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Nivolumab: Drug information

Nivolumab: Drug information
(For additional information see "Nivolumab: Patient drug information" and see "Nivolumab: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Opdivo
Brand Names: Canada
  • Opdivo
Pharmacologic Category
  • Antineoplastic Agent, Anti-PD-1 Monoclonal Antibody;
  • Antineoplastic Agent, Immune Checkpoint Inhibitor;
  • Antineoplastic Agent, Monoclonal Antibody
Dosing: Adult

Note: Do not substitute nivolumab with nivolumab/relatlimab.

Colorectal cancer, metastatic, microsatellite instability-high or mismatch repair deficient; single agent

Colorectal cancer, metastatic, microsatellite instability-high or mismatch repair deficient; single agent: IV: 240 mg once every 2 weeks or 480 mg once every 4 weeks until disease progression or unacceptable toxicity.

Off-label dosing: IV: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Overman 2017).

Colorectal cancer, metastatic, microsatellite instability-high or mismatch repair deficient; combination therapy

Colorectal cancer, metastatic, microsatellite instability-high or mismatch repair deficient; combination therapy: IV: 3 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by nivolumab monotherapy at 240 mg once every 2 weeks or 480 mg once every 4 weeks until disease progression or unacceptable toxicity.

Off-label dosing: IV: 3 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by 3 mg/kg once every 2 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity (Overman 2018).

Esophageal adenocarcinoma, advanced or metastatic

Esophageal adenocarcinoma, advanced or metastatic: IV: 240 mg once every 2 weeks or 360 mg once every 3 weeks (in combination with fluoropyrimidine- and platinum-containing chemotherapy) until disease progression, unacceptable toxicity, or up to 2 years (Janjigian 2021).

Esophageal carcinoma, squamous cell, unresectable advanced, recurrent, or metastatic

Esophageal carcinoma, squamous cell, unresectable advanced, recurrent, or metastatic:

First-line treatment (combination therapy):

IV: 240 mg once every 2 weeks (Doki 2022) or 480 mg once every 4 weeks (in combination with fluoropyrimidine- and platinum-containing chemotherapy); continue nivolumab until disease progression or unacceptable toxicity, or up to 2 years.

IV: 3 mg/kg once every 2 weeks (Doki 2022) or 360 mg once every 3 weeks (in combination with ipilimumab); continue until disease progression or unacceptable toxicity, or up to 2 years.

After prior fluoropyrimidine- and platinum-based therapy: IV: 240 mg once every 2 weeks (Kato 2019) or 480 mg once every 4 weeks until disease progression or unacceptable toxicity.

Esophageal or gastroesophageal junction cancer, resected, adjuvant treatment

Esophageal or gastroesophageal junction cancer, resected, adjuvant treatment: IV: 240 mg once every 2 weeks or 480 mg once every 4 weeks until disease progression or unacceptable toxicity for up to 1 year.

Off-label dosing: IV: 240 mg once every 2 weeks for 16 weeks, followed by 480 mg once every 4 weeks beginning at week 17 until disease progression or unacceptable toxicity for up to 1 year (Kelly 2021).

Gastric cancer or gastroesophageal junction cancer, advanced or metastatic

Gastric cancer or gastroesophageal junction cancer, advanced or metastatic: IV: 240 mg once every 2 weeks or 360 mg once every 3 weeks (in combination with fluoropyrimidine- and platinum-containing chemotherapy) until disease progression, unacceptable toxicity, or up to 2 years (Janjigian 2021).

Head and neck cancer, squamous cell, recurrent or metastatic

Head and neck cancer, squamous cell, recurrent or metastatic: IV: 240 mg once every 2 weeks or 480 mg once every 4 weeks until disease progression or unacceptable toxicity.

Off-label dosing: IV: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Ferris 2016).

Hepatocellular carcinoma

Hepatocellular carcinoma: IV: 1 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by 240 mg once every 2 weeks (Yau 2020) or 480 mg once every 4 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity.

Hodgkin lymphoma, classical

Hodgkin lymphoma, classical: IV: 240 mg once every 2 weeks or 480 mg once every 4 weeks until disease progression or unacceptable toxicity.

Off-label dosing: IV: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Ansell 2015; Younes 2016).

Malignant pleural mesothelioma, unresectable; first-line therapy

Malignant pleural mesothelioma, unresectable; first-line therapy: IV: 360 mg once every 3 weeks (in combination with ipilimumab) until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression.

Melanoma, adjuvant treatment

Melanoma, adjuvant treatment: IV: 240 mg once every 2 weeks or 480 mg once every 4 weeks until disease recurrence or unacceptable toxicity for up to 1 year.

Off-label dosing: IV: 3 mg/kg once every 2 weeks until disease recurrence or unacceptable toxicity for up to 1 year (Ascierto 2020; Weber 2017).

Melanoma, metastatic with brain metastases

Melanoma, metastatic with brain metastases (off-label use): IV: 1 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by 3 mg/kg once every 2 weeks (nivolumab monotherapy); total duration of nivolumab therapy is up to 24 months, or until disease progression or unacceptable toxicity (Tawbi 2018; Tawbi 2021).

Melanoma, unresectable or metastatic, single-agent therapy

Melanoma, unresectable or metastatic, single-agent therapy: IV: 240 mg once every 2 weeks or 480 mg once every 4 weeks until disease progression or unacceptable toxicity.

Off-label dosing: IV: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Robert 2015; Weber 2015).

Melanoma, unresectable or metastatic, combination therapy

Melanoma, unresectable or metastatic, combination therapy: IV: 1 mg/kg once every 3 weeks (in combination with ipilimumab) for a maximum of 4 combination doses or until unacceptable toxicity (whichever occurs earlier), followed by 240 mg once every 2 weeks or 480 mg once every 4 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity.

Off-label dosing: IV: 1 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by 3 mg/kg once every 2 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity (Larkin 2015; Larkin 2019; Wolchok 2017) or (alternative strategy [based on limited data]; may decrease toxicity in patients who experienced severe toxicity) 3 mg/kg once every 3 weeks (in combination with reduced-dose ipilimumab) for 4 combination doses, followed 6 weeks later by 480 mg once every 4 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity (Lebbé 2019).

Non–small cell lung cancer, metastatic, PD-L1-expressing

Non–small cell lung cancer, metastatic, PD-L1-expressing: IV: 360 mg once every 3 weeks (in combination with ipilimumab; refer to Ipilimumab monograph for ipilimumab dosing information) until disease progression, unacceptable toxicity or for up to 2 years in patients without disease progression.

Off-label dosing: IV: 3 mg/kg once every 2 weeks (in combination with ipilimumab) until disease progression or unacceptable toxicity or for up to 2 years of follow up (Hellmann 2019).

Non–small cell lung cancer, metastatic, progressive

Non–small cell lung cancer, metastatic, progressive: IV: 240 mg once every 2 weeks or 480 mg once every 4 weeks until disease progression or unacceptable toxicity.

Off-label dosing: IV: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Borghaei 2015; Brahmer 2015).

Non–small cell lung cancer, metastatic or recurrent

Non–small cell lung cancer, metastatic or recurrent: IV: 360 mg once every 3 weeks (in combination with ipilimumab and 2 cycles of histology-based platinum-doublet chemotherapy; refer to Ipilimumab monograph for ipilimumab dosing information) until disease progression, unacceptable toxicity or for up to 2 years in patients without disease progression (Paz-Ares 2021).

Non–small cell lung cancer, resectable, neoadjuvant therapy

Non–small cell lung cancer, resectable, neoadjuvant therapy: IV: 360 mg once every 3 weeks (in combination with platinum-doublet chemotherapy on the same day) for 3 cycles; in the clinical trial, platinum-doublet chemotherapy could consist of pemetrexed/cisplatin, cisplatin/gemcitabine, or carboplatin/paclitaxel; refer to protocol for further information, including histology details (Forde 2022).

Renal cell carcinoma, advanced, previously treated

Renal cell carcinoma, advanced, previously treated: IV: 240 mg once every 2 weeks or 480 mg once every 4 weeks (as a single agent) until disease progression or unacceptable toxicity.

Off-label dosing: IV: 3 mg/kg once every 2 weeks (as a single agent) until disease progression or unacceptable toxicity (Motzer 2015; Motzer 2020).

Renal cell carcinoma, advanced, first-line treatment, combination therapy

Renal cell carcinoma, advanced, first-line treatment, combination therapy: IV: 240 mg once every 2 weeks (Choueiri 2021) or 480 mg once every 4 weeks (in combination with cabozantinib) until disease progression, unacceptable toxicity, or for up to 2 years. Refer to Cabozantinib monograph for dosing in combination with nivolumab.

Renal cell carcinoma, advanced, first-line treatment; intermediate or poor risk, combination therapy

Renal cell carcinoma, advanced, first-line treatment; intermediate or poor risk, combination therapy: IV: 3 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by 240 mg once every 2 weeks (Motzer 2019) or 480 mg once every 4 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity.

Off-label dosing: IV: 3 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by 3 mg/kg once every 2 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity (Motzer 2018; Motzer 2019).

Urothelial carcinoma, adjuvant therapy following resection

Urothelial carcinoma, adjuvant therapy following resection: IV: 240 mg once every 2 weeks (Bajorin 2021) or 480 mg once every 4 weeks until disease recurrence or unacceptable toxicity for up to 1 year.

Urothelial carcinoma, locally advanced or metastatic

Urothelial carcinoma, locally advanced or metastatic: IV: 240 mg once every 2 weeks or 480 mg once every 4 weeks until disease progression or unacceptable toxicity.

Off-label dosing: IV: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Sharma 2017).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Kidney impairment prior to treatment initiation:

eGFR ≥15 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling; however, eGFR ≥15 mL/minute/1.73 m2 had no clinically important effect on nivolumab clearance.

eGFR <15 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling.

Kidney toxicity during treatment:

Immune-mediated nephritis with kidney dysfunction: If nivolumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to ≤ grade 1, then follow with a corticosteroid taper.

Grade 2 or grade 3 serum creatinine elevation: Withhold nivolumab; resume nivolumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue nivolumab if no complete or partial response within 12 weeks of last nivolumab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 4 serum creatinine elevation: Permanently discontinue nivolumab.

