Nivolumab and Relatlimab (Monograph)

Brand name: Opdualag
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Feb 10, 2024. Written by ASHP.

Introduction

Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody. Relatlimab-rmwb is a lymphocyte activation gene-3 (LAG-3) blocking antibody.

Uses for Nivolumab and Relatlimab

Melanoma

Fixed-dose combination for the treatment of adult and pediatric patients ≥12 years of age with unresectable or metastatic melanoma (designated an orphan drug by FDA for this use).

Guidelines recommend nivolumab and relatlimab-rmbw as one of several first-line treatment options for unresectable or metastatic melanoma.

Nivolumab and Relatlimab Dosage and Administration

General

Pretreatment Screening

- Evaluate liver enzymes, creatinine, and thyroid function at baseline.
- Verify pregnancy status of females of reproductive potential prior to initiating nivolumab and relatlimab-rmwb.

Patient Monitoring

Monitor for infusion-related reactions.
Closely monitor for clinical manifestations of underlying immune-mediated adverse reactions during treatment and after discontinuation.
Monitor liver enzymes, creatinine, and thyroid function periodically during treatment.
Monitor for hyperglycemia or other signs and symptoms of diabetes during treatment.
For patients who have undergone or are undergoing allogeneic hematopoietic stem cell transplantation, monitor closely for transplant-related complications.

Administration

Administer by IV infusion.

Available as a solution in single-dose vials containing 240 mg nivolumab and 80 mg relatlimab per 20 mL (12 mg and 4 mg per mL). Solution is clear to opalescent and colorless to slightly yellow; discard if cloudy, discolored, or contains extraneous particulate matter. Does not contain a preservative.

May administer diluted or undiluted.

If administering undiluted solution, withdraw the required volume of drug and transfer to a compatible IV container. Compatible with di(2-ethylhexyl)phthalate (DEHP) plasticized PVC, ethyl vinyl acetate (EVA), and polyolefin IV bags.

If preparing a diluted solution, dilute drug with 0.9% sodium chloride or 5% dextrose to prepare an infusion meeting the final concentration and maximum infusion volume parameters specified in Table 1. Mix diluted solution by gentle inversion; do not shake.

The concentration range in each group includes 12 mg/mL nivolumab and 4 mg/mL relatlimab as the upper limit, which represents a scenario in which the drug product is infused without dilution.

Table 1. Maximum Infusion Volumes and Concentration Ranges by Patient Group1
Patient Group	Maximum Infusion Volume	Concentration Range
Adult and pediatric patients ≥12 years of age weighing ≥40 kg	160 mL	Nivolumab: 3–12 mg/mL Relatlimab: 1–4 mg/mL
Adult patients weighing <40 kg	4 mL/kg	Nivolumab: 3–12 mg/mL Relatlimab: 1–4 mg/mL

Administer by IV infusion over 30 minutes through an IV line containing a sterile, non-pyrogenic, low protein binding in-line polyethersulfone (PES), nylon, or polyvinylidene fluoride (PVDF) filter (pore size of 0.2–1.2 micrometer). Flush the IV line at the end of the infusion. Do not co-administer other drugs through the same IV line.

Dosage

Pediatric Patients

Melanoma

IV

Pediatric patients ≥12 years of age weighing ≥40 kg: 480 mg nivolumab and 160 mg relatlimab IV every 4 weeks until disease progression or unacceptable toxicity.

Adults

Melanoma

IV

480 mg nivolumab and 160 mg relatlimab IV every 4 weeks until disease progression or unacceptable toxicity.

<C> Dosage Modification for Toxicity

No dosage reduction recommended. In general, withhold nivolumab and relatlimab-rmbw for severe (grade 3) immune-related adverse reactions. Permanently discontinue treatment for life-threatening (grade 4) immune-mediated adverse reactions, recurrent severe (grade 3) immune-mediated adverse reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to ≤10 mg of prednisone or equivalent per day within 12 weeks of initiating steroids. See Table 2 for recommended dosage modifications for adverse reactions that require management different from these general guidelines.

Resume in patients with complete or partial resolution (Grade 0 or 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids.

