OPDIVO 240 mg/24 mL Representative Packaging

NDC 0003-3734-13
Rx only

Opdivo®
(nivolumab)
injection

240 mg/24 mL
(10 mg/mL)

For Intravenous Infusion Only
Single-dose vial; Discard unused portion.
Please provide enclosed Medication Guide to the patient.

Bristol Myers Squibb


4 CONTRAINDICATIONS

None.

RECENT MAJOR CHANGES

3 DOSAGE FORMS AND STRENGTHS

Injection: 40 mg/4 mL (10 mg/mL), 100 mg/10 mL (10 mg/mL), 120 mg/12 mL (10 mg/mL), and 240 mg/24 mL (10 mg/mL) clear to opalescent, colorless to pale- yellow solution in a single-dose vial.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], OPDIVO 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 (see Data). 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 data on OPDIVO use in pregnant women to evaluate a drug-associated risk. Advise pregnant women of the potential risk to a fetus.

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.

Data

Animal Data

A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. 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. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. 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.

8.2 Lactation

Risk Summary

There are no data on the presence of nivolumab in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for 5 months after the last dose of OPDIVO.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

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

Contraception

OPDIVO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for 5 months following the last dose.

8.4 Pediatric Use

The safety and effectiveness of OPDIVO have been established in pediatric patients aged 12 years and older for the following indications: as a single agent and in combination with ipilimumab for the treatment of unresectable or metastatic melanoma, as a single agent for the adjuvant treatment of completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma and, as a single agent or in combination with ipilimumab for the treatment of MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Use of OPDIVO for these indications is supported by evidence from adequate and well-controlled studies in adults with melanoma or MSI-H or dMMR mCRC and additional pharmacokinetic data in pediatric patients. Nivolumab exposure in pediatric patients 12 years and older is comparable to that of adults and the courses of melanoma and MSI-H or dMMR mCRC are similar in pediatric patients aged 12 years and older to that of adults to allow extrapolation of safety and efficacy [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1, 14.10)].

The safety and effectiveness of OPDIVO have not been established for pediatric patients younger than 12 years old with melanoma or MSI-H or dMMR mCRC.

The safety and effectiveness of OPDIVO have not been established in pediatric patients with non-small cell lung cancer, malignant pleural mesothelioma, advanced renal cell carcinoma, classical Hodgkin lymphoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastroesophageal cancer and esophageal adenocarcinoma.

8.5 Geriatric Use

Single Agent

Of 3569 patients with melanoma, NSCLC, renal cell carcinoma, urothelial carcinoma, ESCC, and esophageal or gastroesophageal junction cancer who were randomized to single agent OPDIVO in clinical studies, 41% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients [see Clinical Studies (14.1, 14.2, 14.4, 14.6, 14.9, 14.12)].

In patients with cHL, recurrent head and neck SCC, or dMMR or MSI-H metastatic CRC (mCRC) who were treated with single agent OPDIVO in clinical studies did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients [see Clinical Studies (14.7, 14.8, 14.10)].

In Combination with Ipilimumab

Of the 314 patients with melanoma who were randomized to OPDIVO in combination with ipilimumab, 41% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients [see Clinical Studies (14.1)].

Of the 576 patients with NSCLC who were randomized to OPDIVO in combination with ipilimumab, 48% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (29%) relative to all patients who received OPDIVO with ipilimumab (18%). Of the 396 patients in the primary efficacy population (PD-L1 ≥1%) randomized to OPDIVO in combination with ipilimumab, the hazard ratio for overall survival was 0.70 (95% CI: 0.55, 0.89) in the 199 patients younger than 65 years compared to 0.91 (95% CI: 0.72, 1.15) in the 197 patients 65 years or older [see Clinical Studies (14.3)].

Of the 303 patients with malignant pleural mesothelioma who were randomized to OPDIVO in combination with ipilimumab, 77% were 65 years old or older and 26% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there were higher rates of serious adverse reactions and discontinuation due to adverse reactions in patients aged 75 years or older (68% and 35%, respectively) relative to all patients who received OPDIVO with ipilimumab (54% and 28%, respectively). For patients aged 75 years or older who received chemotherapy, the rate of serious adverse reactions was 34% and the discontinuation rate due to adverse reactions was 26% relative to 28% and 19% respectively for all patients. The hazard ratio for overall survival was 0.76 (95% CI: 0.52, 1.11) in the 71 patients younger than 65 years compared to 0.74 (95% CI: 0.59, 0.93) in the 232 patients 65 years or older randomized to OPDIVO in combination with ipilimumab [see Clinical Studies (14.5)].

