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).

• People who have true hypersensitivity to aspirin should avoid it — rash and bronchospasm are the principal symptoms of hypersensitivity.
• Aspirin is contraindicated in people with active peptic ulceration and those with haemophilia or other bleeding disorders.
• People who can not tolerate aspirin (e.g. they develop severe dyspepsia or have a history of aspirin-induced ulcers) should usually continue to take aspirin with the addition of a proton pump inhibitor.
• Seek specialist advice before initiating aspirin for antithrombotic treatment in a woman who is pregnant or breastfeeding.

[BNF 56, 2008]

• Although the risk of gastrointestinal complications is less with low-dose aspirin than with regular use of other nonsteroidal anti-inflammatory drugs (NSAIDs) at standard doses, it seems reasonable to assume that risk factors for NSAID-induced complications also apply to low-dose aspirin.
• Factors likely to be the most strongly associated with a risk of serious gastrointestinal adverse effects from the use of low-dose aspirin include:
• History of upper gastrointestinal bleeding — consensus suggests that this is probably the most important risk factor [Hawkey and Lanas, 2001].
• History of peptic ulcer disease (even if Helicobacter pylori was not initially present or was subsequently eradicated).
• Taking concomitant drugs known to increase the likelihood of upper gastrointestinal events (e.g. NSAIDs or corticosteroids) [CSM, 2002; CSM, 2003].

• People with severe dyspepsia or a history or aspirin-induced ulcers: aspirin can usually be continued, with the addition of a proton pump inhibitor:
• See the CKS topics on Dyspepsia - unidentified cause and Dyspepsia - proven peptic ulcer for further information.
• People with true hypersensitivity to aspirin (e.g. rash, bronchospasm): switch to clopidogrel.

• Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) with low-dose aspirin should be avoided where possible, because concomitant use increases the risk of gastrointestinal adverse effects and bleeding:
• Do not stop aspirin; cardiovascular protection should take precedence.
• Consider using paracetamol with or without codeine in place of an NSAID.
• If an NSAID is necessary, consider using gastroprotection with a proton pump inhibitor [MacDonald and Wei, 2003; NICE, 2005b].
• For further information on the management of people requiring low-dose aspirin and NSAIDs, see the CKS topic on NSAIDs - prescribing issues.
• Aspirin should be avoided in people taking methotrexate, if possible, as the excretion of methotrexate is reduced and risk of toxicity is increased.
• All antiplatelet drugs should be avoided in people taking anticoagulants, as the risk of bleeding and haemorrhage is increased.

• Do not prescribe clopidogrel for:
• People with severe liver impairment.
• People with active pathological bleeding, such as peptic ulcer or intracranial haemorrhage.
• Women who are breastfeeding.

[ABPI Medicines Compendium, 2007a]

• Clopidogrel should be used with caution in:
• People who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions and in people receiving treatment with aspirin, nonsteroidal anti-inflammatory drugs (including cyclo-oxygenase-2 inhibitors), heparin, or glycoprotein IIb/IIIa inhibitors:
• Monitor for any signs of bleeding, including occult bleeding, especially during the first weeks of treatment and after invasive cardiac procedures or surgery.
• The concomitant administration of clopidogrel with warfarin is not recommended because it may increase the intensity of bleeding.
• People with renal impairment.
• People with moderate hepatic disease who may have bleeding diatheses.
• If the person is awaiting elective surgery which does not require an antiplatelet effect:
• Withhold clopidogrel therapy for 7 days before surgery.
• Advise people prescribed clopidogrel:
• To be aware that clopidogrel can increase bleeding time.
• To report any unusual bleeding (site or duration).
• To inform their dentist or any other relevant healthcare professionals before any surgery is scheduled.

• These recommendations are based on those issued by the manufacturer of clopidogrel [ABPI Medicines Compendium, 2007a].
• Because clinical data are limited, the manufacturer advises caution when using clopidogrel in people with renal impairment or moderate hepatic disease who may have bleeding diatheses.

