Nivolumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Opdivo: 40 mg/4 mL (4 mL); 100 mg/10 mL (10 mL); 240 mg/24 mL (24 mL) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor to block the ligands PD-L1 and PD-L2 from binding. The negative PD-1 receptor signaling that regulates T-cell activation and proliferation is therefore disrupted (Robert 2015). This releases PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.

Combining nivolumab (anti-PD-1) with ipilimumab (anti-CTLA-4) results in enhanced T-cell function that is greater than that of either antibody alone, resulting in improved anti-tumor responses in metastatic melanoma and advanced renal cell carcinoma.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 6.8 L; the predicted exposure after a 30-minute infusion is comparable to that seen with a 60-minute infusion.

Excretion

Clearance (geometric mean at steady state): 8.2 mL/hour

Half-Life Elimination

~25 days

Use: Labeled Indications

Colorectal cancer, metastatic (microsatellite instability high or mismatch repair deficient): Treatment (as a single agent or in combination with ipilimumab) of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) in adults and pediatric patients 12 years and older that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Head and neck cancer, squamous cell (recurrent or metastatic): Treatment of recurrent or metastatic squamous cell carcinoma of the head and neck in patients with disease progression on or after platinum-based therapy.

Hepatocellular carcinoma: Treatment of hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib.

Hodgkin lymphoma, classical: Treatment of classical Hodgkin lymphoma (cHL) in adult patients that have relapsed or progressed following autologous hematopoietic stem cell transplant (HSCT) and brentuximab vedotin, or after 3 or more lines of systemic therapy that included autologous HSCT.

Melanoma:

Adjuvant treatment of melanoma with involvement of lymph nodes or metastatic disease following complete resection

Treatment of unresectable or metastatic melanoma (either as a single agent or in combination with ipilimumab)

Non-small cell lung cancer, metastatic, progressive: Treatment of metastatic non-small cell lung cancer (NSCLC) that has progressed on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression (on approved EGFR- or ALK-directed therapy) prior to receiving nivolumab.

Renal cell cancer, advanced:

Treatment (as a single agent) of advanced renal cell cancer (RCC) in patients who have received prior anti-angiogenic therapy

Treatment of intermediate or poor risk, previously untreated advanced RCC (in combination with ipilimumab)

Small cell lung cancer, metastatic: Treatment of metastatic small cell lung cancer (SCLC) in patients with progression after platinum-based chemotherapy and at least one other line of therapy.

Urothelial carcinoma, locally advanced or metastatic: Treatment of locally advanced or metastatic urothelial carcinoma in patients with disease progression during or following a platinum-containing therapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing therapy.

Use: Off Label

Melanoma, metastatic with brain metastasesb

Data from an open-label, multicenter, phase 2 trial support the use of nivolumab (in combination with ipilimumab) in the treatment of patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis and no neurologic symptoms Tawbi 2018.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to nivolumab or any component of the formulation.

Dosage and Administration

Dosing: Adult

Colorectal cancer, metastatic (microsatellite instability-high or mismatch repair deficient; single agent): IV: 240 mg (flat dose) once every 2 weeks or 480 mg (flat dose) once every 4 weeks until disease progression or unacceptable toxicity.

Off-label dosing: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Overman 2017)

Colorectal cancer, metastatic (microsatellite instability-high or mismatch repair deficient; combination therapy): IV: 3 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by nivolumab monotherapy at 240 mg (flat dose) once every 2 weeks or 480 mg (flat dose) once every 4 weeks until disease progression or unacceptable toxicity. Note: If nivolumab therapy is withheld, ipilimumab should also be withheld.

Off-label dosing: 3 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by 3 mg/kg once every 2 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity (Overman 2018).

Head and neck cancer, squamous cell, recurrent or metastatic: IV: 240 mg (flat dose) once every 2 weeks or 480 mg (flat dose) once every 4 weeks until disease progression or unacceptable toxicity

Off-label dosing: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Ferris 2016)

Hepatocellular carcinoma: IV: 240 mg (flat dose) once every 2 weeks or 480 mg (flat dose) once every 4 weeks until disease progression or unacceptable toxicity

Off-label dosing: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (El-Khoueiry 2017)

Hodgkin lymphoma, classical: IV: 240 mg (flat dose) once every 2 weeks or 480 mg (flat dose) once every 4 weeks until disease progression or unacceptable toxicity

Off-label dosing: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Ansell 2015; Younes 2016)

Melanoma, adjuvant treatment: IV: 240 mg (flat dose) once every 2 weeks or 480 mg (flat dose) once every 4 weeks until disease recurrence or unacceptable toxicity for up to 1 year

Off-label dosing: 3 mg/kg once every 2 weeks until disease recurrence or unacceptable toxicity for up to 1 year (Weber 2017)

