Generic Name: Nivolumab
Class: Antineoplastic Agents
Chemical Name: A fully human IgG4 antibody blocking the programmed cell death-1 receptor
Molecular Formula: C₆₃₆₂H₉₈₆₂N₁₇₁₂O₁₉₉₅S₄₂
CAS Number: 946414-94-4

Medically reviewed on Oct 15, 2018

Introduction

Antineoplastic agent; fully human anti-programmed-death receptor-1 (anti-PD-1) monoclonal antibody.^{1 7 11}

Uses for Opdivo

Melanoma

Used as a single agent for the treatment of unresectable or metastatic melanoma in patients with tumors bearing wild-type b-Raf serine-threonine kinase (BRAF) V600^{1 2 14 15} (designated an orphan drug by FDA for this use).⁴

Used as a single agent for the treatment of unresectable or metastatic melanoma in patients with tumors bearing BRAF V600 mutation^{1 2 15} (designated an orphan drug by FDA for this use).⁴ Accelerated approval based on progression-free survival.¹ Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.^{1 18}

Used in combination with ipilimumab for the treatment of unresectable or metastatic melanoma^{1 15} (designated an orphan drug by FDA for this use).⁴ Accelerated approval based on progression-free survival.¹ Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.^{1 18}

Used as adjuvant therapy for locally advanced or metastatic melanoma following complete resection.^{1 26}

Non-small Cell Lung Cancer (NSCLC)

Treatment of metastatic NSCLC that has progressed during or following therapy with platinum-based chemotherapy and, in patients with epidermal growth factor receptor (EGFR) mutation- or anaplastic lymphoma kinase (ALK)-positive tumors, therapy with an FDA-labeled EGFR or ALK inhibitor.^{1 3 16}

Renal Cell Carcinoma

Treatment of advanced renal cell carcinoma previously treated with antiangiogenic therapy.^{1 17}

Hodgkin Lymphoma

Treatment of classical Hodgkin lymphoma (cHL) that has relapsed or progressed following autologous stem cell transplantation and subsequent therapy with brentuximab vedotin or following failure of ≥3 systemic therapies (including autologous stem cell transplantation)^{1 19 20} (designated an orphan drug by FDA for this cancer).⁴ Accelerated approval based on objective response rate.¹ Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.¹

Head and Neck Cancer

Treatment of metastatic or recurrent squamous cell carcinoma of the head and neck that has progressed during or following therapy with platinum-based chemotherapy.^{1 21}

Urothelial Carcinoma

Treatment of locally advanced or metastatic urothelial carcinoma that has progressed during or following platinum-containing therapy or within 12 months of platinum-containing therapy in the neoadjuvant or adjuvant setting.^{1 23} Accelerated approval based on objective response rate and duration of response.¹ Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.¹

Colorectal Cancer

Treatment of metastatic colorectal cancer with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing therapy.^{1 24} Accelerated approval based on objective response rate and duration of response.¹ Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.¹

Hepatocellular Carcinoma

Treatment of hepatocellular carcinoma previously treated with sorafenib^{1 25} (designated an orphan drug by FDA for this cancer).⁴ Accelerated approval based on objective response rate and duration of response.¹ Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.¹

Opdivo Dosage and Administration

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.¹ Do not administer by rapid IV injection (e.g., IV push or bolus).¹³

Dilute nivolumab injection to an appropriate concentration (see Dilution under Dosage and Administration) for IV infusion over 30 minutes.^{1 13} (See Storage under Stability.)

Do not infuse simultaneously through the same IV line with other drugs.¹

Administer using a sterile, nonpyrogenic, low-protein-binding 0.2- to 1.2-μm inline filter.¹

Dilution

Dilute appropriate dose in a sufficient volume of 0.9% sodium chloride or 5% dextrose injection to a final concentration of 1–10 mg/mL.^{1 13} Total volume of infusion solution must not exceed 160 mL.¹

Mix the diluted solution by gentle inversion; do not shake.¹

Discard any partially used vials.¹

Rate of Administration

Administer by IV infusion over 30 minutes.¹

Dosage

Consult published protocols for information on dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens with nivolumab.