• Avoid the concomitant use of clopidogrel and warfarin as this may increase the intensity of bleeding.
• Risk of bleeding is increased when clopidogrel is combined with:
• Aspirin.
• Nonsteroidal anti-inflammatory drugs: increased risk of gastrointestinal bleeding.
• Other drugs known to increase bleeding (e.g. glycoprotein IIb/IIIa inhibitors, heparin, and thrombolytics).

[ABPI Medicines Compendium, 2007a]

• Bleeding is the most common reaction (reported in post-marketing experience) and was mostly reported during the first month of treatment:
• There have been some reported cases with fatal outcome (especially intracranial, gastrointestinal, and retroperitoneal haemorrhage).
• Serious cases of skin bleeding (purpura), musculoskeletal bleeding (haemarthrosis, haematoma), eye bleeding (conjunctival, ocular, retinal), epistaxis, respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), haematuria, and haemorrhage of operative wounds have also been reported.
• Cases of serious haemorrhage have been reported in people taking clopidogrel concomitantly with aspirin or clopidogrel with aspirin and heparin.
• Common adverse effects listed by the manufacturer of clopidogrel are diarrhoea, abdominal pain, and dyspepsia.
• Clopidogrel is known to cause pruritus and urticaria, but these adverse reactions are generally uncommon.

[Aronson, 2006a; ABPI Medicines Compendium, 2007a]

• Modified-release capsules of dipyridamole (200 mg) are marketed as a single agent (Persantin Retard^®) or in combination with 25 mg aspirin (Asasantin Retard^®).
• Of the two formulations, Persantin Retard^® is preferred because aspirin can be prescribed separately at a dose appropriate to the cardiovascular risk of the individual.
• The immediate-release tablet formulation is not licensed for the secondary prevention of ischaemic stroke and transient ischaemic attacks.

• The modified-release formulation is recommended by the National Institute for Health and Clinical Excellence (NICE) because evidence supports its use for the secondary prevention of ischaemic stroke and transient ischaemic attacks (see the CKS topic on Antiplatelet treatment) [NICE, 2005a].
• Both modified-release formulations are licensed for these indications [ABPI Medicines Compendium, 2007b; ABPI Medicines Compendium, 2008b]:
• NICE does not recommended one product over another.
• Of the two, CKS prefers Persantin Retard^® because:
• The dose of aspirin (25 mg twice daily) in Asasantin Retard^® is lower than the standard dose of aspirin used for secondary prevention (typically 75 mg). For reducing vascular events in high-risk people, the evidence for the benefits of using an aspirin dose of less than 75 mg daily have been less widely assessed [Antithrombotic Trialists' Collaboration, 2002].
• By prescribing dipyridamole modified-release capsules separately, the aspirin can be prescribed at a dose appropriate to the cardiovascular risk of the individual (e.g. 75 mg or more).
• NICE does not recommend the immediate-release tablet formulation, as it is not licensed for the secondary prevention of ischaemic stroke and transient ischaemic attacks.

• There are no specific contraindications for dipyridamole (apart from hypersensitivity).
• Prescribers should be aware that Asasantin Retard^® contains both dipyridamole and aspirin. Because of its aspirin content, this product is contraindicated in people with active gastric or duodenal ulcers, or bleeding disorders.

[ABPI Medicines Compendium, 2007c]

• Because of its activity as a vasodilator, dipyridamole should be used with caution in people with:
• Severe coronary artery disease, including unstable angina or recent myocardial infarction.
• Left ventricular outflow obstruction.
• Haemodynamic instability (e.g. decompensated heart failure).

