VI.2 Elements for a Public Summary VI.2.1 Overview of disease epidemiology Osteoarthritis Osteoarthritis is the most common type of joint disease. It represents a group of conditions that result in changes that can be seen microsopically and by X-Ray. It can be thought of as a worsening condition arising from biochemical breakdown of joint cartilage (protective padding between bones) in the joint cavity. However, the current view is that osteoarthritis involves not only the joint cartilage but also the entire joint, including the bone under the cartilage (subchondral bone) and joint cavity. Osteoarthritis usually involves the weight-bearing joints, including the knees, hips, upper and lower part of the spine, and feet. Other commonly affected joints include the joints of the fingers and wrist. Historically, osteoarthritis has been divided into primary and secondary forms. Secondary osteoarthritis is easier to understand: It refers to disease of flexible (synovial) joints that results from something that has damaged the joint tissues (eg, trauma to joint cartilage or subchondral bone). Secondary osteoarthritis can occur in relatively young individuals. The progression of osteoarthritis is slow, occurring over several years or decades. Over this period, the patient can become less and less active and thus more likely to have problems related to decreasing physical activity (including weight gain). Early in the disease, the joints may appear normal. However, the patient s walking may change in an attempt to avoid pain, if weight-bearing joints are involved. Pain is usually the initial source of problems in osteoarthritis, with the disease s main symptom being deep, achy joint pain worsened by a lot of use. Also, reduced range of motion and grinding sounds (crepitus) are frequently present. Stiffness during rest (gelling) may develop, with morning joint stiffness usually lasting for less than 30 minutes. To begin with, pain can be relieved by rest and may respond to simple pain killers. However, joints may become unstable as the osteoarthritis progresses; therefore, the pain may become worse (even during rest) and may not respond to medications. 1 Rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term inflammatory disease of unknown cause. It is thought that the disease may start after an external trigger (eg, cigarette smoking, infection, or trauma) that causes an autoimmune reaction, leading to changes of the joint cavity such as swelling, new fibrous tissue formation and the fusion of affected joints, along with the potential for manifestations outside of the joints. The common feature of rheumatoid arthritis (RA) is long-term arthritis that affects multiple joints of the hands and feet, although any joint lined by a synovial membrane (a connective tissue that lines the joint and produces lubricating fluid) may be involved. The severity of RA may change over time, but long-term RA most commonly results in some joint destruction, deformity, and a significant decline in ability to use. Involvement of organs such as the skin, heart, lungs, and eyes can also be significant. Patients with RA may report difficulty performing activities of daily living (ADLs), such as dressing, standing, walking, personal hygiene, or use of hands. In addition to articular deterioration, other symptoms (eg, fatigue, feeling generally unwell, morning stiffness, weight loss, and mild fever) may be present. In most patients, RA starts slowly. It may begin with symptoms such as fever, feeling generally unwell, joint pain, and weakness, before the appearance of obvious joint inflammation and swelling. A small percentage (about 10%) of patients with this disease has a quick onset with the development of inflammation of the synovial membrane (synovitis) and symptoms not involving the joints. Improvement is uncommon, especially after the first 3-6 months. 2 Ankylosing spondylitis. PhV-20140049 Page 90/123
Ankylosing spondylitis (AS) is a long-term disorder mainly involving the joints of the hip and spine, although it can also cause other problems such as arthritis, swelling where a tendon or ligament attaches to the bone (enthesitis), and symptoms not involving the joints. The cause of AS is not understood completely; however, a strong genetic link exists. Early diagnosis of AS is important because early medical and physical therapy may improve the outcome. Patient education is important so that the patient knows about the symptoms, course, and treatment of the disease. Treatment measures include medication, physical therapy, and surgical. Symptoms of AS include those related to inflammatory back pain, enthesitis and arthritis, and other symptoms not involving the joints. Chronic pain and stiffness are the most common complaints of patients with AS. More than 70% of patients report daily pain and stiffness. Fatigue is another common complaint, occurring in about 65% of AS patients. Most patients report their fatigue to be moderately severe. Increased levels of fatigue are associated with increased pain and stiffness and decreased ability to function. Fever and weight loss may occur during periods of active disease. 