Dosing and uses of Opdivo (nivolumab)
Adult dosage forms and strengths
IV solution
- 40mg/4mL (10mg/mL)
- 100mg/10mL (10mg/mL)
- Further dilution required before administration
Melanoma
Single agent
- Indicated as a single agent for BRAF V600 wildtype or mutation-positive unresectable or metastatic melanoma
- 240 mg IV q2wk infused over 1 hr
- 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 1 hr, followed by ipilimumab (3 mg/kg IV infused over 90 min) administer on the same day q3wk for 4 doses
- Subsequent doses of nivolumab as a single agent are 240 mg IV q2wk infused over 1 hr 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 q2wk infused over 1 hr
Continue until disease progression or unacceptable toxicity
Renal Cell Carcinoma (RCC)
Indicated for patients with advanced RCC who have received prior anti-angiogenic therapy
240 mg IV q2wk infused over 1 hr
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
3 mg/kg IV infused over 1 hr q2wk until disease progression or unacceptable toxicity
Dosage modifications
Hypothyroidism or hyperthyroidism: No recommended dose modifications
Renal impairment: No dosage modifications required
Mild hepatic impairment: No dosage modifications required
Moderate or severe hepatic impairment: Not studied
Note: When administered in combination with ipilimumab, if nivolumab is withheld, ipilimumab should also be withheld
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)
- AST or ALT >3-5 x ULN or total bilirubin >1.5-3 xULN
- 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
- Immune-mediated encephalitis
- Grade 4 rash or confirmed SJS or TEN
- AST or ALT >5 xULN or total bilirubin >3 xULN
- 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
Dosing Considerations
Melanoma
- Indications for melanoma (as a single agent or in combination) 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: https://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
Orphan Designations
Hepatocellular carcinoma
Glioblastoma
Small-cell lung cancer
Sponsor
- Bristol-Myers Squibb Company; P. O. Box 4000; Princeton, New Jersey 08543
Pediatric dosage forms and strengths
Safety and efficacy not established
Opdivo (nivolumab) adverse (side) 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
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
Colitis reported when used in combination with dacarbazine
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
Immune-mediated hypothyroidism and hyperthyroidism reported; monitor for changes in thyroid function and initiate thyroid hormone replacement as needed
Hypothyroidism reported when used in combination with dacarbazine
Adrenal insufficiency may occur; monitor for signs and symptoms of adrenal insufficiency during and after treatment
Hypophysitis may occur in combination with ipilimumaB
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 immune-mediated adverse reactions (eg, rash) can occur after therapy discontinuation
Immune mediated rash reported in combination with ipilimumab; withhold for severe and permanently discontinue for life-threatening rash
Severe infusion reactions reported (rare, <1%); discontinue if severe or life-threatening, interrupt or slow infusion rate if mild or moderate reaction
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
Pregnancy and lactation
Pregnancy category: 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 of Opdivo (nivolumab)
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
Pharmacokinetics
Time to steady state: 12 wk
Vd: 8 L
Half-life: 26.7 days
Clearance: 9.5 mL/hr
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 1 hr
Infuse IV over 1 hr 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: 4 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