Dosing: Hepatic Impairment: Adult

Hepatic impairment prior to treatment initiation:

Mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 × ULN and any AST) or moderate (total bilirubin >1.5 to 3 × ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, mild or moderate impairment had no clinically important effect on nivolumab clearance.

Severe (total bilirubin >3 × ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Hepatotoxicity during treatment:

If nivolumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to ≤ grade 1, then follow with a corticosteroid taper. Permanently discontinue nivolumab if no complete or partial response within 12 weeks of last nivolumab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Nivolumab monotherapy:

Immune-mediated hepatitis without tumor involvement of the liver:

AST or ALT >3 to ≤8 × ULN or total bilirubin >1.5 to ≤3 × ULN: Withhold nivolumab treatment. Resume nivolumab treatment with complete or partial resolution (to grade 0 or 1) of hepatitis after corticosteroid taper.

AST or ALT >8 × ULN or total bilirubin >3 × ULN: Discontinue nivolumab permanently.

Immune-mediated hepatitis with tumor involvement of the liver: Note: If AST and ALT are ≤ ULN at baseline, follow recommendations for hepatitis without tumor involvement of the liver.

If baseline AST or ALT >1 to ≤3 × ULN and increases to >5 to ≤10 × ULN or baseline AST or ALT >3 to ≤5 × ULN and increases to >8 to ≤10 × ULN: Withhold nivolumab treatment. Resume nivolumab treatment with complete or partial resolution (to grade 0 or 1) of hepatitis after corticosteroid taper.

AST or ALT increases to >10 × ULN or total bilirubin increases to >3 × ULN: Discontinue nivolumab permanently.

Nivolumab in combination with ipilimumab: Note: When receiving combination therapy with nivolumab and ipilimumab, withhold or permanently discontinue both nivolumab and ipilimumab for adverse reactions meeting dosage modification recommendations. Refer to Ipilimumab monograph for information on ipilimumab dosage adjustment for toxicity.

Immune-mediated hepatitis without tumor involvement of the liver or hepatitis with tumor involvement of the liver/non-hepatocellular carcinoma:

AST or ALT >3 to ≤5 × ULN or total bilirubin ≥1.5 to ≤3 × ULN: Withhold treatment. Resume treatment with complete or partial resolution (to grade 0 or 1) of hepatitis after corticosteroid taper.

AST or ALT >5 × ULN or total bilirubin >3 × ULN: Discontinue permanently.

Immune-mediated hepatitis with tumor involvement of the liver/hepatocellular carcinoma: Note: If AST and ALT are ≤ ULN at baseline, follow nivolumab in combination with ipilimumab recommendations for hepatitis without tumor involvement of the liver.

If baseline AST or ALT >1 to ≤3 × ULN and increases to >5 to ≤10 × ULN or baseline AST or ALT >3 to ≤5 × ULN and increases to >8 to ≤10 × ULN: Withhold treatment. Resume treatment with complete or partial resolution (to grade 0 or 1) of hepatitis after corticosteroid taper.

AST or ALT >10 × ULN or total bilirubin >3 × ULN: Discontinue permanently.

Nivolumab in combination with cabozantinib: Note: Refer to Cabozantinib monograph for information on cabozantinib dosage adjustment for toxicity. For liver enzyme elevations when administered in combination with cabozantinib, consider corticosteroid therapy if nivolumab and/or cabozantinib is withheld or discontinued.

ALT or AST >3 to ≤10 × ULN with concurrent total bilirubin <2 × ULN: Withhold both nivolumab and cabozantinib. Upon recovery to grade 0 or 1, may consider rechallenging with nivolumab and/or cabozantinib.

ALT or AST >10 × ULN or >3 × ULN with concurrent total bilirubin ≥2 × ULN: Permanently discontinue both nivolumab and cabozantinib.

Dosing: Pediatric

(For additional information see "Nivolumab: Pediatric drug information")

Note: Do not substitute nivolumab with nivolumab/relatlimab.

Colorectal cancer (CRC), metastatic (microsatellite instability-high or mismatch repair deficient): Note: FDA approval is through an accelerated process; continued approval is dependent upon verification of clinical benefit in further trials.

Single-agent nivolumab therapy: Children ≥12 years and Adolescents: IV:

<40 kg: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity.

≥40 kg: 240 mg once every 2 weeks or 480 mg once every 4 weeks until disease progression or unacceptable toxicity.

Combination therapy with ipilimumab: Children ≥12 years and Adolescents: IV:

<40 kg: 3 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 doses (or less if unacceptable toxicity occurs); followed by 3 mg/kg once every 2 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity. Note: If nivolumab therapy is withheld, ipilimumab should also be withheld.

≥40 kg: 3 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 doses (or less if unacceptable toxicity occurs); followed by 240 mg once every 2 weeks or 480 mg once every 4 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity. Note: If nivolumab therapy is withheld, ipilimumab should also be withheld.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing adjustment for toxicity: Children ≥12 years and Adolescents:

Note: No dosage reductions of nivolumab are recommended. When nivolumab is given in combination with ipilimumab, withhold or permanently discontinue both nivolumab and ipilimumab for adverse reactions meeting dosage modification recommendations. Other concomitant combination therapy medications may also require treatment interruption, dosage reduction, and/or discontinuation.

Immune-mediated adverse reactions (general information): Withhold nivolumab for severe (grade 3) immune-mediated adverse reactions. Permanently discontinue nivolumab for life-threatening (grade 4) immune-mediated adverse reactions, recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or inability to reduce corticosteroid dose to prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating corticosteroids. If nivolumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) until improvement to ≤ grade 1; upon improvement to ≤ grade 1, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants if immune-mediated adverse reaction is not controlled with corticosteroid therapy. Systemic corticosteroids may not be necessary for certain adverse reactions. Hormone replacement therapy may be required for endocrinopathies (if clinically indicated). See table for additional dosage modification guidance.

Nivolumaba Recommended Dosage Modifications for Adverse Reactions

Adverse reaction

Severity

Nivolumab dosage modification

a When receiving combination therapy with nivolumab and ipilimumab, withhold or permanently discontinue both nivolumab and ipilimumab for adverse reactions meeting dosage modification recommendations. Refer to Ipilimumab monograph for information on ipilimumab dosage adjustment for toxicity.

Immune-mediated adverse reactions

Cardiovascular toxicity: Myocarditis

Grade 2, 3, or 4

Permanently discontinue nivolumab.

Dermatologic toxicity

Mild or moderate nonexfoliative rash

May be managed with topical emollients and/or topical corticosteroids.

Exfoliative dermatologic conditions: Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS)

Withhold nivolumab.

Confirmed SJS, TEN, or DRESS

Permanently discontinue nivolumab.

Endocrinopathies

Grade 2

Depending on clinical severity, consider withholding until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.

Grade 3 or 4

Withhold nivolumab until clinically stable or permanently discontinue depending on severity.

Adrenal insufficiency, ≥ grade 2

Initiate symptomatic management (including hormone replacement as clinically indicated). Depending on the severity, withhold nivolumab.

Diabetes, type 1

Initiate insulin as clinically indicated. Depending on the severity, withhold nivolumab.

Hypophysitis

Withhold or discontinue nivolumab (depending on the severity). Initiate hormone replacement therapy as clinically indicated.

Hyperthyroidism

Withhold or discontinue nivolumab (depending on the severity). Initiate medical management as clinically indicated.

Hypothyroidism

Withhold nivolumab (depending on the severity). Initiate thyroid hormone replacement therapy as clinically indicated.

Thyroiditis

Withhold or discontinue nivolumab (depending on the severity). Initiate medical management as clinically indicated.

GI toxicity: Colitis

Grade 2

Withhold therapy; resume after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue therapy if no complete or partial response within 12 weeks of last treatment dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3: Single-agent nivolumab

Withhold nivolumab; resume nivolumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue therapy if no complete or partial response within 12 weeks of last nivolumab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3: Nivolumab with ipilimumab

Permanently discontinue.

Grade 4

Permanently discontinue.

Neurologic toxicities

Grade 2

Withhold nivolumab; resume nivolumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue nivolumab if no complete or partial response within 12 weeks of last nivolumab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3 or 4

Permanently discontinue nivolumab.

Ocular disorders: Vogt-Koyanagi-Harada-like syndrome

May require systemic corticosteroids to reduce the risk of permanent vision loss.

Pulmonary toxicity: Pneumonitis

Grade 2

Withhold nivolumab; resume nivolumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue nivolumab if no complete or partial response within 12 weeks of last nivolumab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3 or 4

Permanently discontinue nivolumab.

Other adverse reactions

Infusion reactions

Grade 1 or 2

Interrupt or slow the rate of nivolumab infusion.

Grade 3 or 4

Permanently discontinue nivolumab.

Dosing: Kidney Impairment: Pediatric

Children ≥12 years and Adolescents:

Baseline renal impairment: No dosage adjustment appears necessary; eGFR ≥15 mL/minute/1.73 m2 had no clinically important effect on nivolumab clearance.

Renal toxicity during treatment (nephritis or renal dysfunction): Immune -mediated nephritis with kidney dysfunction: If nivolumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to ≤ grade 1, then follow with a corticosteroid taper.

Grade 2 or grade 3 serum creatinine elevation: Withhold nivolumab; resume nivolumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue nivolumab if no complete or partial response within 12 weeks of last nivolumab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 4 serum creatinine elevation: Permanently discontinue nivolumab.

Dosing: Hepatic Impairment: Pediatric

Baseline hepatic impairment: Children ≥12 years and Adolescents:

Mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 × ULN and any AST) or moderate (total bilirubin >1.5 to 3 × ULN and any AST) impairment: No dosage adjustment necessary.

Severe (total bilirubin >3 × ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Hepatotoxicity during treatment: Children ≥12 years and Adolescents:

Note: If nivolumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to ≤ grade 1, then follow with a corticosteroid taper.

Nivolumab monotherapy :

Immune-mediated hepatitis without tumor involvement of the liver:

AST or ALT >3 up to 8 × ULN or total bilirubin >1.5 up to 3 × ULN: Withhold nivolumab treatment. Resume nivolumab treatment with complete or partial resolution (to grade 0 or 1) of hepatitis after corticosteroid taper. Permanently discontinue nivolumab if no complete or partial response within 12 weeks of last nivolumab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

AST or ALT >8 times ULN or total bilirubin >3 × ULN: Discontinue nivolumab permanently.