3 VI.2.2 Summary of treatment benefits Osteoarthritis The goals of osteoarthritis treatment include pain relief and improvement of functional status. Ideally, patients should receive a combination of treatment with medication and other treatments. For knee osteoarthritis, the ACR (The American College of Rheumatology) recommends using one of the following: Paracetamol Oral non-steroidal anti-inflammatory drugs (NSAIDs) Topical non-steroidal anti-inflammatory drugs (NSAIDs) Tramadol Corticosteroid injections into the joints The choice of pain relief medication for an individual patient should take into account the trade-off between benefits and adverse effects, which differs across analgesics. Patient age, other disease conditions, and other medication also being taken are key considerations. The goals of medication in osteoarthritis are to ease symptoms and to prevent complications. Medicines injected into the joints include corticosteroid or sodium hyaluronate (ie, hyaluronic acid [HA] or hyaluronan), which may provide pain relief and have an anti-inflammatory effect on the affected joint. Begin treatment with paracetamol for mild or moderate osteoarthritic pain without inflammation. If the response to paracetamol is not satisfactory or if the osteoarthritis is inflammatory, consider using an NSAID. Use the lowest effective dose or intermittent dosing if symptoms are intermittent, then try full doses if the patient s response is not enough. Options in patients at a higher risk of gastrointestinal side-effects from NSAIDs include the addition of other medications (e.g. a proton-pump inhibitor or misoprostol) and the use of the particular NSAIDs (e.g. selective cyclooxygenase (COX)-2 inhibitor celecoxib instead of a nonselective NSAID). Lifestyle changes, particularly exercise and weight loss, are very important in the management of osteoarthritis. Rheumatoid arthritis The best care of patients with rheumatoid arthritis (RA) is achieved by including both medication-based and non-medication-based treatments. Many non-medication-based treatments are available for this disease, including exercise, diet, massage, counseling, stress reduction, physical therapy, and surgery. PhV-20140049 Page 91/123
Medication-based treatments comprise of several types of medicine, including non-steroidal anti-inflammatory drugs (NSAIDs), non-biologic and biologic disease-modifying antirheumatic drugs (DMARDs), immunosuppressants, and corticosteroids. Early therapy with DMARDs has become the standard of care, in that it is capable not only of slowing disease progression better than later treatment but also, potentially, of inducing more remissions. NSAIDs reduce swelling and pain. However, they do not slow joint destruction and so are not sufficient to treat RA when used alone. Like corticosteroids, NSAIDs can be reduced in dose or discontinued with successful DMARD therapy. There are various surgical treatments for RA. Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen, celecoxib, and diclofenac. is approved for the relief of signs and symptoms of RA. It may have fewer gastrointestinal side effects than some other NSAIDs. Administer the lowest possible dose for each patient. Use of celecoxib has been associated with an increased risk of heart-related side effects. Ankylosing spondylitis There is no definite disease-modifying treatment available for people with ankylosing spondylitis (AS). Early diagnosis is important. Patient education is vital to familiarize the patient with the symptoms, course, and treatment of the disease. Treatment measures include medication, surgical, and physical therapy. No drugs have been proved to modify the course of the disease, although tumor necrosis factor alpha (TNF-α) blockers appear to have potential. Hospital care is generally not necessary for patients with AS, apart from those with other diseases and those requiring surgery. Non-steroidal anti-inflammatory drugs (NSAIDs) improve the symptoms of the disease by reducing pain and decreasing inflammation. Numerous choices are available, and they are separated into different groups. If one NSAID is ineffective, another from a different group can often provide relief. Efficacy and side effects differ among NSAIDs. VI.2.3 Unknowns relating to treatment benefits Based on the currently available