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  • CLASSES

    Immunomodulators, Monoclonal Antibodies

    DEA CLASS

    Rx

    DESCRIPTION

    Programmed death receptor-1 (PD-1) blocking human monoclonal antibody
    Used for certain types of melanoma, non-small cell lung cancer, head and neck cancer, renal cell carcinoma, Hodgkin lymphoma, urothelial carcinoma, colorectal cancer, and hepatocellular carcinoma
    Serious immune-mediated adverse reactions (e.g., pneumonitis, colitis, hepatitis, nephritis/renal dysfunction, hypo-/hyperthyroidism) have been reported

    COMMON BRAND NAMES

    Opdivo

    HOW SUPPLIED

    Nivolumab/Opdivo Intravenous Inj Sol: 1mL, 10mg

    DOSAGE & INDICATIONS

    For the treatment of malignant melanoma.
    NOTE: The FDA has designated nivolumab as an orphan drug for the treatment of stage IIB to IV melanoma.
    For the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma.
    Intravenous dosage
    Adults

    240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. At a follow-up of approximately 2 years, the median overall survival (15.7 months vs. 14.4 months; hazard ratio (HR) = 0.95; 95% CI, 0.73 to 1.24) and progression-free survival (3.1 months vs. 3.7 months; HR = 1; 95% CI, 0.78 to 1.436) times were not significantly improved with nivolumab compared with investigator's choice chemotherapy (ICC) in patients with unresectable stage IIIc or IV melanoma in a multicenter, randomized (2:1), open-label, phase III trial (the CheckMate 037 trial; n = 405). The objective response rate (evaluated by an independent radiology review committee) was 27% in the nivolumab arm and 10% in the ICC arm; the median durations of response were 32 months and 13 months, respectively. ICC chemotherapy consisted of dacarbazine 1,000 mg/m2 IV every 3 weeks or carboplatin (AUC 6) plus paclitaxel 175 mg/m2 every 3 weeks.

    For the treatment of BRAF V600 wild-type unresectable or metastatic melanoma as single-agent therapy.
    Intravenous dosage
    Adults

    240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions.

    For the treatment of unresectable or metastatic melanoma, in combination with ipilimumab.
    Intravenous dosage
    Adults

    1 mg/kg IV over 30 minutes followed by ipilimumab 3 mg/kg IV over 90 minutes repeated every 3 weeks for 4 doses followed by nivolumab 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Nivolumab and ipilimumab may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the nivolumab infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions.

    For the adjuvant treatment of melanoma in patients with lymph node involvement or metastatic disease who have undergone complete resection.
    Intravenous dosage
    Adults

    240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity for up to 1 year. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions.

    For the treatment of metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy, and after progression on EGFR- or ALK-targeted therapy if applicable.
    Intravenous dosage
    Adults

    240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In an open-label, randomized, clinical trial of patients with metastatic squamous non-small cell lung cancer (NSCLC), treatment with nivolumab (n = 135) after progression during or after platinum-based chemotherapy was associated with a statistically significant improvement in overall survival (OS) and progression-free survival (PFS) compared with docetaxel (n = 137) at a prespecified interim analysis; PD-L1 expression did not correlate with significantly improved OS. OS was also significantly improved in patients with platinum-resistant metastatic non-squamous NSCLC who received nivolumab (n = 292) compared with docetaxel (n = 290) in a separate randomized, open-label study; the objective response rate was 19% vs. 12%, with a median duration of response of 17 months vs. 6 months, respectively. PFS was not improved in the nivolumab arm. In this study, PD-L1 expression correlated with improved outcomes in both OS and PFS. In a pooled analysis providing a minimum of 2 years follow-up for these studies, OS with nivolumab versus docetaxel was 23% vs. 8% in patients with squamous NSCLC, and 29% vs. 16% in non-squamous NSCLC. Ongoing responses after 2 years of follow-up were evident in 37% of nivolumab-treated patients with squamous NSCLC and 34% of patients with non-squamous NSCLC; no patients who received docetaxel had an ongoing response.

