Previous changes

March 2025 — minor update. Interaction with DOACs added to the prescribing information for diltiazem. 

December 2023 — minor update. Adverse effect of lupus-like syndrome added and also non-cardiogenic pulmonary oedema in overdose for people prescribed diltiazem in line with an update to the manufacturer's SPC.

June 2023 — minor update. Information that nitrates should be prescribed with caution in people with hypoxaemia due to severe anaemia has been added to the prescribing information section of this topic. 

October 2022 — minor update. The text relating to contraindications and cautions for nitrates has been clarified.

January 2022 — minor update. QT-interval prolongation and elevated creatinine levels have been added as uncommon adverse effects of ivabradine.

April to June 2021 — reviewed. A literature search was conducted in April 2021 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. No major changes to the recommendations have been made.

April 2021 — minor update. Adverse effects of nicorandil updated in line with revised manufacturer's SPC. 

November 2020 — minor update. Myoclonus added as an adverse effect of ranolazine in line with updated manufacturer's SPC.

June 2020 — minor update. Adverse reactions for diltiazem added in line with updated manufacturer's SPC.

October 2019 — minor update. The contraindications and cautions section for calcium-channel blockers was updated to clarify that verapamil and diltiazem are contraindicated for people with atrial fibrillation and flutter associated with accessory conducting pathways (for example, Wolff-Parkinson-White-syndrome).

January 2018 — minor update. Revised SPC for Istin (amlodipine) 5 and 10mg tablets. Drug interactions updated as per the revised SPC.

October 2017 — minor update. NSAIDs added as a potential drug interaction with nicorandil. 

January to February 2017 — reviewed. A literature search was conducted in January 2017 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of the topic.  

December 2016 — minor updates.

• The adverse effects, contraindications and interactions for isosorbide mononitrate have been updated in line with the manufacturer's Summary of Product Characteristics.
• The contraindications and interactions for verapamil and diltiazem have been updated in line with the manufacturers' Summary of Product Characteristics.
• Sinus arrest, and cardiac arrest (asystole) have been added as possible adverse effects of diltiazem in line with the manufacturers' Summary of Product Characteristics.
• Medicines and Healthcare products Regulatory Agency (MHRA) advice about the risk of ulcer complications with nicorandil has been updated and clarified.

November 2016 — minor update. The adverse effects of ranolazine have been updated in line with the manufacturer's Summary of Product Characteristics.

October 2015 — minor update. The information on beta blockers in the Prescribing information section, has been re-worded to reflect advice from the manufacturers' Summary of Product Characteristics, in relation to the cautions and contraindications of beta blockers if the person has a form of obstructive airways disease.

June 2015 — minor update. Based on updates to the manufacturers' Summaries of Product Characteristics (SPCs):

• Contraindications to the use of ivabradine have been updated to include people younger than 18 years of age.
• Information on the potential drug interaction of diltiazem and amlodipine with grapefruit and grapefruit juice has been added to the topic.

February 2015 — minor update. The text has been updated to reflect recently published guidance by the Medicines and Healthcare products Regulatory Agency (MHRA) on ivabradine.

September 2014 — minor update. An additional adverse effect for ivabradine has been added.

July 2013 — minor update. Links to the DVLA website have been updated.

June 2013 — minor update. The 2013 QOF options for local implementation have been added to this topic.

January 2013 — minor update. Removed the black triangle status from ivabradine as this is no longer a black triangle drug.

May 2012 — reviewed. This topic has been updated to reflect the National Institute for Health and Care Excellence (NICE) clinical guideline, Management of Stable Angina.

March 2012 — minor update. The 2012/2013 QOF indicators have been added to this topic.

March 2011 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.

March 2011 — minor update. Diagnostic sections and information on referral of suspected angina amended to be consistent with the National Institute for Health and Care Excellence (NICE) guideline Chest pain of recent onset: assessment and diagnosis of recent onset chest pain or discomfort of suspected cardiac origin.

October 2010 — minor update. Text amended to include advice about flying for people with angina, based on the British Heart Foundation (BHF) Factfile, Fitness to fly for passengers with cardiovascular disease, which is derived from the British Cardiovascular Society Working Group's expert guidance.

January 2010 — minor update. Ivabradine is now licensed for use in combination with a beta-blocker in people who are inadequately controlled with an optimal beta-blocker dose and whose heart rate is greater than 60 beats per minute. The recommendations regarding people with poor control on existing treatment have been updated.

April to September 2009 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence. The anti-anginal drug ivabradine has been added as an alternative to a calcium-channel blocker, a nitrate, or nicorandil in people who cannot take a beta-blocker.

May 2009 — minor update. The section on GMS quality indicators in the Goals and outcome measure section has been renamed QOF indicators. 

July 2008 — minor update to the text for nicorandil to reflect recently published drug safety information on nicorandil from the MHRA.

April to September 2006 — reviewed. Validated in September 2006 (update validated in December 2006). Issued in January 2007.

November 2005 — minor update. Reference made to the CKS topic on Antiplatelet treatment, which outlines gastrointestinal issues that need to be considered in the prescribing of low-dose aspirin for the prevention of cardiovascular events. 

November 2002 — reviewed and updated to incorporate the Scottish Intercollegiate Guidelines Network (SIGN) guideline on the Management of Stable Angina (2001). Validated in March 2003 and issued in April 2003.

December 2000 — updated to incorporate the National Service Framework for Coronary Heart Disease (2000) chapter on angina. 

May 1999 — reviewed, in particular taking into account the updated North of England evidence-based guidelines on the management of stable angina (unpublished 1999 update).

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 June 2021.

HTAs (Health Technology Assessments)

No new HTAs since 1 June 2021.

Economic appraisals

No new economic appraisals relevant to England since 1 June 2021.

Systematic reviews and meta-analyses

No new systematic reviews or meta-analysis which reach the CKS threshold for inclusion since 1 June 2021.

Primary evidence

No new primary evidence which reaches the CKS threshold for inclusion published since 1 June 2021.

New policies

No new national policies or guidelines since 1 June 2021.

New safety alerts

No new safety alerts since 1 June 2021.