data, no gaps in knowledge about the effectiveness of the drug in the target population were identified, that would warrant further effectiveness studies. Furthermore, there is no evidence to suggest that treatment results would be different in any subgroup of the target population, for any of the indications, taking into account factors such as age, sex and race or organ impairment. VI.2.4 Summary of safety concerns Important identified risks Gastrointestinal bleeding and Gastrointestinal ulceration Upper gastrointestinal complications [perforations, ulcers or bleedings], some of them causing death, have occurred in patients taking Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs; the elderly, patients using any other NSAID or aspirin at the same time, or patients with a history of gastrointestinal disease, Yes, by informing patients with stomach ulceration or gastrointestinal bleeding to avoid Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs. PhV-20140049 Page 92/123
Cardiovascular events, including heart attacks (myocardial infarctions) and strokes (cerebral apoplexy) Kidney side effects (renal toxicity) fluid retention and swelling (oedema) High blood pressure (hypertension) Allergic reactions (hypersensitivity reactions) Liver damage (hepatotoxicity) such as ulceration and gastrointestinal bleeding. There is further increase in the risk of gastrointestinal side effects for celecoxib (gastrointestinal ulceration or other gastrointestinal complications), when celecoxib is taken at the same time as aspirin (even at low doses). A study has shown an increased number of serious cardiovascular events, mainly heart attack, in people taking Fluid retention and swelling have been observed in patients taking As with all NSAIDS, celecoxib can cause high blood pressure or make existing high blood pressure worse, either of which may contribute to the increased incidence of cardiovascular events. Serious allergic reactions (severe allergic reaction and swollen face, lips, throat, tongue, hands or legs known as angioedema) have been reported in patients receiving Some cases of severe liver reactions, including severe rapid loss of liver function known as fulminant hepatitis (some causing death), liver tissue destruction and liver failure (some causing death As the cardiovascular risks of celecoxib may increase with dose and how long it is taken for, the lowest effective daily dose should be used for the shortest amount of time. should be used with caution in patients with history of heart failure, other heart problems or high blood pressure, and in patients who already have fluid retention and swelling from any other reason, because celecoxib may reduce kidney function and cause fluid retention. Caution is also required in patients taking diuretics ( water tablets ) or at risk of decreased blood volume. Blood pressure should be monitored closely during treatment with should be stopped at the first sign of skin rash, damage to mucous membranes, or any other sign of an allergic reaction. If during treatment, a patient s liver function worsens, appropriate measures should be taken and stopping celecoxib therapy should be considered. PhV-20140049 Page 93/123
Harm caused to unborn babies (fetal toxicity) Use in people known as CYP2C9 poor metabolizers (who have a risk of increased adverse events) Drug-drug interactions (aspirin, drugs to treat depression (SSRI/SNRI), drugs metabolized by CYP2D6, warfarin and other oral anticoagulants, diuretics, ACE inhibitors, ATII antagonists, ciclosporin, tracolimus, lithium, fluconazole, rifampicin, carbamazepine, barbiturates ) Use in patient with heart failure, including left ventricular problems Use in patients with high blood pressure (hypertension) or requiring liver transplant), have been reported with should not be used in pregnancy and in women who might get pregnant unless they are using an effective method of contraception. In people who are CYP2C9 poor metabolisers and so have increased levels of celecoxib in their blood, treatment with CYP2C9 blockers at the same time as celecoxib could result in further increases in celecoxib levels. There is further increase in the risk of gastrointestinal adverse effects for celecoxib (gastrointestinal ulceration or other gastrointestinal complications), when celecoxib is taken at the same time as aspirin (even at low doses). In patients taking celecoxib at the same time as warfarin, serious bleeding has occurred. is a blocker of an enzyme in the body called CYP2D6. If taken at the same time, this can affect the way some other drugs work. Examples of such drugs are antidepressants (tricyclics and SSRIs), tranquillisers, drugs to regulate heartbeat, etc. Taking NSAIDs at the same time as ciclosporin