BRISTOL-MYERS SQUIBB RESEARCH & DEVELOPMENT SWISS SUMMARY OF THE RISK MANAGEMENT PLAN FOR NIVOLUMAB (NIVOLUMAB IS THE ACTIVE SUBSTANCE IN OPDIVO )

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1 BRISTOL-MYERS SQUIBB RESEARCH & DEVELOPMENT SWISS SUMMARY OF THE RISK MANAGEMENT PLAN FOR NIVOLUMAB (NIVOLUMAB IS THE ACTIVE SUBSTANCE IN OPDIVO ) Version Number: 6 Document Date: 21-Aug-2018 Bristol-Myers Squibb Research and Development 311 Pennington Rocky Hill Road Pennington, NJ USA The Risk Management Plan (RMP) is a comprehensive document submitted as part of the application dossier for market approval of a medicine. The RMP summary contains information on the medicine's safety profile and explains the measures that are taken in order to further investigate and follow the risks as well as to prevent or minimize them. The RMP summary for Nivolumab is a concise document and does not claim to be exhaustive. As the RMP is an international document, the summary might differ from the Arzneimittelinformation / Information sur le médicament approved and published in Switzerland, e.g. by mentioning risks occurring in populations or indications not included in the Swiss authorization. Please note that the reference document which is valid and relevant for the effective and safe use of Präparatename in Switzerland is the Arzneimittelinformation/ Information sur le médicament (see approved and authorized by Swissmedic. Bristol-Myers Squibb SA is fully responsible for the accuracy and correctness of the content of the published RMP summary for Nivolumab.

2 TABLE OF CONTENTS SWISS SUMMARY OF THE RISK MANAGEMENT PLAN FOR NIVOLUMAB...1 TABLE OF CONTENTS...2 LIST OF TABLES OVERVIEW OF DISEASE EPIDEMIOLOGY SUMMARY OF TREATMENT BENEFITS UNKNOWNS RELATING TO TREATMENT BENEFITS SUMMARY OF SAFETY CONCERNS MISSING INFORMATION PLANNED POST-AUTHORIZATION DEVELOPMENT PLAN SUMMARY OF CHANGES TO THE RISK MANAGEMENT PLAN OVER TIME

3 LIST OF TABLES Table 1: Important Identified Risks: Nivolumab Monotherapy...8 Table 2: Important Identified Risks : Nivolumab+Ipilimumab Combination Therapy...12 Table 3: Important Potential Risks: Nivolumab Monotherapy...15 Table 4: Important Potential Risks : Nivolumab+Ipilimumab Combination Therapy...15 Table 5: Missing Information: Nivolumab Monotherapy...16 Table 6: Missing Information: Nivolumab+Ipilimumab Combination Therapy...17 Table 7: List of Studies in Post-authorization Development Plan...19 Table 8: Major Changes to the Risk Management Plan Over Time

4 1. OVERVIEW OF DISEASE EPIDEMIOLOGY Melanoma: Opdivo is a medicine which contains the active substance. It is used to treat melanoma (a type of skin cancer) that has metastasised (spread to other parts of the body) or cannot be surgically removed. The number of people diagnosed with this cancer is increasing worldwide. In 2008, around 69,000 new melanomas occurred in 27 European countries. In about 6 out of 100 newly-diagnosed cases, the melanoma is inoperable or has metastasised. This suggests that newly-diagnosed inoperable or metastatic melanomas in these 27 European countries number over 4,000 per year. NSCLC: Opdivo is a cancer medicine used to treat adults with a type of lung cancer known as squamous cell non-small cell lung cancer. Lung cancer is the most common cancer worldwide. It is the leading cause of cancer deaths in men and the second leading cause of cancer deaths in women. In 2012, there were about 410,000 newly diagnosed lung cancer cases in Europe. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and has several subtypes: the squamous cell subtype represents about 20 to 30% of all lung cancer. At diagnosis, 10-15% of NSCLC patients have locally advanced cancer (Stage IIIB), and 40% of patients have metastatic cancer (stage IV, when the cancer has spread to other parts of the body). RCC: Opdivo is a cancer medicine used to treat adults with renal cell carcinomas (RCC). Kidney cancer accounts for approximately 2%-5% of all cancers. Rates of kidney cancer are highest in Europe, North America, and Australia and lowest in India, Japan, Africa, and China. Approximately 10% of kidney carcinomas are comprised of renal pelvis cancers, while 90% of kidney cancers are RCC, which are adenocarcinomas that develop in the renal parenchyma. RCC is heterogeneous and comprised of several histological cell types that differ in their genetics, biology, and pathologic behavior. Renal cell cancer occurs approximately twice as frequently in men as in women, and incidence appears to be the highest for black males. The average of diagnosis is in the early 60 s. RCC has the highest mortality rate of the genitourinary cancers and accounts for approximately 1.5% of all cancer deaths. More than a third of patients with RCC will die from the disease. chl: Classical Hodgkin lymphoma (chl) is a rare human cancer with an estimated worldwide crude incidence rate of 0.9/100,000. Approximately 17,000 new cases occur in Europe annually, and 9,000 in Northern America. chl occurs more often in males than females; however, some variation appears by histopathological subtype. Overall, chl has a bimodal age distribution impacting young adults and the elderly more than middle aged adults. chl is the most commonly diagnosed cancer in adolescents aged years old. Older adults tend to fare significantly worse than young adults. Adults > 50 years old at diagnosis have a relative survival rate at 5 years of 65% compared to 94% for young people < 20 years old. Hodgkin Lymphoma is a potentially curable disease in first-line patients with a cure rate of approximately 80% with the use of modern therapies. For patients who relapse, treatment of choice consists of a chemotherapy regimen (different than that used in the first-line) followed by high dose chemotherapy and autologous stem cell rescue with or without radiation therapy. After the initial multi-drug treatment regimen, approximately 5 to 10% of patients with HL suffer from 4

