OPDIVO (nivolumab) injection
E.R. Squibb & Sons, L.L.C.

E.R. Squibb & Sons, L.L.C.
OPDIVO
nivolumab
NIVOLUMAB
NIVOLUMAB
MANNITOL
PENTETIC ACID
POLYSORBATE 80
SODIUM CHLORIDE
TRISODIUM CITRATE DIHYDRATE
WATER
HYDROCHLORIC ACID
SODIUM HYDROXIDE
OPDIVO
nivolumab
NIVOLUMAB
NIVOLUMAB
MANNITOL
PENTETIC ACID
POLYSORBATE 80
SODIUM CHLORIDE
TRISODIUM CITRATE DIHYDRATE
WATER
HYDROCHLORIC ACID
SODIUM HYDROXIDE
OPDIVO
nivolumab
NIVOLUMAB
NIVOLUMAB
MANNITOL
PENTETIC ACID
POLYSORBATE 80
SODIUM CHLORIDE
TRISODIUM CITRATE DIHYDRATE
WATER
HYDROCHLORIC ACID
SODIUM HYDROXIDE
OPDIVO
nivolumab
NIVOLUMAB
NIVOLUMAB
MANNITOL
PENTETIC ACID
POLYSORBATE 80
SODIUM CHLORIDE
TRISODIUM CITRATE DIHYDRATE
WATER
HYDROCHLORIC ACID
SODIUM HYDROXIDE

Indications and Usage (1)

2/2023

Dosage and Administration (2)

2/2023

1 INDICATIONS AND USAGE

OPDIVO is a programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of:

Melanoma

  • adult and pediatric (12 years and older) patients with unresectable or metastatic melanoma, as a single agent or in combination with ipilimumab. (1.1)
  • adult and pediatric (12 years and older) patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection, in the adjuvant setting. (1.2)

Non-Small Cell Lung Cancer (NSCLC)

  • adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer in the neoadjuvant setting, in combination with platinum-doublet chemotherapy. (1.3)
  • adult patients with metastatic non-small cell lung cancer expressing PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with ipilimumab. (1.4)
  • adult patients with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy. (1.4)
  • adult patients with metastatic non-small cell lung cancer and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO. (1.4)

Malignant Pleural Mesothelioma

  • adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with ipilimumab. (1.5)

Renal Cell Carcinoma (RCC)

  • adult patients with intermediate or poor risk advanced renal cell carcinoma, as a first-line treatment in combination with ipilimumab. (1.6)
  • adult patients with advanced renal cell carcinoma, as a first-line treatment in combination with cabozantinib. (1.6)
  • adult patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. (1.6)

Classical Hodgkin Lymphoma (cHL)

  • adult patients with classical Hodgkin lymphoma that has relapsed or progressed aftera: (1.7) autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or 3 or more lines of systemic therapy that includes autologous HSCT.

Squamous Cell Carcinoma of the Head and Neck (SCCHN)

  • adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy. (1.8)

Urothelial Carcinoma

  • adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC. (1.9)
  • adult patients with locally advanced or metastatic urothelial carcinoma who: have disease progression during or following platinum-containing chemotherapy have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (1.9)

Colorectal Cancer

  • adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, as a single agent or in combination with ipilimumab.a  (1.10)

Hepatocellular Carcinoma (HCC)

  • adult patients with hepatocellular carcinoma who have been previously treated with sorafenib in combination with ipilimumab.a  (1.11)

Esophageal Cancer

  • adult patients with completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease, who have received neoadjuvant chemoradiotherapy (CRT). (1.12)
  • adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma as first-line treatment in combination with fluoropyrimidine- and platinum-containing chemotherapy. (1.12)
  • adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma as first-line treatment in combination with ipilimumab. (1.12)
  • adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. (1.12)

Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma

  • adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma in combination with fluoropyrimidine- and platinum-containing chemotherapy. (1.13)

a   This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

1.1 Unresectable or Metastatic Melanoma

OPDIVO, as a single agent or in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma.

1.2 Adjuvant Treatment of Melanoma

OPDIVO is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

1.3 Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer

OPDIVO, in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC).

1.4 Metastatic Non-Small Cell Lung Cancer

  • OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with metastatic NSCLC whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with no EGFR or ALK genomic tumor aberrations.
  • OPDIVO, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations.
  • OPDIVO is indicated for the treatment of adult patients with metastatic NSCLC with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

1.5 Malignant Pleural Mesothelioma

OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

1.6 Advanced Renal Cell Carcinoma

  • OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced RCC.
  • OPDIVO, in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced RCC.
  • OPDIVO as a single agent is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

1.7 Classical Hodgkin Lymphoma

OPDIVO is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after:

  • autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or
  • 3 or more lines of systemic therapy that includes autologous HSCT.

This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.7)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

1.8 Squamous Cell Carcinoma of the Head and Neck

OPDIVO is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

1.9 Urothelial Carcinoma

OPDIVO is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC [see Clinical Studies (14.9)].

OPDIVO is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who:

  • have disease progression during or following platinum-containing chemotherapy
  • have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

1.10 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer

OPDIVO, as a single agent or in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.10)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

1.11 Hepatocellular Carcinoma

OPDIVO, in combination with ipilimumab, is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.11)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

1.12 Esophageal Cancer

  • OPDIVO is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT).
  • OPDIVO, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).
  • OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).
  • OPDIVO is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

