Opdualag

[Indications of opdualag (nivolumab and relatlimab-rmbw) injection]
Opdualag is suitable for the treatment of adults and children aged 12 or above with unresectable or metastatic melanoma.

[Recommended dosage and administration method of opdualag (nivolumab and relatlimab-rmbw) injection]
First, the recommended dosage
For adult patients weighing at least 40 kg and pediatric patients aged 12 or above, the recommended dose of Opdualag is 480 mg nivolumab and 160 mg relatimalb injected intravenously every 4 weeks until the disease progresses or unacceptable toxicity occurs.
The recommended dose for patients aged 12 or above who weigh less than 40 kg has not been determined.
Second, the dose adjustment
It is not recommended to reduce the dose of Opdualag. Generally speaking, for severe (grade 3) immune-mediated adverse reactions (IMARs), Opdualag should be stopped. For life-threatening (Grade 4) IMARs, recurrent severe (Grade 3) IMARs requiring systemic immunosuppression treatment, or equivalent prednisone drugs that cannot reduce the corticosteroid dosage to 10 mg or less per day within 12 weeks after starting steroid use, Opdualag should be permanently discontinued.
Table 1 summarizes the dosage adjustment of adverse reactions that need to be used differently from the general guidelines.
Table 1: Recommended Dose Adjustment for Adverse Reactions
Severity of Adverse Reactions * Dose Adjustment
Immune-mediated adverse reactions
Pneumonia level 2 pause a
Permanent stop at level 3 or 4
Colitis grade 2 or 3 pause a
Level 4 permanent stop
The aspartate aminotransferase/alanine aminotransferase of hepatitis increased to 3~8 times of ULN.
Or the total bilirubin increases to 1.5~3 times. ULN pauses A.
Regardless of the baseline, aspartate aminotransferase or alanine aminotransferase increased to more than 8 times of ULN.
Or the total bilirubin increased to more than 3 times of ULN. Permanent stop
Endocrine diseases B 3 or 4 are suspended until clinical stability or stopped permanently according to severity.
Nephritis with renal insufficiency 2 or 3 levels of serum creatinine increase pause A
Grade 4 serum creatinine elevation stops permanently.
Exfoliative dermatosis is suspected of SJS, TEN or DRESS pause A.
The diagnosis of SJS, TEN or DRESS is permanently stopped.
Myocarditis is permanently stopped at grade 2, 3 or 4.
Neurotoxic level 2 pause a
Permanent stop at level 3 or 4
Other adverse reactions
Infusion-related reaction level 1 or 2 interrupts or slows down the infusion speed.
Permanent stop at level 3 or 4
* Based on the National Cancer Institute’s general terminology standard for adverse events, version 5.0.
A: Patients with complete or partial regression (grade 0 to 1) after corticosteroid reduction will resume treatment. If it does not completely or partially subside within 12 weeks after the last administration, or if prednisone cannot be reduced to 10mg/day (or equivalent to 10 mg/day) or less within 12 weeks after the start of steroid use, the drug should be stopped permanently.
B: According to the clinical severity, consider suspending the treatment of grade 2 endocrine diseases until hormone replacement therapy improves the symptoms. Once the acute symptoms disappear, please recover immediately.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = drug eruption with eosinophilia and systemic symptoms, SJS = Stevens-Johnson syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal.

Third, preparation and use
Opdualag is a fixed dose combination of nivolumab and relatlimab.
Before administration, visually inspect the solution in the medicine bottle for particulate matter and discoloration. Opdualag is a transparent to milky white, colorless to yellowish solution.

If the solution is turbid, discolored or contains foreign particulate matter except a few translucent to white particles, discard the vial.
Step 1 prepare
1) In the process of preparing infusion, use aseptic technology to ensure sterility, because the product does not contain preservatives.
2)Opdualag can be administered in diluted or undiluted form and at the final concentration specified in Table 2 below.
3) Extract the required amount of Opdualag and transfer it to an intravenous container. Opdualag is compatible with polyvinyl chloride (PVC), ethyl vinyl acetate (EVA) and polyolefin (PO) intravenous bags plasticized by di (2- ethylhexyl) phthalate (DEHP).
4) If Opdualag is diluted before administration:
2. Dilute Opdualag solution with 0.9% sodium chloride injection or 5% glucose injection to prepare infusion solution meeting the final concentration and maximum infusion volume parameters specified in Table 2 below.
3. Then gently invert and mix the diluted solution. Don’t shake.