Melanoma, metastatic with brain metastases (off-label use): IV: 1 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by 3 mg/kg once every 2 weeks (nivolumab monotherapy); total duration of nivolumab therapy is up to 24 months, or until disease progression or unacceptable toxicity (Tawbi 2018)

Melanoma, unresectable or metastatic, single-agent therapy: IV: 240 mg (flat dose) once every 2 weeks or 480 mg (flat dose) once every 4 weeks until disease progression or unacceptable toxicity

Off-label dosing: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Robert 2015; Weber 2015)

Melanoma, unresectable or metastatic, combination therapy: IV: 1 mg/kg once every 3 weeks (in combination with ipilimumab) for a maximum of 4 combination doses or until unacceptable toxicity (whichever occurs earlier), followed by 240 mg (flat dose) once every 2 weeks or 480 mg (flat dose) once every 4 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity. Note: If nivolumab therapy is withheld, ipilimumab should also be withheld.

Off-label dosing: 1 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by 3 mg/kg once every 2 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity (Larkin 2015; Wolchok 2017) or (alternative strategy [based on limited data]; may decrease toxicity in patients who experienced severe toxicity) 3 mg/kg once every 3 weeks (in combination with reduced-dose ipilimumab) for 4 combination doses, followed 6 weeks later by 480 mg (flat dose) once every 4 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity (Lebbé 2019).

Non-small cell lung cancer, metastatic, progressive: IV: 240 mg (flat dose) once every 2 weeks or 480 mg (flat dose) once every 4 weeks until disease progression or unacceptable toxicity

Off-label dosing: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Borghaei 2015; Brahmer 2015)

Renal cell cancer, advanced (previously treated): IV: 240 mg (flat dose) once every 2 weeks or 480 mg (flat dose) once every 4 weeks (as a single agent) until disease progression or unacceptable toxicity

Off-label dosing: 3 mg/kg once every 2 weeks (as a single agent) until disease progression or unacceptable toxicity (Motzer 2015)

Renal cell cancer, advanced (previously untreated; intermediate or poor risk), combination therapy: IV: 3 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by 240 mg (flat dose) once every 2 weeks or 480 mg (flat dose) once every 4 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity. Note: If nivolumab therapy is withheld, ipilimumab should also be withheld.

Off-label dosing: 3 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by 3 mg/kg once every 2 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity (Motzer 2018).

Small cell lung cancer, metastatic: IV: 240 mg (flat dose) once every 2 weeks until disease progression or unacceptable toxicity

Off-label dosing:

Single agent: IV: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Antonia 2016)

Combination therapy: IV: 1 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 combination doses, followed by 3 mg/kg once every 2 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity (Antonia 2016)

Urothelial carcinoma (locally advanced or metastatic): IV: 240 mg (flat dose) once every 2 weeks or 480 mg (flat dose) once every 4 weeks until disease progression or unacceptable toxicity

Off-label dosing: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Sharma 2017)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Colorectal cancer (CRC), metastatic (microsatellite instability-high or mismatch repair deficient): Note: FDA approval is through an accelerated process; continued approval is dependent upon verification of clinical benefit in further trials.

Single agent therapy: Children ≥12 years and Adolescents: IV:

<40 kg: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity.

≥40 kg: 240 mg once every 2 weeks or 480 mg once every 4 weeks until disease progression or unacceptable toxicity.

Combination therapy with ipilimumab: Children ≥12 years and Adolescents: IV:

<40 kg: 3 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 doses (or less if unacceptable toxicity occurs); followed by 3 mg/kg once every 2 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity. Note: If nivolumab therapy is withheld, ipilimumab should also be withheld.

≥40 kg: 3 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 doses (or less if unacceptable toxicity occurs); followed by 240 mg once every 2 weeks or 480 mg once every 4 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity. Note: If nivolumab therapy is withheld, ipilimumab should also be withheld.

Dosing adjustment for toxicity: Children ≥12 years and Adolescents:

Withhold treatment for any of the following; may resume treatment upon recovery to grade 0 or 1 toxicity: Note: If receiving combination therapy with ipilimumab, when nivolumab is withheld, ipilimumab should also be withheld. Refer to ipilimumab monograph for information on ipilimumab dosage adjustment for toxicity.