Pediatric Patients

Colorectal Cancer

IV

Pediatric patients ≥12 years of age: 240 mg every 2 weeks.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Therapy Interruption for Toxicity

IV

Follow recommendations for therapy interruption in adults.¹

Adults

Melanoma

Monotherapy for Unresectable or Metastatic Melanoma

IV

240 mg every 2 weeks or 480 mg every 4 weeks.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Combination Therapy for Unresectable or Metastatic Melanoma

IV

1 mg/kg every 3 weeks for 4 doses (use in combination with ipilimumab) followed by single-agent nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Administer nivolumab prior to ipilimumab.¹

If nivolumab therapy is temporarily interrupted for toxicity, withhold ipilimumab therapy.¹

Adjuvant Therapy for Locally Advanced or Metastatic Melanoma

IV

240 mg every 2 weeks or 480 mg every 4 weeks.¹ Continue therapy for up to 1 year or until disease recurrence or unacceptable toxicity occurs.¹

NSCLC

IV

240 mg every 2 weeks or 480 mg every 4 weeks.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Renal Cell Carcinoma

IV

240 mg every 2 weeks or 480 mg every 4 weeks.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Hodgkin Lymphoma

IV

240 mg every 2 weeks or 480 mg every 4 weeks.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Head and Neck Cancer

IV

240 mg every 2 weeks or 480 mg every 4 weeks.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Urothelial Carcinoma

IV

240 mg every 2 weeks or 480 mg every 4 weeks.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Colorectal Cancer

IV

240 mg every 2 weeks.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Hepatocellular Carcinoma

IV

240 mg every 2 weeks or 480 mg every 4 weeks.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Therapy Interruption for Toxicity

Permanently discontinue therapy in patients experiencing any life-threatening or grade 4 immune-mediated adverse effect, patients with persistent grade 2 or 3 immune-mediated adverse effects lasting ≥12 weeks, and those requiring a corticosteroid dosage of ≥10 mg of prednisone daily (or equivalent) for >12 weeks.¹ (See Warnings/Precautions under Cautions.)

Permanently discontinue therapy if grade 3 immune-mediated adverse effects recur.¹

Immune-mediated Pneumonitis

If grade 2 immune-mediated pneumonitis occurs, interrupt therapy until toxicity resolves to grade 0 or 1.^{1 13} (See Immune-mediated Pneumonitis under Cautions.)

If grade 3 or 4 immune-mediated pneumonitis occurs, permanently discontinue drug.^{1 13}

Immune-mediated GI Effects

If grade 2 or 3 immune-mediated colitis or diarrhea occurs, interrupt therapy until toxicity resolves to grade 0 or 1;^{1 13} however, if grade 3 immune-mediated colitis or diarrhea occurs in patients receiving nivolumab in combination with ipilimumab, permanently discontinue nivolumab.¹ If colitis recurs upon reinitiation of therapy, permanently discontinue drug.¹ (See Immune-mediated GI Effects under Cautions.)

If grade 4 immune-mediated colitis or diarrhea occurs, permanently discontinue drug.^{1 13}

Immune-mediated Hepatic Effects

For ALT or AST concentrations >3 to 5 times the ULN or total bilirubin concentrations >1.5 to 3 times the ULN (i.e., grade 2) in patients without hepatocellular carcinoma, interrupt therapy until toxicity resolves to grade 0 or 1.^{1 13} (See Immune-mediated Hepatic Effects under Cautions.)

