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Immune-Mediated Adverse Reactions Data

Incidence and Onset of Immune-Mediated Adverse Reactions1

Across select tumor types*


OPDIVO® as a Single Agent (n=1994)

  Incidence All Grades
n (%)
Median
Time to
Onset
(Months)
Pneumonitis 61 (3.1) 3.5
(1 day to
22.3 months)
Colitis 58 (2.9) 5.3
(2 days to
20.9 months)
Hepatitis 35 (1.8) 3.3
(6 days to
9 months)
Endocrinopathies
 
  Hypophysitis
 
 
12 (0.6)
 
 
4.9
(1.4 to
11 months)
  Adrenal
  Insufficiency
20 (1) 4.3
(15 days to
21 months)
  Hypothyroidism/
  Thyroiditis
171 (9) 2.9
(1 day to
16.6 months)
  Hyperthyroidism 54 (2.7) 1.5
(1 day to
14.2 months)
  Diabetes 17 (0.9) 4.4
(15 days to
22 months)
Nephritis/Renal
Dysfunction
23 (1.2) 4.6
(23 days to
12.3 months)
Skin§ 171 (9) 2.8
(<1 day to
25.8 months)
Encephalitis 3|| (0.2) --

*The data above did not include Checkmate 141. The chart reflects exposure to OPDIVO as a single agent,
for clinically significant adverse reactions in 1994 patients across select approved indications. Please see OPDIVO US Full Prescribing Information for full safety information.

Fatal cases have been reported.

Two cases of diabetic ketoacidosis occurred.

§OPDIVO can cause skin immune-mediated adverse reactions including Stevens-Johnson syndrome (SJS)
and toxic epidermal necrolysis (TEN); some cases with fatal outcome.

||Fatal limbic encephalitis occurred in 1 patient after 7.2 months of exposure despite discontinuation of
OPDIVO and administration of corticosteroids.
In the other 2 patients, encephalitis occurred
post-allogeneic
hematopoietic stem cell transplantation.

Infusion-Related Reactions

  • Infusion-related reactions occurred in 6.4% (127/1994) of patients
  • Median time to onset not available

Additional Information About Immune-Mediated Adverse Reactions With OPDIVO as a Single Agent1

Pneumonitis (n=61)
Permanently
Discontinued
OPDIVO (%)
1.1
Withheld OPDIVO (%) 1.3
Corticosteroid Use
  (%)

  ~89#
  Median Duration
  (days) (range)
26
(1 day to 6 mos)
Other Treatments --
Resolution (%) 67**
Recurrence After
Re-initiation of
OPDIVO (%)
~8
 
Colitis (n=58)
Permanently
Discontinued
OPDIVO (%)
0.7
Withheld OPDIVO (%) 1
Corticosteroid Use
  (%)

  ~91#
  Median Duration
  (days) (range)
23
(1 day to 9.3 mos)
Other Treatments 4 patients
received infliximab
in addition to
high-dose CS
Resolution (%) 74††
Recurrence After
Re-initiation of
OPDIVO (%)
~16
 
Hepatitis (n=35)
Permanently
Discontinued
OPDIVO (%)
0.7
Withheld OPDIVO (%) 1
Corticosteroid Use
  (%)

100#
  Median Duration
  (days) (range)
23
(1 day to 2 mos)
Other Treatments 2 patients
received
mycophenolic acid
in addition to
high-dose CS
Resolution (%) 74††
Recurrence After
Re-initiation of
OPDIVO (%)
~29
 
Endocrinopathies
Hypophysitis (n=12)
Permanently
Discontinued
OPDIVO (%)
0.1
Withheld OPDIVO (%) 0.2
Corticosteroid Use
  (%)
  33#
  Median Duration
  (days) (range)
14
(5 to 26 days)
Other Treatments ~67%
received HRT
Resolution (%) --
Recurrence After
Re-initiation of
OPDIVO (%)
--
 
Endocrinopathies
Adrenal Insufficiency (n=20)
Permanently
Discontinued
OPDIVO (%)
0.1
Withheld OPDIVO (%) 0.5
Corticosteroid Use
  (%)
  25#
  Median Duration
  (days) (range)
11
(1 day to 1 mo)
Other Treatments ~85%
received HRT
Resolution (%) --
Recurrence After
Re-initiation of
OPDIVO (%)
--
 
Endocrinopathies
Hypothyroidism/Thyroiditis (n=171)
Permanently
Discontinued
OPDIVO (%)
--
Withheld OPDIVO (%) --
Corticosteroid Use
  (%)
--
  Median Duration
  (days) (range)
--
Other Treatments ~79% received
levothyroxine and
4% also required
corticosteroids
Resolution (%) 35
Recurrence After
Re-initiation of
OPDIVO (%)
--
 
