MK 0663 PAGE 121 ETORICOXIB RISK MANAGEMENT PLAN, VERSION 3.2

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1 MK 0663 PAGE 121 ETORICOXIB VI.2 VI.2.1 Elements for a Public Summary Overview of Disease Epidemiology Epidemiology of a disease provides information on The spread of the disease - in different sets of people - in different regions of the world, The causes and effects associated with the disease, and Control of the disease. Osteoarthritis (OA) is a joint disease that is characterized by breakdown of the cartilage (the tissue that cushions the ends of the bones between joints), bony changes, deterioration of tendons and ligaments, and inflammation of the joint lining in the spine, hands, knees, and hips. Prevalence estimates vary significantly depending on the joint, whether estimates are based on symptoms and/or radiographic damage, and increase significantly with age. Prevalence of hand and knee OA can range from 15% to as high as 70-90%. Certain factors have been shown to be associated with a greater risk of arthritis. Non-modifiable risk factors include ageing, gender (more common in women), genetic predisposition, and low bone density. Modifiable risk factors include excess weight (obesity), joint injuries, joint infections, and occupations associated with repetitive knee bending and squatting. Rheumatoid arthritis (RA) is the most common form of autoimmune arthritis (where certain cells of the immune system attack the joints). RA is a chronic (long-term) disease that causes pain, stiffness, swelling, and limited motion and function of many joints. The small joints in the hands and feet tend to be involved most often. RA affects between 0.3 and 2.0% of the population with women affected two to three times as frequently as men. The prevalence varies among geographic regions/climates and in some specific ethnic groups. Incidence / prevalence increases with age, reaching maximum between 50 and 60 years. Although the cause of RA is unknown, it is generally seen as a result of an interaction between genetic factors and environmental exposures. Non-modifiable risk factors include ageing, gender, and genetic predisposition. Modifiable factors include exposure to hormones (oral contraceptives, hormone replacement therapy), tobacco use, dietary factors, and microbial exposures. Gout is a form of arthritis characterized by intense episodes of painful swelling in single joints, most often in the feet, especially the big toe. Gout occurs when excess uric acid (a normal waste product) collects in the body and crystals deposit in the joints. The prevalence is in the range of %.. It is more commonly seen in men. The prevalence increases sharply with age, starting at ages in both genders. In women, the incidence/prevalence is greatest following menopause. Risk factors for gout include ageing, gender, genetic predisposition, obesity, hypertension, certain medicines, dietary factors, excessive alcohol intake, thyroid disease, hyperlipidemia, diabetes, and kidney disease.

2 MK 0663 PAGE 122 ETORICOXIB Ankylosing Spondylitis is a type of arthritis that primarily affects the spine. It differs from other types of arthritis, because it involves the sites where ligaments and tendons attach to bones. Patients may have inflammation causing pain and stiffness and bone destruction affecting the spine and pelvic joints. Prevalence estimates range from %. A higher incidence and prevalence is seen in men than in women. Higher prevalence and incidence reported in North American and European populations than in other parts of the world. Risk factors for AS include age (17-45 years), gender, genetic predisposition (HLA-B27 gene), and frequent gastrointestinal (GI) infections. Etoricoxib is also used to treat pain associated with dental surgery, including third molar surgery. Third molar extraction is one of the most common procedures performed by oral and maxillofacial surgeons, and most patients have some degree of pain following this procedure. Third molar extraction is more commonly performed in patients younger than 40 years of age (mean age 26-27) and is relatively uncommon in patients 60 years or older. Most patients undergoing the procedure are healthy. Preoperative pain, female gender, older age, anxiety, depression, and patient expectations, have been identified as risk factors associated with dental surgery pain. VI.2.2 Summary of Treatment Benefits Efficacy is the capacity of a drug to produce a desired effect. Etoricoxib is a member of a group of medicines called non-steroidal anti-inflammatory agents (NSAIDS). Etoricoxib is also known as a cyclo-oxygenase-2 (COX-2) inhibitor because it works by blocking this enzyme in the body. COX-2 is involved in the production of mediators of pain and inflammation in response to disease. By blocking the action of COX-2, etoricoxib reduces pain and inflammation. In patients with OA, etoricoxib 60 mg once daily reduced pain and improved patients assessments of disease status. These beneficial effects were observed as early as the second day of therapy and were maintained for up to 52 weeks. In patients with RA, etoricoxib 90 mg once daily improved pain, inflammation and mobility. These beneficial effects were maintained over the 12-week treatment period. In patients experiencing acute attacks of gouty arthritis, etoricoxib 120 mg once daily, over an eight-day treatment period, relieved moderate to extreme joint pain and inflammation that was comparable to indomethacin 50 mg three times daily. Pain relief was observed as early as 4 hours after start of treatment. In patients with AS, etoricoxib 90 mg once daily improved spine pain, inflammation, stiffness and function. The beneficial effects of etoricoxib were observed as early as on the second day of therapy and were maintained throughout the 52-week treatment period. In a study assessing pain following dental surgery, etoricoxib 90 mg was administered once daily for up to 3 days. In the subgroup of patients with moderate pain at baseline, etoricoxib 90 mg demonstrated a pain-relieving effect similar to that of ibuprofen 600 mg and greater than that of paracetamol / codeine 600 mg/60 mg and placebo (a pill without active

