Previous changes

October 2025 — minor update. Changes have been made to the recommendation on when to consider referral to a specialist in respiratory medicine to consider starting oral prophylactic antibiotic therapy in line with NICE guideline Chronic obstructive pulmonary disease in over 16s: diagnosis and management and the British Thoracic Society Guideline for the use of long-term macrolides in adults with respiratory disease.

May 2025 — minor update. QOF indicators updated in line with the NHS England Quality and Outcomes Framework guidance for 2025/26.

January 2025 — minor update. A link was added to the NICE HTA Digital technologies to support self-management of COPD: early value assessment, to the text on self-management.

September 2024 — reviewed. A literature search was conducted in August 2024 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. The topic has undergone minor restructuring. No major changes to the recommendations have been made.

August 2024 — minor update. Adverse effects of co-amoxiclav updated in line with manufacturer's SPC.

May 2024 — minor update. Information added stating that concomitant treatment with clarithromycin and ivabradine is now contra-indicated and caution is now advised when co-administering clarithromycin with edoxaban, as per the manufacturer's updated SPC.

March 2024 — minor update. Fixed eruption added as an adverse effect of doxycycline as per the manufacturer's updated SPC.

December 2023 — minor update. Recommendations relating to COVID-19 infection have been removed from this topic. Information about the onset of action of beta-2 agonists aligned to SPC.

September 2023 — minor update. Updated NICE quality statements to align with the publication of revised quality statements for COPD. 

June 2023 — minor update. Added potential adverse effects of co-amoxiclav to include Kounis syndrome (an allergic reaction which can result in myocardial infarction), aseptic meningitis, linear IgA disease (renal deposition of IgA ), and drug-induced enterocolitis syndrome  (all of unknown frequency). These adverse effects were noted in an update to the manufacturer’s summary of product characteristics.

November 2021 — minor update. Dosage recommendations for salbutamol dry powder inhalers have been clarified.

July 2021 — minor update. Contraindications and cautions for carbocisteine have been updated.

May 2021 — minor update. A typographical error has been corrected.

October 2020 — minor update. The initial dose of azithromycin to be used in people starting prophylactic macrolide therapy has been added to this topic. 

August 2020 — minor update. A typographical error has been corrected.

April 2020 — minor update. The topic has been updated to take into account the latest BTS guideline on macrolide use.

April 2020 — minor update. New management scenario created to provide information regarding COVID-19.

September to November 2019 — reviewed. A literature search was conducted in August 2019 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of this topic.

August 2019 — minor update. Topic updated in line with NICE chronic obstructive pulmonary disease in over 16s: diagnosis and management.

March 2019 — minor update. Acetylcysteine is now a licenced mucolytic for COPD, prescribing information has been updated accordingly.

December 2018 — minor update. Information added to acute exacerbation scenario to bring topic in line with NICE guideline Chronic obstructive pulmonary disorder (acute exacerbation): antimicrobial prescribing.

May 2018 — minor update. New product availability. Daxas (roflumilast) 250 micrograms tablets, new strength of tablet (previously only 500mg available). Roflumilast is licensed for maintenance treatment of severe COPD linked to chronic bronchitis in adults with a history of frequent exacerbations as add-on to bronchodilator treatment.

December 2016 — minor update. A metered-dose version of Symbicort® has been added to the available corticosteroids preparations section. Information that an increased risk of pneumonia has been observed in patients with COPD receiving inhaled corticosteroids, and that risk may be increased with increasing steroid dose, has been added to this topic.

July to September 2015 — reviewed. A literature search was conducted in July 2015 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. The topic has undergone minor restructuring. No major changes to the recommendations have been made.

July 2014 — minor update. The text has been updated to replace the Liverpool Care Pathway with new standards of care that have been issued by the Leadership Alliance for the Care of Dying People (www.nhsiq.nhs.uk (pdf)).

March 2014 — minor update. Links to the European Committee for Standardization have been removed (www.cen.eu/) as this no longer has text on the use of nebulisers.

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.

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

March 2012 — minor update. A recommendation to advise people inhaling terbutaline via a turbohaler to rinse their mouth after each use to minimize systemic adverse effects has been added, following an update to the manufacturer's Summary of Product Characteristics. 

