Nivolumab and relatlimab-rmbw
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, DMD, MD[2]
Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
Overview
Nivolumab and relatlimab-rmbw is a combination of nivolumab, a programmed death receptor-1 (PD-1) blocking antibody, and relatlimab, a lymphocyte activation gene-3 (LAG-3) blocking antibody that is FDA approved for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. Common adverse reactions include immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis with renal dysfunction, and immune-mediated myocarditis.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
The recommended dosage of OPDUALAG for adult patients is 480 mg nivolumab and 160 mg relatlimab administered intravenously every 4 weeks until disease progression or unacceptable toxicity occurs.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
The recommended dosage of OPDUALAG for pediatric patients 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab administered intravenously every 4 weeks until disease progression or unacceptable toxicity occurs.
The recommended dosage for pediatric patients 12 years of age or older who weigh less than 40 kg has not been established.
Off-Label Use and Dosage (Pediatric)
Contraindications
None.
Warnings
5.1 Severe and Fatal Immune-Mediated Adverse Reactions OPDUALAG potentially breaks peripheral tolerance and induces immune-mediated adverse reactions (IMARs) [see Clinical Pharmacology (12.1)]. Important IMARs listed under Warnings and Precautions may not include all possible severe and fatal IMARs.
IMARs, which may be severe or fatal, can occur in any organ system or tissue. IMARs can occur at any time after starting treatment with a LAG-3 and PD-1/PD-L1 blocking antibodies. While IMARs usually manifest during treatment, IMARs can also manifest after discontinuation.
Early identification and management of IMARs are essential to ensure safe use. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying IMARs. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected IMARs, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration (2.2)]. In general, if OPDUALAG requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose IMARs are not controlled with corticosteroid therapy.
Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis OPDUALAG can cause immune-mediated pneumonitis, which may be fatal. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.
Immune-mediated pneumonitis occurred in 3.7% (13/355) of patients receiving OPDUALAG, including Grade 3 (0.6%), and Grade 2 (2.3%) adverse reactions. Pneumonitis led to permanent discontinuation of OPDUALAG in 0.8% and withholding of OPDUALAG in 1.4% of patients.
Systemic corticosteroids were required in 100% (13/13) of patients with pneumonitis. Pneumonitis resolved in 85% of the 13 patients. Of the 5 patients in whom OPDUALAG was withheld for pneumonitis, 5 reinitiated OPDUALAG after symptom improvement; of these, none had recurrence of pneumonitis.
Immune-Mediated Colitis OPDUALAG can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus infection/reactivation has been 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 diarrhea or colitis occurred in 7% (24/355) of patients receiving OPDUALAG, including Grade 3 (1.1%) and Grade 2 (4.5%) adverse reactions. Colitis led to permanent discontinuation of OPDUALAG in 2% and withholding of OPDUALAG in 2.8% of patients.
Systemic corticosteroids were required in 100% (24/24) of patients with diarrhea or colitis. Colitis resolved in 83% of the 24 patients. Of the 10 patients in whom OPDUALAG was withheld for colitis, 9 reinitiated OPDUALAG after symptom improvement; of these, 67% had recurrence of colitis.
Immune-Mediated Hepatitis OPDUALAG can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.
Immune-mediated hepatitis occurred in 6% (20/355) of patients receiving OPDUALAG, including Grade 4 (0.6%), Grade 3 (3.4%), and Grade 2 (1.4%) adverse reactions. Hepatitis led to permanent discontinuation of OPDUALAG in 1.7% and withholding of OPDUALAG in 2.3% of patients.
Systemic corticosteroids were required in 100% (20/20) of patients with hepatitis. Hepatitis resolved in 70% of the 20 patients. Of the 8 patients in whom OPDUALAG was withheld for hepatitis, 6 reinitiated OPDUALAG after symptom improvement; of these, 50% had recurrence of hepatitis.
Immune-Mediated Endocrinopathies Adrenal Insufficiency
OPDUALAG can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold OPDUALAG depending on severity [see Dosage and Administration (2.2)].
