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Adapted from NICE - Clinical Knowledge Summaries: Gout Last revised: Feb 2022 - Accessed: May 2022 Background - options Definition Pathogenesis Causes and risk factors Prevalance Complications Prognosis Definition Gout is a purine metabolism disorder → Hyperuricaemia → urate crystal precipitation in joints and other tissues → joint inflammation/arthropathy CKS BMJ MSD CSE LINK TO SOURCE Causes and Risk factors Main risk factor = Hyperuricaemiausually due to impaired renal urate excretion Other risk factors alcohol high purine diet male gender ↑ age medications (diuretics) obesity and metaboic syndrome + more... CKS BMJ MSD CSE Prevalence Most common inflammatory arthritis ~2.5% in the UK male predominance more common in the elderly CKS BMJ MSD CSE Complications Tophi~50% in 10 years if untreated Urinary stones Risk factor for chronic kidney disease, myocardial infarction and cardiovascular disease mortality CKS BMJ MSD CSE Prognosis Acute attack → resolves within 1-2 weeks Diagnosis - options Clinical Assessment Investigations Differential Diagnosis Clinical presentation Natural history asymptomatic hyperuricaemia → intermittent acute gout attacks + intervals between acute flare → chronic tophaceous gout Acute gout typically rapid-onset maximum intensity within 24 hours monoarthritis (red, hot, swollen, painful joint) usually first MTPJ but can be any joint Chronic gout Tophi Sites fingers, hands, feet, olecronon, achilles, pinna Degenerative arthropathy CKS BMJ MSD CSE What investigations should I consider? A definitive diagnosis can be made by synovial fluid analysis but this is usually not practical in primary care. No initial investigations are required when managing people with typical gout-like symptoms if there is no suspicion of other conditions, such as septic arthritis. However, the following tests may be considered as part of ongoing follow up of people with gout-like symptoms: Joint fluid microscopy and culture: A definitive diagnosis of gout can be made if urate crystals are observed in synovial fluid or tophi. However, aspiration of joint fluid is not generally indicated unless the diagnosis of gout is in doubt or septic arthritis is suspected. It should only be carried out by an experienced clinician. Serum uric acid (SUA) is usually measured 4–6 weeks after an acute attack of gout to confirm hyperuricaemia: The formation and deposition of monosodium urate crystals occur when urate levels are persistently above 380 micromol/L. Hyperuricaemia may be present without gout. The presence of hyperuricaemia does not equate with a diagnosis of gout, as most people with hyperuricaemia do not develop gout. Gout may be present without hyperuricaemia and a normal level of urate does not exclude the diagnosis. Normal levels are often found during an acute flare of gout, when plasma urate levels may fall to normal. Joint X-ray: Plain radiographs are often normal. Non specific soft tissue swelling and subcortical cysts may be present. Advanced disease may demonstrate bone erosion. Screen for cardiovascular risk factors and renal disease, if a clinical diagnosis of gout is made - assess cardiovascular risk and any concomitant renal disease. NICE CKS (accessed May 2022) What else might it be? Septic Arthritis Septic arthritis: Septic arthritis must be considered in any person who is systemically unwell (with or without a temperature) and an acutely painful, hot, swollen joint. It is important to diagnose septic arthritis promptly, as late recognition can be fatal. If suspected, refer for emergency joint aspiration and culture. Bursitis, cellulitis, tenosynovitis. Non-urate crystal-induced arthropathy, such as pseudogout. Osteoarthritis. Psoriatic arthritis. Reactive arthritis. Rheumatoid arthritis. Haemochromatosis. Trauma. NICE CKS (accessed May 2022) Management - options Acute Gout Preventing Gout Scenario: Acute gout Acute attacks should be treated as early as possible, usually with either a nonsteroidal anti-inflammatory drug (NSAID), continued until 1-2 days after the attack has resolved (with gastroprotection) or oral colchicine. What treatment is recommended in acute gout? Self-care Advise the person to: Rest and elevate the limb. Avoid trauma to the affected joint. Keep the joint exposed and in a cool environment. Consider the use of an ice pack or bed-cage. Discuss lifestyle issues such as weight loss, exercise, diet, alcohol consumption, and fluid intake. See Lifestyle advice for more information. Pharmacological management: NSAID or Colchicine Prescribe either of the following first-line agents, provided that there are no contraindications: A nonsteroidal anti-inflammatory drug (NSAIDs) at a maximum dose as early as possible, and continue the treatment until 1-2 days after the attack has resolved. Co-prescribe a proton pump inhibitor (PPI) for gastric protection. For more information, see the CKS topic on NSAIDs - prescribing issues. Aspirin is not indicated in gout. Oral colchicine. Choice of first-line agent depends on patient preference, renal function and co-morbidities. Joint aspiration and intra-articular corticosteroids are an option in people with acute monoarticular gout and co-morbidity provided the diagnosis is certain, the person (and joint) are suitable for injecting and the expertise to inject the joint is available. For more information, see the section on intra-articular corticosteroids. A short course of oral corticosteroids or a single intramuscular corticosteroid injection can be considered in people who cannot tolerate NSAIDs or colchicine, and if intra-articular injection is not possible or in oligo-/polyarticular gout. For more information, see the section on oral corticosteroids. Consider paracetamol as an adjunct for pain relief, in addition to other drug treatment, although this is not generally recommended as a primary treatment. For more information, see the CKS topic analgesia - mild-to-moderate pain. Do not stop allopurinol or febuxostat during an acute attack of gout if the person is already established on these drugs. Irrespective of the treatment used, advise the person to return if symptoms get worse, or if there is no improvement after 1-2 days. See Treatment failure for more information. What if treatment fails in acute gout? If there is an inadequate response to treatment after 1-2 days: Review the diagnosis and exclude any other underlying pathology. See Differential diagnosis for more information. Check compliance with medication, and encourage self-care strategies. Ensure that the maximum dose of colchicine (if tolerated) or NSAID is being used and consider adding paracetamol. Ideally, a maximum dose of NSAID should have initially been used - see Treatment of Acute Gout section. If colchicine has been initially prescribed at a lower dose (to avoid adverse effects), consider increasing to the maximum recommended dose if tolerated. If unable to tolerate the chosen treatment, consider switching to an alternative first-line drug provided there are no contraindications. If response to monotherapy is insufficient, consider combining treatments. People with gout are more likely to be elderly and have comorbidities, so are generally more vulnerable to drug adverse effects. If considering combining treatment, make