Adrenal insufficiency (grade 2)

Colitis:

Grade 2 colitis or diarrhea; for grade 2 colitis with a duration >5 days, also administer systemic corticosteroids (prednisone 0.5 to 1 mg/kg/day or equivalent) followed by a corticosteroid taper; may increase to prednisone 1 to 2 mg/kg/day (or equivalent) if colitis worsens or does not improve despite corticosteroid use

Grade 3 colitis or diarrhea (single-agent nivolumab); also administer systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) followed by a corticosteroid taper

Diabetes mellitus, type 1 (grade 3 hyperglycemia)

Encephalitis (new onset moderate or severe neurologic toxicity)

Hypophysitis (grade 2 or 3); also administer high-dose systemic corticosteroids (prednisone 1 mg/kg/day or equivalent)

Pneumonitis (grade 2); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) followed by a corticosteroid taper

Rash (grade 3), suspected Stevens-Johnson syndrome or toxic epidermal necrolysis; also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent)

Other immune-mediated toxicities; also administer high-dose systemic corticosteroids followed by a corticosteroid taper (upon improvement to grade 1 or lower) over at least 1 month

Other treatment-related toxicity (severe or grade 3, first occurrence)

Permanently discontinue for:

Adrenal insufficiency (grade 3 or 4); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent)

Colitis or diarrhea (grade 3, if in combination with ipilimumab) or colitis or diarrhea (grade 4); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) followed by a corticosteroid taper

Colitis (recurrent)

Diabetes mellitus, type 1 (grade 4 hyperglycemia)

Encephalitis (immune mediated); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) followed by a corticosteroid taper

Hypophysitis (grade 4); also administer high-dose systemic corticosteroids (prednisone 1 mg/kg/day or equivalent)

Myocarditis (grade 3); also administer high-dose systemic corticosteroids followed by a corticosteroid taper (upon improvement to grade 1 or lower) over at least 1 month

Pneumonitis (grade 3 or 4); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) followed by a corticosteroid taper

Rash (grade 4), or confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis; also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent)

Any toxicity requiring corticosteroid dose of prednisone ≥10 mg/day (or equivalent) for longer than 12 weeks

Other adverse reactions that are life-threatening or grade 4, severe or grade 3 adverse reactions that recur, or persistent grade 2 or 3 treatment-related toxicity that lasts beyond 12 weeks

Infusion-related reaction:

Mild or moderate reaction: Interrupt or slow the infusion rate

Severe or life-threatening reaction: Discontinue

Thyroid disorder (hyperthyroidism or hypothyroidism): There are no recommended dosage modifications. Initiate antithyroid therapy for hyperthyroidism; administer thyroid hormone replacement therapy for hypothyroidism.

Dosing: Adjustment for Toxicity

Withhold treatment for any of the following (may resume upon recovery to grade 0 or 1 toxicity):

Note: If receiving combination therapy with ipilimumab, when nivolumab is withheld, ipilimumab should also be withheld. Refer to ipilimumab monograph for information on ipilimumab dosage adjustment for toxicity.

Adrenal insufficiency (grade 2)

Colitis:

Grade 2 colitis or diarrhea; for grade 2 colitis with a duration >5 days; also administer systemic corticosteroids (prednisone 0.5 to 1 mg/kg daily or equivalent) followed by a corticosteroid taper; may increase to prednisone 1 to 2 mg/kg daily (or equivalent) if colitis worsens or does not improve despite corticosteroid use

Grade 3 colitis or diarrhea (single-agent nivolumab); also administer systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper

Diabetes mellitus, type 1 (grade 3 hyperglycemia)

Encephalitis (new-onset moderate or severe neurologic toxicity)

Hypophysitis (grade 2 or 3); also administer high-dose systemic corticosteroids (prednisone 1 mg/kg daily or equivalent)

Pneumonitis (grade 2); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper

Rash (grade 3), suspected Stevens-Johnson syndrome or toxic epidermal necrolysis; also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent)

Other immune-mediated toxicities; also administer high-dose systemic corticosteroids followed by a corticosteroid taper (upon improvement to grade 1 or lower) over at least 1 month

Other treatment-related toxicity (severe or grade 3, first occurrence)

Permanently discontinue for:

Adrenal insufficiency (grade 3 or 4); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper

Colitis or diarrhea (grade 3, if in combination with ipilimumab) or colitis or diarrhea (grade 4); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper

Colitis (recurrent)

Diabetes mellitus, type 1 (grade 4 hyperglycemia)

Encephalitis (immune mediated); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper

Hypophysitis (grade 4); also administer high-dose systemic corticosteroids (prednisone 1 mg/kg daily or equivalent)

Myocarditis (grade 3); also administer high-dose systemic corticosteroids followed by a corticosteroid taper (upon improvement to grade 1 or lower) over at least 1 month

Pneumonitis (grade 3 or 4); also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper

Rash (grade 4), or confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis; also administer high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent)

Any toxicity requiring corticosteroid dose of prednisone ≥10 mg/day (or equivalent) for longer than 12 weeks.

Other adverse reactions that are life-threatening or grade 4, severe or grade 3 adverse reactions that recur, or persistent grade 2 or 3 treatment-related toxicity that lasts beyond 12 weeks.

Infusion-related reaction:

Mild or moderate reaction: Interrupt or slow the infusion rate

Severe or life-threatening reaction: Discontinue

Thyroid disorder (hyperthyroidism or hypothyroidism):

There are no recommended dosage modifications. Initiate antithyroid therapy for hyperthyroidism; administer thyroid hormone replacement therapy for hypothyroidism.