December 2011 — minor update. The black triangle has been removed from Serevent Evohaler® (salmeterol CFC-free inhaler); prescriptions have been amended to reflect this. 

October 2011 — minor update. NICE has recommended in its COPD Quality Standard document that people receiving long-term oxygen therapy should have a review at least once a year, which includes pulse oximetry. Further evidence has been added from a recent systematic review and meta-analysis of randomized controlled trials which found that compared with placebo, Spiriva Respimat® 5 micrograms/day was associated with a statistically significant increased risk of mortality. Issued in October 2011.

June 2011 — minor update. The 2011/2012 QOF indicators have been added to this topic. 

February 2011 — minor update. The range of long-acting beta-2 agonist inhaler devices included as prescriptions has been updated. 

November 2010 — minor update. The Medicines and Healthcare products Regulatory Agency (MHRA) has issued advice that the Spiriva Respimat® formulation of tiotropium should be used with caution in people with known cardiac rhythm disorders. 

July to November 2010 — topic updated. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

March 2010 — minor update. All strengths of Beclazone® inhalers have been discontinued. Prescriptions removed. 

January 2010 — minor update to text regarding drug interactions with theophylline. 

October 2009 — minor typographical error corrected. 

July 2009 — minor update. The Medicines and Healthcare products Regulatory Agency (MHRA) has issued advice on the use of long-acting beta-2 agonists and inhaled corticosteroids in COPD. 

June 2009 — minor update. Broken link removed. A budesonide CFC-free pMDI has been launched, and a prescription has been added. The Nebuhaler® spacer device has been discontinued. This prescription has been replaced with the NebuChamber® spacer device.

May 2009 — minor update. The Quality and Outcomes Framework (QOF) indicators for stopping smoking that apply to COPD have been added. 

April 2009 — minor update. The changes to the QOF for 2009/2010 for COPD have been updated in the Goals and outcome measures section. 

May to August 2007 — 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.

May 2006 — updated. Prescriptions for CFC-free and salmeterol pressurized metered-dose inhalers have replaced those for CFC-containing inhalers. Information on changing to CFC-free inhalers included in the Medicines management section.

February 2006 — update to reflect the new supply arrangements for home oxygen. Oxygen prescriptions have been removed and changes to the text in management issues and the oxygen therapy scenario have been made. Volumatic® spacer device re-introduced and prescriptions included; terbutaline pressurized metered-dose inhalers have been discontinued and prescriptions removed. 

November 2005 — minor update. Volumatic® spacer device discontinued and prescriptions removed; advice for using alternative spacer devices included.

July 2005 — updated to incorporate the Referral guidelines for suspected cancer published by the National Institute for Health and Care Excellence. 

March 2004 — reviewed. Validated in May 2004 and issued in July 2004.

October 2000 — reviewed and updated to incorporate recommendations from the Royal College of Physicians 1999 report on domiciliary oxygen therapy services. Validated in November 2000 and issued in October 2001.

October 1997 — rewritten. Replaces guidance on Chronic bronchitis, Emphysema and Acute exacerbation of COAD.

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 August 2024.

HTAs (Health Technology Assessments)

• NICE (2024) Digital technologies to support self-management of COPD: early value assessment. National Institute for Health and Care Excellence. [Free Full-text]
• NICE (2026) Mepolizumab for maintenance treatment of uncontrolled chronic obstructive pulmonary disease with raised blood eosinophils. National Institute for Health and Care Excellence. [Free Full-text]

Economic appraisals

No new economic appraisals relevant to England since 1 August 2024.

Systematic reviews and meta-analyses

No new systematic reviews or meta-analysis which reach the CKS threshold for inclusion since 1 August 2024.

Primary evidence

No new primary evidence which reaches the CKS threshold for inclusion published since 1 August 2024.

New policies

No new national policies or guidelines since 1 August 2024.

New safety alerts

No new safety alerts issued since 1 August 2024.

Changes in product availability

• New product Vivaire 100/6 and 200/6 (beclomethasone/formoterol) micrograms per actuation pressurised inhalation solution. This combined corticosteroid and long-acting beta2-agonist inhaler is licensed for the treatment of asthma, and severe COPD with a history of exacerbations. See more here.

