nivolumab (Rx)

>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

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

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody; complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT; consider benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after allogeneic HSCT

In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies; addition of an alternative immunosuppressive agent to corticosteroid therapy, or replacement of corticosteroid therapy should be considered in corticosteroid-refractory immune-mediated colitis if other causes are excluded

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

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.

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)

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

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