Version July 2025
Dosage guidance:
Safety: Do not substitute nivolumab/hyaluronidase with nivolumab/relatlimab (these are different products).
Dosage form information: Nivolumab/hyaluronidase is for SUBQ administration only. Do not substitute nivolumab (IV) for nivolumab/hyaluronidase on a mg-per-mg basis. Use caution during product selection, preparation, and administration. Patients receiving nivolumab IV (as a single agent or in combination with chemotherapy or cabozantinib) may transition to nivolumab/hyaluronidase SUBQ (at the appropriate/recommended dose) at the next scheduled dose.
Colorectal cancer, metastatic, microsatellite instability high or mismatch repair deficient (as a single agent or as a single agent following treatment with IV nivolumab and ipilimumab combination therapy ): SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks; continue until disease progression or unacceptable toxicity.
Esophageal or gastroesophageal junction cancer, resected, adjuvant treatment (as a single agent): SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks; continue until disease recurrence or unacceptable toxicity for up to 1 year.
Esophageal cancer, squamous cell carcinoma, unresectable advanced, recurrent, or metastatic :
First-line combination therapy: SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks, in combination with fluoropyrimidine- and platinum-containing chemotherapy; continue nivolumab/hyaluronidase and chemotherapy until disease progression or unacceptable toxicity (nivolumab/hyaluronidase may be continued for a maximum of 2 years in patients without disease progression).
Single-agent therapy (after prior fluoropyrimidine- and platinum-based chemotherapy): SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks; continue until disease progression or unacceptable toxicity.
Esophageal cancer , adenocarcinoma, advanced or metastatic: SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 900 mg/hyaluronidase 15,000 units once every 3 weeks, in combination with fluoropyrimidine- and platinum-containing chemotherapy; continue nivolumab/hyaluronidase and chemotherapy until disease progression or unacceptable toxicity (nivolumab/hyaluronidase may be continued for a maximum of 2 years in patients without disease progression).
Gastric cancer or gastroesophageal junction cancer, advanced or metastatic: SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 900 mg/hyaluronidase 15,000 units once every 3 weeks, in combination with fluoropyrimidine- and platinum-containing chemotherapy; continue nivolumab/hyaluronidase and chemotherapy until disease progression or unacceptable toxicity (nivolumab/hyaluronidase may be continued for a maximum of 2 years in patients without disease progression).
Head and neck cancer, squamous cell carcinoma, recurrent or metastatic (as a single agent; following disease progression on or after platinum-based therapy): SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks; continue until disease progression or unacceptable toxicity.
Hepatocellular carcinoma, previously treated (as a single agent following treatment with IV nivolumab and ipilimumab combination therapy; previously treated with sorafenib): SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks; continue until disease progression or unacceptable toxicity.
Melanoma , stage IIB, stage IIC, stage III, and stage IV, resected, adjuvant therapy (as a single agent): SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks; continue until disease recurrence or unacceptable toxicity for up to 1 year.
Melanoma , unresectable or metastatic (as a single agent or as a single agent following treatment with IV nivolumab and ipilimumab combination therapy): SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks; continue until disease progression or unacceptable toxicity.
Non–small cell lung cancer, resectable, neoadjuvant therapy: SUBQ: Nivolumab 900 mg/hyaluronidase 15,000 units once every 3 weeks (in combination with histology-based platinum-based doublet chemotherapy) for 3 cycles.
Non–small cell lung cancer, resectable, neoadjuvant and adjuvant therapy:
Neoadjuvant treatment: SUBQ: Nivolumab 900 mg/hyaluronidase 15,000 units once every 3 weeks (in combination with histology-based platinum-based doublet chemotherapy) for up to 4 cycles or until disease progression or unacceptable toxicity.
Adjuvant treatment: SUBQ: Nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks (as a single agent), after neoadjuvant therapy and surgery; continue for up to 13 cycles (~1 year), or until disease progression, recurrence, or unacceptable toxicity.
Non–small cell lung cancer, metastatic, relapsed or refractory (as a single agent; following progression on or after platinum-based therapy): SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks; continue until disease progression or unacceptable toxicity.
Renal cell carcinoma, advanced, previously untreated:
First-line combination therapy: SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks, in combination with cabozantinib; continue nivolumab/hyaluronidase and cabozantinib until disease progression or unacceptable toxicity, or up to 2 years (nivolumab/hyaluronidase may be continued for a maximum of 2 years in patients without disease progression).
