• This site is intended for U.S. Healthcare Professionals only.
  • For Patients With Advanced
    RCC
    Who
    Received
    Prior Anti-Angiogenic Therapy
  • Full Indication

Treatment Modifications

Adverse Reactions May
Be Managed With
Treatment Modifications1


Recommended Dose Modifications For OPDIVO®

Colitis

Severity*

Dose Modification

Grade 2 diarrhea or colitis

Withhold dose

Grade 3 diarrhea or colitis

Withhold dose

Grade 4 diarrhea or colitis

Permanently discontinue

Pneumonitis

Severity*

Dose Modification

Grade 2 pneumonitis

Withhold dose

Grade 3 or 4 pneumonitis

Permanently discontinue

Hepatitis

Severity*

Dose Modification

AST or ALT >3 and   ≤5x the ULN or total   bilirubin >1.5 and   ≤3x the ULN

Withhold dose

AST or ALT >5x the   ULN or total bilirubin
  >3x the ULN

Permanently discontinue

Hypophysitis

Severity*

Dose Modification

Grade 2 or 3 hypophysitis

Withhold dose

Grade 4
hypophysitis

Permanently discontinue

Adrenal Insufficiency

Severity*

Dose Modification

Grade 2 adrenal insufficiency

Withhold dose

Grade 3 or 4 adrenal insufficiency

Permanently discontinue

Type 1 Diabetes Mellitus

Severity*

Dose Modification

Grade 3
hyperglycemia

Withhold dose

Grade 4
hyperglycemia

Permanently discontinue

Nephritis and Renal Dysfunction

Severity*

Dose Modification

Serum creatinine >1.5 and ≤6x the ULN

Withhold dose

Serum creatinine >6x the ULN

Permanently discontinue

Skin

Severity*

Dose Modification

Grade 3 rash or suspected SJS or
TEN

Withhold dose

Grade 4 rash or confirmed SJS or
TEN

Permanently discontinue

Encephalitis

Severity*

Dose Modification

New-onset of
moderate or severe neurologic signs or
symptoms

Withhold dose

Immune-mediated
encephalitis

Permanently discontinue

Other

Severity*

Dose Modification

Other Grade 3 adverse reaction


Withhold dose

Permanently discontinue

First occurrence

Recurrence of same   Grade 3 adverse   reactions

Life-threatening or Grade 4 adverse reaction

Permanently discontinue

Grade 3 myocarditis

Permanently discontinue

Requirement for
≥10 mg per day prednisone or
equivalent for >12 weeks

Permanently discontinue

Persistent Grade 2 or 3 adverse reactions lasting 12 weeks or longer

Permanently discontinue

*Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) v4.0.

Resume treatment when adverse reaction improves to Grade 0 or 1.

ALT=alanine aminotransferase; AST=aspartate aminotransferase; SJS=Stevens-Johnson syndrome;
TEN=toxic epidermal necrolysis; ULN=upper limit of normal.


The recommended dose of OPDIVO is either 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.1

  • There are no recommended dose modifications for hypothyroidism or hyperthyroidism
  • Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions
  • Discontinue OPDIVO in patients with severe or life-threatening infusion reactions
SEE ALSO:
Adverse Reactions 
More Important Safety Information   Collapse  

Select Important Safety Information

OPDIVO is associated with the following Warning 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 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.

Common Adverse Reactions

  • In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%).

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

References:

  1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2018.
  2. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803-1813.
  3. Sharma P, Tykodi SS, Escudier B, et al. Three-year efficacy and safety update from the phase III CheckMate 025 study of nivolumab versus everolimus in patients with advanced renal cell carcinoma. Oral presentation at the 16th International Kidney Cancer Symposium; November 3-4, 2017; Miami, FL.
  4. Plimack ER, Motzer RJ, Escudier B, et al. Two-year efficacy and safety update from the phase III CheckMate 025 study of nivolumab versus everolimus in patients with advanced renal cell carcinoma. Presented at the 15th International Kidney Cancer Symposium; November 4-5, 2016; Miami, FL.
  5. Data on file. NIVO 067. Bristol-Myers Squibb Company, Princeton, NJ.
  6. Data on file. NIVO 256. Bristol-Myers Squibb Company, Princeton, NJ.
  7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Kidney Cancer V.2.2018. © 2018. National Comprehensive Cancer Network Inc. All rights reserved. Accessed February 2, 2018. To review 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.
  8. 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.
  9. 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.