Diclofenac, Version 1.2. Elements for a public summary. VI.2.1 Overview of disease epidemiology

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1 VI.2 Elements for a public summary VI.2.1 Overview of disease epidemiology It has been estimated that one in five adults suffer from pain worldwide, and one in ten adults are diagnosed with pain each year. 1 The occurrence rate of long term pain in United Kingdom (UK) is about 8-60 in 100 of people, 2 12 in spain, 13 in Ireland, 15 in France, each 16 in Switzerland & Denmark, each 17 in Israel & Germany, each 18 in Netherlands & Sweden, 19 in Finland, 21 in Austria, 23 in Belgium, 26 in Italy, 27 in Poland, and 30 in Norway. 3 A musculoskeletal disorder covers any injury, damage or disorder of the joints or other tissues in the upper/lower limbs or the back. 4 Low back pain is the most reported pain and 84 out of 100 adults will experience low back pain in their lifetime. 5. The overall occurrence of low back pain 100 people was 41.6 in Belgium, 64.2 in Czech Republic, 49.2 in Denmark, 36.4 in Finland, 55.4 in France, 61.8 people in Germany, 32.3 in Greece, 58.9 in Italy, 7.5 in Netherlands, 43.7 in Spain, and 45.6 in Sweden. 6 The latest estimates from the Labour Force Survey show that in Great Britain, the total number of musculoskeletal disorder cases in 2013/14 was 526,000 out of a total 1,241,000 for all work-related illnesses. The number of new cases of musculoskeletal disorders in 2013/14 was 184,000, up from 141,000 in 2011/12. 7 Osteoarthritis affects the joints, causing them to become painful and limiting their movement. A total of 4.71 million people in the UK have taken treatment for osteoarthritis of the knee and 4.11 million people in England have osteoarthritis of knee. 8 The overall occurrence of knee osteoarthritis in100 people was 3.7 in Estonia, 6.5 in Greece, 28.3 in Hungary, 29.8 in Italy, 18.8 in Netherland, 71.1 in Spain, and 53.8 in Sweden. Rheumatoid arthritis is a form of arthritis that causes pain, swelling, stiffness and loss of function in joints. Around 400,000 adults have rheumatoid arthritis in the UK. There are approximately 20,000 new cases of rheumatoid arthritis in the UK every year. Rheumatoid arthritis is more common in women than men. 8 The overall occurrence of Rheumatoid arthritis in 100 people was 0.6 (urban) & 0.7 people (rural) in Czech Republic, 0.3 in France, 0.7 in Greece, 0.3 in Hungary, 0.4 in Ireland, 0.3 in Italy, 0.5 in Netherlands, 0.5 in Spain, and 0.6 in Sweden. 6 A sprain is an injury to the tissues around joints which attach bones together and strain usually means a stretching or tearing of muscle fibers. 9 Sprains of ankle are associated with significant costs and account for an estimated 302,000 admissions to Accident & Emergency Departments in the UK every year. 10 VI.2.2 Summary of treatment benefits Treatment for low back pain includes physical activity and exercise, manual therapy including manipulation, mobilisation and massage, and combined physical and psychological treatment programme. The person is advised to take regular paracetamol as the first medication option. When paracetamol alone provides insufficient pain relief, Non-Steroidal Anti Inflammatory Drugs (NSAIDs) and/or weak opioids are offered. 11 The first-line treatment of osteoarthritis is paracetamol and/or NSAIDs applied to, or affecting a localized area of the body, especially of the skin (topical). Where paracetamol or topical NSAIDs are ineffective for pain relief for people with osteoarthritis, then oral NSAID/cyclooxygenase-2 inhibitor should be considered. 12 Most sprains and strains can be managed at home, using painkillers available for purchase without a special note (called a prescription) from a doctor to ease pain. Minor injuries can be managed by avoiding HARM (heat, alcohol, running, massage) and using PRICE (protection, rest, ice, compression, and elevation) therapy. Paracetamol is usually advised for painful sprains or strains. If this does not help, an additional stronger painkiller such as codeine can be used. Oral NSAIDs can also help reduce swelling and inflammation. 13 Page 39 of 54