1.13 Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma

OPDIVO, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

2 DOSAGE AND ADMINISTRATION

  • Administer by intravenous infusion after dilution based upon recommended infusion rate for each indication. (2)
  • Unresectable or metastatic melanoma Adult and pediatric patients weighing 40 kg or greater: 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)(2.2) Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. (2.2) Adult and pediatric patients weighing 40 kg or greater:1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)(2.2) Pediatric patients weighing less than 40 kg: 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. (2.2)
  • Adjuvant treatment of melanoma Adult and pediatric patients weighing 40 kg or greater: 240 40 mg every 2 weeks or 480 mg every 4 weeks. (2.2)(2.2) Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. (2.2)
  • Neoadjuvant treatment of resectable (tumors ≥4 cm or node positive) non-small cell lung cancer 360 mg with platinum-doublet chemotherapy on the same day every 3 weeks for 3 cycles (2.2)
  • Metastatic non-small cell lung cancer 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks. (2.2) 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy. (2.2) 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
  • Malignant pleural mesothelioma 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks. (2.2)
  • Advanced renal cell carcinoma 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) 240 mg every 2 weeks or 480 mg every 4 weeks administered in combination with cabozantinib 40 mg once daily without food. (2.2) 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
  • Classical Hodgkin lymphoma 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
  • Recurrent or metastatic squamous cell carcinoma of the head and neck 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
  • Adjuvant treatment of urothelial carcinoma 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
  • Locally advanced or metastatic urothelial carcinoma 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
  • Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer Adult and pediatric patients weighing 40 kg or greater: 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks. (2.2) Adult and pediatric patients weighing 40 kg or greater: 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
  • Hepatocellular carcinoma 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
  • Adjuvant treatment of resected esophageal or gastroesophageal cancer 240 mg every 2 weeks or 480 mg every 4 weeks for total treatment duration of 1 year. (2.2)
  • Esophageal squamous cell carcinoma 240 mg every 2 weeks or 480 mg every 4 weeks in combination with chemotherapy regimen of fluoropyrimidine- and platinum-containing chemotherapy. (2.2) 3 mg/kg every 2 weeks or 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks. (2.2) 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
  • Gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC, GEJC, or EAC) 360 mg every 3 weeks with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks. (2.2) 240 mg every 2 weeks with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks. (2.2)
  • See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.

2.1 Patient Selection

Select patients with metastatic NSCLC for treatment with OPDIVO in combination with ipilimumab based on PD-L1 expression [see Clinical Studies (14.4)].

Information on FDA-approved tests for the determination of PD-L1 expression in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

The recommended dosages of OPDIVO as a single agent are presented in Table 1.

Table 1: Recommended Dosages for OPDIVO as a Single Agent
* 30-minute intravenous infusion.

Indication

Recommended OPDIVO Dosage

Duration of Therapy

Metastatic non-small cell lung cancer

240 mg every 2 weeks*

or

480 mg every 4 weeks*

Until disease progression or unacceptable toxicity

Advanced renal cell carcinoma

Classical Hodgkin lymphoma

Squamous cell carcinoma of the head and neck

Locally advanced or metastatic urothelial carcinoma

Esophageal squamous cell carcinoma

Unresectable or metastatic melanoma

Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more:

240 mg every 2 weeks*

or

480 mg every 4 weeks*

Until disease progression or unacceptable toxicity

Pediatric patients age 12 years and older and weighing less than 40 kg:

3 mg/kg every 2 weeks*

or

6 mg/kg every 4 weeks*

Adjuvant treatment of melanoma

240 mg every 2 weeks*

or

480 mg every 4 weeks*

Until disease recurrence or unacceptable toxicity for up to 1 year

Adjuvant treatment of urothelial carcinoma (UC)

Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer

Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more:

240 mg every 2 weeks*

or

480 mg every 4 weeks*

Until disease progression or unacceptable toxicity

Pediatric patients age 12 years and older and weighing less than 40 kg:

3 mg/kg every 2 weeks*

Adjuvant treatment of resected esophageal or gastroesophageal junction cancer

240 mg every 2 weeks*

or

480 mg every 4 weeks*

Until disease progression or unacceptable toxicity for a total treatment duration of 1 year

The recommended dosages of OPDIVO in combination with other therapeutic agents are presented in Table 2. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with OPDIVO for the recommended dosage information, as appropriate.

Table 2: Recommended Dosages of OPDIVO in Combination with Other Therapeutic Agents
* 30-minute intravenous infusion on the same day.

Indication

Recommended OPDIVO Dosage

Duration of Therapy

Unresectable or metastatic melanoma

1 mg/kg every 3 weeks*

with ipilimumab 3 mg/kg intravenously*

In combination with ipilimumab for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier

Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more:

240 mg every 2 weeks*

or

480 mg every 4 weeks*

After completing 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity

Pediatric patients age 12 years and older and weighing less than 40 kg:
3 mg/kg every 2 weeks*

or

6 mg/kg every 4 weeks*

Neoadjuvant treatment of resectable non-small cell lung cancer

360 mg every 3 weeks*

with platinum-doublet chemotherapy on the same day every 3 weeks

In combination with platinum-doublet chemotherapy for 3 cycles

Metastatic non-small cell lung cancer expressing PD-L1

360 mg every 3 weeks*

with ipilimumab 1 mg/kg every 6 weeks*

In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression

Metastatic or recurrent non-small cell lung cancer

360 mg every 3 weeks*

with ipilimumab 1 mg/kg every 6 weeks*

and histology-based platinum

doublet chemotherapy every 3 weeks

In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression

2 cycles of histology-based platinum-doublet chemotherapy

Malignant pleural mesothelioma

360 mg every 3 weeks*

with ipilimumab 1 mg/kg every 6 weeks*

In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression

Advanced renal cell carcinoma

3 mg/kg every 3 weeks*

with ipilimumab 1 mg/kg intravenously*

In combination with ipilimumab
for 4 doses

240 mg every 2 weeks*

or

480 mg every 4 weeks*

Administer OPDIVO in combination with cabozantinib 40 mg orally once daily without food

OPDIVO: Until disease progression, unacceptable toxicity, or up to 2 years

Cabozantinib: Until disease progression or unacceptable toxicity

240 mg every 2 weeks*

or

480 mg every 4 weeks*

After completing 4 doses of combination therapy with ipilimumab, administer as single agent until disease progression or unacceptable toxicity

Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer

3 mg/kg every 3 weeks*

with ipilimumab 1 mg/kg intravenously*

In combination with ipilimumab
for 4 doses

Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more:

240 mg every 2 weeks*

or

480 mg every 4 weeks*

After completing 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity

Pediatric patients age 12 years and older and weighing less than 40 kg:

3 mg/kg every 2 weeks*

Hepatocellular carcinoma

1 mg/kg every 3 weeks*

with ipilimumab 3 mg/kg intravenously*

In combination with ipilimumab
for 4 doses

240 mg every 2 weeks*

or

480 mg every 4 weeks*

After completing 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity

Esophageal squamous cell carcinoma

240 mg every 2 weeks*

or

480 mg every 4 weeks*

Administer OPDIVO in combination with fluoropyrimidine- and platinum-containing chemotherapy

OPDIVO: Until disease progression, unacceptable toxicity, or up to 2 years

Chemotherapy: Until disease progression or unacceptable toxicity

3 mg/kg every 2 weeks*

or

360 mg every 3 weeks*

with ipilimumab 1 mg/kg every 6 weeks*

In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years

Gastric cancer, Gastroesophageal junction cancer, and Esophageal adenocarcinoma

240 mg every 2 weeks*

with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks

or

360 mg every 3 weeks*

with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks

Until disease progression, unacceptable toxicity, or up to 2 years

2.3 Dose Modifications

No dose reduction for OPDIVO is recommended. In general, withhold OPDIVO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue OPDIVO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.