Immune-mediated hepatitis with tumor involvement of the liver: Note: If AST and ALT are ≤ ULN at baseline, follow recommendations for hepatitis without tumor involvement of the liver.

If baseline AST or ALT >1 up to 3 × ULN and increases to >5 up to 10 × ULN or baseline AST or ALT >3 up to 5 × ULN and increases to >8 up to 10 × ULN: Withhold nivolumab treatment. Resume nivolumab treatment with complete or partial resolution (to grade 0 or 1) of hepatitis after corticosteroid taper. Permanently discontinue nivolumab if no complete or partial response within 12 weeks of last nivolumab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

AST or ALT increases to >10 times ULN or total bilirubin increases to >3 × ULN: Discontinue nivolumab permanently.

Nivolumab in combination with ipilimumab: Note: When receiving combination therapy with nivolumab and ipilimumab, withhold or permanently discontinue both nivolumab and ipilimumab for adverse reactions meeting dosage modification recommendations. Refer to Ipilimumab monograph for information on ipilimumab dosage adjustment for toxicity.

Immune-mediated hepatitis without tumor involvement of the liver or hepatitis with tumor involvement of the liver/non-hepatocellular carcinoma:

AST or ALT >3 up to 5 × ULN or total bilirubin >1.5 up to 3 × ULN: Withhold treatment. Resume treatment with complete or partial resolution (to grade 0 or 1) of hepatitis after corticosteroid taper. Permanently discontinue nivolumab if no complete or partial response within 12 weeks of last nivolumab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

AST or ALT >5 times ULN or total bilirubin >3 × ULN: Discontinue permanently.

Immune-mediated hepatitis with tumor involvement of the liver/hepatocellular carcinoma: Note: If AST and ALT are ≤ ULN at baseline, follow nivolumab in combination with ipilimumab recommendations for hepatitis without tumor involvement of the liver.

If baseline AST or ALT >1 up to 3 × ULN and increases to >5 up to 10 × ULN or baseline AST or ALT >3 up to 5 × ULN and increases to >8 up to 10 × ULN: Withhold treatment. Resume treatment with complete or partial resolution (to grade 0 or 1) of hepatitis after corticosteroid taper. Permanently discontinue nivolumab if no complete or partial response within 12 weeks of last nivolumab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

AST or ALT >10 times ULN or total bilirubin >3 × ULN: Discontinue permanently.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Adjustment for Toxicity: Adult

Note: No dosage reductions of nivolumab are recommended. When nivolumab is given in combination with ipilimumab, withhold or permanently discontinue both nivolumab and ipilimumab for adverse reactions meeting dosage modification recommendations. Other concomitant combination therapy medications may also require treatment interruption, dosage reduction, and/or discontinuation.

Immune-mediated adverse reactions (general information): Withhold nivolumab for severe (grade 3) immune-mediated adverse reactions. Permanently discontinue nivolumab for life-threatening (grade 4) immune-mediated adverse reactions, recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or inability to reduce corticosteroid dose to prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating corticosteroids. If nivolumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) until improvement to ≤ grade 1; upon improvement to ≤ grade 1, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants if immune-mediated adverse reaction is not controlled with corticosteroid therapy. Systemic corticosteroids may not be necessary for certain adverse reactions. Hormone replacement therapy may be required for endocrinopathies (if clinically indicated). See table for additional dosage modification guidance.

Additional management recommendations: Consider withholding checkpoint inhibitor therapy for most grade 2 toxicities and resume when symptoms and/or lab values resolve to ≤ grade 1; systemic corticosteroids (initial dose of 0.5 to 1 mg/kg/day prednisone [or equivalent]) may be administered if indicated for grade 2 toxicities (ASCO [Schneider 2021]). Refer to guideline for further information regarding management of immune-mediated adverse reactions associated with checkpoint inhibitor therapy.

Nivolumaba Recommended Dosage Modifications for Adverse Reactions

Adverse reaction

Severity

Nivolumab dosage modification

a When receiving combination therapy with nivolumab and ipilimumab, withhold or permanently discontinue both nivolumab and ipilimumab for adverse reactions meeting dosage modification recommendations. Refer to Ipilimumab monograph for information on ipilimumab dosage adjustment for toxicity.

b Refer to Prednisone monograph for tapering recommendations when used for immune-mediated adverse reactions associated with checkpoint inhibitor therapy.

Immune-mediated adverse reactions

Cardiovascular toxicity: Myocarditis

Grade 2, 3, or 4

Permanently discontinue nivolumab.

Dermatologic toxicity

Mild or moderate nonexfoliative rash

May be managed with topical emollients and/or topical corticosteroids.

Exfoliative dermatologic conditions: Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS)

Withhold nivolumab.

Confirmed SJS, TEN, or DRESS

Permanently discontinue nivolumab.

Endocrinopathies

Grade 2

Depending on clinical severity, consider withholding until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.

Grade 3 or 4

Withhold nivolumab until clinically stable or permanently discontinue depending on severity.

Adrenal insufficiency, ≥ grade 2

Initiate symptomatic management (including hormone replacement as clinically indicated). Depending on the severity, withhold nivolumab.

Diabetes, type 1

Initiate insulin as clinically indicated.

Hypophysitis

Withhold or discontinue nivolumab (depending on the severity).

Hyperthyroidism/Thyroiditis

Withhold or discontinue nivolumab (depending on the severity). Initiate medical management as clinically indicated.

Hypothyroidism

Withhold nivolumab (depending on the severity). Initiate thyroid hormone replacement therapy as clinically indicated.

GI toxicity: Colitis

Grade 2

Withhold therapy; resume after complete or partial (to grade 0 or 1) resolution after corticosteroid taperb. Permanently discontinue therapy if no complete or partial response within 12 weeks of last treatment dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3: Single-agent nivolumab

Withhold nivolumab; resume nivolumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taperb. Permanently discontinue therapy if no complete or partial response within 12 weeks of last nivolumab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3: Nivolumab with ipilimumab

Permanently discontinue.

Grade 4

Permanently discontinue.

Neurologic toxicities

Grade 2

Withhold nivolumab; resume nivolumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taperb. Permanently discontinue nivolumab if no complete or partial response within 12 weeks of last nivolumab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3 or 4

Permanently discontinue nivolumab.

Ocular disorders: Vogt-Koyanagi-Harada-like syndrome

May require systemic corticosteroids to reduce the risk of permanent vision loss.

Pulmonary toxicity: Pneumonitis

Grade 2

Withhold nivolumab; resume nivolumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taperb. Permanently discontinue nivolumab if no complete or partial response within 12 weeks of last nivolumab dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.

Grade 3 or 4

Permanently discontinue nivolumab.

Other adverse reactions

Infusion reactions

Grade 1 or 2

Interrupt or slow the rate of nivolumab infusion.

Grade 3 or 4

Permanently discontinue nivolumab.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Opdivo: 40 mg/4 mL (4 mL); 100 mg/10 mL (10 mL); 120 mg/12 mL (12 mL); 240 mg/24 mL (24 mL) [contains polysorbate 80]

Generic Equivalent Available: US

No

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Opdivo: 40 mg/4 mL (4 mL); 100 mg/10 mL (10 mL) [contains polysorbate 80]

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125554s106lbl.pdf#page=134, must be dispensed with this medication.

Administration: Adult

IV: Administer as an IV infusion over 30 minutes. Refer to protocol for infusion rates in off-label dosing. Infuse through a line with a sterile, nonpyrogenic, low protein binding 0.2 to 1.2 micrometer in-line filter. If administering as part of a combination regimen, use separate infusion bags and filters for each infusion. Do not administer other medications through the same IV line. Flush IV line at the end of the infusion.

Combination therapy with ipilimumab: When administered in combination with ipilimumab, administer nivolumab first followed by ipilimumab on the same day.

Combination therapy with ipilimumab and platinum-based doublet chemotherapy: When administered in combination with ipilimumab and platinum-based doublet chemotherapy, infuse nivolumab first, followed by ipilimumab, and then the platinum-based doublet chemotherapy (all on the same day).

Combination therapy with platinum-based doublet chemotherapy: When administered in combination with platinum-based doublet chemotherapy, infuse nivolumab first, followed by the platinum-based doublet chemotherapy (on the same day).

Combination therapy with fluoropyrimidine- and platinum-containing chemotherapy: When administered in combination with fluoropyrimidine- and platinum-containing chemotherapy, infuse nivolumab first, followed by the fluoropyrimidine- and platinum-containing chemotherapy (on the same day).

Check label to ensure appropriate product is being administered; nivolumab and nivolumab/relatlimab are different products and are NOT interchangeable.

Administration: Pediatric

Note: Check label to ensure appropriate product is being administered; nivolumab and nivolumab/relatlimab are different products and are NOT interchangeable.

IV: Administer as an IV infusion over 30 minutes through a line with a sterile, nonpyrogenic, low protein binding 0.2 to 1.2 micrometer in-line filter. If administering as part of a combination regimen, use separate infusion bags and filters for each infusion. Do not administer other medications through the same IV line. Flush IV line at the end of the infusion. If mild or moderate infusion reaction occurs, interrupt infusion or slow infusion rate; if infusion reaction is severe or life-threatening, discontinue nivolumab.

Combination therapy with ipilimumab: When administered in combination with ipilimumab, infuse nivolumab first followed by ipilimumab on the same day.

Use: Labeled Indications

Colorectal cancer, metastatic (microsatellite instability high or mismatch repair deficient): Treatment (as a single agent or in combination with ipilimumab) of microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer in adults and pediatric patients ≥12 years of age that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Esophageal cancer:

Adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer in adults with residual pathologic disease who have received neoadjuvant chemoradiotherapy.

First-line treatment of unresectable advanced or metastatic esophageal squamous cell carcinoma (in combination with fluoropyrimidine- and platinum-containing chemotherapy) in adults.

First-line treatment of unresectable advanced or metastatic esophageal squamous cell carcinoma (in combination with ipilimumab) in adults.

