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Nivolumab

Pronunciation

(nye VOL ue mab)

Index Terms

  • Anti-PD-1 Human Monoclonal Antibody MDX-1106
  • BMS-936558
  • MDX-1106
  • ONO-4538

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) [contains polysorbate 80]

Brand Names: U.S.

  • Opdivo

Pharmacologic Category

  • Antineoplastic Agent, Anti-PD-1 Monoclonal Antibody
  • Antineoplastic Agent, Immune Checkpoint Inhibitor
  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

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.

Distribution

Vd: ~8 L (single-agent and combination therapy with ipilimumab)

Half-Life Elimination

~27 days (single agent); ~25 days (combination therapy with ipilimumab)

Special Populations Note

Body weight: Clearance increases with increased body weight.

Use: Labeled Indications

US labeling:

Hodgkin lymphoma, classical: Treatment of classical Hodgkin lymphoma (cHL) in patients that have relapsed or progressed following autologous hematopoietic stem cell transplant (HSCT) and post-transplant brentuximab vedotin

Melanoma, unresectable or metastatic: Treatment (as a single agent) of BRAF V600 wild-type or BRAF V600 mutation-positive unresectable or metastatic melanoma; treatment of unresectable or metastatic melanoma (in combination with ipilimumab)

Non-small cell lung cancer, metastatic: 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, clear cell (advanced): Treatment of advanced renal cell cancer in patients who have received prior anti-angiogenic therapy.

Canadian labeling:

Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic BRAF V600 wild-type melanoma in previously untreated adults; treatment of unresectable or metastatic melanoma in patients with disease progression following ipilimumab and (if BRAF V600 mutation-positive) a BRAF inhibitor.

Non-small cell lung cancer, metastatic: 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, metastatic: Treatment of advanced or metastatic renal cell cancer in patients who have received prior anti-angiogenic therapy.

Contraindications

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

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

Dosing: Adult

US labeling:

Hodgkin lymphoma, classical: IV: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Ansell 2015; Younes 2016).

Melanoma, unresectable or metastatic: IV: 3 mg/kg once every 2 weeks (as a single agent) until disease progression or unacceptable toxicity (Robert 2015; Weber 2015).

Melanoma, unresectable or metastatic, first-line combination therapy: IV: 1 mg/kg once every 3 weeks (in combination with ipilimumab) for 4 doses, followed by 3 mg/kg once every 2 weeks (nivolumab monotherapy) until disease progression or unacceptable toxicity (Larkin 2015). Note: If nivolumab therapy is withheld, ipilimumab should also be withheld.

Non-small cell lung cancer, metastatic: IV: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Borghaei 2015; Brahmer 2015).

Renal cell cancer, clear cell (advanced): IV: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Motzer 2015)

Canadian labeling:

Melanoma, unresectable or metastatic: IV: 3 mg/kg once every 2 weeks (as a single agent), continue as long as benefiting clinically or until unacceptable toxicity occurs.

Non-small cell lung cancer, metastatic: IV: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity

Renal cell cancer (metastatic): IV: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity

Head and neck cancer, squamous cell, recurrent or metastatic (off-label use): IV: 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Ferris 2016).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Renal impairment prior to treatment initiation:

US labeling: No dosage adjustment necessary.

Canadian labeling:

Mild to moderate impairment: No dosage adjustment necessary.

Severe impairment: There is no dosage adjustment provided in the manufacturer’s labeling (insufficient data).

Renal toxicity during treatment:

US labeling:

Creatinine >1.5 to 6 times ULN or >1.5 times baseline: Withhold treatment; administer corticosteroids (prednisone 0.5 to 1 mg/kg daily or equivalent) followed by a corticosteroid taper; may resume therapy upon recovery to grade 0 or 1 toxicity. If toxicity worsens or does not improve, permanently discontinue and increase corticosteroid dose to prednisone 1 to 2 mg/kg daily (or equivalent).

Creatinine >6 times ULN or life-threatening: Permanently discontinue; initiate high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper.

Canadian labeling:

Creatinine >1.5 to 3 times baseline or >1.5 to 3 times ULN: Withhold treatment and manage with corticosteroids (0.5 to 1 mg/kg methylprednisolone equivalent) followed by a taper; may resume therapy upon recovery to baseline and corticosteroid management is complete. If toxicity worsens or does not improve, permanently discontinue and increase corticosteroid dose (1 to 2 mg/kg methylprednisolone equivalent).