For ALT or AST concentrations >5 times the ULN or total bilirubin concentrations >3 times the ULN (i.e., grade 3 or greater) in patients without hepatocellular carcinoma, permanently discontinue drug.^{1 13}

For ALT or AST concentrations >3 to 5 times the ULN in patients with hepatocellular carcinoma and baseline ALT and AST concentrations within normal limits, interrupt therapy until toxicity resolves to baseline.¹

For ALT or AST concentrations >5 to 10 times the ULN in patients with hepatocellular carcinoma and baseline ALT or AST concentrations exceeding the ULN but ≤3 times the ULN, interrupt therapy until toxicity resolves to baseline.¹

For ALT or AST concentrations >8 to 10 times the ULN in patients with hepatocellular carcinoma and baseline ALT or AST concentrations >3 to 5 times the ULN, interrupt therapy until toxicity resolves to baseline.¹

For ALT or AST concentrations >10 times the ULN or total bilirubin concentrations >3 times the ULN in patients with hepatocellular carcinoma, permanently discontinue drug.¹

Immune-mediated Endocrine Effects

If grade 2 or 3 immune-mediated hypophysitis, grade 2 immune-mediated adrenal insufficiency, or grade 3 immune-mediated hyperglycemia occurs, interrupt therapy until toxicity resolves to grade 0 or 1 and glucose concentrations have stabilized.¹ (See Immune-mediated Endocrine Effects under Cautions.)

If grade 4 immune-mediated hypophysitis, grade 3 or 4 immune-mediated adrenal insufficiency, or grade 4 immune-mediated hyperglycemia occurs, permanently discontinue drug.¹

Manufacturer states there are no recommended dosage modifications for immune-mediated hypothyroidism or hyperthyroidism.¹

Immune-mediated Renal Effects

For S_cr concentrations >1.5 to 6 times the ULN or >1.5 times baseline values (i.e., grade 2 or 3), interrupt therapy until toxicity resolves to grade 0 or 1.^{1 13} (See Immune-mediated Renal Effects under Cautions.)

For S_cr concentrations >6 times the ULN (i.e., grade 4), permanently discontinue drug.^{1 13}

Immune-mediated Dermatologic Effects

If grade 3 immune-mediated rash occurs or Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, interrupt therapy until toxicity resolves to grade 0 or 1.¹ (See Immune-mediated Dermatologic Effects under Cautions.)

If grade 4 immune-mediated rash occurs or Stevens-Johnson syndrome or toxic epidermal necrolysis is confirmed, permanently discontinue drug.¹

Immune-mediated CNS Effects

If new-onset moderate or severe neurologic signs or symptoms occur, interrupt therapy until toxicity resolves to grade 0 or 1.¹ (See Immune-mediated CNS Effects under Cautions.)

If immune-mediated encephalitis occurs, permanently discontinue drug.¹

Other Immune-mediated Adverse Effects

If grade 3 immune-mediated myocarditis occurs, permanently discontinue drug.¹

If any other grade 3 immune-mediated adverse effects occur, interrupt therapy until toxicity resolves to grade 0 or 1.^{1 13} If grade 3 adverse effect recurs, permanently discontinue drug.¹ (See Other Immune-mediated Effects under Cautions.)

Infusion-related Reactions

If mild or moderate infusion-related reactions occur, interrupt infusion or reduce infusion rate.¹ (See Infusion-related Effects under Cautions.)

If severe or life-threatening infusion-related reactions occur, permanently discontinue drug.¹

Special Populations

Hepatic Impairment

Mild or moderate preexisting hepatic impairment: No dosage adjustment required.¹ (See Special Populations under Pharmacokinetics.)

Severe preexisting hepatic impairment: Not studied; no dosage recommendations at this time.¹

Renal Impairment

Mild, moderate, or severe preexisting renal impairment: No dosage adjustment required.¹ (See Special Populations under Pharmacokinetics.)

Geriatric Patients

No special dosage recommendations at this time.¹ (See Geriatric Use under Cautions.)

Cautions for Opdivo

Contraindications

• No known contraindications.¹

Warnings/Precautions

Immune-mediated Pneumonitis

Immune-mediated pneumonitis, sometimes fatal, reported.^{1 3}

Monitor patients clinically and by radiographic imaging for manifestations of pneumonitis.¹

If grade 2 or greater immune-mediated pneumonitis occurs, temporarily withhold or discontinue nivolumab and initiate systemic corticosteroid therapy at a dosage of 1–2 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage.¹ (See Therapy Interruption for Toxicity under Dosage and Administration.)