Of the 550 patients with renal cell carcinoma who were randomized to OPDIVO in combination with ipilimumab, 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients. In elderly patients with intermediate or poor risk, no overall difference in effectiveness was reported [see Clinical Studies (14.6)].

Of the 49 patients with hepatocellular carcinoma who were treated with OPDIVO in combination with ipilimumab, 29% were between 65 years and 74 years of age and 8% were 75 years or older. Clinical studies of OPDIVO in combination with ipilimumab did not include sufficient numbers of patients with hepatocellular carcinoma aged 65 and over to determine whether they respond differently from younger patients [see Clinical Studies (14.11)].

Of the 325 patients with ESCC who were randomized to OPDIVO in combination with ipilimumab, 43% were 65 years old or older and 7% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (38%) relative to all patients who received OPDIVO with ipilimumab (23%). For patients aged 75 years or older who received chemotherapy, the discontinuation rate due to adverse reactions was 33% relative to 23% for all patients [see Clinical Studies (14.12)].

In Combination with Platinum-Containing Chemotherapy

Of the 179 patients with NSCLC who were randomized to OPDIVO in combination with platinum-doublet chemotherapy, 48% were 65 years old or older and 6% were 75 years old or older. No overall differences in safety or effectiveness were reported between patients older and younger than 65 years [see Clinical Studies (14.3)].

Of the 1,110 patients with ESCC, GC, GEJC, or EAC who were randomized to OPDIVO in combination with fluoropyrimidine- and platinum-containing chemotherapy), 42% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients [see Clinical Studies (14.12, 14.13)].

Of the 304 patients with UC who were treated with OPDIVO in combination with gemcitabine and platinum-doublet chemotherapy, 40% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age and over and younger patients. Clinical studies of OPDIVO with platinum-doublet chemotherapy did not include sufficient numbers of patients aged 75 years and over to determine whether safety and effectiveness differs compared to younger patients. [see Clinical Studies (14.9)].

In Combination with Ipilimumab and Platinum-Doublet Chemotherapy

Of the 361 patients with NSCLC who were randomized to OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy, 51% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (43%) relative to all patients who received OPDIVO with ipilimumab and chemotherapy (24%). For patients aged 75 years or older who received chemotherapy only, the discontinuation rate due to adverse reactions was 16% relative to all patients who had a discontinuation rate of 13%. Based on an updated analysis for overall survival, of the 361 patients randomized to OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy, the hazard ratio for overall survival was 0.61 (95% CI: 0.47, 0.80) in the 176 patients younger than 65 years compared to 0.73 (95% CI: 0.56, 0.95) in the 185 patients 65 years or older [see Clinical Studies (14.4)].

In Combination with Cabozantinib

Of the 320 patients with renal cell carcinoma who were treated with OPDIVO in combination with cabozantinib, 41% were 65 years or older and 9% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients [see Clinical Studies (14.6)].

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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 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.

Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in enhanced T-cell function that is greater than the effects of either antibody alone, and results in improved anti-tumor responses in metastatic melanoma and advanced RCC. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased anti-tumor activity.

12.2 Pharmacodynamics

There are no clinically significant exposure-response relationships for efficacy or safety for nivolumab monotherapy across the approved dosing regimens, regardless of cancer type.

12.3 Pharmacokinetics

Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single agent OPDIVO and OPDIVO with ipilimumab. The PK of nivolumab was studied in patients over a dose range of 0.1 mg/kg to 20 mg/kg administered as a single dose or as multiple doses of OPDIVO as a 60-minute intravenous infusion every 2 or 3 weeks. The exposure to nivolumab increases dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The predicted exposure of nivolumab after a 30-minute infusion is comparable to that observed with a 60-minute infusion. Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was 3.7-fold.

Distribution

The geometric mean volume of distribution at steady state (Vss) and coefficient of variation (CV%) is 6.8 L (27.3%).

Elimination

Nivolumab clearance (CL) decreases over time, with a mean maximal reduction from baseline values (CV%) of 24.5% (47.6%) resulting in a geometric mean steady-state clearance (CLss) (CV%) of 8.2 mL/h (53.9%) in patients with metastatic tumors; the decrease in CLss is not considered clinically relevant. Nivolumab clearance does not decrease over time in patients with completely resected melanoma, as the geometric mean population clearance is 24% lower in this patient population compared with patients with metastatic melanoma at steady state.