3 MK 0663 PAGE 123 ETORICOXIB medicine) as measured by total pain relief over the first 6 hours. Out of every 100 patients treated with the medicines under study, the proportion of patients reporting the use of rescue medicines (pain-killers apart from those under study) within the first 24 hours of dosing was 41 for etoricoxib, 25 for ibuprofen, and 47 for paracetamol / codeine compared to 76 for placebo. VI.2.3 Unknowns Relating to Treatment Benefits Etoricoxib has not been studied and should not be used in patients who: are pregnant or breastfeeding are less than 16 years of age have severe kidney disease have severe liver impairment

4 MK 0663 PAGE 124 ETORICOXIB VI.2.4 Summary of Safety Concerns Important Identified Risks Important identified risks are safety issues or undesirable effects for which there is sufficient proof of an association or link with the use of the medicine of interest. Table 51 provides information on the important identified risks and their preventability. Table 51 Summary of Important Identified Risks Risk What is known Preventability Serious gastrointestinal events/ Serious digestive system events Ulcers, obstruction, bleeding and perforation (formation of holes) in the stomach and small intestine are known risks associated with the use of non-selective non-steroidal anti-inflammatory agents. (NSAIDs that block both COX enzymes, COX-1 and COX-2). They have also been reported to occur with etoricoxib use. Etoricoxib is associated with a lower rate of upper digestive tract events as compared to non-selective non-steroidal anti-inflammatory agents. (NSAIDs that block both COX enzymes, COX-1 and COX- 2). Signs and symptoms of bleeding in the digestive tract are black or tarry stools, blood mixed with stool, weakness, dizziness, shortness of breath, crampy abdominal pain, diarrhoea and paleness. Symptoms of stomach outlet obstruction are repeated episodes of vomiting with large amounts of vomit containing undigested food, a persistent feeling of bloating or fullness, and unexplained weight loss. Stomach or intestinal perforation may lead to peritonitis (infection and inflammation of the lining of the abdomen), which may be life threatening. The most common symptom of peritonitis is the sudden onset of abdominal pain, which gets worse steadily. Patients with a history of such events and those aged above 65 years have a higher risk for these events. Etoricoxib should not be used in patients with active stomach or small intestinal ulcers or active bleeding from these organs. Etoricoxib should be used at the lowest effective dose and for the shortest duration possible. Since ulcers, bleedings and perforations of the stomach and small intestine can occur without any warning patients should understand the importance of periodic follow-ups.

5 MK 0663 PAGE 125 ETORICOXIB Table 51 Summary of Important Identified Risks Risk What is known Preventability Thrombotic cardiovascular events/ Events associated with blood clot formation within blood vessels Heart attack, angina (chest pain), sudden blockage of an artery of the lungs (pulmonary embolism), stroke due to interruption of blood supply to the brain (ischaemic stroke) and sudden death are known risks associated with the use of nonselective non-steroidal anti-inflammatory agents. (NSAIDs that block both COX enzymes, COX-1 and COX-2). They have also been reported to occur with etoricoxib use. Etoricoxib is associated with a similar rate of events of blood clot formation within blood vessels compared to non-selective NSAIDs. Signs and symptoms of angina and heart attack are chest pain or discomfort; pain or discomfort in one or both arms, back, shoulders, neck, jaw, or upper part of the stomach; cold sweats; nausea; lightheadedness; and shortness of breath. Signs and symptoms of pulmonary embolism are sudden shortness of breath; sharp chest pain which gets worse while coughing or breathing; and coughing pink, foamy mucus. Signs and symptoms of ischaemic stroke are sudden numbness or weakness of the face, arm or leg, especially involving one side of the body; sudden confusion; trouble speaking or understanding; loss of vision in one or both eyes; trouble walking; dizziness; loss of balance or coordination; and sudden, severe headache with no known cause. Etoricoxib should not be used by patients who have a disease in which there is plaque formation within the arteries supplying the heart (ischaemic heart disease), limbs (peripheral arterial disease) and / or brain (cerebrovascular disease). Patients with significant risk factors for serious heart diseases (e.g. high blood pressure, presence of excess lipids in the blood (hyperlipidaemia], diabetes and smoking) should only be treated with etoricoxib after careful consideration. Etoricoxib should be used at the lowest effective dose and for the shortest duration possible. Patients having any signs or symptoms of such events should report them promptly to their physicians.