Immune-mediated GI Effects

Immune-mediated colitis, sometimes fatal, reported.^{1 3}

Monitor patients for manifestations of colitis.¹

If grade 2 or greater immune-mediated colitis occurs, temporarily withhold or discontinue nivolumab and initiate systemic corticosteroid therapy.¹ (See Therapy Interruption for Toxicity under Dosage and Administration.)

For grade 3 or 4 immune-mediated colitis, initiate systemic corticosteroid therapy at a dosage of 1–2 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage.¹

For grade 2 immune-mediated colitis lasting >5 days, initiate systemic corticosteroid therapy at a dosage of 0.5–1 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage; if immune-mediated colitis worsens or fails to improve, increase dosage to 1–2 mg/kg of prednisone daily (or equivalent).¹

Immune-mediated Hepatic Effects

Immune-mediated hepatitis reported.¹

Perform liver function tests prior to initiation of therapy and periodically during therapy.¹

If immune-mediated hepatitis occurs, temporarily withhold or discontinue nivolumab and initiate systemic corticosteroid therapy.¹ (See Therapy Interruption for Toxicity under Dosage and Administration.)

For grade 3 or 4 elevations in ALT or AST concentrations (with or without concomitant elevations of total bilirubin concentrations) in patients without hepatocellular carcinoma, initiate systemic corticosteroid therapy at a dosage of 1–2 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage.¹ For grade 2 elevations in ALT or AST concentrations in patients without hepatocellular carcinoma, initiate systemic corticosteroid therapy at a dosage of 0.5–1 mg/kg of prednisone daily (or equivalent).¹

For patients with hepatocellular carcinoma, initiate systemic corticosteroid therapy at a dosage of 1–2 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage whenever nivolumab is temporarily interrupted or discontinued because of immune-mediated hepatitis.¹

Immune-mediated Endocrine Effects

Immune-mediated endocrinopathies (e.g., hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes mellitus, diabetic ketoacidosis) reported.¹

Hypophysitis

Monitor for manifestations of hypophysitis.¹

If grade 2 or greater immune-mediated hypophysitis occurs, temporarily withhold or discontinue nivolumab; initiate systemic corticosteroid therapy at a dosage of 1 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage; and, if indicated, initiate hormone replacement therapy.¹ (See Therapy Interruption for Toxicity under Dosage and Administration.)

Adrenal Insufficiency

Monitor for manifestations of adrenal insufficiency.¹

If grade 2 or greater immune-mediated adrenal insufficiency occurs, temporarily withhold or discontinue nivolumab.¹ (See Therapy Interruption for Toxicity under Dosage and Administration.)

For grade 3 or 4 immune-mediated adrenal insufficiency, initiate systemic corticosteroid therapy at a dosage of 1–2 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage.¹

Thyroid Dysfunction

Evaluate thyroid function prior to initiation of therapy and periodically during therapy.¹

If immune-mediated hypothyroidism occurs, initiate thyroid hormone replacement therapy as clinically indicated.¹

If immune-mediated hyperthyroidism occurs, initiate appropriate medical therapy.¹

Diabetes Mellitus

Monitor for hyperglycemia.¹

If grade 3 or greater immune-mediated hyperglycemia occurs, temporarily withhold or discontinue nivolumab.¹ (See Therapy Interruption for Toxicity under Dosage and Administration.)

Immune-mediated Renal Effects

Immune-mediated nephritis reported.¹

Evaluate renal function prior to initiation of therapy and periodically during therapy.¹

If elevations in S_cr concentrations (>1.5 times the ULN) occur, temporarily withhold or discontinue nivolumab.¹ (See Therapy Interruption for Toxicity under Dosage and Administration.)