    For the treatment of advanced renal cell cancer (RCC).
    For the first-line treatment of intermediate or poor risk advanced renal cell cancer (RCC), in combination with ipilimumab.
    Intravenous dosage
    Adults

    3 mg/kg IV over 30 minutes on day 1, followed by ipilimumab (1 mg/kg IV over 30 minutes) on day 1, every 3 weeks for 4 doses. After completion of 4 doses of nivolumab plus ipilimumab, continue nivolumab as monotherapy (240 mg IV over 30 minutes every 2 weeks or 480 mg IV over 30 minutes every 4 weeks) until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a randomized, open-label study, treatment with nivolumab plus ipilimumab significantly improved median overall survival (not estimated vs. 25.9 months) and objective response rate (41.6% vs. 26.5%) compared with sunitinib in patients with intermediate/poor risk patients with previously untreated RCC; a complete response was achieved in 9.4% of patients in the nivolumab plus ipilimumab arm compared with 1.2% of those who received sunitinib. Median progression-free survival was 11.6 months compared with 8.4 months, respectively. In a separate analysis, the combination of nivolumab plus ipilimumab in patients with favorable risk disease did not significantly improve overall survival; efficacy in this population has not been established.

    For the treatment of advanced renal cell cancer (RCC) in patients who have received prior anti-angiogenic therapy, as monotherapy.
    Intravenous dosage
    Adults

    240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The primary outcome of overall survival was significantly improved in patients with advanced RCC who received nivolumab after prior anti-angiogenic therapy compared with everolimus (25 vs. 19.6 months), regardless of PD-L1 expression level, in a randomized, open-label clinical trial. The confirmed objective response rate (ORR) was 21.5% in nivolumab-treated patients with a median time to onset of 3 months, compared to 3.9% ORR in those who received everolimus and a time to onset of 3.7 months. Responses lasted for a median duration of 23 months and 13.7 months, respectively.

    For the treatment of Hodgkin lymphoma.
    NOTE: The FDA has designated nivolumab as an orphan drug for the treatment of Hodgkin lymphoma.
    For the treatment of classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin.
    Intravenous dosage
    Adults

    240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The investigator-assessed objective response rate (ORR) was 87% in a cohort of patients with relapsed or refractory classical Hodgkin lymphoma (HL) who received nivolumab (median therapy duration of 36 weeks; range, 13 to 77 weeks) in a phase I trial (n = 23; median age, 35 years; range, 20 to 54 years); the complete response (CR) rate was 17% in these patients. In 15 patients that had previously received an autologous HSCT and post-transplant brentuximab vedotin, the ORR was 87% and the CR rate was 7%. At a median follow-up time of 40 weeks (range, 0 to 75 weeks), the median overall survival (OS) time had not been reached and the 24-week progression-free survival (PFS) rate was 86%. In this study, 78% of patients had previously received brentuximab vedotin therapy, 78% of patients had undergone a prior autologous HSCT, and 65% of patients had received 4 or more prior therapies. In a multinational, multicohort, phase II trial, the ORR (primary endpoint assessed by an independent radiological review committee) was 66.3% in 80 patients with classical HL who had failed to respond to autologous SCT and had either relapsed after or failed to respond to brentuximab vedotin; the CR rate was 9% in these patients. The median response duration was 7.8 months. All patients (median age, 37 years) had previously received brentuximab vedotin; patients had received a median of 4 prior therapies. At a median follow-up of 8.9 months, the 6-month PFS and OS rates were 76.9% and 98.7%, respectively. At 12 months, the median PFS time was 10 months.

    For the treatment of classical Hodgkin lymphoma that has relapsed or progressed after 3 or more lines of systemic therapy that includes an autologous hematopoietic stem cell transplantation (HSCT) .
    Intravenous dosage
    Adults

    240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a pooled analysis from 2 clinical studies (n = 258), the objective response rate was 69% in patients who had relapsed or progressive classical Hodgkin lymphoma following an autologous HSCT; the complete remission rate was 14%. In this analysis, patients had received a median of 4 prior systemic regimens (range, 2 to 15 regimens) and 76% of patients had received prior brentuximab vedotin.