5 primary refractory disease, and an additional 10 to 30% will relapse. Patients with relapsed or refractory disease have an estimated median survival of less than 3 years. Once a subject undergoes ASCT and subsequently relapses, the outcomes are generally poor and efficacious therapeutic options are limited. SCCHN: Opdivo is a cancer medicine used to treat adults with squamous cell cancer of the head and neck (SCCHN). Head and neck carcinomas are the sixth most common cancer in the world, accounting for more than 550,000 cases and around 300,000 deaths each year. About ~90% of all head and neck cancer cancers are squamous cell carcinomas. Most SCCHN arise from the epithelial lining of the oral cavity, oropharynx, larynx, and hypopharynx. The most important risk factors identified in SCCHN include tobacco and alcohol use, and in a subgroup of SCCHN (particularly oropharynx tumors), human papilloma virus (HPV) has been identified as a strong independent prognostic factor, with HPV-positive infected tumors associated with more favorable clinical outcomes. At initial diagnosis, about a third of patients present with early stage (33%; Stage I/II), whereas the majority present with locally advanced disease (52-60%; Stage III/IVA/IV-B). Only a small minority presents with metastatic disease initially (~10%; Stage IV-C). With standard of care treatment, the 5-year survival is 80%, 50%, and 25% for early stage, locally advanced, and metastatic disease, respectively. UC: Opdivo is a cancer medicine used to treat adults with urothelial cancer (UC). UC is one of the ten most common cancers in the world with approximately 430,000 cases diagnosed annually. The highest incidence of UC is in Europe and the United States and the lowest in Sub-Saharan Africa, Asia, and South America. New cases predominantly occur in men compared to women and is a disease of the elderly with the highest rates observed in people aged 65 and older. Approximately 250,000 people worldwide die annually from UC. CRC: Opdivo is a cancer medicine used to treat adults with colorectal cancer (CRC). CRC is the third most common form of cancer in men and second most common in women. The majority (5075%) of CRC cases were diagnosed after age 65. Incidences of CRC vary ten-fold in both sexes worldwide, the highest estimated rates being in Denmark, Australia/New Zealand, and the lowest in Western Africa. Each year, there are about 608,000 deaths from colon cancer, which is approximately 8% of all cancer deaths, making colon cancer the fourth most common cause of cancer death. Although the prevalence in early stage CRC is 15%, an estimated 5% of metastatic CRC cases are microsatellite instability high (MSI-H)/mismatch repair deficient (dmmr). GC or GEJC: Opdivo is a cancer medicine used to treat adults with advanced or recurrent gastric (GC) cancer or gastroesophageal junction cancer (GEJC) after 2 or more prior systemic therapies. GC is the third most common cause of cancer death worldwide with approximately 1 million new cases diagnosed annually. The geographic distribution is varied across the globe, with the highest burden of disease seen in Eastern and Western Asia, Central and Eastern Europe, South America, and Central America. GEJC anatomically straddles the distal esophagus and proximal stomach. However, the incidence of GEJC tumors has increased considerably due to increases in risk factors such as obesity and gastroesophageal reflux disease in western countries. 5

6 At the time of diagnosis the reported 1-year survival is approximately 30% for those with advanced disease. Approximately 723,000 people worldwide die annually from GC. 2. SUMMARY OF TREATMENT BENEFITS Melanoma Nivolumab Monotherapy: Opdivo as monotherapy has been shown to be effective in treating patients with advanced malignant melanoma (melanoma that could not be treated by surgery or had spread throughout the body) in two main studies. The first study looked at 418 previously untreated advanced melanoma patients who received either Opdivo or a standard cancer medicine (dacarbazine). The study found that patients treated with Opdivo survived longer (on average for over 14 months) than patients who received dacarbazine (around 12 months). The second study looked at 405 advanced melanoma patients whose disease had got worse despite previous treatment with a standard cancer medicine. Patients were given Opdivo or the investigator s choice of cancer treatment (dacarbazine or a combination of carboplatin and paclitaxel). In this study, where patients were followed up for at least 6 months, around 32% (38 out of 120) of patients given Opdivo responded to treatment and had a reduction in their tumours compared with about 11% (5 out of 47) of patients given investigator s choice of treatment. Nivolumab+Ipilimumab Combination Therapy: Opdivo in combination with ipilimumab has been shown to be effective in treating patients with advanced malignant melanoma in two main studies. In the first study, a total of 945 patients were randomised to receive in combination with ipilimumab (N = 314), as monotherapy (N = 316), or ipilimumab alone (N = 315). Patients in the combination arm received 1 mg/kg over 60 minutes and ipilimumab 3 mg/kg over 90 minutes administered intravenously every 3 weeks for the first 4 doses, followed by 3 mg/kg as monotherapy every 2 weeks. With a minimum follow-up of 18 months, median PFS was 11.5 months for in combination with ipilimumab. Overall survival (OS) was not mature at time of this analysis. In the second study, 142 patients with advanced (unresectable or metastatic) melanoma were randomised to receive in combination with ipilimumab compared with ipilimumab alone. Investigator assessed objective response rate (ORR) in patients with BRAF wild-type melanoma (N=72 in the in combination with ipilimumab arm and N=37 in the ipilimumab arm) was the primary efficacy outcome measure. With a minimum follow-up of 11 months among patients with BRAF wild-type melanoma, ORR was 61% in the in combination with ipilimumab arm and 11% in the ipilimumab arm. The estimated 12 and 18 months OS rates were 79% and 73%, respectively, in the combination arm and 62% and 56%, respectively, in the ipilimumab arm. 6