Dosage modifications for OPDIVO or OPDIVO in combination for adverse reactions that require management different from these general guidelines are summarized in Table 3 and Table 4.

When OPDIVO is administered in combination with ipilimumab, withhold or permanently discontinue both ipilimumab and OPDIVO for an adverse reaction meeting these dose modification guidelines.

Table 3: Recommended Dosage Modifications for Adverse Reactions
a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids.
b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO based on recommendations for hepatitis with no liver involvement.
c Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal

Adverse Reaction

Severity

Dosage Modification

Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]

Pneumonitis

Grade 2

Withholda

Grades 3 or 4

Permanently discontinue

Colitis

 

For colitis in patients treated with combination therapy with ipilimumab, see Table 4.

Grade 2 or 3

Withholda

Grade 4

Permanently discontinue

Hepatitis with no tumor involvement of the liver

 

For liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4.

AST/ALT increases to >3 and ≤8 times ULN

or

Total bilirubin increases to >1.5 and ≤3 times ULN.

Withholda

AST or ALT increases to >8 times ULN

or

Total bilirubin increases to >3 times ULN.

Permanently discontinue

Hepatitis with tumor involvement of the liverb

 

For liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4.

Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULN

or

Baseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN.

Withholda

AST/ALT increases to >10 times ULN

or

Total bilirubin increases to >3 times ULN.

Permanently discontinue

Endocrinopathiesc

Grade 3 or 4

Withhold until clinically stable or permanently discontinue depending on severity

Nephritis with Renal Dysfunction

Grade 2 or 3 increased blood creatinine

Withholda

Grade 4 increased blood creatinine

Permanently discontinue

Exfoliative Dermatologic Conditions

Suspected SJS, TEN, or DRESS

Withhold

Confirmed SJS, TEN, or DRESS

Permanently discontinue

Myocarditis

Grades 2, 3, or 4

Permanently discontinue

Neurological Toxicities

Grade 2

Withholda

Grade 3 or 4

Permanently discontinue

Other Adverse Reactions

Infusion-Related Reactions

[see Warnings and Precautions (5.2)]

Grade 1 or 2

Interrupt or slow the rate of infusion

Grade 3 or 4

Permanently discontinue
Table 4: Recommended Dosage Modifications for Adverse Reactions in Patients Treated with Combination Therapy
a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids.
 b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO in combination with ipilimumab based on recommendations for hepatitis with no liver involvement.
c Consider corticosteroid therapy for hepatic adverse reactions if OPDIVO is withheld or discontinued when administered in combination with cabozantinib.
d After recovery, rechallenge with one or both of OPDIVO and cabozantinib may be considered. If rechallenging with cabozantinib with or without OPDIVO, refer to cabozantinib Prescribing Information.

Treatment

Adverse Reaction

Severity

Dosage Modification

OPDIVO in combination with ipilimumab

Colitis

Grade 2

Withholda

Grade 3 or 4

Permanently discontinue

Hepatitis with no tumor involvement of the liver

or

Hepatitis with tumor involvement of the liver/non-HCC

AST/ALT increases to >3 times ULN and ≤5 times ULN

or

Total bilirubin increases to ≥1.5 and ≤3 times ULN.

Withholda

AST or ALT >5 times ULN or

Total bilirubin >3 times ULN.

Permanently discontinue

Hepatitis with tumor involvement of the liverb/HCC

Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULN

or

Baseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN.

Withholda

AST/ALT increases to >10 times ULN

or

Total bilirubin increases to >3 times ULN.

Permanently discontinue

OPDIVO in combination with cabozantinib

Liver enzyme elevations

ALT or AST >3 times ULN but ≤10 times ULN with concurrent total bilirubin <2 times ULN

Withholdc both OPDIVO and cabozantinib until adverse reactions recoverd to Grades 0-1

ALT or AST >10 times ULN

or >3 times ULN with concurrent total bilirubin ≥2 times ULN

Permanently discontinuec both OPDIVO and cabozantinib

2.4 Preparation and Administration

Visually inspect for particulate matter and discoloration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard if cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake.

Preparation

  • Withdraw the required volume of OPDIVO and transfer into an intravenous container.
  • Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. The total volume of infusion must not exceed 160 mL.     For adult and pediatric patients with body weight 40 kg or greater, do not exceed a total volume of infusion of 160 mL.     For adult and pediatric patients with body weight less than 40 kg, do not exceed a total volume of infusion of 4 mL/kg of body weight.
  • Mix diluted solution by gentle inversion. Do not shake.
  • Discard partially used vials or empty vials of OPDIVO.
  • The product does not contain a preservative.

      

  • After preparation, store the diluted solution either:     at room temperature and room light for no more than 8 hours from the time of preparation to end of the infusion. Discard diluted solution if not used within 8 hours from the time of preparation; or     under refrigeration at 2°C to 8°C (36°F to 46°F) and protected from light for no more than 7 days from the time of preparation to end of infusion. Discard diluted solution if not used within 7 days from the time of preparation.
  • Do not freeze.

Administration

  • Administer the infusion, after dilution, over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).
  • Administer OPDIVO in combination with other therapeutic agents as follows: oWith ipilimumab: administer OPDIVO first followed by ipilimumab on the same day. oWith platinum-doublet chemotherapy: administer OPDIVO first followed by platinum-doublet chemotherapy on the same day oWith ipilimumab and platinum-doublet chemotherapy: administer OPDIVO first followed by ipilimumab and then platinum-doublet chemotherapy on the same day. oWith fluoropyrimidine- and platinum-containing chemotherapy: administer OPDIVO first followed by fluoropyrimidine- and platinum-containing chemotherapy on the same day.
  • Use separate infusion bags and filters for each infusion.
  • Flush the intravenous line at end of infusion.
  • Do not co-administer other drugs through the same intravenous line.

