than or equal to symbols
have replaced all epsilon symbols.
In the Table 4 heading and the
text following the table, Trial 4 replaces Trial 5
Table 6 and Table 7
Greater than or equal to replaces
all epsilon symbols throughout this section.
Trial 6 replaces all references to
Trial 7 throughout this section.
Following
Table 7:
Metastatic Non-Small
Cell Lung Cancer
The safety of OPDIVO in metastatic
NSCLC was evaluated in Trial 2, a randomized
open-label, multicenter trial in
patients with metastatic squamous NSCLC and progression on or after one
prior platinum doublet-based chemotherapy regimen and Trial 3, a randomized, open-label,
multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one
prior platinum doublet-based chemotherapy regimen. Patients received 3 mg/kg of OPDIVO administered intravenously over 60 minutes every 2 weeks or docetaxel administered intravenously at 75 mg/m2 every 3 weeks. The median duration of therapy in OPDIVO-treated patients in
Trial 2 was 3.3 months (range:
1 day to 21.7+ months)
and in Trial 3 was 2.6 months (range: 0 to 24.0+ months). In Trial 2, 36% of patients
received OPDIVO for at least 6 months and 18% of patients received OPDIVO for at least 1
year and in Trial 3, 30% of patients
received OPDIVO for greater than 6 months and 20% of patients received OPDIVO for greater than 1 year.
Trial 2 and Trial 3 excluded patients with active autoimmune disease,
medical conditions requiring systemic immunosuppression, or with symptomatic
interstitial lung disease.
Across both trials, the median age of OPDIVO-treated patients
was 61 years (range: 37
to 85); 38% were greater than or equal to 65 years of age, 61% were male, and 91% were white. Ten
percent of patients had brain metastases
and ECOG performance status was 0 (26%)
or 1 (74%).
OPDIVO was discontinued in 11% of patients, and was delayed
in 28% of patients for an
adverse reaction. Serious
adverse reactions occurred
in 46% of patients receiving OPDIVO. The
most frequent serious adverse reactions
reported in at least 2% of patients
receiving OPDIVO were pneumonia, pulmonary
embolism, dyspnea,
pyrexia, pleural effusion,
pneumonitis, and respiratory failure. In Trial 3, in the OPDIVO arm, seven deaths were due to infection including one case of Pneumocystis jirovecii pneumonia,
four were due to pulmonary embolism, and one death was due to limbic encephalitis. Across both trials, the most common adverse
reactions (reported in at least 20% of patients)
were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.
Table 8 summarizes
selected adverse reactions occurring more frequently in at least 10% of
OPDIVO-treated patients.
Table 8
and Table 9:
The
greater than or equal to symbol replaces all the epsilon symbols.
Table
8 and 9 data have been revised; please refer to label.
Trials
2 and 3 replaces all Trial 3 references.
Following
Table 8:
Other clinically important
adverse reactions observed in patients treated with OPDIVO and which
occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in
section 6 include: fatigue/asthenia (48% Grade 1-4, 5% Grade 3-4), musculoskeletal pain (33%), pleural
effusion (4.5%), pulmonary
embolism (3.3%).
Following
Table 9:
superscript a: Each test incidence
is based on the number of patients
who had both baseline and at least one on-study laboratory
measurement available:
OPDIVO
group
(range: 405 to 417
patients) and docetaxel group (range: 372 to
390 patients); TSH: OPDIVO group n=314 and
docetaxel group
n=297.
Table 10 and Table 11
Trial 5 replaces Trial 6
Following Table 10:
superscript d:
Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular rash, maculopapular rash,
papular rash, pruritic
rash, erythema multiforme, and
erythema.
Other clinically important adverse reactions in Trial
5 were:…
Table 12 and Table 13:
The greater than or equal to symbol replaces all the epsilon
symbols in the Table title.
Trials 7 and 8 replace Trials 8 and 9
Following Table 12:
Additional information
regarding clinically important
adverse reactions:
Immune-mediated pneumonitis: In
Trials 7 and 8, pneumonitis, including interstitial lung disease, occurred
in 4.9% (13/263) of
patients receiving OPDIVO.
Immune-mediated pneumonitis occurred in
3.4% (9/263) of patients receiving
OPDIVO (one Grade 3 and eight
Grade 2). The median time to onset was 2.2
months (range: 1 day to 10.1 months). All nine
patients received systemic corticosteroids, with resolution in
seven. One patient permanently
discontinued OPDIVO due to Grade 2 pneumonitis. Dose delay occurred in three patients. Five patients resumed OPDIVO, of whom none had recurrence of
pneumonitis.
8
Use in Specific Populations
8.5 Geriatric Use
Of the 272 patients randomized to
OPDIVO in Trial 1, 35% were 65 years or older and 15% were 75 years or older.
Of the 427 patients randomized to OPDIVO in Trials 2 and 3, 38%
were 65 years or older and 7% were 75 years or older. Of the 210 patients
randomized to OPDIVO in Trial 4, 50% were 65 years or older and 13% were
75 years or older. Of the 406 patients treated with OPDIVO in Trial 5,
37% were 65 years or older and 8% were 75 years or older. Of the 316 patients
randomized to OPDIVO in Trial 6, 37% were 65 years or older and 12% were
75 years or older. No overall differences in safety or efficacy were reported
between elderly patients and younger patients. In Trials 7 and 8,
single-agent OPDIVO for cHL did not include sufficient numbers of
patients aged 65 years and older to determine whether they respond differently
from younger patients.
Of
the 314 patients randomized to OPDIVO administered with ipilimumab in Trial 6,
41% were 65 years or older and 11% were 75 years or older...
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Reformatted; please refer to label.
PATIENT COUNSELING INFORMATION
Skin Adverse Reactions replaces Rash bullet
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