6 MK 0663 PAGE 126 ETORICOXIB Table 51 Summary of Important Identified Risks Risk What is known Preventability Renovascular events: Oedema, hypertension, and CHF /Events related to blood vessels of the kidneys: oedema, high blood pressure and congestive heart failure In patients with impaired blood flow to the kidneys due to any reason, certain mediators maintain the perfusion of the kidneys. Use of non-selective non-steroidal anti-inflammatory agents. (NSAIDs that block both COX enzymes, COX-1 and COX-2).in such patients blocks the production of these compensatory mediators and compromises blood flow to the kidneys. This leads to impairment of kidney function. Impairment of blood flow to the kidneys and kidney function may lead to fluid build-up in the legs and feet (oedema), high blood pressure and congestive heart failure. Patients at risk of such events are those with pre-existing impaired kidney function, heart failure or oedema. Signs and symptoms of oedema are swelling of the feet, ankles and legs. People with high blood pressure may have no signs and symptoms. In some people, there may be dull headaches, dizzy spells and more nosebleeds than normal. Signs and symptoms of congestive heart failure are shortness of breath, oedema of the legs and feet, weight gain, palpitations, getting tired easily, and feeling weak and dizzy. Etoricoxib should not be used in patients with advanced kidney impairment, persistent uncontrolled high blood pressure and moderate and severe congestive heart failure. Etoricoxib should be used at the lowest effective dose and for the shortest duration possible. Blood pressure should be monitored frequently in patients on etoricoxib. Patients having any signs or symptoms of oedema, high blood pressure and congestive heart failure should report them promptly to their physicians.

7 MK 0663 PAGE 127 ETORICOXIB Table 51 Summary of Important Identified Risks Risk What is known Preventability Hypersensitivity-related events and serious skin reactions /Allergic reactions and serious skin reactions Allergic reactions can occur with any medicine and are known to occur with non-selective non-steroidal anti-inflammatory agents. (NSAIDs that block both COX enzymes, COX-1 and COX- 2). Serious allergic reactions, such as anaphylactic reactions and angioedema, may also occur. Anaphylactic reaction is a whole body reaction that develops suddenly. Symptoms of anaphylaxis are difficulty breathing, wheezing, coughing, difficulty swallowing, swelling of the throat, low blood pressure, hives, itchiness and rash. In angioedema, there is swelling of the deeper layer of the skin, and the lining of the throat and intestines. Swelling of the eyes, face, lips, tongue, throat and bowels may occur. In severe cases, there may be difficulty breathing or swallowing. Serious skin reactions, such as Stevens-Johnson Syndrome and toxic epidermal necrolysis, may occur; however, these are very rare. In Stevens-Johnson syndrome and toxic epidermal necrolysis, the outermost layer of the skin (epidermis) separates from the adjacent layer (dermis) because of an allergic reaction. Stevens-Johnson syndrome is the milder form of the two. Signs and symptoms of Stevens-Johnson syndrome and toxic epidermal necrolysis are flulike symptoms, muscle and joint pain, swelling of the tongue and / or face, a red or purple burning skin rash that spreads, blisters on the skin and mucous membranes (such as in the eyes, nose and mouth), and shedding (sloughing) of the skin. Etoricoxib should not be used by people who are allergic to aspirin or other NSAIDs, including other COX-2 inhibitors. Patients should be alert to the signs and symptoms of allergic reactions and serious skin reactions and visit their doctor immediately, should these occur. Etoricoxib should be discontinued at the first appearance of skin rash, ulcers in the mouth or nose, or any other signs of allergy. Important Potential Risks Important potential risks are the safety issues or undesirable effects for which there is some basis for suspicion of a link with the use of the medicine of interest, but this association has not been confirmed. There are no important potential risks with the use of etoricoxib.

