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).

• Beta-blockers are contraindicated in people with:
• A history of asthma or bronchospasm.
• Severe bradycardia.
• Second- or third-degree heart block.
• Uncontrolled heart failure.
• Severe hypotension.
• Severe peripheral vascular disease (including intermittent claudication).
• Sick sinus syndrome.
• Cardiogenic shock or phaeochromocytoma (without a concomitant alpha-blocker).
• Beta-blockers can be used in people with chronic obstructive pulmonary disease, but caution should be used if disease is severe.

This information is taken from the manufacturers' Summary of Product Characteristics [ABPI Medicines Compendium, 2007a; ABPI Medicines Compendium, 2007e; ABPI Medicines Compendium, 2008b; ABPI Medicines Compendium, 2010].

History of asthma or bronchospasm

• The Commission on Human Medicines (formerly the Committee on Safety of Medicines) has advised that beta-blockers (including those considered to be cardioselective) should not be given to people with a history of asthma or bronchospasm [CSM, 1996; BNF 57, 2009].

• Atenolol, acebutolol, metoprolol, nadolol, oxprenolol, and propranolol are licensed to treat atrial fibrillation.
• The choice of beta-blocker will usually depend on the person's comorbidities, local recommendations, and cost.
• For people with atrial fibrillation alone, atenolol may be preferred because it may be taken once a day and is less expensive than other beta-blockers.
• For people with hypertension and angina, atenolol or metoprolol may be preferred. For more information, see the CKS topic on Angina.
• For people who have atrial fibrillation and have had a previous myocardial infarction (without heart failure), metoprolol (standard release), propranolol (standard release), or atenolol may be preferred. For more information, see the CKS topic on MI - secondary prevention.
• For people with atrial fibrillation and heart failure, bisoprolol, carvedilol, and nebivolol may be preferred. For more information, see the CKS topic on Heart failure - chronic.

• The National Institute for Health and Clinical Excellence (NICE) does not specify which beta-blocker should be used to treat atrial fibrillation. This recommendation is based on practical advice. The choice of beta-blocker will ultimately depend on the person's comorbidities, local recommendations, and cost.

• Atenolol
• Start with a low dose (25 mg daily).
• The usual maintenance dose is 50–100 mg daily.
• Check pulse and blood pressure 1 week after each dose titration to assess response to treatment.

• These doses are based on information taken from the manufacturers' Summary of Product Characteristics [ABPI Medicines Compendium, 2007e; ABPI Medicines Compendium, 2008b].

• Cold extremities, paraesthesiae, and numbness can occur and are more common in people with peripheral vascular disease. If troublesome, beta-blockers might need to be stopped — this is most likely in people with severe peripheral vascular disease.
• Sleep disturbance or nightmares can occur but are less likely with water-soluble beta-blockers, such as atenolol, because these drugs are less likely to cross the blood–brain barrier.
• Fatigue: an incidence of approximately 18 per 1000 people treated with a beta-blocker has been reported, but in clinical trials, only 0.4% of people stopped taking their beta-blocker for this reason.
• Sexual dysfunction (impotence and loss of libido) occurs in approximately 5 per 1000 people on treatment, leading to discontinuation of treatment in 2 people per 1000 person-years. The person should be directly questioned about whether they are having sexual problems because this adverse effect is often not volunteered owing to embarrassment.
• Depression has been claimed to be an adverse effect of beta-blockers, but a recent meta-analysis found no significant increased risk of depressive symptoms in people taking beta-blockers.
• Warning signs of hypoglycaemia (such as tremor and tachycardia) can be masked by non-selective beta-blockers. A selective beta-blocker is therefore preferred in people with diabetes. Avoid beta-blockers in people who experience frequent hypoglycaemia.

• These recommendations are based on the British National Formulary [BNF 57, 2009], published expert opinion [Ko et al, 2002; Lopez-Sendon et al, 2004], and the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2007e].