    For the treatment of recurrent or metastatic head and neck cancer (squamous cell) with disease progression on or after platinum-containing chemotherapy.
    Intravenous dosage
    Adults

    240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. In clinical trials, nivolumab could be continued beyond disease progression, as long as clinical benefit was evident. In a multicenter, randomized, open-label clinical trial, nivolumab significantly improved overall survival compared with investigator’s choice of weekly monotherapy with cetuximab, methotrexate, or docetaxel (7.5 months vs. 5.1 months; HR 0.7; p = 0.01) in patients with recurrent, platinum-resistant, squamous-cell cancer of the head and neck.

    For the treatment of locally advanced or metastatic urothelial carcinoma, in patients with disease progression on or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
    Intravenous dosage
    Adults

    240 mg IV infusion over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Patients with platinum-resistant, locally advanced or metastatic urothelial cancer treated with nivolumab (n = 270) had an objective response rate of 19.6% (complete response (CR), 2.6%; partial response (PR), 17%) in an open-label, single-arm clinical trial. The median duration of response was 10.3 months (range, 1.9 months to 12+ months). Patients with PD-L1 expression of 1% or higher (n = 124) had an objective response rate of 25% (CR, 4.8%; PR, 20.2%) and those with PD-L1 expression less than 1% had an objective response rate of 15.1% (CR, 0.7%; PR, 14.4%).

    For the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
    Intravenous dosage
    Adults

    240 mg IV over 30 minutes every 2 weeks until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The objective response rate (ORR) as assessed by independent radiographic review committee using RECIST 1.1 was 28% (n = 15) (95% CI: 17, 42) in the 53 patients who received prior fluoropyrimidine, oxaliplatin, and irinotecan. Responses lasted 6 or more months for 67% (95% CI: 38, 88) of patients. There was 1 complete response and 14 partial responses. The ORR was 32% (n = 24) (95% CI: 22, 44) among the 74 patients in the overall population.

    Children and Adolescents 12 to 17 years

    240 mg IV over 30 minutes every 2 weeks until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Efficacy for pediatric patients has been extrapolated from results from clinical trials in adult MSI-H patients with additional population pharmacokinetic data. The objective response rate (ORR) as assessed by independent radiographic review committee using RECIST 1.1 was 28% (n = 15) (95% CI: 17, 42) in the 53 patients who received prior fluoropyrimidine, oxaliplatin, and irinotecan. Responses lasted 6 or more months for 67% (95% CI: 38, 88) of patients. There was 1 complete response and 14 partial responses. The ORR was 32% (n = 24) (95% CI: 22, 44) among the 74 patients in the overall population.

    For the treatment of hepatocellular cancer, after disease progression on or intolerance to sorafenib therapy.
    Intravenous dosage
    Adults

    240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. In a subgroup analysis of a multicenter, open-label clinical trial (CHECKMATE-040; n = 154), patients with hepatocellular cancer who progressed on or were intolerant to sorafenib were treated with nivolumab monotherapy. The overall response rate as assessed by a blinded independent central review (BICR) was 14.3% by RECIST v1.1 (complete response (CR), 1.9%; partial response (PR), 12.3%) and 18.2% by mRECIST (CR, 3.2%; PR, 14.9%). Of the 22 patients who responded to therapy, 91% had a duration of at least 6 months, while 55% maintained their response for 12 months or longer.

    MAXIMUM DOSAGE

    Adults

    Monotherapy: 480 mg IV every 4 weeks or 240 mg IV every 2 weeks.
    Combination with ipilimumab: 3 mg/kg IV every 3 weeks.

    Geriatric

    Monotherapy: 480 mg IV every 4 weeks or 240 mg IV every 2 weeks.
    Combination with ipilimumab: 3 mg/kg IV every 3 weeks.

    Adolescents

    Single agent (colorectal cancer only): 240 mg IV.

