Dosing & Uses
Dosage Forms & Strengths
IV solution
- 10mg/mL (4mL, 10mL)
- Further dilution required before administration
Adjuvant Treatment of Melanoma
Indicated for melanoma in patients with lymph node involvement or metastatic disease who have undergone complete resection, in the adjuvant setting
240 mg IV q2Weeks or 480 mg IV q4Weeks
Continue until disease progression or unacceptable toxicity for up to 1 year
Unresectable or Metastatic Melanoma
Indicated as a single agent or in combination with ipilimumab
Single agent
- 240 mg IV q2Weeks or 480 mg IV q4Weeks
- Continue until disease progression or unacceptable toxicity
Combination with ipilimumab
- Nivolumab 1 mg/kg IV q3Weeks PLUS
- Ipilimumab 3 mg/kg IV on the same day for maximum of 4 doses
- After completing 4 doses of combination therapy: Administer nivolumab 240 mg IV q2Weeks or 480 mg IV q4Weeks
- Continue until disease progression or unacceptable toxicity
Non-Small Cell Lung Cancer (NSCLC)
Monotherapy
- Indicated for metastatic NSCLC with progression in patients on or after platinum-based chemotherapy
- Patients with EGFR or ALK genomic tumor aberrations should have disease progression prior to initiation
- 240 mg IV q2Weeks or 480 mg IV q4Weeks
- Continue until disease progression or unacceptable toxicity
Combination therapy with ipilimumab
- Indicated in combination with ipilimumab for first-line treatment of metastatic NSCLC in adults whose tumors express PD-L1 (≥1%) with no EGFR or ALK genomic tumor aberrations
- Nivolumab 3 mg/kg IV q2Weeks, PLUS
- Ipilimumab 1 mg/kg IV q6Weeks
- Continue until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression
Combination with ipilimumab and platinum chemotherapy
- Indicated in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy for first-line treatment of metastatic or recurrent NSCLC in adults with no EGFR or ALK genomic tumor aberrations
- Nivolumab 360 mg/kg IV q3Weeks, PLUS
- Ipilimumab 1 mg/kg IV q6Weeks, PLUS
- Histology-based platinum doublet chemotherapy q3Weeks for 2 cycles
- Continue until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression
Advanced Renal Cell Carcinoma
Single agent
- Indicated for advanced renal cell carcinoma in patients who have received prior antiangiogenic therapy
- 240 mg IV q2Weeks or 480 mg IV q4Weeks
- Continue until disease progression or unacceptable toxicity
Combination with ipilimumab
- Indicated for patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma
- Nivolumab 3 mg/kg IV q3Weeks PLUS
- Ipilimumab 1 mg/kg IV on the same day for 4 doses
- After completing 4 doses of combination therapy: Administer nivolumab 240 mg IV q2Weeks or 480 mg IV q4Weeks
- Continue until disease progression or unacceptable toxicity
- Also see ipilimumab drug monograph for dose
Hodgkin Lymphoma
Indicated for classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin, or ≥3 lines of systemic therapy (eg, autologous HSCT)
240 mg IV q2Weeks or 480 mg IV q4Weeks
Continue until disease progression or unacceptable toxicity
Recurrent of Metastatic Squamous Head & Neck Carcinoma
Indicated for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in patients with disease progression on or after a platinum-based therapy
240 mg IV q2Weeks or 480 mg IV q4Weeks
Continue until disease progression or unacceptable toxicity
Advanced or Metastatic Urothelial Carcinoma
Indicated for locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
240 mg IV q2Weeks or 480 mg IV q4Weeks
Continue until disease progression or unacceptable toxicity
Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer
Indicated as a single agent or in combination with ipilimumab for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan
Single agent
- 240 mg IV q2Weeks or 480 mg IV q4Weeks
- Continue until disease progression or unacceptable toxicity
Combination with ipilimumab
- Nivolumab 3 mg/kg IV q3Weeks PLUS
- Ipilimumab 1 mg/kg IV on the same day for 4 doses
- After completing 4 doses of combination therapy: Administer nivolumab 240 mg IV q2Weeks or 480 mg IV q4Weeks
- Continue until disease progression or unacceptable toxicity
Hepatocellular Carcinoma
Indicated as a single agent or in combination with ipilimumab for hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib
Single agent
- 240 mg IV q2Weeks or 480 mg IV q4Weeks
- Continue until disease progression or unacceptable toxicity
Combination with ipilimumab