If grade 4 elevations in S_cr concentrations occur, initiate systemic corticosteroid therapy at a dosage of 1–2 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage.¹

If grade 2 or 3 elevations in S_cr concentrations occur, initiate systemic corticosteroid therapy at a dosage of 0.5–1 mg/kg of prednisone daily (or equivalent); if renal function worsens or fails to improve, increase dosage to 1–2 mg/kg of prednisone daily (or equivalent).¹

Immune-mediated Dermatologic Effects

Immune-mediated rash (sometimes fatal), including Stevens-Johnson syndrome and toxic epidermal necrolysis, reported.¹

Depending on nature and severity of immune-mediated rash, temporarily withhold or discontinue nivolumab.¹ (See Therapy Interruption for Toxicity under Dosage and Administration.)

If grade 3 or 4 immune-mediated rash occurs, initiate systemic corticosteroid therapy at a dosage of 1–2 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage.¹

Immune-mediated CNS Effects

Immune-mediated encephalitis, sometimes fatal, reported.¹

Depending on severity of neurologic symptoms, temporarily withhold or discontinue nivolumab.¹ (See Therapy Interruption for Toxicity under Dosage and Administration.)

If new moderate to severe neurologic manifestations suggestive of encephalitis (e.g., headache, pyrexia, confusion, memory loss, hallucinations, fatigue/asthenia, somnolence, drowsiness, seizures, stiff neck) occur, ensure adequate evaluation (e.g., consultation with neurologist, brain magnetic resonance imaging [MRI] scan, lumbar puncture) to exclude other causes (e.g., infection).¹ If immune-mediated encephalitis is confirmed, initiate systemic corticosteroid therapy at a dosage of 1–2 mg/kg of prednisone daily (or equivalent) followed by tapering of the corticosteroid dosage.¹

Other Immune-mediated Effects

Other immune-mediated adverse effects (e.g., myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis [Kikuchi lymphadenitis], motor dysfunction, vasculitis, myasthenic syndrome), sometimes fatal, reported.¹ Onset may occur following discontinuance of therapy.¹

If an immune-mediated adverse effect is suspected, ensure adequate evaluation to exclude other causes.¹

Depending on severity of immune-mediated adverse effect, temporarily withhold or permanently discontinue nivolumab; initiate high-dose systemic corticosteroid therapy; and, if indicated, initiate hormone replacement therapy.¹ (See Therapy Interruption for Toxicity under Dosage and Administration.) Once toxicity has resolved to grade 0 or 1, taper corticosteroid dosage over ≥1 month.¹ If clinically appropriate, may restart nivolumab following completion of corticosteroid taper.¹

If uveitis occurs in conjunction with other immune-mediated adverse effects, consider possibility of a Vogt-Koyanagi-Harada-like syndrome (reported in patients receiving nivolumab as a single agent or in combination with ipilimumab).¹ Systemic corticosteroid therapy may be required to reduce risk of permanent vision loss.¹

Infusion-related Effects

Infusion-related reactions, sometimes severe, reported.¹

Frequency of infusion-related reactions not substantially different following 30- or 60-minute IV infusion.¹

Depending on severity of infusion-related reaction, interrupt infusion, reduce infusion rate, or permanently discontinue nivolumab.¹ (See Infusion-related Reactions under Dosage and Administration.)

Allogeneic Stem Cell Transplantation-related Complications

Complications (i.e., graft-versus-host disease [GVHD], febrile syndrome requiring systemic corticosteroid therapy, hepatic veno-occlusive disease), sometimes fatal, reported in patients who underwent allogeneic stem cell transplantation following therapy with nivolumab.¹ Complications may occur despite other intervening therapy between nivolumab administration and transplantation.¹

Closely monitor patients for early manifestations of stem cell transplantation-related complications and manage promptly.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.^{1 5} May disrupt maternal immune tolerance to the fetus and increase risk of fetal loss (abortion, stillbirth) or neonatal death; also may increase risk of immune-mediated disorders.^{1 5} Effects may be greater during the second and third trimesters of pregnancy.¹

Avoid pregnancy during therapy.¹ Women of childbearing potential should use an effective contraceptive method while receiving the drug and for ≥5 months after the last dose.¹ If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.¹