Depending on clinical severity, consider withholding for grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.

DRESS, drug rash with eosinophilia and systemic symptoms; SJS, Stevens Johnson syndrome; TEN, toxic epidermal necrolysis.

Table 2. Recommended Dosage Modifications for Adverse Reactions1
Adverse Reaction	Severity	Dose Modification
*Immune-mediated Adverse Reactions*
Pneumonitis	Grade 2	Withhold
	Grade 3 or 4	Permanently discontinue
Colitis	Grade 2 or 3	Withhold
	Grade 4	Permanently discontinue
Hepatitis	AST or ALT increases to >3 and ≤8 times ULN or total bilirubin increases to >1.5 and ≤3 times ULN	Withhold
	AST or ALT increases to >8 times ULN regardless of baseline or total bilirubin increases to >3 times ULN	Permanently discontinue
Endocrinopathies	Grade 3 or 4	Withhold until clinically stable or permanently discontinue depending on severity
Nephritis with renal dysfunction	Grade 2 or 3 increased blood creatinine	Withhold
	Grade 4 increased blood creatinine	Permanently discontinue
Exfoliative dermatologic reactions	Suspected SJS, TEN, or DRESS	Withhold
	Confirmed SJS, TEN, or DRESS	Permanently discontinue
Myocarditis	Grade 2, 3, or 4	Permanently discontinue
Neurological toxicities	Grade 2	Withhold
	Grade 3 or 4	Permanently discontinue
*Other Adverse Reactions*
Infusion-related reactions	Grade 1 or 2	Interrupt or slow the rate of infusion
	Grade 3 or 4	Permanently discontinue

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Nivolumab and Relatlimab

Contraindications

None.

Warnings/Precautions

Severe and Fatal Immune-Mediated Adverse Reactions

Potentially breaks peripheral tolerance and induces immune-mediated adverse reactions; reactions may be severe or fatal and occur in any organ system or tissue. Reactions may occur any time after starting treatment; reactions usually occur during treatment, but may also manifest after treatment discontinuation.

Early identification and management of immune-mediated adverse reactions is essential. Monitor patients closely for symptoms and signs that may be clinical manifestations of immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. If an immune-mediated adverse reaction is suspected, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Depending on reaction severity, withhold or permanently discontinue nivolumab and relatlimab-rmbw. In general, if treatment requires interruption or discontinuation, administer systemic corticosteroid therapy (1–2 mg/kg per day prednisone or equivalent) until improvement to grade 1 or less. Upon improvement, initiate corticosteroid taper and continue taper over at least 1 month. Consider use of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Immune-mediated pneumonitis

Immune-mediated pneumonitis reported, sometimes leading to treatment interruption or discontinuation. Most cases resolved with use of systemic corticosteroids. In patients treated with other programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) blocking antibodies, incidence of pneumonitis is higher among patients with prior thoracic radiation.

Immune-mediated colitis

Immune-mediated colitis or diarrhea reported, sometimes leading to treatment interruption or discontinuation. Most cases resolved with use of systemic corticosteroids.

Cytomegalovirus infection or reactivation reported in patients with corticosteroid-refractory immune-mediated colitis; in cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated hepatitis

Immune-mediated hepatitis reported, sometimes leading to treatment interruption or discontinuation. Most cases resolved with use of systemic corticosteroids.

Immune-mediated endocrinopathies

Primary and secondary adrenal insufficiency reported, sometimes leading to treatment interruption or discontinuation. For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold nivolumab and relatlimab-rmbw depending on severity.

Immune-related hypophysitis reported; may present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue nivolumab and relatlimab-rmbw depending on severity.

Immune-related thyroid disorders reported, including thyroiditis, hyperthyroidism, and hypothyroidism. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue nivolumab and relatlimab-rmbw depending on severity.

Type 1 diabetes can occur and may present as diabetic ketoacidosis. Monitor for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue nivolumab and relatlimab-rmbw depending on severity.

Immune-mediated nephritis with renal dysfunction

Immune-related nephritis reported, sometimes leading to treatment interruption or discontinuation. Most cases resolved with use of systemic corticosteroids. Withhold or permanently discontinue nivolumab and relatlimab-rmbw depending on severity.