• Verapamil and diltiazem
• The combination of a beta-blocker and verapamil should not be prescribed in primary care because bradycardia, asystole, severe hypotension, and heart failure can occur.
• The combination of a beta-blocker and diltiazem should not be prescribed in primary care because bradycardia and atrioventricular (AV) block can occur. Asystole and sudden death have also been reported.
• Combining a beta-blocker with either verapamil or diltiazem may be initiated in secondary care.
• Class I antiarrhythmics (for example quinidine and flecainide)
• The combination of a beta-blocker and a class I antiarrhythmic is not recommended in primary care because bradycardia and myocardial depression can occur. This combination may be initiated in secondary care.
• Class III antiarrhythmics (for example amiodarone)
• The combination of a beta-blocker and amiodarone should be prescribed with caution — monitor pulse and blood pressure and check for signs of worsening heart failure, as there is an increased risk of bradycardia, AV block, and myocardial depression.
• Digoxin
• Concomitant administration of a beta-blocker and digoxin can reduce heart rate and prolong AV conduction time, increasing the risk of AV block and bradycardia — monitor pulse carefully.
• Other drugs that reduce blood pressure (for example angiotensin-converting enzyme inhibitors)
• An additive hypotensive effect may occur — monitor for signs of hypotension (such as dizziness, light-headedness, and confusion).

• These recommendations are based on the manufacturer's Summary of Product Characteristics, and the British National Formulary [ABPI Medicines Compendium, 2007c; ABPI Medicines Compendium, 2007d; ABPI Medicines Compendium, 2010; BNF 57, 2009].

• People with the following conditions should not receive a rate-limiting calcium-channel blocker:
• Heart failure — they may precipitate heart failure.
• Cardiac outflow obstruction (significant aortic stenosis or obstructive hypertrophic cardiomyopathy) — vasodilatation may result in reduced cardiac output.
• High-degree atrioventricular block — verapamil and diltiazem may induce complete atrioventricular block.
• People taking beta-blockers should avoid verapamil and diltiazem. They can be co-prescribed but only on specialist advice.

• These recommendations are based on published expert opinion [Eisenberg et al, 2004; Thadani, 2004] and information published by the product manufacturers [ABPI Medicines Compendium, 2009b; ABPI Medicines Compendium, 2009d].

• Diltiazem (off-label) or verapamil (standard release) may be used to treat atrial fibrillation. Diltiazem is preferred because verapamil causes a negative inotropic effect (decrease in myocardial contractility) and interacts with digoxin.

• This recommendation is based on guidance issued by the National Institute for Health and Clinical Excellence [National Collaborating Centre for Chronic Conditions, 2006].

• Start with a low dose and titrate upwards until atrial fibrillation is controlled.
• Diltiazem (off-label)
• The usual starting dose is 60 mg three times a day (60 mg twice a day in elderly people).
• Maintenance doses range from 60 mg to 180 mg three times a day.
• Once-daily preparations may also be used.
• Verapamil (standard-release)
• The usual starting dose is 40 mg three times a day.
• The maximum dose is 120 mg three times a day.
• Check the person's pulse and blood pressure 1 week after each dose titration to assess response to treatment.

• The dosing information for verapamil is taken from the British National Formulary [BNF 57, 2009].
• Diltiazem is not licensed for treating atrial fibrillation. The recommended doses for diltiazem are based on published US guidelines [Fuster et al, 2006a] and from doses used in clinical trials [Roth et al, 1986; Farshi et al, 1999; Hohnloser et al, 2000].
• CKS expert reviewers agreed with the doses of diltiazem recommended here and suggested that once-daily preparations could be used to improve compliance.

• Verapamil commonly causes constipation.
• Advise the person to eat more fibre (for example fruit, vegetables, cereals, and wholemeal bread), to try to drink at least 12 cups (equivalent to eight glasses or eight mugs) of liquid a day, and to avoid drinks with a high caffeine content because these may make constipation worse.
• Bradycardia can result from taking diltiazem or verapamil.
• Vasodilatory adverse effects (flushing, headaches, and ankle swelling) are less common with rate-limiting calcium-channel blockers than with dihydropyridine calcium-channel blockers and often improve with continued use. Diuretics should not be routinely prescribed to relieve ankle swelling, but they may help if there is marked oedema.