Adrenal insufficiency occurred in 4.2% (15/355) of patients receiving OPDUALAG, including Grade 3 (1.4%) and Grade 2 (2.5%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDUALAG in 1.1% and withholding of OPDUALAG in 0.8% of patients.
Approximately 87% (13/15) of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 87% (13/15) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 33% of the 15 patients. Of the 3 patients in whom OPDUALAG was withheld for adrenal insufficiency, all 3 reinitiated OPDUALAG after symptom improvement.
Hypophysitis
OPDUALAG can cause immune-mediated hypophysitis. Hypophysitis can 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 OPDUALAG depending on severity [see Dosage and Administration (2.2)].
Hypophysitis occurred in 2.5% (9/355) of patients receiving OPDUALAG, including Grade 3 (0.3%) and Grade 2 (1.4%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDUALAG in 0.3% and withholding of OPDUALAG in 0.6% of patients.
All (9/9) of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 100% (9/9) of patients with hypophysitis. Hypophysitis resolved in 22% of the 9 patients. Of the 2 patients in whom OPDUALAG was withheld for hypophysitis, none reinitiated OPDUALAG after symptom improvement.
Thyroid Disorders
OPDUALAG can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration (2.2)].
Thyroiditis
Thyroiditis occurred in 2.8% (10/355) of patients receiving OPDUALAG, including Grade 2 (1.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of OPDUALAG. Thyroiditis led withholding of OPDUALAG in 0.3% of patients.
Systemic corticosteroids were required in 20% (2/10) of patients with thyroiditis. Thyroiditis resolved in 90% of the 10 patients. For the 1 patient in whom OPDUALAG was withheld for thyroiditis, OPDUALAG was reinitiated after symptom improvement without recurrence of thyroiditis.
Hyperthyroidism
Hyperthyroidism occurred in 6% (22/355) of patients receiving OPDUALAG, including Grade 2 (1.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of OPDUALAG. Hyperthyroidism led to withholding of OPDUALAG in 0.3% of patients.
Systemic corticosteroids were required in 23% (5/22) of patients. Hyperthyroidism resolved in 82% of the 22 patients. For the 1 patient in whom OPDUALAG was withheld for hyperthyroidism, OPDUALAG was reinitiated after symptom improvement without recurrence of hyperthyroidism.
Hypothyroidism
Hypothyroidism occurred in 17% (59/355) of patients receiving OPDUALAG, including Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDUALAG in 0.3% and withholding of OPDUALAG in 2.5% of patients.
None of the patients with hypothyroidism required systemic corticosteroids. Hypothyroidism resolved in 12% of the 59 patients. Of the 9 patients in whom OPDUALAG was withheld for hypothyroidism, 6 reinitiated OPDUALAG after symptom improvement; of these, 33% had recurrence of hypothyroidism.
Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration (2.2)].
Diabetes occurred in 0.3% (1/355) of patients receiving OPDUALAG, a Grade 3 (0.3%) adverse reaction, and no cases of diabetic ketoacidosis. Diabetes did not lead to the permanent discontinuation or withholding of OPDUALAG in any patient.
Immune-Mediated Nephritis with Renal Dysfunction OPDUALAG can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology. Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration (2.2)].
Immune-mediated nephritis and renal dysfunction occurred in 2% (7/355) of patients receiving OPDUALAG, including Grade 3 (1.1%) and Grade 2 (0.8%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of OPDUALAG in 0.8% and withholding of OPDUALAG in 0.6% of patients.
Systemic corticosteroids were required in 100% (7/7) of patients with nephritis and renal dysfunction. Nephritis and renal dysfunction resolved in 71% of the 7 patients. Of the 2 patients in whom OPDUALAG was withheld for nephritis or renal dysfunction, 1 reinitiated OPDUALAG after symptom improvement without recurrence of nephritis or renal dysfunction.
Immune-Mediated Dermatologic Adverse Reactions OPDUALAG can cause immune-mediated rash or dermatitis, defined as requiring use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, and Drug Rash with Eosinophilia and Systemic Symptoms has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue OPDUALAG depending on severity [see Dosage and Administration (2.2)].