Single-agent therapy (following treatment with IV nivolumab and ipilimumab combination therapy): SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks; continue until disease progression or unacceptable toxicity.
Renal cell carcinoma, advanced, previously treated (as a single agent; following prior antiangiogenic therapy): SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks; continue until disease progression or unacceptable toxicity (Ref).
Urothelial carcinoma , resected, high risk of recurrence, adjuvant therapy (as a single agent): SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks; continue until disease recurrence or unacceptable toxicity for up to 1 year.
Urothelial carcinoma, locally advanced or metastatic, previously treated (as a single agent; with disease progression during or following a platinum-containing chemotherapy or with disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy): SUBQ: Nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks; continue until disease progression or unacceptable toxicity.
Urothelial carcinoma, unresectable or metastatic:
First-line combination therapy: SUBQ: Nivolumab 900 mg/hyaluronidase 15,000 units once every 3 weeks (in combination with cisplatin and gemcitabine) for up to 6 cycles, followed by nivolumab 600 mg/hyaluronidase 10,000 units once every 2 weeks or nivolumab 1,200 mg/hyaluronidase 20,000 units once every 4 weeks; continue nivolumab/hyaluronidase (as a single agent) until disease progression, unacceptable toxicity, or for up to 2 years from first dose in patients without disease progression.
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 ≥24 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling; however, no clinically significant effect on nivolumab clearance was observed with eGFR 24 to 124 mL/minute/1.73 m2.
eGFR <24 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/hyaluronidase 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 over at least 1 month. Consider administration of other systemic immunosuppressants if immune-mediated adverse reaction is not controlled with corticosteroid therapy.
Grade 2 or grade 3 serum creatinine elevation: Withhold nivolumab/hyaluronidase; resume nivolumab/hyaluronidase after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue nivolumab/hyaluronidase 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/hyaluronidase.
Hepatic impairment prior to treatment initiation: There are no dosage adjustments provided in the manufacturer's labeling.
Acute hepatotoxicity during treatment:
If nivolumab/hyaluronidase 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 over at least 1 month. Consider administration of other systemic immunosuppressants if immune-mediated adverse reaction is not controlled with corticosteroid therapy. Permanently discontinue nivolumab/hyaluronidase if no complete or partial response within 12 weeks of last nivolumab/hyaluronidase dose, or if unable to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation.
Nivolumab/hyaluronidase single-agent therapy:
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/hyaluronidase treatment. Resume nivolumab/hyaluronidase 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: Permanently discontinue nivolumab/hyaluronidase.
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/hyaluronidase treatment. Resume nivolumab/hyaluronidase 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: Permanently discontinue nivolumab/hyaluronidase.
Nivolumab/hyaluronidase in combination with cabozantinib: Note: For liver enzyme elevations when administered in combination with cabozantinib, consider corticosteroid therapy if nivolumab/hyaluronidase (and/or cabozantinib) is withheld or discontinued.
ALT or AST >3 to ≤10 × ULN with concurrent total bilirubin <2 × ULN: Withhold both nivolumab/hyaluronidase and cabozantinib. Upon recovery to grade 0 or 1, may consider rechallenging with nivolumab/hyaluronidase and/or cabozantinib.
ALT or AST >10 × ULN or >3 × ULN with concurrent total bilirubin ≥2 × ULN: Permanently discontinue both nivolumab/hyaluronidase 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) (Ref).
Grade 3 or 4 immune-mediated hepatitis: Withhold ICI; initiate corticosteroids (methylprednisolone 1 to 2 mg/kg or equivalent) (Ref). 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 (Ref).
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 (Ref).
Note: No dosage reductions of nivolumab/hyaluronidase are recommended. Other concomitant anticancer therapies may also require treatment interruption, dosage reduction, and/or discontinuation.