a decision based on the risks and benefits. Consider seeking specialist advice, especially if the person may be at risk of adverse effects, if there is diagnostic uncertainty or if there is failure to respond to standard treatment. What follow up is recommended after an acute attack of gout? After an acute attack of gout has resolved, follow up the person after 4–6 weeks, and: Check their Serum uric acid level. Measure blood pressure and arrange additional blood testing for HbA1c, renal function, and lipid profile. Identify and manage underlying conditions such as hypertension, diabetes, dyslipidaemia or renal impairment, and assess the person's overall cardiovascular risk. Provide advice on risk factors such as obesity, diet, excessive alcohol consumption, smoking and exercise - see Lifestyle advice section. Advise that acute flares of gout should be treated as early as possible. Consider providing an advance prescription of effective treatment for future attacks of gout. Discuss the use of urate-lowering therapy (ULT). If a person is taking ULT (allopurinol or febuxostat), see What follow up is recommended for someone taking ULT section. Review cardiovascular risk factors and screen for renal disease at least annually, and provide ongoing lifestyle advice. For more information, see the CKS topic on CVD risk assessment and management. In a person with hypertension taking a diuretic, consider changing to an alternative antihypertensive, provided that blood pressure is controlled. For more information, see the CKS topic on Hypertension. In a person with heart failure, continue diuretics during an acute attack. If using a nonsteroidal anti-inflammatory drug (NSAID) for pain relief, monitor renal function closely. For more information, see the CKS topic on Heart failure - chronic. When should I refer? Admit the person if septic arthritis is suspected. Refer to a specialist or seek specialist advice when: The diagnosis is uncertain, there is a suspicion of an underlying systemic illness (for example rheumatoid arthritis or connective tissue disorder), or gout occurs during pregnancy or in a young person (under 30 years of age). A person has persistent symptoms during an acute attack despite maximum doses of anti-inflammatory medication (alone or in combination). An intra-articular steroid injection is indicated but the facilities or expertise are not available. A person requires urate lowering-therapy and: Allopurinol and febuxostat are not tolerated or contraindicated; or Allopurinol or febuxostat is at maximum dose but there is failure to reach urate level target or the person is still having recurrent attacks of gout. Complications are present, including urate kidney stones, urate nephropathy, recurrent urinary tract infection, joint damage or troublesome tophi. The person is at risk of adverse effects of drug treatment. NICE CKS (accessed May 2022) Scenario: Preventing gout Urate-lowering therapy (ULT) should be discussed and offered to all people with a diagnosis of gout. Allopurinol is the recommended first-line urate-lowering agent. What drug treatment is recommended to prevent recurrent attacks of gout? Urate-lowering therapy (ULT) should be discussed and offered to all people with a diagnosis of gout. In particular it is important to advise the use of urate-lowering therapy to people with: Two or more attacks of acute gout in 12 months. Tophi. Chronic gouty arthritis. Joint damage. Renal impairment (eGFR less than 60 ml/min). A history of urinary stones. Diuretic use. Young age of onset of primary gout. Start urate-lowering therapy after the acute attack has resolved. In circumstances where attacks are so frequent that this is not possible, the initiation of allopurinol can be considered before inflammation has completely settled. Allopurinol is the recommended first-line urate-lowering agent. Start at a low dose and titrate upwards (where tolerated) every four weeks until the serum uric acid (SUA) level is below 300 micromol/L. For people with renal impairment starting dose and titration guidance may differ. See Managing renal impairment. Consider febuxostat as an alternative second-line therapy if allopurinol is not tolerated or is contraindicated (for example if renal impairment prevents adequate allopurinol dose increases). Check liver function tests prior to initiation. Start at a low dose and increase after 4 weeks if SUA level is above 300 micromol/L. Note: a prior history of hypersensitivity to allopurinol and/or renal disease may indicate potential hypersensitivity to febuxostat. Consider prescribing colchicine when initiating or increasing the dose of a ULT as prophylaxis against acute attacks secondary to ULT, and continue for up to 6 months. If colchicine cannot be tolerated, consider a low-dose NSAID or coxib with gastroprotection as an alternative provided there are no contraindications. Carefully consider the risk to benefit balance when considering long-term gout flare prophylaxis, particularly in people with comorbidities or taking medication with potential for interaction. The risk of gout flare is particularly high when initiating febuxostat. Advise the person that: Urate-lowering medication is normally lifelong and regular monitoring is needed. Allopurinol or febuxostat may increase the risk of acute attacks of gout just after initiating treatment, and for some weeks afterwards. Explain that they should start their anti-inflammatory treatment as soon as possible and not to stoptheir allopurinol or febuxostat during acute attacks. Primary prevention of gout, tophi, cardiovascular disease or renal disease with ULT in people with asymptomatic hyperuricaemia is not recommended although lifestyle advice can be considered. Can urate-lowering treatment be reduced or stopped in chronic gout? Once allopurinol or febuxostat is started, treatment is usually lifelong. After some years of treatment, once serum uric acid target is reached and clinical 'cure' has been achieved (acute attacks have stopped and tophi have resolved), consider reducing the dose of ULT to maintain the serum uric acid level between 300-360 micromol/L. Although in most people ULT will be required lifelong, consider stopping allopurinol or febuxostat only in people who have achieved a clinical 'cure', successfully addressed modifiable risk factors and had a normal serum uric acid level for many years. If considering discontinuing urate-lowering medication, explain that there is no certainty that a further episode of gout will not recur. Continue to regularly monitor serum uric acid levels. Consider providing an advance prescription of effective treatment for future attacks of gout but advise them not to start allopurinol or febuxostat immediately if an acute attack develops, and to seek medical advice. Stress the importance of a healthy lifestyle and avoidance of trigger factors. Provide early and close follow up as needed. What lifestyle advice is recommended in someone with gout? Advise people with gout to: Aim for an ideal body weight if overweight, using dietary modification to achieve a gradual weight reduction — but avoid 'crash' dieting. Eat sensibly — encourage a well-balanced diet which is low in fat and added sugar, and high in fibre and vegetables. Avoid excessive consumption of sugar-sweetened soft