3 DOSAGE FORMS AND STRENGTHS

Injection: 40 mg/4 mL (10 mg/mL), 100 mg/10 mL (10 mg/mL), 120 mg/12 mL (10 mg/mL), and 240 mg/24 mL (10 mg/mL) clear to opalescent, colorless to pale-yellow solution in a single-dose vial.

  • Injection: 40 mg/4 mL (10 mg/mL), 100 mg/10 mL (10 mg/mL), 120 mg/12 mL (10 mg/mL), and 240 mg/24 mL (10 mg/mL) solution in a single-dose vial. (3)

4 CONTRAINDICATIONS

None.

  • None. (4)

5 WARNINGS AND PRECAUTIONS

  • Immune-Mediated Adverse Reactions: (5.1) oImmune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis and hepatotoxicity, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, and immune-mediated nephritis and renal dysfunction. oMonitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. oWithhold or permanently discontinue based on severity and type of reaction. (2.3)
  • Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue OPDIVO based on severity of reaction. (5.2)
  • Complications of allogeneic HSCT: Fatal and other serious complications can occur in patient who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. (5.3)
  • Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. (5.4, 8.1, 8.3)
  • Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials. (5.5)

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

OPDIVO is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3)]. In general, if OPDIVO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis, which is defined as requiring use of steroids and no clear alternate etiology. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

OPDIVO as a Single Agent

Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%) adverse reactions. Pneumonitis led to permanent discontinuation of OPDIVO in 1.1% and withholding of OPDIVO in 0.8% of patients.

Systemic corticosteroids were required in 100% (61/61) of patients with pneumonitis. Pneumonitis resolved in 84% of the 61 patients. Of the 15 patients in whom OPDIVO was withheld for pneumonitis, 14 reinitiated OPDIVO after symptom improvement; of these, 4 (29%) had recurrence of pneumonitis.

OPDIVO with Ipilimumab

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: 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. 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. Pneumonitis resolved in 72% of the patients. Approximately 13% (2/16) of patients had recurrence of pneumonitis after reinitiation of OPDIVO with ipilimumab.

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

OPDIVO as a Single Agent

Immune-mediated colitis occurred in 2.9% (58/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (1.7%) and Grade 2 (1%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 0.9% of patients.

Systemic corticosteroids were required in 100% (58/58) of patients with colitis. Four patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 86% of the 58 patients. Of the 18 patients in whom OPDIVO was withheld for colitis, 16 reinitiated OPDIVO after symptom improvement; of these, 12 (75%) had recurrence of colitis.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated colitis occurred in 25% (115/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.4%), Grade 3 (14%), and Grade 2 (8%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO with ipilimumab in 14% and withholding of OPDIVO with ipilimumab in 4.4% of patients.

Systemic corticosteroids were required in 100% (115/115) of patients with colitis. Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 93% of the 115 patients. Of the 20 patients in whom OPDIVO with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 9 (56%) had recurrence of colitis.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated colitis occurred in 9% (60/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (4.4%) and Grade 2 (3.7%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO with ipilimumab in 3.2% and withholding of OPDIVO with ipilimumab in 2.7% of patients with RCC or CRC.

Systemic corticosteroids were required in 100% (60/60) of patients with colitis. Approximately 23% of patients with immune-mediated colitis required addition of infliximab to high-dose corticosteroids. Colitis resolved in 95% of the 60 patients. Of the 18 patients in whom OPDIVO with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 10 (63%) had recurrence of colitis.

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.

OPDIVO as a Single Agent

Immune-mediated hepatitis occurred in 1.8% (35/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%) adverse reactions. Hepatitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 0.6% of patients.

Systemic corticosteroids were required in 100% (35/35) of patients with hepatitis. Two patients required the addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 35 patients. Of the 12 patients in whom OPDIVO was withheld for hepatitis, 11 reinitiated OPDIVO after symptom improvement; of these, 9 (82%) had recurrence of hepatitis.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated hepatitis occurred in 15% (70/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of OPDIVO with ipilimumab in 8% or withholding of OPDIVO with ipilimumab in 3.5% of patients.

Systemic corticosteroids were required in 100% (70/70) of patients with hepatitis. Approximately 9% of patients with immune-mediated hepatitis required the addition mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 70 patients. Of the 16 patients in whom OPDIVO with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 8 (57%) had recurrence of hepatitis.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated hepatitis occurred in 7% (48/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of OPDIVO with ipilimumab in 3.6% and withholding of OPDIVO with ipilimumab in 2.6% of patients with RCC or CRC.

Systemic corticosteroids were required in 100% (48/48) of patients with hepatitis. Approximately 19% of patients with immune-mediated hepatitis required addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 88% of the 48 patients. Of the 17 patients in whom OPDIVO with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 10 (71%) had recurrence of hepatitis.

OPDIVO with Cabozantinib

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt OPDIVO and cabozantinib and consider administering corticosteroids [see Dosage and Administration (2.3)].

With the combination of OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients [see Adverse Reactions (6.1)]. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either OPDIVO (n=11) or cabozantinib (n=9) administered as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving OPDIVO, 2 patients receiving cabozantinib, and 7 patients receiving both OPDIVO and cabozantinib.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

OPDIVO can cause primary or secondary adrenal insufficiency. For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold OPDIVO depending on severity [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

Adrenal insufficiency occurred in 1% (20/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.4%) and Grade 2 (0.6%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO in 0.4% of patients.

Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 90% (18/20) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 35% of the 20 patients. Of the 8 patients in whom OPDIVO was withheld for adrenal insufficiency, 4 reinitiated OPDIVO after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Adrenal insufficiency occurred in 8% (35/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO with ipilimumab in 0.4% and withholding of OPDIVO with ipilimumab in 2.0% of patients.

Approximately 71% (25/35) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 37% of the 35 patients. Of the 9 patients in whom OPDIVO with ipilimumab was withheld for adrenal insufficiency, 7 reinitiated treatment after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Adrenal insufficiency occurred in 7% (48/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO with ipilimumab in 1.2% and withholding of OPDIVO with ipilimumab in 2.1% of patients with RCC or CRC.

Approximately 94% (45/48) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 29% of the 48 patients. Of the 14 patients in whom OPDIVO with ipilimumab was withheld for adrenal insufficiency, 11 reinitiated treatment after symptom improvement; of these, all received hormone replacement therapy and 2 (18%) had recurrence of adrenal insufficiency.