7 NSCLC: Opdivo monotherapy contains the active substance and is given by infusion (drip) into a vein. It has been shown to improve patients survival in one main study involving 272 patients with previously treated squamous NSCLC that was advanced or had spread throughout the body. Treatment with Opdivo was compared with another cancer medicine, docetaxel, and the main measure of effectiveness was overall survival (how long patients lived). The average survival among 135 patients given Opdivo was around 9 months, whereas among the 137 patients given docetaxel it was 6 months. Supportive information was also provided from another study indicating that Opdivo could produce a response in patients whose disease had progressed despite several previous treatments. RCC: Opdivo monotheray has been shown to be effective in treating patients with advanced RCC who received prior anti-angiogenic therapy in one main study. This study looked at 1054 subjects with advanced RCC who received either Opdivo (N=410) or everolimus (N=411). The study found that patients treated with Opdivo survived longer (median 25 months) than patients who received everolimus (median 19.6 months). chl: Opdivo has been shown to be effective in treating patients with chl after ASCT and brentuximab vedotin treatment. Data from this study in 80 Opdivo-treated subjects demonstrated IRRC-assessed confirmed overall response rate of 66.3% (95% CI: 54.8, 76.4) in subjects with at least 6 months of follow-up. The median duration of response was 7.79 months, although this estimate is unstable due to early censoring. The potential for even longer durability is suggested by the observation that the majority (33/53, 62.3%) of responders had their response ongoing at the time of this analysis. Of the 5 Opdivo-treated ASCT-naive subjects in a Phase 1 study, 4 subjects had an objective response both per IRRC and investigator, which occurred early during treatment and the duration of response was long in 2 subjects. SCCHN: Opdivo monotheray has been shown to be effective in treating patients with recurrent or metastatic SCCHN after platinum-based therapy in one main study. This study looked at 361 subjects who received either Opdivo (N=240) or investigator s choice therapy (N=121; cetuximab, methotrexate, or docetaxel). The study found that patients treated with Opdivo survived longer (median 7.5 months) than patients who received investigator s choice therapy (median 5.1 months). UC: Opdivo monotheray has been shown to be effective in treating patients with locally advanced or metastatic UC who have progressed or recurred following treatment with a platinum agent. This study looked at 270 subjects with urothelial carcinoma who received Opdivo. The study found an overall response rate of 19.6% regardless of tumor PD-L1 expression, which compared favorably to single-agent chemotherapy historical control. In another study of heavily pretreated subjects with advanced or metastatic UC, monotherapy demonstrated substantial, durable clinical activity, regardless of tumor PD-L1 expression at baseline. dmmr or MSI-H mcrc: Opdivo monotherapy has been shown to be effective in treating patients with CRC whose unresectable or metastatic colorectal cancer is dmmr or MSI-H. Data from this study in 74 Opdivo-treated subjects as well as in a subset of subjects who had received prior 5FU + oxaliplatin + irinotecan (5FU-Oxa-Iri) (at any time during prior therapy) demonstrated 7

8 evidence of clinical benefit based on clinically meaningful Blinded Independent Radiologic Review Committee (BIRC)-assessed RECIST 1.1 objective response rate (ORR). The median PFS was 7.6 months in the all monotherapy treated subjects and 4.9 months in subjects with prior 5FU-Oxa-Iri. The median OS has not been reached for either all monotherapy treated subjects or the subset of subjects with prior 5FU-Oxa-Iri. GC or GEJC: Opdivo monotherapy has been shown to be effective in treating patients with gastric and GEJC who received 2 or more prior treatment regimens. The first study was conducted in Asian subjects (Japan, Taiwan, Korea; N = 330), and showed that patients treated with Opdivo survived longer (median 5.26 months) than patients who received placebo (median 4.86 months). A second study was conducted in EU and US (N = 42), and showed that patients treated with Opdivo had an average survival of 8.97 months. 3. UNKNOWNS RELATING TO TREATMENT BENEFITS Melanoma: The benefits of Opdivo on its own or in combination in previously untreated patients or in those who did not respond to previous treatment are still being studied. Studies in children are also being carried out. NSCLC: Studies to confirm the longer-term effects of Opdivo in patients with NSCLC are ongoing. The safety and effectiveness of the medicine in patients less than 18 years of age, as well as those with severely reduced liver and kidney function, or with auto-immune diseases (conditions where the immune system attacks the patient s own body) have not been formally studied. Other Indications - RCC, chl, SCCHN, UC, dmmr or MSI-H mcrc, and GC or GEJC: The safety and effectiveness of Opdivo in patients less than 18 years of age, as well as those with severely reduced liver and kidney function, or with auto immune diseases (conditions where the immune system attacks the patient s own body) have not been formally studied. 4. SUMMARY OF SAFETY CONCERNS Important Identified Risks: monotherapy A summary of safety concerns under important identified risks for monotherapy is provided in Table 1. Table 1: Important Identified Risks: Nivolumab Monotherapy Risk What is known Preventability Immune-related pneumonitis (lung inflammation resulting from activity of the immune system) Opdivo increases the risk of lung inflammation. In clinical trials, lung inflammation developed between 2% and 3% patients with melanoma, between 5% and 7% patients with NSCLC, in 5% patients with RCC, between 1% and 4% patients with chl, in 2% patients with SCCHN, and between 3% and 4% patients In the event of lung inflammation, doctors might consider stopping treatment with Opdivo temporarily or permanently, depending on the severity. Prompt recognition of signs and symptoms and implementation of the recommended management guidelines may prevent serious complications such as respiratory failure. Patients will be provided 8

