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.
• Beta-blockers can be used in people with chronic obstructive pulmonary disease, but caution should be used if disease is severe.
• Second- or third-degree heart block (in the absence of a permanent pacemaker).
• Sick sinus syndrome.
• Sinus bradycardia (heart rate less than 50 beats per minute at the start of treatment).
• Severe hypotension.
• Severe peripheral arterial disease (pain at rest and sometimes intermittent claudication) — the blood pressure-lowering properties of beta-blockers can exacerbate symptoms.
• Uncontrolled heart failure.
• Seek specialist advice before starting a beta-blocker in people with a current or recent exacerbation of heart failure.

This information is taken from the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2008b; ABPI Medicines Compendium, 2008c; ABPI Medicines Compendium, 2008d; ABPI Medicines Compendium, 2009a].

History of asthma or bronchospasm

• The Commission on Human Medicines (formerly the Committee on Safety of Medicines) and the Medicines and Healthcare products Regulatory Agency have advised that beta-blockers (including those considered to be cardioselective) should not be given to people with a history of asthma or bronchospasm.
• Beta-blockers can be used in people with chronic obstructive pulmonary disease, but caution should be used if disease is severe.

[CSM, 1996; BNF 57, 2009]

• CKS recommends atenolol, bisoprolol, or metoprolol as first-choice beta-blockers for the management of angina.
• The following beta-blockers are licensed for the treatment of angina: propranolol, acebutolol, atenolol, bisoprolol, carvedilol, metoprolol, nadolol, oxprenolol, pindolol, and timolol.
• For people who have had a previous myocardial infarction, metoprolol (standard release), propranolol (standard release), timolol, or atenolol may be preferred.
• For more information, see the CKS topic on MI - secondary prevention.
• For people with angina and heart failure, bisoprolol, carvedilol, or nebivolol may be preferred.
• For more information, see the CKS topic on Heart failure - chronic.

• There is no good evidence that any one beta-blocker is better than any other in the management of stable angina. The efficacy of beta-blockers is thought to be due to a class effect rather than the effects of individual drugs, and such factors as comorbidity, compliance, and cost should be considered when selecting a beta-blocker. Occasionally, an individual may respond better to one beta-blocker than another.
• Atenolol, bisoprolol, and metoprolol are licensed for the treatment of angina, and they are widely recommended for the management of stable angina [Fox et al, 2006a; SIGN, 2007].
• Atenolol, bisoprolol, and metoprolol are cardioselective and do not exhibit intrinsic sympathomimetic activity [BNF 57, 2009].
• Cardioselective beta-blockers may be preferred because of advantages in terms of adverse effects and precautions compared with non-selective beta-blockers.
• Beta-blockers with intrinsic sympathomimetic activity may be less cardioprotective than those without intrinsic sympathomimetic activity.

[Fox et al, 2006a]

• Titrate the dose of beta-blocker to the target dose (or maximum tolerated dose), according to the person's response and heart rate control (at rest and during exercise).
• Recommended target doses are:
• Atenolol 100 mg once a day or 50 mg twice a day (twice-daily dosing may provide better symptom control).
• Bisoprolol 10 mg once a day.
• Metoprolol 100 mg three times a day (standard-release) or 200 mg once a day (modified-release).

• Recommended doses of beta-blockers are from guidelines from the European Society of Cardiology and the Scottish Intercollegiate Guidelines Network [Fox et al, 2006a; SIGN, 2007], and the British National Formulary [BNF 57, 2009].