Immune-mediated adverse reactions (general information): Withhold nivolumab/hyaluronidase for severe (grade 3) immune-mediated adverse reactions. Permanently discontinue nivolumab/hyaluronidase 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/hyaluronidase 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 (Ref). Refer to guideline for further information regarding management of immune-mediated adverse reactions associated with checkpoint inhibitor therapy.
|
Adverse reaction |
Severity |
Nivolumab/Hyaluronidase dosage modification |
|---|---|---|
|
a SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; DRESS = drug rash with eosinophilia and systemic symptoms. | ||
|
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/hyaluronidase. |
|
Dermatologic toxicity |
Mild or moderate nonexfoliative rash |
May be managed with topical emollients and/or topical corticosteroids. |
|
Exfoliative dermatologic conditions: Suspected SJS, TEN, or DRESS |
Withhold nivolumab/hyaluronidase. | |
|
Confirmed SJS, TEN, or DRESS |
Permanently discontinue nivolumab/hyaluronidase. | |
|
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/hyaluronidase 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/hyaluronidase. | |
|
Diabetes, type 1 |
Initiate insulin as clinically indicated. Withhold or discontinue nivolumab/hyaluronidase (depending on the severity). | |
|
Hypophysitis |
Withhold or discontinue nivolumab/hyaluronidase (depending on the severity). Initiate hormone-replacement therapy as clinically indicated. | |
|
Hyperthyroidism/Thyroiditis |
Withhold or discontinue nivolumab/hyaluronidase (depending on the severity). Initiate medical management as clinically indicated. | |
|
Hypothyroidism |
Withhold nivolumab/hyaluronidase (depending on the severity). Initiate thyroid hormone-replacement therapy as clinically indicated. | |
|
GI toxicity: Colitis |
Grade 2 or 3 |
Withhold nivolumab/hyaluronidase; resume after complete or partial (to grade 0 or 1) resolution after corticosteroid taperb. Permanently discontinue nivolumab/hyaluronidase 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 4 |
Permanently discontinue nivolumab/hyaluronidase. | |
|
Neurologic toxicities |
Grade 2 |
Withhold nivolumab/hyaluronidase; resume nivolumab/hyaluronidase after complete or partial (to grade 0 or 1) resolution after corticosteroid taperb. Permanently discontinue nivolumab/hyaluronidase if no complete or partial response within 12 weeks of last nivolumab/hyaluronidase 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/hyaluronidase. | |
|
Ocular disorders: Vogt-Koyanagi-Harada-like syndrome |
Any |
May require systemic corticosteroids to reduce the risk of permanent vision loss. |
|
Pulmonary toxicity: Pneumonitis |
Grade 2 |
Withhold nivolumab/hyaluronidase; resume nivolumab/hyaluronidase after complete or partial (to grade 0 or 1) resolution after corticosteroid taperb. Permanently discontinue nivolumab/hyaluronidase if no complete or partial response within 12 weeks of last nivolumab/hyaluronidase 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/hyaluronidase. | |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see individual agents.
>10%:
Dermatologic: Pruritus (16%), skin rash (7% to 15%)
Endocrine & metabolic: Decreased serum albumin (25%), decreased serum sodium (34%), hypothyroidism (9% to 12%), increased serum calcium (29%), increased serum potassium (34%)
Gastrointestinal: Diarrhea (11%; grades 3/4: <1%)
Hematologic & oncologic: Decreased hemoglobin (46%; grades 3/4: 7%), lymphocytopenia (36%; grades 3/4: 6%)
Hepatic: Increased serum alanine aminotransferase (21%), increased serum alkaline phosphatase (32%)
Nervous system: Fatigue (20%)
Neuromuscular & skeletal: Musculoskeletal pain (31%)
Renal: Increased serum creatinine (38%)
Respiratory: Cough (11%)
1% to 10%:
Cardiovascular: Edema (5%), myocarditis (<5%)
Dermatologic: Erythema of skin (<5%), psoriasis (<5%)
Endocrine & metabolic: Adrenocortical insufficiency (2%), hyperglycemia (9%)
Gastrointestinal: Abdominal pain (10%), colitis (3%), constipation (8%), decreased appetite (9%), pancreatitis (<5%), nausea (8%), vomiting (6%; grades 3/4: <1%)
Hematologic & oncologic: Eosinophilia (<5%)
Hepatic: Hepatitis (2%)
Hypersensitivity: Hypersensitivity reaction (<5%)
Local: Injection-site reaction (8%)
Nervous system: Peripheral neuropathy (<5%)
Neuromuscular & skeletal: Arthritis (<5%)
Ophthalmic: Uveitis (<5%)
Renal: Kidney impairment (grade 2: ≤1%), nephritis (grade 2: ≤1%)
Respiratory: Dyspnea (<5%), pneumonitis (3%)
<1%: Endocrine & metabolic: Diabetes mellitus (grade 3), hyperthyroidism, thyroiditis
Frequency not defined:
Hematologic & oncologic: Hemorrhage
Neuromuscular & skeletal: Myositis
Respiratory: Pleural effusion
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Adverse reactions (immune mediated): PD-1/PD-L1 blockers (including nivolumab/hyaluronidase) 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/hyaluronidase initiation); reactions may also occur after nivolumab/hyaluronidase discontinuation. Early identification and management of immune-mediated adverse reactions are necessary to ensure safe use of nivolumab/hyaluronidase. 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: Nivolumab/hyaluronidase may cause immune-mediated rash or dermatitis (defined as requiring the use of steroids and no clear alternate etiology). Exfoliative dermatitis, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms, has occurred with PD-1/PD-L1–blocking antibodies. Immune-mediated rash has occurred, including grade 2 and 3 events. Systemic corticosteroids were required in nearly half of patients with immune-mediated rash; rash resolved in a majority of these patients. Of the small number of patients in whom nivolumab/hyaluronidase was withheld for immune-mediated rash, all reinitiated therapy after symptom improvement with immune-mediated rash recurrence.