drinks and foods rich in purines (such as meats and seafood). Encourage a diet inclusive of skimmed milk, low-fat yoghurt, soybeans and cherries. Drink alcohol sensibly — avoid excessive alcohol intake and binge drinking, especially beers and spirits. See the sections on Safer drinking limits and Unit of alcohol in the CKS topic on Alcohol - problem drinking for more information. People with renal stones should be advised to avoid dehydration and encouraged to drink more than 2 litres of water a day. Take regular exercise — but avoid intense muscular exercise and trauma to joints. Stop smoking — see the CKS topic on Smoking cessation. Consider taking vitamin C supplements. Provide written information and patient support such as resources via the UK Gout Society. For more information, see www.ukgoutsociety.org. What follow up is needed in someone taking urate-lowering therapy? If taking urate-lowering therapy (ULT) (allopurinol or febuxostat), check the serum uric acid (SUA) level and renal function every 4 weeks until SUA is in target range, then annually thereafter, and aim for a SUA level below 300 micromol/L. Titrate the dose of ULT if appropriate and SUA target is not reached - see Drug treatment for preventing gout section. If taking febuxostat, monitor liver function tests periodically, where clinically indicated. If the person is still having frequent attacks of gout despite ULT: Assess compliance with prophylactic medication or increase the dose if appropriate. Review any trigger factors such as medication (for example diuretics), trauma, diet, weight gain, and excess alcohol consumption. Consider providing an advance prescription of effective treatment for future attacks of gout. Consider referral to secondary care. After some years of treatment, once serum uric acid target is reached and clinical 'cure' has been achieved (acute attacks have stopped and tophi have resolved), consider reducing the dose of ULT to maintain the serum uric acid level between 300-360 micromol/L. Review cardiovascular risk factors and screen for renal disease at least annually, and provide ongoing lifestyle advice. For more information, see the CKS topic on CVD risk assessment and management. In a person with hypertension taking a diuretic, consider changing to an alternative antihypertensive, provided that blood pressure is controlled. For more information, see the CKS topic on Hypertension. In a person with heart failure, continue diuretics during an acute attack. If using a nonsteroidal anti-inflammatory drug (NSAID) for pain relief, monitor renal function closely. For more information, see the CKS topic on Heart failure - chronic. When is referral recommended in someone with gout? Admit the person if septic arthritis is suspected. Refer to a specialist or seek specialist advice when: The diagnosis is uncertain, there is a suspicion of an underlying systemic illness (for example rheumatoid arthritis or connective tissue disorder), or gout occurs during pregnancy or in a young person (under 30 years of age). A person has persistent symptoms during an acute attack despite maximum doses of anti-inflammatory medication (alone or in combination). An intra-articular steroid injection is indicated but the facilities or expertise are not available. A person requires urate-lowering treatment and: Allopurinol and febuxostat are not tolerated or contraindicated; or Allopurinol or febuxostat is at maximum dose but there is failure to reach urate level target or the person is still having recurrent attacks of gout. Complications are present, including urate kidney stones, urate nephropathy, recurrent urinary tract infection, joint damage or troublesome tophi. The person is at risk of adverse effects of drug treatment. NICE CKS (accessed May 2022) Prescribing information - options NSAIDs Colchicine Corticosteroids Allopurinol Febuxostat Paracetamol Nonsteroidal anti-inflammatory drugs Prescribe nonsteroidal anti-inflammatory drugs (NSAIDs) at the lowest effective dose for the shortest possible duration. What should I consider when initiating NSAIDs? Prescribe nonsteroidal anti-inflammatory drugs (NSAIDs) at the lowest effective dose for the shortest possible duration. When prescribing NSAIDs, take into account the person's individual risk factors for adverse effects and consider if: An alternative to an NSAID may be suitable, for example: A topical NSAID. Physiotherapy, or referral for consideration of surgery. A different oral analgesic (such as paracetamol, or an opioid). The person has any contraindications to oral NSAIDs. There are any potentially hazardous drug interactions. The person is already using an NSAID — for example, ibuprofen or aspirin purchased over-the-counter. Gastroprotection is indicated. For example, because the person is: At increased risk of gastrointestinal adverse effects (for example, people that require long-term treatment). Experiencing dyspepsia from standard NSAIDs. More frequent review and monitoring for adverse effects is required — for example, for people who are: At risk of multiple adverse effects (for example, the elderly, people with comorbidities). Taking drugs which may interact with an NSAID. At increased risk of gastrointestinal or cardiovascular or renal adverse effects. Contraindications Do not prescribe nonsteroidal anti-inflammatory drugs (NSAIDs) to people with: Active gastrointestinal (GI) bleeding, or active GI ulcer. A history of GI bleeding related to previous NSAID therapy, or a history of GI perforation related to previous NSAID therapy. A history of recurrent GI haemorrhage (two or more distinct episodes), or history of recurrent GI ulceration (two or more distinct episodes). A history of hypersensitivity/severe allergic reaction to an NSAID (including aspirin) — for example, asthma, rhinitis, angioedema or urticaria. Severe heart failure. Severe hepatic impairment — serum albumin less than 25 g/L or Child-Pugh score of 10 or more. Severe renal impairment — estimated glomerular filtration rate (eGFR) less than 30 mL/minute/1.73 m2. Do not prescribe COX-2 inhibitors, diclofenac, aceclofenac or high dose ibuprofen (more than 2400 mg daily) to people with: Ischaemic heart disease. Inflammatory bowel disease (COX-2 inhibitors only). Peripheral arterial disease. Cerebrovascular disease. Congestive heart failure (New York Heart Association [NYHA] classification II–IV). Do not prescribe etoricoxib or high dose ibuprofen to people with uncontrolled hypertension (persistently above 140/90 mmHg). Prescribe NSAIDs with caution to people with: A history of peptic ulceration (standard NSAIDs are contraindicated), or people at high risk of GI adverse effects (for example, the elderly). Allergic disorders. Cardiac impairment, or heart failure — NSAIDs may impair renal function. Cerebrovascular disease. Coagulation disorders. Connective-tissue disorders. Hypertension — NSAIDs may impair renal function. Inflammatory bowel disease — NSAIDs may increase the risk of developing or cause exacerbations of ulcerative colitis or Crohn's disease. Ischaemic heart disease. Peripheral arterial disease. Risk factors for cardiovascular events — for example, hypertension, hyperlipidaemia, diabetes mellitus, smoking. Hepatic impairment — dose reductions may be necessary. Renal impairment (avoid if