    Children

    12 years: Single agent (colorectal cancer only): 240 mg IV.
    1 to 11 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Mild or moderate hepatic impairment (total bilirubin level less than or equal to the upper limit of normal (ULN) and any AST level greater than the ULN OR a total bilirubin level less than 3 times the ULN and any AST level): No dosage adjustment necessary.
    Severe hepatic impairment (total bilirubin greater than 3 times the ULN and any AST level): Nivolumab has not been evaluated in these patients; dosage adjustment recommendations are not available.
    Treatment-Related Hepatitis, patient WITHOUT hepatocellular carcinoma
    Grade 2 toxicity (AST or ALT level 3 to 5 times the upper limit of normal (ULN) or a total bilirubin level 1.5 to 3 times the ULN): Hold nivolumab and administer prednisone 0.5 to 1 mg/kg per day (or equivalent) followed by a corticosteroid taper. Consider resuming therapy when toxicity resolves to grade 1 or less.
    Grade 3 or 4 toxicity (AST or ALT level greater than 5 times the ULN or a total bilirubin level greater than 3 times the ULN): Permanently discontinue nivolumab and administer prednisone 1 to 2 mg/kg per day (or equivalent) followed by a corticosteroid taper.
    Treatment-Related Hepatitis, patient WITH hepatocellular carcinoma
    AST/ALT 3 to 5 times the ULN (within normal limits at baseline): Hold nivolumab and administer prednisone 1 to 2 mg/kg per day (or equivalent) followed by a corticosteroid taper. Resume treatment when AST/ALT returns to baseline.
    AST/ALT 5 to 10 times the ULN (1 to 3 times ULN at baseline): Hold nivolumab and administer prednisone 1 to 2 mg/kg per day (or equivalent) followed by a corticosteroid taper. Resume treatment when AST/ALT returns to baseline.
    AST/ALT 8 to 10 times the ULN (3 to 5 times ULN at baseline): Hold nivolumab and administer prednisone 1 to 2 mg/kg per day (or equivalent) followed by a corticosteroid taper. Resume treatment when AST/ALT returns to baseline.
    AST/ALT more than 10 times ULN, or total bililrubin more than 3 times ULN: Permanently discontinue nivolumab and administer prednisone 1 to 2 mg/kg per day (or equivalent) followed by a corticosteroid taper.

    Renal Impairment

    Baseline Renal Impairment
    No nivolumab dosage adjustment recommended.
    Treatment-Related Nephrotoxicity
    Grade 2 or 3 toxicity (serum creatinine (SCr) 1.5 to 6 times the upper limit of normal (ULN)): Hold nivolumab and administer prednisone 0.5 to 1 mg/kg/day (or equivalent) followed by a corticosteroid taper. Consider resuming therapy when the toxicity resolves to grade 1 or less. If the toxicity does not improve or worsens on prednisone 0.5 to 1 mg/kg/day (or equivalent), increase the prednisone dose to 1 to 2 mg/kg/day (or equivalent) and permanently discontinue therapy.
    Grade 4 toxicity (SCr greater than 6 times the ULN): Permanently discontinue therapy and administer high-dose corticosteroids (e.g., prednisone 1 to 2 mg/kg/day or equivalent) followed by corticosteroid taper.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Nivolumab is a clear to opalescent, colorless to pale-yellow solution. Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles.
    Do not shake nivolumab.

    Intravenous Administration

    Preparation:
    Withdraw the required volume of drug and transfer into an intravenous container.
    Dilute nivolumab with either 0.9% sodium chloride injection or 5% dextrose injection, to prepare an infusion with a final concentration ranging from 1 to 10 mg/mL. The total volume must not exceed 160 mL.
    Mix the diluted solution by gentle inversion. Do not shake.
    Discard partially used or empty vials of nivolumab.
    Storage: After preparation, store either at room temperature for no more than 8 hours (this includes storage time in the IV container and time for administration of the infusion) or under refrigeration (2 to 8 degrees C or 36 to 46 degrees F) for no more than 24 hours. Do not freeze.
     
    Intravenous Infusion:
    Administer the diluted infusion over 30 minutes through an intravenous line containing sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 to 1.2 micrometer).
    Do not coadminister with other drugs through the same intravenous line.
    With combination therapy, infuse nivolumab first followed by ipilimumab; use separate infusion bags and filters for each drug.
    Flush the intravenous line at the end of infusion.

    STORAGE

    Opdivo:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Pneumonitis, pulmonary disease

    Use nivolumab with caution in patients with pre-existing pulmonary disease. Immune-mediated pneumonitis, including interstitial lung disease, has been reported with nivolumab therapy; some cases were fatal. Monitor patients for signs (e.g., chest X-ray) or symptoms (e.g., new or worsening chest pain or shortness of breath) of pneumonitis. Therapy interruption or permanent discontinuation of therapy may be necessary in patients who develop pneumonitis; administer high-dose corticosteroids (followed by a corticosteroid taper) for grade 2 or higher pneumonitis. The time to onset of immune-mediated pneumonitis ranged from 1 day to 22.3 months in clinical trials.

