Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://emc.medicines.org.uk), or the British National Formulary (BNF) (www.bnf.org).

See the CKS topic on NSAIDs - prescribing issues for a detailed discussion on the contraindications, adverse effects, monitoring issues, and interactions of NSAIDs, as this is beyond the scope of this CKS topic.

• Consider comorbidity when prescribing nonsteroidal anti-inflammatory drugs (NSAIDs).
• NSAIDs commonly cause gastrointestinal adverse effects, and can worsen asthma, hypertension, renal impairment, and heart failure.
• In people at risk of cardiovascular adverse events, ibuprofen up to 1200 mg per day or naproxen up to 1000 mg per day are recommended as first-line options.
• For people with gout who are at high risk of gastrointestinal adverse events, CKS recommends using a gastroprotective agent with a standard NSAID. CKS considers that a less preferred alternative option is to use a cyclooxygenase-2 selective NSAID alone.
• For advice on the management of dyspepsia due to NSAIDs, see the CKS topics on Dyspepsia - unidentified cause and Dyspepsia - proven peptic ulcer.

For the treatment of an acute attack of gout, CKS recommends prescribing diclofenac, indometacin, or naproxen.

• Doses recommended are:
• Diclofenac 50 mg three times a day [ABPI Medicines Compendium, 2007c].
• Indometacin 50 mg three or four times a day [Micromedex, 2007].
• Naproxen initially 750 mg (initial dose), then 250 mg every 8 hours [ABPI Medicines Compendium, 2007b].
• If effective, continue the NSAID until 48 hours after the attack has finished (up to 1–2 weeks). As the pain resolves, the dose of the NSAID should be rapidly reduced.

For the prevention of gout (while urate-lowering therapy is initiated), CKS recommends prescribing ibuprofen, diclofenac, or naproxen.

• These NSAIDs are preferred because of their more favourable adverse-effect profiles. Lower doses are widely co-prescribed by physicians when initiating allopurinol treatment, with the aim of preventing a flare of disease. Similar regimes should be considered if starting febuxostat urate-lowering therapy. CKS recommends:
• Ibuprofen 400 mg three times a day.
• Diclofenac 25–50 mg three times a day.
• Naproxen 250 mg three times a day.
• Prophylactic NSAIDs are usually given for up to 3 months when using allopurinol, but may be needed for up to 6 months when using febuxostat [ABPI Medicines Compendium, 2010].

• Diclofenac, naproxen, and indometacin are recommended as preferred choices of nonsteroidal anti-inflammatory drug (NSAID). Diclofenac and naproxen are widely considered to have acceptable adverse-effect profiles [CSM, 2002]. Indometacin has been studied more in gout than any other NSAID, and similar to diclofenac and naproxen, its safety profile is classed as intermediate risk of causing serious gastrointestinal (GI) adverse effects, although it is associated with more GI adverse events than naproxen or diclofenac.
• For the treatment of an acute attack of gout, other NSAIDs may be used but are less preferred:
• Ketoprofen, piroxicam, and sulindac are other standard NSAIDs that are licensed for the treatment of gout, but they are less frequently used and their adverse-effect profiles are probably less favourable than diclofenac or naproxen. Although adverse effects are commonly reported with indometacin, it has been used more that other NSAIDs in trials investigating acute gout.
• Ibuprofen and other standard NSAIDs not listed here are not licensed for the treatment of acute gout.
• Of the cyclooxygenase-2 selective NSAIDs, only etoricoxib is licensed for the treatment of gout and there are trial data to support its effect [Schumacher et al, 2002; Rubin et al, 2004]. Etoricoxib may be associated with a slightly lower rate of gastrointestinal events compared with standard NSAIDs, but there may be a small increased risk of cardiovascular thrombotic events associated with its use [Aldington et al, 2005], and people with gout often have associated cardiovascular morbidity.
• Modified-release NSAIDs offer no benefit in terms of efficacy over standard preparations.
• The recommendation for needing gout flare prophylaxis for at least 6 months when using febuxostat is based on the Summary of Product Characteristics [ABPI Medicines Compendium, 2010].

• Avoid colchicine in people with blood dyscrasias and bone marrow disease [ABPI Medicines Compendium, 2004].
• Ideally colchicine should be avoided in people with poor renal function, poor liver function, gastrointestinal disease, cardiac disease, and the elderly [MHRA, 2009].
• Colchicine has a narrow therapeutic index and is extremely toxic in overdose. These patient groups are at particular risk of toxicity [MHRA, 2009].
• Colchicine is excreted by the kidneys and, in people with renal impairment, there is the potential for accumulation and toxicity [ABPI Medicines Compendium, 2004].
• In overdose, colchicine can cause confusion, reduced cardiac output, cardiac arrhythmias, renal damage, liver damage, respiratory distress, hyperpyrexia, and bone-marrow depression [MHRA, 2009].
• Colchicine is also best avoided in people with severe heart failure as it constricts blood vessels [ABPI Medicines Compendium, 2004].
• In elderly people, who are more prone to dehydration, colchicine is also best avoided because of its relatively high risk of causing diarrhoea [Jordan et al, 2007].
• 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.