Reconstitution

Withdraw the required volume and transfer into an IV container. Dilute with either NS or D5W to a final concentration of 1 to 10 mg/mL; the total volume of infusion must not exceed 160 mL for patients ≥40 kg (or 4 mL/kg for patients <40 kg). Mix by gentle inversion; do not shake.

Administration

IV: Administer as an IV infusion over 30 minutes. Refer to protocol for infusion rates in off-label dosing. Infuse through a line with a sterile, nonpyrogenic, low protein binding 0.2 to 1.2 micrometer in-line filter. Do not administer other medications through the same IV line. Flush IV line at the end of the infusion.

Combination therapy with ipilimumab: When administered in combination with ipilimumab, administer nivolumab first followed by ipilimumab on the same day. Use separate infusion bags and filters for each infusion. If nivolumab therapy is withheld, ipilimumab should also be withheld.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Do not shake. After preparation in NS or D5W, store the diluted infusion solution at room temperature for no more than 8 hours (including infusion time) or refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours (including infusion time). Infusion must be completed within 8 hours of preparation (if stored at room temperature) or 24 hours of preparation (if refrigerated). Do not freeze solutions prepared for infusion.

Drug Interactions

Immunosuppressants: May diminish the therapeutic effect of Nivolumab. Consider therapy modification

Adverse Reactions

Incidence of adverse reactions includes unapproved dosing regimens.

>10%:

Cardiovascular: Edema (≤13%), peripheral edema (≤13%), hypertension (11%)

Central nervous system: Fatigue (≤59%), malaise (≤46%), headache (16% to 23%), dizziness (≤14%), peripheral neuropathy (≤14%; grade 3: <1%)

Dermatologic: Skin rash (1% to 40%; immune-mediated: 9% to 16%), pruritus (10% to 28%), vitiligo (≤11%)

Endocrine & metabolic: Hyperglycemia (19% to 46%), hyponatremia (19% to 41%), increased serum triglycerides (32%), hyperkalemia (11% to 30%), increased thyroid stimulating hormone level (≥10% to 26%), hypocalcemia (10% to 26%), increased serum cholesterol (21%), hypercalcemia (2% to 19%), thyroiditis (≤12% to 18%; including immune-mediated events), hypomagnesemia (14% to 17%), hypokalemia (14% to 16%), thyroid dysfunction (15%), hypothyroidism (≤12%; including immune-mediated events)

Gastrointestinal: Diarrhea (1% to 43%), nausea (20% to 34%), abdominal pain (13% to 34%), increased serum lipase (20% to 33%), decreased appetite (14% to 28%), vomiting (12% to 28%), constipation (10% to 23%), increased serum amylase (13% to 19%)

Genitourinary: Urinary tract infection (2% to 17%)

Hematologic & oncologic: Anemia (26% to 50%; grades 3/4: 3% to 8%), lymphocytopenia (27% to 42%; grades 3/4: ≤11%), leukopenia (11% to 38%; grades 3/4: ≤5%), thrombocytopenia (15% to 37%; grades 3/4: 1% to 3%), neutropenia (13% to 37%; grades 3/4: 4% to 5%)

Hepatic: Increased serum alkaline phosphatase (10% to 37%), increased serum aspartate aminotransferase (22% to 33%), increased serum alanine aminotransferase (23% to 32%), increased serum bilirubin (11% to 14%)

Immunologic: Graft versus host disease (20%; within 14 days of stem cell infusion), antibody development (11%; neutralizing: <1%)

Neuromuscular & skeletal: Asthenia (≤57%), musculoskeletal pain (20% to 42%), back pain (21%), arthralgia (10% to 21%)

Renal: Increased serum creatinine (12% to 42%)

Respiratory: Upper respiratory tract infection (2% to 44%), cough (≤36%), productive cough (≤36%), dyspnea (≤27%), dyspnea on exertion (≤27%), bronchopneumonia (≤13%), pneumonia (≤13%), nasal congestion (11%)

Miscellaneous: Febrile reaction (35%; events without an infectious cause that required steroids), fever (≤29%; may include tumor-associated fever), infusion-related reaction (≤14%)

1% to 10%:

Cardiovascular: Pulmonary embolism (2% to 3%)

Central nervous system: Neuritis (<10%), peripheral nerve palsy (peroneal: <10%), insomnia (9%)

Dermatologic: Erythema of skin (10%), xeroderma (7%)

Endocrine & metabolic: Weight loss (7% to 8%), hyperthyroidism (3% to 6%; including immune-mediated events), adrenocortical insufficiency (1%; including immune-mediated events), increased gamma-glutamyl transferase

Gastrointestinal: Intestinal perforation (<10%), stomatitis (<10%), colitis (including immune-mediated events: ≤6%)