Cor pulmonale

• Cor pulmonale is right heart failure secondary to lung disease, and is caused by pulmonary hypertension as a consequence of hypoxia.
• Suspect cor pulmonale in people with:
  • Peripheral oedema.
  • Raised jugular venous pressure.
  • Systolic parasternal heave.
  • A loud pulmonary second heart sound (over the second left intercostal space).
  • Hepatomegaly.
• Other causes of peripheral oedema should be considered.

How should I assess a person with suspected COPD?

Take a history asking about:

• Onset, variability, and progression of symptoms such as:
  • Breathlessness — assess severity using the Medical Research Council (MRC) dyspnoea scale.
  • Cough and sputum production — ask about haemoptysis and consider other causes.
  • Peripheral oedema — consider cor pulmonale.
  • Weight loss – consider other causes.
• Exposure to risk factors including:
  • Smoking — if the person is a current smoker document pack-years smoked (the number of cigarettes smoked per day, divided by 20, multiplied by number of years smoked).
  • Occupational or environmental exposures.
• Impact of symptoms on daily life and occupation:
  • The impact of COPD on wellbeing and daily life can be assessed using the COPD Assessment test (CAT) — available in the GOLD guidelines.
• Previous exacerbations or hospitalization.
• Past medical history and comorbidities including:
  • Anxiety and depression.
  • Cardiovascular disease and metabolic syndrome.
  • Lung or liver disease.
  • Osteoporosis.
  • Asthma.
• Family history including:
  • Lung or liver disease – consider underlying causes such as alpha-1-antitrypsin deficiency.

Examine the person:

• Carry out a general examination including vital signs (such as heart rate, blood pressure, temperature, and pulse oximetry).
• Examine the chest and check for peripheral oedema and other signs of cor pulmonale.
• Measure weight and height to calculate body mass index (weight in kg/height in m²).

Arrange investigations including:

• Chest X-ray — to help exclude other causes (such as lung cancer, bronchiectasis, tuberculosis, and heart failure).
• Full blood count — to identify anaemia or polycythaemia.
• Spirometry.
  • Measure post-bronchodilator spirometry to confirm the diagnosis of COPD — do not routinely perform reversibility testing as part of diagnostic work up.

Depending on the clinical situation, additional investigations may be indicated such as:

• Sputum culture – if sputum is purulent and persistent (to identify organisms).
• Serial home peak flow measurements – to exclude asthma if diagnosis is in doubt.
  • For more information, see the CKS topic on Asthma.
• ECG and serum natriuretic peptides – if cardiac disease or pulmonary hypertension are suspected.
  • Echocardiogram may also be indicated.
• CT thorax – if symptoms seem disproportionate to spirometry measurements; another diagnosis (such as fibrosis or bronchiectasis) is suspected, or an abnormality on chest x-ray requires further investigation.
  • Seek specialist advice where appropriate.
• Serum alpha-1-antitrypsin.
  • Consider alpha-1-antitrypsin deficiency in people with early onset of symptoms, minimal smoking history or a positive family history.
  • Referral to a specialist for management and screening of family members is required if alpha-1-antitrypsin deficiency is identified.

Spirometry

Spirometry should be performed at diagnosis, when the diagnosis is reconsidered, and for monitoring of disease severity and progression.

• Post-bronchodilator spirometry should be performed and interpreted by an appropriately trained health professional to confirm the diagnosis of chronic obstructive pulmonary disease (COPD).
  • Spirometry should be carried out 15–20 minutes after the person has inhaled a short-acting bronchodilator (for example 400 micrograms of salbutamol delivered via a spacer device — local protocols may vary).
  • Airflow obstruction is defined as a post-bronchodilator ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of less than 0.7.
    • Other causes should be considered in older people who have a FEV1/FVC ratio below 0.7 but do not have typical symptoms of COPD.
    • COPD should be considered in younger people with typical symptoms even if the FEV1/FVC ratio is above 0.7.
• Where post-bronchodilator FEV1/FVC ratio is less than 0.7, the severity of airflow obstruction is graded according to the reduction in FEV1 compared to appropriate reference values (based on age, sex, height, and ethnicity):
  • Stage 1, mild — FEV1 80% of predicted value or higher.
  • Stage 2, moderate — FEV1 50–79% of predicted value.
  • Stage 3, severe — FEV1 30–49% of predicted value.
  • Stage 4, very severe — FEV1 less than 30% of predicted value or FEV1 less than 50% with respiratory failure.
• Routine spirometry reversibility testing is not recommended.

