• This site is intended for U.S. Healthcare Professionals only.
  • For adults with relapsed or progressed classical
    Hodgkin lymphoma after autologous HSCT and
    brentuximab vedotin, or after 3 or more lines
    of therapy including autologous HSCT

  • Full Indication

IMMUNE-MEDIATED ADVERSE REACTIONS DATA

Incidence and Onset of Immune-Mediated
Adverse Reactions1


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)

*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 (%)
 

At least 40 mg prednisone equivalents per day.

||Complete resolution following CS taper.

#Complete resolution following CS use.

Auto-HSCT=autologous hematopoietic stem cell transplantation; 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; complications of allogeneic hematopoietic stem cell transplantation; 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.
  • In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

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.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

  • Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.
  • Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.

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 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT.

Common Adverse Reactions

  • In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%), and pruritus (20%).

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

References

  1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
  2. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283-1294.
  3. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311-319.
  4. Data on File. NIVO 117. Princeton, NJ: Bristol-Myers Squibb Company.
  5. 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.
  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.