Nivolumab
Dosing in kidney impairment
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis and hepatotoxicity, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, and immune-mediated nephritis and renal dysfunction.
Immune-Mediated Endocrinopathies Adrenal Insufficiency OPDIVO can cause primary or secondary adrenal insufficiency. For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold OPDIVO depending on severity [see Dosage and Administration ] . OPDIVO as a Single Agent Adrenal insufficiency occurred in 1% (20/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.4%) and Grade 2 (0.6%) adverse reactions.
Adrenal insufficiency led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO in 0.4% of patients. Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 90% (18/20) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 35% of the 20 patients.
Of the 8 patients in whom OPDIVO was withheld for adrenal insufficiency, 4 reinitiated OPDIVO after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency. OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Adrenal insufficiency occurred in 8% (35/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%) adverse reactions.
Adrenal insufficiency led to permanent discontinuation of OPDIVO with ipilimumab in 0.4% and withholding of OPDIVO with ipilimumab in 2% of patients. Approximately 71% (25/35) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 37% of the 35 patients.
Of the 9 patients in whom OPDIVO with ipilimumab was withheld for adrenal insufficiency, 7 reinitiated treatment after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Adrenal insufficiency occurred in 7% (48/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%) adverse reactions.
| Indication | Recommended OPDIVO Dosage | Duration of Therapy |
| Metastatic non-small cell lung cancer | 240 mg every 2 weeksor480 mg every 4 weeks | Until disease progression or unacceptable toxicity |
| Advanced renal cell carcinoma | ||
| Classical Hodgkin lymphoma | ||
| Squamous cell carcinoma of the head and neck | ||
| Locally advanced or metastatic urothelial carcinoma | ||
| Esophageal squamous cell carcinoma | ||
| Unresectable or metastatic melanoma | Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more:240 mg every 2 weeksor480 mg every 4 weeks | Until disease progression or unacceptable toxicity |
| Pediatric patients aged 12 years and older and weighing less than 40 kg:3 mg/kg every 2 weeksor6 mg/kg every 4 weeks | ||
| Adjuvant treatment of melanoma | Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more:240 mg every 2 weeksor480 mg every 4 weeks | Until disease recurrence or unacceptable toxicity for up to 1 year |
| Pediatric patients aged 12 years and older and weighing less than 40 kg:3 mg/kg every 2 weeksor6 mg/kg every 4 weeks | ||
| Adjuvant treatment of urothelial carcinoma (UC) | 240 mg every 2 weeksor480 mg every 4 weeks | Until disease recurrence or unacceptable toxicity for up to 1 year |
| Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following prior treatment for metastatic disease | Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more:240 mg every 2 weeksor480 mg every 4 weeks | Until disease progression or unacceptable toxicity |
| Pediatric patients aged 12 years and older and weighing less than 40 kg:3 mg/kg every 2 weeks | ||
| Adjuvant treatment of resected esophageal or gastroesophageal junction cancer | 240 mg every 2 weeksor480 mg every 4 weeks | Until disease progression or unacceptable toxicity for a total treatment duration of 1 year |
| Indication | Recommended OPDIVO Dosage | Duration of Therapy |
| Unresectable or metastatic melanoma | 1 mg/kg every 3 weeks with ipilimumab 3 mg/kg | In combination with ipilimumab for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier |
| Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more:240 mg every 2 weeks or 480 mg every 4 weeks | After completing 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity | |
| Pediatric patients aged 12 years and older and weighing less than 40 kg:3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks | ||
| Neoadjuvant treatment of resectable non-small cell lung cancer | 360 mg every 3 weeks with platinum-doublet chemotherapy on the same day every 3 weeks | In combination with platinum-doublet chemotherapy for 3 cycles |
| Neoadjuvant and adjuvant treatment of resectable non-small cell lung cancer | Neoadjuvant: 360 mg every 3 weeks with platinum-doublet chemotherapy on the same day every 3 weeks | Neoadjuvant treatment in combination with chemotherapy for up to 4 cycles or until disease progression or unacceptable toxicity, followed by adjuvant treatment with OPDIVO as a single agent after surgery for up to 13 cycles (approximately 1 year) or until disease recurrence or unacceptable toxicity |