Immunogenicity

Potential for immunogenicity.¹ Development of binding antibodies and neutralizing antibodies to nivolumab reported.¹

Effects on safety (including infusion-related reactions) or pharmacokinetics of the drug not observed in patients receiving single-agent nivolumab.¹

Effects on safety (including infusion-related reactions) not observed in patients receiving nivolumab in combination with ipilimumab; however, clearance of nivolumab increased by 42% in presence of anti-nivolumab antibodies.¹

Specific Populations

Pregnancy

May cause fetal harm.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether nivolumab is distributed into milk.¹ Discontinue nursing.¹

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age with melanoma, NSCLC, renal cell carcinoma, cHL, squamous cell carcinoma of the head and neck, urothelial carcinoma, or hepatocellular carcinoma.¹

Safety and efficacy not established in pediatric patients <12 years of age with MSI-H or dMMR metastatic colorectal cancer.¹

Safety and efficacy for treatment of MSI-H or dMMR metastatic colorectal cancer in adolescents ≥12 years of age are supported by extrapolation of data from clinical studies of nivolumab in adults, population pharmacokinetic analyses indicating that age and body weight do not affect exposure to nivolumab, and evidence that exposure to monoclonal antibodies generally is similar in adults and adolescents.¹

Geriatric Use

Nivolumab monotherapy: Insufficient experience in some studies in patients with melanoma, cHL, squamous cell carcinoma of the head and neck, MSI-H or dMMR metastatic colorectal cancer, or hepatocellular carcinoma to determine whether patients ≥65 years of age respond differently than younger adults; however, no overall differences in safety or efficacy compared with younger adults observed in other studies in patients with melanoma, NSCLC, renal cell carcinoma, or urothelial carcinoma.¹

Combination therapy with ipilimumab: No overall differences in safety and efficacy compared with younger adults.¹

Hepatic Impairment

Clearance not affected by mild or moderate hepatic impairment.¹ Not studied in patients with severe hepatic impairment.¹ (See Special Populations under Pharmacokinetics.)

Renal Impairment

Clearance not affected by mild, moderate, or severe renal impairment.¹ (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Monotherapy in patients with unresectable or metastatic melanoma (incidence ≥10% and higher [by ≥5%] than with chemotherapy): Fatigue,^{1 14} musculoskeletal pain,¹ elevated ALT or AST concentrations,¹ hyponatremia,¹ elevated alkaline phosphatase concentrations,¹ rash,^{1 14} pruritus,^{1 14} cough,¹ hyperkalemia,¹ upper respiratory infection,¹ elevated bilirubin concentrations,¹ edema,¹ vitiligo,^{1 14} erythema.¹

Monotherapy in patients with unresectable or metastatic melanoma (incidence ≥20% and higher [by ≥5%] than with ipilimumab): Lymphopenia,¹ elevated concentrations of lipase.¹

Combination therapy with ipilimumab in patients with unresectable or metastatic melanoma (incidence ≥20% and higher [by ≥5%] than with ipilimumab): Fatigue,^{1 15} elevated ALT or AST concentrations,¹ rash,^{1 15} diarrhea,^{1 15} anemia,¹ hyponatremia,¹ elevated lipase or amylase concentrations,¹ elevated alkaline phosphatase concentrations,¹ nausea,^{1 15} pyrexia,^{1 15} lymphopenia,¹ hypocalcemia,¹ vomiting,^{1 15} elevated S_cr concentrations,¹ dyspnea.^{1 15}

Single-agent adjuvant therapy in patients with completely resected locally advanced or metastatic melanoma (incidence ≥10% and higher [by ≥5%] than with ipilimumab): Musculoskeletal pain,¹ lymphopenia,¹ upper respiratory infection,¹ arthralgia,¹ leukopenia,¹ neutropenia.¹

Monotherapy in patients with metastatic NSCLC (incidence ≥10% and higher [by ≥5%] than with docetaxel): Cough,¹ decreased appetite,^{1 3} elevated ALT or AST concentrations,¹ elevated alkaline phosphatase concentrations,¹ elevated S_cr concentrations,¹ elevated TSH concentrations,¹ pruritus.¹