[BMJ Best Practice, 2024b; GOLD, 2024]

Medical Research Council (MRC) dyspnoea scale

Table 1. Medical Research Council (MRC) dyspnoea scale.

What else might it be?

• The differential diagnosis of chronic obstructive pulmonary disease (COPD) includes:
  • Asthma — COPD and asthma can be difficult to distinguish clinically and may co-exist.
    • Consider asthma if the person has a family history, other atopic disease, or nocturnal or variable symptoms, is a non-smoker, or experienced onset of symptoms at younger than 35 years of age.
    • For more information, see the CKS topic on Asthma.
  • Bronchiectasis — clinical features include copious sputum, frequent chest infections, a history of childhood pneumonia, and coarse lung crepitations.
    • For more information, see the CKS topic on Bronchiectasis.
  • Heart failure — clinical features include breathlessness when lying flat, a history of ischaemic heart disease, and fine lung crepitations.
    • For more information, see the CKS topic on Heart failure - chronic.
  • Lung cancer — consider if the person has a persistent cough, haemoptysis, weight loss, or persistent hoarse voice.
    • For more information, see the CKS topic on Lung and pleural cancers - recognition and referral.
  • Interstitial lung disease (such as asbestosis, pneumoconiosis, fibrosing alveolitis, or sarcoidosis) — clinical features include a dry cough and fine lung crepitations.
  • Anaemia — clinical features include fatigue, breathlessness, and palpitations.
    • For more information, see the CKS topics on Anaemia - iron deficiency and Anaemia - B12 and folate deficiency.
  • Tuberculosis (TB) — clinical features include persistent productive cough, which may be associated with breathlessness and haemoptysis. May co-exist with COPD.
    • For more information, see the CKS topic on Tuberculosis.
  • Cystic fibrosis.
  • Upper airway obstruction (for example tracheal tumour).
• For detailed information on the differential diagnosis of cough and breathlessness, see the CKS topics on Cough and Breathlessness.

[BMJ Best Practice, 2024b; GOLD, 2024]

Basis for recommendation

The information on the clinical features of COPD is based on the clinical guidelines All Wales Medicine Strategy group COPD management and prescribing guideline [AWTTC, 2023], COPD-X: concise guide for primary care [Lung Foundation Australia, 2024], Global initiative for chronic obstructive lung disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2024 report [GOLD, 2024] and Chronic obstructive pulmonary disease in over 16s: diagnosis and management [NICE, 2019], and expert opinion in review articles [Gentry, 2017; BMJ Best Practice, 2024b].

• Chronic progressive breathlessness is characteristic of COPD — up to 30% of people with COPD have cough productive of sputum [GOLD, 2024].
• It can be very difficult to differentiate COPD from asthma (especially in older adults and smokers) — in some people clinical features of both conditions may be present [GINA and GOLD, 2017].

Assessment

The recommendations on assessment of a person with suspected COPD are based on the clinical guidelines All Wales Medicine Strategy group COPD management and prescribing guideline [AWTTC, 2023] , COPD-X: Handbook [Lung Foundation Australia, 2024], Chronic obstructive pulmonary disease (COPD): best practice guide [Scottish Government, 2017], Global initiative for chronic obstructive lung disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2024 report [GOLD, 2024], Chronic obstructive pulmonary disease in over 16s: diagnosis and management [NICE, 2019] and expert opinion in review articles [Kahnert, 2023; BMJ Best Practice, 2024b].