Creatinine >3 times baseline or >3 times ULN: Permanently discontinue; initiate high-dose systemic corticosteroids (1 to 2 mg/kg methylprednisolone equivalent).

Dosing: Hepatic Impairment

Hepatic impairment prior to treatment initiation:

Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin <1 to 1.5 times ULN and any AST): No dosage adjustment necessary.

Moderate (total bilirubin >1.5 to 3 times ULN and any AST) to severe (total bilirubin >3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Hepatotoxicity during treatment:

AST or ALT >3 to 5 times ULN or total bilirubin >1.5 to 3 times ULN: Withhold treatment; may resume therapy upon recovery to grade 0 or 1 toxicity.

AST or ALT >5 times ULN or total bilirubin >3 times ULN: Permanently discontinue.

Immune-mediated hepatitis:

Grade 2 transaminase elevations (with or without total bilirubin elevations): Withhold treatment and initiate high-dose systemic corticosteroids (prednisone 0.5 to 1 mg/kg daily or equivalent)

Severe (grade 3) or life-threatening (grade 4): Permanently discontinue treatment and initiate high-dose systemic corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent)

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.

Adrenal insufficiency (grade 2); Canadian labeling: Also initiate physiologic corticosteroid replacement.

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); also administer insulin as clinically necessary

Encephalitis (new onset moderate or severe neurologic toxicity)

Hypophysitis (grade 2 or 3 [US labeling] or grade 2 [Canadian labeling]); 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); 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 (over 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)

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): also administer insulin as clinically necessary

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 [US labeling] or grade 3 or 4 [Canadian labeling]); also administer high-dose systemic corticosteroids (prednisone 1 mg/kg daily or equivalent)

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

Inability to reduce corticosteroid dose to prednisone ≤10 mg/day (or equivalent) within 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 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):

US labeling: There are no recommended dosage modifications.

Canadian labeling:

Hyperthyroidism, symptomatic grade 2 or 3: Withhold nivolumab and initiate antithyroid therapy.

Hypothyroidism, symptomatic grade 2 or 3: Withhold nivolumab and initiate thyroid hormone replacement therapy.

Hyperthyroidism or hypothyroidism, grade 4: Permanently discontinue.

Severe symptoms: Also consider corticosteroids (methylprednisolone 1 to 2 mg/kg daily or equivalent)

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. Mix by gentle inversion; do not shake.

Administration

IV: Administer over 60 minutes 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, infuse 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 infusion solution at room temperature for no more than 4 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 24 hours of preparation. Do not freeze solutions prepared for infusion.

Drug Interactions

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

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

Adverse Reactions

Frequency not always defined.

Cardiovascular: Edema (12%), peripheral edema (10% to 12%), ventricular arrhythmia (<10%), pulmonary embolism (2% to 4%), vasculitis

Central nervous system: Malaise (≤56%), fatigue (≤49% to ≤56%), dizziness (<10%), peripheral neuropathy (<10%), peripheral sensory neuropathy (<10%), peroneal nerve palsy (<10%), motor dysfunction (<2%), headache, migraine, myasthenia

Dermatologic: Skin rash (including immune-mediated events: 9% to 40%; grade 3/4: ≤2%), pruritus (11% to 23%), vitiligo (≤11%), erythema (10%), erythema multiforme (<10%), exfoliative dermatitis (<10%), psoriasis (<10%), urticaria (1%), Palmar-Plantar erythrodysesthesia

Endocrine & metabolic: Hyponatremia (20% to 35%), increased serum triglycerides (32%), hyperkalemia (15% to 30%), increased thyroid stimulating hormone level (17% to 26%), hypocalcemia (13% to 23%), increased serum cholesterol (21%), hypercalcemia (19%), hypothyroidism (7% to 9%), hyperthyroidism (1% to 4%), adrenocortical insufficiency (≤2%), diabetes mellitus (≤2%), diabetic ketoacidosis (≤2%), weight loss

Gastrointestinal: Diarrhea (≤17% to ≤31%; grade 3/4: ≤4%), colitis (including immune-mediated events: ≤17% to ≤31%; grades 3/4: ≤2%), decreased appetite (23% to 29%), increased serum lipase (<10% to 29%), nausea (28%), constipation (23%), vomiting (16% to 17%), increased serum amylase (<10% to 15%), abdominal pain

Hematologic & oncologic: Lymphocytopenia (39% to 42%; grade 3/4: 4% to 6%), anemia (39%; grade 3/4: 3% to 8%)