or tacrolimus may cause kidney damage. Patients at greatest risk of kidney damage are those with reduced kidney function, heart failure, liver problems, and the elderly. As with all NSAIDS, celecoxib can cause high blood pressure or make existing high blood pressure worse, If a woman becomes pregnant during treatment, celecoxib should be stopped. Yes, by treating with caution patients known to be CYP2C9 poor metabolisers. Caution should be taken when combining celecoxib with acetylsalicylic acid (aspirin), drugs to treat depression (SSRI/SNRI), drugs metabolized by CYP2D6, warfarin and other oral blood thinning medication (anticoagulants), medication to increase urine output (diuretics), medication to treat high blood pressure or heart failure (ACE inhibitors, ATII antagonists), ciclosporin, tracolimus, lithium, fluconazole, rifampicin, carbamazepine, barbiturates warfarin and other oral anticoagulants. Such patients should be carefully monitored while receiving treatment with Blood pressure should be monitored closely during treatment with PhV-20140049 Page 94/123
Use in patients with allergy to sulphonamide (an antibiotic) Skin reactions including red, itchy and scaly skin (exfoliative dermatitis) and severe ulceration of mucous membranes and skin (Steven- Johnson syndrome, Toxic epidermal necrolysis) A decrease in the number of blood cells (leucopenia, thrombocytopenia, pancytopenia) Bleeding Use in women over 65 years of age Use in patients with liver problems either of which may contribute to the increased incidence of cardiovascular events. Patients with a history of an allergy to sulphonamide (an antibiotic) or any medicine allergy may be at greater risk of serious skin reactions or allergic reactions. Serious skin reactions, some of them fatal, (including exfoliative dermatitis, Stevens- Johnson syndrome, and toxic epidermal necrolysis) have been reported very rarely after use of has as rare side effects: decrease of whiteblood cell count (leucopenia), decrease of platelets in blood (thrombocytopenia). Bleeding has been reported, mainly in the elderly, in patients receiving celecoxib at the same time as warfarin. This has sometimes been caused death. The concentration of celecoxib in the blood is about twice as much in elderly women over 65 years of age. Some cases of severe liver reactions, including severe rapid loss of liver function known as fulminant hepatitis (some causing death), liver cell death and, liver failure (some causing death or requiring liver transplant), have been reported with should be stopped at the first sign of skin rash, damage to mucous membranes, or any other sign of allergic reaction. Yes, by treating with caution patients with a history of skin reactions (including exfoliative dermatitis, Steven- Johnson syndrome, Toxic epidermal necrolysis). Yes, by monitoring for early symptoms. Yes, by monitoring for early symptoms. Yes, by monitoring for early signs of increasing drug concentration. Treatment should be started at half the recommended dose in patients with particular known liver problems. Important potential risks Risk NA What is known (Including reason why it is considered a potential risk) None proposed PhV-20140049 Page 95/123
Important missing information Risk What is known Use in pregnancy Use in patients with kidney problems Use in patients with severe liver problems should not be used in pregnancy and in women who might get pregnant unless they are using an effective method of contraception. has been shown to cause damage to the offspring in the two animal species studied. The risk to humans in pregnancy is unknown, but cannot be excluded. There is no data available on pregnancies where celecoxib has been taken. Studies in animals (rats and rabbits) have shown that harm is caused, including damage to the offspring. The risk to humans in pregnancy is unknown, but cannot be excluded. There in not much experience with celecoxib in patients with mild or moderate kidney damage, so such patients should be treated with caution. Patients with severe kidney damage should not take There in not much experience with celecoxib in patients with severe liver problems so patients with severe liver problems should not take VI.2.5 Summary of risk minimisation 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 minimising 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 minimisation measures. This medicine has no additional risk minimisation measures. VI.2.6 Planned post authorisation development plan No post-authorisation safety or efficacy studies are ongoing or are planned to be conducted for VI.2.7 Summary of changes to the Risk Management Plan over time NA since version 1.0 and version 2.0 were not approved. PhV-20140049 Page 96/123