Immune-mediated rash occurred in 9% (33/355) of patients receiving OPDUALAG, including Grade 3 (0.6%) and Grade 2 (3.4%) adverse reactions. Immune-mediated rash did not lead to permanent discontinuation of OPDUALAG. Immune-mediated rash led to withholding of OPDUALAG in 1.4% of patients.
Systemic corticosteroids were required in 88% (29/33) of patients with immune-mediated rash. Rash resolved in 70% of the 33 patients. Of the 5 patients in whom OPDUALAG was withheld for immune-mediated rash, 4 reinitiated OPDUALAG after symptom improvement; of these, 25% had recurrence of immune-mediated rash.
Immune-Mediated Myocarditis OPDUALAG can cause immune-mediated myocarditis, which is defined as requiring use of steroids and no clear alternate etiology. The diagnosis of immune-mediated myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, withhold dose, promptly initiate high dose steroids (prednisone or methylprednisolone 1 to 2 mg/kg/day) and promptly arrange cardiology consultation with diagnostic workup. If clinically confirmed, permanently discontinue OPDUALAG for Grade 2-4 myocarditis [see Dosage and Administration (2.2)].
Myocarditis occurred in 1.7% (6/355) of patients receiving OPDUALAG, including Grade 3 (0.6%), and Grade 2 (1.1%) adverse reactions. Myocarditis led to permanent discontinuation of OPDUALAG in 1.7% of patients.
Systemic corticosteroids were required in 100% (6/6) of patients with myocarditis. Myocarditis resolved in 100% of the 6 patients.
Other Immune-Mediated Adverse Reactions The following clinically significant IMARs occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDUALAG or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.
Cardiac/Vascular: Pericarditis, vasculitis.
Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.
Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other IMARs, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.
Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.
Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatica.
Endocrine: Hypoparathyroidism.
Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.
5.2 Infusion-Related Reactions OPDUALAG can cause severe infusion-related reactions. Discontinue OPDUALAG in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions [see Dosage and Administration (2.2)].
In patients who received OPDUALAG as a 60-minute intravenous infusion, infusion-related reactions occurred in 7% (23/355) of patients.
5.3 Complications of Allogeneic Hematopoietic Stem Cell Transplantation Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 receptor blocking antibody. Transplant-related complications 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) [see Adverse Reactions (6.1)]. These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 receptor blocking antibody prior to or after an allogeneic HSCT.
5.4 Embryo-Fetal Toxicity Based on its mechanism of action and data from animal studies, OPDUALAG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDUALAG for at least 5 months after the last dose of OPDUALAG [see Use in Specific Populations (8.1, 8.3)].
Adverse Reactions
Clinical Trials Experience
Severe and Fatal IMARs Infusion-Related Reactions Complications of Allogeneic HSCT
Postmarketing Experience
There is limited information regarding Nivolumab and relatlimab-rmbw Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Nivolumab and relatlimab-rmbw Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Nivolumab and relatlimab-rmbw in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nivolumab and relatlimab-rmbw in women who are pregnant.
Labor and Delivery
Risk Summary
Based on findings in animals and mechanism of action, OPDUALAG can cause fetal harm when administered to a pregnant woman. Administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death (see Data). Human IgG4 is known to cross the placenta; therefore, nivolumab and relatlimab have the potential to be transmitted from the mother to the developing fetus. The effects of OPDUALAG are likely to be greater during the second and third trimesters of pregnancy. There are no available data on OPDUALAG in pregnant women to evaluate a drug-associated risk. Advise the patient of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
OPDUALAG injection for intravenous use contains nivolumab and relatlimab [see Description (11)].
Nivolumab:
One function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining immune tolerance to the fetus. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg (based on AUC). Nivolumab administration resulted in a non-dose-related increase in spontaneous abortion and increased neonatal death. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period.
Relatlimab:
There are no available animal data on relatlimab. The effects of a murine surrogate anti-LAG-3 antibody was evaluated in mice using syngeneic and allogeneic breeding models. When anti-LAG-3 antibodies were administered beginning on gestation day 6, there were no maternal or developmental effects in either syngeneic or allogeneic breedings.