- Nivolumab 1 mg/kg IV q3Weeks PLUS
- Ipilimumab 3 mg/kg IV on the same day for 4 doses
- After completing 4 doses of combination therapy: Administer nivolumab 240 mg IV q2Weeks or 480 mg IV q4Weeks
- Continue until disease progression or unacceptable toxicity
Esophageal Squamous Cell Carcinoma
Indicated for unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) in patients previously treated with fluoropyrimidine- and platinum-based chemotherapy
240 mg IV q2Weeks or 480 mg IV q4Weeks
Continue until disease progression or unacceptable toxicity
Malignant Pleural Mesothelioma
Indicated as first-line treatment for unresectable malignant pleural mesothelioma in combination with ipilimumab
Nivolumab 360 mg IV q3Weeks, PLUS
Ipilimumab 1 mg/kg IV q6Weeks
Continue in combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression
Dosage Modifications
No dose reductions are recommended
Hypothyroidism or hyperthyroidism: No recommended dose modifications
Note: When administered in combination with ipilimumab, if nivolumab is withheld, ipilimumab should also be withheld
Renal impairment
- All severities: No dosage modifications required
Hepatic impairment
- Mild or moderate: No dosage modifications required
- Severe: Not studied
Pneumonitis
- Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 3 or 4: Permanently discontinue
Colitis
- Grade 2 or 3: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 4: Permanently discontinue
Hepatitis with no tumor involvement of the liver
- AST or ALT increases to >3 and ≤8x ULN or total bilirubin increases to >1.5 and <3x ULN: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- AST or ALT increases to >8x ULN or total bilirubin increases to >3x ULN: Permanently discontinue
Hepatitis with tumor involvement of the liver
-
Withhold therapy
- Baseline AST or ALT >1 and ≤3x ULN and increases to >5 and ≤10x ULN
- Baseline AST or ALT >3 and ≤5x ULN and increases to >8 and ≤10x ULN
- Resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
-
Permanently discontinue
- AST or ALT increases to >10x ULN or total bilirubin increases to >3x ULN
Endocrinopathies
- 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: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 4 increased blood creatinine: Permanently discontinue
Exfoliative dermatologic conditions
- Suspected Steven Johnson Syndrome (SJS), toxic epidermal necrosis (TEN), or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS): Withhold therapy
- Confirmed SJS, TEN, or DRESS: Permanently discontinue
Myocarditis
- Grade 2, 3, or 4: Permanently discontinue
Neurologic toxicities
- Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 3 or 4: Permanently discontinue
Infusion-related reactions
- Grade 1 or 2: Interrupt or slow infusion rate
- Grade 3 or 4: Permanently discontinue
Dosing Considerations
Patient selection
- For the MSI-H/dMMR indications, select patients for treatment as a single agent based on MSI-H/dMMR status in tumor specimens
- For the TMB-H indication, select patients for treatment as a single agent based on TMB-H status in tumor specimens
- An FDA-approved test for the detection of MSI-H or dMMR is not currently available
-
Select patients for treatment based on the presence of positive PD-L1 expression in
- NSCLC
- HNSCC
- Metastatic urothelial carcinoma
- Metastatic gastric cancer
- Metastatic esophageal cancer
- Recurrent or metastatic cervical cancer
- Information on FDA-approved tests for the detection of PD-L1 expression and TMB status is available at: http://www.fda.gov/CompanionDiagnostics
Orphan Designations
Glioblastoma
Anal cancer
Primary mediastinal B-cell lymphoma
Orphan sponsor
- Bristol-Myers Squibb Company; P. O. Box 4000; Princeton, New Jersey 08543
Dosage Forms & Strengths
IV solution
- 10mg/mL (4mL, 10mL)
- Further dilution required before administration
Microsatellite Instability-High Cancer
Indicated as a single agent or in combination with ipilimumab for patients aged ≥12 years with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan
<12 years: Safety and efficacy not established
≥12 year
-
Single agent
-
Combination with ipilimumab
- Nivolumab 3 mg/kg IV q3Weeks PLUS
- Ipilimumab 1 mg/kg IV on the same day for 4 doses
- After completing 4 doses of combination therapy: Administer nivolumab 3 mg/kg IV q2Weeks (patients <40 kg); 240 mg IV q2Weeks or 480 mg IV q4Weeks (patients ≥40 kg)