• Stepwise approach to diagnosis
  • Clinical guidance from GOLD and NICE agree on a stepwise approach to the diagnosis of COPD through thorough history and examination followed by confirmation on spirometry. 
  • Symptoms of COPD may precede airflow limitation on spirometry or conversely, significant airflow limitation may be identified in the absence of symptoms such as chronic breathlessness and/or cough and sputum production [GOLD, 2024].
• Comorbidities
  • COPD is often an element of multimorbid presentations (especially in older people). Identification and appropriate treatment of comorbid conditions (such as cardiovascular disease, metabolic syndrome, osteoporosis, anxiety, depression and lung cancer) can reduce risk of mortality and hospitalization and improve quality of life [BMJ Best Practice, 2024b; GOLD, 2024; Lung Foundation Australia, 2024].
  • A meta-analysis (11 studies, n=47,695,183 with COPD and 47,924,876 without COPD) found that the prevalence of cardiovascular comorbidities [OR 1.90, 95% CI 1.59-2.28], cerebrovascular comorbidities (OR 1.84, 95% CI 1.47-2.31), hypertension (OR 1.45, 95% CI 1.31-1.61), diabetes mellitus (OR 1.22, 95% CI 1.07-1.38), neurological and psychiatric disorders (OR 1.78, 95% CI 1.48-2.14), gut and renal disorders (OR 1.96, 95% CI 1.43-2.68), musculoskeletal disorders (OR 1.51, 95% CI 1.27-1.78), and cancer (OR 1.67, 95% CI 1.25-2.23; P = .0005) were significantly higher in COPD patients than in non-COPD controls [Yin, 2017].
• Assessment of severity is important in guiding treatment decisions and prognosis
  • NICE guidance states that as COPD is a heterogeneous condition, no single measure can adequately assess disease severity. Instead many factors associated with prognosis such as FEV1; smoking status; breathlessness on the MRC scale; presence of chronic hypoxia and/or cor pulmonale; low BMI; severity and frequency of exacerbations; hospital admissions; symptom burden (for example, on the COPD Assessment Test [CAT] score); exercise capacity; criteria for long-term oxygen therapy/home non-invasive ventilation; multimorbidity; and frailty should be taken into account. Use of multidimensional indices (such as BODE) should not be used to assess prognosis as they are unreliable and time-consuming [NICE, 2019].
• Examination
  • Clinical signs of COPD may not develop until lung function becomes severely impaired – absence of physical signs does not exclude a diagnosis of COPD [BMJ Best Practice, 2024b; GOLD, 2024].
  • Pulse oximetry should not be used as a diagnostic tool but can be helpful in determining severity of COPD and help direct treatment [NICE, 2019; AWTTC, 2023].
  • Body mass index (BMI) — weight loss is common in severe and very severe COPD and negatively affects COPD prognosis. It may also be a sign of serious co-existing disease such as TB or lung cancer and always requires investigation [NICE, 2019; GOLD, 2024].
• Investigations
  • Spirometry — clinical guidance [NICE, 2019; AWTTC, 2023] agree that post-bronchodilator spirometry is a reproducible and objective measurement of airflow limitation and should be used for confirmation of COPD diagnosis following thorough clinical assessment.
    • Spirometry should not be used in isolation to clinically diagnose COPD [GOLD, 2024] — 20-30% of patients who have a clinical diagnosis of COPD do not have airflow limitation on spirometry [BMJ Best Practice, 2024b].
    • In people with borderline spirometry, other causes should be considered and investigated appropriately (referral may be indicated) [Postma, 2015; Lung Foundation Australia, 2024].
    • Limitations associated with the use of a fixed FEV1/FVC ratio for all ages include the possibility of over-diagnosis in the elderly (FEV1:FVC ratio reduces with age due to age-related physiological changes) and under-diagnosis in adults aged under 45 years (especially in mild disease) [NICE, 2019; GOLD, 2024].
    • NICE guidance [NICE, 2019] recommends that routine reversibility testing (which should not be confused with or equated to post-bronchodilator spirometry measurement) is not needed for most people as:
      • Repeated FEV1 measurements can show small spontaneous fluctuations.
      • Results of reversibility test performed on different occasions can be inconsistent and not reproducible.
      • Over-reliance on single reversibility test may be misleading unless change in FEV1 is greater than 400ml.
      • The definition of significant change is arbitrary.
    • Recommendations on the choice, dose, and delivery of bronchodilator, and how long after inhalation spirometry should be done, are based on expert opinion from previous external reviewers of this CKS topic, a guideline on diagnostic spirometry in primary care published by the GP Airways Group [Levy, 2009] and the primary care commissioning (PCC) Guide to Performing Quality Assured Diagnostic Spirometry [PCC, 2013].
  • Imaging — clinical guidelines [NICE, 2019; AWTTC, 2023; GOLD, 2024] recommend chest X-ray to help exclude other causes of symptoms.
    • Be aware that emphysema on CT scan is an independent risk factor for lung cancer [NICE, 2019].
  • Full blood count is recommended to identify anaemia and polycythaemia. In addition, in some people with COPD there may be an increase in eosinophils [NICE, 2019; AWTTC, 2023; BMJ Best Practice, 2024b].
  • The recommendation regarding additional investigations (including sputum culture, peak flow, and further cardiac investigations) are taken from the NICE guideline [NICE, 2019].