possible) — sodium and water retention may occur leading to a deterioration in renal function and, possibly renal failure. If the person cannot avoid using an NSAID and has impaired renal function, monitor creatinine clearance or eGFR. Also prescribe NSAIDs with caution in: Women trying to conceive — NSAIDs may impair female fertility. The elderly — increased risk of cardiovascular, renal, and serious GI adverse effects (including GI bleeding and perforation, which may be fatal). For detailed information on specific medicines, see the summary of product characteristics, available at the electronic Medicines Compendium (eMC) (www.medicines.org.uk). Adverse effects The risks of adverse effects varies among individual nonsteroidal anti-inflammatory drugs (NSAIDs) and is influenced by the dose and duration of use. Adverse effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. Dyspepsia and other upper gastrointestinal (GI) complications are the most common adverse effects of NSAIDs — for example, ulcer, perforation, obstruction or bleeding. People are at increased risk of serious NSAID–induced GI adverse events if they have one or more risk factor. Cardiovascular and renal complications are less common but serious NSAID adverse effects — for example, myocardial infarction, stroke, cardiac failure, hypertension, and renal failure. All NSAID use is associated with a small increased risk of thrombotic events independent of baseline cardiovascular risk factors or duration of NSAID use. However, the greatest risk may be in those receiving high doses long-term. People with certain risk factors have an increased risk of serious cardiac or renal adverse events. Other adverse effects include: Prolonged bleeding (for example, after surgery) as a result of inhibition of platelet aggregation. Bronchospasm — NSAIDs may exacerbate or precipitate asthma. Stop the NSAID if it is suspected to have precipitated bronchospasm. Severe skin reactions and angioedema (for example, exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis) — stop the NSAID if these occur. Anastomotic leakage. [ABPI, 2019] 'Kounis syndrome' (allergic acute coronary syndrome). [ABPI, 2019] Very rarely, NSAIDs can precipitate severe hepatic reactions (such as hepatitis, liver necrosis, or hepatic failure). If there are symptoms or signs of liver damage (for example, nausea, vomiting, abdominal pain, and jaundice), or persistently abnormal liver enzymes, stop the NSAID. For detailed information on specific medicines, see the summary of product characteristics, available at the electronic Medicines Compendium (eMC) (www.medicines.org.uk). What are the risk factors for cardiovascular and renal adverse effects? Cardiovascular (CV) effects Inhibition of COX-2 leads to suppression of prostacyclin (which normally protects endothelial cells, produces vasodilation and interacts with platelets to antagonize aggregation). Inhibition of COX-1 inhibits conversion of arachidonic acid to thromboxane A2 (a potent platelet aggregator and vasoconstrictor). Selective COX-2 inhibition presents a CV risk, as it shifts the prothrombotic/antithrombotic balance and favours thrombosis. Renal effects NSAIDs inhibit prostaglandins PGE2 and PGI2 synthesis which may result in sodium retention, reduced renal blood flow, and renal failure. The risk for serious cardiac or renal adverse events (including myocardial infarction, heart failure, and hypertension) is increased in people with: Cerebrovascular disease. Heart failure. Ischaemic heart disease. Peripheral arterial disease. Renal impairment. People with risk factors for cardiovascular disease (for example, hypertension, hyperlipidaemia, diabetes mellitus, smoking) and all elderly people (aged 65 years or over) are also at increased risk. For more information, see the CKS topic on CVD risk assessment and management. How should I manage the risk of cardiovascular and renal adverse effects? For people with heart failure: Severe heart failure — do not prescribe nonsteroidal anti-inflammatory drugs (NSAIDs). Mild to moderate heart failure — do not prescribe a COX-2 inhibitor, diclofenac, or high-dose ibuprofen (2400 mg or more daily). Prescribe a standard NSAID and monitor the person closely. Ibuprofen up to 1200 mg daily, or naproxen up to 1000 mg daily are first-line options. For people with ischaemic heart disease, cerebrovascular disease, or peripheral arterial disease, prescribe: Ibuprofen up to 1200 mg per day or naproxen up to 1000 mg daily are first-line options. COX-2 inhibitors, diclofenac, and high-dose ibuprofen are contraindicated. For people with severe renal impairment (estimated glomerular filtration rate [eGFR] less than 30 mL/minute/1.73 m2): Ideally, avoid prescribing NSAIDs. If an NSAID is used, monitor the person closely. For people with risk factors for cardiovascular (CV) disease or the elderly, prescribe: Ibuprofen up to 1200 mg per day or naproxen up to 1000 mg daily. Diclofenac should only be initiated after careful consideration of the associated risks in people with risk factors for CV disease. For people with hypertension: Avoid prescribing etoricoxib or high-dose ibuprofen in people with uncontrolled hypertension (blood pressure persistently above 140/90 mmHg). Consider whether monitoring is needed. What are the risk factors for gastrointestinal (GI) adverse effects? Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclo-oxygenase-1 (COX-1) — this is thought to be responsible for gastrointestinal (GI) toxicity. COX-2 inhibitors (such as etoricoxib and celecoxib) selectively inhibit cyclo-oxygenase-2 and have a reduced risk for GI toxicity. Risk factors for NSAID–induced gastrointestinal (GI) adverse events include: Aged over 65 years. A high dose of an NSAID. A history of gastroduodenal ulcer, GI bleeding, or gastroduodenal perforation. Concomitant use of medications that are known to increase the likelihood of upper GI adverse events (for example, anticoagulants, corticosteroids, selective serotonin reuptake inhibitors [SSRIs]). A serious comorbidity, such as cardiovascular disease, hepatic or renal impairment (including dehydration), diabetes, or hypertension. Heavy smoking. Excessive alcohol consumption. Previous adverse reaction to NSAIDs. Prolonged requirement for NSAIDs. People are considered at: High risk if they have a history of previously complicated ulcer, or multiple (more than two) risk factors. Moderate risk if they have 1–2 risk factors. Low risk if they have no risk factors. Additional risk factors for NSAID-induced GI adverse events include: The type of NSAID used. The presence of Helicobacter pylori infection. For more information on risk factors, see the CKS topic on Dyspepsia - proven GORD. How should I manage the risk of GI adverse effects? To prevent gastrointestinal (GI) adverse effects associated with the use of a nonsteroidal anti-inflammatory drug (NSAID): Avoid prescribing more than one NSAID at a time. Avoid concomitant use of an NSAID with low-dose aspirin (if possible) — if this is essential, monitor closely. Prescribe the lowest dose of NSAID for the shortest period of time. Use a short-acting NSAID (such as ibuprofen) in preference to a long-acting NSAID (such as naproxen). Consider an alternative analgesic if appropriate. For people: With osteoarthritis and rheumatoid