• For acute gout:
• The British Society for Rheumatology (BSR) guideline recommends colchicine should be used in doses of 500 micrograms, two to four times a day, until relief of pain is achieved, or diarrhoea or vomiting occurs [Jordan et al, 2007]. Consider using a low starting dose of 500 micrograms twice a day in people with moderate renal impairment.
• A maximum of colchicine 6 mg in total should be used (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 treatment should not be repeated within 3 days.
• The licensed daily dose of colchicine (1 mg followed by 500 micrograms every 2–3 hours, up to a maximum of 6 mg) [ABPI Medicines Compendium, 2004] has been found to commonly cause gastrointestinal adverse effects [Morris et al, 2003], although there may be a faster clinical response than with the dose recommended by the BSR [Jordan et al, 2007].
• For prophylaxis of gout (during urate-lowering treatment):
• The BSR recommends colchicine 500 micrograms twice a day (low-dose) should be given following initiation of long-term treatment with allopurinol (or uricosuric drugs), for up to 6 months [Jordan et al, 2007]. Colchicine 500 micrograms two to three times a day is the licensed dose for prophylaxis. Doses varying from colchicine 500 micrograms once a day to colchicine 500 micrograms three times a day have historically been commonly used [ABPI Medicines Compendium, 2004; Jordan et al, 2007].
• Prophylactic treatment is usually given for up to 3 months when using allopurinol [BNF 53, 2007], but may be needed for at least 6 months when starting febuxostat therapy [ABPI Medicines Compendium, 2010].
• In elderly people, and in people with moderate renal impairment, use colchicine 500 micrograms once a day for prophylaxis of gout.

• Gastrointestinal adverse effects, such as nausea and vomiting, diarrhoea, and abdominal pain, are common with colchicine use, and can be severe enough to limit treatment [ABPI Medicines Compendium, 2004].
• The severity of adverse effects of colchicine is dose dependent.
• Colchicine has a narrow therapeutic index and is extremely toxic in overdose [MHRA, 2009].

• Oral prednisolone should normally be taken as a single dose in the morning to reduce the disturbance to circadian cortisol secretion [BNF 53, 2007].
• People using corticosteroids should be given a 'steroid card' which gives guidance on minimizing risk and provides details of prescriber, drug, dosage, and duration of treatment, if steroids are needed for more than 3 weeks duration [BNF 53, 2007]. Adverse effects are uncommon with occasional short courses of oral corticosteroids. For more information, see the CKS topic on Corticosteroids - oral.
• People that require oral prednisolone for prevention of an acute attack of gout when starting long-term urate-lowering therapy need monitoring for:
• High blood pressure.
• Diabetes mellitus.
• Osteoporosis.
• Administration of an intra-articular corticosteroid may cause atrophy of subcutaneous tissues and local skin depigmentation as a result of corticosteroid peri-articular leakage. The risk is greatest if large or repeated doses of a long-acting, potent corticosteroid are given. See the section on Intra-articular injections for more information.

• For acute gout:
• A short course of a moderately high dose of oral prednisolone is recommended e.g. prednisolone 20–40 mg once a day for 5 days. CKS could find no studies on the optimum dose and duration of oral corticosteroids for gout, and recommendations were pragmatic based on expert opinion. A short course of prednisolone 40 mg or less is relatively safe and is likely to have a rapid response in acute gout flare ups [BNF 53, 2007; Man et al, 2007].
• Historically, lower doses of prednisolone have been used for the treatment of acute gout in UK clinical practice.
• For prophylaxis of gout (during urate-lowering treatment):
• Prednisolone 5–10 mg orally once a day for 4 to 12 weeks is recommended based on the professional opinion of expert reviewers.

• Intramuscular corticosteroids are not specifically licensed for the treatment of gout.
• Triamcinolone acetonide or methylprednisolone can be given as a one-off deep intramuscular injection to relieve the symptoms of gout. In order to avoid the danger of subcutaneous fat atrophy, the corticosteroid should be deeply injected into the gluteal muscle [ABPI Medicines Compendium, 2003; ABPI Medicines Compendium, 2007a].
• The dose depends upon the size of the joint and the severity of the condition.
• For methylprednisolone, doses ranging from 40–120 mg are licensed (although not specifically for use in people with gout).
• For triamcinolone, doses ranging from 40–80 mg are licensed (although not specifically for use in people with gout).

• Intra-articular corticosteroids are not specifically licensed for the treatment of gout.
• Specific corticosteroids are recommended for different joints according to their size. Atrophy of subcutaneous tissues and local skin depigmentation may occur from peri-articular leakage of corticosteroid. The risk is greatest if large or repeated doses of a long-acting, potent corticosteroid are given. In general, for:
• Smaller joints: methylprednisolone or hydrocortisone is recommended.
• Larger joints: methylprednisolone or triamcinolone is recommended.

• Avoid administering intra-articular injections unless the necessary training has been fulfilled and the person feels confident in carrying out the procedure.
• Avoid injecting:
• Prosthetic joints.
• When there is any possibility of sepsis.
• Joints within 3 months of a previous injection.
• Inject with caution if the person is taking anticoagulant medication.