Endocrinopathies
Hyperthyroidism (n=54)
Permanently
Discontinued
OPDIVO (%)
--
Withheld OPDIVO (%) --
Corticosteroid Use
  (%)
  9
  Median Duration
  (days) (range)
--
Other Treatments ~26% received
methimazole;
~9% received
carbimazole;
~4% received
propylthiouracil
Resolution (%) 76
Recurrence After
Re-initiation of
OPDIVO (%)
--
 
Endocrinopathies
Diabetes (n=17)
Permanently
Discontinued
OPDIVO (%)
--
Withheld OPDIVO (%) --
Corticosteroid Use
  (%)
--
  Median Duration
  (days) (range)
--
Other Treatments --
Resolution (%) --
Recurrence After
Re-initiation of
OPDIVO (%)
--
 
Nephritis/Renal Dysfunction (n=23)
Permanently
Discontinued
OPDIVO (%)
0.3
Withheld OPDIVO (%) 0.8
Corticosteroid Use
  (%)
  100#
  Median Duration
  (days) (range)
21
(1 day to 15.4 mos)
Other Treatments --
Resolution (%) 48††
Recurrence After
Re-initiation of
OPDIVO (%)
0
 
Skin (n=171)
Permanently
Discontinued
OPDIVO (%)
0.3
Withheld OPDIVO (%) 0.8
Corticosteroid Use
  (%)
  ~16#
  Median Duration
  (days) (range)
12
(1 day to 8.9 mos)
Other Treatments 85% received
topical CS
Resolution (%) 48††
Recurrence After
Re-initiation of
OPDIVO (%)
1.4
 
Encephalitis (n=3)
Permanently
Discontinued
OPDIVO (%)
--
Withheld OPDIVO (%) --
Corticosteroid Use
  (%)
--
  Median Duration
  (days) (range)
--
Other Treatments --
Resolution (%) --
Recurrence After
Re-initiation of
OPDIVO (%)
--
 

Resolution defined in the context of the IMAE time-to-resolution analyses; resolution date was defined as the investigator-assessed IMAE resolution date. In the analyses of complete resolution, complete resolution was defined as improved to Grade 0 or baseline grade per investigator assessment with completion of corticosteroid treatment (or other medical intervention).

#At least 40 mg prednisone equivalents per day.

**Complete resolution following CS taper.

††Complete resolution following CS use.

CS=corticosteroids; HRT=hormone replacement therapy; mos=months.

More Important Safety Information   Collapse  

Select Important Safety Information

OPDIVO is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; and embryo-fetal toxicity.

Important Safety Information

Immune-Mediated Pneumonitis

  • OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients.

Immune-Mediated Colitis

  • OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients.

Immune-Mediated Hepatitis

  • OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients.

Immune-Mediated Endocrinopathies

  • OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.
  • In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients.

Immune-Mediated Nephritis and Renal Dysfunction

  • OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients.

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. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients.

Immune-Mediated Encephalitis

  • OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids.

Other Immune-Mediated Adverse Reactions

  • Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <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.
  • If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Infusion Reactions

  • OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO.

Embryo-Fetal Toxicity

  • Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO-containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

  • It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

  • In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis.

Common Adverse Reactions

  • In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO (n=236) were cough and dyspnea at a higher incidence than investigator’s choice.

Please see U.S. Full Prescribing Information for OPDIVO.

References:

  1. OPDIVO [package insert]. Princeton, NJ:
    Bristol-Myers Squibb Company; 2018.
  2. Ferris RL, Blumenschein G, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016: DOI:10.1056/NEJMoa1602252.
  3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Head and Neck Cancer V.1.2018.
    © 2018 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed March 8, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network Inc.
  4. Data on file. NIVO 203. Princeton, NJ:
    Bristol-Myers Squibb Company.
  5. Data on file. NIVO 205. Princeton, NJ:
    Bristol-Myers Squibb Company.
  6. Zhao X, Ivaturi V, Gopalakrishnan M, et al. A model-based exposure–response (E–R) assessment of a nivolumab (NIVO) 4-weekly (q4w) dosing schedule across multiple tumor types. Poster presented at: American Association for Cancer Research (AACR) Annual Meeting; April 1–5, 2017; Washington, DC. Poster CT101.
  7. Wang C, Thudium KB, Han M, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. 2014;2(9):846-856.