9 Table 1: Important Identified Risks: Nivolumab Monotherapy Risk What is known with UC, and between 2% and 5% patients with GC or GEJC. Cases were sometimes fatal. There was no case of lung inflammation in patients with dmmr or MSI-H mcrc. Signs or symptoms may include dry cough and shortness of breath. Preventability with an alert card warning them of the risk of lung inflammation and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Immune-related colitis (inflammation of the gut resulting from activity of the immune system) Opdivo increases the risk of diarrhoea or colitis. In clinical trials, diarrhoea or colitis developed in 17% patients with melanoma, between 16% and 18% patients with NSCLC, in 13% patients with RCC, between 10% and 17% patients with chl, in 7% patients with SCCHN, between 9% and 10% patients with UC, in 24% patients with dmmr or MSI-H mcrc, and between 7% and 17% patients with GC or GEJC. Signs and symptoms may include watery, loose or soft stools, an increased number of bowel movements, blood in stools or darkcoloured stools and pain or tenderness in the stomach area. In the event of diarrhoea or colitis, doctors might consider stopping treatment with Opdivo temporarily or permanently, depending on the severity. Prompt recognition of signs and symptoms and implementation of the recommended management guidelines may prevent serious complications such as gut perforation (developing a hole in the wall of the gut) or severe colitis requiring colectomy (surgery to remove a part of the gut). Patients will be provided with an alert card warning them of the risk of gut inflammation and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Immune-related hepatitis (liver inflammation resulting from activity of the immune system) Opdivo increases the risk of hepatitis. In clinical trials, abnormal liver tests developed between 3% and 8% patients with melanoma, between 2% and 3% patients with NSCLC, in 11% patients with RCC, between 6% and 9% patients with chl, in 2% patients with SCCHN, between 4% and 5% patients with UC, in 8% patients with dmmr or MSI-H mcrc, and between 5% and 6% patients with GC or GEJC. Signs and symptoms of hepatitis may include eye or skin yellowing (jaundice), pain on the right side of the stomach area and tiredness. Patients should be monitored for signs and symptoms of hepatitis such as an increase in blood levels of transaminases and total bilirubin levels. In the event of abnormal liver enzyme tests, doctors might consider stopping treatment with Opdivo temporarily or permanently. Prompt review of blood tests, recognition of signs and symptoms and implementation of the recommended management guidelines may prevent serious complications. Patients will be provided with an alert card warning them of the risk of hepatitis and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Immune-related nephritis (kidney inflammation) or kidney problems resulting from activity of the immune system Opdivo increases the risk of kidney inflammation. In clinical trials, kidney inflammation developed in 2% patients with melanoma, between 5% and 12% patients with NSCLC, in 7% patients with RCC, in 2% patients with chl in <1% patients with SCCHN, between 1% and 9% patients with UC, 4% patients with dmmr or MSI-H mcrc, and in <1% patients with GC or GEJC. Patients should be monitored for signs and symptoms of kidney problems. In the event of nephritis or kidney dysfunction, doctors might consider stopping treatment with Opdivo temporarily or permanently. Prompt recognition of signs and symptoms, prompt review of blood tests and implementation of the recommended management guidelines may prevent serious complications. 9

