Opdivo

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

Introduction

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

Uses for Opdivo

Melanoma

Treatment of unresectable or metastatic melanoma following failure of ipilimumab and, in patients with tumors bearing the b-Raf serine-threonine kinase (BRAF) V600 mutation, therapy with a BRAF inhibitor^{1 2} (designated an orphan drug by FDA for this use).⁴

Efficacy based on overall response rate and response duration; improvement in patient-reported outcomes and overall survival not demonstrated.¹

Non-small Cell Lung Cancer (NSCLC)

Treatment of metastatic squamous NSCLC that has progressed during or following therapy with platinum-based chemotherapy.^{1 3}

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 60 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

For IV infusion over 60 minutes, 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} 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 60 minutes.¹

Dosage

Adults

Melanoma

IV

3 mg/kg every 2 weeks.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

NSCLC

IV

3 mg/kg every 2 weeks.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Therapy Interruption for Toxicity

Discontinue therapy in patients experiencing any life-threatening immune-mediated adverse effect, patients with persistent grade 2 or 3 immune-mediated adverse effects that do not recover to grade 0 or 1 within 12 weeks of the last dose of nivolumab, and those unable to reduce corticosteroid dosage to ≤10 mg of prednisone daily (or equivalent) within 12 weeks.¹ (See Warnings/Precautions under Cautions.)

Discontinue therapy if severe or 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, discontinue drug.^{1 13}

Immune-mediated GI Effects

If grade 2 or 3 immune-mediated colitis occurs, interrupt therapy until toxicity resolves to grade 0 or 1.^{1 13} If colitis recurs upon reinitiation of therapy, discontinue drug.^{1 13} (See Immune-mediated GI Effects under Cautions.)

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

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), discontinue drug.^{1 13}

Immune-mediated Endocrine Effects

No specific dosage recommendations at this time.¹ (See Immune-mediated Endocrine Effects under Cautions.)

Other Immune-mediated Adverse Effects

If any other severe or grade 3 immune-mediated adverse effects occur, interrupt therapy until toxicity resolves to grade 0 or 1.¹ (See Other Immune-mediated Effects under Cautions.)

Special Populations

Hepatic Impairment

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

Moderate or 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

Severe pneumonitis or interstitial lung disease, including immune-mediated pneumonitis, sometimes fatal, reported.^{1 3}

Monitor patients for manifestations of pneumonitis.¹ If grade 2 or greater immune-mediated pneumonitis occurs, temporarily withhold or discontinue nivolumab and initiate systemic corticosteroid therapy (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

Diarrhea or colitis, including immune-mediated colitis, 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 and hepatotoxicity (i.e., elevations in serum ALT or AST, alkaline phosphatase, or total bilirubin concentrations) reported.¹

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

If grade 2 or greater elevations in ALT or AST concentrations (with or without concomitant elevations of total bilirubin concentrations) occur, initiate systemic corticosteroid therapy (1–2 mg/kg of prednisone daily [or equivalent]).¹ If immune-mediated hepatitis occurs, temporarily withhold or discontinue nivolumab.¹ (See Therapy Interruption for Toxicity under Dosage and Administration.)

Immune-mediated Renal Effects

Immune-mediated nephritis and elevated S_cr concentrations reported.¹

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

If grade 4 elevations in S_cr concentrations occur, 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

If grade 2 or 3 elevations in S_cr concentrations occur, temporarily withhold nivolumab and 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 renal function worsens or fails to improve, increase dosage to 1–2 mg/kg of prednisone daily (or equivalent) and permanently discontinue nivolumab.¹ (See Therapy Interruption for Toxicity under Dosage and Administration.)

Immune-mediated Endocrine Effects

Immune-mediated endocrinopathies, including hypothyroidism and hyperthyroidism, reported.¹

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

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

If immune-mediated hyperthyroidism occurs, initiate appropriate medical therapy.¹ (See Therapy Interruption for Toxicity under Dosage and Administration.)

Other Immune-mediated Effects

Other immune-mediated adverse effects (e.g., adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction, vasculitis, hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, myasthenic syndrome) reported.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 nivolumab and initiate high-dose systemic corticosteroid therapy and, if indicated, 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 severe or grade 3 immune-mediated adverse effects occur, temporarily withhold or discontinue nivolumab.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 drug is discontinued.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 pharmacokinetics or toxicity of the drug not observed.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.¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.¹ In CheckMate-037 study (unresectable or metastatic melanoma), 35% of patients receiving nivolumab were ≥65 years of age and 15% were ≥75 years of age.¹ In CheckMate-063 study (metastatic squamous NSCLC), 50% of patients receiving nivolumab were ≥65 years of age and 14% were ≥75 years of age.¹

Hepatic Impairment

Clearance not affected by mild hepatic impairment.¹ Not studied in patients with moderate or 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

Patients with unresectable or metastatic melanoma, following failure of prior therapy: Elevated ALT or AST concentrations,¹ elevated alkaline phosphatase concentrations,¹ hyponatremia,¹ rash,¹ pruritus,¹ cough,¹ hyperkalemia,¹ upper respiratory infection,¹ peripheral edema.¹

Patients with metastatic squamous NSCLC, following failure of prior therapy: Fatigue,^{1 3} lymphopenia,¹ dyspnea,¹ hyponatremia,¹ musculoskeletal pain,¹ decreased appetite,^{1 3} cough,¹ nausea,^{1 3} anemia,¹ constipation,¹ elevated S_cr concentrations,¹ hypercalcemia,¹ hypokalemia,¹ hypomagnesemia,¹ asthenia,^{1 3} vomiting,¹ diarrhea,^{1 3} hypocalcemia,¹ hyperkalemia,¹ edema,¹ pyrexia,¹ abdominal pain,¹ rash,¹ thrombocytopenia,¹ elevated ALT or AST concentrations,¹ arthralgia,¹ chest pain,¹ weight loss,¹ pruritus,¹ pain,¹ pneumonia,¹ elevated alkaline phosphatase concentrations.¹

Interactions for Opdivo

No formal drug interaction studies to date.¹

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; systemic accumulation is threefold when administered every 2 weeks.^{1 11}

Distribution

Extent

Not known whether nivolumab is distributed into milk.¹

Elimination

Half-life

26.7 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) does not affect clearance.¹ Data not available for moderate or severe hepatic impairment (total bilirubin concentration >1.5 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, gender, race, baseline LDH, programmed death ligand 1 (PD-L1) expression, tumor type, and tumor burden do not have meaningful effects on clearance of nivolumab.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 4 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}

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 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 thyroid dysfunction (i.e., hypothyroidism, hyperthyroidism).¹ Importance of informing clinician immediately if symptoms of abnormal thyroid function (e.g., hair loss, weight gain or loss, feeling cold) occur.¹

• Importance of laboratory monitoring during nivolumab therapy.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 discontinuance of therapy.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.