2 In a study, diclofenac sodium and ibuprofen was given to 40 patients with arthritis (26 rheumatoid and 14 osteoarthrosis). It was observed that, there was a low occurrence of side effects on both the treatments. In patients with osteoarthrosis, diclofenac was shown to be significantly better than ibuprofen. Also, diclofenac was shown to be equally effective to ibuprofen for patients with rheumatoid arthritis. 14 VI.2.3 Unknowns relating to treatment benefits Not applicable. VI.2.4 Summary of safety concerns Important identified risks Harmful effects or damage to gut including a stomach or duodenal ulcer, or bleeding or hole that develops through the line of the digestive tract [gastrointestinal toxicity including perforation, ulceration and bleeding (PUB)] Bleeding in the digestive tract (this can include blood in vomit, bleeding when emptying bowels, fresh blood in faeces or black, tarry faeces), ulcers or a holes in the wall of stomach (perforation), which can lead to death has been reported with all NSAIDs including diclofenac and may occur at any time during treatment, with or without warning symptoms or a previous history of serious digestive tract events. The risk of digestive tract bleeding, ulceration or holes in digestive tract (perforation) is higher with increasing NSAID doses including diclofenac, and in patients with a history of ulcer, particularly if complicated with bleeding or perforation. There are more chances to develop side effects to NSAIDs especially bleeding and perforation in older people which may be life threatening. Simultaneous use of diclofenac with other NSAIDs or corticosteroids (antiinflammatory medicines) or medicines used to treat low mood (selective serotonin reuptake inhibitors) or blood thinning medicines may increase the risk of digestive tract bleeding or ulceration. Nausea, vomiting, diarrhoea, heart burn, stomach pain including upper part of stomach, wind, loss of appetite in patients who have or ever had, a stomach (gastric) or duodenal (peptic) ulcer, or bleeding in the digestive tract (blood in vomit, bleeding when emptying bowels, fresh blood in faeces or black, tarry faeces), and in patients with stomach or bowel problems after taking NSAIDs. If digestive tract bleeding or ulceration occurs in patients receiving diclofenac, the medicine should be stopped. As with all NSAIDs, including diclofenac close medical supervision is necessary and particular care should be taken when using diclofenac in patients with symptoms suggestive of digestive tract problems, or with a history suggestive of stomach or intestinal ulcers, bleeding or perforation. The treatment should be started and maintained at the lowest effective dose in patients with history of ulcers, particularly if complicated with bleeding or perforation. Combination therapy with protective agents, used to treat Page 40 of 54

3 are common (may affect up to 1 in 10 treated people), stomach ulcers or bleeding, inflammation, irritation or swelling of the stomach lining (gastritis), vomiting of blood, diarrhoea with blood in it or bleeding from the back passage, black, tarry faeces or stools are rare (may affect up to 1 in 1000 treated people), constipation, inflammation of the tongue, mouth ulcers, inflammation of the inside of the mouth or lips, lower gut disorders (including inflammation of the colon or worsening of ulcerative colitis or Crohn s disease) are very rare (may affect up to 1 in 10,000 treated people) and inflammation and injury of the large intestine due to poor blood supply of unknown frequency side effects observed with diclofenac treatment. ulcers of stomach (e.g. misoprostol or proton pump inhibitors) should be advised for these patients, and also for patients requiring simultaneous use of medicinal products containing low dose acetylsalicylic acid (ASA/ aspirin) or medicinal products likely to increase digestive tract risk. Patients with a history of stomach problems, particularly if older, must inform the treating doctor straight away if they notice any unusual symptoms. Patients should inform treating doctor or pharmacist or nurse before taking diclofenac if they suffers from any stomach or bowel disorders such as ulcerative colitis or Crohn s disease. Care should be taken in patients receiving simultaneous medicines which could increase the risk of ulcers or bleeding, such as systemic corticosteroids (medicine used to reduce swelling), selective serotonin-reuptake inhibitors (medicine used for low mood), anticoagulants (blood thinning tablets like warfarin) and any other NSAID or COX-2 (cyclooxgenase-2) inhibitor, for example aspirin or ibuprofen. Care should be taken in patients with bowel disorders (ulcerative colitis or Crohn's disease) as these conditions may get worsen. Patient should stop taking diclofenac tablets if notices stomach pain, indigestion, heartburn, wind, nausea (feeling sick) or vomiting (being sick) or any sign of bleeding in the stomach or Page 41 of 54