    Colitis, Crohn's disease, diarrhea, inflammatory bowel disease, ulcerative colitis

    Use nivolumab with caution in patients with inflammatory bowel disease such as ulcerative colitis or Crohn's disease. Diarrhea and immune-mediated colitis have been reported with nivolumab therapy. Monitor patients for signs and symptoms of colitis (e.g., diarrhea or severe abdominal pain). Therapy interruption or permanent discontinuation of therapy may be necessary in patients who develop colitis; administer high-dose corticosteroids (followed by a corticosteroid taper) for grade 2 or higher immune-mediated colitis. If therapy discontinuation is necessary, stop both nivolumab and ipilimumab in patient receiving combination therapy. The time to onset of immune-mediated colitis ranged from 2 days to 20.9 months in clinical trials.

    Hepatic disease, hepatitis, jaundice

    Use nivolumab with caution in patients with hepatic disease; it has not been evaluated in patients with moderate or severe hepatic impairment. Immune-mediated hepatitis has been reported in patients who received single-agent nivolumab or nivolumab in combination with ipilimumab. Monitor for signs of hepatotoxicity (e.g., jaundice); obtain liver function tests at baseline and periodically during therapy. Interruption of therapy, treatment with corticosteroids, or permanent discontinuation of therapy may be necessary in patients who develop transaminitis or hyperbilirubinemia. The median time to hepatitis onset ranged from 6 days to 11 months.

    Renal disease, renal impairment

    Immune-mediated nephritis or renal impairment/dysfunction has been reported with nivolumab therapy. Monitor renal function (e.g., serum creatinine levels) at baseline and periodically during therapy. No initial dose adjustment is recommended in patients with renal dysfunction; however, use nivolumab with caution in patients with renal disease or renal impairment. For grade 2 or higher renal toxicity, hold nivolumab therapy and administer corticosteroids followed by a corticosteroid taper. Permanently discontinue nivolumab in patients who develop grade 4 renal toxicity. The median time to immune-mediated nephritis onset ranged from 1 days to 13.2 months.

    Adrenal insufficiency, hypophysitis, hypopituitarism

    Immune-mediated hypophysitis (onset range, 27 days to 11 months) and adrenal insufficiency (onset range, 15 days to 22.3 months) including hypopituitarism have been reported with nivolumab therapy. Monitor patients for signs and symptoms of adrenal insufficiency (e.g., hypotension, decreased cortisol level, fatigue, weakness, and weight loss) and hypophysitis (e.g., decreased pituitary hormone levels, pituitary gland inflammation, severe intractable headache, and vision impairment) during and after nivolumab treatment. Therapy interruption or discontinuation and treatment with high-dose corticosteroids (followed by a corticosteroid taper) may be necessary in patients who develop severe endocrinopathies.

    Autoimmune disease, immunosuppression, organ transplant, systemic lupus erythematosus (SLE)

    Use nivolumab with caution in patients with autoimmune disease (e.g., systemic lupus erythematosus (SLE)) or conditions that require immunosuppression (e.g., chronic corticosteroid use) and in patients who have previously had an organ transplant. Patients with autoimmune disease and patients receiving chronic immunosuppression were excluded from clinical trials and nivolumab is associated with many immune-mediated adverse reactions.

    Hyperthyroidism, hypothyroidism, thyroid disease

    Thyroid disease/disorders such as hypothyroidism and hyperthyroidism have been reported in patients who received nivolumab therapy. Monitor thyroid function (e.g., thyroid stimulating hormone (TSH) levels) at baseline and periodically during treatment. Manage treatment-related thyroid disorders as clinically appropriate (e.g., thyroid replacement therapy for hypothyroidism; radioactive iodine, thyroidectomy, or medication such as methimazole, carbimazole, and propylthiouracil for hyperthyroidism); a nivolumab dose adjustment is not necessary. The time to hypothyroidism onset ranged from 1 day to 21.4 months; the time to hyperthyroidism onset ranged from 1 day to 14.2 months.