10 Table 1: Important Identified Risks: Nivolumab Monotherapy Risk What is known Signs or symptoms may include production of smaller amounts of urine. Preventability Patients will be provided with an alert card warning them of the risk of kidney problems and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Immune-related endocrinopathies (problems with hormone producing organs resulting from activity of the immune system) Opdivo increases the risk of inflammation of hormone-producing glands (thyroid, pancreas, adrenal, or pituitary glands) and may affect how these glands work. In clinical trials, disorders of hormone-producing glands developed in 9% patients with melanoma, between 7% to 9% patients with NSCLC, in 10% patients with RCC, between 9% and 14% patients with chl, in 8% patients with SCCHN, between 8% and 14% patients with UC, 8% in patients with dmmr or MSI-H mcrc, and between 5% and 10% patients with GC or GEJC. Signs or symptoms of endocrine gland problems may include headaches, tiredness and weight changes. Patients should be monitored for signs and symptoms of endocrinopathies. In the event of an endocrinopathy, treatment with Opdivo should be stopped temporarily or permanently. Prompt recognition of signs and symptoms and implementation of the recommended management guidelines may prevent serious complications such as adrenal crisis. Patients will be provided with an alert card warning them of the risk of endocrine gland problems and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Immune-related skin ARs Opdivo increases the risk of skin ARs. In clinical trials, skin ARs developed between 35% and 41% patients with melanoma, 18% and 23% patients with NSCLC, in 25% patients with RCC, between 18% and 26% patients with chl, in 16 % patients with SCCHN, between 17% and 42% patients with UC, in 22% patients with dmmr or MSI-H mcrc, and 16% and 24% patients with GC or GEJC. Signs or symptoms of severe skin reaction may include skin rash with or without itching, peeling of the skin, and dry skin. Early detection and timely treatment are key to recovery and to prevent severe complications. Patients will be provided with an alert card warning them of the risk of skin problems and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Physicians may start treatment with corticosteroids (in order to prevent more severe complications and reduce the symptoms). If skin reactions occur, doctors may manage them with corticosteroids; treatment with Opdivo may be stopped temporarily or permanently depending on the severity. Opdivo must be permanently stopped for Grade 4 rash, and Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Toxic Epidermal Necrolysis (TEN)1 Across the ongoing clinical program, a new adverse drug reaction (ADR) of toxic epidermal necrolysis (TEN) was identified based on one additional case of TEN with fatal outcome reported on monotherapy (2 previous cases included 1 case that occurred on subsequent Bactrim after discontinuation from and Patients should be monitored for signs and symptoms of TEN. In the event of TEN, doctors might consider stopping treatment with temporarily or permanently. Prompt recognition of signs and symptoms, and implementation of the recommended management guidelines may prevent serious complications. 10

11 Table 1: Important Identified Risks: Nivolumab Monotherapy Risk What is known ipilimumab [one dose] due to colitis, and one case occurred on subsequent ipilimumab after discontinuation from due to erythema multiforme). The estimated frequency of TEN is rare (3 cases [0.03%; 3/8,490]). Preventability Opdivo must be permanently stopped for Grade 4 rash, and SJS or TEN. Other immunerelated ARs Other selected immune-related adverse reactions, which are uncommon but considered important identified risks, include uveitis (inflammation of the middle layer of the eye), pancreatitis (inflammation of the pancreas), demyelination (loss of the protective layer surrounding certain nerve cells), Guillain-Barré syndrome (a nerve disorder that can result in pain, numbness, muscle weakness and difficulty walking), myasthenic syndrome (another disorder resulting in muscle weakness), myositis, myocarditis, rhabdomyolysis (muscle damage), encephalitis (an acute inflammation of the brain that is caused by either a viral infection or by the immune system mistakenly attacking brain tissue and impairing function), solid organ transplant rejection, and VKH (a multisystem autoimmune disorder principally affecting pigmented tissues in the ocular, auditory, integumentary, and central nervous system). These immune-related adverse reactions can be serious and life-threatening. If immune-related adverse reactions are suspected, adequate evaluation should be performed. Based on the severity of adverse reactions, Opdivo should be temporarily stopped and corticosteroids (antiinflammatory medicines) administered. Upon improvement. Opdivo may be resumed after corticosteroid taper. Opdivo must be permanently stopped if any severe immunerelated adverse reaction persists or returns and for any life-threatening immune-related adverse reaction. Opdivo must be permanently stopped for severe myocarditis. If a patient develops signs and symptoms of myotoxicity (myositis, myocarditis, and rhabdomyolysis), close monitoring should be implemented, and the patient referred to a specialist for assessment and treatment without delay. Based on the severity of myotoxicity, or in combination with ipilimumab should be withheld or discontinued, and appropriate treatment instituted. Severe infusion reactions Severe reactions to infusion (drip) of Opdivo into a vein were observed in clinical trials in melanoma, NSCLC, RCC, chl, SCCHN, UC, dmmr or MSI-H mcrc (between 1% and 7% patients), and GC or GEJC (between 1% and 7% patients). Serious acute infusion reactions were infrequent. However, life-threatening reactions may occur. Signs or symptoms may include throat or chest tightness, wheezing, skin rash or hives, dizziness, or light-headedness. Patients should not be given Opdivo if they have a history of allergic reactions to or any other ingredients. Patients should seek medical attention immediately if they start feeling unwell during or soon after the infusion of Opdivo.. 1 TEN is subsumed under immune-related skin ARs as an important identified risk and this reflects the BMS company position for the categorization of this Safety Concern. In accordance with the Swissmedic request, TEN has been listed as an individual important identified risk. A summary of safety concerns under important identified risks for in combination with ipilimumab in the treatment of melanoma is provided in Table 2. 11

