PACKAGE LABEL.PRINCIPAL 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

RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

DESCRIPTION SECTION

11 DESCRIPTION

Nivolumab and relatlimab-rmbw is a fixed-dose combination of two IgG4 kappa monoclonal antibodies (mAbs). Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody that has a calculated molecular mass of 146 kDa and is expressed in a recombinant Chinese Hamster Ovary (CHO) cell line. Relatlimab is a lymphocyte activation gene-3 (LAG-3) blocking antibody that has a calculated molecular mass of 148 kDa and is expressed in a recombinant CHO cell line.

OPDUALAG (nivolumab and relatlimab-rmbw) injection is a sterile, preservative- free, clear to opalescent, colorless to slightly yellow solution that may contain few translucent-to-white particles. OPDUALAG is supplied as 240 mg of nivolumab and 80 mg of relatlimab in a 20 mL single-dose vial for intravenous use. Each mL of OPDUALAG solution contains 12 mg of nivolumab, 4 mg of relatlimab, and histidine (1.1 mg), L-histidine hydrochloride monohydrate (2.7 mg), pentetic acid (0.008 mg), polysorbate 80 (0.5 mg), sucrose (85.6 mg), and Water for Injection, USP. The pH is 5.8.

INDICATIONS & USAGE SECTION

Highlight: OPDUALAG 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, indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. (1)

1 INDICATIONS AND USAGE

OPDUALAG™ is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.

DOSAGE & ADMINISTRATION SECTION

Highlight: •

Adult patients and pediatric patients 12 years of age or older who weigh at least 40 kg: 480 mg nivolumab and 160 mg relatlimab intravenously every 4 weeks. (2)

•

Administer OPDUALAG as an intravenous infusion over 30 minutes. (2)

•

See full Prescribing Information for dosage modifications for adverse reactions (2.2) and preparation and administration instructions for the injection (2.3).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of OPDUALAG for adult patients and 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 [see Use in Specific Populations (8.4)].

2.2 Dosage Modifications

No dose reduction for OPDUALAG is recommended. In general, withhold OPDUALAG for severe (Grade 3) immune-mediated adverse reactions (IMARs). Permanently discontinue OPDUALAG for life-threatening (Grade 4) IMARs, recurrent severe (Grade 3) IMARs that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.

Dosage modifications for adverse reactions that require management different from these general guidelines are summarized in Table 1.

2.3 Preparation and Administration

OPDUALAG is a fixed-dose combination of nivolumab and relatlimab.

Visually inspect the solution in the drug product vial for particulate matter and discoloration prior to administration. OPDUALAG is a clear to opalescent, colorless to slightly yellow solution. Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white particles.

Preparation

•

During preparation of the infusion solution, use aseptic technique to assure sterility, as the product does not contain a preservative. 

•

OPDUALAG can be administered diluted or undiluted and administered at a final concentration as specified in Table 2 below.

•

Withdraw the required volume of OPDUALAG and transfer into an intravenous container. OPDUALAG is compatible with di(2-ethylhexyl)phthalate (DEHP)-plasticized polyvinyl chloride (PVC), ethyl vinyl acetate (EVA), and polyolefin (PO) intravenous bags. 

•

If diluting OPDUALAG prior to administration:

- Dilute OPDUALAG solution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion meeting the final concentration and maximum infusion volume parameters as specified in Table 2 below.

Then mix the diluted solution by gentle inversion. Do not shake.

•

Discard partially used vials or empty vials following infusion preparation.  

Storage of Prepared Solution

Store the prepared solution either:

•

at room temperature and room light for no more than 8 hours from the time of preparation to the end of the infusion. Discard the prepared solution if not used within 8 hours from the time of preparation;

-or-

under refrigeration at 2°C to 8°C (36°F to 46°F) with protection from light for no more than 24 hours from the time of preparation, which includes the time allowed for equilibration of the infusion bag to room temperature and the duration of the infusion. Discard the prepared solution if not used within 24 hours from the time of preparation.

Do not freeze.

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.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: •

Injection: 240 mg of nivolumab and 80 mg of relatlimab per 20 mL (12 mg and 4 mg per mL) in a single-dose vial. (3)

3 DOSAGE FORMS AND STRENGTHS

Injection: 240 mg nivolumab and 80 mg relatlimab per 20 mL (12 mg and 4 mg per mL) as a clear to opalescent, colorless to slightly yellow solution in a single-dose vial.