• Cold extremities, paraesthesiae, and numbness can occur, and beta-blockers can worsen symptoms in people with peripheral vascular disease. This effect is less pronounced with cardioselective beta-blockers (such as atenolol, bisoprolol, and metoprolol) [Lopez-Sendon et al, 2004].
• 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 [Lopez-Sendon et al, 2004].
• Fatigue: an incidence of approximately 18 per 1000 people per year treated with a beta-blocker has been reported, but in clinical trials, only 4 per 1000 people per year stopped taking their beta-blocker for this reason [Ko et al, 2002].
• Sexual dysfunction (impotence and loss of libido) occurs in approximately 5 per 1000 people treated with a beta-blocker for one year, leading to discontinuation of treatment in 2 per 1000 people treated with a beta-blocker for one year [Ko et al, 2002]. 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 meta-analysis found no significant increased risk of depressive symptoms in people taking beta-blockers [Ko et al, 2002].
• Warning signs of hypoglycaemia (such as tremor and tachycardia) can be masked by non-selective beta-blockers. A cardioselective beta-blocker is therefore preferred in people with diabetes [Lopez-Sendon et al, 2004].

• Verapamil and diltiazem
• The combination of a beta-blocker and verapamil must not be prescribed because bradycardia, asystole, severe hypotension, and heart failure can occur.
• The combination of a beta-blocker and diltiazem should only be prescribed on specialist advice.
• Class I antiarrhythmics (such as quinidine, disopyramide, flecainide, lidocaine)
• The combination of a beta-blocker and a class I antiarrhythmic is not recommended because bradycardia and myocardial depression can occur.
• 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. Amiodarone should not be initiated in primary care unless on specialist advice.
• 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.
• Other drugs that reduce blood pressure
• An additive hypotensive effect may occur — monitor for signs of hypotension (such as dizziness, light-headedness, and confusion).

[Baxter, 2008; BNF 57, 2009]

• Rate-limiting calcium-channel blockers (verapamil and diltiazem) are contraindicated in people with:
• Heart failure.
• Bradycardia or atrioventricular block.
• Cardiac outflow obstruction (significant aortic stenosis or obstructive hypertrophic cardiomyopathy): vasodilatation may result in reduced cardiac output.
• Dihydropyridine calcium-channel blockers should not be started in people with uncontrolled heart failure (but amlodipine and felodipine can be used if heart failure is stable).

These recommendations are based on information in the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009d; ABPI Medicines Compendium, 2009e] and on expert opinion in published reviews [Eisenberg et al, 2004; Thadani, 2004].

Heart failure

• All calcium-channel blockers (CCBs) can precipitate heart failure in people with heart failure because of their negative inotropic effects [Eisenberg et al, 2004].
• Verapamil and diltiazem should not be used in people with heart failure.
• Dihydropyridines rarely aggravate heart failure (any negative inotropic effect is offset by a reduction in left ventricular work). However, they should not be started in people with uncontrolled heart failure.

Cardiac outflow obstruction (significant aortic stenosis or obstructive hypertrophic cardiomyopathy)

• Vasodilatation may result in reduced cardiac output. Although people with hypertrophic cardiomyopathy may benefit from treatment with verapamil or diltiazem (by reducing obstruction), CCBs should only be initiated by a cardiologist in people with left ventricular outflow obstruction.

High-degree atrioventricular block

• Verapamil and diltiazem may induce complete atrioventricular block [Thadani, 2004].

• Monotherapy (when a beta-blocker is contraindicated or not tolerated): expert opinion suggests using a rate-limiting calcium-channel blocker (CCB) (diltiazem or verapamil) in preference to a dihydropyridine CCB. Reasons for this include [Fox et al, 2006a]:
• Rate-limiting CCBs, such as verapamil and diltiazem, have the additional action of decreasing myocardial contractility and heart rate.
• Dihydropyridine CCBs can sometimes cause reflex tachycardia, which may increase angina symptoms, although this is more likely to be a problem with short-acting dihydropyridines than with longer-acting preparations.
• Combination therapy
• People taking a beta-blocker: prescribe a dihydropyridine CCB (amlodipine, felodipine, or modified-release nifedipine).
• People not taking a beta-blocker: a rate-limiting CCB may be preferred (see above).
• If the person has concomitant heart failure: prescribe a amlodipine or felodipine.