12 Table 2: Important Identified Risks : Nivolumab+Ipilimumab Combination Therapy Risk What is known Preventability Immune-related pneumonitis (lung inflammation resulting from activity of the immune system) Opdivo increases the risk of lung inflammation. In clinical trials with +ipilimumab combination therapy, between 5% and 10% patients developed lung inflammation, sometimes fatal. Signs or symptoms may include dry cough and shortness of breath. In the event of lung inflammation, treatment with Opdivo may need to be temporarily or permanently stopped by the doctor, depending on the severity. Prompt recognition of signs and symptoms and implementation of the recommended management guidelines may help prevent serious complications such as respiratory failure. Patients will be provided with an alert card warning them of the risk of lung inflammation and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Immune-related colitis (inflammation of the gut resulting from activity of the immune system) Opdivo increases the risk of diarrhoea or colitis. In clinical trials with + ipilimumab combination therapy, between 37% and 47% patients developed diarrhoea or colitis with the medicine. Signs and symptoms may include watery, loose or soft stools, an increased number of bowel movements, blood in stools or darkcoloured stools and pain or tenderness in the stomach area. In the event of diarrhoea or colitis, treatment with Opdivo may need to be temporarily or permanently stopped by the doctor, depending on the severity. Prompt recognition of signs and symptoms and implementation of the recommended management guidelines may help prevent serious complications such as gut perforation (developing a hole in the wall of the gut) or severe colitis requiring colectomy (surgery to remove a part of the gut). Patients will be provided with an alert card warning them of the risk of gut inflammation and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Immune-related hepatitis (liver inflammation resulting from activity of the immune system) Opdivo increases the risk of hepatitis. In clinical trials with +ipilimumab combination therapy, between 15% and 30% patients developed abnormal liver test results. Signs and symptoms of hepatitis may include eye or skin yellowing (jaundice), pain on the right side of the stomach area and tiredness. Patients should be monitored for signs and symptoms of hepatitis such as an increase in blood levels of transaminases and total bilirubin levels. In the event of abnormal liver enzyme tests, doctors might consider stopping treatment with Opdivo temporarily or permanently. Prompt review of blood tests, recognition of signs and symptoms and implementation of the recommended management guidelines may help prevent serious complications. Patients will be provided with an alert card warning them of the risk of hepatitis and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Immune-related nephritis (kidney inflammation) or kidney problems resulting from Opdivo increases the risk of kidney inflammation. In clinical trials with +ipilimumab combination therapy, between 2% and 5% patients developed kidney inflammation. Patients should be monitored for signs and symptoms of hepatitis such as an increase in blood levels of transaminases and total bilirubin levels. In the event of abnormal liver enzyme tests, doctors might consider stopping 12

13 Table 2: Important Identified Risks : Nivolumab+Ipilimumab Combination Therapy Risk activity of the immune system What is known Signs or symptoms may include passing less urine. Preventability treatment with Opdivo temporarily or permanently. Prompt review of blood tests, recognition of signs and symptoms and implementation of the recommended management guidelines may help prevent serious complications. Patients will be provided with an alert card warning them of the risk of hepatitis and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Immune-related endocrinopathies (problems with hormone producing organs resulting from activity of the immune system) Opdivo increases the risk of inflammation of hormone-producing organs (endocrine glands such as thyroid, adrenal, or pituitary glands) and may affect how these glands work. In clinical trials with +ipilimumab combination therapy, between 29% and 30% patients developed disorders of hormone-producing glands. Signs or symptoms of endocrine gland problems may include headaches, tiredness, and weight changes. Patients should be monitored for signs and symptoms of endocrinopathies. In the event of an endocrinopathy, treatment with Opdivo should be stopped temporarily or permanently. Prompt recognition of signs and symptoms and implementation of the recommended management guidelines may help prevent serious complications such as adrenal crisis. Patients will be provided with an alert card warning them of the risk of endocrine gland problems and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Immune-related skin ARs Opdivo increases the risk of skin ARs. In clinical trials with +ipilimumab combination therapy, between 59% and 83% patients developed skin ARs. Signs or symptoms of severe skin reaction may include skin rash with or without itching, peeling of the skin, and dry skin. Early detection and timely treatment are key to recovery and to prevent severe complications. Patients will be provided with an alert card warning them of the risk of skin problems and how to recognise the symptoms, and should contact their doctor right away if these occur or worsen. Physicians may start treatment with corticosteroids (in order to prevent more severe complications and reduce the symptoms). If skin reactions occur, doctors may manage them with corticosteroids; treatment with Opdivo may be stopped temporarily or permanently depending on the severity. Opdivo must be permanently stopped for Grade 4 rash, and Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Toxic Epidermal Necrolysis (TEN)2 Across the ongoing clinical program, a new adverse drug reaction (ADR) of toxic epidermal necrolysis (TEN) was identified based on one additional case of TEN with fatal outcome reported on monotherapy (2 previous cases included 1 case that occurred on subsequent Bactrim Patients should be monitored for signs and symptoms of TEN. In the event of TEN, doctors might consider stopping treatment with temporarily or permanently. Prompt recognition of signs and symptoms, and implementation of the recommended 13