Hepatic: Hepatitis (immune-mediated: 2% to 3%)

Immunologic: Sjogren's syndrome (<10%)

Infection: Sepsis (≥2%, systemic inflammatory response)

Neuromuscular & skeletal: Myopathy (<10%), rheumatism (spondyloarthropathy: <10%)

Renal: Acute renal failure (≥2%), nephritis (≤1%; immune-mediated), renal insufficiency (≤1%; immune-mediated)

Respiratory: Interstitial pulmonary disease (6%), pneumonitis (≤6%; including immune-mediated events), pleural effusion (1% to 5%), respiratory failure (≥2%)

Frequency not defined:

Central nervous system: Migraine

Dermatologic: Acneiform eruption, bullous dermatitis, dermatitis, erythematous rash, exfoliative dermatitis, maculopapular rash, morbilliform rash, palmar-plantar erythrodysesthesia, psoriasiform eruption, pustular rash, Stevens-Johnson syndrome, toxic epidermal necrolysis

Endocrine & metabolic: Dehydration

Gastrointestinal: Abdominal distress

Neuromuscular & skeletal: Limb pain

<1%, postmarketing, and/or case reports: Demyelinating disease (immune-mediated), diabetic ketoacidosis, duodenitis (immune-mediated), encephalitis (limbic/lymphocytic/viral; may be immune-mediated), facial nerve paralysis (immune-mediated), gastritis (immune-mediated), Guillain-Barré syndrome, hepatic sinusoidal obstruction syndrome, hypophysitis (including immune-mediated events), immunological signs and symptoms (hemophagocytic lymphohistiocytosis) (Hantel 2018), iritis (immune-mediated), lymphadenitis (immune-mediated; histiocytic necrotizing lymphadenitis [Kikuchi lymphadenitis]), motor dysfunction (immune-mediated), myasthenia (myasthenic syndrome), myocarditis (immune-mediated), myositis (immune-mediated), neuropathy (autoimmune; immune-mediated), pancreatitis (immune-mediated), pituitary insufficiency (immune-mediated), pneumonia due to Pneumocystis jirovecii, polymyalgia rheumatica (immune-mediated), rhabdomyolysis (immune-mediated), sarcoidosis (immune-mediated), sixth nerve palsy (abducens nerve palsy; immune-mediated), subacute cutaneous lupus erythematosus (Zitouni 2019), type I diabetes mellitus (immune-mediated event), uveitis (immune-mediated), vasculitis, Vogt-Koyanagi-Harada syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal insufficiency: Adrenal insufficiency may occur; may require hormone replacement therapy and/or corticosteroid therapy. The median time to onset across several clinical trials was 3 to 4.3 months (range: 15 days to 22.3 months). In studies, the median duration of high-dose systemic corticosteroid therapy was 9 to 12 days (range: 1 day to 5.6 months). Monitor for signs/symptoms of adrenal insufficiency both during and after treatment. Administer corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent followed by a taper) for severe (grade 3) or life-threatening (grade 4) adrenal insufficiency. Withhold nivolumab for moderate (grade 2) and permanently discontinue for severe (grade 3) or life-threatening (grade 4) toxicity.
• Dermatologic toxicity: Immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been observed in patients receiving nivolumab; some cases have been fatal. The median time to onset of immune-mediated rash ranged was 18 days to 2.8 months (range: <1 day to 25.8 months) after nivolumab initiation. Withhold treatment for signs or symptoms of SJS or TEN and refer to specialist for assessment and treatment; discontinue permanently if confirmed. Withhold treatment for grade 3 rash and permanently discontinue for life-threatening (grade 4) rash and administer corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent followed by a taper) for severe (grade 3) or life-threatening (grade 4) immune-mediated rash. High-dose systemic corticosteroids (followed by a corticosteroid taper) were administered to some patients for a median duration of 12 to 22 days (range: 1 day to 23 months); topical corticosteroids were also used to manage dermatologic toxicity. Complete resolution occurred in nearly half to two-thirds of patients; some patients experienced recurrence with rechallenge.
• Diabetes mellitus: Type 1 diabetes mellitus may occur, including cases of diabetic ketoacidosis. The median time to onset was 2.5 to 4.4 months (range: 15 days to 22 months). Monitor for hyperglycemia. Withhold nivolumab for severe (grade 3) hyperglycemia until blood sugar has been appropriately controlled. Permanently discontinue for life-threatening (grade 4) hyperglycemia.
• Encephalitis: Immune-mediated encephalitis (without clear etiology) may occur. In studies, encephalitis occurred after 15 days to 7.2 months of exposure. Fatal limbic encephalitis has been reported (case report). Withhold nivolumab for new-onset moderate to severe neurologic signs/symptoms; evaluate to rule out other neurologic causes or infection. Evaluate with neurology consultation, brain MRI, and lumbar puncture. For confirmed immune-mediated encephalitis felt to be caused by nivolumab (if other etiologies are ruled out), administer corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent), followed by a corticosteroid taper. Permanently discontinue nivolumab if immune-mediated encephalitis occurs. Rarely, infliximab was required for management of encephalitis (in addition to systemic corticosteroids).