Rate-limiting calcium-channel blockers (CCBs)

• Rate-limiting CCBs (verapamil and diltiazem) may be preferred as monotherapy in people who cannot take a beta-blocker because these drugs also reduce myocardial contractility, heart rate, and atrioventricular node conduction [Fox et al, 2006a; SIGN, 2007].
• Verapamil is contraindicated in combination with a beta-blocker; diltiazem should only be combined with a beta-blocker on the advice of a cardiologist (see Drug interactions for more information).
• Rate-limiting CCBs are contraindicated in people with heart failure (see Cautions and contraindications for more information).

Dihydropyridines

• Long-acting dihydropyridines (such as amlodipine) or modified-release formulations of short-acting CCBs (such as nifedipine or felodipine) should be used to minimize fluctuations of plasma concentrations and increased cardiovascular effects [Eisenberg et al, 2004; Fox et al, 2006a].
• There is conflicting evidence on the safety of nifedipine in people with angina. A meta-analysis suggests that nifedipine monotherapy or short-acting nifedipine in combination with other drugs for angina may increase the risk of cardiovascular events [Stason et al, 1999].

• Vasodilatory adverse effects (facial flushing, headaches, postural hypotension, and ankle swelling) may occur; they are more common with dihydropyridine calcium-channel blockers (CCBs) than rate-limiting CCBs [Fox et al, 2006a; BNF 57, 2009].
• Vasodilatory effects usually reduce in severity with continued treatment, although ankle swelling often persists.
• Diuretics should not be routinely prescribed for ankle oedema, as they only partially reduce ankle oedema caused by CCBs.
• Verapamil commonly causes constipation [Kumar and Hall, 2003; Eisenberg et al, 2004].
• Advise the person to eat more fibre (such as 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 can make constipation worse).

• Beta-blockers
• The combination of a beta-blocker and verapamil should not be prescribed because bradycardia, asystole, severe hypotension, and heart failure can occur.
• The combination of a beta-blocker and diltiazem should only be prescribed on specialist advice.
• Digoxin
• Verapamil increases the plasma concentration of digoxin by up to 80% over 2 weeks; therefore, reduce the digoxin dose by one-third to one-half and monitor digoxin concentrations.
• Diltiazem may increase the plasma concentration of digoxin and dosage reductions may be necessary, although there are also reports of cases where no interaction was experienced.
• Grapefruit
• Grapefruit inhibits the metabolism of calcium-channel blockers (other than amlodipine and diltiazem), resulting in increased plasma concentrations that could be clinically important [CSM, 1997].

[Baxter, 2008; BNF 57, 2009]

• Nitrates should be used with caution in people with:
• Left ventricular outflow obstruction (significant aortic stenosis or obstructive hypertrophic cardiomyopathy) because vasodilatation can result in reduced cardiac output.
• Closed-angle glaucoma, which can be precipitated by nitrates.
• The combination of a nitrate and a phosphodiesterase inhibitor (sildenafil, tadalafil, or vardenafil) is contraindicated (see Drug interactions for more information) [Baxter, 2008].

[BNF 57, 2009; Micromedex, 2009]

• Short-acting, sublingual glyceryl trinitrate (GTN) should be used for immediate relief of an episode of angina, or before activities that are likely to precipitate angina.
• Long-acting oral nitrates should be used regularly to decrease the frequency and severity of anginal symptoms.
• Isosorbide mononitrate is generally preferred to isosorbide dinitrate.

These recommendations are consistent with guidelines from the European Cardiovascular Society and the Scottish Intercollegiate Guidelines Network [Fox et al, 2006a; SIGN, 2007].

• Isosorbide mononitrate may be preferred over isosorbide dinitrate because a wider variety of mononitrate preparations is available and dinitrate requires more frequent dosing, which may be less convenient.