Hepatic: Increased serum AST (24% to 33%; grade 3/4: 2% to 4%), increased serum alkaline phosphatase (21% to 32%), increased serum ALT (16% to 25%; grade 3/4: 2% to 3%), increased serum bilirubin (9% to 13%; grade 3/4: 3%), hepatitis (immune-mediated ≤2%; grade 3: ≤1%)

Hypersensitivity: Hypersensitivity reaction (≤6%)

Immunologic: Antibody development (12%; neutralizing ≤1%; no evidence of altered pharmacokinetic profile)

Neuromuscular & skeletal: Weakness (≤49% to ≤56%), musculoskeletal pain (≤32% to 36%), back pain (21%), arthralgia (20%), spondyloarthropathy (<10%), limb pain

Ophthalmic: Iridocyclitis (<10%)

Renal: Increased serum creatinine (11% to 42%; grades 3/4: ≤2%), renal disease (7%; grade >3: 2%), nephritis (≤5%; immune-mediated), renal insufficiency (including immune-mediated events: ≤5%)

Respiratory: Productive cough (≤34%), cough (17% to ≤34%), dyspnea on exertion (≤27%), dyspnea (12% to ≤27%), upper respiratory tract infection (11% to 18%), pleural effusion (2% to 6%), pneumonitis (1% to 5%; grade 3: ≤2%; grade 4: <1%; including interstitial pulmonary disease and immune-mediated events), pneumonia (≥2%), respiratory failure (≥2%)

Miscellaneous: Fever (14% to 17%), infusion related reaction (<10%)

<1% (Limited to important or life-threatening): Duodenitis (immune-mediated), encephalitis (autoimmune/limbic), facial paralysis (immune-mediated), gastritis (immune-mediated), Guillain-Barré syndrome (immune-mediated), hepatic failure, hypophysitis, neuropathy (autoimmune; immune-mediated), pancreatitis (immune-mediated), pituitary insufficiency (immune-mediated), pneumonia due to Pneumocystis jiroveci, polymyalgia rheumatic (immune-mediated), sarcoidosis (immune-mediated)

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal insufficiency: Adrenal insufficiency may occur. The median time to onset across several clinical trials was 3 to 5.8 months (range: 15 days to 20.9 months). Monitor for signs/symptoms of adrenal insufficiency both during and after treatment. Administer corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) 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: In clinical trials, immune-mediated rash (including grade 2, 3, and 4 toxicity) was observed in patients receiving nivolumab (as a single agent or in combination with ipilimumab, although the incidence was higher with combination therapy). Fatal toxic epidermal necrolysis occurred rarely. The median time to onset ranged from 1 day to 25.8 months after nivolumab initiation. Monitor closely; administer corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) for severe (grade 3) or life-threatening (grade 4) rash. Topical corticosteroids have been used to manage immune-mediated rash (alone for lower grade rash or in combination with systemic corticosteroids if indicated). Withhold treatment for grade 3 rash and permanently discontinue for life-threatening (grade 4) rash.

• Diabetes mellitus: Type 1 diabetes mellitus may occur, including cases of new onset diabetes mellitus and diabetic ketoacidosis. The time to onset of diabetic ketoacidosis or diabetes mellitus ranged from 1.3 to 21.8 months. Monitor for hyperglycemia; administer insulin when clinically necessary. 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 with both single-agent and combination nivolumab therapy may occur (rarely); may be fatal. Withhold nivolumab for new-onset moderate to severe neurologic signs/symptoms; evaluate to rule out infection or other neurologic causes. Brain MRI and/or lumbar puncture may be necessary. For confirmed immune-mediated encephalitis felt to be caused by nivolumab, administer corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent), followed by a corticosteroid taper. Permanently discontinue if immune-mediated encephalitis occurs.

• Gastrointestinal 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 5.6 months (range: 2 days to 19 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 2.9 weeks to 4.2 months (range: 1 day to 11.7 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, or colitis that recurs upon reinitiation (single-agent therapy) or for severe or life-threatening colitis (grade 3 or 4) or for colitis that recurs upon reinitiation (in combination with ipilimumab)

• 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 time to onset ranged from ~6 days to ~11 months after nivolumab initiation (one case developed after nivolumab was discontinued for other reasons). Immune-mediated hepatitis was managed with high-dose systemic corticosteroids; in some cases, mycophenolate or infliximab was added to corticosteroid therapy. 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, several 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. Immune-mediated hepatitis recurred following nivolumab reinitiation in a NSCLC trial, leading to permanent nivolumab discontinuation. Monitor liver function at baseline and periodically for changes. 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 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.