Differential diagnosis

The information regarding differential diagnosis of COPD is based on the clinical guideline Global initiative for chronic obstructive lung disease, Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2024 report [GOLD, 2024], and expert opinion in review articles [Kahnert, 2023; BMJ Best Practice, 2024b].

What else might it be?

Conditions which may present with similar symptoms to an acute exacerbation of chronic obstructive pulmonary disease (COPD) include:

• Pneumonia.
  • For more information, see the CKS topic on Chest infections - adult.
• Pulmonary embolism.
  • For more information, see the CKS topic on Pulmonary embolism.
• Pneumothorax.
• Acute heart failure.
• Pleural effusion.
• Cardiac ischaemia or arrhythmia.
  • For more information, see the CKS topics on Angina and Atrial fibrillation.
• Lung cancer.
  • For more information, see the CKS topic on Lung and pleural cancers - recognition and referral.
• Upper airway obstruction.

Basis for recommendation

The information on symptoms and differential diagnosis of an acute exacerbation of chronic obstructive pulmonary disease (COPD) is based on expert opinion in clinical guidelines Management of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline [Wedzicha, 2017a], Global initiative for chronic obstructive lung disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2024 report  [GOLD, 2024], and Chronic obstructive pulmonary disease in over 16s: diagnosis and management [NICE, 2019], and review articles [Ritchie, 2020; BMJ Best Practice, 2023].

When should I refer a person with COPD?

What treatment should I offer a person with COPD?

What information should self-management plans offer for people with COPD?

• Self-management plans should be developed in collaboration with each person with COPD and their family members/carers (where appropriate) and provide personalized information and advice on:
  • COPD and its symptoms.
  • Non-pharmacological measures including diet, physical activity, pulmonary rehabilitation, smoking cessation, and avoidance of passive smoking (where relevant).
  • The importance of vaccinations.
  • Appropriate use of inhaled therapies (including inhaler technique and the importance of adherence).
  • Early recognition and management of exacerbations including:
    • How to adjust short-acting bronchodilator therapy to treat symptoms and, if there is no response, when to contact a healthcare professional.
    • When to take short courses of oral corticosteroids and antibiotics prescribed to keep at home for exacerbations and when to contact a healthcare professional.
  • Details of local and national organisations and online resources that can provide more information and support such as the British Lung Foundation, which has patient guides on COPD.
• Review self-management plans regularly.
• Consider a digital technology for adults to support self-management of COPD.

What advice should I give to a person with COPD?

How should I follow up a person with COPD?