• Standard-release nitrate preparations: use an asymmetric dosing interval to minimize nitrate tolerance.
• For mononitrate preparations, this can be achieved with twice-daily dosing, for example at 8 a.m. and 3 p.m., or 2 p.m. and 10 p.m.
• For dinitrate preparations, dosing may be more complicated because dinitrate requires more frequent administration than mononitrate.
• Modified-release nitrate preparations: use a once-daily dose to maintain a nitrate-low period and thus minimize tolerance.
• Modified-release preparations are significantly more expensive than standard-release preparations, but they may be useful for people who find it difficult to comply with an asymmetric dosing regimen.

These recommendations are consistent with guidelines from the European Society of Cardiology and the Scottish Intercollegiate Guidelines Network [Fox et al, 2006a; SIGN, 2007], and the British National Formulary [BNF 57, 2009].

• Nitrate tolerance quickly develops if nitrates are given continuously over 24 hours, and their anti-anginal effects are then reduced. Tolerance can be minimized or avoided by means of a daily nitrate-free or nitrate-low period. However, this has been associated with rebound myocardial ischaemia and adverse effects on performance during the nitrate-free period [Liu et al, 2005].
• Compliance to treatment has been shown to improve in people who have switched from multiple-daily to once-daily dose regimens [SIGN, 2007].

• Transient hypotension that manifests as dizziness, weakness, and palpitations has been reported with isosorbide mononitrate. Hypotension often presents as postural hypotension occurring shortly after drug administration.
• Headache occurs in more than 60% of people receiving glyceryl trinitrate (GTN) and 25–40% of people receiving isosorbide dinitrate or mononitrate. In addition, GTN may precipitate a migraine headache in people with a history of migraine.
• Tolerance to headache usually occurs over 1–2 weeks, although 10–20% of people cannot tolerate nitrates because of headache.
• To minimize the risk of headache, start at a low dose (for example 10 mg twice a day) and titrate up.
• Burning, stinging, or tingling of the mouth is experienced by some people taking sublingual GTN tablets.
• If this is bothersome, consider using a lower dose of GTN tablets, or a GTN sublingual spray.

[Micromedex, 2009]

• The concurrent use of phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil) with nitrates is contraindicated. This combination can produce excessive hypotension and possibly precipitate myocardial infarction.
• A nitrate should not be given for at least 24 hours after the last dose of sildenafil or vardenafil, and for at least 48 hours after the last dose of tadalafil.
• Sildenafil and vardenafil should not be used for at least 24 hours after the last dose of a nitrate, and tadalafil should not be used for at least 48 hours after the last dose of a nitrate.
• Advise people with angina who are taking a phosphodiesterase inhibitor that they must not use glyceryl trinitrate if they have an episode of angina during sexual intercourse. Advise them to stop sexual activity and, if their pain does not resolve, they should call for an ambulance.

[ABPI Medicines Compendium, 2008a; Baxter, 2008; ABPI Medicines Compendium, 2009b; ABPI Medicines Compendium, 2009f]

• Instruct the person in the correct use of their sublingual glyceryl trinitrate (GTN), and what to do if their angina attack does not respond to sublingual GTN [Fox et al, 2006a].
• Key points for discussion include:
• Why GTN has been prescribed (it helps the heart work better, but it is not a painkiller).
• How to use the spray or tablets.
• When to use GTN to treat chest pain and to prevent pain if it can be precipitated.
• Likely adverse effects.
• What to do if pain persists after two doses or beyond 15 minutes.
• The short shelf-life of GTN tablets once opened (8 weeks), and how to obtain further supplies.

• Nicorandil is contraindicated in people with:
• Left ventricular failure.
• Hypotension.
• The concomitant use of nicorandil and a phosphodiesterase inhibitor (sildenafil, tadalafil, or vardenafil) is contraindicated (see Drug interactions for more information).

[ABPI Medicines Compendium, 2009c]

• Headache is the most common adverse effect, occurring in 22–48% of people taking nicorandil.
• Headache is usually seen during the first 2 weeks of treatment; it is dose related and tends to diminish with continued use.
• Careful dose titration can reduce the incidence of headache and the number of people who stop treatment because of it.
• Hypotension has been occasionally reported with nicorandil, especially after high starting doses. However, long-term treatment of stable angina with oral nicorandil has not been associated with significant changes in blood pressure or heart rate.
• Hypotension can be minimized by careful dose titration.