arthritis — co-prescribe a proton pump inhibitor (PPI) with an NSAID (see Table 1 for licensed doses of PPIs for gastroprotection). Who are elderly — co-prescribe a PPI with an NSAID. With low back pain, axial spondyloarthritis, psoriatic arthritis and other peripheral spondyloarthritides — consider gastroprotection when prescribing an NSAID. For people at: High risk of GI adverse events — prescribe a COX-2 selective NSAID (for example, etoricoxib, or celecoxib) instead of a standard NSAID, and co-prescribe a PPI. Moderate risk of GI adverse events — prescribe a COX-2 inhibitor alone, or an NSAID plus a PPI. Low risk of GI events — prescribe a non-selective NSAID. Managing GI adverse effects The management of GI adverse effects in people using an NSAID depends on whether they have been investigated (for example, with endoscopy or a test for H. pylori) and whether 'alarm' symptoms are present. For full details, see the CKS topics on: Dyspepsia - pregnancy-associated Dyspepsia - proven functional Dyspepsia - proven peptic ulcer Dyspepsia - unidentified cause For detailed information on the use of low-dose aspirin, including advice on how to minimize the risk of GI adverse events, see the CKS topic on Antiplatelet treatment. Licensed doses of proton pump inhibitors used for gastroprotection for people who require continued NSAID treatment Table 1. Licensed doses of proton pump inhibitors used for gastroprotection for people who require continued NSAID treatment. Proton Pump Inhibitor Dose for NSAID prophylaxis Lansoprazole 15–30 mg once daily Omeprazole 20 mg once daily Esomeprazole 20 mg once daily Pantoprazole 20 mg once daily Information from: [BNF 75, 2018] Drug interactions Alendronate — concurrent use with nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of upper gastrointestinal (GI) adverse effects. Monitor for signs of GI irritation. Angiotensin-converting enzyme (ACE) inhibitors or an angiotensin-II receptor antagonists (AIIRAs) — concurrent use with NSAIDs may increase blood pressure, the risk of renal impairment and rarely hypokalaemia. Monitor blood pressure if an NSAID is started, and consider monitoring urea and electrolytes. Consider intermittent use of NSAIDs as a possible cause if erratic blood pressure control occurs. Anticoagulants (for example, warfarin, dabigatran) — all NSAIDs can cause GI irritation and reduce platelet aggregation, which can worsen any bleeding event. Avoid concomitant use if possible. If concurrent use is necessary be aware of the potential risks of bleeding. Consider giving gastroprotection (such as a proton pump inhibitor [PPI]). Antidepressants — increased risk of upper GI bleeding when some antidepressants (selective serotonin reuptake inhibitors, and serotonin noradrenaline reuptake inhibitors) and an NSAID are taken concomitantly. If an NSAID is considered necessary, weigh the risks and benefits of treatment and consider prescribing gastroprotection. Antiplatelets (low dose aspirin, clopidogrel) — NSAIDs may antagonize the antiplatelet effects of aspirin, and increase the risk of GI bleeds when taken concurrently with other antiplatelets. If concomitant use is unavoidable consider prescribing gastroprotection with a PPI. Beta blockers — NSAIDs may reduce the efficacy of beta blockers given for heart failure. Consider monitoring blood pressure if an NSAID is started or stopped. Note: NSAIDs should generally be avoided in people with heart failure. Corticosteroids — the incidence and/or severity of ulceration associated with NSAIDs, and the possibility of GI bleeding may be increased. Consider giving gastroprotection. Ciclosporin — NSAIDs may reduce renal function, and lead to increased ciclosporin levels. If concurrent is necessary, monitor renal function and consider reducing the dose of the NSAID. Fluconazole, voriconazole — the peak plasma level of some NSAIDs (for example, ibuprofen) may be increased. Monitor for NSAID adverse effects (for example, dyspepsia, nausea, dizziness). Consider using the lowest NSAID dose and titrate accordingly. Lithium — NSAIDs can reduce lithium excretion, and increase the risk of lithium toxicity. Avoid concomitant use especially if risk factors for lithium toxicity (such as advanced age or renal impairment) are present, unless lithium levels can be closely monitored, and the dose adjusted accordingly. Advise people to report lithium adverse effects (tremor, dysarthria, ataxia, confusion). Loop diuretics (for example, furosemide) — NSAIDs may reduce the antihypertensive effects of loop diuretics and exacerbate congestive heart failure. Consider an alternative non-NSAID analgesic, but if concurrent use is essential, monitor the diuretic effects, renal function and electrolytes closely, and increase the dose of the loop diuretic if required. Methotrexate — NSAIDs may reduce the excretion of methotrexate and increase the risk of methotrexate toxicity. Advise people to report symptoms such as sore throat, dyspnoea or cough. If high-dose methotrexate is given with an NSAID, monitor methotrexate levels and increase routine methotrexate monitoring (full blood count, liver function tests). Nicorandil — there may be an increased risk of GI ulceration, perforation or haemorrhage if taken concurrently with an NSAIDs. Monitor for GI adverse effects. Potassium-sparing diuretics (for example, spironolactone) — several cases of acute renal impairment have been reported with concurrent use with NSAIDs. Avoid concurrent use. Probenecid — probenecid reduces excretion of NSAIDs. Avoid concurrent use. If concurrent use is unavoidable, use a lower dose of NSAID. Ketorolac is specifically contraindicated in people taking probenecid. Quinolones (for example, ciprofloxacin) — possible increased risk of convulsions if taken concurrently. This is rare, therefore in most cases, the concomitant use of a quinolone and an NSAID is acceptable. However concurrent use should be avoided in people with epilepsy or people who are predisposed to convulsions. Thiazide-type diuretics (for example, bendroflumethiazide) — some NSAIDS (for example, indometacin) may reduce the antihypertensive effect of thiazides. If concurrent use is indicated monitor blood pressure regularly and increase the thiazide dose as necessary. Zidovudine — the risk of haematological toxicity and risk of bleeding may be increased if given concurrently with NSAIDs. Note: combined treatment with an NSAID, plus an ACE inhibitor or AIIRA and a diuretic (the so called 'triple whammy') significantly increases the risk of acute kidney injury (AKI) and should be avoided if possible. For more information on people most at risk of AKI and how to manage them, see the CKS topic on Acute kidney injury. Monitoring Review the appropriateness of non-steroidal anti-inflammatory drug (NSAID) prescribing widely and on a routine basis, especially in people who are at higher risk of gastrointestinal, renal and cardiovascular morbidity and mortality (for example, older people). Consider the risks and the response to treatment, and use clinical judgement to decide what must be monitored and how frequently. Enquire about, and manage, adverse effects. Monitor blood pressure in the elderly and people: Taking COX-2 inhibitors. Before starting treatment. Two weeks after treatment for etoricoxib. Periodically during