Changes in product availability

• New product Xytencorg (propranolol) 10 mg Orodispersible tablets. This new orodispersible formulation of propranolol, also available in a 40mg strength, is licensed for treatment of hypertension, angina, MI, cardiomyopathy, dysrhythmias, thyrotoxicosis, essential tremor, anxiety, and prophylaxis of upper GI bleeding and migraine. See more here.

Basis for recommendation

The recommendations on assessing stable chest pain are based on expert opinion in the National Institute for Health and Care Excellence (NICE) guideline Chest pain of recent onset: assessment and diagnosis [NICE, 2016a].

Basis for recommendation

The recommendations on confirming a diagnosis of stable angina are based expert opinion in the National Institute for Health and Care Excellence (NICE) guideline Chest pain of recent onset: assessment and diagnosis [NICE, 2016a].

Basis for recommendation

The recommendations on how to manage people waiting for diagnostic testing are based on the National Institute for Health and Care Excellence (NICE) guidelines Stable angina: management [NICE, 2016b] and Chest pain of recent onset: assessment and diagnosis [NICE, 2016a].

• The recommendation to prescribe sublingual glyceryl trinitrate (GTN) is based on the assumption that the working diagnosis of angina is correct, and is considered by CKS to be good clinical practice.

Use of sublingual glyceryl trinitrate

• NICE recommends calling an ambulance if a second dose of GTN does not relieve angina symptoms within 5 minutes. However, the manufacturers of Nitrolingual Pump Spray^® [ABPI, 2019a] and glyceryl trinitrate tablets [ABPI, 2019b] recommend seeking prompt medical attention if symptoms are not relieved after three doses. 

What information and support should I provide for a person with stable angina?

• Provide information and support for people with newly diagnosed angina.
  • Clearly explain the diagnosis of stable angina to the person. The explanation should include:
    • Factors which can provoke angina, such as exertion, emotional stress, exposure to cold, or eating a large meal.
    • The long-term progression and prognosis of angina.
    • Information on how angina is managed.
  • Encourage the person to ask questions about their angina and its management.
  • Explore and address any misconceptions the person might have about their angina. This includes:
    • Implications for daily activities.
    • Risk of myocardial infarction.
    • Life expectancy.
  • Advise the person to seek medical help if there is a sudden worsening in the frequency or severity of their angina.
  • Discuss the reasons for treatment, as well as the benefits and adverse effects (such as flushing, headache, and light-headedness). For more information, see the section on Prescribing information.
    • Provide information on how to use a short-acting sublingual nitrate and when to administer it. 
  • Assess the person's need for lifestyle advice to manage their cardiovascular risk.
  • Explore and address issues according to the person's needs, which may include:
    • Self-management skills such as pacing their activities and goal setting.
    • Concerns about the impact of stress, anxiety, or depression on angina.
    • Advice about physical exertion including sexual activity.
    • Advice about other activities such as driving, flying, and work.
  • Advise people that the aim of anti-anginal drug treatment is to prevent episodes of angina and the aim of secondary prevention treatment is to prevent cardiovascular events such as heart attack and stroke.

What drug treatments should I prescribe for a person with stable angina?

• Drug treatment for symptom relief:
  • Prescribe sublingual glyceryl trinitrate (GTN) for the rapid relief of symptoms of angina and for use before performing activities known to cause symptoms of angina.
  • Instruct the person that if they experience chest pain they should:
    • Stop what they are doing and rest.
    • Use their glyceryl trinitrate spray or tablets as instructed.
    • Take a second dose after 5 minutes if the pain has not eased.
    • Call 999 for an ambulance if the pain has not eased 5 minutes after the second dose, or earlier if the pain is intensifying or the person is unwell.
  • Prescribe a beta-blocker or a calcium-channel blocker (CCB) as first-line regular treatment to reduce the symptoms of stable angina, depending on the person's comorbidities, contraindications, and preference. 
    • If the person cannot tolerate the beta-blocker or calcium-channel blocker, consider switching to the other option (calcium-channel blocker or beta-blocker).
  • If both beta-blockers and CCBs are contraindicated or not tolerated, consider monotherapy with one of the following drugs. Decide which drug to use based on comorbidities, contraindications, the person's preference, and cost:
    • A long-acting nitrate (such as isosorbide mononitrate).
    • Nicorandil.
    • Ivabradine.
    • Ranolazine.
  • Review response to treatment, including any adverse effects, 2–4 weeks after starting or changing drug treatment.
    • Titrate the dose against symptoms, where necessary up to the maximum licensed or tolerated dose.
    • If there is a poor response to treatment, see the scenario Poor control on treatment.
• Drug treatment for secondary prevention:
  • Consider antiplatelet treatment in all people with stable angina, taking into account the person's risk of bleeding and comorbidities.
    • For most people this will be low-dose aspirin (75 mg daily) — people with stroke or peripheral arterial disease should already be taking clopidogrel rather than aspirin, and should continue taking clopidogrel.
    • For information on antiplatelet prophylaxis, including advice on what to do if the person is allergic to aspirin or is at risk of gastrointestinal adverse effects, see the CKS topic on Antiplatelet treatment.
  • Consider treatment with an angiotensin-converting enzyme (ACE) inhibitor for people with stable angina and diabetes mellitus.
    • Ensure that people with coexisting hypertension, heart failure, asymptomatic left ventricular dysfunction, chronic kidney disease, or previous myocardial infarction have been prescribed an ACE inhibitor in line with current guidance unless this is contraindicated or not tolerated.
    • For more information, see the CKS topics on Chronic kidney disease, Diabetes - type 1, Diabetes - type 2, Heart failure - chronic, Hypertension, and MI - secondary prevention.
  • Offer a statin. For further information see the CKS topic on Lipid modification - CVD prevention.
  • Offer antihypertensive treatment. For more information, see the CKS topic on Hypertension.

When should I refer a person with newly diagnosed angina?

• Consider hospital admission for people with the following symptoms, as they may have unstable angina:
  • Pain at rest (which may occur at night).
  • Pain on minimal exertion.
  • Angina that seems to be progressing rapidly despite increasing medical treatment.
• Indications for early referral to a cardiologist include:
  • Previous myocardial infarction, coronary artery bypass graft, or percutaneous transluminal coronary angioplasty and development of angina.
  • ECG (electrocardiographic) evidence of previous myocardial infarction or other significant abnormality.
  • Newly diagnosed atrial fibrillation and angina.
  • Heart failure and angina.
  • An ejection systolic murmur suggesting aortic stenosis.
  • Any suggestion of hypertrophic cardiomyopathy (for example by family history, physical examination, or ECG).
• Further reasons to refer people to a cardiologist include:
  • Doubt about the diagnosis.
  • The presence of several risk factors or a strong family history.
  • The person's preference for referral.