4 intestine, for example, when emptying bowels, blood in vomit or black, tarry faeces and should inform treating doctor straight away. The treating doctor may advise to take a dose that is lower than the usual adult dose if the patient is an old-aged. Allergic reactions including serious allergic reactions, narrowing of air passage in patients with asthma, swollen face, lips, hands or fingers (hypersensitivity/ allergic reactions, including anaphylactic and anaphylactoid reactions; bronchospasm in patients with asthma; asthma attacks, angioedema) Signs of an allergic reaction include swelling of the face and mouth (angioedema), breathing problems, runny nose, skin rash or any other allergic type reaction. Serious skin reactions, some of them life-threatening, including scaling of the skin often with itching, skin redness and hair loss (exfoliative dermatitis), skin eruption, allergy to sun light, have been reported very rarely with the use of NSAIDs, including diclofenac. In patients with asthma, seasonal runny nose, nasal polyps, long-term lung disease or infection, reactions with NSAIDs like asthma worsening are more frequent than in other patients. This also occurs in patients who are allergic to other substances, e.g. with skin reactions, rashes. Diclofenac and other NSAIDs can precipitate narrowing of air passage if given to patients suffering from, or with a past history of asthma. Skin rash or spots is common (may affect up to 1 in 10 treated people), skin rash and itching are rare (may affect up to 1 in 1000 treated people) side effects observed with diclofenac use. This medicinal product should not be used in patients allergic to diclofenac sodium, aspirin, ibuprofen or any other NSAID, or to any of the other contents of this medicinal product. Patient should seek medical advice immediately if notices skin rash or appearance of lesions after starting this medicine. Patient should stop taking diclofenac tablets and should inform treating doctor straight away if notices allergic reactions which can include swelling of the face and mouth (angioedema), breathing problems, runny nose, skin rash or any other allergic type reaction. in patients with asthma, swollen face, lips, hands or fingers; skin reactions with itching and rashes; runny nose, nasal polyps precipitated by painkillers such as ibuprofen, acetylsalicylic acid or other NSAIDs. Patient should inform treating doctor or pharmacist or nurse before taking diclofenac if he/she suffers from runny nose, nasal polyps, long-term lung disease or long-term lung infection. Page 42 of 54

5 Heart problems and stroke (Cardiovascular effects including myocardial infarction, stroke and cardiac failure) Bleeding, stroke and heart attack due to bleeding (Bleeding, including cerebrovascular events) There is a small increased risk of heart attack or stroke when any medicine like diclofenac tablets is taken. The risk is higher if a high dose for a long time is taken. Unusual awareness of one's own heartbeat, chest pain, cardiac failure, heart attack, stroke, high blood pressure, and inflammation of the blood vessels side effects observed with diclofenac treatment. Simultaneous use of cardiac glycosides (for example digoxin; medicines used to treat heart problems) and NSAIDs may worsen heart failure and increase blood levels of glycoside. Platelets are type of blood cells involved in clotting of blood. in patients with severe thrombocytopenia (severe decrease in blood platelets). Diclofenac may stop blood clot formation and increases risk of bleeding. in patients with heart failure. in patients with heart and blood vessels related disease e.g. if patient ever had a heart attack, stroke, mini-stroke or blockages to blood vessels to the heart or brain or an operation to clear bypass blockages or having or had problems with blood circulation (peripheral arterial disease). Care should be taken in patients with risk factors for developing heart and blood vessel related problems (high blood pressure, raised cholesterol, diabetes, or if patient smokes). Patient should use lowest effective daily dose for the possible shortest duration. Patients with uncontrolled high blood pressure and heart failure should only be treated with diclofenac after careful consideration. Patient should inform the treating doctor or pharmacist if they are taking cardiac glycosides drugs. Patients should always follow the treating doctor s instructions for how long and how much dose to be taken of the medicinal product. in patients with severe thrombocytopenia (severe decrease in blood platelets). Patients should talk to the treating doctor or pharmacist or nurse before taking Diclofenac Tablets if they have any blood or bleeding disorder. Page 43 of 54