[Micromedex, 2009]

• Gastrointestinal ulceration (including aphthous ulcers and anal ulceration) has been reported with nicorandil. Advice from the Medicines and Healthcare products Regulatory Agency states that [MHRA, 2008]:
• GPs and other healthcare professionals should consider nicorandil treatment as a possible cause in people who present with symptoms of gastrointestinal ulceration.
• Ulcers that result from nicorandil are usually refractory to treatment; they respond only to withdrawal of nicorandil.
• Nicorandil withdrawal should take place only under the supervision of a cardiologist.

• The concomitant use of nicorandil and a phosphodiesterase inhibitor (sildenafil, tadalafil, or vardenafil) is contraindicated.

• The concomitant use of nitrates and phosphodiesterase inhibitors can cause potentially serious hypotension and may precipitate myocardial infarction. Nicorandil is expected to interact in the same way as nitrates.

[Baxter, 2008]

• Advise people taking nicorandil that they should not drive or operate machinery until it is established that nicorandil does not impair their performance [ABPI Medicines Compendium, 2009c].
• Advise the person that if they develop symptoms suggestive of gastrointestinal ulceration, they should seek medical advice. Although these adverse effects are rare, they are frequently missed.

• Ivabradine is contraindicated in:
• Acute myocardial infarction or unstable angina.
• Severe hypotension (blood pressure less than 90/50 mmHg).
• Heart failure (New York Heart Association class III or IV).
• Sino-atrial block or 3rd degree AV-block.
• Severe hepatic insufficiency.
• Ivabradine should not be started in anyone with a resting heart rate less than 60 beats per minute.
• Ivabradine is contraindicated in women who are pregnant or breastfeeding because data are lacking to support its use in these women.

[ABPI Medicines Compendium, 2010]

• Visual disturbances, including luminous phenomena (phosphenes) and blurred vision, have been commonly reported in people taking ivabradine.
• Luminous phenomena occur in about 15% of people taking ivabradine, usually starting within the first 2 months of treatment and resolving either on continued treatment or on stopping treatment.
• In one long-term study, four people (1%) withdrew because of visual adverse effects [López-Bescós et al, 2007].
• People taking ivabradine should be advised to be careful when driving or using machines at times when there could be sudden changes in light intensity (especially when driving at night) if they experience luminous phenomena [Servier Laboratories Limited, 2009].
• Bradycardia is noted in about 4% of people taking ivabradine. Monitor heart rate closely within the first 2–3 months of treatment.
• If heart rate decreases below 50 beats per minute at rest or the person experiences symptoms related to bradycardia such as dizziness, fatigue, or hypotension reduce the dose.
• If heart rate less than 50 beats per minute or symptoms of bradycardia persist, stop treatment with ivabradine.
• Headache is a common adverse effect experienced by people taking ivabradine. This is usually transient and resolves within the first month of treatment.

[ABPI Medicines Compendium, 2010]

• CYP3A4 enzyme inhibitors (such as azole antifungals, macrolide antibiotics, and protease inhibitors) should not be given concomitantly with ivabradine. Concomitant administration of a CYP3A4 enzyme inhibitor may increase the plasma concentration of ivabradine, increasing the risk of bradycardia.
• Drugs which prolong the QT interval (such as quinidine, amiodarone, and erythromycin) should not be given concomitantly with ivabradine. QT prolongation may be exacerbated by the heart rate reduction experienced with ivabradine.
• Grapefruit can increase the plasma concentration of ivabradine up to two-fold. People should be advised not to eat grapefruit or drink grapefruit juice whilst taking ivabradine.
• Rate-limiting calcium-channel blockers: concomitant use of ivabradine with verapamil or diltiazem is not recommended, because it can result in excessive reduction of heart rate.

[ABPI Medicines Compendium, 2010]