Treatment of advanced or metastatic esophageal adenocarcinoma (in combination with fluoropyrimidine- and platinum-containing chemotherapy) in adults.

Treatment of unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma after prior fluoropyrimidine- and platinum-based chemotherapy in adults.

Gastric cancer and gastroesophageal junction cancer, advanced or metastatic: Treatment of advanced or metastatic gastric cancer and gastroesophageal junction cancer (in combination with fluoropyrimidine- and platinum-containing chemotherapy) in adults.

Head and neck cancer, squamous cell (recurrent or metastatic): Treatment of recurrent or metastatic squamous cell carcinoma of the head and neck in adults with disease progression on or after platinum-based therapy.

Hepatocellular carcinoma: Treatment of hepatocellular carcinoma (in combination with ipilimumab) in adults who have been previously treated with sorafenib.

Hodgkin lymphoma, classical: Treatment of classical Hodgkin lymphoma in adults that have relapsed or progressed following autologous hematopoietic stem cell transplant (HSCT) and brentuximab vedotin, or after ≥3 lines of systemic therapy that included autologous HSCT.

Malignant pleural mesothelioma, unresectable: First-line treatment (in combination with ipilimumab) of unresectable malignant pleural mesothelioma in adults.

Melanoma:

Adjuvant treatment of melanoma with involvement of lymph nodes or metastatic disease following complete resection in adults.

Treatment of unresectable or metastatic melanoma (either as a single agent or in combination with ipilimumab) in adults.

Non–small cell lung cancer:

Neoadjuvant treatment (in combination with platinum-doublet chemotherapy) of resectable (tumors ≥4 cm or node positive) non–small cell lung cancer (NSCLC) in adults.

First-line treatment of metastatic NSCLC (in combination with ipilimumab) in adults whose tumors express PD-L1 (≥1%) as determined by an approved test, and with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

First-line treatment of metastatic or recurrent NSCLC (in combination with ipilimumab and 2 cycles of platinum doublet chemotherapy) in adults with no EGFR or ALK genomic tumor aberrations.

Treatment of metastatic NSCLC that has progressed on or after platinum-based chemotherapy in adults. Patients with EGFR or ALK genomic tumor aberrations should have disease progression (on approved EGFR- or ALK-directed therapy) prior to receiving nivolumab.

Renal cell carcinoma, advanced:

Treatment (as a single agent) of advanced renal cell carcinoma (RCC) in adults who have received prior anti-angiogenic therapy.

First-line treatment of advanced RCC (in combination with cabozantinib) in adults.

First-line treatment of intermediate or poor risk advanced RCC (in combination with ipilimumab) in adults.

Urothelial carcinoma:

Adjuvant treatment of urothelial carcinoma in adults who are at high risk of recurrence after undergoing radical resection.

Treatment of locally advanced or metastatic urothelial carcinoma in adults with disease progression during or following a platinum-containing therapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing therapy.

Use: Off-Label: Adult

Melanoma, metastatic with brain metastases

Medication Safety Issues
Sound-alike/look-alike issues:

Nivolumab may be confused with atezolizumab, avelumab, cemiplimab, dostarlimab, durvalumab, ipilimumab, naxitamab, necitumumab, nivolumab/relatlimab, pembrolizumab.

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Other safety concerns:

Nivolumab (Opdivo) may be confused with nivolumab/relatlimab (Opdualag); these products are not interchangeable. Verify product prior to preparation and administration to prevent medication errors.

Adverse Reactions (Significant): Considerations
Cardiovascular toxicity

Acute coronary syndrome (Ref), vasculitis, immune-mediated myocarditis, and pericarditis (Ref) have rarely occurred. Cardiovascular events are potentially fatal (Ref). Myocarditis and pericarditis may overlap with myositis and myasthenia gravis in patients receiving immune checkpoint inhibitors. Death occurred in 46% of patients with severe myocarditis (Ref). Vasculitis has been reported in large, medium, and small vessels as well as the CNS (Ref).

Mechanism: Non–dose-related; exact mechanism is unknown. Evolving data suggest the presence of common high frequency T‐cell receptors in cardiac muscle (Ref).

Onset: Varied; median reported onset of myocarditis is ~30 to 65 days, with most cases occurring in the first 3 months of treatment (Ref). Late presentations of up to 454 days have also been reported (Ref). Median onset of vasculitis is 3 months (Ref).

Risk factors:

• Autoimmune disease (Ref)

• Diabetes mellitus (Ref)

• Combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 (Ref)

• Preexisting cardiovascular disease (Ref)

Dermatologic toxicity

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS) (Ref), toxic epidermal necrolysis ([TEN] some fatal) (Ref), exfoliative dermatitis, and bullous pemphigoid (Ref) may occur with nivolumab (Ref). Among the diverse immune-related adverse events (irAEs), cutaneous toxicities, such as skin rash, pruritus, and vitiligo, are by far the most common and the earliest to occur (Ref); however, rarer rashes, such as lichenoid (eg, lichenoid dermatitis), and bullous disorders, including bullous pemphigoid, SJS, and TEN are of special interest due to their severity and potentially life-threatening consequences (Ref). Additional reported mucosal toxicities include stomatitis, gingivitis, and Sjögren syndrome-like symptoms (Ref). Although most cutaneous toxicities are transient, they can cause significant morbidity and impairment of patients’ health-related quality of life; some adverse reactions (eg, Sjögren syndrome) may not fully resolve, necessitating long-term treatment (Ref).

Mechanism: Non–dose-related; exact mechanism unknown. May involve blockade of a common antigen (co-expressed on a patient's tumor cells and those of the dermo-epidermal junction and/or other levels of the skin) (Ref).

Onset: Intermediate; for most patients, dermatologic toxicity is the earliest irAE experienced and has been reported with nivolumab at a median onset ranging from 2.8 to 6.1 weeks (range: <1 day to 25.8 months) after treatment initiation and may occur in patients with any tumor type (Ref). Median time to onset for Sjögren syndrome-like symptoms is 70 days ((Ref).

Endocrine toxicity

Endocrine toxicities include primary hypothyroidism, hyperthyroidism, adrenocortical insufficiency (primary and secondary), hypophysitis (inflammation of the pituitary gland), and type 1 diabetes mellitus (including diabetic ketoacidosis) (Ref). In rare cases, patients may present with adrenal crisis (Ref). Hypothyroidism and hyperthyroidism are frequently asymptomatic (or present with vague symptoms) (Ref). Immune-mediated endocrinopathies usually require permanent hormone replacement (Ref).

Mechanism: Non–dose-related; mechanisms not fully understood. Thyroid dysfunction may be due to the development of antithyroglobulin or antithyroid peroxidase antibodies. In rare cases, Graves disease may arise due to the development of anti-thyroid-stimulating hormone receptor antibodies (Ref). Hypophysitis may be due to humoral immunity against the pituitary gland, with involvement of the complement system (Ref).

Onset: Varied; often delayed and can appear at any time throughout treatment with immune checkpoint inhibitors (Ref). Adrenal insufficiency: Median onset of 10 weeks (Ref). Hypophysitis: Median onset of 76 days (Ref). Hypothyroidism: Median onset of 10 weeks (Ref). Diabetes mellitus: Median onset of 4.4 months (range: 15 days to 22 months). Thyrotoxicosis: Median onset of 5 weeks (Ref). Type 1 diabetes mellitus: Up to a year after initiation (Ref).

Risk factors:

• Autoimmune disorders (Ref)

• Combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 (Ref)

GI toxicity

Immune-mediated colitis has occurred, including cases of grade 2 to 4 colitis. Diarrhea and colitis represent a clinical spectrum in which diarrhea is defined as increased stool frequency and colitis involves symptoms of abdominal pain and either clinical or radiologic evidence of colonic inflammation (Ref). Colitis affecting the descending colon is one of the most common complications leading to hospitalization and increased morbidity (Ref). Enteritis with small bowel obstruction has been reported (Ref). Complications, such as intestinal perforation, ischemia, necrosis, bleeding, and toxic megacolon may occur (Ref). Colitis-related mortality is associated with delayed reporting, noncompliance with an antidiarrheal regimen, and delays in drug withholding (Ref). In a retrospective study, when re-challenged, up to 34% of patients experienced a recurrence of colitis (Ref).

Mechanism: Non–dose-related; immunologic (Ref).

Onset: Varied; median onset of 5 to 10 weeks (Ref). Median onset with nivolumab has been reported at 4.9 weeks to 5.3 months (range: <1 day to 22.75 months) (Ref). Nivolumab plus ipilimumab combination median onset of colitis ranges from 1.6 to 2.4 months (range: 2 days to 19.2 months).

Risk factors:

• Autoimmune disorders of the GI tract (Ref)

• Combination therapy with anti-PD-(L)1 inhibitors and anti-CTLA-4 inhibitors (Ref)

• Gut microbiome (bacteria of the phylum Firmicutes) (Ref)

• Prior treatment with NSAIDs (Ref)

Hematologic toxicity

Hematologic immune-related adverse events occur less frequently. Severity varies from mild, asymptomatic cytopenias to more significant reports of immune thrombocytopenia, autoimmune hemolytic anemia (AIHA), acquired blood coagulation disorder (hemophilia) (Ref), and disseminated intravascular coagulation (Ref). Development of higher grades of anemia have led to treatment discontinuation in a small percentage of patients treated for head and neck cancers, urothelial and cervical cancer, and non-small cell lung cancer (Ref). Although the incidence for AIHA is rare, it can result in fatalities (Ref). AIHA was significantly more common with anti-PD-1/PD-L1 monoclonal antibodies (ie, nivolumab, pembrolizumab, atezolizumab) than with anti-CTLA-4 monoclonal antibodies (ie, ipilimumab) in a review of 68 case reports (Ref). Several cases of autoimmune pure red cell aplasia, neutropenia, thrombocytopenia, and even pancytopenia have also been reported (Ref). Hemophagocytic lymphohistiocytosis has been reported in patients receiving immunotherapy with nivolumab plus ipilimumab (Ref). This is a rare but potentially fatal syndrome of excessive immune activation, resulting in multiorgan failure, including cytopenias and bleeding (Ref).