OPDIVO with Cabozantinib

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received OPDIVO with cabozantinib, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO and cabozantinib in 0.9% and withholding of OPDIVO and cabozantinib in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom OPDIVO with cabozantinib was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Hypophysitis

OPDIVO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

Hypophysitis occurred in 0.6% (12/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.2%) and Grade 2 (0.3%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO in <0.1% and withholding of OPDIVO in 0.2% of patients.

Approximately 67% (8/12) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 42% of the 12 patients. Of the 3 patients in whom OPDIVO was withheld for hypophysitis, 2 reinitiated OPDIVO after symptom improvement; of these, none had recurrence of hypophysitis.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hypophysitis occurred in 9% (42/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (2.4%) and Grade 2 (6%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO with ipilimumab in 0.9% and withholding of OPDIVO with ipilimumab in 4.2% of patients.

Approximately 86% of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 88% (37/42) of patients with hypophysitis. Hypophysitis resolved in 38% of the 42 patients. Of the 19 patients in whom OPDIVO with ipilimumab was withheld for hypophysitis, 9 reinitiated treatment after symptom improvement; of these, 1 (11%) had recurrence of hypophysitis.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hypophysitis occurred in 4.4% (29/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO with ipilimumab in 1.2% and withholding of OPDIVO with ipilimumab in 2.1% of patients with RCC or CRC.

Approximately 72% (21/29) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 59% of the 29 patients. Of the 14 patients in whom OPDIVO with ipilimumab was withheld for hypophysitis, 11 reinitiated treatment after symptom improvement; of these, 2 (18%) had recurrence of hypophysitis.

Thyroid Disorders

OPDIVO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3)].

Thyroiditis

OPDIVO as a Single Agent

Thyroiditis occurred in 0.6% (12/1994) of patients receiving OPDIVO as a single agent, including Grade 2 (0.2%) adverse reactions. Thyroiditis led to permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.2% of patients.

Systemic corticosteroids were required in 17% (2/12) of patients with thyroiditis. Thyroiditis resolved in 58% of the 12 patients. Of the 3 patients in whom OPDIVO was withheld for thyroiditis, 1 reinitiated OPDIVO after symptom improvement without recurrence of thyroiditis.

Hyperthyroidism

OPDIVO as a Single Agent

Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (<0.1%) and Grade 2 (1.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.4% of patients.

Approximately 19% of patients with hyperthyroidism received methimazole, 7% received carbimazole, and 4% received propylthiouracil. Systemic corticosteroids were required in 9% (5/54) of patients. Hyperthyroidism resolved in 76% of the 54 patients. Of the 7 patients in whom OPDIVO was withheld for hyperthyroidism, 4 reinitiated OPDIVO after symptom improvement; of these, none had recurrence of hyperthyroidism.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hyperthyroidism occurred in 9% (42/456) of patients with melanoma or HCC who received OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.9%) and Grade 2 (4.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of OPDIVO with ipilimumab in no patients and withholding of OPDIVO with ipilimumab in 2.4% of patients.

Approximately 26% of patients with hyperthyroidism received methimazole and 21% received carbimazole. Systemic corticosteroids were required in 17% (7/42) of patients. Hyperthyroidism resolved in 91% of the 42 patients. Of the 11 patients in whom OPDIVO with ipilimumab was withheld for hyperthyroidism, 8 reinitiated treatment after symptom improvement; of these, 1 (13%) had recurrence of hyperthyroidism.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hyperthyroidism occurred in 12% (80/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (4.5%) adverse reactions. Hyperthyroidism led to permanent discontinuation of OPDIVO with ipilimumab in no patients and withholding of OPDIVO with ipilimumab in 2.3% of patients with RCC or CRC.

Of the 80 patients with RCC or CRC who developed hyperthyroidism, approximately 16% received methimazole and 3% received carbimazole. Systemic corticosteroids were required in 20% (16/80) of patients with hyperthyroidism. Hyperthyroidism resolved in 85% of the 80 patients. Of the 15 patients in whom OPDIVO with ipilimumab was withheld for hyperthyroidism, 11 reinitiated treatment after symptom improvement; of these, 3 (27%) had recurrence of hyperthyroidism.

Hypothyroidism

OPDIVO as a Single Agent

Hypothyroidism occurred in 8% (163/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.2%) and Grade 2 (4.8%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.5% of patients.

Approximately 79% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 3.1% (5/163) of patients with hypothyroidism. Hypothyroidism resolved in 35% of the 163 patients. Of the 9 patients in whom OPDIVO was withheld for hypothyroidism, 3 reinitiated OPDIVO after symptom improvement; of these, 1 (33%) had recurrence of hypothyroidism.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hypothyroidism occurred in 20% (91/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.4%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDIVO with ipilimumab in 0.9% and withholding of OPDIVO with ipilimumab in 0.9% of patients.

Approximately 89% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 2.2% (2/91) of patients with hypothyroidism. Hypothyroidism resolved in 41% of the 91 patients. Of the 4 patients in whom OPDIVO with ipilimumab was withheld for hypothyroidism, 2 reinitiated treatment after symptom improvement; of these, none had recurrence of hypothyroidism.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hypothyroidism occurred in 18% (122/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to permanent discontinuation of OPDIVO with ipilimumab in 0.2% and withholding of OPDIVO with ipilimumab in 1.4% of patients with RCC or CRC.

Of the 122 patients with RCC or CRC who developed hypothyroidism, approximately 82% received levothyroxine. Systemic corticosteroids were required in 7% (9/122) of patients with hypothyroidism. Hypothyroidism resolved in 27% of the 122 patients. Of the 9 patients in whom OPDIVO with ipilimumab was withheld for hypothyroidism, 5 reinitiated treatment after symptom improvement; of these, 1 (20%) had recurrence of hypothyroidism.

Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold OPDIVO depending on severity [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

Diabetes occurred in 0.9% (17/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.4%) and Grade 2 (0.3%) adverse reactions, and two cases of diabetic ketoacidosis. Diabetes led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.1% of patients.

No patients (0/17) with diabetes required systemic corticosteroids. Diabetes resolved in 29% of the 17 patients. Of the 2 patients in whom OPDIVO was withheld for diabetes, both reinitiated OPDIVO after symptom improvement; of these, neither had recurrence of diabetes.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology.