How should I manage the cardiovascular risk in a person with angina?

All people with angina are assumed to be at high risk for cardiovascular events, and their cardiovascular risk factors should be managed accordingly.

• Optimize the management of comorbid conditions that present an increased risk of cardiovascular events, such as Atrial fibrillation, Chronic kidney disease, Diabetes - type 1, Diabetes - type 2, Heart failure - chronic, Hypertension, Obesity, Rheumatoid arthritis, and Stroke and TIA.
• Advise and assist all people who smoke to stop. For more information, see the CKS topic on Smoking cessation.
• Encourage people to eat a cardioprotective diet. For more information, see the section on Secondary prevention in the CKS topic on MI - secondary prevention.
  • Do not offer vitamin or fish oil supplements to treat stable angina — inform people that there is no evidence that they help stable angina.
• Offer advice and support to achieve and maintain a healthy weight to people who are overweight or obese. For more information, see the CKS topic on Obesity.
• Encourage people to increase their physical activity levels within the limits set by their symptoms. For more information on the recommended levels of physical activity for cardiovascular protection, see the section on Lifestyle advice in the CKS topic on CVD risk assessment and management.
• Encourage people to limit their alcohol consumption.
  • Advise men and women to limit their alcohol intake to 14 units a week and to spread this evenly over 3 days or more. 
  • For more information, see the CKS topic on Alcohol - problem drinking.

What advice should I give about work?

• Advise people with angina that:
  • Many people with angina can continue to work as before.
  • If their job involves heavy manual work, they may need to alter their work practices.
  • If their job involves driving, they should consult the Driver and Vehicle Licensing Agency (DVLA).
• If the person's employer has an occupational health department, they should be encouraged to discuss any issues with them.
• Further information is available from the British Heart Foundation (BHF) which produces the booklets Returning to work with a heart condition and Angina.

What advice should I give about driving?

• Advise the person that it is their responsibility to inform the Driver and Vehicle Licensing Agency (DVLA) of any condition that may affect their ability to drive.
• The DVLA's medical rules regarding angina are:
  • For group 1 entitlement (cars, motorcycles):
    • Driving must cease when symptoms occur at rest, with emotion, or whilst driving.
    • Driving may recommence when satisfactory symptom control is achieved.
    • The DVLA need not be notified.
  • For group 2 entitlement (lorries, buses):
    • The person must not drive and must notify the DVLA when symptoms occur.
    • Refusal or revocation of a driver's licence may occur if symptoms (treated or untreated) continue.
    • Re-licensing may be permitted thereafter, provided that the person has been free from angina for at least 6 weeks, exercise or other functional test requirements can be met, and there is no other disqualifying condition.
• The person should check with their insurer to ensure that their insurance cover is appropriate with a diagnosis of angina.

What advice should I give about sexual activity?

• Advise the person that many people with angina continue sexual intercourse, and that it is just as safe as other equally energetic forms of exercise.
• If sexual activity does precipitate an episode of angina, sublingual glyceryl trinitrate (GTN) taken immediately before intercourse may help prevent subsequent attacks.
• The concomitant use of nitrates or nicorandil with phosphodiesterase inhibitors (avanafil, sildenafil, vardenafil, and tadalafil), often used in the treatment of erectile dysfunction, is generally contraindicated.
• Where concurrent use is considered to be medically essential, advise people who take a phosphodiesterase inhibitor that:
  • There should be at least 12 hours between a dose of avanafil and a nitrate, 24 hours between a dose of sildenafil and a nitrate, and 48 hours between a dose of tadalafil and a nitrate. Concurrent use of nitrates and vardenafil is contraindicated.
  • If they have an episode of angina during sexual intercourse, they must not use glyceryl trinitrate (GTN). They should stop sexual activity and, if their pain does not resolve within 10 minutes, they should call 999 for an ambulance.

What advice should I give about air travel?

• Give the person the following advice depending on the severity of their angina symptoms:
  • Chest pain on considerable exertion with no recent change in symptoms or medication — no restriction on air travel.
  • Chest pain on minimal exertion with no recent change of symptoms or medication — consider airport assistance and possible in-flight oxygen.
  • Chest pain at rest or a change in symptoms and/or medication — defer travel until stable, or travel with a medical escort and ensure in-flight oxygen is available.

How should I review a person with established angina?

• Review the person every 6 months to 1 year depending on the stability of their angina and their comorbidities.
• Check for ongoing symptoms of angina (at rest or with exercise):
  • If the person is taking anti-anginal treatment but has persistent symptoms, see Scenario: Poor control on treatment for advice on further treatment and referral.
• Assess cardiovascular disease risk and identify any modifiable cardiovascular risk factors.
  • For information on cardiovascular risk factors, see Managing cardiovascular risk.
• Check for any complications of angina or treatment:
  • Check the person's heart rate and blood pressure.
  • Check for signs and symptoms of heart failure (for example breathlessness, fatigue, or ankle swelling). For more information, see the CKS topic on Heart failure - chronic. 
  • Screen for low mood or depression. For more information, see the CKS topic on Depression.
• Review the person's medication.
  • If the person is taking treatment for symptom control, ensure that they are taking a beta-blocker or a calcium-channel blocker (unless both are contraindicated or not tolerated).
  • Ensure that the person is taking drugs for secondary prevention as appropriate.
  • See Drug treatments in Scenario: New diagnosis for further information.
  • Check compliance, and identify and manage drug interactions and complications of treatment.
  • Reiterate how to use glyceryl trinitrate for rapid relief of symptoms (see Drug treatments in Scenario: New diagnosis).
• Provide information and advice on angina.
  • Provide written information and advice (if this has not already been given) about:
    • Managing cardiovascular risk.
    • Physical exertion, including sexual activity.
    • Driving. 
    • Air travel.
    • Work.
  • Explain when to seek further medical advice (such as worsening symptoms).