Monotherapy in patients with advanced renal cell carcinoma (incidence ≥15% and higher [by ≥5%] than with everolimus): Hyponatremia,¹ hyperkalemia,¹ constipation,¹ back pain,¹ arthralgia,¹ hypercalcemia,¹ pruritus,¹ upper respiratory infection.¹

Monotherapy in patients with cHL (incidence ≥10%): Upper respiratory infection,¹ fatigue,¹ leukopenia,¹ neutropenia,¹ thrombocytopenia,¹ cough,¹ elevated ALT or AST concentrations,¹ diarrhea,¹ lymphopenia,¹ pyrexia,¹ anemia,¹ musculoskeletal pain,¹ rash,¹ elevated lipase or amylase concentrations,¹ elevated alkaline phosphatase concentrations,¹ hyponatremia,¹ nausea,¹ pruritus,¹ vomiting,¹ headache,¹ abdominal pain,¹ arthralgia,¹ hypokalemia,¹ elevated S_cr concentrations,¹ hypocalcemia,¹ hyperkalemia,¹ dyspnea,¹ constipation,¹ hypomagnesemia,¹ infusion-related reactions,¹ pneumonia,¹ hypothyroidism/thyroiditis,¹ peripheral neuropathy,¹ elevated bilirubin concentrations,¹ nasal congestion.¹

Monotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (incidence ≥10% and higher than with chemotherapy): Cough,¹ dyspnea,¹ elevated alkaline phosphatase concentrations,¹ elevated amylase concentrations,¹ hypercalcemia,¹ hyperkalemia,¹ elevated TSH concentrations.¹

Monotherapy in patients with locally advanced or metastatic urothelial carcinoma (incidence ≥10%): Asthenia/fatigue/malaise,^{1 23} hyperglycemia,¹ lymphopenia,¹ hyponatremia,¹ anemia,¹ elevated S_cr concentrations,¹ elevated alkaline phosphatase concentrations,¹ musculoskeletal pain,¹ hypocalcemia,¹ elevated ALT or AST concentrations,¹ decreased appetite,¹ elevated lipase or amylase concentrations,¹ nausea,¹ hyperkalemia,¹ cough,¹ diarrhea,¹ pyrexia,¹ urinary tract infection,¹ constipation,¹ hypomagnesemia,¹ rash,¹ thrombocytopenia,¹ thyroid disorders,¹ dyspnea,¹ abdominal pain,¹ edema,¹ pruritus,¹ vomiting,¹ leukopenia,¹ arthralgia.¹

Monotherapy in patients with advanced hepatocellular carcinoma: Adverse effects generally similar to those observed in other malignancies except for higher incidence of elevated ALT, AST, and bilirubin concentrations.¹

Interactions for Opdivo

No formal drug interaction studies to date.¹

Specific Drugs

Opdivo Pharmacokinetics

Absorption

Bioavailability

Steady-state concentrations achieved within 12 weeks.¹

Exposure is dose proportional over the dosage range of 0.1–10 mg/kg every 2 weeks;^{1 11} systemic accumulation is 3.7-fold when administered every 2 weeks.¹

Based on dose-exposure relationships, no clinically important differences in safety and efficacy observed between nivolumab dosages of 240 mg every 2 weeks and 3 mg/kg every 2 weeks in patients with melanoma, NSCLC, renal cell carcinoma, urothelial carcinoma, MSI-H metastatic colorectal cancer, or hepatocellular carcinoma.²⁷

Predicted exposure following 30-minute IV infusion is comparable to that observed following 60-minute IV infusion.¹

Distribution

Extent

Not known whether nivolumab is distributed into milk.¹

Elimination

Half-life

Approximately 25 days.¹

Special Populations

Mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration >1 to 1.5 times the ULN with any AST concentration) or moderate hepatic impairment (total bilirubin concentration >1.5 to 3 times the ULN with any AST concentration) does not affect clearance.¹ Data not available for severe hepatic impairment (total bilirubin concentration >3 times the ULN with any AST concentration).¹