Nursing Mothers
Risk Summary
There are no data on the presence of nivolumab and relatlimab in human milk, the effects on the breastfed child, or the effects on milk production. Because nivolumab and relatlimab may be excreted in human milk and because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with OPDUALAG and for at least 5 months after the last dose.
Pediatric Use
The safety and effectiveness of OPDUALAG for the treatment of unresectable or metastatic melanoma have been established in pediatric patients 12 years of age or older who weigh at least 40 kg. Use of OPDUALAG for this indication is supported by evidence from an adequate and well-controlled study in adults and additional data analyses that suggest that nivolumab and relatlimab exposures in pediatric patients 12 years of age who weigh at least 40 kg are expected to result in similar safety and efficacy to that of adults. The pharmacokinetics of monoclonal antibodies and the course of unresectable or metastatic melanoma are sufficiently similar in adults and pediatric patients 12 years of age or older to allow extrapolation of data from adult patients to pediatric patients 12 years of age or older (who weigh at least 40 kg). A recommended dosage for pediatric patients 12 years of age or older who weigh less than 40 kg has not been established.
The safety and effectiveness of OPDUALAG have not been established in pediatric patients 12 years of age or older who weigh less than 40 kg, and pediatric patients younger than 12 years of age.
Geriatic Use
Of the 355 patients treated with OPDUALAG in RELATIVITY-047, 47% of patients were 65 years or older, 29% were 65 to 74 years, 17% were 75 to 84 years, and 1.7% were 85 years and older. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.
Gender
There is no FDA guidance on the use of Nivolumab and relatlimab-rmbw with respect to specific gender populations.
Race
There is no FDA guidance on the use of Nivolumab and relatlimab-rmbw with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Nivolumab and relatlimab-rmbw in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Nivolumab and relatlimab-rmbw in patients with hepatic impairment.
Females of Reproductive Potential and Males
OPDUALAG can cause fetal harm when administered to a pregnant woman
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating OPDUALAG
Contraception
Advise females of reproductive potential to use effective contraception during treatment and for at least 5 months following the last dose of OPDUALAG
Immunocompromised Patients
There is no FDA guidance one the use of Nivolumab and relatlimab-rmbw in patients who are immunocompromised.
Administration and Monitoring
Administration
Administer the infusion over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line polyethersulfone (PES), nylon, or polyvinylidene fluoride (PVDF) filter (pore size of 0.2 micrometer to 1.2 micrometer). • Flush the intravenous line at the end of the infusion. • Do not coadminister other drugs through the same intravenous line.
Monitoring
There is limited information regarding Nivolumab and relatlimab-rmbw Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Nivolumab and relatlimab-rmbw and IV administrations.
Overdosage
There is limited information regarding Nivolumab and relatlimab-rmbw overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Nivolumab and relatlimab-rmbw Pharmacology in the drug label.
Mechanism of Action
Relatlimab is a human IgG4 monoclonal antibody that binds to the LAG-3 receptor, blocks interaction with its ligands, including MHC II, and reduces LAG-3 pathway-mediated inhibition of the immune response. Antagonism of this pathway promotes T cell proliferation and cytokine secretion.
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human IgG4 monoclonal antibody that binds to the PD-1 receptor, blocks interaction with its ligands PD-L1 and PD-L2, and reduces PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.
The combination of nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) results in increased T-cell activation compared to the activity of either antibody alone. In murine syngeneic tumor models, LAG-3 blockade potentiates the anti-tumor activity of PD-1 blockage, inhibiting tumor growth and promoting tumor regression.
Structure
There is limited information regarding Nivolumab and relatlimab-rmbw Structure in the drug label.
Pharmacodynamics
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of OPDUALAG have not been fully characterized.
Pharmacokinetics
The pharmacokinetics (PK) of relatlimab following the administration of OPDUALAG were characterized in patients with cancer who received relatlimab 20 to 800 mg every 2 weeks (0.25 to 10 times the approved recommended dosage) or 160 to 1440 mg every 4 weeks (1 to 9 times the approved recommended dosage) either as a monotherapy or in combination with nivolumab dosages of 80 or 240 mg every 2 weeks or 480 mg every 4 weeks.
