BRIEF DETAILS-

NIVOLUMAB-( Mar 2022)

Indn- to treat unresectable or Metastatic Melonoma   

Dosage- 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.

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.

  Administer OPDUALAG as an intravenous infusion over 30 minutes.

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

CI- None.

WARNINGS AND PRECAUTIONS-

 Immune-Mediated Adverse Reactions:                                                                        Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: 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.

 Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.

Pat inform-

Immune-Mediated Adverse Reactions (IMAR)-                                                               Inform patients of the risk 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.

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U.S. FDA APPROVED DRUGS SURING 2022                                        

Serial No 9

Name of the Drug-   OPDUALAG

Active Ingredient -   NIvolumab & Relatimab 

Pharmacological Classification- To treat unresectable or Metastatic Melonoma                                                                                                                                                             

 Date of Approval-          3/18/22   

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                    OPDUALAG safely and effectively.                                                                                 See full prescribing information for OPDUALAG. OPDUALAG™ (nivolumab and relatlimab-rmbw) injection, for intravenous use

Initial U.S. Approval: 2022

INDICATIONS AND USAGE

 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.

ADVERSE REACTIONS-

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

CONTRAINDICATIONS-                                                                                                     • None.

WARNINGS AND PRECAUTIONS-

 • Immune-Mediated Adverse Reactions:                                                                       o Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: 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.

o Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.

o Withhold or permanently discontinue based on severity and type of reaction.

 • Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue OPDUALAG based on severity of reaction.

 • Complications of allogeneic HSCT: Fatal and other serious complications can occur in patient who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody.

 • Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception.

DOSAGE AND ADMINISTRATION

• 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.

 • Administer OPDUALAG as an intravenous infusion over 30 minutes.

 • See full Prescribing Information for dosage modifications for adverse reactions and preparation and administration instructions for the injection

DOSAGE FORMS AND STRENGTHS-                                                                              • 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.

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

Use in Specific Populations  • 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.

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713

CLINICAL PHARMACOLOGY

1. 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 res

2. Pharmacodynamics-                                                                                                     The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of OPDUALAG have not been fully characterized.

3. 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.

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%).

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 olderwho weigh at least 40 kg are expected to be in the range of exposures in adult patients at the recommended dosage. 12.6 Immunogenicity.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.

Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including studies of nivolumab and relatlimab-rmbw products, or nivolumab products.

USE IN SPECIFIC POPULATIONS

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.

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.

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.

3.Females and Males of Reproductive Potential-                                           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.

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..

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.

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.