    Infusion-related reactions

    Severe infusion-related reactions have been reported with nivolumab therapy. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions; discontinue nivolumab in patients who develop severe or life-threatening infusion reactions.

    Pregnancy

    Based on its mechanism of action and data from animal studies, nivolumab may cause fetal harm or increase the risk of fetal immune-mediated disorders or altered immune response when administered to women during pregnancy. Advise pregnant women of the potential risk to a fetus. There are no adequate and well-controlled studies of nivolumab use in pregnant women. In animal reproduction studies in pregnant cynomolgus monkeys, increased rates of abortion and premature infant death were observed with twice weekly nivolumab administration at doses resulting in AUC values of 9 to 42 times higher than the clinical human dose of 3 mg/kg.

    Serious rash

    Serious rash including immune-mediated rash, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported with nivolumab therapy; some cases were fatal. Monitor patients for rash. Hold therapy in patients who develop grade 3 immune-mediated rash or have suspected SJS or TEN; permanently discontinue therapy in patients with grade 4 rash or confirmed SJS or TEN. Administer high-dose corticosteroids (followed by a corticosteroid taper) for grade 3 or 4 rash. The time to rash onset ranged from less than 1 day to 25.8 months.

    Encephalopathy, mental status changes

    Immune-mediated encephalitis has been reported in patients who received single-agent nivolumab or nivolumab in combination with ipilimumab in clinical trials; one case of fatal limbic encephalitis occurred after 7.2 months of exposure to nivolumab. Monitor patients for signs or symptoms of encephalopathy or mental status changes. For any new-onset moderate to severe neurologic signs or symptoms, hold nivolumab therapy and evaluate (e.g., neurology consult, brain MRI, lumbar puncture) to rule out infectious or other causes. If immune-mediated encephalitis is diagnosed, permanently discontinue nivolumab therapy and administer high-dose corticosteroids followed by a corticosteroid taper.

    Contraception requirements, reproductive risk

    Counsel patients about the reproductive risk of nivolumab and discuss the contraception requirements during nivolumab treatment. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 5 months after treatment with nivolumab. Women who become pregnant while receiving nivolumab should contact their healthcare provider.

    Diabetes mellitus, diabetic ketoacidosis, hyperglycemia, type 1 diabetes mellitus

    Use nivolumab with caution in patients with pre-existing diabetes mellitus. Immune-mediated endocrinopathies, including type 1 diabetes mellitus and diabetic ketoacidosis, have been reported in patients who received nivolumab in clinical trials. Monitor patients for hyperglycemia. Hold therapy in patients who develop grade 3 hyperglycemia until metabolic control is achieved. Permanently discontinue nivolumab in patients who develop grade 4 hyperglycemia. The time to diabetes mellitus or diabetic ketoacidosis onset ranged from 15 days to 22 months.

    Breast-feeding

    It is not known whether nivolumab is present in human milk. Many drugs are excreted in human milk including antibodies. Due to the potential for serious adverse reactions in nursing infants from nivolumab, advise women to discontinue breastfeeding during treatment. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Allogeneic stem cell transplant

    Serious adverse events including severe or refractory graft versus host disease (GVHD), a steroid-requiring febrile syndrome, and sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) occurred in patients with classical Hodgkin lymphoma who received an allogeneic stem cell transplant (SCT) after treatment with nivolumab; fatalities have been reported. Monitor patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe acute GVHD, steroid-requiring febrile syndrome, SOS, and other immune-mediated adverse reactions; treat adverse events promptly. These complications may occur despite intervening therapy between PD-1 blockade with nivolumab and allogeneic HSCT. The median patient age at the time of SCT was 33 years (range, 18 to 56 years); patients had received a median of 9 nivolumab doses (range, 4 to 16 doses).