• Endocrinopathies: Nivolumab/hyaluronidase may cause endocrinopathies, including adrenal insufficiency, hypophysitis, thyroid disorders (eg, hyperthyroidism, hypothyroidism, thyroiditis), and type 1 diabetes (including diabetic ketoacidosis).
- Adrenal insufficiency: Adrenal insufficiency (primary and secondary) may occur. Grade 2 and 3 events have been reported (rare). Systemic corticosteroids were required in all patients who developed adrenal insufficiency; adrenal insufficiency resolved in less than one-fourth of cases. Adrenal insufficiency occurred at slightly higher rates in patients who received IV nivolumab in combination with cabozantinib.
- Diabetes mellitus: Type 1 diabetes mellitus has occurred with nivolumab/hyaluronidase, including a grade 3 event (which did not resolve). Diabetes may present with diabetic ketoacidosis. Diabetes development did not require systemic corticosteroids.
- Hypophysitis: Nivolumab/hyaluronidase may cause immune-mediated hypophysitis, which may present with acute mass effect symptoms, including headache, photophobia, or visual field defects. Hypophysitis may cause hypopituitarism. Hypophysitis has occurred with IV nivolumab in a small number of patients (including rare grade 2 and 3 events); approximately two-thirds of these patients received hormone replacement therapy, including systemic corticosteroids.
- Thyroid disorders: Nivolumab/hyaluronidase may cause immune-mediated thyroid disorders. Thyroiditis has occurred (rarely) and can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Hyperthyroidism occurred in rare cases, including a grade 2 event; hyperthyroidism resolved in half of the cases. Hypothyroidism has occurred with nivolumab/hyaluronidase, including grade 2 events. Systemic corticosteroids were not required to manage thyroiditis, hyperthyroidism, or hypothyroidism associated with nivolumab/hyaluronidase.
• GI adverse effects: Nivolumab/hyaluronidase may cause immune-mediated colitis (defined as requiring use of corticosteroids and no clear alternate etiology). Diarrhea was a common symptom of colitis. Cytomegalovirus infection/reactivation has been observed in patients with corticosteroid-refractory immune-mediated colitis. Consider initiating or repeating infectious workup in patients with corticosteroid-refractory colitis to exclude alternative etiologies. Immune-mediated colitis occurred in a small number of patients, including grade 2 and 3 events. Systemic corticosteroids were required in all patients who developed colitis. Colitis resolved in a majority of these patients. Some patients in whom nivolumab/hyaluronidase was withheld for colitis restarted nivolumab/hyaluronidase after symptom improvement, and two-thirds of these patients experienced colitis recurrence. Pancreatitis (including serum amylase and lipase increases), gastritis, and duodenitis have also been observed (with either nivolumab/hyaluronidase, IV nivolumab, or other PD-1/PD-L1 blockers).
• Hepatotoxicity: Nivolumab/hyaluronidase may cause immune-mediated hepatitis (defined as requiring use of corticosteroids and no clear alternate etiology). Immune-mediated hepatitis occurred in a small percentage of patients, including grade 2 and 3 events. Systemic corticosteroids were required in all patients who developed hepatitis. Hepatitis resolved in a majority of these patients. Of patients in whom nivolumab/hyaluronidase was withheld for hepatitis, some restarted therapy (after symptom improvement), with half of these patients experiencing hepatitis recurrence. IV nivolumab in combination with cabozantinib is associated with a higher frequency of grades 3 or 4 ALT and AST elevations (compared to single-agent IV nivolumab); systemic corticosteroids were used to manage hepatotoxicity in some of these patients; of patients with grade ≥2 ALT or AST elevations who restarted either IV nivolumab or cabozantinib or both, following symptom improvement, some experienced recurrence.