The geometric mean elimination half-life (t1/2) is 25 days (77.5%).

Specific Populations

The following factors had no clinically important effect on the clearance of nivolumab: age (29 to 87 years), weight (35 to 160 kg), sex, race, baseline LDH, PD-L1 expression, solid tumor type, tumor size, renal impairment (eGFR ≥ 15 mL/min/1.73 m2), and mild (total bilirubin [TB] less than or equal to the 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). Nivolumab has not been studied in patients with severe hepatic impairment (TB greater than 3 times ULN and any AST).

Pediatric Patients

The exposures of nivolumab in pediatric patients 12 years of age or older are comparable to those in adults at the recommended dosage [see Dosage and Administration (2.2)].

Drug Interaction Studies

When OPDIVO 3 mg/kg every 3 weeks was administered in combination with ipilimumab 1 mg/kg every 3 weeks, the CL of nivolumab and ipilimumab were unchanged compared to nivolumab or ipilimumab administered alone.

When OPDIVO 1 mg/kg every 3 weeks was administered in combination with ipilimumab 3 mg/kg every 3 weeks, the CL of nivolumab was increased by 29% compared to OPDIVO administered alone and the CL of ipilimumab was unchanged compared to ipilimumab administered alone.

When OPDIVO 3 mg/kg every 2 weeks was administered in combination with ipilimumab 1 mg/kg every 6 weeks, the CL of nivolumab was unchanged compared to OPDIVO administered alone and the CL of ipilimumab was increased by 30% compared to ipilimumab administered alone.

When OPDIVO 360 mg every 3 weeks was administered in combination with ipilimumab 1 mg/kg every 6 weeks and chemotherapy, the CL of nivolumab was unchanged compared to OPDIVO administered alone and the CL of ipilimumab increased by 22% compared to ipilimumab administered alone.

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 those of OPDIVO or of other nivolumab products.

Anti-drug antibody and neutralizing antibody responses were monitored throughout the treatment period where the benefit to risk ratio was assessed. Incidence of anti-drug antibodies and neutralizing antibodies are presented in Table 51.

Effects of Anti-Drug Antibodies

Presence of treatment-emergent anti-nivolumab antibodies increased nivolumab clearance by up to 20% after administration of nivolumab as monotherapy or in combination with ipilimumab. These anti-drug antibody-associated pharmacokinetic changes were not considered to be clinically significant. There was no identified clinically significant effect of anti-drug antibodies on incidence of infusion-related reactions. The effects of anti-drug antibodies on effectiveness have not been fully characterized.

11 DESCRIPTION

Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated molecular mass of 146 kDa. It is expressed in a recombinant Chinese Hamster Ovary (CHO) cell line.

OPDIVO is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-yellow liquid that may contain light (few) particles.

OPDIVO (nivolumab) injection for intravenous use is supplied in single-dose vials. Each mL of OPDIVO solution contains nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, USP. May contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to assess the potential of nivolumab for carcinogenicity or genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.

13.2 Animal Toxicology and/or Pharmacology

In animal models, inhibition of PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis–infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

16 HOW SUPPLIED/STORAGE AND HANDLING

OPDIVO® (nivolumab) Injection is a clear to opalescent, colorless to pale- yellow solution in a single-dose vial available as follows:

Store under refrigeration at 2°C to 8°C (36°F to 46°F). Protect from light by storing in the original package until time of use. Do not freeze or shake.

new or worsening cough

shortness of breath

chest pain

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

stools 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 of your ankles

loss of appetite

rash

itching

skin blistering or peeling

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

Chest pain, irregular heartbeat, shortness of breath or swelling of 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 and older with a type of skin cancer called melanoma:**

OPDIVO may be used alone or in combination with ipilimumab to treat melanoma that has spread or cannot be removed by surgery (advanced melanoma),**or**

OPDIVO may be used alone to help prevent Stage IIB, Stage IIC, Stage III or Stage IV melanoma from coming back after it has been completely removed by surgery.

**adults with a type of lung cancer called non-small cell lung cancer (NSCLC).**

OPDIVO may be used in combination with chemotherapy that contains platinum and another chemotherapy medicine before you have surgery for early-stage NSCLC.

OPDIVO may be used in combination with ipilimumab as your first treatment for NSCLC:

when your lung cancer has spread to other parts of your body (metastatic), and 

your tumors are positive for PD-L1, but do not have an abnormal EGFR or ALK gene.