1) After infusion preparation, discard some used vials or empty vials.
Table 2: Maximum infusion volume and concentration range by patients.
Maximum infusion volume (mL or ml/kg) concentration range (mg/mL)*
Adult patients weighing at least 40 kg and children aged 12 or above weighing at least 40 kg 160 mL nivolumab：3 mg/mL/ml to 12 mg/mL.
Relatlibab: 1 mg/ml to 4 mg/mL.
Adult patients weighing less than 40 kg 4 mL/kg nivolumab：3 mg/mL 3 mg/ml to 12 mg/mL.
Relatlibab: 1 mg/ml to 4 mg/mL.
* The concentration range of each group is 12 mg/mL nivolumab and 4 mg/mL relatlimab as the upper limit, which represents the scene of undiluted infusion of pharmaceutical products.
4. Storage of preparation solution

Store the prepared solution in:
1. Under room temperature and indoor light, the time from preparation to the end of infusion shall not exceed 8 hours. If it is not used within 8 hours after preparation, discard the prepared solution;
or
2. Store in the cold storage condition of 2 C to 8 C in the dark for no more than 24 hours from the preparation time, including the time when the infusion bag is balanced to room temperature and the infusion duration. If it is not used within 24 hours after preparation, please discard the prepared solution.
Don’t freeze.
V. Use
1. Infusion is carried out within 30 minutes through an intravenous tube containing sterile, pyrogen-free, low-protein-binding series polyethersulfone (PES), nylon or polyvinylidene fluoride (PVDF) filter (pore size 0.2 micron to 1.2 micron).
2. Rinse the intravenous tube at the end of infusion.
3. Don’t use other drugs through the same intravenous catheter at the same time.

[Adverse reaction of opdualag (nivolumab and relatlimab-rmbw) injection]
1.Opdualag may cause serious side effects, including urticaria, dyspnea, swelling of face, lips, tongue or throat, dizziness, chills, rash, facial flushing, shortness of breath, fainting, fever and back or neck pain. If you have any of the above symptoms, please see a doctor immediately.
2. The most common side effects of 2.Opdualag include: muscle or bone pain, rash, fatigue, itching, diarrhea, increased liver function test results, decreased red blood cells and white blood cells, and decreased salt (sodium) in blood. Tell your doctor if you have any disturbing or persistent side effects.
3. These are not all possible side effects of Opdualag. Please ask your doctor or pharmacist for more information.

[the use of opdualag (nivolumab and relatlimab-rmbw) injection in special population]
1. Pregnancy
According to the results of animal studies and the mechanism of action, when pregnant women take drugs, Opdualag may cause harm to the fetus. During the period from organogenesis to delivery, giving nivolumab to cynomolgus monkeys led to an increase in abortion and premature death. It is known that human IgG4 can cross the placenta; Therefore, nivolumab and relatlimab may be transmitted from mother to developing fetus. The influence of Opdualag may be greater in the second and third trimester of pregnancy. There is no available Opdualag data for pregnant women to assess drug-related risks. Inform patients of the potential risks to the fetus.
In the general population of the United States, the estimated risk of major birth defects and abortion in clinically recognized pregnancy is 2% to 4% and 15% to 20%, respectively.
2. lactation
There are no data on the existence of nivolumab and relatlimab in human milk, their effects on breast-fed children or their effects on milk production. Because nivolumab and relatlimab may be excreted through breast milk, and breast-fed children may have serious adverse reactions, patients are advised not to breast-feed during the treatment with Opdualag and for at least 5 months after the last administration.
3. Male and female patients with reproductive potential

Opdualag may cause harm to the fetus when administered to pregnant women.
1) Pregnancy test
Before starting to use Opdualag, check the pregnancy status of women with reproductive potential.
2) Contraception
Inform women with reproductive potential to use effective contraceptive methods during treatment and at least 5 months after the last use of Opdualag.
4. Pediatric use
The safety and efficacy of Opdualag in the treatment of unresectable or metastatic melanoma have been determined in children aged at least 40 kg. A well-controlled study in adults and evidence from other data analysis support the use of Opdualag for this indication. These evidences show that the exposure of nivolumab and relatlimab in 12-year-old children weighing at least 40 kg is expected to produce similar safety and efficacy as adults. The pharmacokinetics of monoclonal antibodies and the course of unresectable or metastatic melanoma are very similar in adults and children aged 12 or above, so the data of adult patients can be extrapolated to children aged 12 or above (at least 40 kg). The recommended dose for children aged 12 or above who weigh less than 40 kg has not been determined.
The safety and efficacy of Opdualag have not been determined in children aged 12 or above who weigh less than 40 kg and children under 12 years old.
5. Use in the elderly
Among the 355 patients treated with Opdualag in RELATIVITY-047, 47% were aged 65 or above, 29% were aged 65 to 74, 17% were aged 75 to 84, and 1.7% were aged 85 or above. No overall difference in safety or efficacy was observed between elderly patients and young patients.