When should I refer a person with established angina?

• If the person has poorly controlled angina symptoms, see the Scenario: Poor control on treatment.
• If the person's symptoms are satisfactorily controlled on optimal treatment, consider referral for functional or non-invasive anatomical testing to identify whether they are at high risk, and might benefit from revascularization.
  • Functional or non-invasive anatomical testing may have already been done as part of diagnosis, and additional investigations may not be necessary.
• The decision to refer should be made with the person, once the prognosis without revascularization, the likelihood of left main stem disease, or proximal three-vessel disease has been explained, as well as the benefits and risks of the procedure.

How should I manage a person with uncontrolled angina symptoms?

People on monotherapy

• Ensure that the person is taking the maximum licensed or highest tolerated dose.
• If the person is taking a beta-blocker:
  • Switch to, or add, a long-acting dihydropyridine calcium-channel blocker (CCB), such as amlodipine, modified-release nifedipine, or modified-release felodipine.
    • Do not combine a beta-blocker with a rate-limiting CCB (diltiazem or verapamil), as severe bradycardia and heart failure can occur.
  • If a dihydropyridine CCB is contraindicated or not tolerated, consider adding a nitrate, nicorandil, ivabradine (if their heart rate is 70 beats per minute or more), or ranolazine (consider seeking specialist advice when initiating ivabradine or ranolazine).
    • If ivabradine has been initiated and the person's angina symptoms do not improve, or there is limited improvement after 3 months, seek specialist advice. Treatment is usually discontinued.
• If the person is taking a CCB:
  • Switch to or add a beta-blocker.
    • Do not combine a beta-blocker with a rate-limiting CCB (diltiazem or verapamil) as severe bradycardia and heart failure can occur.
  • If a beta-blocker is contraindicated or not tolerated, consider adding a nitrate, nicorandil, ivabradine, or ranolazine (consider seeking specialist advice when initiating ivabradine or ranolazine).
    • Do not combine ivabradine with a rate-limiting CCB because it can result in excessive bradycardia.

People on dual therapy

• Ensure that the person is taking the maximum licensed or highest tolerated dose of each drug.
• If symptom control is poor on the maximum licensed or tolerated doses of two drugs, refer to a cardiologist (for assessment for revascularization).
  • Consider starting a third anti-anginal drug whilst waiting for specialist assessment.

When should I refer a person with uncontrolled angina symptoms?

• Consider hospital admission for people presenting with the following symptoms, as they may have unstable angina:
  • Pain at rest (which may occur at night).
  • Pain on minimal exertion.
  • Angina that seems to be progressing rapidly despite increasing medical treatment.
• Refer to a cardiologist for angiography (and possible revascularization) if:
  • The person has evidence of extensive ischaemia on ECG (electrocardiograph).
  • Angina persists despite optimal drug treatment (maximum therapeutic doses of two drugs) and lifestyle interventions.

Choice of nitrate

• Short-acting, sublingual glyceryl trinitrate (GTN) should be offered 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. They are used:
  • In monotherapy if both of the usual first-line options (beta-blockers and calcium-channel blockers) are contraindicated and/or not tolerated.
  • As adjunctive treatment when beta-blocker or calcium-channel blocker monotherapy does not result in adequate control of symptoms and the other first-line option for adjunctive treatment (calcium-channel blocker or beta-blocker) is contraindicated or not tolerated.
  • As a possible adjunctive treatment for people whose symptoms remain uncontrolled despite dual therapy with a beta-blocker and a calcium-channel blocker. 

[NICE, 2016b; SIGN, 2018b]

Dose and formulation

Short-acting sublingual nitrates

• Glyceryl trinitrate tablets — one tablet at the onset of an attack, or prior to a precipitating event. 
  • A second tablet can be taken after 5 minutes if the pain has not eased. 
  • An ambulance should be called if the pain has not eased 5 minutes after the second dose, or earlier if the pain is intensifying or the person is unwell.
• Glyceryl trinitrate spray — one or two 400 microgram metered doses sprayed under the tongue at the onset of an attack, or prior to a precipitating event.
  • A second dose of sublingual trinitrate can be taken after 5 minutes if the pain has not eased. 
  • An ambulance should be called if the pain has not eased 5 minutes after the second dose, or earlier if the pain is intensifying or the person is unwell.

Long-acting nitrates

• Standard-release nitrate preparations: use an asymmetric dosing interval to maintain a daily nitrate-free time of 10–14 hours to minimize development of nitrate tolerance. 
  • Isosorbide mononitrate dose —10 mg twice daily to 120 mg daily in divided doses.
  • Isosorbide dinitrate dose — 30–120 mg daily in divided doses. 
• Modified-release nitrate preparations: use a once-daily dose to maintain a nitrate-low period and thus minimize tolerance.
  • Isosorbide mononitrate dose — 25–120 mg once daily depending on the product prescibed. 
    • Note: modified-release preparations are more expensive than standard-release preparations, but they may be useful for people who find it difficult to comply with an asymmetric dosing regimen.

For further details on titration of doses and dosing for specific products, please see the British National Formulary.

[NICE, 2016b; BNF, 2021]

Contraindications and cautions

• Nitrates should not be used in people with:
  • Acute myocardial infarction (MI) with low filling pressure, acute circulatory failure, (shock, vascular collapse), or very low blood pressure.
  • Hypertrophic obstructive cardiomyopathy (HOCM), constrictive pericarditis, cardiac tamponade, low cardiac filling pressures, or aortic/mitral valve stenosis. 
  • Diseases associated with a raised intracranial pressure (for example following a head trauma, including cerebral haemorrhage).
  • Severe anaemia.
  • Closed-angle glaucoma.
  • Severe hypotension, or hypovolaemia.
• Nitrates should be used with caution in people with:
  • A recent history of MI or low filling pressures.
  • Hypothyroidism. 
  • Hypothermia.
  • Hypoxaemia due to severe anaemia.
  • Malnutrition.
  • Severe liver disease.
  • Chronic kidney disease.
  • Impaired left ventricular function.
  • Susceptibility to closed-angle glaucoma (which can be precipitated by nitrates). 