Mechanism: Non–dose-related; exact mechanism unknown. AIHA may be a result of augmenting or redirecting patients' immune surveillance. In addition, it is speculated that the random activation of the immune system results in the formation of autoantibodies, activation of T‐cell clones, and the lessening of regulatory T-cell function (Ref). This is different from other drug-induced AIHA in which a drug is absorbed to the red blood cell membrane and triggers the development of autoantibodies to the red cell membrane (Ref).

Onset: Varied; AIHA occurred between 2 and 78 weeks with a median of 10 weeks (Ref). Median time to onset has been reported: Neutropenia (10 weeks), autoimmune hemolytic anemia (3.9 weeks), pancytopenia or aplastic anemia (21.7 weeks) (Ref); hemophagocytic lymphohistiocytosis (26 days), immune thrombocytopenia (41 days), pure red cell aplasia (89 days) (Ref).

Risk factors:

• Combination immunotherapy and chemotherapy (Ref)

• Combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 (Ref)

Hepatotoxicity

Immune-mediated hepatitis (grades 2 to 4) may occur with nivolumab. Hepatitis is associated with increased serum aspartate transaminase, increased serum alanine transaminase, and occasionally increased serum bilirubin (Ref). Although clinically significant hepatotoxicity occurs infrequently, fatal immune-related liver injury has been observed (Ref). Hepatoxicity typically involves a hepatocellular or cholestatic pattern of injury and can range from mild laboratory findings to acute liver failure (Ref). Immune-mediated hepatitis ranges in severity from mild to life-threatening and has both similarities and differences with idiopathic autoimmune hepatitis (Ref). The incidence of immune-mediated hepatotoxic effects is lower in patients treated with anti- PD-1 monoclonal antibodies like nivolumab in comparison to those treated with anti‐CTLA‐4 monoclonal antibodies (Ref). Most studies have demonstrated a higher incidence of liver injury in patients treated with combination regimens of anti‐CTLA‐4 and anti‐PD-1/PD-L1 therapy (Ref).

Mechanism: Possibly dose- and time-related; immunologic (Ref).

Onset: Varied; hepatotoxicity typically occurs within 1 to 15 weeks but may be delayed by months or years (Ref).

Risk factors:

• Cumulative dose (Ref)

• Preexisting autoimmune diathesis (Ref)

• Chronic infection (Ref)

• Tumor infiltration of the liver parenchyma (Ref)

• Combinations of nivolumab with a second immune checkpoint inhibitor or other antineoplastic agents (Ref)

• Autoimmune liver injury (Ref)

• Prior exposure to chemotherapy, radiation therapy, transarterial chemoembolization, or radioembolization (Ref)

Nephrotoxicity

Immune-mediated nephritis has rarely occurred. Although an increased serum creatinine is common, acute kidney injury occurs less frequently (Ref) and may manifest as acute tubular necrosis, autoimmune reactivation of membranous nephropathy, glomerular disease, prerenal disease, or tubulointerstitial nephritis (Ref).

Mechanism: Non–dose-related; immunologic (Ref).

Onset: Varied. Increase in serum creatinine occurs 12 to 48 weeks after initiation (Ref). Acute kidney injury: Median onset of 13 weeks; case reports of earlier onset of 3 weeks after initiation (Ref).

Neurologic toxicity

Neurologic toxicity is rare and has been reported with use of nivolumab alone, in combination with ipilimumab, or in combination with chemotherapy (Ref). These include cerebral hemorrhage (Ref), confusion, myasthenia gravis, and reversible posterior leukoencephalopathy syndrome (Ref). More common peripheral nervous adverse reactions include myasthenia gravis, peripheral neuropathy, and Guillain-Barre syndrome. More common CNS reactions include aseptic meningitis (Ref), encephalitis, and transverse myelitis (Ref). Isolated cases of myasthenia gravis have been reported in studies combining anti-PD-1/PD-L1 with anti-CTLA-4 monoclonal antibodies (Ref). Neurologic toxicity may be fatal or cause permanent impairment (Ref).

Onset: Varied; typically develop within 3 to 4 months of initiation (Ref). Guillain-Barre syndrome: Onset typically within the first 3 cycles (Ref).

Ophthalmic toxicity

Uveitis (anterior, posterior, or panuveitis (Ref) has been reported in patients receiving both single agent and combination anti-PD-1 and anti-CTLA-4 monoclonal antibodies (Ref). Other ocular events reported include blurred vision, dry eye syndrome (Ref), color changes, blepharoptosis, inflammation of the eyelid, keratitis, ocular myasthenia, Vogt-Koyanagi-Harada disease (Ref), and photophobia (Ref).

Onset: Varied; median onset of 5 weeks (range: 1 to 72 weeks) (Ref) .

Pulmonary toxicity

Immune-mediated pneumonitis has occurred less frequently, including grade 3 and 4 and fatal cases. A higher incidence was observed in patients who received combination therapy and patients treated with combination immunotherapy may be less likely to experience resolution of the immune-related adverse event compared with patients with monotherapy (Ref). Recurrent pneumonitis following resolution of symptoms has occurred in patients who were re-challenged with immune checkpoint inhibitor therapy and in patients who were not re-challenged; chronic courses may also occur (Ref).

Mechanism: Non–dose-related; immunologic (Ref).

Onset: Varied; ranging from 2 to 24 months with a median onset of ~3 months (Ref). The median time to development was 3.5 months (range: 1 day to 22.3 months). Onset can occur earlier with combination therapy (Ref). In combination with ipilimumab, median onset ranged from 1.6 to 2.6 months (range: 8 days to 10.1 months).

Risk factors:

• Combination therapy (Ref)

• Prior thoracic radiation in non-small cell lung cancer patients (Ref)

• Treatment-naive patients (Ref)

• Asthma and/or smoking (higher grade) (Ref)

• Treatment for non-small cell lung cancer or renal cell carcinoma (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidence of adverse reactions includes unapproved dosing regimens. Reported adverse reactions are for adults.

>10%:

Cardiovascular: Edema (12%), hypertension (11%)

Dermatologic: Pruritus (13% to 30%) (table 1), skin rash (21% to 40%) (table 2), vitiligo (10% to 11%)

Nivolumab: Adverse Reaction: Pruritus

Drug (Nivolumab)

Comparator

Placebo

Dose

Indication

Number of Patients (Nivolumab)

Number of Patients (Comparator)

Number of Patients (Placebo)

13%

N/A

6%

240 mg IV infused over 30 minutes once every 2 weeks x 16 weeks; followed by 480 mg infused over 30 minutes every 4 weeks beginning on week 17

Adjunctive treatment of resected esophageal or gastroesophageal junction cancer

532

N/A

260

28%

Ipilimumab: 37%

N/A

3 mg/kg over 60 minutes every 2 weeks

Adjuvant treatment of melanoma

452

453

N/A

30%

N/A

16%

240 mg over 30 minutes every 2 weeks

Adjuvant treatment of urothelial carcinoma

351

N/A

348

23%

Dacarbazine: 12%

N/A

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

206

205

N/A

Nivolumab: Adverse Reaction: Skin Rash

Drug (Nivolumab)

Comparator

Placebo

Dose

Indication

Number of Patients (Nivolumab)

Number of Patients (Comparator)

Number of Patients (Placebo)

21%

N/A

10%

240 mg IV infused over 30 minutes once every 2 weeks x 16 weeks; followed by 480 mg infused over 30 minutes every 4 weeks beginning on week 17

Adjunctive treatment of resected esophageal or gastroesophageal junction cancer

532

N/A

260

35%

Ipilimumab: 47%

N/A

3 mg/kg over 60 minutes every 2 weeks

Adjuvant treatment of melanoma

452

453

N/A

36%

N/A

19%

240 mg over 30 minutes every 2 weeks

Adjuvant treatment of urothelial carcinoma

351

N/A

348

40%

Ipilimumab: 42%

N/A

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

313

311

N/A

28%

Dacarbazine: 12%

N/A

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

206

205

N/A

Endocrine & metabolic: Hypercalcemia (12%), hyperglycemia (46%), hyperkalemia (12% to 32%), hyperthyroidism (6% to 11%) (table 3), hypocalcemia (10% to 17%), hypokalemia (12%), hypomagnesemia (16%), hyponatremia (16% to 22%), hypothyroidism (11% to 12%), increased serum albumin (21%), weight loss (7% to 13%) (table 4)

Nivolu mab: Adverse Reaction: Hyperthyroidism

Drug (Nivolumab)

Comparator (Ipilimumab)

Placebo

Dose

Indication

Number of Patients (Nivolumab)

Number of Patients (Ipilimumab)

Number of Patients (Placebo)

11%

N/A

1%

240 mg over 30 minutes every 2 weeks

Adjuvant treatment of urothelial carcinoma

351

N/A

348

6%

1%

N/A

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

313

311

N/A

Nivolumab: Adverse Reaction: Hypothyroidism

Drug (Nivolumab)

Comparator (Ipilimumab)

Placebo

Dose

Indication

Number of Patients (Nivolumab)

Number of Patients (Ipilimumab)

Number of Patients (Placebo)

11%

N/A

2%

240 mg IV infused over 30 minutes once every 2 weeks x 16 weeks; followed by 480 mg infused over 30 minutes every 4 weeks beginning on week 17

Adjunctive treatment of resected esophageal or gastroesophageal junction cancer

532

N/A

260

12%

8%

N/A

3 mg/kg over 60 minutes every 2 weeks

Adjuvant treatment of melanoma

452

453

N/A

11%

N/A

2%

240 mg over 30 minutes every 2 weeks

Adjuvant treatment of urothelial carcinoma

351

N/A

348

11%

5%

N/A

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

313

311

N/A

Gastrointestinal: Abdominal pain (17% to 21%) (table 5), decreased appetite (13% to 22%), diarrhea (29% to 37%; grades 3/4: ≤5%) (table 6), increased serum amylase (17% to 34%), increased serum lipase (25% to 33%), nausea (16% to 30%; grades 3/4: <1%), vomiting (20%; grades 3/4: ≤1%)

Nivolumab: Adverse Reaction: Abdominal Pain

Drug (Nivolumab)

Comparator (Ipilimumab)

Placebo

Dose

Indication

Number of Patients (Nivolumab)

Number of Patients (Ipilimumab)

Number of Patients (Placebo)