• This information is taken from the manufacturers' Summary of Product Characteristics [ABPI Medicines Compendium, 2007b; ABPI Medicines Compendium, 2008a] and the British National Formulary [BNF 57, 2009].
• The recommendation regarding managing constipation is a pragmatic recommendation based on published expert opinion [Kumar and Hall, 2003; Eisenberg et al, 2004].

• Grapefruit may inhibit the metabolism of verapamil, resulting in increased plasma concentrations which could be clinically important.
• Verapamil should not be used with a beta-blocker because of the risk of reduced cardiac output and heart failure.
• Diltiazem should not be prescribed with a beta-blocker because bradycardia and atrioventricular block can occur. Asystole and sudden death have also been reported.

• This information is taken from: the manufacturers' Summary of Product Characteristics [ABPI Medicines Compendium, 2007b]; Stockley's drug interactions: a source book of interactions, their mechanisms, clinical importance and management [Baxter, 2008]; and the Commission on Human Medicines (formerly the Committee on Safety of Medicines) [CSM, 1997].

• Digoxin should be avoided in people with:
• Some supraventricular arrhythmias, such as Wolff–Parkinson–White syndrome.
• Heart conduction problems, such as intermittent complete heart block or atrioventricular heart block.
• Ventricular tachycardia.
• Hypertrophic obstructive cardiomyopathy.

• These recommendations are taken from information published by the manufacturer [ABPI Medicines Compendium, 2009c].

• Prescribe a loading dose of 250 micrograms to 500 micrograms daily for 1–2 days, followed by a maintenance dose.
• A clinical response is usually seen within 1 week.
• Seek specialist advise for people who are elderly and who have renal impairment. The loading dose of digoxin will need to be reduced.
• The usual maintenance dose is 62.5 micrograms to 250 micrograms daily; this is adjusted according to the heart rate response.
• Check the person's pulse rate and apical rate 1 week after initiation and after any change in dose.

• A more rapid response may be achieved by prescribing 1–1.5 mg in divided doses over 24 hours [BNF 57, 2009], although CKS expert reviewers suggest that usually no more than 1000 micrograms (1 mg) is needed in 24 hours.
• If a more rapid clinical response is required, consider referral to secondary care.

• This information is taken from the British National Formulary [BNF 57, 2009] and the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009c].

• Non-cardiac adverse effects are usually associated with overdose and include:
• Nausea, vomiting, and (less commonly) diarrhoea. Nausea in particular is indicative of overdose.
• Visual abnormalities (blurred or yellow vision).
• Central nervous system effects, such as weakness, dizziness, confusion, apathy, malaise, headache, depression, and psychosis.
• Cardiac adverse effects are usually associated with overdose, although electrolyte imbalances may predispose the person to cardiac adverse effects so that they occur even at therapeutic concentrations. They include various conduction and rhythm disturbances, such as:
• Sinoatrial and atrioventricular block.
• Premature ventricular contractions (resulting in bigeminy or trigeminy).
• PR prolongation and ST-segment depression.

• Digoxin has a narrow therapeutic window — there is only a small range of plasma concentrations between which the drug is ineffective because of underdosing and toxic because of overdosing. Adverse effects usually occur at serum concentrations above the upper limit of the therapeutic window, and they are dose-dependent. If significant adverse effects occur, serum levels of digoxin should be measured.

• This information is taken from the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009c], the British National Formulary [BNF 57, 2009], and published expert opinion [European Society of Cardiology, 2008].

• Digoxin has a narrow therapeutic window, and measurement of serum levels may be considered in the following instances:
• Shortly after initiation, to check that drug levels are in the correct therapeutic range (not standard practice).
• When there is a dose change.
• When there are adverse effects suggestive of overdosing.
• When there are factors that may affect digoxin serum levels, such as use of a concomitant drug that affects digoxin serum levels, or deteriorating renal function.
• When noncompliance is suspected.
• The therapeutic range of digoxin is between 0.7 nanograms/mL and 2.0 nanograms/mL.
• Blood samples should be taken at least 6 hours after the previous dose, but ideally 8–12 hours afterwards.
• Monitoring should be performed several days after the last dose change.
• The likelihood of toxicity depends on the serum concentration of digoxin.
• Levels less than 1.5 nanograms/mL in the absence of hypokalaemia indicate that digoxin toxicity is unlikely.
• Levels greater than 3.0 nanograms/mL indicate that digoxin toxicity is likely.
• With levels between 1.5 nanograms/mL and 3.0 nanograms/mL, digoxin toxicity should be considered a possibility.
• In addition, blood chemistry measurements (electrolytes, urea, and creatinine) should be done at least annually. These tests will often be done routinely, as renal function is likely to be monitored owing to the use of nephrotoxic drugs (such as diuretics and drugs affecting the renin-angiotensin system).