| Adjuvant: 480 mg every 4 weeks | ||
| Metastatic non-small cell lung cancer expressing PD‑L1 | 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks | In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression |
| Metastatic or recurrent non-small cell lung cancer | 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and histology-based platinum‑doublet chemotherapy every 3 weeks | In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression |
| In combination with histology-based platinum‑doublet chemotherapy for up to 2 cycles | ||
| Malignant pleural mesothelioma | 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks | In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression |
| Advanced renal cell carcinoma | 3 mg/kg every 3 weeks with ipilimumab 1 mg/kg | In combination with ipilimumab for 4 doses |
| 240 mg every 2 weeks or 480 mg every 4 weeks | After completing 4 doses of combination therapy with ipilimumab, administer as single agent until disease progression or unacceptable toxicity | |
| 240 mg every 2 weeks or 480 mg every 4 weeksAdminister OPDIVO in combination with cabozantinib 40 mg orally once daily without food | OPDIVO: Until disease progression, unacceptable toxicity, or up to 2 years | |
| Cabozantinib: Until disease progression or unacceptable toxicity | ||
| First-line unresectable or metastatic urothelial carcinoma | 360 mg every 3 weeks Administer OPDIVO in combination with cisplatin and gemcitabine on the same day every 3 weeks | In combination with cisplatin and gemcitabine for up to 6 cycles |
| 240 mg every 2 weeks or 480 mg every 4 weeks | After completing up to 6 cycles of combination therapy, administer as single agent until disease progression, unacceptable toxicity, or up to 2 years from first dose | |
| Previously untreated classical Hodgkin lymphoma | Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more:240 mg every 2 weeks | In combination with doxorubicin, vinblastine, and dacarbazine (AVD) for 6 cycles.GCSF administration is recommended starting with cycle 1. |
| Pediatric patients aged 12 years and older and weighing less than 40 kg:3 mg/kg every 2 weeks | ||
| Microsatellite instability-high (MSI‑H) or mismatch repair deficient (dMMR) metastatic colorectal cancer | Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more:240 mg every 3 weeks with ipilimumab 1 mg/kg | In combination with ipilimumabfor a maximum of 4 doses |
| Pediatric patients aged 12 years and older and weighing less than 40 kg: 3 mg/kg every 3 weeks with ipilimumab 1 mg/kg | ||
| Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more:240 mg every 2 weeks or 480 mg every 4 weeks | After completing a maximum of 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity, or up to 2 years | |
| Pediatric patients aged 12 years and older and weighing less than 40 kg:3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks | ||
| Hepatocellular carcinoma | 1 mg/kg every 3 weeks with ipilimumab 3 mg/kg | In combination with ipilimumab for a maximum of 4 doses |
| 240 mg every 2 weeks or 480 mg every 4 weeks | After completing a maximum of 4 doses of combination therapy, administer as single agent until disease progression, unacceptable toxicity, or up to 2 years | |
| Esophageal squamous cell carcinoma | 240 mg every 2 weeks or 480 mg every 4 weeksAdminister OPDIVO in combination with fluoropyrimidine- and platinum‑containing chemotherapy | OPDIVO: Until disease progression, unacceptable toxicity, or up to 2 years |
| Chemotherapy: Until disease progression or unacceptable toxicity | ||
| 3 mg/kg every 2 weeks or 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks | In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years | |
| Gastric cancer, Gastroesophageal junction cancer, and Esophageal adenocarcinoma | 240 mg every 2 weeks with fluoropyrimidine- and platinum‑containing chemotherapy every 2 weeks or 360 mg every 3 weeks with fluoropyrimidine- and platinum‑containing chemotherapy every 3 weeks | Until disease progression, unacceptable toxicity, or up to 2 years |
| a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO based on recommendations for hepatitis with no liver involvement. c Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved. ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal | ||
| Adverse Reaction | Severity | Dosage Modification |
| Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] | ||
| Pneumonitis | Grade 2 | Withholda |
| Grades 3 or 4 | Permanently discontinue | |
| ColitisFor colitis in patients treated with combination therapy with ipilimumab, see Table 4. | Grade 2 or 3 | Withholda |
| Grade 4 | Permanently discontinue | |