treatment. With hypertension — for example, 1–4 weeks after starting long-term treatment, or increasing the dose of the NSAID. Monitor renal function at least annually. For people with renal impairment — monitor renal function 1–2 weeks after starting or increasing the dose of the NSAID, and then regularly thereafter. Monitor liver function in people: With hepatic impairment. On long-term NSAID therapy. Monitor haemoglobin levels in people at high risk of gastrointestinal adverse effects 1–4 weeks after NSAID treatment has started. Consider monitoring blood pressure, renal function, and features of heart failure 1–2 weeks after starting or increasing the dose of the NSAID, and then regularly thereafter, in the elderly and people with: Ischaemic heart disease. Risk factors for cardiovascular disease. Cerebrovascular disease. Peripheral vascular disease. Heart failure. Also consider monitoring renal function in people who are taking additional drugs that can affect renal function (for example, ACE inhibitors, angiotensin-II receptor antagonists, or diuretics). For more specific advice check the drug's summary of product characteristics (SPC). Conception Avoid nonsteroidal anti-inflammatory drugs (NSAIDs) during conception. Paracetamol is the analgesic and/or antipyretic of choice during conception. Pregnancy Paracetamol is the analgesic and/or antipyretic of choice during pregnancy. However, if during the first or second trimester paracetamol is ineffective and an NSAID is clinically indicated: Ibuprofen is the preferred NSAID — however, it should only be used before 30 weeks of pregnancy. COX-2 inhibitors are contraindicated. As with all people who are prescribed an NSAID, use the lowest effective dose for the shortest duration possible. If regular use is clinically indicated, such as in a woman with rheumatoid arthritis, seek specialist advice. NSAIDs must not be used from 30 weeks of pregnancy onwards without specialist advice and regular fetal monitoring. Use after 30 weeks of pregnancy is associated with premature closure of the ductus arteriosus. For more information, contact the UK Teratology Information Service (UKTIS) on 0844 892 0909. Breastfeeding Paracetamol is the drug of choice for women who are breastfeeding. Seek expert advice if the: Infant is pre-term, or low birthweight. Absorption, distribution, metabolism, or excretion of paracetamol may be affected by an underlying medical condition. If a nonsteroidal anti-inflammatory drug (NSAID) is clinically indicated: Ibuprofen is preferred. Use the lowest effective dose for the shortest time possible. If a COX-2 inhibitor is clinically indicated: Celecoxib is preferred. If a non-preferred NSAID is required, monitor the infant for gastrointestinal adverse effects, and avoid repeated use of drugs with a long half-life (for example, naproxen) where possible, due to the potential risk of accumulation in the infant. Single doses of non-preferred NSAIDs may be used if required without the need for monitoring. What advice should I give someone when prescribing an NSAIDs? Advise the person about the adverse effects associated with NSAIDs including the cardiovascular and renal and gastrointestinal (GI) adverse effects. Explain that adverse effects may be minimized by: Using an alternative treatment to an oral NSAID (for example paracetamol, or a topical NSAID if appropriate). Using an NSAID at the lowest effective dose and for no longer than is necessary. Taking an NSAID with or after food. Taking a proton pump inhibitor if they have an increased risk of GI adverse effects. Explain that they may need close monitoring to determine the response to treatment and manage any adverse effects. Advise them to read the patient information leaflet that comes with their medicine. Provide the person with a Medicine Sick Day Rules Card, and explain that they should: Stop the NSAID (and any of the other medicines mentioned on the card) when they are unwell with vomiting or diarrhoea (unless minor), or fever, sweats and shaking (unless minor). Restart when they are well (after 24–48 hours of normal eating and drinking). How should my management vary when considering the possibility of COVID-19? NSAIDs are commonly used over the counter and prescribed by clinicians for people suffering symptoms resulting from acute respiratory infections (ARI). The advice on prescribing NSAIDs to someone with proven or suspected COVID-19 infection is that this should be done with caution. For each person, the following should be taken into account: Comorbidities and medical history. Risks in each person. Contraindications. Interactions. Monitoring requirements. If NSAIDs are prescribed, then this should be at the lowest dose and for the shortest period. The need for continued NSAIDs should be reviewed using clinical judgement. Naproxen and low-dose ibuprofen (up to 1200 mg per day) are considered first-choice options. For people who are taking NSAIDs long term for other indications, the advice is that there no need for them to stop their treatment. NICE CKS (accessed May 2022) Colchicine For acute gout: Give 500 micrograms of colchicine, two to four times a day, until pain relief is achieved, or diarrhoea or vomiting occurs. For prophylaxis (during ULT): Give 500 micrograms of colchicine once or twice a day following initiation of long-term treatment with allopurinol or febuxostat. What dosing regimen of colchicine should I use? For acute gout: Give 500 micrograms of colchicine, two to four times a day, until pain relief is achieved, or diarrhoea or vomiting occurs. Do not exceed a total dose of 6 mg of colchicine (i.e. up to 6 days with colchicine 500 micrograms twice a day, or up to 3 days with colchicine 500 micrograms four times a day), and Do not repeat treatment within three days. In the elderly or people with an eGFR of 10-50 mL/minute/1.73m2 use a reduced dose or increase the dosage interval. Colchicine is contraindicated in people with an eGFR less than 10 mL/minute/1.72m2. For prophylaxis of gout (during urate-lowering treatment): Give 500 micrograms of colchicine once or twice a day following initiation of long-term treatment with allopurinol or febuxostat. For more information, see the sections on Allopurinol and Febuxostat. Use colchicine for prophylaxis of gout with caution in people with renal impairment. Limit the dose to: 500 micrograms once a day for people with an eGFR of 30-60 mL/minute/1.72m2. 