OPDIVO as a Single Agent

Immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.4% of patients.

Systemic corticosteroids were required in 100% (23/23) of patients with nephritis and renal dysfunction. Nephritis and renal dysfunction resolved in 78% of the 23 patients. Of the 7 patients in whom OPDIVO was withheld for nephritis or renal dysfunction, 7 reinitiated OPDIVO after symptom improvement; of these, 1 (14%) had recurrence of nephritis or renal dysfunction.

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis, defined as requiring the use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

Immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.5% of patients.

Systemic corticosteroids were required in 100% (171/171) of patients with immune-mediated rash. Rash resolved in 72% of the 171 patients. Of the 10 patients in whom OPDIVO was withheld for immune-mediated rash, 9 reinitiated OPDIVO after symptom improvement; of these, 3 (33%) had recurrence of immune-mediated rash.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated rash occurred in 28% (127/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (4.8%) and Grade 2 (10%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO with ipilimumab in 0.4% and withholding of OPDIVO with ipilimumab in 3.9% of patients.

Systemic corticosteroids were required in 100% (127/127) of patients with immune-mediated rash. Rash resolved in 84% of the 127 patients. Of the 18 patients in whom OPDIVO with ipilimumab was withheld for immune-mediated rash, 15 reinitiated treatment after symptom improvement; of these, 8 (53%) had recurrence of immune-mediated rash.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated rash occurred in 16% (108/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (3.5%) and Grade 2 (4.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO with ipilimumab in 0.5% of patients and withholding of OPDIVO with ipilimumab in 2.0% of patients with RCC or CRC.

Systemic corticosteroids were required in 100% (108/108) of patients with immune-mediated rash. Rash resolved in 75% of the 108 patients. Of the 13 patients in whom OPDIVO with ipilimumab was withheld for immune-mediated rash, 11 reinitiated treatment after symptom improvement; of these, 5 (46%) had recurrence of immune-mediated rash.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO or OPDIVO in combination with ipilimumab, or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular: Myocarditis, pericarditis, vasculitis

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss

Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis

Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatic

Endocrine: Hypoparathyroidism

Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection

5.2 Infusion-Related Reactions

OPDIVO can cause severe infusion-related reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

In patients who received OPDIVO as a 60-minute intravenous infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients.

In a trial assessing the pharmacokinetics and safety of a more rapid infusion, in which patients received OPDIVO as a 60-minute intravenous infusion or a 30-minute intravenous 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.

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.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg

Infusion-related reactions occurred in 5.1% (28/547) of patients with RCC and 4.2% (5/119) of patients with CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, respectively. Infusion-related reactions occurred in 12% (37/300) of patients with malignant pleural mesothelioma who received OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks.

5.3 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) [see Adverse Reactions (6.1)]. 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.

5.4 Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for 5 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

5.5 Increased Mortality in Patients with Multiple Myeloma when OPDIVO Is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of a PD-1 blocking antibody, including OPDIVO, to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling.

  • Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
  • Infusion-Related Reactions [see Warnings and Precautions (5.2)]
  • Complications of Allogeneic HSCT [see Warnings and Precautions (5.3)]

Most common adverse reactions (incidence ≥20%) in patients were:

  • As a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, vomiting, and urinary tract infection. (6.1)
  • In combination with ipilimumab: fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness. (6.1)
  • In combination with platinum-doublet chemotherapy: nausea, constipation, fatigue, decreased appetite, and rash. (6.1)
  • In combination with ipilimumab and platinum-doublet chemotherapy: fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus. (6.1)
  • In combination with cabozantinib: diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysaesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. (6.1)
  • In combination with fluoropyrimidine- and platinum-containing chemotherapy: nausea, peripheral neuropathy, decreased appetite, fatigue, constipation, stomatitis, diarrhea, vomiting, abdominal pain, and musculoskeletal pain. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO as a single agent in 1994 patients enrolled in CHECKMATE-037, CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, CHECKMATE-067, CHECKMATE-205, 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); OPDIVO 3 mg/kg administered with ipilimumab 1 mg/kg (n=666) in patients enrolled in CHECKMATE-214 or CHECKMATE-142; OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks in patients enrolled in CHECKMATE-227 (n=576) or CHECKMATE-743 (n=300); OPDIVO 360 mg with ipilimumab 1 mg/kg and 2 cycles of platinum-doublet chemotherapy in CHECKMATE-9LA (n=361); and OPDIVO 240 mg with cabozantinib 40 mg in patients enrolled in CHECKMATE-9ER (n=320).

Unresectable or Metastatic Melanoma

Previously Treated Metastatic Melanoma

The safety of OPDIVO was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.1)]. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/m2 intravenously every 3 weeks or carboplatin AUC 6 mg/mL/min and paclitaxel 175 mg/m2 intravenously every 3 weeks. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in OPDIVO-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received OPDIVO for >6 months and 3% of patients received OPDIVO for >1 year.

The population characteristics in the OPDIVO group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%).

Serious adverse reactions occurred in 41% of patients receiving OPDIVO. OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a dose interruption for an adverse reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (reported in ≥20% of patients) was rash.

Tables 5 and 6 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037.

Table 5: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037
Toxicity was graded per NCI CTCAE v4.
a Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform dermatitis.
b Includes rhinitis, pharyngitis, and nasopharyngitis.

Adverse Reaction

OPDIVO
(n=268)

Chemotherapy
(n=102)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Skin and Subcutaneous Tissue

     Rasha

21

0.4

7

0

     Pruritus

19

0

3.9

0

Respiratory, Thoracic and Mediastinal

     Cough

17

0

6

0

Infections

     Upper respiratory tract infectionb

11

0

2.0

0

General

     Peripheral edema

10

0

5

0

Clinically important adverse reactions in <10% of patients who received OPDIVO were:

Cardiac Disorders: ventricular arrhythmia

Eye Disorders: iridocyclitis

General Disorders and Administration Site Conditions: infusion-related reactions

Investigations: increased amylase, increased lipase

Nervous System Disorders: dizziness, peripheral and sensory neuropathy

Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis

Table 6: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037
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: 252 to 256 patients) and chemotherapy group (range: 94 to 96 patients).