• GI toxicity: Diarrhea or colitis occurred commonly in patients receiving nivolumab (some cases were fatal). Immune-mediated colitis (defined as no other clear etiology and requiring corticosteroid use), including cases of grades 2 and 3 colitis, occurred in some patients. The median time to onset of colitis was 1.6 to 5.3 months (range: 2 days to 21 months) from nivolumab initiation; some cases developed after nivolumab was discontinued for other reasons. In studies, the median duration of high-dose systemic corticosteroid therapy was 21 days to 1.1 months (range: 1 day to 27 months). Most patients with grade 2 or 3 immune-related colitis had complete resolution (improvement to grade 0); after resolution, nivolumab was reinitiated in some patients without recurrence, although was permanently discontinued in other patients. Monitor for signs and symptoms of colitis. May require treatment interruption, corticosteroid therapy, and/or permanent discontinuation. Severe colitis (grade 3) or life-threatening colitis (grade 4) should be managed with corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. Moderate colitis (grade 2) of >5 days duration should be managed with corticosteroids (prednisone 0.5 to 1 mg/kg daily or equivalent) followed by a corticosteroid taper; may increase to prednisone 1 to 2 mg/kg daily (or equivalent) if colitis worsens or does not improve despite corticosteroid therapy. Some cases required the addition of infliximab to corticosteroid therapy. Permanently discontinue nivolumab for grade 4 colitis or diarrhea, colitis that recurs upon reinitiation (single-agent therapy), severe or life-threatening colitis (grade 3 or 4), or for colitis that recurs upon reinitiation (in combination with ipilimumab). Corticosteroid-refractory, immune-mediated colitis has been reported. Cytomegalovirus infection/reactivation has been reported in patients who develop corticosteroid-refractory, immune-mediated colitis; if corticosteroid-refractory colitis develops, consider repeat infection workup to exclude other etiologies. If other causes have been excluded, consider addition of an alternative immunosuppressive agent to corticosteroid therapy or replacement of the corticosteroid therapy in corticosteroid-refractory, immune-mediated colitis.
• Hepatotoxicity: ALT, AST, alkaline phosphatase, and total bilirubin elevations have occurred in nivolumab-treated patients. Immune-mediated hepatitis (defined as no other clear etiology and requiring corticosteroid use) occurred in patients receiving nivolumab; most cases included grade 2 and grade 3 hepatitis, although grade 4 toxicity also occurred. The median time to onset was 2 to 3.3 months (range: 6 days to 27 months) after nivolumab initiation. Immune-mediated hepatitis was managed with high-dose systemic corticosteroids; in some cases, mycophenolate was added to corticosteroid therapy. In studies, the median duration of high-dose systemic corticosteroid therapy was 23 days to 1.1 months (range: 1 day to 13.2 months). Immune-mediated hepatitis resolved and did not recur with continued corticosteroid use in some patients, although some patients experienced recurrence and permanently discontinued treatment. When used in combination with ipilimumab, a majority of patients had complete resolution of hepatitis after completion of steroid therapy, and some patients had recurrence or worsening hepatitis when nivolumab and ipilimumab were restarted. Monitor liver function at baseline and periodically for changes. In patients without hepatocellular carcinoma (HCC), initiate corticosteroids (prednisone 0.5 to 1 mg/kg daily or equivalent for grade 2 or prednisone 1 to 2 mg/kg daily or equivalent followed by a corticosteroid taper for grade 3 or 4) transaminase elevations (with or without total bilirubin elevations). Withhold treatment for moderate (grade 2) immune-mediated hepatitis; permanently discontinue for severe (grade 3) or life-threatening (grade 4) immune-mediated hepatitis. In patients with HCC, administer corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent followed by a taper) when nivolumab is withheld or discontinued due to immune-mediated hepatitis. Permanently discontinue, withhold, or continue nivolumab based on the severity of immune-mediated hepatitis as well as transaminase levels or changes from baseline transaminase levels.
• Hypophysitis: Hypophysitis may occur; some patients developed grades 1, 2, or 3 toxicity. Most patients received corticosteroids; combination therapy was restarted for the majority of the patients without worsening hypophysitis (several patients continued on corticosteroid therapy). The median time to onset was 2.7 to 4.9 months (range: from 27 days to 11 months). Monitor for signs/symptoms of hypophysitis. Administer hormone replacement therapy as clinically indicated and corticosteroids (prednisone 1 mg/kg/day or equivalent followed by a taper) for ≥ grade 2 toxicity. In studies, the median duration of high-dose systemic corticosteroid therapy was 13 to 19 days (range: 1 day to 2 months). Withhold nivolumab for moderate (grade 2) or severe (grade 3) and permanently discontinue treatment for life-threatening (grade 4) hypophysitis.
• Infusion-related reactions: Infusion-related reactions have occurred with both single-agent nivolumab and when used in combination with ipilimumab; severe reactions, although rare, were observed when given as a single agent. Monitor closely; discontinue for severe or life-threatening reactions. Mild or moderate reactions may be managed by interrupting or decreasing the infusion rate. A pharmacokinetic study that looked at the safety of a shortened nivolumab infusion time found similar incidences of infusion-related reactions when nivolumab was administered over 60 or 30 minutes. Small percentages of patients receiving the 60-minute or 30-minute infusion experienced reactions within 48 hours of infusion, which resulted in dose delay, permanent discontinuation, or withholding of nivolumab (0.5% and 1.4%, respectively).