500 micrograms every 2-3 days in people with eGFR 10-30 mL/minute/1.72m2. What are the adverse effects of colchicine? Adverse effects of colchicine include: Gastrointestinal — nausea and vomiting, abdominal pain. Common, and can be severe enough to limit treatment. Alopecia Blood disorders Inhibition of spermatogenesis Myopathy and peripheral neuritis The severity of adverse effects of colchicine is dose-dependent. A low-dose regime may produce fewer adverse effects. Colchicine has a narrow therapeutic index and is extremely toxic in overdose. Refer for medical assessment in overdose even if the person has no symptoms. Who should avoid taking colchicine? Colchicine has a narrow therapeutic index and is extremely toxic in overdose. Avoid colchicine in people: With blood disorders. With an eGFR less than 10, as colchicine is excreted by the kidneys and, in people with renal impairment, there is the potential for accumulation and toxicity Who are pregnant or breastfeeding. In the rare event of a pregnant or breastfeeding woman presenting with gout, colchicine should be avoided and the woman should be referred to a specialist if she requires treatment. With severe hepatic impairment. Taking P-glycoprotein inhibitors, such as clarithromycin, erythromycin, ritonavir and verapamil, or strong CYP3A4 inhibitors, such as clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir. Ideally, colchicine should also be avoided in: The elderly, who are more prone to dehydration, colchicine is also best avoided because of its relatively high risk of causing diarrhoea. People with poor renal function, poor liver function, gastrointestinal disease, or cardiac disease. Women of childbearing age unless using effective contraception. Use caution in people also receiving a statin. In overdose, colchicine can cause confusion, reduced cardiac output, cardiac arrhythmias, renal damage, liver damage, respiratory distress, hyperpyrexia, and bone-marrow depression. These recommendations regarding colchicine prescribing are based on a guideline produced by the British Society for Rheumatology [Hui, 2017], the British National Formulary [BNF 74, 2017] the summary of product characteristics (SPC) [ABPI Medicines Compendium, 2017b] and [MHRA, 2009]. NICE CKS (accessed May 2022) Corticosteroids For acute gout, a short course of a moderately high dose of oral prednisolone is recommended (for example prednisolone 30–35 mg once a day for 3-5 days). What issues do I need to consider when prescribing a corticosteroid? For general prescribing issues see the CKS topic on Corticosteroids - oral. For acute gout, a short course of a moderately high dose of oral prednisolone is recommended (for example prednisolone 30–35 mg once a day for 3-5 days). Intra-articular corticosteroids are not specifically licensed for the treatment of gout. Intramuscular corticosteroids are not specifically licensed for the treatment of gout. A one-off deep intramuscular injection can be used to relieve the symptoms of acute gout. The dose should be individualised and will depend on the severity of the condition. Consult product literature. The British Society of Rheumatology (BSR) recommend joint aspiration and injection of corticosteroid as a highly effective treatment of acute monoarticular gout and state that it may be the treatment of choice in people with acute illness and co-morbidity [Hui, 2017]. The BSR recommend that a short course of oral corticosteroid or single injection of intramuscular corticosteroid can be used in people unable to tolerate NSAIDs or colchicine and where intra-articular injection is not feasible [Hui, 2017]. CKS could find no studies on the optimum dose and duration of oral corticosteroids for gout. The suggested dose of 30-35 mg once a day for 3-5 days is based on a recommendation from the European League Against Rheumatism (EULAR) guideline on the management of gout [Richette, 2017]. A short course of low to moderate dose prednisolone is relatively safe and is likely to have a rapid response in acute gout flare ups [Man et al, 2007]. Historically, lower doses of prednisolone have been used for the treatment of acute gout in UK clinical practice. NICE CKS (accessed May 2022) Allopurinol Start allopurinol after the acute attack has resolved. Start allopurinol at a low dose of 50-100 mg once a day (preferably taken with food), increased by 100 mg increments approximately every 4 weeks until the serum uric acid (SUA) level is below 300 micromol/L. How should I prescribe allopurinol? Start allopurinol after the acute attack has resolved. In circumstances where attacks are so frequent that this is not possible, the initiation of allopurinol can be considered before inflammation has completely settled. Start allopurinol at a low dose of 50-100 mg once a day (preferably taken with food), increased by 100 mg increments approximately every 4 weeks until the serum uric acid (SUA) level is below 300 micromol/L. For people with renal impairment starting dose and titration guidance may differ. See Managing renal impairment. The maximum dose of allopurinol for gout prophylaxis is 900mg daily in divided doses (lower in renal impairment). Allopurinol is usually given once a day. However, doses of over 300 mg per day should be taken in divided doses to help minimize any gastrointestinal adverse effects. Use a reduced dose in elderly people and in those with hepatic impairment: Prescribe an allopurinol starting dose of 50 mg once a day (allopurinol 50 mg tablets are not available, so when providing a 50 mg dose check that the 100 mg tablets are scored). When starting or up-titrating allopurinol, flare prophylaxis using colchicine or an NSAID is recommended - see Gout prevention section. If a gout flare occurs during treatment with allopurinol: Advise that allopurinol should not be discontinued. Manage the flare as appropriate for the person. Reassure the person that continuous treatment with allopurinol will decrease the frequency and intensity of further gout flares. Screening for HLA-B*5801 should be considered before starting treatment with allopurinol in patient subgroups where the prevalence of this allele is known to be high (for example people of Han Chinese, Thai and Korean origin). Information on prescribing allopurinol is based mainly on a guideline produced by expert representatives of the British Society for Rheumatology (BSR) [Hui, 2017] and the Manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2017a; ABPI, 2018a]. How should I manage the adverse effects of allopurinol? There is a risk of precipitating acute attacks of gout after starting allopurinol. Advise people who experience acute attacks of gout after initiation of treatment with allopurinol, or during established treatment, to continue taking allopurinol. Rashes are common and can occur any time after starting allopurinol. Advise people who experience a rash to stop allopurinol immediately and seek prompt medical advice. Rarely, exfoliative rashes such as Stevens Johnsons syndrome (SJS) or toxic epidermal necrolysis (TEN) can occur. A rash can be the first sign of a rare hypersensitivity reaction. If SJS/TEN or a serious hypersensitivity reaction cannot be ruled out, allopurinol should not be re-introduced at any time. If the rash was mild and subsequently resolved, gradually reintroduce the allopurinol. If the rash recurs, immediately discontinue the allopurinol. Somnolence, vertigo, and ataxia have been reported with allopurinol use. Advise that when starting allopurinol, people should be cautious about driving or using machinery until they are reasonably certain that allopurinol does not adversely affect their performance. Since allopurinol and its metabolites are excreted by the kidney, impaired renal function may lead to retention of the drug and/or its metabolites, with consequent prolongation of plasma half-life. People with chronic renal impairment who also take allopurinol may be at increased risk of hypersensitivity reactions. Treatment should be stopped immediately if a hypersensitivity reaction occurs. Overall, adverse effects are rare but their incidence (particularly rashes) is higher in the presence of renal or hepatic