Laboratory Abnormality

OPDIVO

Chemotherapy

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Increased AST

28

2.4

12

1.0

Hyponatremia

25

5

18

1.1

Increased alkaline phosphatase

22

2.4

13

1.1

Increased ALT

16

1.6

5

0

Hyperkalemia

15

2.0

6

0

Previously Untreated Metastatic Melanoma

CHECKMATE-066

The safety of OPDIVO was also evaluated in CHECKMATE-066, a randomized, double-blind, active-controlled trial in 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies (14.1)]. The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=206) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=205). The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in OPDIVO-treated patients. In this trial, 47% of patients received OPDIVO for >6 months and 12% of patients received OPDIVO for >1 year.

The trial population characteristics in the OPDIVO group and dacarbazine group: 59% male, median age 65 years, 99.5% White, 61% with M1c stage disease, 74% with cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH at baseline. There were more patients in the OPDIVO group with ECOG performance status 0 (71% vs. 59%).

Serious adverse reactions occurred in 36% of patients receiving OPDIVO. Adverse reactions led to permanent discontinuation of OPDIVO in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of OPDIVO discontinuations. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO.

The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were increased gamma-glutamyl transferase (3.9%) and diarrhea (3.4%). The most common adverse reactions (reported in ≥20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.

Tables 7 and 8 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066.

Table 7: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-066
Toxicity was graded per NCI CTCAE v4.
a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral edema, pulmonary edema, and lymphedema.
b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain.
c Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative dermatitis, acneiform dermatitis, drug eruption, and skin reaction.
d Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis.

Adverse Reaction

OPDIVO
(n=206)

Dacarbazine
(n=205)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

General

     Fatigue

49

1.9

39

3.4

     Edemaa

12

1.5

4.9

0

Musculoskeletal and Connective Tissue

     Musculoskeletal painb

32

2.9

25

2.4

Skin and Subcutaneous Tissue

     Rashc

28

1.5

12

0

     Pruritus

23

0.5

12

0

     Vitiligo

11

0

0.5

0

     Erythema

10

0

2.9

0

Infections

     Upper respiratory tract infectiond

17

0

6

0

Clinically important adverse reactions in <10% of patients who received OPDIVO were:

Nervous System Disorders: peripheral neuropathy

Table 8: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-066
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: 194 to 197 patients) and dacarbazine group (range: 186 to 193 patients).

Laboratory Abnormality

OPDIVO

Dacarbazine

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Increased ALT

25

3.0

19

0.5

Increased AST

24

3.6

19

0.5

Increased alkaline phosphatase

21

2.6

14

1.6

Increased bilirubin

13

3.1

6

0

CHECKMATE-067

The safety of OPDIVO, administered with ipilimumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma [see Clinical Studies (14.1)]. The trial excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV.

Patients were randomized to receive:

  • OPDIVO 1 mg/kg over 60 minutes with ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by OPDIVO as a single agent at a dose of 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (OPDIVO and ipilimumab arm; n=313), or
  • OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (OPDIVO arm; n=313), or
  • Ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for up to 4 doses (ipilimumab arm; n=311).

The median duration of exposure to OPDIVO was 2.8 months (range: 1 day to 36.4 months) for the OPDIVO and ipilimumab arm and 6.6 months (range: 1 day to 36.0 months) for the OPDIVO arm. In the OPDIVO and ipilimumab arm, 39% were exposed to OPDIVO for ≥6 months and 30% exposed for >1 year. In the OPDIVO arm, 53% were exposed for ≥6 months and 40% for >1 year.

The population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with American Joint Committee on Cancer (AJCC) Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a history of brain metastasis, and 22% had received adjuvant therapy.

Serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO and ipilimumab arm relative to the OPDIVO arm.

The most frequent (≥10%) serious adverse reactions in the OPDIVO and ipilimumab arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). The most frequent adverse reactions leading to discontinuation of both drugs in the OPDIVO and ipilimumab arm and of OPDIVO in the OPDIVO arm, respectively, were colitis (10% and 0.6%), diarrhea (8% and 2.2%), increased ALT (4.8% and 1.0%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%).

The most common (≥20%) adverse reactions in the OPDIVO and ipilimumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases. The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue, rash, musculoskeletal pain, diarrhea, nausea, cough, pruritus, upper respiratory tract infection, decreased appetite, headache, constipation, arthralgia, and vomiting.

Tables 9 and 10 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.

Table 9: Adverse Reactions Occurring in ≥10% of Patients on the OPDIVO and Ipilimumab Arm or the OPDIVO Arm and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia and fatigue.
b Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash.
c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
d Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.
e Includes hypertension and blood pressure increased.

Adverse Reaction

OPDIVO and Ipilimumab
(n=313)

OPDIVO
(n=313)

Ipilimumab
(n=311)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

General

     Fatiguea

62

7

59

1.6

51

4.2

     Pyrexia

40

1.6

16

0

18

0.6

Gastrointestinal

     Diarrhea

54

11

36

5

47

7

     Nausea

44

3.8

30

0.6

31

1.9

     Vomiting

31

3.8

20

1.0

17

1.6

Skin and Subcutaneous Tissue

     Rashb

53

6

40

1.9

42

3.5

     Vitiligo

9

0

10

0.3

5

0

Musculoskeletal and Connective Tissue

     Musculoskeletal painc

32

2.6

42

3.8

36

1.9

     Arthralgia

21

0.3

21

1.0

16

0.3

Metabolism and Nutrition

     Decreased appetite

29

1.9

22

0

24

1.3

Respiratory, Thoracic and Mediastinal

     Cough/productive cough

27

0.3

28

0.6

22

0

     Dyspnea/exertional dyspnea

24

2.9

18

1.3

17

0.6

Infections

     Upper respiratory tract infectiond

23

0

22

0.3

17

0

Endocrine

     Hypothyroidism

19

0.6

11

0

5

0

     Hyperthyroidism

11

1.3

6

0

1

0

Investigations

     Decreased weight

12

0

7

0

7

0.3

Vascular

     Hypertensione

7

2.2

11

5

9

2.3

Clinically important adverse reactions in <10% of patients who received OPDIVO with ipilimumab or OPDIVO as a single agent were:

Gastrointestinal Disorders: stomatitis, intestinal perforation

Skin and Subcutaneous Tissue Disorders: vitiligo

Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy, myositis (including polymyositis)

Nervous System Disorders: neuritis, peroneal nerve palsy

Table 10: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥20% of Patients Treated with OPDIVO with Ipilimumab or Single-Agent OPDIVO and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067
Laboratory Abnormality OPDIVO and Ipilimumab OPDIVO Ipilimumab
All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%)
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 and ipilimumab (range: 75 to 297); OPDIVO (range: 81 to 306); ipilimumab (range: 61 to 301).