Immune-mediated dermatologic adverse reactions

Immune-related rash or dermatitis reported, sometimes leading to treatment interruption. Exfoliative dermatitis, including Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) reported with other PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue nivolumab and relatlimab-rmbw depending on severity.

Immune-mediated myocarditis

Immune-related myocarditis reported. Assess patients with cardiac or cardiopulmonary symptoms for potential myocarditis. If myocarditis is suspected, withhold dose, promptly initiate high dose steroids (prednisone or methylprednisolone 1–2 mg/kg per day), and promptly arrange cardiology workup. If grade 2, 3, or 4 myocarditis is clinically confirmed, permanently discontinue nivolumab and relatlimab-rmbw.

Other immune-mediated adverse reactions

Other clinically significant immune-mediated adverse reactions reported in patients receiving nivolumab and relatlimab-rmbw or other PD-1/PD-L1 blocking antibodies include: pericarditis, vasculitis, meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy, uveitis, iritis, pancreatitis (including increases in serum amylase and lipase), gastritis, duodenitis, myositis/polymyositis, rhabdomyolysis and associated sequelae, arthritis, polymyalgia rheumatica, hypoparathyroidism, hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, and solid organ transplant rejection.

Uveitis, iritis, and other ocular inflammatory toxicities can occur; some cases may be associated with retinal detachment, and various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome; may require treatment with systemic corticosteroids to reduce risk of permanent vision loss.

Infusion-Related Reactions

Severe infusion-related reactions reported. Discontinue for severe or life-threatening reactions, and interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Serious and fatal complications reported in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with PD-1/PD-L1 receptor blocking antibodies. Transplant-related complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT, and may include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome without an identified infectious cause.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider benefits and risks of PD-1/PD-L1 receptor blocking antibody treatment prior to or after allogeneic HSCT.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and data from animal studies. Advise pregnant females of the potential risk to a fetus. Verify pregnancy status of females of reproductive potential prior to starting treatment with nivolumab and relatlimab-rmbw. Advise females of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose of nivolumab and relatlimab-rmbw.

Immunogenicity

Anti-drug antibodies and neutralizing antibodies reported; effects on pharmacokinetics, pharmacodynamics, safety, or effectiveness of nivolumab and relatlimab-rmbw unknown.

Specific Populations

Pregnancy

No data available in pregnant females to evaluate a drug-associated risk. Based on animal data and the mechanism of action, nivolumab and relatlimab-rmbw can cause fetal harm when administered to pregnant females. Human IgG₄ is known to cross the placenta; therefore, nivolumab and relatlimab-rmbw may be transmitted from the mother to the developing fetus. Effects of nivolumab and relatlimab-rmbw likely to be greater during the second and third trimesters of pregnancy. Advise patients of the potential risk to a fetus, and verify pregnancy status of females of reproductive potential prior to initiating therapy.

Lactation

No data available regarding the presence of nivolumab and relatlimab-rmbw in human milk, effects on the breastfed infant, or effects on milk production. Because nivolumab and relatlimab-rmwb may be excreted in human milk and potential for serious adverse effects in the breastfed infant exists, advise patients not to breastfeed during treatment with nivolumab and relatlimab-rmbw and for at least 5 months after the last dose.

Females and Males of Reproductive Potential

May cause fetal harm when administered during pregnancy.

Verify the pregnancy status of females of reproductive potential prior to initiating treatment.

Advise females of reproductive potential to use effective contraception during treatment and for at least 5 months following the last dose.

Pediatric Use

Safety and effectiveness for the treatment of unresectable or metastatic melanoma established in pediatric patients ≥12 years of age weighing ≥40 kg.

Safety and effectiveness not established in pediatric patients ≥12 years of age weighing <40 kg, or pediatric patients <12 years of age.

Geriatric Use

No overall differences in safety or effectiveness observed between elderly and younger patients.