Steady-state concentrations of relatlimab were reached by 16 weeks with an every 4-week regimen and the systemic accumulation was 1.9-fold. The average concentration (Cavg) of relatlimab after the first dose increased dose proportionally at doses ≥160 mg every 4 weeks.
Following the recommended dosage, the geometric mean [coefficient of variation (CV%)] maximum and average concentrations (Cmax and Cavg) of relatlimab at steady state were 62.2 (30%), and 28.8 (45%) μg/mL, respectively; and the mean Cmax and Cavg of nivolumab at steady state were 187 (33%) and 94.4 (43%) μg/mL, respectively.
In RELATIVITY-047, the nivolumab geometric mean minimum concentration (Cmin) at steady state in the OPDUALAG arm was comparable to the nivolumab arm.
Distribution
The geometric mean (CV%) volume of distribution at steady state of relatlimab is 6.6 L (20%) and 6.6 L (19%) of nivolumab.
Elimination
The geometric mean (CV%) clearance of relatlimab is 5.5 mL/h (41%) at steady state, 10% lower than after the first dose [6 mL/h (39%)]. Following OPDUALAG (nivolumab 480 mg and relatlimab 160 mg administered every 4 weeks) administration, the geometric mean (CV%) effective half-life (t1/2) of relatlimab is 26.2 days (37%).
The geometric mean (CV%) clearance of nivolumab is 7.6 mL/h (40%) at steady state, 21% lower than after the first dose [9.6 mL/h (40%)] and the terminal t1/2 is 26.5 days (36%).
Specific Populations
The following factors had no clinically important effect on the clearance of nivolumab and relatlimab: age (17 to 92 years), sex, race (White, Asian, and Black/African American), mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2), mild hepatic impairment (total bilirubin [TB] less than or equal to upper limit of normal [ULN] and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST) or moderate hepatic impairment (TB greater than 1.5 to 3 times ULN and any AST). The effects of severe renal impairment, or severe hepatic impairment on the pharmacokinetics of nivolumab and relatlimab are unknown.
Pediatric patients:
The exposures of nivolumab and relatlimab in pediatric patients 12 years of age or older who weigh at least 40 kg are expected to be in the range of exposures in adult patients at the recommended dosage.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility OPDUALAG contains nivolumab and relatlimab.
No studies have been performed to assess the potential of nivolumab or relatlimab for carcinogenicity or genotoxicity. Fertility studies have not been performed with nivolumab or relatlimab.
Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis–infected PD-1 knockout mice exhibited markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade using a primate anti-PD-1 antibody was also shown to exacerbate M. tuberculosis infection in rhesus macaques. PD-1 and PD-L1 knockout mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.
Inhibition of PD-1 and LAG-3 results in autoimmunity in preclinical models. Mice deficient in both PD-1 and LAG-3 develop lethal systemic autoimmunity that includes myocarditis.
In a 1-month study in monkeys dosed with nivolumab and relatlimab, inflammation within the central nervous system (choroid plexus, vasculature, meninges, spinal cord) and the reproductive tract (epididymis, seminal vesicles, and testes) was observed.
Clinical Studies
The efficacy of OPDUALAG was investigated in RELATIVITY-047 (NCT03470922), a randomized (1:1), double-blinded trial in 714 patients with previously untreated metastatic or unresectable Stage III or IV melanoma. Patients were allowed to have received prior adjuvant or neoadjuvant melanoma therapy: anti-PD-1, anti-CTLA-4, or BRAF-MEK inhibitors were allowed if received at least 6 months between the last dose of therapy and date of recurrence; interferon therapy was allowed if the last dose was at least 6 weeks prior to randomization. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic treatment with moderate or high dose corticosteroids or immunosuppressive medications, uveal melanoma, and active or untreated brain or leptomeningeal metastases. Patients were randomized to receive OPDUALAG (nivolumab 480 mg and relatlimab 160 mg) by intravenous infusion every 4 weeks (n=355) or nivolumab 480 mg by intravenous infusion every 4 weeks (n=359) until disease progression or unacceptable toxicity. Randomization was stratified by tumor PD-L1 expression (≥1% vs. <1%) using PD-L1 IHC 28-8 pharmDx test, LAG-3 expression (≥1% vs. <1%) using a clinical trial assay, BRAF V600 mutation status (V600 mutation positive vs. wild type), and M stage per the American Joint Committee on Cancer (AJCC) version 8 staging system (M0/M1any[0] vs. M1any[1]).