CONTRAINDICATIONS SECTION

Highlight: •

None. (4)

4 CONTRAINDICATIONS

None.

USE IN SPECIFIC POPULATIONS SECTION

Highlight: •

Lactation: Advise not to breastfeed. (8.2)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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.

8.2 Lactation

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 [see Pharmacokinetics (12.3)].

8.3 Females and Males of Reproductive Potential

OPDUALAG can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating OPDUALAG [see Use in Specific Populations (8.1)].

Contraception

Advise females of reproductive potential to use effective contraception during treatment and for at least 5 months following the last dose of OPDUALAG [see Clinical Pharmacology (12.3)].

8.4 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 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

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.

8.5 Geriatric 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.

ADVERSE REACTIONS SECTION

Highlight: The most common adverse reactions (≥20%) are musculoskeletal pain, fatigue, rash, pruritus, and diarrhea. (6.1)

The most common laboratory abnormalities (≥20%) are decreased hemoglobin, decreased lymphocytes, increased AST, increased ALT, and decreased sodium. (6.1)

**To report SUSPECTED ADVERSE REACTIONS, contactBristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or **www.fda.gov/medwatch.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling.

•

Severe and Fatal IMARs [see Warnings and Precautions (5.1)]

•

Infusion-Related Reactions [see Warnings and Precautions (5.2)]

•

Complications of Allogeneic HSCT [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of OPDUALAG was evaluated in RELATIVITY-047, a randomized (1:1), double-blinded trial in 714 patients with previously untreated metastatic or unresectable melanoma [see Clinical Studies (14)]. Patients received intravenous OPDUALAG (nivolumab 480 mg and relatlimab 160 mg) every 4 weeks (n=355) or nivolumab 480 mg by intravenous infusion every 4 weeks (n=359). Patients were treated with OPDUALAG or nivolumab until disease progression or unacceptable toxicity. The median duration of exposure was 6 months (range: 0 to 31 months) in OPDUALAG-treated patients and 5 months (range: 0 to 32 months) in nivolumab-treated patients.

Serious adverse reactions occurred in 36% of patients treated with OPDUALAG. The most frequent serious adverse reactions reported in ≥1% of patients treated with OPDUALAG were adrenal insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia (1.4%), acute myocardial infarction (1.1%), back pain (1.1%), diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%). Fatal adverse reaction occurred in 3 (0.8%) patients who were treated with OPDUALAG; these included hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis.

OPDUALAG was permanently discontinued due to adverse reactions in 18% of patients. Adverse reactions which resulted in permanent discontinuation of OPDUALAG in ≥1% of patients included myocarditis (1.7%) and pneumonitis (1.4%).

Dosage interruptions due to an adverse reaction occurred in 43% of patients who received OPDUALAG. Adverse reactions that required dosage interruption in ≥2% of patients who received OPDUALAG were diarrhea (3.9%), troponin increased (3.9%), AST increased (2.8%), troponin T increased (2.8%), ALT increased (2.3%), arthralgia (2.3%), hypothyroidism (2.3%), anemia (2%), fatigue (2%), pneumonitis (2%), and rash (2%).

The most common (≥20%) adverse reactions that occurred in patients treated with OPDUALAG were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%). The most common (≥20%) laboratory abnormalities that occurred in patients treated with OPDUALAG were decreased hemoglobin (37%), decreased lymphocytes (32%), increased AST (30%), increased ALT (26%), and decreased sodium (24%).

Tables 3 and 4 summarize both the adverse reactions and laboratory abnormalities, respectively, in RELATIVITY-047.

Clinically relevant adverse reactions in <15% of patients who received OPDUALAG included vitiligo, adrenal insufficiency, myocarditis, and hepatitis.

CLINICAL STUDIES SECTION

14 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. The final analysis of OS was not statistically significant. Efficacy results are shown in Table 5 and Figure 1.

Figure 1: Progression-free Survival - RELATIVITY-047


INFORMATION FOR PATIENTS SECTION

17 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 [see Warnings and Precautions (5.1)].