17%

N/A

20%

240 mg IV infused over 30 minutes once every 2 weeks x 16 weeks; followed by 480 mg infused over 30 minutes every 4 weeks beginning on week 17

Adjunctive treatment of resected esophageal or gastroesophageal junction cancer

532

N/A

260

21%

23%

N/A

3 mg/kg over 60 minutes every 2 weeks

Adjuvant treatment of melanoma

452

453

N/A

Nivolumab: Adverse Reaction: Diarrhea

Drug (Nivolumab)

Comparator (Ipilimumab)

Placebo

Dose

Indication

Number of Patients (Nivolumab)

Number of Patients (Ipilimumab)

Number of Patients (Placebo)

All grades: 29%

N/A

29%

240 mg IV infused over 30 minutes once every 2 weeks x 16 weeks; followed by 480 mg infused over 30 minutes every 4 weeks beginning on week 17

Adjunctive treatment of resected esophageal or gastroesophageal junction cancer

532

N/A

260

Grades 3/4: 0.9%

N/A

0.8%

240 mg IV infused over 30 minutes once every 2 weeks x 16 weeks; followed by 480 mg infused over 30 minutes every 4 weeks beginning on week 17

Adjunctive treatment of resected esophageal or gastroesophageal junction cancer

532

N/A

260

All grades: 37%

55%

N/A

3 mg/kg over 60 minutes every 2 weeks

Adjuvant treatment of melanoma

452

453

N/A

Grades 3/4: 2%

11%

N/A

3 mg/kg over 60 minutes every 2 weeks

Adjuvant treatment of melanoma

452

453

N/A

All grades: 30%

N/A

27%

240 mg over 30 minutes every 2 weeks

Adjuvant treatment of urothelial carcinoma

351

N/A

348

Grades 3/4: 3%

N/A

2%

240 mg over 30 minutes every 2 weeks

Adjuvant treatment of urothelial carcinoma

351

N/A

348

All grades: 36%

47%

N/A

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

313

311

N/A

Grades 3/4: 5%

7%

N/A

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

313

311

N/A

Hematologic & oncologic: Anemia (26% to 41%; grades 3/4: ≤3%) (table 7), leukopenia (14%), lymphocytopenia (27% to 44%; grades 3/4: ≤17%), neutropenia (11% to 24%; grades 3/4: ≤2%) (table 8)

Nivolumab: Adverse Reaction: Anemia

Drug (Nivolumab)

Comparator (Ipilimumab)

Placebo

Dose

Indication

Number of Patients (Nivolumab)

Number of Patients (Ipilimumab)

Number of Patients (Placebo)

All grades: 27%

N/A

21%

240 mg IV infused over 30 minutes once every 2 weeks x 16 weeks; followed by 480 mg infused over 30 minutes every 4 weeks beginning on week 17

Adjunctive treatment of resected esophageal or gastroesophageal junction cancer

532

N/A

260

Grades 3/4: 0.8%

N/A

0.4%

240 mg IV infused over 30 minutes once every 2 weeks x 16 weeks; followed by 480 mg infused over 30 minutes every 4 weeks beginning on week 17

Adjunctive treatment of resected esophageal or gastroesophageal junction cancer

532

N/A

260

All grades: 26%

34%

N/A

3 mg/kg over 60 minutes every 2 weeks

Adjuvant treatment of melanoma

452

453

N/A

Grades 3/4: 0%

0.5%

N/A

3 mg/kg over 60 minutes every 2 weeks

Adjuvant treatment of melanoma

452

453

N/A

All grades: 30%

N/A

28%

240 mg over 30 minutes every 2 weeks

Adjuvant treatment of urothelial carcinoma

351

N/A

348

Grades 3/4: 1%

N/A

0.9%

240 mg over 30 minutes every 2 weeks

Adjuvant treatment of urothelial carcinoma

351

N/A

348

All grades: 41%

41%

N/A

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

313

311

N/A

Grades 3/4: 3%

6%

N/A

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

313

311

N/A

Nivolumab: Adverse Reaction: Neutropenia

Drug (Nivolumab)

Comparator (Ipilimumab)

Placebo

Dose

Indication

Number of Patients (Nivolumab)

Number of Patients (Ipilimumab)

Number of Patients (Placebo)

All grades: 24%

N/A

23%

240 mg IV infused over 30 minutes once every 2 weeks x 16 weeks; followed by 480 mg infused over 30 minutes every 4 weeks beginning on week 17

Adjunctive treatment of resected esophageal or gastroesophageal junction cancer

532

N/A

260

Grades 3/4: 2%

N/A

0.4%

240 mg IV infused over 30 minutes once every 2 weeks x 16 weeks; followed by 480 mg infused over 30 minutes every 4 weeks beginning on week 17

Adjunctive treatment of resected esophageal or gastroesophageal junction cancer

532

N/A

260

All grades: 13%

6%

N/A

3 mg/kg over 60 minutes every 2 weeks

Adjuvant treatment of melanoma

452

453

N/A

Grades 3/4: 0%

0.5%

N/A

3 mg/kg over 60 minutes every 2 weeks

Adjuvant treatment of melanoma

452

453

N/A

All grades: 11%

N/A

10%

240 mg over 30 minutes every 2 weeks

Adjuvant treatment of urothelial carcinoma

351

N/A

348

Grades 3/4: 0.6%

N/A

0.3%

240 mg over 30 minutes every 2 weeks

Adjuvant treatment of urothelial carcinoma

351

N/A

348

Hepatic: Hepatitis (2% to 11%), increased serum alanine aminotransferase (20% to 25%) (table 9), increased serum alkaline phosphatase (21% to 27%), increased serum aspartate aminotransferase (24% to 29%) (table 10), increased serum bilirubin (13%) (table 11)

Nivolumab: Adverse Reaction: Increased Serum Alanine Aminotransferase

Drug (Nivolumab)

Comparator

Placebo

Dose

Indication

Number of Patients (Nivolumab)

Number of Patients (Comparator)

Number of Patients (Placebo)

20%

N/A

16%

240 mg IV infused over 30 minutes once every 2 weeks x 16 weeks; followed by 480 mg infused over 30 minutes every 4 weeks beginning on week 17

Adjunctive treatment of resected esophageal or gastroesophageal junction cancer

532

N/A

260

25%

Ipilimumab: 40%

N/A

3 mg/kg over 60 minutes every 2 weeks

Adjuvant treatment of melanoma

452

453

N/A

23%

N/A

15%

240 mg over 30 minutes every 2 weeks

Adjuvant treatment of urothelial carcinoma

351

N/A

348

25%

Ipilimumab: 29%

N/A

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

313

311

N/A

25%

Dacarbazine: 19%

N/A

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

206

205

N/A

Nivolumab: Adverse Reaction: Increased Serum Aspartate Aminotransferase

Drug (Nivolumab)

Comparator

Placebo

Dose

Indication

Number of Patients (Nivolumab)

Number of Patients (Comparator)

Number of Patients (Placebo)

27%

N/A

22%

240 mg IV infused over 30 minutes once every 2 weeks x 16 weeks; followed by 480 mg infused over 30 minutes every 4 weeks beginning on week 17

Adjunctive treatment of resected esophageal or gastroesophageal junction cancer

532

N/A

260

24%

Ipilimumab: 33%

N/A

3 mg/kg over 60 minutes every 2 weeks

Adjuvant treatment of melanoma

452

453

N/A

24%

N/A

16%

240 mg over 30 minutes every 2 weeks

Adjuvant treatment of urothelial carcinoma

351

N/A

348

29%

Ipilimumab: 29%

N/A

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

313

311

N/A

24%

Dacarbazine: 19%

N/A

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

206

205

N/A

Nivolumab: Adverse Reaction: Increased Serum Bilirubin

Drug (Nivolumab)

Comparator (Dacarbazine)

Dose

Indication

Number of Patients (Nivolumab)

Number of Patients (Dacarbazine)

13%

6%

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

206

205

Immunologic: Antibody development (11%; neutralizing: <1%)

Nervous system: Dizziness (11%), fatigue (≤59%), headache (23%)

Neuromuscular & skeletal: Arthralgia (10% to 21%), asthenia (≤59%), musculoskeletal pain (21% to 42%)

Renal: Increased serum creatinine (12% to 19%) (table 12), renal insufficiency (≤17%)

Nivolumab: Adverse Reaction: Increased Serum Creatinine

Drug (Nivolumab)

Comparator (Ipilimumab)

Dose

Indication

Number of Patients (Nivolumab)

Number of Patients (Ipilimumab)

12%

13%

3 mg/kg over 60 minutes every 2 weeks

Adjuvant treatment of melanoma

452

453

19%

17%

3 mg/kg over 60 minutes every 2 weeks

Previously untreated metastatic melanoma

313

311

Respiratory: Cough (≤28%), dyspnea (≤18%), dyspnea on exertion (≤18%), productive cough (≤28%), upper respiratory tract infection (17% to 22%)

Miscellaneous: Fever (16%)

1% to 10%:

Dermatologic: Erythema of skin (10%)

Endocrine & metabolic: Adrenocortical insufficiency (1%), increased gamma-glutamyl transferase (grade 3/4: 4%)

Gastrointestinal: Colitis (≤6%; severe colitis: 2%), constipation (10%), intestinal perforation (<10%), stomatitis (<10%)

Immunologic: Sjögren's syndrome (<10%) (SITC [Brahmer 2021])

Nervous system: Neuritis (<10%), peripheral nerve palsy (peroneal: <10%), peripheral neuropathy (<10%)

Neuromuscular & skeletal: Myopathy (<10%), myositis (<10%), polymyositis (<10%), rheumatism (spondyloarthropathy: <10%)

Renal: Nephritis (≤1%)

Respiratory: Pneumonitis (3%)

Miscellaneous: Infusion-related reaction (≤6%; severe infusion-related reaction: <1%)

<1%:

Cardiovascular: Myocarditis, vasculitis (including acral ischemia [Suenaga 2021])

Endocrine & metabolic: Diabetic ketoacidosis, hypoparathyroidism, hypophysitis, thyroiditis, type I diabetes mellitus

Gastrointestinal: Duodenitis, gastritis, pancreatitis

Hematologic & oncologic: Aplastic anemia (Comito 2019), hemolytic anemia, immune thrombocytopenia, lymphadenitis (histiocytic necrotizing lymphadenitis [Kikuchi lymphadenitis]), sarcoidosis