[ABPI Medicines Compendium, 2007c]

• Cholinesterase inhibitors:
• Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis.
• Evidence is sparse. However, dipyridamole should be used with caution in people with myasthenia gravis, as there is a case report of dipyridamole increasing myasthenic symptoms [Baxter, 2008].
• Antihypertensive drugs:
• Because of its vasodilating activity, the manufacturer of dipyridamole (Persantin Retard^®) warns that the drug may increase the hypotensive effect of antihypertensive drugs.
• Dipyridamole does not appear to interact with warfarin:
• The manufacturer of Persantin Retard^® reported that bleeding was no greater in frequency or severity than that observed when warfarin was administered alone.

[ABPI Medicines Compendium, 2007b]

• Vomiting, diarrhoea, and such symptoms as dizziness, nausea, headaches, dyspepsia, and myalgia have been observed for dipyridamole:
• These tend to occur early after initiating treatment and may disappear with continued treatment.
• Headache was the most commonly reported adverse effect for people treated with dipyridamole in the European Stroke Prevention Study-2 (n = 6602) [Diener et al, 1996]:
• Headache and gastrointestinal adverse effects were major reasons for early discontinuation of treatment in people receiving a dipyridamole-containing regimen.
• Because of its vasodilating properties, dipyridamole may cause hypotension, hot flushes, and tachycardia:
• It may lead to worsening of the symptoms of coronary heart disease, such as angina and arrhythmias.
• Other adverse effects reported are:
• Increased bleeding during or after surgery (very rare).
• Thrombocytopenia (isolated case reports).

[ABPI Medicines Compendium, 2007b]

• Five proton pump inhibitors (PPIs) are currently available in the UK: esomeprazole (an isomer of omeprazole), lansoprazole, omeprazole, pantoprazole, and rabeprazole:
• Differences among the PPIs in terms of clinical efficacy and safety are minimal [Aronson, 2006b; MeReC, 2006].
• Of the five PPIs available, lansoprazole and omeprazole are preferred because they are both available generically and are considerably less expensive than other PPIs.
• When prescribing a PPI for people on low-dose aspirin who are at high risk of gastrointestinal adverse effects or who continue to have dyspepsia:
• Offer a dose licensed for gastroprotection, for example:
• For lansoprazole: 15 mg once daily (if necessary, increasing to 30 mg daily).
• For omeprazole: 20 mg once daily.
• PPIs are generally well tolerated, and adverse reactions have generally been mild and reversible.
• The type and frequency of adverse effects reported with lansoprazole, omeprazole, pantoprazole, and rabeprazole are similar. The most common adverse effects include headache, diarrhoea, nausea, abdominal pain, constipation, dizziness, and rash.
• Drug interactions:
• PPIs undergo extensive hepatic metabolism. In people with liver disease, do not exceed 20 mg daily for omeprazole, pantoprazole, and esomeprazole and 30 mg daily for lansoprazole. There are no data on the use of rabeprazole in people with severe hepatic impairment, and the manufacturer advises caution.
• Occasional and unpredictable bleeding have been reported with warfarin and certain proton pump inhibitors (esomeprazole, omeprazole, and lansoprazole). The interaction is not thought to occur with rabeprazole or pantoprazole [Baxter, 2006].
• There are case reports of omeprazole, esomeprazole, and lansoprazole interacting with phenytoin (causing an increase in phenytoin level). The mechanism is not well understood, and information is very limited. No special precautions would normally seem necessary if lansoprazole or omeprazole is given with phenytoin, but prescribers should be aware of this possible interaction if concurrent use is necessary. Pantoprazole and rabeprazole appear not to interact with warfarin [Baxter, 2006].
• Because of decreased intragastric acidity, the absorption of ketoconazole or itraconazole may be reduced during PPI treatment.
• PPIs can significantly reduce the efficacy of clopidogrel by inhibition of the CYP2C19 isoenzyme. The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that concomitant use of clopidogrel and any PPI should be avoided unless considered essential [MHRA, 2009].

[Aronson, 2006b; ABPI Medicines Compendium, 2008a]