    ADVERSE REACTIONS

    Severe

    erythema multiforme / Delayed / 0-28.0
    enterocolitis / Delayed / 0-25.0
    elevated hepatic enzymes / Delayed / 0.7-18.0
    hepatitis / Delayed / 1.8-13.0
    hyperamylasemia / Delayed / 0-12.0
    pulmonary edema / Early / 0-12.0
    diarrhea / Early / 1.5-11.0
    hyponatremia / Delayed / 1.1-11.0
    lymphopenia / Delayed / 0.4-11.0
    GI perforation / Delayed / 0-10.0
    exfoliative dermatitis / Delayed / 0-10.0
    ventricular tachycardia / Early / 0-10.0
    anemia / Delayed / 2.1-8.0
    asthenia / Delayed / 0.9-8.0
    fatigue / Early / 0.9-8.0
    hyperbilirubinemia / Delayed / 0-7.0
    malaise / Early / 0-7.0
    neutropenia / Delayed / 0-6.0
    abdominal pain / Early / 0-5.0
    rash / Early / 0.4-5.0
    pleural effusion / Delayed / 1.0-4.5
    leukopenia / Delayed / 0-4.5
    musculoskeletal pain / Early / 0-4.0
    hyperkalemia / Delayed / 0-4.0
    vomiting / Early / 0-3.5
    nausea / Early / 0-3.5
    back pain / Delayed / 0-3.4
    dyspnea / Early / 0.4-3.3
    pulmonary embolism / Delayed / 2.0-3.3
    hypokalemia / Delayed / 0-3.2
    hypercalcemia / Delayed / 0-3.2
    thrombocytopenia / Delayed / 0-3.2
    renal failure (unspecified) / Delayed / 0-2.7
    hyperglycemia / Delayed / 0-2.4
    colitis / Delayed / 0-2.2
    anorexia / Delayed / 1.2-2.2
    interstitial nephritis / Delayed / 1.2-2.2
    hypertriglyceridemia / Delayed / 0-2.0
    fever / Early / 0-1.6
    edema / Delayed / 0-1.5
    peripheral edema / Delayed / 0-1.5
    arthralgia / Delayed / 0-1.3
    hypocalcemia / Delayed / 0-1.2
    hypomagnesemia / Delayed / 0-1.2
    headache / Early / 0-1.1
    pancreatitis / Delayed / 0-1.0
    uveitis / Delayed / 0-1.0
    Vogt-Koyanagi-Harada syndrome / Delayed / 0-1.0
    cranial nerve palsies / Delayed / 0-1.0
    hyperesthesia / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    dysesthesia / Delayed / 0-1.0
    hypoesthesia / Delayed / 0-1.0
    diabetic ketoacidosis / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    infusion-related reactions / Rapid / 0-1.0
    vasculitis / Delayed / 0-1.0
    aplastic anemia / Delayed / 0-1.0
    pericarditis / Delayed / 0-1.0
    cough / Delayed / 0-0.7
    constipation / Delayed / 0-0.5
    pruritus / Rapid / 0-0.5
    hypothyroidism / Delayed / 0-0.4
    hypercholesterolemia / Delayed / 0-0.3
    encephalopathy / Delayed / 0-0.2
    sinusitis / Delayed / 1.1
    rhinitis / Early / 1.1
    infection / Delayed / 0.8
    pharyngitis / Delayed / 1.1
    pneumonitis / Delayed / 2.0
    adrenocortical insufficiency / Delayed / 2.0
    hypophysitis / Delayed / 2.0
    graft-versus-host disease (GVHD) / Delayed / Incidence not known
    sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
    veno-occlusive disease (VOD) / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 0.5-37.8
    dehydration / Delayed / 17.0-17.0
    hypoglycemia / Early / 0-16.0
    myopathy / Delayed / 0-10.0
    stomatitis / Delayed / 0-10.0
    neuritis / Delayed / 0-10.0
    psoriasis / Delayed / 0-10.0
    gastritis / Delayed / 0-1.0
    iritis / Delayed / 0-1.0
    hypopituitarism / Delayed / 0-1.0
    migraine / Early / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known

    Mild

    nasal congestion / Early / 0-11.0
    vertigo / Early / 0-11.0
    dizziness / Early / 0-11.0
    skin hypopigmentation / Delayed / 0-11.0
    arthropathy / Delayed / 0-10.0
    paresthesias / Delayed / 0-1.0
    weight loss / Delayed / Incidence not known

    DRUG INTERACTIONS

    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.