6 There is a small increased risk of heart attack or stroke when any medicine like diclofenac tablets are taken. The risk is higher if a high dose for a long time is taken. Decrease in platelets (thrombocytopenia), decrease in white blood cells (leucopoenia), decrease in red blood cells (anaemia) and lack of type of white blood cells (agranulocytosis) and inflammation of the blood vessels are very rare (may affect up to 1 in 10,000 treated people) side effects reported with diclofenac use. Care should be taken in patients receiving simultaneous medicines which could increase the risk of bleeding, such as, anticoagulants (blood thinning agents) such as warfarin, or another type of blood thinning agents (antiplatelet agents) such as acetylsalicylic acid. Care should be taken while treating diclofenac in heart problems or stroke patients. Patients should inform the treating doctor if they are taking any blood thinning medicines like warfarin or aspirin. Patients should talk to the treating doctor if they develop blood related problems. Harmful effects on kidney (renal toxicity) Fluid retention and swelling of the legs has been reported with NSAIDs therapy including diclofenac. Simultaneous use of medicines used to treat some inflammatory diseases and after organ transplants (ciclosporin and tacrolimus) with diclofenac may lead to harmful effects on kidney. Simultaneous use of cardiac glycosides and NSAIDs may lead to harmful effects on kidney. Kidney disease, presence of blood or protein in the urine are very rare (may affect up to 1 in 10,000 treated people) side effects observed with diclofenac use. in patients with severe kidney problems or kidney failure. Patient should inform treating doctor or pharmacist or nurse before taking diclofenac if they suffer from kidney problems. Patients should inform treating doctor or pharmacist if they are taking diuretics (water tablets) for example spironolactone and medicines used to treat heart conditions or high blood pressure, for example betablockers or angiotensin converting enzyme (ACE) inhibitors. Particular care should be taken in patients with heart or kidney problems, history of high blood pressure, old-aged patients, patients receiving simultaneous treatment with water pills or medicinal products that can affect kidney function, and in patients with volume depletion from any cause, e.g. before or Page 44 of 54

7 after major surgery. Monitoring of kidney function is advised as a careful measure when using diclofenac in such cases. Treatment is stopped followed by recovery to the pretreatment state. Inflammation of liver, scarring of liver tissue due to cell death and liver failure (hepatitis, hepatic necrosis and hepatic failure) Serious life threatening skin reactions including rash and blistering or peeling of the skin (serious skin reactions including SJS and TEN) Swelling of liver (hepatitis) may occur with use of diclofenac. As with other NSAIDs, including diclofenac, values of one or more liver proteins (enzymes) may increase. Raised levels of liver enzymes in the blood is a common (may affect up to 1 in 10 treated people), liver disorders including swelling of liver, a condition in which a person's skin and the whites of the eyes are yellow (jaundice) are rare (may affect up to 1 in 1000 treated people) and severe liver disorders including liver failure are very rare (may affect up to 1 in 10, 000 treated people) side effects observed with diclofenac treatment. Serious skin reactions, some of them may be life-threatening, serious body wide allergic reaction with a characteristic rash called Stevens- Johnson syndrome and, syndrome in which a large portion of the skin becomes intensely red and peels off; often accompanied by blisters called toxic epidermal necrolysis or Lyell s syndrome, have been reported very rarely with the use of NSAIDs, including diclofenac. in patients with severe liver problems or liver failure. Patients should talk to the treating doctor or pharmacist or nurse before taking Diclofenac Tablets if they have liver problems or have a disease called porphyria (symptoms of porphyria are discolouration of the urine, serious skin disorders, anaemia, abdominal pain and severe mental disorder). Close monitoring is required when prescribing diclofenac to patients with problem of liver function as the condition may worsen. During prolonged treatment with diclofenac, regular monitoring of liver function is suggested as a preventive measure. If blood tests suggests liver problems or patients have signs or symptoms consistent with liver problems, diclofenac should be stopped. Patients should stop taking this medicine and inform the treating doctor straight away if they notice a serious skin reaction such as rash, blistering or peeling of the skin (SJS, exfoliative dermatitis and TEN). Page 45 of 54