- Continue until disease progression or unacceptable toxicity
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10% (All grades)
Melanoma
- Increased AST (28%)
- Hyponatremia (25%)
- Increased alkaline phosphatase (22%)
- Rash (21%)
- Pruritus (19%)
- Cough (17%)
- Increased ALT (16%)
- Hyperkalemia (15%)
- URTI (11%)
NSCLC
- Fatigue (50%)
- Lymphopenia (47%)
- Dyspnea, hyponatremia (38%)
- Musculoskeletal pain (36%)
- Cough (32%)
- Nausea (29%)
- Increases creatinine (22%)
- Hypercalcemia, hypokalemia, hypomagnesemia (20%)
- Vomiting, asthenia (19%)
- Hypocalcemia, hyperkalemia, diarrhea (18%)
- Edema, pyrexia (17%)
- Abdominal pain, rash, increased AST (16%)
- Increased alkaline phosphatase, thrombocytopenia (14%)
- Chest pain, arthralgia, decreased appetite and weight (13%)
- Increased ALT (12%)
1-10% (all grades)
Melanoma
- Peripheral edema (10%)
NSCLC
- Pneumonia (10%)
- Pain (10%)
1-10% (grades 3-4)
Melanoma
- Hyponatremia (5%)
- Increased AST (2.4%)
- Increased alkaline phosphatase (2.4%)
- Hyperkalemia (2%)
- Increased ALT (1.6%)
NSCLC
- Dyspnea (9%)
- Fatigue (7%)
- Musculoskeletal pain (6%)
- Pneumonia (5%)
- Decreased appetite (2.6%)
- Pain (2.6%)
- Nausea (1.7%)
- Abdominal pain (1.7%)
- Asthenia (1.7%)
- Edema (1.7%)
- Cough (1.7%)
1-10% (other clinically important adverse effects)
Melanoma
- Cardiac disorders: Ventricular arrhythmia
- Eye disorders: Iridocyclitis
- General disorders and administration site conditions: Infusion-related reactions
- Immune-mediated disorders: Severe pneumonitis or interstitial lung disease, including fatal cases; colitis; hepatitis; nephritis; thyroid disorders; other immune disorders (pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, facial and abducens nerve paresis, hypophysitis, polymyalgia rheumatica, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, myasthenic syndrome)
- Investigations: Increased amylase, increased lipase
- Nervous system disorders: Dizziness, peripheral and sensory neuropathy
- Skin and subcutaneous tissue disorders: Exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis
NSCLC
- General disorders and administration site conditions: Stomatitis
- Nervous system disorders: Peripheral neuropathy
- Infections and infestations: Bronchitis, upper respiratory tract infection
Postmarketing Reports
Eye disorders: Vogt-Koyanagi-Harada (VKH) syndrome
Complications of treatment after allogeneic HSCT: Treatment refractory, severe acute and chronic graft versus host disease (GVHD)
Pyrexia
Ascites
Back pain
General physical health deterioration
Abdominal pain
Pneumonia
Anemia
Hemophagocytic lymphohistiocytosis (HLH)
Autoimmune hemolytic anemia
Warnings
Contraindications
None
Cautions
Severe infusion-related reactions can occur; discontinue in patients with severe or life-threatening infusion reactions
Fatal or serious graft-versus-host disease (GVHD) can occur in patients who receive a CTLA-4 receptor blocking antibody either before or after allogeneic hematopoietic stem cell transplantation (HSCT); closely monitor for evidence of GVHD and intervene promptly; consider benefit versus risks of treatment with a CTLA-4 receptor blocking antibody after allogeneic HSCT
May cause fetal harm when administered to pregnant females
When used in combination with ipilimumab, refer to prescribing information for additional risk information that applies to the combination use treatment
In clinical trials in multiple myeloma patients, the addition of a PD-1 blocking antibody to a thalidomide analogue plus dexamethasone resulted in increased mortality
Immune-mediated adverse reactions
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, and immune-mediated nephritis and renal dysfunction; reactions may be severe or fatal; monitor for early identification and management; evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment
- Immune-mediated encephalitis can occur; withhold therapy in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out infectious or other causes of moderate to severe neurologic deterioration
- Other clinically significant and potentially fatal immune-mediated adverse reactions (eg, myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis) can occur after discontinuation
-
Immune-mediated endocrinopathies
- Immune-mediated hypophysitis; monitor