• 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 time to onset across several clinical trials ranged from 27 days to 11 months. Monitor for signs/symptoms of hypophysitis. Administer corticosteroids (prednisone 1 mg/kg/day or equivalent) for grade 2 or higher toxicity. 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 administration, both as a single agent and in combination; 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. Some patients have received systemic corticosteroids to manage hypersensitivity/infusion reactions.

• Nephrotoxicity: Creatinine elevations have 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 time to onset for grade 2 or higher events ranged from ~1 week to ~12 months after nivolumab initiation; patients received high-dose systemic corticosteroids and treatment was withheld and discontinued. In clinical trials, immune-mediated nephritis resolved and did not recur with continued corticosteroid use in some patients, although other patients experienced ongoing renal dysfunction. 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, permanently discontinue and increase to prednisone 1 to 2 mg/kg daily (or equivalent).

• Pulmonary toxicity: Immune-mediated pneumonitis (severe pneumonitis or interstitial lung disease) has been observed, including cases which were fatal. Immune-mediated pneumonitis is defined as no other clear etiology and requiring corticosteroid use. The median time to development was 1.6 to 7.2 months (range: 1 day to 22.3 months) across several clinical trials. Some cases developed after nivolumab was discontinued for other reasons. With high-dose systemic corticosteroids (followed by a corticosteroid taper), 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. Grade 2 or higher pneumonitis should be managed with corticosteroids (prednisone 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. 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 3 months (range: Up to 14.2 months); most cases resolved (may require medical management, including corticosteroids and methimazole). Hypothyroidism occurred with a median onset of ~2 to 5 months (range: 1 day to 16.6 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 to control hyperthyroidism. There are case reports of patients receiving nivolumab in combination with ipilimumab who developed hypothyroidism after resolution of grade 1 hyperthyroidism.

• Other immune-mediated toxicities: Other clinically relevant immune-mediated disorders may occur; may develop after discontinuation of nivolumab. Immune-mediated adverse reactions observed included abducens nerve paresis, autoimmune neuropathy, demyelination, duodenitis, facial nerve paralysis, gastritis, Guillain-Barré syndrome, hypopituitarism, motor dysfunction, myasthenic syndrome, pancreatitis, polymyalgia rheumatica, sarcoidosis, systemic inflammatory response syndrome, uveitis, iritis, and vasculitis. If an immune-mediated adverse event is suspected, evaluate to exclude other causes. Based on symptom severity, withhold 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:

• Hematopoietic stem cell transplant: Patients who received allogeneic hematopoietic stem cell transplant (HSCT) following discontinuation of nivolumab therapy experienced complications (some fatal) including severe or refractory acute graft versus host disease (some cases occurring within 14 days after stem cell infusion), noninfectious febrile syndrome (requiring corticosteroids), lymphocytic encephalitis, viral encephalitis, and sinusoidal obstructive syndrome (SOS; formerly called veno-occlusive disease). These complications may occur despite intervening therapy between nivolumab and HSCT. Monitor closely for early signs/symptoms of transplant-related complications and manage promptly.

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.

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. Monitor for signs/symptoms of adrenal insufficiency, hypophysitis, thyroid disorders, immune-mediated colitis, pneumonitis, rash, encephalitis (changes in neurologic function); monitor for infusion reactions.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Nivolumab may be expected to cross the placenta; effects to the fetus may be greater in the second and third trimesters. Based on its mechanism of action, nivolumab is expected to cause fetal harm if used during pregnancy. Women of reproductive potential should use highly effective contraception during therapy and for at least 5 months after nivolumab treatment has been discontinued.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, bone pain, constipation, lack of appetite, nausea, or vomiting. Have patient report immediately to prescriber signs of infusion reaction, signs of thyroid, pituitary, or adrenal gland problems (mood changes, behavioral changes, weight changes, constipation, deeper voice, dizziness, passing out, cold sensation, severe fatigue, hair loss, persistent headache, or decreased libido); signs of encephalitis (confusion, fatigue, loss of strength and energy, fever, hallucinations, memory problems, seizures, stiff neck, or severe headache); bloody stools; dark, tarry, or sticky stools; diarrhea; severe abdominal pain; signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain); signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice); signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting); signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit); signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes); bruising; bleeding; severe muscle pain; severe muscle weakness; severe joint pain; swelling of arms or legs; vision changes; angina; severe loss of strength and energy; or abnormal heartbeat (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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