[ABPI, 2020a; BNF, 2021; Micromedex, 2021]

Adverse effects

• Transient hypotension that manifests as dizziness, weakness, and palpitations has been reported. Hypotension often presents as postural hypotension occurring shortly after drug administration.
• Headache — this is very common at the start of treatment, but usually subsides after 1–2 weeks.
  • To minimize the risk of headache, start at a low dose and titrate up.
  • Glyceryl trinitrate (GTN) may precipitate a migraine headache in people with a history of migraine.
• Burning, stinging, or tingling of the mouth is experienced by some people taking sublingual GTN tablets.
  • If this occurs, lower strength GTN tablets can be used, or a GTN sublingual spray.

[ABPI, 2019b; ABPI, 2020a; BNF, 2021; Micromedex, 2021]

Drug interactions

• Phosphodiesterase inhibitors (avanafil, sildenafil, tadalafil, and vardenafil) — concurrent use with nitrates is generally contraindicated, as this can produce excessive hypotension, and may precipitate myocardial infarction.
  • Where concurrent use is considered to be medically essential, advise that:
    • There should be at least 12 hours between a dose of avanafil and a nitrate, 24 hours between dose of sildenafil and a nitrate, and 48 hours between a dose of tadalafil and a nitrate. Concurrent use of nitrates and vardenafil is contraindicated as a safe interval between doses has not been established.
    • If an episode of angina occurs during sexual intercourse, the person must not use glyceryl trinitrate (GTN). They should stop sexual activity and, if their pain does not resolve within 10 minutes, they should call 999 for an ambulance.
• Soluble guanylate cyclase stimulator, riociguat — this potentiates the hypotensive effect of nitrates. Concomitant use is contraindicated.  
• Antihypertensives (for example beta-blockers, calcium-channel blockers, vasodilators, and angiotensin II receptor antagonists) — these potentiate the hypotensive effects of nitrates.

[ABPI, 2020a; Knuuti, 2020; BNF, 2021; Preston, 2021]

Dose

• Do not start ivabradine if the resting heart rate is below 70 beats per minute. 
• People aged 74 years or under — initially 5 mg twice daily for 3–4 weeks, then increased if necessary to 7.5 mg twice daily (if the dose is tolerated and resting heart rate remains above 60 beats per minute). 
  • Reduce the dose if it is not tolerated to 2.5–5 mg twice daily (the heart rate at rest should not be allowed to fall below 50 beats per minute).
  • If the heart rate decreases below 50 beats per minute, or the person experiences symptoms of bradycardia, reduce the dose including the lowest dose of 2.5 mg twice daily. 
    • Ivabradine should be stopped if the heart rate remains below 50 beats per minute or symptoms of bradycardia persist despite the dose reduction. 
• People aged 75 years or over — initially 2.5 mg twice daily, increased if necessary to 7.5 mg twice daily (the heart rate at rest should not be allowed to fall below 50 beats per minute). 
• Ivabradine should be stopped if symptoms do not improve within 3 months.

[MHRA, 2014; ABPI, 2021b; BNF, 2021]

Contraindications and cautions

• Ivabradine is contraindicated in:
  • Acute myocardial infarction or unstable angina.
  • Severe hypotension (blood pressure less than 90/50 mmHg).
  • Sino-atrial block or third degree AV block.
  • Severe hepatic insufficiency.
  • Unstable or acute heart failure.
  • Women who are pregnant or breastfeeding — data are lacking to support its use in these women.
  • People younger than 18 years of age — data are lacking to support its use in this population.
  • People with a pacemaker where the heart rate is imposed exclusively by the device.
  • People also taking a rate-limiting calcium-channel blocker (verapamil or diltiazem) [MHRA, 2014].
• Ivabradine should not be started in anyone with a resting heart rate less than 70 beats per minute [MHRA, 2014].
• Ivabradine should be used with caution in:
  • Atrial fibrillation.
  • People who have had a recent stroke.
  • Second degree AV block. 

[ABPI, 2021b; BNF, 2021]

Adverse effects

• Eye disorders — visual disturbances such as blurred vision (common), luminous phenomena (phosphenes — brief spots or flashes of light) is very common. 
  • Phosphenes 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.
  • 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.
• Bradycardia — occurs in around 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 remains less than 50 beats per minute following a dose reduction, or symptoms of bradycardia persist, stop treatment with ivabradine.
• Atrial fibrillation — people taking ivabradine should be regularly monitored for the occurrence of atrial fibrillation. If atrial fibrillation develops, treatment should be reviewed and the benefits and risks of ivabradine use should be considered [MHRA, 2014].
• Headache — this is common, but is usually transient and resolves within the first month of treatment.
• Gastrointestinal disorders — nausea, constipation, diarrhoea, and abdominal pain are uncommon adverse effects of ivabradine.
• Other uncommon adverse effects include:
  • Angioedema.
  • Dyspnoea.
  • Eosinophilia.
  • Muscle cramps.
  • Vertigo.
  • QT-interval prolongation.
  • Elevated creatinine levels.

[ABPI, 2021b; BNF, 2021]

Drug interactions

Drug interactions with ivabradine include:

• Potent CYP3A4 inhibitors (such as azole antifungals [ketoconazole, itraconazole], macrolide antibiotics [clarithromycin, erythromycin], and protease inhibitors [nelfinavir, ritonavir]) — concomitant administration is contraindicated, as they may increase the plasma concentration of ivabradine, increasing the risk of bradycardia.
  • Moderate CYP3A4 inhibitors (such as fluconazole) — the starting dose may need to be reduced to 2.5 mg twice daily and the heart rate monitored.
• CYP3A4 inducers (such as rifampicin, barbiturates, phenytoin, and St John's Wort) — concomitant use may reduce plasma levels of ivabradine and require an adjustment of the dose of ivabradine. Concomitant use of St John's Wort should be avoided.
• Drugs which prolong the QT interval (such as quinidine, amiodarone, and erythromycin) — should not be given concomitantly with ivabradine, as QT prolongation may be exacerbated by the heart rate reduction caused by ivabradine.
• Grapefruit — the plasma concentration of ivabradine can increase by up to two-fold. People should avoid eating grapefruit or drinking 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, 2021b; BNF, 2021]

Choice of calcium-channel blocker

• Monotherapy (when a beta-blocker is contraindicated or not tolerated).
  • A rate-limiting calcium-channel blocker (CCB) (such as diltiazem or verapamil) is preferred to a dihydropyridine CCB. 
    • 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.
  • The different classes of CCB are equally efficacious, so the choice of CCB should be based on the person's preference, comorbidities, potential drug interactions, and adverse effects.
• Combination therapy
  • For people taking a beta-blocker, prescribe a dihydropyridine CCB (such as amlodipine, felodipine, or modified-release nifedipine).
  • For people not taking a beta-blocker, a rate-limiting CCB may be preferred.
• If the person has concomitant heart failure — prescribe amlodipine or felodipine.