- Immune-mediated hypothyroidism and hyperthyroidism reported; monitor for changes in thyroid function and initiate thyroid hormone replacement as needed; administer hormone-replacement therapy for hypothyroidism; initiate medical management for control of hyperthyroidism
- Adrenal insufficiency may occur; monitor for signs and symptoms of adrenal insufficiency during and after treatment
- May cause type 1 diabetes mellitus; monitor for hyperglycemia
-
Immune-mediated skin reactions
- May cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN); for symptoms or signs of SJS or TEN, withhold therapy and refer patient for specialized care for assessment and treatment
- Immune-mediated rash reported in combination with ipilimumab; withhold for severe and permanently discontinue for life-threatening rash
-
Immune-mediated colitis
- Therapy can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology; common symptom in definition of colitis reported to be diarrhea
- Cytomegalovirus (CMV) infection/reactivation reported in patients with corticosteroid refractory immune-mediated colitis; in cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies
Pregnancy & Lactation
Pregnancy
Based on its mechanism of action and data from animal studies, fetal harm may occur when administered to a pregnant woman
There are no available human data informing the drug-associated risk
Animal data
- In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death
- Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus
- Effects of nivolumab are likely to be greater during the second and third trimesters of pregnancy
Contraception
- Females of reproductive potential: Verify pregnancy status prior to initiating therapy; use effective contraception during treatment with nivolumab and for at least 5 months following last dose of therapy
Lactation
Unknown if distributed in human breast milk; advise women to discontinue breastfeeding during treatment
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Monoclonal antibody to programmed cell death-1 protein (PD-1); blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2
PD-1 and PD-L1
- PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions; PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound
- This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation
- Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells
Absorption
Time to steady state: 12 wk (monotherapy)
Distribution
Vd: 6.8L (monotherapy); 7.92 L (combined with ipilimumab)
Elimination
Clearance: 8.2 mL/h (monotherapy); 10 mL/hr (combined with ipilimumab)
Half-life: 25 days (monotherapy); 24.8 days (combined with ipilimumab)
Administration
IV Preparation
Visually inspect drug for particulate matter and discoloration; it should be a clear to opalescent, colorless to pale-yellow solution
Discard vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles
Do not shake the vial
Admixture
- Withdraw required volume for calculated dose and transfer to an IV container
- Dilute with either 0.9% NaCl or D5W to a final concentration ranging from 1-10 mg/mL
- Total volume of infusion must not exceed 160 mL
- Mix diluted solution by gentle inversion; do NOT shake
- Discard partially used vials or empty vials
IV Administration
Infuse IV over 30-60 min in an IV line containing a sterile, nonpyrogenic, low protein-binding inline filter (pore size of 0.2-1.2 microns)
For adult and pediatric patients (<40 kg): Total volume of infusion must not exceed 4 mL/kg of body weigh
Do not coadminister other drugs through the same IV line
When administered in combination with ipilimumab, infuse nivolumab first followed by ipilimumab on the same day; use separate infusion bags and filters for each infusion
When administered in combination with chemotherapy on the same day, administer prior to chemotherapy
Flush the IV line at end of infusion
Storage
Does not contain preservatives
Unopened vials
- Refrigerate at 2-8°C (36-46°F)
- Protect from light by storing in the original package
- Do not freeze
Diluted admixture
- Room temperature: Store for up to 8 hr from time of preparation; this includes room temperature storage of the admixture in the IV container and time for administration of the infusion OR
- Refrigerate at 2-8°C (36-46°F) for no more than 24 hr from the time of admixture preparation
- Do not freeze
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Patient Handout
Formulary
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