• Kidney toxicity: Nivolumab/hyaluronidase may cause immune-mediated nephritis (defined as requiring use of steroids and no clear alternate etiology). Grade 2 immune-mediated nephritis and kidney dysfunction occurred in a small number of patients. Systemic corticosteroids were required in all patients who developed nephritis and kidney dysfunction; nephritis and kidney dysfunction resolved in all of these patients. In one case, following symptom improvement, nivolumab/hyaluronidase was restarted following treatment interruption without recurrence of nephritis or kidney dysfunction.
• Ocular toxicity: Ocular toxicities have been observed with nivolumab/hyaluronidase, IV nivolumab, or other PD-1/PD-L1 blockers, including uveitis, iritis, and other ocular inflammatory toxicities; some cases may be associated with retinal detachment. Various grades of visual impairment, including blindness, may occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome.
• Pulmonary toxicity: Nivolumab/hyaluronidase may cause immune-mediated pneumonitis (defined as requiring use of steroids and no clear alternate etiology). In patients treated with other PD-1/PD-L1 blockers, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Grades 2 and 3 immune-mediated pneumonitis have been reported with nivolumab/hyaluronidase; treatment interruption and discontinuation was required in some cases. Systemic corticosteroids were required in all patients who developed pneumonitis. Pneumonitis resolved in some of those patients. Some patients were able to reinitiate nivolumab/hyaluronidase after it was withheld; pneumonitis recurred in one case.
• Other immune-mediated toxicities: Other clinically relevant immune-mediated adverse reactions have been observed rarely in patients who received nivolumab/hyaluronidase, IV nivolumab (as a single agent or in combination with chemotherapy or immunotherapy), or with other PD-1/PD-L1 blockers and may affect any organ system (may be severe or fatal), including myocarditis, pericarditis, vasculitis, meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy, myositis/polymyositis, rhabdomyolysis (and associated sequelae including kidney failure), arthritis, polymyalgia rheumatic, hypoparathyroidism, hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, and/or other transplant (including corneal graft) rejection.
Disease-related concerns:
• Hematopoietic cell transplantation: Fatal and other serious complications may occur in patients who receive allogeneic hematopoietic cell transplant (HCT) 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 HCT. 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 allogeneic HCT.
• 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 IV nivolumab) to a thalidomide analogue plus dexamethasone. Nivolumab/hyaluronidase 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 (Ref).
Dosage form specific issues:
• Do not interchange: Nivolumab/hyaluronidase (for SUBQ administration) and nivolumab (for IV administration) have different dosing and are NOT interchangeable on a mg-per-mg basis.
• 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 (Ref). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Ref). See manufacturer's labeling.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous [preservative free]:
Opdivo Qvantig: Nivolumab 600 mg and hyaluronidase 10,000 units per 5 mL (5 mL) [contains polysorbate 80]
No
Solution (Opdivo Qvantig Subcutaneous)
600-10000MG-UT/5ML (per mL): $1,868.96
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Note: Check label to ensure appropriate product is being administered; nivolumab/hyaluronidase and nivolumab/relatlimab are different products and are NOT interchangeable. Nivolumab/hyaluronidase (SUBQ) and nivolumab (IV) should not be substituted on a mg-per-mg basis.
SUBQ: For SUBQ use only. If stored refrigerated, allow to come to room temperature prior to administration. Administer over 3 to 5 minutes into the SUBQ tissue of 1 of the 4 quadrants of the abdomen, or thigh. Alternate injection sites for successive injections. Do not administer into areas where the skin is tender, red, or bruised, or areas where there are scars or moles. If administration is interrupted, continue administration using the same site, or at an alternate site. Do not administer other SUBQ medications at the same sites as nivolumab/hyaluronidase.
Use a 23G to 25G, 3/8- to 5/8-inch injection needle or SUBQ administration set (eg, winged/butterfly) for administration. No incompatibilities were observed between nivolumab/hyaluronidase and polyethylene, polyurethane, PVC, and fluorinated ethylene propylene SUBQ administration sets.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Opdivo Qvantig: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761429s000lbl.pdf#page=148
Colorectal cancer, metastatic, microsatellite instability high or mismatch repair deficient: Treatment (as a single agent, or as a single agent following treatment with IV nivolumab and ipilimumab combination therapy) of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) in adults, that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
Limitations of use: Nivolumab/hyaluronidase is not indicated in combination with ipilimumab for the treatment of MSI-H or dMMR metastatic CRC.