Chemistry

     Increased ALT

55

16

25

3.0

29

2.7

     Hyperglycemia

53

5.3

46

7

26

0

     Increased AST

52

13

29

3.7

29

1.7

     Hyponatremia

45

10

22

3.3

26

7

     Increased lipase

43

22

32

12

24

7

     Increased alkaline phosphatase

41

6

27

2.0

23

2.0

     Hypocalcemia

31

1.1

15

0.7

20

0.7

     Increased amylase

27

10

19

2.7

15

1.6

     Increased creatinine

26

2.7

19

0.7

17

1.3

Hematology

     Anemia

52

2.7

41

2.6

41

6

     Lymphopenia

39

5

41

4.9

29

4.0

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 905 patients with completely resected Stage IIIB/C or Stage IV melanoma received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=452) or ipilimumab 10 mg/kg by intravenous infusion every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year (n=453) [see Clinical Studies (14.2)]. 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 >6 months.

Serious adverse reactions occurred in 18% of OPDIVO-treated patients. 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 ≥2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. The most common adverse reactions (at least 20%) 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%).

Tables 11 and 12 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-238.

Table 11: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients - CHECKMATE-238
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, and abdominal tenderness.
c Includes dermatitis described as acneiform, allergic, bullous, or exfoliative and rash described as generalized, erythematous, macular, papular, maculopapular, pruritic, pustular, vesicular, or butterfly, and drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, spinal pain, and pain in extremity.
e Includes postural dizziness and vertigo.
f Includes upper respiratory tract infection including viral respiratory tract infection, lower respiratory tract infection, rhinitis, pharyngitis, and nasopharyngitis.
g Includes secondary hypothyroidism and autoimmune hypothyroidism.

Adverse Reaction

OPDIVO
(n=452)

Ipilimumab 10 mg/kg
(n=453)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

General

     Fatiguea

57

0.9

55

2.4

Gastrointestinal

     Diarrhea

37

2.4

55

11

     Nausea

23

0.2

28

0

     Abdominal painb

21

0.2

23

0.9

     Constipation

10

0

9

0

Skin and Subcutaneous Tissue

     Rashc

35

1.1

47

5.3

     Pruritus

28

0

37

1.1

Musculoskeletal and Connective Tissue

     Musculoskeletal paind

32

0.4

27

0.4

     Arthralgia

19

0.4

13

0.4

Nervous System

     Headache

23

0.4

31

2.0

     Dizzinesse

11

0

8

0

Infections

     Upper respiratory tract infectionf

22

0

15

0.2

Respiratory, Thoracic and Mediastinal

     Cough/productive cough

19

0

19

0

     Dyspnea/exertional dyspnea

10

0.4

10

0.2

Endocrine

     Hypothyroidismg

12

0.2

7.5

0.4
Table 12: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of OPDIVO-Treated Patients - CHECKMATE-238
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: 400 to 447 patients) and ipilimumab 10 mg/kg group (range: 392 to 443 patients).

Laboratory Abnormality

OPDIVO

Ipilimumab 10 mg/kg

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Hematology

     Lymphopenia

27

0.4

12

0.9

     Anemia

26

0

34

0.5

     Leukopenia

14

0

2.7

0.2

     Neutropenia

13

0

6

0.5

Chemistry

     Increased Lipase

25

7

23

9

     Increased ALT

25

1.8

40

12

     Increased AST

24

1.3

33

9

     Increased Amylase

17

3.3

13

3.1

     Hyponatremia

16

1.1

22

3.2

     Hyperkalemia

12

0.2

9

0.5

     Increased Creatinine

12

0

13

0

     Hypocalcemia

10

0.7

16

0.5

Neoadjuvant Treatment of Resectable (Tumors ≥4 cm or Node Positive) Non-Small Cell Lung Cancer

The safety of OPDIVO in combination with platinum-doublet chemotherapy was evaluated in CHECKMATE-816, a randomized, open-label, multicenter trial in patients with resectable NSCLC [see Clinical Studies (14.3)]. Patients received either OPDIVO 360 mg administered in combination with platinum-doublet chemotherapy administered every 3 weeks for 3 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 3 cycles.

The median age of patients who received OPDIVO in combination with platinum-doublet chemotherapy or platinum-doublet chemotherapy was 65 years (range: 34 – 84); 72% male; 47% White, 50% Asian, and 2% Black/African-American.

Serious adverse reactions occurred in 30% of patients who were treated with OPDIVO in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received OPDIVO in combination with platinum-doublet chemotherapy.

Study therapy with OPDIVO in combination with platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 10% of patients and 30% had at least one treatment withheld for an adverse reaction. The most common adverse reactions (≥1%) resulting in permanent discontinuation of OPDIVO in combination with platinum-doublet chemotherapy were anaphylactic reaction (1.7%), acute kidney injury (1.1%), rash (1.1%), and fatigue (1.1%).

The most common (>20%) adverse reactions were nausea, constipation, fatigue, decreased appetite, and rash. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were neutropenia, hyperglycemia, leukopenia, lymphopenia, increased amylase, anemia, thrombocytopenia, and hyponatremia.

Tables 13 and 14 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-816.

Table 13: Adverse Reactions in >10% of Patients with Early-Stage NSCLC Receiving Neoadjuvant OPDIVO and Platinum-Doublet Chemotherapy in CHECKMATE-816
Toxicity was graded per NCI CTCAE v4.
a Includes fatigue and asthenia
b Includes rash, dermatitis, acneiform dermatitis, atopic dermatitis, bullous dermatitis, drug eruption, maculopapular rash, and pruritic rash.
c Includes peripheral neuropathy, dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensory neuropathy.

Adverse Reaction

OPDIVO and Platinum-Doublet Chemotherapy
(n=176)

Platinum-Doublet Chemotherapy
(n=176)

All Grades

(%)

Grades 3 or 4 (%)

All Grades

(%)

Grades 3 or 4 (%)

Gastrointestinal

     Nausea

38

0.6

45

1.1

     Constipation

34

0

32

1.1

     Vomiting

11

1.1

13

0.6

General

     Fatiguea

26

2.3

23