nivolumab (Rx)

Brand and Other Names:Opdivo
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

IV solution

  • 40mg/4mL (10mg/mL)
  • 100mg/10mL (10mg/mL)
  • Further dilution required before administration
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Melanoma

Single agent

  • Indicated as a single agent for BRAF V600 wildtype or BRAF V600 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

Indicated for patients with advanced renal cell carcinoma (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

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

3 mg/kg IV q2wk infused over 1 hr

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 q2wk infused over 1 hr

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 q2wk infused over 1 hr

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

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 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

Orphan Designations

Hepatocellular carcinoma

Glioblastoma

Small-cell lung cancer

Gastric cancer, including gastro-esophageal junction cancer

Sponsor

  • Bristol-Myers Squibb Company; P. O. Box 4000; Princeton, New Jersey 08543

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 1 hr
  • Continue until disease progression or unacceptable toxicity
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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
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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 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

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
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Pregnancy & 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.

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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)

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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
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Formulary

FormularyPatient Discounts

Adding plans allows you to compare formulary status to other drugs in the same class.

To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

Adding plans allows you to:

  • View the formulary and any restrictions for each plan.
  • Manage and view all your plans together – even plans in different states.
  • Compare formulary status to other drugs in the same class.
  • Access your plan list on any device – mobile or desktop.

The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

Tier Description
1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
NC NOT COVERED – Drugs that are not covered by the plan.
Code Definition
PA Prior Authorization
Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
QL Quantity Limits
Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
ST Step Therapy
Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
OR Other Restrictions
Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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