Immunologic: Organ transplant rejection (solid)

Infection: Systemic inflammatory response syndrome

Nervous system: Demyelinating disease, encephalitis (including limbic), exacerbation of myasthenia gravis, Guillain-Barré syndrome, meningitis, myasthenia (myasthenic syndrome), neuropathy (autoimmune), paresis (nerve)

Neuromuscular & skeletal: Arthritis, myelitis, polymyalgia rheumatica, rhabdomyolysis

Ophthalmic: Iritis, uveitis (Tampio 2021)

Postmarketing:

Cardiovascular: Acute coronary syndrome (Cancela-Diez 2020), heart failure (Samejimi 2020), pericardial effusion (Sawada 2021), pericarditis (de Almeida 2018)

Dermatologic: Bullous pemphigoid (Panariello 2018), nail discoloration (bluish-gray) (Ocampo 2021), Stevens-Johnson syndrome (Dasanu 2019), toxic epidermal necrolysis (Basu 2020)

Endocrine & metabolic: Graves' disease (Yamada 2020)

Gastrointestinal: Cholangitis (SITC [Brahmer 2021]), cholecystitis (SITC [Brahmer 2021]), esophagitis (SITC [Brahmer 2021]), exacerbation of ulcerative colitis (Iwamoto 2020), ileitis (Dasanu 2020), oral mucosa ulcer (lip) (Sato 2021), sclerosing cholangitis (Hirasawa 2021), xerostomia (SITC [Brahmer 2021])

Hematologic & oncologic: Acquired blood coagulation disorder (hemophilia) (Gokozan 2019), autoimmune hemolytic anemia (Palla 2016; Shaikh 2018), disseminated intravascular coagulation (Tanios 2019), granuloma (annulare) (Fawaz 2021), immunological signs and symptoms (hemophagocytic lymphohistiocytosis) (Hantel 2018), pancytopenia (Uehara 2020), pure red cell aplasia (SITC [Brahmer 2021]), T-cell lymphoma (peripheral, after long term therapy) (Koda 2021), thrombotic thrombocytopenic purpura (Gergi 2020), tumor lysis syndrome (Sugimoto 2020)

Hypersensitivity: Cytokine release syndrome (Oda 2019)

Immunologic: Graft versus host disease (treatment refractory, severe acute and chronic) (Amerikanou 2021)

Nervous system: Aseptic meningitis (Cordes 2019), cerebral hemorrhage (Hasegawa 2019), myasthenia gravis (Mehta 2017), reversible posterior leukoencephalopathy syndrome (Hussein 2017)

Neuromuscular & skeletal: Costochondritis (Kuba 2020), dermatomyositis (Messer 2020), inflammatory polyarthropathy (Abe 2022), Lambert-Eaton syndrome (Gill 2021), myalgia (SITC [Brahmer 2021]), subacute cutaneous lupus erythematosus (Zitouni 2019)

Ophthalmic: Blepharoptosis (Campredon 2018), dry eye syndrome (SITC [Brahmer 2021]), keratitis (Baughman 2017), Vogt-Koyanagi-Harada disease (Arai 2017)

Otic: Hearing loss (bilateral sensorineural hearing loss [BSHL]) (Tampio 2021)

Renal: Acute kidney injury (SITC [Brahmer 2021]), Cortazar 2016)

Respiratory: Pleural effusion (Sawada 2021)

Miscellaneous: Inflammation (periaortitis) (Hotta 2020)

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to nivolumab or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

• Adverse reactions (immune mediated): PD-1/PD-L1 blockers (including nivolumab) remove immune response inhibition, thus potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Severe and fatal immune-mediated adverse reactions may occur in any organ system or tissue. Reactions generally occur during treatment (may occur at any time after nivolumab initiation); reactions may also occur after nivolumab discontinuation. Early identification and management of immune-mediated adverse reactions are necessary to ensure safe use of nivolumab. If suspected immune-mediated reactions occur, initiate appropriate workup to exclude alternative causes (including infection). Medically manage immune-mediated adverse reactions promptly and refer for specialty consultation as appropriate.

• Dermatologic toxicity: Immune-mediated rash or dermatitis, defined as requiring the use of corticosteroids and the absence of another clear etiology, may occur. Immune-mediated dermatologic adverse reactions (including grade 2 and 3 events) occurred with nivolumab, either when administered as monotherapy or in combination with ipilimumab. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis has occurred with anti-PD-1/PD-L1 monoclonal antibodies. Immune-mediated dermatologic reactions were treated with systemic corticosteroids in all patients, and reactions resolved in over 70% of patients. In cases where nivolumab was withheld, most reinitiated treatment after symptom improvement; immune-mediated dermatologic toxicity recurred in some patients.

• Endocrinopathies: Nivolumab is associated with immune-mediated endocrinopathies.

- Adrenal insufficiency: Primary and secondary adrenal insufficiency have occurred with both single agent and combination therapy, including cases of grade 2 to 4 adrenal insufficiency. The majority of patients received hormonal replacement therapy, and systemic corticosteroids were required in most cases; many of patients remained on corticosteroid therapy. Adrenal insufficiency resolved in approximately one-quarter to one-third of patients. In cases where nivolumab was withheld for adrenal insufficiency, most reinitiated treatment after symptom improvement with recurrence of adrenal insufficiency in some patients.

- Diabetes mellitus: Type 1 diabetes mellitus has occurred (including diabetic ketoacidosis). Long-term insulin therapy may be required. In cases where nivolumab was withheld for diabetes, all reinitiated treatment after symptom improvement with no recurrence of diabetes.

- Hypophysitis: Immune-mediated hypophysitis has occurred when administered as monotherapy or in combination with ipilimumab (grades 2, 3, and 4), and may present with acute mass effect symptoms (headache, photophobia, or visual field defects). Hypophysitis may lead to hypopituitarism. Most hypophysitis cases were managed with hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in ~40% to 60% of cases. In cases where nivolumab was withheld for hypophysitis, many reinitiated treatment after symptom improvement, with some recurrence of hypophysitis.

- Thyroid disorders: Immune-mediated hyperthyroidism, hypothyroidism, and thyroiditis have occurred. Grade 2 and grade 3 hyperthyroidism have been reported when nivolumab was administered as monotherapy or in combination with ipilimumab. Medical managements (eg, methimazole) and systemic corticosteroids were required in some patients; hyperthyroidism resolved in the majority of patients. Hypothyroidism (including grade 2 and grade 3 events) have occurred when administered as monotherapy or in combination with ipilimumab, and was managed in most patients with hormone replacement therapy; some patients required systemic corticosteroids. In cases where nivolumab was withheld for hypo/hyperthyroidism, some reinitiated nivolumab after symptom improvement with occasional recurrence of hypo/hyperthyroidism. Hypothyroidism may follow hyperthyroidism. Thyroiditis may present with or without endocrinopathy. Thyroiditis occurred rarely. Systemic corticosteroids were required in some patients with thyroiditis; thyroiditis resolved in over 50% of patients. In one case where nivolumab was withheld for thyroiditis, nivolumab was reinitiated without recurrence of thyroiditis.

• GI toxicity: Immune-mediated colitis (which is defined as requiring the use of systemic corticosteroids and the absence of another clear etiology; with diarrhea as a common symptom) has occurred (may present with diarrhea) when administered as monotherapy or in combination with ipilimumab, including cases of grade 2 to 4 colitis. Systemic corticosteroids were administered to all patients for immune-mediated colitis; additional immunosuppressant therapy was necessary in some patients. Most patients with colitis experienced resolution. In cases where nivolumab was withheld for colitis, most reinitiated treatment after symptom improvement; colitis recurred in over 50% of patients. Cytomegalovirus infection or reactivation has been observed in patients with corticosteroid-refractory immune-mediated colitis. Pancreatitis (including increased serum amylase and lipase levels), gastritis, and duodenitis have also been reported.

• Hepatotoxicity: Immune-mediated hepatitis (which is defined as requiring the use of systemic corticosteroids and the absence of another clear etiology) has occurred with nivolumab when administered as monotherapy or in combination with ipilimumab (grades 2 to 4 hepatitis). Hepatitis has led to nivolumab treatment interruption or discontinuation. Systemic corticosteroids were used to manage immune-mediated hepatitis in all patients; additional immunosuppressants were necessary in some cases. Hepatitis resolved in most patients. In cases where nivolumab was withheld for hepatitis, most patients reinitiated treatment after symptom improvement; hepatitis recurred in over 50% of patients. Increased frequencies of grade 3 and 4 ALT and AST elevations may occur when nivolumab is administered in combination with cabozantinib (compared to nivolumab alone). Transaminase elevations may require nivolumab and cabozantinib therapy interruption; consider corticosteroid administration as clinically appropriate. ALT or AST elevations may recur when rechallenged with nivolumab and/or cabozantinib.

• Infusion-related reactions: Infusion-related reactions have occurred with both single-agent nivolumab and when used in combination with ipilimumab; severe reactions, although rare, were observed.

• Nephrotoxicity: Immune-mediated nephritis (which is defined as requiring the use of systemic corticosteroids and the absence of another clear etiology) and renal dysfunction has occurred, including grade 2 to grade 4 cases. All patients required systemic corticosteroids. In cases where nivolumab was withheld for nephritis, all reinitiated treatment after symptom improvement with rare recurrence of nephritis. Nephritis resolved in over three-fourths of affected patients.

• Ocular toxicity: Uveitis, iritis, and other ocular inflammatory toxicities may occur (some cases may be associate with retinal detachment). If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome.

• Pulmonary toxicity: Immune-mediated pneumonitis (which is defined as requiring the use of systemic corticosteroids and the absence of another clear etiology) has been observed when administered as monotherapy or in combination with ipilimumab; grades 2 to 4 events and fatal cases have been reported. All patients required management with systemic corticosteroids. Pneumonitis resolved in over 70% of the affected patients. In cases where nivolumab was withheld for pneumonitis, most patients reinitiated nivolumab after symptom improvement; pneumonitis recurred in some patients. In patients treated with other anti-PD-1/PD-L1 monoclonal antibodies, the incidence of pneumonitis was higher in patients with a history of prior thoracic radiation.