OPDIVO may be used in combination with ipilimumab and 2 cycles of chemotherapy that contains platinum and another chemotherapy medicine, as the first treatment of your NSCLC when your lung cancer:

has spread or grown, or comes back,**and**

your tumor does not have an abnormal EGFR or ALK gene.

OPDIVO may be used when your lung cancer:

has spread or grown,**and**

you have tried chemotherapy that contains platinum, and it did not work or is no longer working.

If your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes,**and** it did not work or is no longer working.

**adults with a type of cancer that affects the lining of the lungs and chest wall called malignant pleural mesothelioma.**

OPDIVO may be used in combination with ipilimumab as your first treatment for malignant pleural mesothelioma that cannot be removed by surgery.

**adults with kidney cancer (renal cell carcinoma).**

OPDIVO may be used in combination with ipilimumab in certain adults when their cancer has spread (advanced RCC), and you have not already had treatment for your advanced RCC.

OPDIVO may be used in combination with cabozantinib when your cancer has spread (advanced RCC), and you have not already had treatment for your advanced RCC.

OPDIVO may be used alone when your cancer has spread or grown after treatment with other cancer medicines.

**adults with a type of blood cancer called classical Hodgkin lymphoma.**

**OPDIVO may be used if:**

your cancer has come back or spread after a type of stem cell transplant that uses your own stem cells (autologous),**and**

you used the medicine brentuximab vedotin before or after your stem cell transplant,**or**

you received at least 3 kinds of treatment including a stem cell transplant that uses your own stem cells (autologous).

**adults with head and neck cancer (squamous cell carcinoma).**

**OPDIVO may be used when your head and neck cancer:**

has come back or spread,**and**

you have tried chemotherapy that contains platinum and it did not work or is no longer working.

**adults with cancer of the lining of the urinary tract (urothelial carcinoma).**

**OPDIVO may be used to help prevent cancer of the urinary tract from coming back after it was removed by surgery.**

**OPDIVO may be used in combination with chemotherapy medicines cisplatin and gemcitabine as your first treatment when your urinary tract cancer has spread (metastastic) or cannot be removed by surgery.**

**OPDIVO may be used when your urinary tract cancer has spread or grown (locally advanced or metastatic), and:**

you have tried chemotherapy that contains platinum, and it did not work or is no longer working,**or**

your cancer worsened within 12 months of treatment with chemotherapy that contains platinum, either before or after surgery to remove your cancer.

**adults and children 12 years of age and older, with a type of colon or rectal cancer (colorectal cancer).**

OPDIVO may be used alone or in combination with ipilimumab when your colon or rectal cancer:

has spread to other parts of the body (metastatic),

is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR),**and**

you have tried treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer working.

**adults with liver cancer (hepatocellular carcinoma).**

OPDIVO may be used in combination with ipilimumab if you have previously received treatment with sorafenib.

**adults with cancer of the tube that connects your throat to your stomach (esophageal cancer).**

OPDIVO may be used to help prevent your esophageal or gastroesophageal junction cancer from coming back when:

your esophageal or gastroesophageal junction cancer has been treated with chemoradiation followed by surgery to completely remove the cancer,**but**

some cancer cells were still present in the removed tumor or lymph nodes.

OPDIVO may be used in combination with chemotherapy that contains fluoropyrimidine and platinum when your esophageal cancer:

is a type called squamous cell carcinoma,**and**

cannot be removed with surgery (advanced), or has spread to other parts of the body (metastatic),**and**

you have not already had treatment for your advanced or metastatic esophageal cancer.

OPDIVO may be used in combination with ipilimumab when your esophageal cancer:

is a type called squamous cell carcinoma,**and**

cannot be removed with surgery (advanced), or has spread to other parts of the body (metastatic),**and**

you have not already had treatment for your advanced or metastatic esophageal cancer.

OPDIVO may be used alone when your esophageal cancer:

is a type called squamous cell carcinoma,**and**

cannot be removed with surgery,**and**

has come back or spread to other parts of the body after you have received chemotherapy that contains fluoropyrimidine and platinum.

**adults with cancer of the stomach (gastric cancer), cancer where the esophagus joins the stomach (gastroesophageal junction cancer), and in adults with esophageal adenocarcinoma.**

OPDIVO may be used in combination with chemotherapy that contains fluoropyrimidine and platinum when your gastric, gastroesophageal junction, or esophageal cancer:

cannot be removed with surgery,**or**

has spread to other parts of the body.

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 received radiation treatment to your chest area in the past and have received other medicines that are like OPDIVO

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

are pregnant or plan to become pregnant. OPDIVO can harm your unborn baby.  