8 MK 0663 PAGE 128 ETORICOXIB Missing Information Important missing information is the information about the safety of a medicine or pill which is not available at the time of submission of a particular risk management plan. Examples of missing information include populations not studied (e.g. pregnant women or patients with severe renal impairment) or where there is a high likelihood of off-label use (pill used for indication other than what it is approved for). Table 52 provides important missing information with the medicinal product. Table 52 Summary of Important Missing Information Missing information What is known Use during pregnancy and breastfeeding Etoricoxib should not be used by pregnant and breastfeeding women. Use of etoricoxib and other non-selective non-steroidal anti-inflammatory agents. (NSAIDs that block both COX enzymes, COX-1 and COX-2) during pregnancy has the potential to cause premature closure of the ductus arteriosus and absence of effective uterine contractions during labour. Use in children and adolescents (patients less than 16 years of age) The ductus arteriosus is a normal blood vessel in an unborn child that connects two major arteries, the aorta and the lung artery, and carries blood away from the heart in the developing baby. Premature closure of the ductus arteriosus may result in right heart failure and oedema in the foetus, which may even result in death of the baby. Etoricoxib should not be used in patients less than 16 years of age, as it has not been studied in patients of this age group. Use in patients with renal insufficiency/use in patients with advanced kidney impairment Use in patients with hepatic impairment/use in patients with severe liver impairment Etoricoxib has not been studied in patients who have severe kidney impairment and should not be used in such patients. Etoricoxib has not been studied in patients who have severe liver impairment and should not be used in such patients. VI.2.5 Summary of Risk Minimization Measures by Safety Concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimizing them. An abbreviated version of this in lay language is provided in the form of the Package Leaflet (PL). The measures in these documents are known as routine risk minimization measures. This medicine has no additional risk minimization measures.

9 MK 0663 PAGE 129 ETORICOXIB VI.2.6 VI Planned Post-Authorization Development Plan List of Studies in Post-Authorization Development Plan Some studies are conducted after a medicine has been approved for general use. These studies are conducted with the aim of further gaining information that helps in assessing potential and unexpected serious risks associated with the use of the medicine. Interim results are obtained while the study is in progress, before the completion of the study, whereas final results are obtained after the completion of the study. Table 53 List of Studies in Post-Authorization Development Plan Study / Activity Objectives Safety Concerns Addressed Status Etoricoxib Prescribing To quantify whether the risk Serious Patterns and Adverse minimization measures are gastrointestinal Events of Interest effectively communicating events during Etoricoxib important risk information to Thrombotic Treatment HCPs and to determine the cardiovascular in UK Primary Care incidence of adverse events in events (CPRD) (Observational the target population under Renovascular study, Category 3) marketed use in the UK. events A nested case-control Describe the use of etoricoxib Serious PASS of etoricoxib and and the characteristics of gastrointestinal other anti-inflammatory those who use it for AS in the events therapies in a cohort of UK, France, and Germany Thrombotic patients with AS in the Assess the safety profile of Cardiovascular UK, France, and etoricoxib relative to other events Germany NSAIDs Renovascular (Observational study, events Category 3) Post-authorization Describe the use of etoricoxib Serious Ongoing safety study: Safety and thecharacteristics of those gastrointestinal Data on Etoricoxib who use it for AS/SpA in events from Swedish Sweden Thrombotic Registries of Assess the safety profile of cardiovascular Spondyloarthropathy / etoricoxib relative to other events Ankylosing Spondylitis NSAIDs and non-use Renovascular Patients (Observational events study, Category 3) Understanding the use Off label use for Ongoing of etoricoxib in patients dental pain with dental pain including use in (Observational study, children under 16 Category 3) To describe dispensed etoricoxib prescribed by dentists including the associated dental procedures and, patient demographics To describe off-label use by dentists in patients - less than 16 years of age - with doses >90 mg/day To describe the duration of use / number of tablets dispensed Date for Submission of Interim / Final Reports (Target Dates) Ongoing Updated 2Q2014: The MAH will continue to update the study annually until 2017 Ongoing Updated 3Q2014: The MAH will continue to update this study annually until 2017 First report submitted 3Q2014. Final results expected 2016 Report expected to be submitted 2017

10 MK 0663 PAGE 130 ETORICOXIB VI Studies which are a Condition of the Marketing Authorization There are no studies that are a condition to the marketing authorization. VI.2.7 Table 54 Summary of Changes to the Risk Management Plan Over Time Major Changes to the Risk Management Plan RMP version Date Safety concerns Comment JUN-2011 No new safety concerns have been identified in this updated RMP 3.0/ MAY-2015 No new safety concerns have been identified in this updated RMP To support the filing for an acute pain indication (dental pain), a revised and updated RMP was submitted. To support the filing for a postapproval commitment as a followup measure (FUM) for Protocol 107 (etoricoxib 60 and 90 mg) monitoring the efficacy and safety in the Rheumatoid Arthritis, Development Programme, a revised and updated RMP was submitted. To support the filing for a postapproval commitment as a followup measure (FUM) for Protocol 108 (etoricoxib 60 and 90 mg) monitoring the efficacy and safety in Ankylosing Spondylitis patients, a revised and updated RMP was submitted.