Mild, moderate, or severe renal impairment (estimated GFR 15–89 mL/minute per 1.73 m²) does not affect clearance.¹

Age, body weight, gender, race, baseline LDH, programmed death ligand 1 (PD-L1) expression, solid tumor type, and tumor burden do not have meaningful effects on clearance of nivolumab.¹

In patients with metastatic tumors, clearance decreases by about 25% from baseline to steady state; not considered clinically important.¹ In patients with completely resected melanoma, clearance does not decrease over time but is 24% lower than the steady-state clearance in patients with metastatic melanoma.¹

Stability

Storage

Parenteral

Injection

2–8°C.¹ Do not freeze; protect from light.¹ Discard unused solution after initial entry into vial.¹

Diluted solution may be stored at room temperature for up to 8 hours after dilution (including infusion time) or 2–8°C for up to 24 hours after dilution.¹ Do not freeze.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Actions

• An IgG₄ kappa immunoglobulin that is selective for PD-1, an immune-checkpoint receptor expressed on activated T-cells, monocytes, B-cells, natural killer (NK) T-cells, and dendritic cells.^{1 3 7 8 11}

• Overexpression of PD-1 ligands on surface of tumor cells results in activation of PD-1 activity and suppression of cytotoxic T-cell activity.^{1 6 7 10 12}

• Blocks interaction between PD-1 and its ligands, resulting in enhanced immune response, including enhanced antitumor immune response.^{1 3 6 10 12}

• Enhanced T-cell function, including enhanced antitumor immune response, demonstrated when combined with an anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) antibody (i.e., ipilimumab) compared with either drug alone.¹

Advice to Patients

• Importance of reading the manufacturer’s medication guide before beginning treatment and each time nivolumab is administered.¹

• Risk of immune-mediated pneumonitis.¹ Importance of informing clinician immediately if new or worsening cough, chest pain, or shortness of breath occurs.¹

• Risk of immune-mediated colitis.¹ Importance of informing clinician immediately if diarrhea, severe abdominal pain, or changes in stool occur.¹

• Risk of immune-mediated hepatitis.¹ Importance of informing clinician immediately if signs and symptoms of liver damage (e.g., jaundice, severe nausea or vomiting, abdominal pain [particularly in the right upper quadrant], lethargy, easy bruising or bleeding, lack of appetite, dark urine, drowsiness) occur.¹

• Risk of immune-mediated endocrine effects.¹ Importance of informing clinician immediately if manifestations of hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufficiency, or diabetes mellitus occur.¹

• Risk of immune-mediated nephritis or renal dysfunction.¹ Importance of informing clinician immediately if signs and symptoms of nephritis (e.g., decreased urine output, hematuria, peripheral edema, lack of appetite) occur.¹

• Risk of immune-mediated rash.¹ Importance of informing clinician immediately if a rash develops.¹

• Risk of immune-mediated encephalitis.¹ Importance of informing clinician immediately if signs and symptoms of encephalitis (e.g., headache, fever, confusion, memory loss, hallucinations, fatigue, asthenia, somnolence, drowsiness, seizures, stiff neck) occur.¹

• Risk of infusion-related reactions.¹ Importance of informing clinician immediately if signs and symptoms of such reactions (e.g., dizziness, chills, fever, breathing difficulty, pruritus, flushing, feeling of faintness) occur.¹

• Risk of allogeneic stem cell transplantation-related complications.¹

• Risk of fetal harm.¹ Necessity of advising women of childbearing potential that they should use an effective method of contraception while receiving the drug and for ≥5 months after the last dose.¹ Importance of women informing clinicians if they are or plan to become pregnant.¹ If pregnancy occurs, advise pregnant women of potential risk to the fetus.¹

• Importance of advising women to avoid breast-feeding while receiving nivolumab therapy.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., autoimmune disorders, history of organ transplantation, liver damage, pulmonary disorders).¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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