    PREGNANCY AND LACTATION

    Pregnancy

    Based on its mechanism of action and data from animal studies, nivolumab may cause fetal harm or increase the risk of fetal immune-mediated disorders or altered immune response when administered to women during pregnancy. Advise pregnant women of the potential risk to a fetus. There are no adequate and well-controlled studies of nivolumab use in pregnant women. In animal reproduction studies in pregnant cynomolgus monkeys, increased rates of abortion and premature infant death were observed with twice weekly nivolumab administration at doses resulting in AUC values of 9 to 42 times higher than the clinical human dose of 3 mg/kg.

    It is not known whether nivolumab is present in human milk. Many drugs are excreted in human milk including antibodies. Due to the potential for serious adverse reactions in nursing infants from nivolumab, advise women to discontinue breastfeeding during treatment. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Nivolumab is a fully human IgG4 monoclonal antibody that inhibits the programmed death receptor-1 (PD-1) immune checkpoint protein, one of the key checkpoint molecules that mediates tumor-induced immune suppression. PD-1 receptors are expressed on T cells, B cells, monocytes, and natural killer T cells, following their activation in response to inflammatory signals. PD-1 has two known ligands, programmed death-ligand-1 (PD-L1) and programmed death-ligand-2 (PD-L2), which are expressed on antigen-presenting cells, including dendritic cells. PD-L1, which is also expressed on some nonhematopoietic cells, is believed to be the primary mediator of PD-1-dependent immunosuppression. The PD-1 pathway regulates the balance between T-cell activation and the protection of healthy tissues from immune-mediated damage. In tumor cells, the PD-1 pathway is thought to play an important role in the interaction of tumor cells with the host immune response, and PD-L1 expression in a tumor cell may provide adaptive immune resistance and lead to a poor outcome. Nivolumab selectively binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, which causes a release of the PD-1 pathway-mediated inhibition of the immune response. This prevents the negative regulatory signal mediated by the receptor (PD-1)-ligand interaction and thus promotes the host immune response in which the tumor cells are recognized as foreign and eliminated. Syngeneic mouse tumor models have shown that blocking the PD-1 pathway results in decreased growth of tumors. The combination of nivolumab and the anti-cytotoxic T-lymphocyte-associated protein-4 antibody, ipilimumab, appear to have additive inhibitory effects on T-cell function and result in improved tumor response in melanoma.

    PHARMACOKINETICS

    Nivolumab is administered intravenously. In patients who received nivolumab 0.1 to 20 mg/kg IV once or as multiple IV doses every 2 or 3 weeks, the geometric mean volume of distribution at steady state was 6.8 L (coefficient of variation (CV%), 27.3%), and the geometric mean half-life was 25 days (CV%, 77.5%). Nivolumab clearance decreases over time, with mean maximal reduction from baseline of approximately 24.5% (CV%, 47.6%); this reduction is not clinically relevant. The geometric mean clearance at steady state of 8.2 mL/hour (CV%, 53.9%). In patients with completely resected melanoma, nivolumab clearance does not decrease over time; the geometric mean population clearance is 24% lower in this patient population compared with patients with metastatic melanoma at steady-state. When nivolumab 1 mg/kg was administered with ipilimumab 3 mg/kg, the clearance of nivolumab increased by 29% and the clearance of ipilimumab was unchanged; clearance of both nivolumab and ipilimumab were unchanged when nivolumab 3 mg/kg was given in combination with ipilimumab 1 mg/kg. When nivolumab was administered in combination with ipilimumab, the clearance of nivolumab was increased by 20% in the presence of anti-nivolumab antibodies and the clearance of ipilimumab was unchanged in the presence of anti-ipilimumab antibodies.
     
    When administered at 3 mg/kg every 2 weeks, steady state was reached by 12 weeks and systemic accumulation was approximately 3.7-fold. Nivolumab exposure increased in a dose-proportional manner over 0.1 to 10 mg/kg every 2 weeks. There are no clinically significant differences in safety and efficacy between a nivolumab dose of 240 mg or 3 mg/kg when administered every 2 weeks in patients with melanoma, non-small cell lung cancer (NSCLC), renal cell cancer (RCC), and urothelial carcinoma.

    Intravenous Route

    The predicted exposure of nivolumab after a 30-minute infusion is comparable to that observed with a 60-minute infusion.