• Intra-articular corticosteroids are not specifically licensed in the treatment of gout.
• The licensed dose of intra-articular injection depends upon the steroid chosen, size of the joint, and the severity of the condition.
• Methylprednisolone: 40–80 mg (1–2 mL) for large joints, 20–40 mg (0.5–1 mL) for medium joints, 10–20 mg (0.25–0.5 mL) for small joints.
• Triamcinolone acetonide: 40 mg (1 mL) for large joints, 20–40 mg (0.5–1 mL) for medium joints.
• Hydrocortisone acetate: 12.5–25 mg (0.5–1 mL) for small joints.

• Allopurinol should not be started until an acute attack of gout has completely subsided, as the drug may precipitate further attacks.
• In most people, allopurinol 100 mg once a day can be started (preferably taken after food) [Jordan et al, 2007]. The dose can then be increased by 50–100 mg increments approximately every 2–3 weeks until a dose of 300 mg is reached, then check the person's serum uric acid (SUA) level and renal function at 3 months.
• Increase doses further to achieve a SUA level below 300 micromol/L. The maintenance dose is often in the region of allopurinol 300 mg a day, but maintenance doses may vary between 100–900 mg a day depending on the severity of the gout, and the dose required to maintain the SUA at an appropriate level.
• Allopurinol is usually given once a day. Doses over 300 mg per day should be taken in divided doses, which will help minimize any gastrointestinal adverse effects.
• It is important that allopurinol dose adjustment is based on:
• SUA levels (i.e. the aim is to achieve a SUA level below 300 micromol/L).
• Renal function (urea and electrolytes).
• Clinical response and how well the allopurinol is tolerated.
• The time it takes serum urate to reach target level will depend on the severity of the gout (takes longer in people with tophi), and the number of joints affected.
• In elderly people, those with frequent attacks, those with renal impairment (glomerular filtration rate less than 60 mL/min), and those with hepatic impairment, it may be safer to start with allopurinol 50 mg a day. See Managing renal impairment for more information. Note: allopurinol 50 mg tablets are not available, so when providing a 50 mg dose, check that the 100 mg tablets are scored for easier dose administration.

[ABPI Medicines Compendium, 2006; Jordan et al, 2007]

• There is a risk of precipitating acute attacks of gout for approximately 12 months after starting allopurinol [Jordan et al, 2007]. People who experience acute attacks of gout after initiation of treatment with allopurinol, or during established treatment, should not stop taking the allopurinol.
• Pruritic maculopapular skin rashes may occur in up to 10% of people who take allopurinol — a rash can be the first sign of a rare hypersensitivity reaction, so advise them to immediately stop the allopurinol if this occurs and to seek medical advice promptly [DynaMed, 2007].
• If the rash was mild and subsequently resolves, gradually reintroduce the allopurinol. If the rash recurs, immediately discontinue the allopurinol.
• When starting on allopurinol, people should be cautious about driving or using machinery until they are reasonably certain that it does not adversely affect performance, as somnolence, vertigo, and ataxia have been reported.
• 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.
• Overall, adverse effects are rare but their incidence (particularly rashes) is higher in the presence of renal impairment [Jordan et al, 2007].

[ABPI Medicines Compendium, 2006]

Febuxostat may be used second-line in people with chronic symptomatic gout who are intolerant of allopurinol, or for whom allopurinol is contraindicated. It should not be started until an acute attack of gout has completely subsided, as the drug may precipitate further attacks.

• The recommended oral dose is febuxostat 80 mg once daily. If the serum uric acid (SUA) level is greater than 360 micromol/L after 2–4 weeks, the dose may be increased to 120 mg once daily, aiming for a therapeutic target SUA level of below 360 micromol/L.
• The febuxostat Summary of Product Characteristics recommends gout flare prophylaxis with a nonsteroidal anti-inflammatory drug or colchicine, for at least 6 months. If a gout flare occurs during treatment with febuxostat, it should not be discontinued. See Recurrent gout for more information.
• Where possible, febuxostat should be avoided in people with ischaemic heart disease, heart failure, or cancer.
• 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 < 30 ml/min).
• Liver function tests (LFTs) should be checked before starting febuxostat treatment, as mild liver test abnormalities have been observed. LFTs should be checked periodically thereafter, based on clinical judgement. In people with mild hepatic impairment, febuxostat 80 mg is recommended. There is limited information regarding the use of febuxostat in people with more severe hepatic impairment, according to the Summary of Product Characteristics.

[NICE, 2008; ABPI Medicines Compendium, 2010]

• There is a risk of precipitating acute attacks of gout for at least 6 months after starting febuxostat. People who experience acute attacks of gout after initiation of treatment, or during established treatment, should not stop 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 (see Prescribing febuxostat), diarrhoea, headache, nausea, and rash.
• When starting febuxostat, people should be cautious about driving or using machinery until they are reasonably certain that it does not adversely affect performance, as somnolence, dizziness, and paraesthesia have been reported.

[ABPI Medicines Compendium, 2010]