[NICE, 2016b; SIGN, 2018b; Knuuti, 2020]

Contraindications and cautions

• Rate-limiting calcium-channel blockers (CCBs) (such as verapamil and diltiazem) are contraindicated in people with:
  • Atrial flutter or fibrillation associated with accessory conducting pathways (for example Wolff-Parkinson-White syndrome).
  • Heart failure or history of heart failure.
  • Severe bradycardia.
  • Second or third degree heart block (in the absence of a permanent pacemaker).
  • Sick sinus syndrome.
  • Cardiac outflow obstruction (significant aortic stenosis or obstructive hypertrophic cardiomyopathy) — vasodilatation may result in reduced cardiac output.
• Dihydropyridine CCBs (such as amlodipine and felodipine) are contraindicated in people: 
  • With uncontrolled heart failure.
  • Severe hypotension.
  • Cardiac outflow obstruction (for example high grade aortic stenosis).
• Prescribe rate-limiting CCBs with caution to people:
  • With hepatic impairment — dose adjustments may be necessary.
  • With myasthenia gravis.
  • At risk of developing an intestinal obstruction — CCBs have an inhibitory effect on intestinal motility.
• Prescribe dihydropyridine CCBs with caution to people with:
  • Heart failure.
  • A predisposition to tachycardia.
  • Hepatic impairment — the initial dose may need to be reduced. 

 [ABPI, 2020b; ABPI, 2020c; ABPI, 2020d; ABPI, 2020e; BNF, 2021]

Adverse effects

• Vasodilatory adverse effects (facial flushing, headaches, postural hypotension, and ankle swelling) — these are more common with dihydropyridine calcium-channel blockers (CCBs) than with rate-limiting CCBs.
  • Vasodilatory effects usually reduce in severity with continued treatment, although ankle swelling often persists.
• Other adverse effects include: 
  • Dizziness (common).
  • Gastrointestinal disorders, for example constipation, nausea, and dyspepsia (common).
  • Atrioventricular block, palpitations (common with diltiazem). 
  • Malaise and fatigue (uncommon, but common with diltiazem).
  • Myalgia and arthralgia (uncommon).
  • Erythema multiforme (rare).
  • Acute renal failure secondary to decreased renal perfusion has been reported in patients taking diltiazem who have reduced left ventricular function, severe bradycardia, or severe hypotension. For people prescribed diltiazem be aware that a lupus-like syndrome may develop and also that there is a risk of non-cardiogenic pulmonary oedema in overdose.

     

[ABPI, 2020b; ABPI, 2020c; ABPI, 2020d; ABPI, 2020e; ABPI, 2020f; BNF, 2021; EMC, 2023]

Drug interactions

Key drug interactions with calcium-channel blockers (CCBs) include:

• Antiarrhythmics — there is an increased risk of bradycardia, AV block, and myocardial depression when the rate-limiting CCBs, diltiazem, and verapamil are prescribed concomitantly with the antiarrhythmic drugs amiodarone and dronedarone.
• Anticoagulants — verapamil can increase plasma concentrations of dabigatran. Dose adjustments of dabigatran may be necessary.
• Antifungals (itraconazole and ketoconazole) — metabolism of amlodipine and felodipine is inhibited. Avoid concomitant use. 
• Antiretrovirals (ritonavir) — plasma levels of amlodipine. Dose of amlodipine may need to be reduced. 
• Anticonvulsants (carbamazepine) — verapamil and diltiazem may increase carbamazepine plasma levels. The dose of carbamazepine may need to be adjusted.  
• Beta-blockers — verapamil should not be prescribed with a beta-blocker, as bradycardia, asystole, severe hypotension, and heart failure can occur.
  • A beta-blocker and diltiazem should only be prescribed on specialist advice.
• Direct oral anti-coagulants — diltiazem (an inhibitor of CYP3A4 and P-gp) may increase the plasma concentrations of DOACs (i.e. apixaban, rivaroxaban, dabigatran) metabolised through these pathways with resulting increases in pharmacodynamic effects such as bleeding risk.
• Immunosuppressants (ciclosporin) — verapamil and diltiazem may increase levels of ciclosporin. The dose of ciclosporin may need to be reduced, and renal function monitored. 
• Digoxin — diltiazem and verapamil may increase the plasma concentration of digoxin. Dose reductions of digoxin may be necessary.
• Grapefruit — grapefruit (and grapefruit juice) may inhibit the metabolism of CCBs, resulting in increased plasma concentrations that could be clinically important. 
• Ivabradine — concomitant use of ivabradine with verapamil or diltiazem is contraindicated due to the additional heart rate lowering effect.
• Macrolide antibiotics — the metabolism of CCBs can be reduced by the macrolide antibiotics clarithromycin or erythromycin, leading to an increased risk of adverse effects.
• Statins — increases in statin plasma levels have been noted with atorvastatin, lovastatin, or simvastatin when given with diltiazem or verapamil. Fluvastatin, pravastatin, and rosuvastatin are not significantly metabolized by CYP3A4 and are less likely to interact.
  • In a person already taking simvastatin, atorvastatin, or lovastatin, consider reducing the dose of the statin if verapamil or diltiazem are started.
  • In a person already taking verapamil or diltiazem, treatment with simvastatin, atorvastatin, or lovastatin should be started at a low dose and gradually titrated up.
• mTOR inhibitors (sirolimus, temsirolimus, everolimus) — amlodipine is a weak CYP3A inhibitor, concomitant use with these drugs may increase their levels.