The major efficacy outcome measure was progression-free survival (PFS) determined by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Additional efficacy outcome measures were overall survival (OS) and overall response rate (ORR) determined by BICR using RECIST v1.1. Tumor assessments were conducted 12 weeks after randomization and continued every 8 weeks up to week 52 and then every 12 weeks.
The trial population characteristics were: median age 63 years (range: 20 to 94); 58% male; 97% White 0.7% African American, and American Indian/Alaskan Native 0.1%; Hispanic 7%; and ECOG performance score was 0 (67%) or 1 (33%). Disease characteristics were: PD-L1 expression ≥1% (41%), LAG-3 expression ≥1% (75%), AJCC Stage IV disease (92%), M1c disease (39%); M1d disease (2.4%), elevated LDH (36%), and BRAF V600 mutation-positive melanoma (39%).
The trial demonstrated a statistically significant improvement in PFS for patients randomized to the OPDUALAG arm compared with the nivolumab arm.
How Supplied
OPDUALAG (nivolumab and relatlimab-rmbw) injection is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution for intravenous use supplied in a single-dose vial containing 240 mg of nivolumab and 80 mg of relatlimab per 20 mL (12 mg and 4 mg per mL) per carton (NDC 0003-7125-11).
Storage
Store OPDUALAG refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. Do not freeze or shake.
Images
Drug Images
{{#ask: Page Name::Nivolumab and relatlimab-rmbw |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}
Package and Label Display Panel
OPDUALAG 240 mg and 80 mg/20 mL Representative Packaging NDC 0003-7125-11
Rx only
OpdualagTM
(nivolumab and relatlimab -rmbw)
Injection
240 mg and 80 mg/20 mL
(12 mg and 4 mg/mL)
For Intravenous Infusion Only
Single-dose vial; Discard unused portion.
Please provide enclosed Medication Guide to the patient.
Bristol Myers Squibb
{{#ask: Label Page::Nivolumab and relatlimab-rmbw |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Immune-Mediated Adverse Reactions (IMAR)
Inform patients of the risk of IMARs that may require corticosteroid treatment and withholding or discontinuation of OPDUALAG, including:
• Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath. • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain. • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding. • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, thyroiditis, hypothyroidism, hyperthyroidism, and diabetes mellitus. • Nephritis with Renal Dysfunction: 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. • Skin Adverse Reactions: Advise patients to contact their healthcare provider immediately for rash. • Myocarditis: 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.
Infusion-Related Reactions
• Advise patients of the potential risk of infusion-related reactions. Complications of Allogeneic HSCT
• Advise patients of potential risk of post-transplant complications. Embryo-Fetal Toxicity
• 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 OPDUALAG and for at least 5 months following the last dose. Lactation
• Advise women not to breastfeed during treatment with OPDUALAG and for 5 months after the last dose.
Precautions with Alcohol
Alcohol-Nivolumab and relatlimab-rmbw interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
OPDUALAG
Look-Alike Drug Names
There is limited information regarding Nivolumab and relatlimab-rmbw Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
{{#subobject:
|Page Name=Nivolumab and relatlimab-rmbw
|Pill Name=Nivolumab and relatlimab-rmbw label.png
|Drug Name=
|Pill Ingred=|+sep=;
|Pill Imprint=
|Pill Dosage={{{dosageValue}}} {{{dosageUnit}}}
|Pill Color=|+sep=;
|Pill Shape=
|Pill Size (mm)=
|Pill Scoring=
|Pill Image=
|Drug Author=
|NDC=
}}