impairment. [ABPI Medicines Compendium, 2017a; Hui, 2017] How should I manage the adverse effects of allopurinol? Since allopurinol and its metabolites are excreted by the kidney, impaired renal function may lead to retention of the drug and/or its metabolites, with consequent prolongation of plasma half-life. The target serum uric acid level is the same as for people without renal impairment. However, when adjusting the dose, the maximum allopurinol dose increment should be 50mg. In people with an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73m2 : Prescribe an allopurinol starting dose of 50 mg once a day (allopurinol 50 mg tablets are not available, so when providing a 50 mg dose check that the 100 mg tablets are scored). Increasing the initial dose interval may be required for people with severe renal impairment. Suggested safe starting doses are: eGFR 16-30 mL/min/1.73m2 - 50mg every 2 days. eGFR 5-15 mL/min/1.73m2 - 50mg twice weekly. eGFR less than mL/min/1.73m2 - 50mg per week. Once allopurinol has been started, it is best to check urate levels and renal function every 2–4 weeks for the first 3 months. People with chronic renal impairment who also take allopurinol may be at increased risk of hypersensitivity reactions and other adverse reactions - see adverse reactions. Information on prescribing allopurinol is based mainly on a guideline produced by expert representatives of the British Society for Rheumatology (BSR) [Hui, 2017] and the Manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2017a; ABPI, 2018a] . NICE CKS (accessed May 2022) Febuxostat Consider febuxostat as an alternative second-line therapy if allopurinol is not tolerated or is contraindicated How should I prescribe febuxostat? Consider febuxostat as an alternative second-line therapy if allopurinol is not tolerated or is contraindicated (for example if renal impairment prevents adequate allopurinol dose increases). Prescribers should be aware that a prior history of hypersensitivity to allopurinol and/or renal disease may indicate potential hypersensitivity to febuxostat. Start febuxostat after the acute attack has resolved. Perform liver function tests (LFTs) before starting febuxostat treatment, as mild liver test abnormalities have been observed. Check LFTs periodically thereafter, based on clinical judgement. Prescribe febuxostat at a starting dose of 80 mg once daily. If the serum uric acid (SUA) level is greater than 300 micromol/L after 4 weeks, increase the dose of febuxostat to 120 mg once daily, aiming for a therapeutic target SUA level of below 300 micromol/L. In people with mild hepatic impairment, a maximum dose of 80 mg daily is recommended. There is limited information regarding the use of febuxostat in people with more severe hepatic impairment. No dose adjustment is needed for the elderly, or those with mild or moderate renal impairment. Febuxostat has not been fully evaluated in people with severe renal impairment (creatinine clearance less than 30 ml/min). When starting or up-titrating febuxostat, flare prophylaxis using colchicine or an NSAID is recommended - see Gout prevention section. If a gout flare occurs during treatment with febuxostat: Advise that febuxostat should not be discontinued. Manage the flare as appropriate for the person. Reassure the person that continuous treatment with febuxostat will decrease the frequency and intensity of further gout flares. Avoid febuxostat in people with ischaemic heart disease or heart failure. Information on prescribing febuxostat is based mainly on a guideline produced by expert representatives of the British Society for Rheumatology (BSR) [Hui, 2017], the Technology Appraisal: Febuxostat for the management of hyperuricaemia in people with gout, published by the National Institute for Health and Clinical Excellence [NICE, 2008b] and the Summary of Product Characteristics for Adenuric® film-coated tablets [ABPI, 2017]. The BSR recommend The Summary of Product Characteristics for Adenuric® film-coated tablets and the British National Formulary recommend that a prophylactic nonsteroidal anti-inflammatory drug (NSAID) or colchicine is co-prescribed for at least 6 months when starting febuxostat [ABPI, 2017; BNF 74, 2017]. The BSR advises that prophylaxis with colchicine can be given for up to 6 months [Hui, 2017]. Hepatic impairment The manufacturers recommend that a maximum dose of 80 mg once daily is prescribed to people with mild hepatic impairment [ABPI, 2017]. How should I manage the adverse effects of febuxostat? There is a risk of precipitating acute attacks of gout after starting febuxostat. Advise people who experience acute attacks of gout after initiation of treatment with febuxostat, or during established treatment, to continue taking febuxostat. The most commonly reported adverse effects in clinical trials of febuxostat have been mostly mild or moderate in severity. The most common adverse effects are liver abnormalities, diarrhoea, headache, nausea, and rash. There have been post-marketing reports of rare serious rashes, generalised skin rashes, and severe hypersensitivity reactions occurring mostly during the first month of treatment with febuxostat. Some of the people affected reported previous hypersensitivity to allopurinol. Following on from this, the Medicines and Healthcare products Regulatory Agency have advised that: Febuxostat should be stopped immediately if signs or symptoms of serious hypersensitivity reactions occur; early withdrawal is associated with a better prognosis. If a hypersensitivity reaction occurs with febuxostat, including Stevens-Johnson syndrome, febuxostat must not be re-started at any time. Anyone taking febuxostat should be advised of the signs and symptoms of severe hypersensitivity reactions or Stevens-Johnson syndrome. A prior history of hypersensitivity to allopurinol and/or renal disease may indicate potential hypersensitivity to febuxostat. Somnolence, dizziness, and paresthesia have been reported with febuxostat use. Advise that when starting febuxostat, people should be cautious about driving or using machinery until they are reasonably certain that febuxostat does not adversely affect their performance. [MHRA, 2012; ABPI, 2017] Drug interactions Mercaptopurine and azathioprine. Concomitant use with mercaptopurine or azathioprine is not recommended. The manufacturers SPC details that where this combination cannot be avoided the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose. Inducers of glucuronidation. Potent inducers might possibly lead to increased metabolism and decreased efficacy of febuxostat. Monitoring of serum uric acid is therefore recommended 1-2 weeks after start of treatment with a potent inducer of glucuronidation. These drugs include rifampicin, phenytoin and phenobarbitone. Conversely, cessation of treatment of an inducer might lead to increased plasma levels of febuxostat. [ABPI, 2018b] NICE CKS (accessed May 2022) Paracetamol For prescribing information on paracetamol, see the CKS topic on Analgesia - mild-to-moderate pain. NICE CKS (accessed May 2022) © NICE 2018. Chronic heart failure in adults: diagnosis and management. Available from: nice.org.uk/ng106. All rights reserved. Subject to Notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication. Hide top image Hide NHS image