[ABPI, 2016; ABPI, 2020b; ABPI, 2020d; ABPI, 2020e; BNF, 2021; Preston, 2021]

Dose and titration

• The initial dose of ranolazine is 375 mg twice a day.
• After 2–4 weeks increase the dose to 500 mg twice a day.
• If the person is still experiencing symptoms of angina, and is tolerating ranolazine, increase the dose to a maximum of 750 mg twice a day.

[ABPI, 2020g]

Contraindications and cautions

• Ranolazine is contraindicated in:
  • Severe renal impairment (avoid if creatinine clearance is less than 30 mL/min/1.73 m²).
  • Moderate or severe hepatic impairment.
  • People who are also taking a potent CYP3A4 enzyme inhibitor (such as azole antifungals, macrolide antibiotics, and protease inhibitors). For more information, see the section on Drug interactions.
  • People who are also taking Class Ia (such as quinidine) or Class III antiarrhythmics (such as sotalol), other than amiodarone.
• Caution is advised in people who are elderly, and people with:
  • Moderate to severe chronic heart failure (NYHA Class III–IV).
  • Hepatic impairment. 
  • Mild to moderate renal impairment (creatinine clearance 30–80 mL/min).
  • Low body weight — 60 kg or less. 
  • A history of congenital or a family history of long QT syndrome, anyone with known acquired QT interval prolongation, and anyone treated concomitantly with drugs affecting the QT interval. For more information, see the section on Drug interactions.

[ABPI, 2020g; BNF, 2021]

Adverse effects

• Common adverse effects include:
  • Constipation, nausea, vomiting.
  • Dizziness, headache.
  • Asthenia.
• Uncommon adverse effects include:
  • Anorexia, decreased appetite, dehydration.
  • Anxiety, insomnia, hallucination.
  • Lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness, paresthesia.
  • Blurred vision, visual disturbance, diplopia.
  • Hot flush, hypotension.
  • Dyspnoea, cough, epistaxis.
  • Abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort.
  • Pruritus, hyperhydrosis.
  • Muscle cramp.
  • Dysuria, haematuria, chromaturia.
•  Rare adverse effects include: hyponatraemia, disorientation, amnesia, gait disturbances, angio-oedema, allergic dermatitis, acute renal failure, erectile dysfunction, and myoclonus.
• Adverse effects tend to occur more frequently in older people (over 75 years), people with a body weight of 60 kg or less, and in those with renal impairment.

[ABPI, 2020g; BNF, 2021]

Drug interactions

Key drug interactions with ranolazine include:

• CYP3A4 inhibitors (such as azole antifungals, macrolide antibiotics, and protease inhibitors) increase the plasma levels of ranolazine. Concomitant use is contraindicated.
  • Grapefruit juice is also a potent CYP3A4 inhibitor and the person should be advised to avoid grapefruit juice and grapefruit-containing products.
  • Moderate inhibitors (such as diltiazem and verapamil) should be given concomitantly with caution. The dose of ranolazine may need to be reduced.
• CYP3A4 inducers (such as carbamazepine, rifampicin, phenytoin, phenobarbital, and St John's wort) decrease the plasma levels of ranolazine. Concomitant use is contraindicated.
• Statins (such as atorvastatin, simvastatin, lovastatin) — ranolazine may increase plasma concentrations. Dose adjustment of statins may be required. For more information, see the CKS topic Lipid modification - CVD prevention.
• Immunosuppressants (tacrolimus, ciclosporin, sirolimus, everolimus) — ranolazine may increase plasma levels. Monitor blood levels and adjust dose accordingly. 
• QT interval prolongation — concomitant administration of other drugs that prolong the QT interval may increase the risk of ventricular arrhythmias. These include antihistamines (astemizole, mizolastine), class I antiarrhythmics (for example quinidine), class III antiarrhythmics (for example sotalol), erythromycin, and tricyclic antidepressants.

[ABPI, 2020g; BNF, 2021; Preston, 2021]

Choice of beta-blocker

• The following beta-blockers are licensed for the treatment of angina: propranolol, acebutolol, atenolol, bisoprolol, carvedilol, metoprolol, nadolol, oxprenolol, pindolol, and timolol.
• 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.
  • Factors such 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 cardioselective and do not exhibit intrinsic sympathomimetic activity.
  • 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.

[SIGN, 2018b; BNF, 2021]

Dose and titration

• 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 doses are:
  • Atenolol 100 mg once a day or 50 mg twice a day (twice-daily dosing may provide better symptom control).
  • Bisoprolol 5–10 mg once a day.
  • Metoprolol 50–100 mg two to three times a day (standard-release) or 200–400 mg once a day (modified-release).

[SIGN, 2018b; BNF, 2021]

Contraindications and cautions

• Do not prescribe beta-blockers to people with:
  • A history of asthma or bronchospasm.
  • Reversible or severe chronic obstructive pulmonary disease (COPD). Beta-blockers can be used in people with COPD without significant reversible airways obstruction.
  • Known intolerance or hypersensitivity to beta-blockers.
  • Severe or symptomatic bradycardia (heart rate less than 60 beats per minute).
  • Sinoatrial block, second or third degree heart block (unless there is a pacemaker in place).
  • Severe or uncontrolled heart failure.
  • Severe or symptomatic hypotension (systolic blood pressure less than 90 mmHg).
  • Severe peripheral arterial disease (including intermittent claudication) or Raynaud's syndrome.
  • Sick sinus syndrome.
  • Cardiogenic shock or phaeochromocytoma (without a concomitant alpha-blocker).
  • People with frequent episodes of hypoglycaemia.
  • Clinically significant hepatic dysfunction (carvedilol and nebivolol).
  • Some beta-blocker preparations contain lactulose and should not be used by people with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency.
• Prescribe beta-blockers with caution to people with:
  • Heart failure with chronic kidney disease (CKD), hypotension, ischaemic heart disease, or less severe peripheral arterial disease.
  • Prinzmetal's angina.
  • Current or recent (within 4 weeks) exacerbation of heart failure — seek specialist advice.
  • First degree atrioventricular heart block.
  • Portal hypertension (risk of deterioration in liver function).
  • Diabetes mellitus (affects carbohydrate metabolism and symptoms of hypoglycaemia may be masked).
  • COPD.
  • Myasthenia gravis.
  • Psoriasis.
  • Thyrotoxicosis (symptoms may be masked).
  • People who wear contact lenses (reduced secretion of lacrimal fluid).
  • History of hypersensitivity to allergens — beta-blockers may increase sensitivity to allergens and result in a more serious hypersensitivity response, and may reduce response to adrenaline (epinephrine).
  • CKD.