• Nephrotoxicity: Renal dysfunction has occurred with nivolumab therapy. Immune-mediated nephritis (defined as renal dysfunction or ≥ grade 2 creatinine elevations with no other clear etiology and requiring corticosteroid use) or autoimmune nephritis may occur with nivolumab treatment. The median time to onset was 2.7 to 4.6 months (range: 1 day to 13.2 months). For single-agent nivolumab, all patients received high-dose systemic corticosteroids (at least 40 mg prednisone or equivalent per day) for a median duration of 3 weeks (range: 1 day to 15.4 months); complete resolution occurred in about one-half of patients, with no recurrence upon rechallenge. When used in combination with ipilimumab, two-thirds to three-quarters of patients received high-dose systemic corticosteroids (at least 40 mg prednisone or equivalent per day) for a median duration of 13.5 to 17 days (range: 1 day to 6 months); complete resolution occurred in a majority of patients, some patients resumed combination therapy with no recurrence. Monitor serum creatinine at baseline and periodically during treatment. Initiate corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper for life-threatening (grade 4) serum creatinine elevation and permanently discontinue nivolumab. Withhold treatment for moderate (grade 2) and severe (grade 3) creatinine elevations and administer corticosteroids (prednisone 0.5 to 1 mg/kg daily or equivalent) followed by a corticosteroid taper; if toxicity worsens or does not improve, increase to prednisone 1 to 2 mg/kg daily (or equivalent).
• Ocular toxicity: Uveitis and iritis have been reported. 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 nivolumab (as a single agent and in combination with ipilimumab) and may require systemic corticosteroids to reduce the risk of permanent vision loss.
• Pulmonary toxicity: Nivolumab may cause immune-mediated pneumonitis (severe pneumonitis or interstitial lung disease); fatal cases have been reported. Immune-mediated pneumonitis is defined as no other clear etiology and requiring corticosteroid use. The median time to onset was 1.6 to 3.5 months (range: 1 day to 22.3 months) across several clinical trials. Some cases developed after nivolumab was discontinued for other reasons. High-dose systemic corticosteroids (followed by a corticosteroid taper) were administered for a median duration of 19 to 30 days (range: 1 day to 11.8 months). Most patients improved to grade 0 or 1; some patients with grade 2 or 3 pneumonitis had complete resolution (after completing corticosteroid therapy) and nivolumab was reinitiated without recurrence in some patients. Monitor for signs (with radiographic imaging) and symptoms of pneumonitis. May require treatment interruption, corticosteroid therapy, and/or permanent discontinuation. Grades 2, 3, or 4 pneumonitis should be managed with corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. Some cases required the addition of infliximab to corticosteroid therapy. Withhold treatment until resolution for moderate (grade 2) immune-mediated pneumonitis; permanently discontinue for severe (grade 3) or life-threatening (grade 4) immune-mediated pneumonitis.
• Thyroid disorders: Immune-mediated hyperthyroidism and hypothyroidism/thyroiditis have occurred, mostly grades 1 and 2 hyper-/hypothyroidism (one patient receiving nivolumab in combination with ipilimumab experienced grade 3 autoimmune thyroiditis). The median onset for hyperthyroidism was 23 days to 1.5 months (range: 1 day to 14.2 months); most cases resolved (may require medical management, including corticosteroids and methimazole). Hypothyroidism occurred with a median onset of 2 to 3 months (range: 1 day to 21.4 months). Most patients received subsequent nivolumab (with or without ipilimumab) treatment while continuing thyroid replacement therapy. Monitor thyroid function at baseline and for changes periodically during treatment (in one study, patients were evaluated at baseline, treatment day 1, and every 6 weeks). Isolated hypothyroidism may be managed with hormone replacement therapy; initiate medical management (eg, methimazole) to control hyperthyroidism.
• Other immune-mediated toxicities: Other clinically relevant and potentially fatal immune-mediated disorders may occur; may develop after discontinuation of nivolumab. Immune-mediated adverse reactions observed included facial/abducens nerve paresis, aplastic anemia, autoimmune neuropathy, demyelination, duodenitis, gastritis, Guillain-Barré syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), hypopituitarism, motor dysfunction, myasthenic syndrome, myocarditis, myositis, pancreatitis, pericarditis, polymyalgia rheumatica, rhabdomyolysis, sarcoidosis, systemic inflammatory response syndrome, and vasculitis. If an immune-mediated adverse event is suspected, evaluate to exclude other causes. Based on symptom severity, withhold or permanently discontinue nivolumab, administer high-dose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement to grade 0 or 1, begin corticosteroid taper (over at least 1 month). After corticosteroid taper is completed and based on the severity of the reaction, may consider reinitiating nivolumab.

