DRUG INTERACTIONS

No formal pharmacokinetic drug-drug interaction studies have been conducted with OPDIVO.

ADVERSE REACTIONS

Most common adverse reactions (20%) in patients were:

 OPDIVO as a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia.

OPDIVO with ipilimumab: fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and dyspnea. (

CONTRAINDICATIONS

None. 

WARNINGS AND PRECAUTIONS

 Immune-mediated pneumonitis:                                                                              Withhold for moderate and permanently discontinue for severe or life-threatening pneumonitis. 

Immune-mediated colitis:                                                                                     Withhold OPDIVO when given as a single agent for moderate or severe and permanently discontinue for life-threatening colitis.

Withhold OPDIVO when given with ipilimumab for moderate and permanently discontinue for severe or life-threatening colitis. 

 Immune-mediated hepatitis:                                                                                     Monitor for changes in liver function. Withhold for moderate and permanently discontinue for severe or life-threatening transaminase or total bilirubin elevation. 

 Immune-mediated endocrinopathies:                                                                           Withhold for moderate or severe and permanently discontinue for life-threatening hypophysitis.

Withhold for moderate and permanently discontinue for severe or life-threatening adrenal insufficiency. Monitor for changes in thyroid function. Initiate thyroid hormone replacement as needed. Monitor for hyperglycemia.

Withhold for severe and permanently discontinue for life-threatening hyperglycemia. 

 Immune-mediated nephritis and renal dysfunction:                                                  Monitor for changes in renal function. Withhold for moderate or severe and permanently discontinue for life-threatening serum creatinine elevation. 

Immune-mediated skin adverse reactions:                                                              Withhold for severe and permanently discontinue for life-threatening rash. 

 Immune-mediated encephalitis:                                                                                 Monitor for changes in neurologic function.

Withhold for new-onset moderate to severe neurological signs or symptoms and permanently discontinue for immune-mediated encephalitis. 

 Infusion reactions:                                                                                                   Discontinue OPDIVO for severe and life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. 

Complications of allogeneic HSCT after OPDIVO:                                                        Monitor for hyperacute graft-versus-host-disease (GVHD), grade 3-4 acute GVHD, steroidrequiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions. Transplant-related mortality has occurred. 

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

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and withholding or discontinuation of OPDIVO, 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, hypothyroidism, hyperthyroidism, and diabetes mellitus 

 Nephritis and 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 

 Encephalitis:                                                                                                                Advise patients to contact their healthcare provider immediately for neurological signs or symptoms of encephalitis 

 Infusion Reactions:                                                                                                        Advise patients of the potential risk of infusion reaction]

Complications of allogeneic HSCT after OPDIVO:                                                          Advise patients of potential risk of post-transplant complications 

Females of Reproductive Potential:                                                                       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 OPDIVO and for at least 5 months following the last dose of OPDIVO.

  Lactation:                                                                                                                 Advise women not to breastfeed while taking OPDIVO.

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

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing 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.

2. Pharmacodynamics

Based on dose/exposure efficacy and safety relationships, there are no clinically significant differences in safety and efficacy between a nivolumab dose of 240 mg or 3 mg/kg every 2 weeks in patients with melanoma, NSCLC, RCC, urothelial carcinoma, and MSI-H CRC.

3. Pharmacokinetics

Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single-agent OPDIVO and OPDIVO with ipilimumab. OPDIVO as a single agent: The PK of single-agent nivolumab was studied in patients over a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of OPDIVO every 2 or 3 weeks.

Nivolumab clearance decreases over time, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline values of approximately 24.5% (47.6%) resulting in a geometric mean steady state clearance (CLss) (CV%) of 8.2 mL/h (53.9%); the decrease in CLss is not considered clinically relevant.

The geometric mean volume of distribution at steady state (Vss) (CV%) is 6.8 L (27.3%), and geometric mean elimination halflife (t1/2) is 25 days (77.5%).

Steady-state concentrations of nivolumab were reached by approximately 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was approximately 3.7-fold. The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks.

OPDIVO with ipilimumab: The geometric mean (CV%) CL, Vss, and terminal half-life of nivolumab were 10.0 mL/h (50.3%), 7.92 L (30.1%), and 24.8 days (94.3%), respectively.

When administered in combination, the CL of nivolumab was increased by 24%, whereas there was no effect on the clearance of ipilimumab. When administered in combination, the clearance of nivolumab increased by 42% in the presence of anti-nivolumab antibodies. There was no effect of anti-ipilimumab antibodies on the clearance of ipilimumab.

Specific Populations:                                                                                                        The population PK analysis suggested that the following factors had no clinically important effect on the clearance of nivolumab: age (29 to 87 years), weight (35 to 160 kg), gender, race, baseline LDH, PD-L1 expression, solid tumor type, tumor size, renal impairment, and mild hepatic impairment.

Renal Impairment:                                                                                                         The effect of renal impairment on the clearance of nivolumab was evaluated by a population PK analysis in patients with mild (eGFR 60 to 89 mL/min/1.73 m2 ; n=313), moderate (eGFR 30 to 59 mL/min/1.73 m2 ; n=140), or severe (eGFR 15 to 29 mL/min/1.73 m2 ; n=3) renal impairment.

No clinically important differences in the clearance of nivolumab were found between patients with renal impairment and patients with normal renal function 

Hepatic Impairment:                                                                                                         The effect of hepatic impairment on the clearance of nivolumab was evaluated by population PK analyses in patients with mild hepatic impairment (total bilirubin [TB] less than or equal to the upper limit of normal [ULN] and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST; n=92).

No clinically important differences in the clearance of nivolumab were found between patients with mild hepatic impairment and patients with normal hepatic function.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman.

Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to be greater during the second and third trimesters of pregnancy.

There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies

2. Lactation Risk Summary

It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment with OPDIVO.

3.Females and Males of Reproductive Potential Contraception

Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman                                                                                                      Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO.

4.Pediatric Use

The safety and effectiveness of OPDIVO have been established in pediatric patients age 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Use of OPDIVO for this indication is supported by evidence from adequate and well-controlled studies of OPDIVO in adults with MSI-H or dMMR mCRC with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the steady state exposure of nivolumab, that drug exposure is generally similar between adults and pediatric patients age 12 years and older for monoclonal antibodies, and that the course of MSI-H or dMMR mCRC is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients.

The recommended dose in pediatric patients 12 years of age or greater for this indication is the same as that in adults 

The safety and effectiveness of OPDIVO have not been established (1) in pediatric patients less than 12 years old with MSI-H or dMMR mCRC or (2) in pediatric patients for the other approved indications.

5.Geriatric Use

Of the 1359 patients randomized to single-agent OPDIVO in various studies, 39% were 65 years or older and 9% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients. 

No overall differences in safety or effectiveness were reported between elderly patients and younger patients, However the studies  did not include tsufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

6.Renal Impairment

Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment

7. Hepatic Impairment

Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment. OPDIVO has not been studied in patients with moderate or severe hepatic impairment 

8.OVERDOSAGE

There is no information on overdosage with OPDIVO.