Esophageal cancer:
Adjuvant treatment (as a single agent) of completely resected esophageal or gastroesophageal junction cancer in adults with residual pathologic disease who have received neoadjuvant chemoradiotherapy.
First-line treatment (in combination with fluoropyrimidine- and platinum-containing chemotherapy) of unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) in adults.
Treatment (as a single agent) of unresectable advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy in adults.
Treatment (in combination with fluoropyrimidine- and platinum-containing chemotherapy) of advanced or metastatic esophageal adenocarcinoma in adults.
Limitations of use: Nivolumab/hyaluronidase is not indicated in combination with ipilimumab for the treatment of patients with unresectable advanced or metastatic ESCC.
Gastric and gastroesophageal junction cancer, advanced or metastatic: Treatment (in combination with fluoropyrimidine- and platinum-containing chemotherapy) of advanced or metastatic gastric and gastroesophageal junction cancer in adults.
Head and neck cancer, squamous cell carcinoma, recurrent or metastatic: Treatment (as a single agent) 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, previously treated: Treatment (as a single agent following treatment with IV nivolumab and ipilimumab combination therapy) of hepatocellular carcinoma (HCC) in adults who have been previously treated with sorafenib.
Limitations of use: Nivolumab/hyaluronidase is not indicated in combination with ipilimumab for the treatment of patients with HCC.
Melanoma:
Adjuvant treatment (as a single agent) of stage IIB, stage IIC, stage III, or stage IV melanoma following complete resection in adults.
Treatment (as a single agent or as a single agent following treatment with IV nivolumab and ipilimumab combination therapy) of unresectable or metastatic melanoma in adults.
Limitations of use: Nivolumab/hyaluronidase is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic melanoma.
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.
Treatment of resectable (tumors ≥4 cm or node positive) NSCLC, as neoadjuvant treatment (in combination with platinum-doublet chemotherapy), followed by adjuvant treatment (as a single agent) after surgical resection in adults with no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.
Treatment (as a single agent) 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/hyaluronidase.
Limitations of use: Nivolumab/hyaluronidase is not indicated for the treatment of metastatic NSCLC in combination with ipilimumab.
Renal cell carcinoma, advanced:
First-line treatment (as a single agent following treatment with IV nivolumab and ipilimumab combination therapy) of intermediate or poor risk advanced renal cell carcinoma (RCC) in adults.
Limitations of use: Nivolumab/hyaluronidase is not indicated in combination with ipilimumab for the treatment of RCC.
First-line treatment (in combination with cabozantinib) of advanced RCC in adults.
Treatment (as a single agent) of advanced RCC in adults who have received prior antiangiogenic therapy.
Urothelial carcinoma:
Adjuvant treatment (as a single agent) of urothelial carcinoma in adults who are at high risk of recurrence after undergoing radical resection.
First-line treatment (in combination with cisplatin and gemcitabine) of unresectable or metastatic urothelial carcinoma in adults.
Treatment (as a single agent) of locally advanced or metastatic urothelial carcinoma in adults with disease progression during or following a platinum-containing chemotherapy or with disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy.
Nivolumab/hyaluronidase may be confused with atezolizumab/hyaluronidase, daratumumab/hyaluronidase, efgartigimod alfa/hyaluronidase, naxitamab, necitumumab, nivolumab, nivolumab/relatlimab, ocrelizumab/hyaluronidase, pertuzumab/trastuzumab/hyaluronidase, rituximab/hyaluronidase, trastuzumab/hyaluronidase.
Opdivo Qvantig may be confused with Odomzo, Onivyde, Opdivo, Opdualag, Opfolda.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) that have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
Nivolumab/hyaluronidase is for SUBQ administration only. Do not substitute nivolumab (IV) for nivolumab/hyaluronidase (SUBQ). Use caution during product selection, preparation, and administration.
Nivolumab/hyaluronidase (Opdivo Qvantig) may be confused with nivolumab/relatlimab (Opdualag); these products are not interchangeable on a mg-per-mg basis. Verify product prior to preparation and administration to prevent medication errors.