Hepatic Impairment

Mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN, or total bilirubin >1 to 1.5 times ULN with any AST) and moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN with any AST) did not have a clinically important effect on clearance of nivolumab and relatlimab. Effects of severe hepatic impairment unknown.

Renal Impairment

Mild or moderate renal impairment (eGFR 30–89 mL/min/1.73m²) did not have a clinically important effect on clearance of nivolumab and relatlimab-rmwb. Effects of severe renal impairment unknown.

Common Adverse Effects

The most common adverse reactions (incidence ≥20%) are musculoskeletal pain, fatigue, rash, pruritus, diarrhea. The most common laboratory abnormalities (incidence ≥20%) are decreased hemoglobin, decreased lymphocytes, increased AST, increased ALT, decreased sodium.

Drug Interactions

No formal drug inteaction studies conducted.

Nivolumab and Relatlimab Pharmacokinetics

Absorption

Bioavailability

Steady-state concentrations achieved by 16 weeks with an every 4-week regimen; systemic accumulation was 1.9-fold.

Average concentration of relatlimab-rmwb after the first dose increases dose proportionally at doses ≥160 mg every 4 weeks.

Special Populations

Exposures of nivolumab and relatlimab-rmwb in pediatric patients ≥12 years of age weighing ≥40 kg expected to be in the range of exposures in adult patients at the recommended dosage.

Distribution

Extent

No data available regarding presence in human milk.

Elimination

Half-life

Relatlimab: 26.2 days.

Nivolumab: 26.5 days.

Special Populations

Age (17–92 years), sex, and race had no clinically important effect on clearance.

Stability

Storage

Parenteral

Solution for injection

Unopened vials: 2–8ºC in the original carton to protect from light.

Prepared solution: May store at room temperature and room light for no more than 8 hours from time of preparation to end of the infusion; discard if not used within 8 hours of preparation. May also be stored under refrigeration at 2–8°C with protection from light for no more than 24 hours from time of preparation: this includes time allowed for the bag to come to room temperature and the duration of the infusion. Discard refrigerated solution if not used within 24 hours from time of preparation.

Actions

Fixed-dose combination of 2 human IgG₄ monoclonal antibodies, nivolumab (a programmed death receptor-1 [PD-1] blocking antibody) and relatlimab-rmwb (a lymphocyte activation gene-3 [LAG-3] blocking antibody).
Binding of programmed death ligand-1 (PD-L1) and PD-L2 to the PD-1 receptor on T cells inhibits T-cell proliferation and cytokine production; upregulation of PD-1 ligands occurs in some tumors and contributes to inhibition of active T-cell immune surveillance of tumors. Nivolumab binds to PD-1, blocks interaction with PD-L1 and PD-L2, and reduces PD-1 pathway-mediated inhibition of the immune response.
Relatlimab-rmwb binds to LAG-3 receptor, blocks interaction with its ligands (including major histocompatibility complex [MHC] II), and reduces LAG-3 pathway-mediated inhibition of the immune response. Antagonism of this pathway promotes T-cell proliferation and cytokine secretion.
Combination of nivolumab and relatlimab-rmwb results in increased T-cell activation compared to the activity of either antibody alone.
In murine syngeneic tumor models, LAG-3 blockage potentiates anti-tumor activity of PD-1 blockage, inhibiting tumor growth and promoting tumor regression.

Advice to Patients

Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and withholding or discontinuation of nivolumab and relatlimab-rmbw.
Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath.
Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain.
Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of the abdomen, lethargy, or easy bruising or bleeding.
Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, thyroiditis, hypothyroidism, hyperthyroidism, and diabetes mellitus.
Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis, including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction.
Advise patients to contact their healthcare provider immediately for rash.
Advise patients to contact their healthcare provider immediately for signs or symptoms of new or worsening chest pain, palpitations, shortness of breath, fatigue, or swelling in ankles.
Advise patients of the potential risk of infusion-related reactions.
Advise patients of the potential risk of post-transplant complications.
Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with nivolumab and relatlimab-rmbw and for at least 5 months following the last dose.
Advise patients not to breastfeed during treatment with nivolumab and relatlimab-rmbw and for at least 5 months following the last dose.
Advise patients to inform their healthcare provider of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.