Dosing & Uses
Dosage Forms & Strengths
IV solution
- 40mg/4mL (10mg/mL)
- 100mg/10mL (10mg/mL)
- Further dilution required before administration
Adjuvant Melanoma
Indicated for adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection
240 mg IV q2Weeks or 480 mg IV q4Weeks over 30 min
Continue until disease progression or unacceptable toxicity for up to 1 year
Unresectable or Metastatic Melanoma
Single agent
- Indicated as a single agent for BRAF V600 wildtype or BRAF V600 mutation-positive unresectable or metastatic melanoma
- 240 mg IV q2Weeks or 480 mg IV q4Weeks infused over 30 min
- Continue until disease progression or unacceptable toxicity
Combination with ipilimumab
- Indicated in combination with ipilimumab for treatment of patients with BRAF unresectable or metastatic melanoma
- 1 mg/kg IV infused over 30 min, followed by ipilimumab (3 mg/kg IV infused over 90 min) administer on the same day q3Weeks for 4 doses
- Subsequent doses of nivolumab as a single agent are 240 mg IV q2Weeks or 480 mg IV q4Weeks infused over 30 min until disease progression or unacceptable toxicity
Non-Small Cell Lung Cancer
Indicated for metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy
Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab
240 mg IV q2Weeks or 480 mg IV q4Weeks infused over 30 min
Continue until disease progression or unacceptable toxicity
Renal Cell Carcinoma
Single agent
- Indicated as a single agent for patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy
- 240 mg IV q2Weeks or 480 mg IV q4Weeks infused over 30 min
- Continue until disease progression or unacceptable toxicity
Combination with ipilimumab
- Indicated in combination with ipilimumab for patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma
- 3 mg/kg IV infused over 30 min, followed by ipilimumab 1 mg/kg IV infused over 30 min on the same day; repeat every 3 weeks for 4 doses
- After completing 4 doses of the combination
- Administer nivolumab as a single agent, either:
- 240 mg IV q2Weeks or 480 mg IV q4Weeks infused over 30 min
- Continue until disease progression or unacceptable toxicity
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
240 mg IV or 480 mg IV q4Weeks infused over 30 min q2Weeks
Continue until disease progression or unacceptable toxicity
Head & Neck Cancer
Indicated for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after a platinum-based therapy
240 mg IV q2Weeks or 480 mg IV q4Weeks infused over 30 min
Continue until disease progression or unacceptable toxicity
Urothelial Carcinoma
Indicated for locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
240 mg IV q2Weeks or 480 mg IV q4Weeks infused over 30 min
Continue until disease progression or unacceptable toxicity
Microsatellite Instability-High Cancer
Indicated for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer which progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan
240 mg IV q2Weeks infused over 30 min
Continue until disease progression or unacceptable toxicity
Hepatocellular Carcinoma
Indicated for hepatocellular carcinoma (HCC) in patients previously treated with sorafenib
240 mg IV q2Weeks or 480 mg IV q4Weeks infused over 30 min
Continue until disease progression or unacceptable toxicity
Dosage Modifications
Infusion reactions: Interrupt or slow infusion rate with mild or moderate reactions; discontinue if severe or life-threatening infusion reactions occur
Hypothyroidism or hyperthyroidism: No recommended dose modifications
Renal impairment: No dosage modifications required
Note: When administered in combination with ipilimumab, if nivolumab is withheld, ipilimumab should also be withheld
Hepatic impairment
- Mild or moderate: No dosage modifications required
- Severe: Not studied
Withhold for any of the following
- Grade 2 pneumonitis
- Grade 2 diarrhea or colitis
- Grade 3 diarrhea or colitis (single-agent nivolumab)
- Grade 2 or 3 hypophysitis
- Grade 2 adrenal insufficiency
- Grade 3 hyperglycemia
- Encephalitis, new-onset moderate or severe neurologic signs or symptoms
- Grade 3 rash or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)
- Serum creatinine >1.5-6 xULN or >1.5 times baseline
- Any other severe or grade 3 treatment-related adverse reaction
- May resume treatment for patients whose adverse reactions recover to grade 0-1
Permanently discontinue for any of the following
- Any life-threatening or grade 4 adverse reactions
- Grade 3 or 4 pneumonitis
- Grade 3 diarrhea or colitis (nivolumab in combination with ipilimumab)
- Grade 4 diarrhea or colitis
- Grade 4 hypophysitis
- Grade 3 or 4 adrenal insufficiency
- Grade 4 hyperglycemia
- Grade 3 myocarditis
- Immune-mediated encephalitis
- Grade 4 rash or confirmed SJS or TEN
- Serum creatinine >6 xULN
- Any severe or grade 3 treatment-related adverse reaction that recurs
- Inability to reduce corticosteroid dose to ≤10 mg/day of prednisone or equivalent within 12 weeks
- Persistent grade 2 or 3 treatment-related adverse reactions that do not recover to grade 0-1 within 12 weeks after the last dose
Hepatitis/non-HCC
- AST or ALT >3 to 5x ULN, or total bilirubin >1.5 to 3xULN: Withhold dose
- AST or ALT >5x ULN or total bilirubin >3x ULN: Permanently discontinue
Hepatitis/HCC
- AST or ALT within normal limits at baseline and increases to >3 to 5x ULN: Withhold dose
- AST or ALT >1 to 3x ULN at baseline and increases to >5 to 10x ULN: Withhold dose
- AST or ALT >3 to 5x ULN at baseline and increases to >8 to 10x ULN: Withhold dose
- AST or ALT increases to >10x ULN or total bilirubin increases to >3x ULN: Permanently discontinue
Dosing Considerations
Melanoma
- Indications for unresectable or metastatic melanoma (as a single agent for BRAF V600 mutation-positive or in combination with ipilimumab) were approved under an accelerated approval based on tumor response rate and durability of response; continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials
- Information on FDA-approved tests for detection of PD-L1 expression in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics
cHL
- Indication for cHL approved under accelerated approval based on overall response rate
- Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials
Urothelial carcinoma
- Indication for urothelial carcinoma was approved under accelerated approval based on tumor response rate and duration of response
- Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials
MSI-H or dMMR mCRC
- Indication for MSI-H or dMMR mCRC was approved under accelerated approval based on tumor response rate and duration of response
- Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials
HCC
- Indication for HCC was approved under accelerated approval based on tumor response rate and durability of response
- Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials
Orphan Designations
Glioblastoma
Small-cell lung cancer
Gastric cancer, including gastro-esophageal junction cancer
Anal cancer
Mesothelioma (with and without ipilimumab)
Sponsor
- Bristol-Myers Squibb Company; P. O. Box 4000; Princeton, New Jersey 08543
Dosage Forms & Strengths
IV solution
- 40mg/4mL (10mg/mL)
- 100mg/10mL (10mg/mL)
- Further dilution required before administration
Microsatellite Instability-High Cancer
Indicated for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer which progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan in adults and adolescents aged ≥12 yr
<12 years: Safety and efficacy not established
≥12 year
- 240 mg IV q2wk infused over 30 min
- Continue until disease progression or unacceptable toxicity
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%), anemia (28%), constipation (24%)
- 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%), pruritus (11%)
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
Warnings
Contraindications
None
Cautions
Immune-mediated pneumonitis may occur; withhold for moderate and permanently discontinue for severe or life-threatening pneumonitis
Immune-mediated colitis reported; withhold for moderate or severe and permanently discontinue for life-threatening colitis
Immune-mediated hepatitis observed in clinical trials; monitor for changes in liver function; withhold for moderate and permanently discontinue for severe or life-threatening transaminase or total bilirubin elevation
Immune-mediated nephritis and renal dysfunction may occur; monitor for changes in renal function; withhold for moderate and permanently discontinue for severe or life-threatening serum creatinine elevation; withhold therapy for moderate (Grade 2) or severe (Grade 3) increased serum creatinine; permanently discontinue therapy for life-threatening (Grade 4) increased serum creatinine
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; evaluation may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture; if other etiologies ruled out, administer corticosteroids at a dose of 1 - 2 mg/kg/day prednisone equivalents for patients with immune-mediated encephalitis, followed by corticosteroid taper; permanently discontinue therapy for immune-mediated encephalitis
Other clinically significant and potentially fatal immune-mediated adverse reactions (eg, myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis) can occur after therapy discontinuation
Severe infusion reactions reported (rare, <1%); discontinue if severe or life-threatening; interrupt or slow rate of infusion in patients with mild or moderate infusion reactions
Can cause fetal harm; advise of potential risk to a fetus and use of effective contraception (see Pregnancy and Lactation)
Monitor for hyperacute graft-versus-host-disease (GVHD), grade 3-4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions; transplant-related mortality has occurred
If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt- Koyanagi-Harada-like syndrome, which has been observed in patients receiving drug alone or in combination with ipilimumab, which may require treatment with systemic steroids to reduce risk of permanent vision loss
Immune-mediated endocrinopathies
- Immune-mediated hypophysitis; monitor; withhold therapy for moderate (Grade 2) or severe (Grade 3); permanently discontinue therapy for life-threatening (Grade 4
- 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, withhold if severe (Grade 3) hyperglycemia until metabolic control is achieved, permanently discontinue if life-threatening (Grade 4) 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; if SJS or TEN is confirmed, permanently discontinue therapy; for immune-mediated rash, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by a corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) rash
- Immune mediated rash reported in combination with ipilimumab; withhold for severe and permanently discontinue for life-threatening rash
Pregnancy & Lactation
Pregnancy
Based on its mechanism of action and data from animal studies, can cause fetal harm when administered to a pregnant woman; advise females of reproductive potential to use effective contraception during treatment and for at least 5 months following the last dose
In animal reproduction studies, administration 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 IgG4; therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus
The effects of nivolumab are likely to be greater during the second and third trimesters of pregnancy; there are no available human data informing the drug-associated risk
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
- 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)
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
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: 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
Images
Patient Handout
Formulary
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