•

Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.1)].

•

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 [see Warnings and Precautions (5.1)].

•

Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, thyroiditis, hypothyroidism, hyperthyroidism, and diabetes mellitus [see Warnings and Precautions (5.1)].

•

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 [see Warnings and Precautions (5.1)].

•

Skin Adverse Reactions: Advise patients to contact their healthcare provider immediately for rash [see Warnings and Precautions (5.1)].

•

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 [see Warnings and Precautions (5.1)].

Infusion-Related Reactions

•

Advise patients of the potential risk of infusion-related reactions [see Warnings and Precautions (5.2)].

Complications of Allogeneic HSCT

•

Advise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

•

Advise females of reproductive potential to use effective contraception during treatment with OPDUALAG and for at least 5 months following the last dose [see Use in Specific Populations (8.3)].

Lactation

•

Advise women not to breastfeed during treatment with OPDUALAG and for 5 months after the last dose [see Use in Specific Populations (8.2)].

Manufactured by:

Bristol-Myers Squibb Company

Princeton, NJ 08543 USA

U.S. License No. 1713

SPL MEDGUIDE SECTION

Medication Guide

new or worsening cough

shortness of breath

chest pain

diarrhea (loose stools) or more frequent bowel movements than usual

stool that are black, tarry, sticky, or have blood or mucus

severe stomach-area (abdominal) pain or tenderness

yellowing of your skin or the whites of your eyes

severe nausea or vomiting

pain on the right side of your stomach area (abdomen)

dark urine (tea colored)

bleeding or bruising more easily than normal

headaches that will not go away or unusual headaches

eye sensitivity to light

eye problems

rapid heartbeat

increased sweating

extreme tiredness

weight gain or weight loss

feeling more hungry or thirsty than usual

urinating more often than usual

hair loss

feeling cold

constipation

your voice gets deeper

dizziness or fainting

changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness

decrease in your amount of urine

blood in your urine

swelling in your ankles

loss of appetite

rash

itching

skin blistering or peeling

painful sore or ulcers in mouth or nose, throat, or genital area

new or worse chest pain

irregular heartbeat or feel like your heart is racing

shortness of breath

tiredness

swelling in your ankles

Confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs

Double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight

Persistent or severe muscle pain or weakness, muscle cramps

Low red blood cells, bruising

adults and children 12 years of age or older with a type of skin cancer called melanoma that has spread or cannot be removed by surgery.

in children 12 years of age or older who weigh less than 88 pounds (40 kg), or

in children younger than 12 years of age.

have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus

have received an organ transplant

have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)

have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome

are pregnant or plan to become pregnant. OPDUALAG can harm your unborn baby.
**Females who are able to become pregnant:**

Your healthcare provider should do a pregnancy test before you start receiving OPDUALAG.

You should use an effective method of birth control during and for at least 5 months after the last dose of OPDUALAG. Talk to your healthcare provider about birth control methods that you can use during this time.

Tell your healthcare provider right away if you become pregnant during treatment with OPDUALAG.

are breastfeeding or plan to breastfeed. It is not known if OPDUALAG passes into your breast milk. Do not breastfeed during treatment with OPDUALAG and for 5 months after the last dose of OPDUALAG.

Your healthcare provider will give you OPDUALAG into your vein through an intravenous (IV) line over 30 minutes.

OPDUALAG is usually given every 4 weeks.

Your healthcare provider will decide how many treatments you need.

Your healthcare provider will do blood tests to check you for side effects.

If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.

**See “What is the most important information I should know about OPDUALAG?”**

**Severe infusion reactions.** Tell your healthcare provider or nurse right away if you get these symptoms during an infusion of OPDUALAG:

chills or shaking

itching or rash

flushing

shortness of breath

dizziness

feel like passing out

fever

back or neck pain

**Complications of stem cell transplant that uses donor stem cells (allogeneic).**These complications can be severe and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with OPDUALAG. Your healthcare provider will monitor you for signs of complications if you have an allogeneic stem cell transplant.

muscle and bone pain

tiredness

decreased red blood cell and white blood cell counts

increased liver function test results

rash

itching

diarrhea

decreased salt (sodium) in your blood

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: March 2022

HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

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).

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.