[ABPI, 2017; ABPI, 2019c; ABPI, 2020h; BNF, 2021]

Adverse effects

• Adverse effects of beta-blockers include:
  • Deteriorating symptoms of heart failure (such as symptoms of fluid overload and fatigue).
  • Hypotension.
  • Bradycardia.
  • Dizziness, headache, and syncope.
  • Nausea, vomiting, diarrhoea, and constipation.
  • Sexual dysfunction — including erectile dysfunction and loss of libido.
  • Cold extremities, paraesthesia, and numbness — these are more common in people with peripheral arterial disease. If these are troublesome, the beta-blocker may need to be stopped.
  • Effect on carbohydrate metabolism — hypo- or hyperglycaemia in people with or without diabetes mellitus.
  • Effect on metabolic and autonomic response to hypoglycaemia — possible masking of hypoglycaemia warning signs such as tremor and tachycardia.
  • Fatigue and asthenia (lack of energy and strength) — is a common adverse effect of bisoprolol.
  • Sleep disturbance, nightmares, and depression.
  • Bronchospasm.
  • Reduction of secretion of lacrimal fluid (may affect people who wear contact lenses).

[ABPI, 2017; ABPI, 2019c; ABPI, 2020h; BNF, 2021]

Drug interactions

Important drug interactions with beta-blockers include:

• Antipsychotics and antidepressants (tricyclic, barbiturates, and phenothiazines) — risk of hypotension.
• Baclofen — prescribe with caution due to increased hypotensive effect.
• Dihydropyridine calcium-channel blockers (including amlodipine, felodipine, and nifedipine) — risk of increased hypotension and worsening heart failure.
• Verapamil — concurrent beta-blocker and verapamil should not be prescribed because of the risk of bradycardia, asystole, severe hypotension, and heart failure.
• Diltiazem — obtain specialist advice before prescribing diltiazem with a beta-blocker.
  • Heart rate and blood pressure should be monitored carefully, as bradycardia and atrioventricular (AV) block can occur. Asystole and sudden death have been reported.
• Class I antiarrhythmics (such as quinidine, flecainide) — concurrent treatment should be avoided due to bradycardia, myocardial depression, and potentiation of AV conduction time.
• Class III antiarrhythmics (such as amiodarone) — concurrent treatment should be prescribed with caution.
  • Monitor heart rate and blood pressure and check for signs of worsening heart failure, as risk of bradycardia, AV block, and myocardial depression is increased.
• Digoxin — concurrent treatment can reduce heart rate and prolong AV conduction time, increasing the risk of AV block and bradycardia.
  • Monitor pulse carefully.
  • Monitor for signs of digoxin toxicity with carvedilol (confusion, anorexia, nausea, disturbance of colour vision) as an increase in plasma digoxin levels has been reported with carvedilol.
• Insulin and oral antidiabetic drugs — prescribe with caution due to masking of symptoms of hypoglycaemia.
• Sympathomimetic agents — risk of hypertension, severe bradycardia, and heart block.
• Any other drugs that reduce blood pressure (including nitrates) — risk of additive hypotensive effect or worsening of heart failure.

[ABPI, 2019d; ABPI, 2019c; ABPI, 2020h; BNF, 2021; Preston, 2021]

Dose

• Initial dose — 10 mg twice daily, ideally in the morning and in the evening.
  • A lower starting dose of 5 mg twice daily can be used in people prone to headaches. 
• Maintenance dose — 10–20 mg twice daily, titrated up to 40 mg twice daily, if required and tolerated.

[ABPI, 2021c]

Contraindications and cautions

• Nicorandil is contraindicated in people with:
  • Cardiogenic shock.
  • Severe hypotension.
  • Left ventricular failure with low filling pressure or cardiac decompensation.
  • Hypovolaemia.
  • Acute pulmonary oedema.
• Nicorandil should be used with caution in people with:
  
  • Diverticular disease.
  • Hyperkalaemia.
  • Heart failure.
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency.

[ABPI, 2021c; BNF, 2021]

Adverse effects

Adverse effects of nicorandil include: 

• Headache (very common) — occurs in 22–48% of people taking nicorandil, and usually during the first 2 weeks of treatment. It is dose related and tends to diminish with continued use, although 10% of people stop using it as a result.
• Other common adverse effects include: dizziness, heart rate increases, cutaneous vasodilation with flushing, vomiting, nausea, weakness. 
• Uncommon adverse effects include: hypotension, angio-oedema, and myalgia.
• Third and sixth nerve paralysis, often associated with headache (frequency unknown).
• Ulceration:
  • Gastrointestinal ulceration (including aphthous ulcers and anal ulceration) has been reported with nicorandil (rarely). This may progress to perforation, haemorrhage, fistula, or abscess. Almost two-thirds of reported gastrointestinal ulcers are serious.
  • Serious skin, mucosal, and eye ulceration (very rarely).
    • Ulcers that result from nicorandil are usually refractory to treatment, and respond only to withdrawal of nicorandil — withdrawal should take place under the supervision of a cardiologist.

[MHRA, 2016; ABPI, 2021c; BNF, 2021]

Drug interactions

Key drug interactions with nicorandil include:

• Phosphodiesterase inhibitors (such as avanafil, sildenafil, tadalafil, vardenafil)— concomitant use with nicorandil is contraindicated, as it can cause potentially serious hypotension.
• Soluble guanylate cyclase stimulators (such as riociguat) — concomitant use with nicorandil is contraindicated, as it can lead to serious hypotension.
• Corticosteroids (such as prednisolone) — gastrointestinal ulceration has been reported in people concomitantly taking nicorandil with corticosteroids, and caution is advised if given concurrently.
• Antihypertensives — concomitant use with nicorandil may enhance the blood pressure lowering effect. Caution is advised. 
• Nonsteroidal anti-inflammatory drugs — concomitant use with nicorandil, there is an increased risk of severe complications such as gastrointestinal ulceration, perforation, and haemorrhage. 

[ABPI, 2021c; BNF, 2021; Preston, 2021]