Version July 2023
Note: Do not substitute nivolumab with nivolumab/relatlimab.
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: 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: 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:
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: 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: 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: 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: 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: 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: 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.
Off-label dosing: IV: 3 mg/kg once every 2 weeks (in combination with ipilimumab) until disease progression, unacceptable toxicity, or for up to 2 years (Baas 2021; Peters 2022).
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 (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: 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: 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).
Merkel cell carcinoma, unresectable, recurrent, or stage IV (off-label use): IV: 240 mg once every 2 weeks (in combination with ipilimumab) until disease progression or unacceptable toxicity (Kim 2022).
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: 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: 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: 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, first-line single-agent therapy (off-label use):
Note: May be used as monotherapy in patients with limited burden, favorable-risk disease when ipilimumab-based regimens or antiangiogenic agents are not appropriate options (ASCO [Rathmell 2022]; Atkins 2022a; George 2022).
IV: 240 mg once every 2 weeks or 480 mg once every 4 weeks until disease progression, unacceptable toxicity, or (in patients without disease recurrence) up to 96 weeks (Atkins 2022b).
Renal cell carcinoma, advanced, first-line combination therapy:
Note: May be used in combination with cabozantinib regardless of risk stratification (Choueiri 2021). May be used in combination with ipilimumab in patients with intermediate- or poor-risk disease, and the ipilimumab combination may also be considered (off label) in patients with favorable-risk disease (ASCO [Rathmell 2022]; Atkins 2022a; George 2022; Motzer 2019).
In combination with cabozantinib: IV: 240 mg once every 2 weeks (Choueiri 2021) or 480 mg once every 4 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 2 years.
In combination with ipilimumab: IV: 3 mg/kg once every 3 weeks for 4 combination doses, followed by nivolumab monotherapy administered either as 240 mg once every 2 weeks (Motzer 2019) or 480 mg once every 4 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 2 years.
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).
Renal cell carcinoma, advanced, previously treated, single-agent therapy:
Note: May be used in patients with progression on initial treatment with an antiangiogenic agent (Motzer 2015; Motzer 2020).
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).
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: 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.
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.
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.
Additional recommendations:
Grade 2 immune-mediated hepatitis: Withhold immune checkpoint inhibitor (ICI); if no improvement within 3 to 5 days after ICI is withheld, consider initiation of corticosteroids (prednisone 0.5 to 1 mg/kg/day or equivalent) (ASCO [Schneider 2021]).
Grade 3 or 4 immune-mediated hepatitis: Withhold ICI; initiate corticosteroids (methylprednisolone 1 to 2 mg/kg or equivalent) (ASCO [Schneider 2021]). Based on data from a retrospective cohort study in patients with grade 3 or 4 immune-mediated hepatitis, initial treatment with methylprednisolone 1 mg/kg/day demonstrated similar time to ALT normalization (compared with higher methylprednisolone doses), while reducing the potential for corticosteroid-related complications (Li 2022).
(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.
|
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. | |
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.
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.
Refer to adult dosing.
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2 : The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status (ASCO [Griggs 2021]).
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 anticancer therapies 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.
|
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. | |
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]
No
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]
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125554s119lbl.pdf#page=135, must be dispensed with this medication.
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.
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.
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 and pediatric patients ≥12 years of age.
Treatment of unresectable or metastatic melanoma (either as a single agent or in combination with ipilimumab) in adults and pediatric patients ≥12 years of age.
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.
Melanoma, metastatic with brain metastases; Merkel cell carcinoma, unresectable, recurrent, or stage IV; Renal cell carcinoma, advanced, first-line single-agent therapy
Nivolumab may be confused with atezolizumab, avelumab, cemiplimab, dostarlimab, durvalumab, ipilimumab, naxitamab, necitumumab, nivolumab/relatlimab, pembrolizumab.
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.
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.
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)
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 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)
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 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)
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)
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 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).
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) .
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)
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%)
|
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 |
|
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%) (table 4), increased serum albumin (21%), weight loss (7% to 13%)
|
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 |
|
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%)
|
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 |
|
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)
|
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 |
|
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)
|
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 |
|
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 |
|
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%)
|
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 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]), colitis (cytomegalovirus) (Ismayilov 2022), 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), drug reaction with eosinophilia and systemic symptoms (Ai 2021, Lu 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)
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to nivolumab or any component of the formulation.
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. See "Dosing for Toxicity" for specific instructions.
• 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.
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.
None known.
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.
Acetaminophen: May diminish the therapeutic effect of Immune Checkpoint Inhibitors. Risk C: Monitor therapy
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
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 5 months after nivolumab treatment has been discontinued.
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).
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.
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 kidney 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).
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.
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.
Solution (Opdivo Intravenous)
40 mg/4 mL (per mL): $359.72
100 mg/10 mL (per mL): $359.71
120MG/12ML (per mL): $359.71
240MG/24ML (per mL): $359.71
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