• These recommendations are taken from the National Institute of Health and Clinical Excellence guidance Chronic heart failure: management of chronic heart failure in adults in primary and secondary care [NICE, 2003].

• Beta-blockers
• Concomitant administration of a beta-blocker and digoxin can reduce heart rate and prolong atrioventricular (AV) conduction time, increasing the risk of AV block and bradycardia — monitor pulse carefully.
• An increase in plasma digoxin levels has been noted with carvedilol — monitor for signs of digoxin toxicity (confusion, anorexia, nausea, and disturbance of colour vision) when starting, adjusting, or stopping carvedilol.
• Calcium-channel blockers
• The plasma concentration of digoxin is increased by diltiazem and verapamil and possibly by nifedipine — monitor for signs and symptoms of toxicity.
• There is an increased risk of AV block and bradycardia with verapamil.
• Amiodarone
• The plasma concentration of digoxin is increased by amiodarone — halve the dose of digoxin and monitor for signs and symptoms of toxicity.
• Antimicrobials
• The plasma concentration of digoxin is increased by itraconazole, macrolide antibiotics, tetracycline, and trimethoprim — monitor for signs and symptoms of toxicity.
• St John's wort
• The plasma concentration of digoxin may be reduced by St John's wort — advise people taking digoxin that they should not use St John's wort, and that they should check with their pharmacist before using any other over-the-counter medications.

• These recommendations are based on guidance on heart failure published by the National Institute for Health and Clinical Excellence [NICE, 2003]; the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009c]; and Stockley's drug interactions: a source book of interactions, their mechanisms, clinical importance and management [Baxter, 2008].

• See the CKS topic on Anticoagulation - oral for a detailed discussion on how to initiate warfarin, how to monitor people who take warfarin, and for other prescribing information on warfarin.

• See the CKS topic on Antiplatelet treatment for a detailed discussion on the medicines management of aspirin.

• Amiodarone is usually initiated in secondary care. Primary care practitioners may be expected to continue prescribing amiodarone and monitor the person for adverse effects (depending on locally agreed shared care guidelines).
• The usual maintenance dose is 200 mg daily, or less if appropriate.

• This information is taken from the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009a].

• Amiodarone is always initiated in secondary care, where the following baseline assessments are performed:
• Thyroid function tests.
• Liver function tests.
• Serum electrolyte and urea measurement.
• Chest radiography.
• Electrocardiography.
• Regular monitoring is required for the following:
• Thyroid function tests — every 6 months and for 12 months after discontinuation.
• Seek specialist advice if thyroid function tests are abnormal.
• Liver function tests — every 6 months.
• Serum electrolyte and urea measurement — every 6 months.
• Electrocardiography — every 12 months.
• The manufacturer recommends annual eye examinations; however, expert opinion suggests that these are only necessary for people with visual symptoms.
• Regular monitoring may be performed in primary or secondary care (depending on locally agreed shared care guidelines).

These recommendations are based on published expert opinion [Vanderpump et al, 1996; DTB, 2003; BTA et al, 2006; London and South East Medicines Information Service et al, 2008] and the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009a].

• Eye examinations
• This recommendation is based on published expert opinion [DTB, 2003].