8 Serious skin reactions such as rash, blistering or peeling of the skin (SJS, exfoliative dermatitis and TEN) are very rare (may affect up to 1 in 10,000 treated people) side effects observed with diclofenac use. Use during pregnancy and lactation Diclofenac may interact with other drugs results in alteration of effectiveness or metablosim of diclofenac (Drug-drug interactions) Inhibition of formation of hormone like substances produced in the body called prostaglandin may seriously affect the pregnancy and/or unborn baby development. Data from studies shows an increased risk of miscarriage and/or heart defects and defect in stomach wall after use of a prostaglandin synthesis inhibitor in early pregnancy. The risk for heart related problems was increased from 1 to 2 per 100 people. The risk is believed to increase with dose and duration of therapy. During the last three months of pregnancy, harmful effects to lungs, heart and kidney may occur. Prolongation of bleeding time may occur even at very low doses in mother and newborn baby and delayed or prolonged labour may occur. Diclofenac passes into breast milk in small amounts. Diclofenac increase the blood level concentration of lithium (antidepressant), digoxin (drug to treat heart failure) and phenytoin (drug to treat fits) drugs when given simultaneously. Monitoring of these drug levels should be done. Simultaneous use of diclofenac with water pills and other blood pressure lowering drugs may decrease effectiveness of water pills and other blood pressure lowering drugs. Patient should be sufficiently hydrated and their kidney function should be checked regularly as there is chance of if patient is pregnant for more than 6-month as it may affect the baby s circulation. If patient is less than 6 months pregnant, she should ask treating doctor for advice before taking this medicine. If diclofenac is used by a woman during the 1 st three months of pregnancy, the dose should be kept low and duration of treatment as short as possible. during breast feeding in order to avoid side effects in the baby. Drug levels of lithium, digoxin, and phenytoin should be checked on regular basis. Simultaneous use of diclofenac with water pills and other blood pressure lowering drugs should be done cautiously especially in elder patients. Patient should be advised to drink plenty of water and kidney function test needs to be performed regularly. Patients should inform treating doctor or pharmacist if they are Page 46 of 54

9 damage to kidney. Simultaneous use of diclofenac with water pills (potassium-sparing diuretics for example spironolactone), medicines used to treat some inflammatory diseases and after transplants (ciclosporin, tacrolimus) or medicine used to prevent or treat urinary tract infections (trimethoprim) may be associated with increased potassium levels in blood. There are reports of side effects of increased chance of bleeding while using diclofenac simultaneously with blood thinning medicines. Therefore, close monitoring is necessary while giving together. Simultaneous use of diclofenac with other pain killers & steroids (antiinflammatory medicines), and antidepreesants may associate with increased risk of bleeding and ulcer formation in the gut. There are side effects of low & high blood glucose level while simultaneous use of diclofenac with blood glucose lowering drugs. Therefore, blood glucose should be regularly monitored. There are side effects due to high concentration of methotrexate in blood while simultaneous use of diclofenac with methotrexate (an anti-cancer drug). Therefore, caution is recommended. There is a risk of damage to the kidney while simultaneous use of diclofenac with ciclosporin and tacrolimus (immunity suppressant drugs). Therefore, the low dose of diclofenac should be given. Fits may occur when using diclofenac with quinolone antibiotics (a class of anti-bacterial to treat bacterial infection). Therefore, caution should be exercised when considering the use of a quinolone in patients who are already receiving an NSAID. There is delay or decrease in taking potassium sparing diuretics, ciclosporin, tacrolimus or trimethoprim. Potassium level in the blood should be monitored frequently. Regular blood test is required in patients when using diclofenac simultaneously with blood thinning medicines Simultaneous use of diclofenac with other pain killers and steroids should be avoided. Blood glucose level should be checked regularly. Attention is required while simultaneous use of diclofenac with methotrexate. Low dose of diclofenac should be given in patients receiving diclofenac and immunity suppressant drugs. Caution should be taken when using diclofenac and quinolone antibiotics as there is possibility of fits. Page 47 of 54