Refer to individual components.
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 drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetaminophen: May decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor
Alpha-/Beta-Agonists: Hyaluronidase may increase vasoconstricting effects of Alpha-/Beta-Agonists. Management: Do not use hyaluronidase to enhance the dispersion or absorption of alpha-/beta-agonists. Use of hyaluronidase for other purposes in patients receiving alpha-/beta-agonists may be considered as clinically indicated. Risk D: Consider Therapy Modification
Antibiotics: May decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor
Antihistamines: May decrease therapeutic effects of Hyaluronidase. Risk C: Monitor
Corticosteroids (Systemic): May decrease therapeutic effects of Hyaluronidase. Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Risk D: Consider Therapy Modification
Desmopressin: Hyponatremia-Associated Agents may increase hyponatremic effects of Desmopressin. Risk C: Monitor
Efgartigimod Alfa: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Estrogen Derivatives: May decrease therapeutic effects of Hyaluronidase. Risk C: Monitor
Inhibitors of the Proton Pump (PPIs and PCABs): May decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor
Ketoconazole (Systemic): Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies) may increase hepatotoxic effects of Ketoconazole (Systemic). Risk C: Monitor
Local Anesthetics: Hyaluronidase may increase adverse/toxic effects of Local Anesthetics. Risk C: Monitor
Nipocalimab: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Opioid Agonists: Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies) may decrease therapeutic effects of Opioid Agonists. Opioid Agonists may decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor
Phenylephrine (Systemic): Hyaluronidase may increase vasoconstricting effects of Phenylephrine (Systemic). Management: Do not use hyaluronidase to enhance the dispersion or absorption of phenylephrine. Use of hyaluronidase for other purposes in patients receiving phenylephrine may be considered as clinically indicated. Risk D: Consider Therapy Modification
Rozanolixizumab: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Salicylates: May decrease therapeutic effects of Hyaluronidase. Risk C: Monitor
Vitamin K Antagonists: Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies) may increase anticoagulant effects of Vitamin K Antagonists. Risk C: Monitor
Verify pregnancy status prior to initiating treatment in patients who could become pregnant.
Patients who could become pregnant should use effective contraception during therapy and for 5 months after the last nivolumab and hyaluronidase dose.
Nivolumab can be detected in cord blood (Ref).
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to nivolumab and hyaluronidase may cause fetal harm.
Also refer to the Nivolumab and Hyaluronidase monographs for additional information.
Nivolumab is present in breast milk (Ref); excretion of hyaluronidase is unknown.
Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends discontinuing breastfeeding during treatment and for 5 months after the last nivolumab dose.
Also refer to the Nivolumab and Hyaluronidase monographs for additional information.
Monitor hepatic function (ALT, AST, and total bilirubin; baseline and periodically during treatment; consider monitoring LFTs more frequently when nivolumab/hyaluronidase is administered in combination with cabozantinib or chemotherapy) 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 patients closely for signs/symptoms that may be clinical manifestations of underlying immune-mediated adverse 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 (Ref) 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.
Cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (Ref). Obtain baseline ECG, natriuretic peptides, and troponins in all patients; obtain a baseline echocardiogram in high-risk patients; consider serial ECGs and cardiac troponins prior to doses 2, 3, and 4, and if normal, reduce to every 3 doses until completion of therapy; cardiovascular risk assessment every 6 to 12 months in high-risk patients who require long-term therapy (>12 months therapy, consider cardiovascular risk assessment every 6 to 12 months in all patients requiring long-term therapy) (Ref). Refer to a cardiologist when clinically indicated.
Additional suggested monitoring (Ref):
Prior to therapy: CBC with differential, serum chemistries, creatine kinase, comprehensive clinical assessment including performance status, weight, body mass index, heart rate, BP, 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 BP, 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 an 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 (Ref). This releases PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.
Hyaluronidase increases permeability of the SUBQ tissue by temporarily depolymerizing hyaluronan, allowing for increased dispersion and absorption of coadministered drugs when administered SUBQ. At the recommended dose, hyaluronidase acts locally and the effects are reversible, and permeability of the SUBQ tissue is restored within 24 to 48 hours.
Distribution: Vdss: 6.8 L.
Bioavailability: Nivolumab: SUBQ: 74%.
Half-life elimination: 25 days.
Time to peak: Nivolumab: SUBQ: 6 days.
Excretion: Clearance (geometric mean at steady state): 8.2 mL/hour.