Disease-related concerns:

• Autoimmune disorders: Anti-PD-1 monoclonal antibodies generate an immune response that may aggravate underlying autoimmune disorders or prior immune-related adverse events. A retrospective study analyzed the safety and efficacy of treatment with anti-PD-1 monoclonal antibodies (eg, nivolumab or pembrolizumab) in melanoma patients with preexisting autoimmune disease or prior significant ipilimumab-mediated adverse immune events. Results showed that while immune toxicities associated with this class of therapy did occur, most reactions were mild and easily manageable, and did not require permanent drug therapy discontinuation. A significant percentage of patients achieved clinical response with anti-PD-1 monoclonal antibody therapy, despite baseline autoimmunity or prior ipilimumab-related adverse events (Menzies 2017).
• Hematopoietic stem cell transplant: Patients who received allogeneic hematopoietic stem cell transplant (HSCT) prior to or following anti-PD-1 antibody therapy experienced complications (some serious or fatal). Transplant-related complications included hyperacute graft versus host disease (GVHD), acute GVHD, chronic GVHD, and sinusoidal obstructive syndrome (SOS; formerly called veno-occlusive disease) following reduced intensity conditioning, and noninfectious febrile syndrome (requiring corticosteroids). Transplant complications may occur despite intervening therapy between anti-PD-1 antibody therapy and allogeneic HSCT. Monitor closely for signs/symptoms of transplant-related complications and manage promptly. Assess benefit versus risks of treatment with an anti-PD-1 antibody prior to or after allogeneic HSCT.
• Multiple myeloma: An increase in mortality was noted in randomized studies of patients with multiple myeloma who received the addition of a PD-1 blocking agent (including nivolumab) to a thalidomide analogue plus dexamethasone. Multiple myeloma is not an approved indication for nivolumab; the use of nivolumab in combination with a thalidomide analogue and dexamethasone for the treatment of multiple myeloma is not recommended outside the setting of a clinical trial.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Monitoring Parameters

Hepatic and renal function tests (baseline and periodic), thyroid function (baseline and periodically [eg, at treatment day 1 and every 6 weeks]); blood glucose. Verify pregnancy status prior to treatment initiation (in females of reproductive potential). Monitor for signs/symptoms of adrenal insufficiency, hypophysitis, thyroid disorders, immune-mediated colitis, pneumonitis, rash/dermatologic toxicity, encephalitis (changes in neurologic function); monitor for infusion reactions.

Pregnancy

Pregnancy Considerations

Based on information from animal reproduction studies and the mechanism of action, nivolumab may cause fetal harm if administered during pregnancy. Nivolumab is a humanized monoclonal antibody (IgG₄). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).

Verify pregnancy status prior to treatment initiation in females of reproductive potential. Females of reproductive potential should use highly effective contraception during therapy and for at least 5 months after the last nivolumab dose.

Patient Education

What is this drug used for?

• It is used to treat cancer.

Frequently reported side effects of this drug

• Headache
• Bone pain
• Constipation
• Lack of appetite
• Abdominal pain
• Common cold symptoms
• Trouble sleeping
• Nausea
• Vomiting

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infusion reaction
• Thyroid, pituitary, or adrenal gland problems like mood changes, behavioral changes, weight changes, constipation, deeper voice, dizziness, passing out, cold sensation, severe fatigue, hair loss, persistent headache, or decreased sex drive.
• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting.
• Encephalitis like confusion, fatigue, loss of strength and energy, fever, sensing things that seem real but are not, memory problems, seizures, stiff neck, or severe headache.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting.
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse.
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.
• Colitis like bloody stools; dark, tarry, or sticky stools; diarrhea; or severe abdominal pain.
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Bruising
• Bleeding
• Muscle pain
• Muscle weakness
• Severe joint pain
• Swelling of arms or legs
• Burning or numbness feeling
• Vision changes
• Eye pain
• Severe eye irritation
• Chest pain
• Severe loss of strength and energy
• Abnormal heartbeat
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.