| Hepatitis with no tumor involvement of the liverFor liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4. | AST/ALT increases to >3 and ≤8 times ULNorTotal bilirubin increases to >1.5 and ≤3 times ULN. | Withholda |
| AST or ALT increases to >8 times ULNorTotal bilirubin increases to >3 times ULN. | Permanently discontinue | |
| Hepatitis with tumor involvement of the liverbFor liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4. | Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULNorBaseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN. | Withholda |
| AST/ALT increases to >10 times ULNorTotal bilirubin increases to >3 times ULN. | Permanently discontinue | |
| Endocrinopathiesc | Grade 3 or 4 | Withhold until clinically stable or permanently discontinue depending on severity |
| Nephritis with Renal Dysfunction | Grade 2 or 3 increased blood creatinine | Withholda |
| Grade 4 increased blood creatinine | Permanently discontinue | |
| Exfoliative Dermatologic Conditions | Suspected SJS, TEN, or DRESS | Withhold |
| Confirmed SJS, TEN, or DRESS | Permanently discontinue | |
| Myocarditis | Grades 2, 3, or 4 | Permanently discontinue |
| Neurological Toxicities | Grade 2 | Withholda |
| Grade 3 or 4 | Permanently discontinue | |
| Other Adverse Reactions | ||
| Infusion-Related Reactions[see Warnings and Precautions (5.2)] | Grade 1 or 2 | Interrupt or slow the rate of infusion |
| Grade 3 or 4 | Permanently discontinue | |
Dosing in liver impairment
| a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO in combination with ipilimumab based on recommendations for hepatitis with no liver involvement. c Consider corticosteroid therapy for hepatic adverse reactions if OPDIVO is withheld or discontinued when administered in combination with cabozantinib or AVD. d After recovery, rechallenge with OPDIVO, cabozantinib, and AVD may be considered. If rechallenging with cabozantinib or doxorubicin and vinblastine with or without OPDIVO, refer to cabozantinib or doxorubicin and vinblastine Prescribing Information. e Refer to doxorubicin, vinblastine, and dacarbazine Prescribing Information. | |||
| Treatment | Adverse Reaction | Severity | Dosage Modification |
| OPDIVO in combination with ipilimumab | Colitis | Grade 2 | Withholda |
| Grade 3 or 4 | Permanently discontinue | ||
| Hepatitis with no tumor involvement of the liverorHepatitis with tumor involvement of the liver/non-HCC | AST/ALT increases to >3 times ULN and ≤5 times ULNorTotal bilirubin increases to ≥1.5 and ≤3 times ULN. | Withholda | |
| AST or ALT >5 times ULNorTotal bilirubin >3 times ULN. | Permanently discontinue | ||
| Hepatitis with tumor involvement of the liverb/HCC | Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULNorBaseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN. | Withholda | |
| AST/ALT increases to >10 times ULNorTotal bilirubin increases to >3 times ULN. | Permanently discontinue | ||
| OPDIVO in combination with cabozantinib | Liver enzyme elevations | ALT or AST >3 times ULN but ≤10 times ULN with concurrent total bilirubin <2 times ULN | Withholdc both OPDIVO and cabozantinib until adverse reactions recoverd to Grades 0‑1 |
| ALT or AST >10 times ULNor >3 times ULN with concurrent total bilirubin ≥2 times ULN | Permanently discontinuec both OPDIVO and cabozantinib | ||
| OPDIVO in combination with AVDe | Liver enzyme elevations | ALT or AST >3 times ULN but ≤8 times ULN | Withholdc OPDIVO until adverse reactions recoverd to Grades 0-1 |
| ALT or AST >8 times ULNor >3 times ULN with concurrent total bilirubin >2 times ULN | Permanently discontinuec OPDIVO | ||
| Bilirubin >2 times ULN but ≤5 times ULN | Consider dose reduction of doxorubicin and vinblastine.e | ||
| Bilirubin >5 times ULN | Permanently discontinuec OPDIVO. Consider holding doxorubicin and vinblastine.e | ||
| Neutropenia | Grade 3 or 4 | Administer G-CSF prophylaxis for subsequent cycles. Consider additional doses for protracted Grade 4 neutropenia. | |
| Febrile neutropenia, infection | Grade 3 or 4 | Consider holding treatment until recovery to ≤ Grade 2.Administer G-CSF prophylaxis with subsequent cycles. | |
| Peripheral neuropathy | Grade 3 | Consider withholding vinblastine and restarting at a reduced dose as indicated. If OPDIVO-related, withhold OPDIVO until improves to Grade 2. | |
| Grade 4 | Permanently discontinue vinblastine. If OPDIVO-related, permanently discontinue OPDIVO. | ||
Preparation and administration
Preparation and Administration Visually inspect for particulate matter and discoloration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard if cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake. Preparation
Withdraw the required volume of OPDIVO and transfer into an intravenous container.
Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. The total volume of infusion must not exceed 160 mL.
For adult and pediatric patients with body weight 40 kg or greater, do not exceed a total volume of infusion of 160 mL.
For adult and pediatric patients with body weight less than 40 kg, do not exceed a total volume of infusion of 4 mL/kg of body weight.
Mix diluted solution by gentle inversion. Do not shake.
Discard partially used vials or empty vials of OPDIVO.
The product does not contain a preservative.
After preparation, store the diluted solution either:
at room temperature at 20°C to 25°C (68°F to 77°F) and room light for no more than 8 hours from the time of preparation to end of the infusion. Discard diluted solution if not used within 8 hours from the time of preparation; or
under refrigeration at 2°C to 8°C (36°F to 46°F) and protected from light for no more than 7 days from the time of preparation to end of infusion. Discard diluted solution if not used within 7 days from the time of preparation.
Do not freeze. Administration
Administer the infusion, after dilution, over 30 minutes through an intravenous line containing a sterile, nonpyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).
Administer OPDIVO in combination with other therapeutic agents as follows: [See table below.]
Use separate infusion bags and filters for each infusion.
Flush the intravenous line at end of infusion.
Do not co-administer other drugs through the same intravenous line.
| a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO based on recommendations for hepatitis with no liver involvement. c Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved. ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal | ||
| Adverse Reaction | Severity | Dosage Modification |
| Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] | ||
| Pneumonitis | Grade 2 | Withholda |
| Grades 3 or 4 | Permanently discontinue | |
| ColitisFor colitis in patients treated with combination therapy with ipilimumab, see Table 4. | Grade 2 or 3 | Withholda |
| Grade 4 | Permanently discontinue | |
| Hepatitis with no tumor involvement of the liverFor liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4. | AST/ALT increases to >3 and ≤8 times ULNorTotal bilirubin increases to >1.5 and ≤3 times ULN. | Withholda |
| AST or ALT increases to >8 times ULNorTotal bilirubin increases to >3 times ULN. | Permanently discontinue | |
| Hepatitis with tumor involvement of the liverbFor liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4. | Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULNorBaseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN. | Withholda |
| AST/ALT increases to >10 times ULNorTotal bilirubin increases to >3 times ULN. | Permanently discontinue | |
| Endocrinopathiesc | Grade 3 or 4 | Withhold until clinically stable or permanently discontinue depending on severity |
| Nephritis with Renal Dysfunction | Grade 2 or 3 increased blood creatinine | Withholda |
| Grade 4 increased blood creatinine | Permanently discontinue | |
| Exfoliative Dermatologic Conditions | Suspected SJS, TEN, or DRESS | Withhold |
| Confirmed SJS, TEN, or DRESS | Permanently discontinue | |
| Myocarditis | Grades 2, 3, or 4 | Permanently discontinue |
| Neurological Toxicities | Grade 2 | Withholda |
| Grade 3 or 4 | Permanently discontinue | |
| Other Adverse Reactions | ||
| Infusion-Related Reactions[see Warnings and Precautions (5.2)] | Grade 1 or 2 | Interrupt or slow the rate of infusion |
| Grade 3 or 4 | Permanently discontinue | |