• Nausea, vomiting, and taste disturbance commonly occur with loading doses but resolve with dose reduction.
• Pulmonary toxicity
• Pulmonary toxicity may present as dyspnoea (which may be severe and unexplained by the current cardiac status), non-productive cough, and deterioration in general health (fatigue, weight loss, and fever). If pulmonary toxicity is suspected, seek immediate specialist advice; the person may require admission.
• Thyroid dysfunction
• Approximately 4% of people taking maintenance doses of amiodarone may develop hypothyroidism or hyperthyroidism. People taking amiodarone should have their thyroid function checked every 6 months. If thyroid function tests are abnormal, seek specialist advice.
• Hepatotoxicity
• An asymptomatic increase in liver function test values is common in people taking amiodarone. Persistent elevation of liver function test values greater than 2 to 3 times the upper limit of normal (or twice previously elevated levels) occurs in 1.2% of people taking maintenance doses of amiodarone. Hepatotoxicity is rare, and death caused by severe hepatotoxicity is rarer still. Liver function should be monitored evey 6 months, and treatment with amiodarone should be stopped if severe liver function abnormalities or clinical signs of liver disease (for example jaundice) develop.
• Cardiac toxicity
• Maintenance doses of amiodarone may cause dose-dependent sinus bradycardia and conduction disturbances.
• Visual disturbances
• Most people develop corneal microdeposits; these rarely interfere with vision, but drivers may be dazzled by headlights at night. If vision is impaired or if optic neuritis (very rare) or neuropathy occurs, amiodarone must be stopped, to prevent blindness, and expert opinion sought. The manufacturer recommends annual eye examinations; however, expert opinion suggests that these are only necessary for people with visual symptoms.
• Neurological symptoms
• Amiodarone has been associated with neurological symptoms, such as tremor, ataxia, and (rarely) peripheral neuropathy. These are usually seen with loading doses and improve when maintenance treatment is started. Peripheral neuropathy may occur in people who have been taking amiodarone for a long time.
• Skin toxicity
• A blue-grey skin discolouration has been reported in approximately 2% of people taking amiodarone. This discolouration occurs in unprotected light-exposed skin and is slowly (and occasionally incompletely) reversible after stopping amiodarone.
• Advise the person to:
• Shield their skin from light during treatment and for several months after stopping treatment.
• Use a wide spectrum sunscreen with a sun protection factor of at least 30 (for example Uvistat^® or Sunsense^® Ultra).

• These recommendations are based on information taken from the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009a], published expert opinion [DTB, 2003], the British National Formulary [BNF 57, 2009], and an evidence database [Micromedex, 2009].

• Beta-blockers
• Only specialists should co-prescribe beta-blockers and amiodarone. Hypotension, bradycardia, ventricular fibrillation, and asystole have been seen in a few people given amiodarone with propranolol, metoprolol, or sotalol.
• Calcium-channel blockers
• Amiodarone should be avoided or used with caution with diltiazem or verapamil because cardiac depression can occur.
• Drugs that prolong the QT interval
• Only specialists should co-prescribe drugs that prolong the QT interval. This is because of the risk of additive effects, which may lead to serious and potentially life-threatening torsades de pointes arrhythmias. Examples of drugs that are known to have a high risk of causing QT prolongation include:
• Antiarrhythmics, such as sotalol, disopyramide, and quinidine.
• Antihistamines, such as astemizole.
• Antipsychotics, such as amisulpride, haloperidol, and droperidol.
• Simvastatin
• Rarely, myopathy and rhabdomyolysis have been reported in people taking amiodarone with high doses of simvastatin. The dose of simvastatin should not exceed 20 mg each day in people taking amiodarone unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.
• Warfarin
• The anticoagulant effects of warfarin are increased by amiodarone. The onset of this interaction may be slow (up to 2 weeks), with the peak effect occurring about 7 weeks after warfarin treatment is started. The dose of warfarin should be reduced by one-third to two-thirds if amiodarone is added. The international normalized ratio should be monitored once a week for the first 7 weeks of concurrent treatment.
• Digoxin
• Amiodarone increases levels of digoxin because of reduced renal digoxin clearance. The dose of digoxin should be reduced by half, and concentrations of digoxin should be monitored closely in view of potential toxicity.
• Grapefruit
• People taking amiodarone should not eat grapefruit or drink grapefruit juice. Grapefruit appears to completely inhibit the metabolism of amiodarone to its major active metabolite.

Amiodarone has a long half-life (25–100 days); thus, interactions may occur for some time after drug withdrawal.