• Other immune-mediated toxicities: Other clinically relevant immune-mediated disorders have been observed rarely with nivolumab (or other anti-PD-1/PD-L1 monoclonal antibodies) and may affect any organ system (may be fatal), including myocarditis, pericarditis, vasculitis, meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy, myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatic, hypoparathyroidism, hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, and solid organ transplant rejection.

Disease-related concerns:

• Autoimmune disorders: Anti-PD-1 monoclonal antibodies generate an immune response that may aggravate underlying autoimmune disorders or prior immune-related adverse events. A retrospective study analyzed the safety and efficacy of treatment with anti-PD-1 monoclonal antibodies (eg, nivolumab or pembrolizumab) in patients with melanoma with preexisting autoimmune disease or prior significant ipilimumab-mediated adverse immune events. Results showed that while immune toxicities associated with this class of therapy did occur, most reactions were mild and easily manageable, and did not require permanent drug therapy discontinuation. A significant percentage of patients achieved clinical response with anti-PD-1 monoclonal antibody therapy, despite baseline autoimmunity or prior ipilimumab-related adverse events (Menzies 2017).

• Hematopoietic stem cell transplant: Fatal and other serious complications may occur in patients who receive allogeneic hematopoietic stem cell transplant (HSCT) before or after treatment with an anti-PD-L1/PD-1 monoclonal antibody. Transplant-related complications included hyperacute graft-versus-host disease (GVHD), acute or chronic GVHD, hepatic veno-occlusive disease (also known as sinusoidal obstruction syndrome) after reduced-intensity conditioning, and steroid-requiring febrile syndrome (with no identified infectious etiology). These complications may occur despite intervening therapy between PD-L1/PD-1 blockade and HSCT. Manage early signs/symptoms of transplant-related complications promptly. Assess the risks/benefits of treatment with an anti-PD-L1/PD-1 monoclonal antibody prior to or after an allogenic HSCT.

• Multiple myeloma: An increase in mortality was noted in randomized studies of patients with multiple myeloma who received the addition of a PD-1 blocking agent (including nivolumab) to a thalidomide analogue plus dexamethasone. Nivolumab should not be used to treat multiple myeloma unless part of a clinical trial.

• Myasthenia gravis: Checkpoint inhibitors may worsen or precipitate new myasthenia gravis (MG), especially within the first 16 weeks of treatment; use with caution. Patients with well-controlled MG may be considered for checkpoint inhibitor therapy if MG treatment is maintained (or reinitiated in patients whose MG is in remission), combination therapy (eg, anti–CTLA-4 with anti–PD-a/PD-L1 monoclonal antibodies) is avoided, and respiratory and bulbar function are closely followed. In patients who develop overt MG during checkpoint inhibitor therapy, early aggressive treatment with plasma exchange or IVIG in combination with high-dose corticosteroids may be required (AAN [Narayanaswami 2021]).

Special populations:

• Older adult: In patients with metastatic (unresectable) non–small cell lung cancer who received nivolumab/ipilimumab or nivolumab/ipilimumab with platinum-based doublet chemotherapy, patients ≥75 years of age experienced a higher discontinuation rate due to adverse reactions, compared to younger patients. In the malignant pleural mesothelioma study of nivolumab in combination with ipilimumab, patients ≥75 years of age experienced a higher rate of serious adverse reactions and discontinuation due to adverse reactions.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Appropriate use: Select patients for first-line nivolumab/ipilimumab treatment of metastatic NSCLC based on PD-L1 expression. Information on tests to detect PD-L1 expression may be found at http://www.fda.gov/companiondiagnostics.

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Antibiotics: May diminish the therapeutic effect of Immune Checkpoint Inhibitors. Risk C: Monitor therapy

Corticosteroids (Systemic): May diminish the therapeutic effect of Immune Checkpoint Inhibitors. Management: Carefully consider the need for corticosteroids, at doses of a prednisone-equivalent of 10 mg or more per day, during the initiation of immune checkpoint inhibitor therapy. Use of corticosteroids to treat immune related adverse events is still recommended Risk D: Consider therapy modification

Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy

Inhibitors of the Proton Pump (PPIs and PCABs): May diminish the therapeutic effect of Immune Checkpoint Inhibitors. Risk C: Monitor therapy

Ketoconazole (Systemic): Immune Checkpoint Inhibitors may enhance the hepatotoxic effect of Ketoconazole (Systemic). Risk C: Monitor therapy

Reproductive Considerations

Verify pregnancy status prior to treatment initiation in patients who could become pregnant. Patients who could become pregnant should use highly effective contraception during therapy and for at least 5 months after nivolumab treatment has been discontinued.

Pregnancy Considerations

Based on information from animal reproduction studies and the mechanism of action, nivolumab may cause fetal harm if administered during pregnancy. Nivolumab is a humanized monoclonal antibody (IgG4). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).

Breastfeeding Considerations

It is not known if nivolumab is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends to discontinue breastfeeding during treatment and for 5 months after the last nivolumab dose.

Monitoring Parameters

PD-L1 expression (first-line nivolumab/ipilimumab treatment of metastatic non–small cell lung cancer). Monitor hepatic (ALT, AST, and total bilirubin; baseline and periodically during treatment; consider monitoring LFTs more frequently when nivolumab is administered in combination with cabozantinib) and renal function (serum creatinine; baseline and periodically during treatment), thyroid function (baseline and periodically during treatment); monitor blood glucose (for hyperglycemia). Verify pregnancy status prior to treatment initiation (in patients who could become pregnant). Monitor closely for signs/symptoms of immune-mediated adverse reactions, including adrenal insufficiency, hypophysitis, thyroid disorders, diabetes mellitus, diarrhea/colitis (consider initiating or repeating infectious workup in patients with corticosteroid-refractory immune-mediated colitis to exclude alternative causes), pneumonitis, rash/dermatologic toxicity, ocular disorders, encephalitis (changes in neurologic function). Monitor for signs/symptoms of infusion-related reactions. If received/receiving hematopoietic stem cell transplant, monitor closely for early signs/symptoms of transplant-related complications.

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Additional suggested monitoring (ASCO [Schneider 2021):

Prior to therapy: CBC with differential, serum chemistries, creatine kinase, comprehensive clinical assessment including performance status, weight, body mass index, heart rate, blood pressure, and oxygen saturation; consider chest x-ray, electrocardiogram, and CT scan; assess history of autoimmune conditions, organ-specific disease, endocrinopathies, neuropathy, and infectious disease; assess bowel habits, respiratory symptoms, skin (for rash), arthralgias, and neurologic symptoms.

During therapy: Assess blood pressure, weight, heart rate, and oxygen saturation; assess for infections, screen for hyperglycemia/diabetes (polyuria, polydipsia, weight loss); eye exam (including intraocular pressure after 6 weeks), CBC with differential, serum chemistries, and creatine kinase; monitor bone mineral density (with long-term therapy).

Mechanism of Action

Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor to block the ligands PD-L1 and PD-L2 from binding. The negative PD-1 receptor signaling that regulates T-cell activation and proliferation is therefore disrupted (Robert 2015). This releases PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.

Combining nivolumab (anti-PD-1) with ipilimumab (anti-CTLA-4) results in enhanced T-cell function that is greater than that of either antibody alone, resulting in improved anti-tumor responses in metastatic melanoma and advanced renal cell carcinoma.

Pharmacokinetics

Distribution: Vdss: 6.8 L; the predicted exposure after a 30-minute infusion is comparable to that seen with a 60-minute infusion.

Half-life elimination: ~25 days.

Excretion: Clearance (geometric mean at steady state): 8.2 mL/hour; compared to nivolumab monotherapy, nivolumab clearance is increased 29% when 1 mg/kg nivolumab is administered every 3 weeks in combination with ipilimumab.

Pricing: US

Solution (Opdivo Intravenous)

40 mg/4 mL (per mL): $345.75

100 mg/10 mL (per mL): $345.75

120MG/12ML (per mL): $345.75

240MG/24ML (per mL): $345.75

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Opdivo (AT, AU, BE, BH, CH, CR, CZ, DE, DK, DO, ES, FI, FR, GB, GR, GT, HK, HN, HR, HU, IE, IL, IS, JP, KR, KW, LB, LT, LU, NI, NL, NO, NZ, PA, PL, PT, RO, SA, SE, SG, SK, SV, TH, TW)


For country abbreviations used in Lexicomp (show table)
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  2. Alade SL, Brown RE, Paquet A Jr. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]
  3. Alessandrino F, Tirumani SH, Krajewski KM, et al. Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre: chemotherapy, haematopoietic stem cell transplantation, molecular targeted therapies, and immune checkpoint inhibitors. Clin Radiol. 2017;72(7):521-533. doi:10.1016/j.crad.2017.04.003 [PubMed 28476244]
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  5. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311-319. [PubMed 25482239]
  6. Arai T, Harada K, Usui Y, Irisawa R, Tsuboi R. Case of acute anterior uveitis and Vogt-Koyanagi-Harada syndrome-like eruptions induced by nivolumab in a melanoma patient. J Dermatol. 2017;44(8):975-976. doi:10.1111/1346-8138.13612 [PubMed 27649838]
  7. Ascierto PA, Del Vecchio M, Mandalá M, et al. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020;21(11):1465-1477. doi:10.1016/S1470-2045(20)30494-0 [PubMed 32961119]
  8. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114. doi:10.1056/NEJMoa2034442 [PubMed 34077643]
  9. Barroso-Sousa R, Barry WT, Garrido-Castro AC, et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol. 2018;4(2):173-182. doi:10.1001/jamaoncol.2017.3064 [PubMed 28973656]
  10. Basu P, Tong Y, Hinds BR, Schneider JA. Nivolumab-induced toxic epidermal necrolysis with retiform purpura. Br J Dermatol. 2020;183(2):e32. doi:10.1111/bjd.19031 [PubMed 32281097]
  11. Baughman DM, Lee CS, Snydsman BE, Jung HC. Bilateral uveitis and keratitis following nivolumab treatment for metastatic melanoma. Med Case Rep (Wilmington). 2017;3(2):8. doi:10.21767/2471-8041.100044 [PubMed 28856338]
  12. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639. [PubMed 26412456]
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