10 diclofenac absorption from the gut when diclofenac used simultaneous with colestipol and cholestyramine (drugs used to treat elevated cholesterol levels). Therefore, diclofenac should be given one before or 4 to 6 hours after giving colestipol/ cholestyramine. Simultaneous use of cardiac glycosides (drugs are used to treat heart failure) and diclofenac in patients may further worse heart failure, reduces kidney s function and increase glycoside drug levels in blood. Diclofenac reduces the effectiveness of mifepristone (a sex hormone used for termination of developing pregnancy) when used together. Therefore, diclofenac should not be used for 8-12 days after mifepristone administration. Diclofenac concentration in the blood increases when used with strong CYP2C9 (a primary enzyme responsible for metabolizing diclofenac) inhibitors such as voriconazole (an antifungal drug). Therefore, caution is necessary while using both together. Diclofenac should be given one before or 4 to 6 hours after giving colestipol/ cholestyramine. for 8-12 days after taking mifepristone. Caution is necessary while using Diclofenac with strong CYP2C9 inhibitors. Important Potential Risks RISK Impairment of female s ability to reproduce (impairment of female fertility) WHAT IS KNOWN As with other NSAIDs, the use of diclofenac may impair female s ability to reproduce (fertility) and is not advised in women attempting to conceive. Diclofenac may make it more difficult to become pregnant. In women who may have difficulties conceiving or who are undergoing tests of infertility, stoppage of diclofenac should be considered. Missing information None Page 48 of 54

11 VI.2.5 Summary of additional 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. No additional risk minimisation measures are planned for this product. VI.2.6 Planned post authorisation development plan There is no planned post authorisation development plan for Diclofenac sodium by Medreich Plc. VI.2.7 Summary of changes to the risk management plan over time Version Date Safety Concerns Comment Oct-2015 Important identified risks: Gastrointestinal toxicity including perforation, ulceration and bleeding (PUB) Hypersensitivity/ allergic reactions, including anaphylactic and anaphylactoid reactions; bronchospasm in patients with asthma; asthma attacks, angioedema, urticarial or acute rhinitis in patients with prior hypersensitivity to ibuprofen, other NSAIDs or aspirin. Arterial thrombotic events (myocardial infarction, stroke) Cardiac failure, hypertension Bleeding (inhibition of platelet function) Blood dyscrasia including agranulocytosis and aplastic anaemia Renal toxicity Hepatitis, hepatic necrosis and hepatic failure Serious skin reactions including Stevens Johnson syndrome and Toxic Epidermal Necrolysis Developmental and maternal toxicity during pregnancy Use during breast-feeding Hyperkalaemia with concurrent use of Initial RMP Page 49 of 54

12 potassium sparing diuretics, ciclosporin, tacrolimus or trimethoprim Important potential risks: Aseptic meningitis in patients with systemic lupus erythematosus (SLE) or other connective tissue disease Impairment of female fertility Missing information: Use in patients with mild-moderate hepatic impairment Use in patients with mild-moderate renal impairment 1.2 Important identified risks: Gastrointestinal toxicity including perforation, ulceration and bleeding (PUB) Hypersensitivity/ allergic reactions, including anaphylactic and anaphylactoid reactions; bronchospasm in patients with asthma; asthma attacks, angioedema Cardiovascular effects including myocardial infarction, stroke and cardiac failure Bleeding, including cerebrovascular events Renal toxicity Hepatitis, hepatic necrosis and hepatic failure Serious skin reactions including Stevens Johnson syndrome and Toxic Epidermal Necrolysis Use during pregnancy and lactation Drug-drug interactions Important potential risks: Impairment of female fertility Missing information: None RMP updated in line with the RFI (RMS Day 70 preliminary assessment report). Page 50 of 54