14 Table 2: Important Identified Risks : Nivolumab+Ipilimumab Combination Therapy Risk What is known after discontinuation from and ipilimumab [one dose] due to colitis, and one case occurred on subsequent ipilimumab after discontinuation from due to erythema multiforme). The estimated frequency of TEN is rare (3 cases [0.03%; 3/8,490]). Preventability management guidelines may prevent serious complications. Opdivo must be permanently stopped for Grade 4 rash, and SJS or TEN. Other immunerelated ARs Selected other immune-related reactions, which are uncommon but considered important identified risks, include uveitis (inflammation of the middle layer of the eye), pancreatitis (inflammation of the pancreas), demyelination (loss of the protective insulating sheath around the nerves), Guillain-Barré syndrome (an immune system disorder that causes nerve inflammation and can result in pain, numbness, muscle weakness and difficulty walking), and myasthenic syndrome (another disorder resulting in muscle weakness), myositis, myocarditis, rhabdomyolysis (muscle damage), encephalitis (an acute inflammation of the brain that is caused by either a viral infection or by the immune system mistakenly attacking brain tissue and impairing function), solid organ transplant rejection, and VKH (a multisystem autoimmune disorder principally affecting pigmented tissues in the ocular, auditory, integumentary, and central nervous systems). These immune-related reactions can be serious and life-threatening. For suspected immune-related reactions, appropriate testing should be carried out to see if they may be related to treatment. The medicine should be stopped either temporarily or permanently, depending on the severity of the reaction, and appropriate treatment such as corticosteroids (anti-inflammatory medicines) should be given. Opdivo must be permanently stopped if any severe immune-related adverse reaction persists or returns and for any lifethreatening immune-related adverse reaction. Opdivo must be permanently stopped for severe myocarditis. If a patient develops signs and symptoms of myotoxicity (myositis, myocarditis, and rhabdomyolysis), close monitoring should be implemented, and the patient referred to a specialist for assessment and treatment without delay. Based on the severity of myotoxicity, or in combination with ipilimumab should be withheld or discontinued, and appropriate treatment instituted. Severe infusion reactions Severe reactions to infusion (drip) into a vein affect between 2% and 4% patients in clinical trials with +ipilimumab combination therapy. Life-threatening reactions may occur. Signs or symptoms may include throat or chest tightness, wheezing, skin rash or hives, dizziness, or lightheadedness. Patients should not be given Opdivo if they have a history of allergic reactions to or any other ingredients of the medicine. Patients should seek medical attention immediately if they start feeling unwell during or soon after the infusion of Opdivo. 2 TEN is subsumed under immune-related skin ARs as an important identified risk and this reflects the BMS company position for the categorization of this Safety Concern. In accordance with the Swissmedic request, TEN has been listed as an individual important identified risk. 14

15 Important Potential Risks A summary of safety concerns under important potential risks for monotherapy is provided in Table 3. Table 3: Important Potential Risks: Nivolumab Monotherapy Risk Effects on the developing baby (embryofetal toxicity) What is known Based on its mechanism of action and data from animal studies, may cause fetal harm when administered to a pregnant woman. A study in experimental models revealed damaged to the fetus, which suggested that pregnant women exposed to Opdivo may be at risk of losing their fetus in the third trimester or of giving birth prematurely. Therefore, Opdivo is not recommended in pregnant women, nor in women of childbearing potential not using effective contraception unless the benefit outweighs the potential risks. Effective contraception should be used for at least 5 months following the last dose of Opdivo. Development of antibodies (immune response) against the medicine (Immunogenicity) Theoretically, immunogenicity may lead to infusion reactions or reduced effectiveness. Although low rates of immunogenicity were seen, no impact has been observed on safety or efficacy, even following prolonged dose interruptions and re-administration of the medicine. Cardiac arrhythmias (heart rhythm problems) (Previously Treated Melanoma) In a study with previously untreated patients who were not eligible for surgery due to spread of their melanoma the incidence of cardiac arrhythmia with Opdivo was lower than with dacarbazine. However, in another study comparing with cancer medicines called anti-ctla4 medicines or BRAF inhibitors, the incidence of arrhythmias was higher in those given. Complications of allogeneic HSCT following therapy There is biologic plausibility for a potential risk of acute graft versus host disease (GVHD) and other transplant complications following therapy based on mechanism of action. Cases of moderate to severe acute GVHD and transplant-related mortality (TRM) were reported in subjects with relapsed chl who received a post- allogeneic hematopoetic stem cell transplant (HSCT). A summary of safety concerns under important potential risks for in combination with ipilimumab in the treatment of melanoma is provided in Table 4. Table 4: Important Potential Risks : Nivolumab+Ipilimumab Combination Therapy Risk What is known Effects on the developing baby (embryofetal toxicity) Based on its mechanism of action and data from animal studies, may cause fetal harm when administered to a pregnant woman. A study in experimental models revealed damaged to the fetus, which suggested that pregnant women exposed to Opdivo may be at risk of losing their fetus in the third trimester or of giving birth prematurely. 15

16 Table 4: Important Potential Risks : Nivolumab+Ipilimumab Combination Therapy Risk What is known Therefore, Opdivo is not recommended in pregnant women, nor in women of childbearing potential not using effective contraception unless the benefit outweighs the potential risks. Effective contraception should be used for at least 5 months following the last dose of Opdivo. Development of antibodies (immune response) against the medicine (immunogenicity) Theoretically, immunogenicity may lead to infusion reactions or reduced effectiveness. Although low rates of immunogenicity were seen, no impact has been observed on safety or efficacy, even following prolonged dose interruptions and re-administration of the medicine. 5. MISSING INFORMATION Missing information for monotherapy is provided in Table 5. Table 5: Missing Information: Nivolumab Monotherapy What is known (including reason why it is considered a potential risk) Risk Use in children The effect of Opdivo in patients below 18 years old is not known. Opdivo should not be used in children below 18 years of age. Use in elderly patients with: Data from patients with classical Hodgkin lymphoma 65 years of age or older, and with squamous cell cancer of the head and neck and mismatch repair deficient (dmmr) or microsatellite instability high (MSI-H) metastatic colorectal cancer 75 years of age or older are limited. - chl 65 years of age - SCCHN 75 years of age - dmmr or MSI-H mcrc 75 years of age Severely reduced liver and/or kidney function (severe liver and/or renal impairment) The effect of Opdivo in patients with severely reduced liver or kidney function has not been studied. Opdivo must be given with caution in patients with moderately or severely reduced liver function. Patients with autoimmune diseases No formal study with Opdivo has been conducted in patients with autoimmune diseases. Patients already receiving systemic immunosuppressants (medicines that suppress the immune system) before starting No formal study has been conducted. Use in patients who have undergone influenza vaccination No formal study has been conducted. Patients with brain metastases: Advanced melanoma, SCCHN, and UC active brain or leptomeningeal metastases NSCLC active brain metastases RCC any history of or concurrent brain metastases No formal study has been conducted. 16