• These recommendations are based on Stockley's drug interactions: a source book of interactions, their mechanisms, clinical importance and management [Baxter, 2008] and published expert opinion [DTB, 2003].

• Sotalol is usually initiated and titrated up to an appropriate dose in secondary care. A primary care practitioner may be expected to continue prescribing sotalol and monitor for adverse effects.
• The usual maintenance dose of sotalol is 80 mg to 160 mg twice a day [BNF 57, 2009].

• Sotalol may aggravate a preexisting arrhythmia or provoke a new arrhythmia and may cause torsades de pointes. Women may be at increased risk of torsades de pointes. In addition, sotalol may cause similar adverse effects to those of other beta-blockers:
• Cold extremities, paraesthesiae, and numbness can occur and are more common in people with peripheral vascular disease. If troublesome, beta-blockers might need to be stopped — this is most likely in people with severe peripheral vascular disease.
• Sleep disturbance or nightmares can occur but are less likely with water-soluble beta-blockers such as atenolol, because these drugs are less likely to cross the blood–brain barrier.
• Fatigue: an incidence of approximately 18 per 1000 people treated with a beta-blocker has been reported, but in clinical trials, only 0.4% of people stopped taking their beta-blocker for this reason.
• Sexual dysfunction (impotence and loss of libido) occurs in approximately 5 per 1000 people on treatment, leading to discontinuation of treatment in 2 people per 1000 person-years. The person should be directly questioned about whether they are having sexual problems because this adverse effect is often not volunteered owing to embarrassment.
• Depression has been claimed to be an adverse effect of beta-blockers, but a recent meta-analysis found no significant increased risk of depressive symptoms in people taking beta-blockers.
• Warning signs of hypoglycaemia (such as tremor and tachycardia) can be masked by non-selective beta-blockers. A selective beta-blocker is therefore preferred in people with diabetes. Avoid beta-blockers in people who experience frequent hypoglycaemia.

[ABPI Medicines Compendium, 2007e]

• Sotalol prolongs the QT interval, and only specialists should co-prescribe drugs that prolong the QT interval. This is because of the risk of additive effects, which may lead to serious and potentially life-threatening torsades de pointes arrhythmias. Examples of drugs that are known to have a high risk of causing QT prolongation include:
• Antiarrhythmics, such as amiodarone, disopyramide, and quinidine.
• Antipsychotics, such as amisulpride, haloperidol, and droperidol.
• Antibiotics, such as erythromycin and clarithromycin.
• In addition, sotalol may interact with other drugs (in common with other beta-blockers).
• Verapamil and diltiazem
• The combination of a beta-blocker and verapamil should not be prescribed in primary care because bradycardia, asystole, severe hypotension, and heart failure can occur.
• The combination of a beta-blocker and diltiazem should not be prescribed in primary care because bradycardia and atrioventricular block can occur. Asystole and sudden death have also been reported.
• Combining a beta-blocker with either verapamil or diltiazem may be initiated in secondary care.
• Class I antiarrhythmics (for example quinidine and flecainide)
• The combination of a beta-blocker and a class I antiarrhythmic is not recommended in primary care because bradycardia and myocardial depression can occur. This combination may be initiated in secondary care.
• Class III antiarrhythmics (for example amiodarone)
• The combination of a beta-blocker and amiodarone should be prescribed with caution — monitor pulse and blood pressure and check for signs of worsening heart failure, as there is an increased risk of bradycardia, atrioventricular (AV) block, and myocardial depression.
• Digoxin
• Concomitant administration of a beta-blocker and digoxin can reduce heart rate and prolong AV conduction time, increasing the risk of AV block and bradycardia — monitor pulse carefully.
• Other drugs that reduce blood pressure (for example angiotensin-converting enzyme inhibitors)
• An additive hypotensive effect may occur — monitor for signs of hypotension (such as dizziness, light-headedness, and confusion).

These recommendations are based on the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2007c; ABPI Medicines Compendium, 2007d; ABPI Medicines Compendium, 2007e; ABPI Medicines Compendium, 2010] and the British National Formulary [BNF 57, 2009].