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

You should use an effective method of birth control during treatment and for 5 months after your last dose of OPDIVO. 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 OPDIVO.

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

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

When OPDIVO is used alone, it is usually given every 2 weeks or 4 weeks depending on the dose you are receiving.

When OPDIVO is used in combination with ipilimumab (except for treating NSCLC), OPDIVO is usually given every 3 weeks, for a total of 4 doses. Ipilimumab will be given on the same day. After that, OPDIVO will be given alone every 2 weeks or 4 weeks depending on the dose you are receiving.

For NSCLC before you have surgery, OPDIVO is given in combination with chemotherapy every 3 weeks for 3 cycles.

For NSCLC that has spread to other parts of your body, when OPDIVO is used in combination with ipilimumab, OPDIVO is given every 3 weeks, and ipilimumab is given every 6 weeks for up to 2 years. Your healthcare provider will determine if you will also need to receive chemotherapy every 3 weeks for 2 cycles.

For malignant pleural mesothelioma, OPDIVO is given every 3 weeks and ipilimumab is given every 6 weeks for up to 2 years.

For RCC, when used in combination with cabozantinib, OPDIVO is usually given every 2 weeks or 4 weeks depending on the dose you are receiving. Cabozantinib is given once daily by mouth.

For UC that has spread to other parts of your body or cannot be removed by surgery, when OPDIVO is used in combination with chemotherapy medicines cisplatin and gemcitabine, OPDIVO is given every 3 weeks for up to 6 cycles. Chemotherapy will be given on the same day. After that, OPDIVO will be given alone every 2 weeks or 4 weeks depending on the dose you are receiving.

When OPDIVO is used in combination with chemotherapy for treating esophageal squamous cell carcinoma (ESCC), OPDIVO is given either every 2 weeks or every 4 weeks, for up to 2 years.

When OPDIVO is used in combination with ipilimumab for esophageal squamous cell carcinoma, OPDIVO is given every 2 weeks or 3 weeks and ipilimumab is given every 6 weeks for up to 2 years.

For gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma, when used in combination with fluoropyrimidine and platinum-containing chemotherapy, OPDIVO is given every 2 weeks or 3 weeks depending on the dose you are receiving, for up to 2 years. Chemotherapy will be given on the same day.

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 OPDIVO?”**

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

chills or shaking

itching or rash

flushing

shortness of breath or wheezing

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 OPDIVO. Your healthcare provider will monitor you for signs of complications if you have an allogeneic stem cell transplant.

feeling tired

rash

pain in muscles, bones, and joints

itchy skin

diarrhea

nausea

weakness

cough

vomiting

shortness of breath

constipation

decreased appetite

back pain

upper respiratory tract infection

fever

headache

stomach-area (abdominal) pain

urinary tract infection

feeling tired

diarrhea

rash

itching

nausea

pain in muscles, bones, and joints

fever

cough

decreased appetite

vomiting

stomach-area (abdominal) pain

shortness of breath

upper respiratory tract infection

headache

low thyroid hormone levels (hypothyroidism)

constipation

decreased weight

dizziness

nausea

feeling tired

pain in muscles, bones and joints

constipation

decreased appetite

rash

vomiting

numbness, pain, tingling, or burning in your hands and feet

feeling tired

pain in muscles, bones, and joints

nausea

diarrhea

rash

decreased appetite

constipation

itching

diarrhea

feeling tired or weak

liver problems. See “What is the most important information I should know about OPDIVO?”

rash, redness, pain, swelling or blisters on the palms of your hands or soles of your feet

mouth sores

rash

high blood pressure

low thyroid hormone levels

pain in muscles, bones, and joints

decreased appetite

nausea

change in the sense of taste

stomach-area (abdominal) pain

cough

upper respiratory tract infection

nausea

numbness, pain, tingling, or burning in your hands or feet

decreased appetite

feeling tired

constipation

mouth sores

diarrhea

vomiting

stomach-area (abdominal) pain

pain in muscles, bones, and joints

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: March 2024

17 PATIENT COUNSELING INFORMATION

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

Immune-Mediated Adverse Reactions

Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and withholding or discontinuation of OPDIVO, including:

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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)].

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

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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)].

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

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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 [see Warnings and Precautions (5.1)].

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

Infusion-Related Reactions

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

Complications of Allogeneic HSCT

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

Embryo-Fetal Toxicity

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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)].

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

Lactation

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Advise women not to breastfeed during treatment with OPDIVO 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