17 Missing information for in combination with ipilimumab in the treatment of melanoma is provided in Table 6. Table 6: Missing Information: Nivolumab+Ipilimumab Combination Therapy What is known (including reason why it is considered a potential risk) Risk Use in children The effect of Opdivo in patients below 18 years old is not known. Opdivo should not be used in children below 18 years of age. Severely reduced liver and/or kidney function (severe liver and/or renal impairment) The effect of Opdivo in patients with severe hepatic or renal impairment has not been studied. Opdivo must be given with caution in patients with moderately or severely reduced liver function. Patients with autoimmune diseases No formal clinical study has been conducted with Opdivo in patients with autoimmune disease. Patients already receiving systemic immunosuppressants (medicines that suppress the immune system) before starting No formal study has been conducted. Use in patients who have undergone influenza vaccination No formal study has been conducted. Patients with brain metastases: Advanced melanoma, SCCHN, and UC active brain or leptomeningeal metastases NSCLC active brain metastases RCC any history of or concurrent brain metastases No formal study has been conducted. 17

18 Summary of risk minimization measures by safety concern All medicines have a Product Information which provides physicians, pharmacists, and other healthcare professionals with details on how to use the medicine, and also describes the risks and recommendations for minimizing them. Information for patients is also available. The measures listed in these documents are known as routine risk minimization measures. The Product Information for Opdivo active substance () can be found under section Arzneimittelinformation on the Swissmedic homepage (see This medicine has special conditions and restrictions for its safe and effective use (additional risk minimization measures), which were agreed with Swissmedic at the time the marketing authorization was granted. These additional risk minimization measures are for the following risks: Immune-related pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, endocrinopathies, skin ARs including TEN3, and other immune-related adverse reactions, and the potential risk of acute graft versus host disease (GVHD) and transplant-related mortality (TRM) in subjects with relapsed chl who received a post- allogeneic haematopoeitic stem-cell transplantation (HSCT). Early recognition and appropriate management are important to prevent more severe complications and ensure that the benefits of the medicine continue to outweigh the risks. Additional educational materials are intended to ensure that healthcare professionals and patients are aware of these risks and their appropriate management guidelines. Additional risk minimization measure: Healthcare professional and patient educational material. Objective and rationale: See above. Description: 1. Adverse Reaction Management Guide for healthcare professionals, reminding them of the important identified risks related to the immune system, how to recognize these risks, and their appropriate management. 2. An Alert Card for patients, warning them of the risks and how to recognize symptoms, and reminding them of the importance of contacting their doctor promptly should these occur or worsen. 18

19 6. PLANNED POST-AUTHORIZATION DEVELOPMENT PLAN Table 7: Study / activity (including study number) List of Studies in Post-authorization Development Plan Objectives Safety concerns / efficacy issue addressed Status Planned date for submission of (interim and) final reports CA209067: Phase 3, randomized, doubleblind study in subjects treated with monotherapy, ipilimumab monotherapy, and combined with ipilimumab To compare overall survival Clinical efficacy in subjects with previously untreated, unresectable (non-operable) or metastatic (spread) melanoma Ongoing CA209205: Phase 2, non-comparative, multicohort, single-arm, open-label study of (BMS936558) in chl subjects after failure of ASCT To assess PFS and OS Clinical efficacy in subjects with chl Ongoing 30-Jun-2017 Monotherapy: CA and CA analyses To further investigate the value biomarkers other than PD-L1 expression status at tumour cell membrane level by immunohistochemis try (IHC) or genomics-based methods as predictive of efficacy Efficacy in advanced melanoma Started 30-Sep-2017 Combination with ipilimumab: CA209038, CA and CA To further investigate the value of biomarkers in melanoma by IHC or genomics-based methods as predictive of + ipilimumab combination therapy efficacy. Levels of myeloid-derived suppressor cells in Efficacy in advanced melanoma Started 31-Mar-2019 Interim CSR submission: 3Q2015 / Final CSR submission: 31-Mar

20 Table 7: Study / activity (including study number) List of Studies in Post-authorization Development Plan Objectives circulation will be explored in study CA Safety concerns / efficacy issue addressed Status Planned date for submission of (interim and) final reports CA209017, CA209057, and CA To further investigate the value biomarkers other than PD-L1 expression status at tumour cell membrane level by IHC or genomicsbased methods as predictive of efficacy Efficacy in NSCLC Started 31-Mar-2018 CA and CA To further investigate the value biomarkers other than PD-L1 expression status at tumour cell membrane level by IHC or genomicsbased methods as predictive of efficacy Efficacy in RCC Started 31-Mar-2018 CA and CA To further investigate the value biomarkers other than PD-L1 expression status at tumour cell membrane level by IHC or genomicsbased methods as predictive of efficacy. Efficacy in UC Started 30-Jun-2018 CA209009, CA and CA analyses To further investigate the relation between PD-L1 and PD-L2 expression in Phase 1 studies Relationship between PD-L1 and PD-L2 expression Started 31-Mar