• Frequency of follow up
  • Review people with mild (forced expiratory volume in 1 second [FEV1] at least 80% of predicted value), moderate (FEV1 50–79% of predicted value), or severe (FEV1 30–49% of predicted value) COPD at least once a year.
  • Review people with very severe COPD (FEV1 less than 30% of predicted value or FEV1 less than 50% with respiratory failure) at least twice a year.
  • Specialists should arrange regular reviews of people with severe COPD who require interventions such as long-term non-invasive ventilation.
• In all people with COPD, at review:
  • Assess the adequacy of symptom control and impact of COPD on life including:
    • Severity of symptoms (using the Medical Research Council [MRC] dyspnoea scale).
    • Exacerbation frequency and severity (including hospitalizations and treatment required).
    • Consider the possibility of alternative causes for symptoms (for example asthma, bronchiectasis, or lung cancer) — arrange further management as appropriate.
  • Review current medications — check inhaler technique, adherence and adverse effects.
  • Record smoking status and body mass index — offer smoking cessation support where appropriate and consider the need for nutritional support.
  • Ensure that all people with COPD have been offered an annual influenza vaccination, COVID-19 vaccinations, and a once-only pneumococcal vaccination.
  • Assess for complications (such as cor pulmonale) or comorbidities (such as obstructive sleep apnoea, lung cancer, cardiovascular disease, osteoporosis, anxiety, and depression).
  • Carry out spirometry — to identify decline in FEV1 and forced vital capacity (FVC).
    • Record absolute and per cent predicted values.
    • A loss of 500 ml or more over 5 years indicates rapidly progressing disease — consider the need for specialist referral and investigation.
  • Consider the need for further investigations, referral to a respiratory specialist, for pulmonary rehabilitation, or for social services and occupational therapy input.
• In people with very severe COPD, also assess the following at review:
  • Oxygen saturation using pulse oximetry — consider the need for referral to a respiratory specialist for assessment for oxygen therapy.
• Adjust treatment based on symptoms and exacerbations.
  • Consider the need for referral to secondary care for consideration of additional therapies (such as roflumilast or long-term antibiotics).

How should I assess a person with an acute exacerbation of COPD?

• If an acute exacerbation is suspected, assess its severity:
  • Features suggestive of an acute exacerbation include:
    • Worsening breathlessness.
    • Increased sputum volume and purulence.
    • Cough.
    • Wheeze.
    • Fever without an obvious source.
    • Upper respiratory tract infection in the past 5 days.
    • Increased respiratory rate or heart rate increase 20% above baseline.
  • A severe exacerbation may be suggested by:
    • Marked breathlessness and tachypnoea.
    • Pursed-lip breathing and/or use of accessory muscles at rest.
    • New-onset cyanosis or peripheral oedema.
    • Acute confusion or drowsiness.
    • Marked reduction in activities of daily living.
• Carry out a thorough clinical assessment:
  • Check vital signs (including temperature, oxygen saturation [using pulse oximetry], blood pressure, and heart rate).
  • Assess for confusion or impaired consciousness.
  • Examine the chest.
  • Check ability to cope at home.
• Consider the need for hospital admission.
• Do not send sputum samples for culture routinely.
• Consider other causes of symptoms (such as myocardial infarction, worsening heart failure, pulmonary embolus, and pneumonia).

When should I arrange hospital admission for a person with an acute exacerbation of COPD?

• Consider emergency admission if the person has any of the following:
  • Severe breathlessness.
  • Inability to cope at home (or living alone).
  • Poor or deteriorating general condition including significant comorbidity (such as cardiac disease or insulin-dependent diabetes).
  • Rapid onset of symptoms.
  • Acute confusion or impaired consciousness
  • Cyanosis.
  • Oxygen saturation less than 90% on pulse oximetry.
    • Give oxygen (if available) while awaiting emergency transfer to hospital and monitor response with pulse oximetry — refer to local protocols (or follow instructions on the person's oxygen alert card if available).
    • Otherwise, initially give patients with COPD oxygen via a Venturi 24% mask at 2-3 l/min or Venturi 28% mask at a flow rate of 4 l/min or nasal cannula at a flow rate of 1-2 l/min (if a 24% mask is not available).
    • The target oxygen saturation should be 88– 92% in most cases.
  • Worsening peripheral oedema.
  • New arrhythmia.
  • Failure of exacerbation to respond to initial treatment.
  • Already receiving long-term oxygen therapy.
  • Changes on chest X-ray.
• Where available, hospital-at-home schemes may be appropriate as an alternative to admission.

How should I treat a person with an acute exacerbation of COPD who does not require admission?

• If admission is not indicated, advise the person to increase the doses or frequency of short-acting bronchodilators (not exceeding the maximum dose).
  • If possible, keep to the same delivery system (inhaler, inhaler with spacer, or nebulizer) as is used on a day-to-day basis — take into account the dose of drug needed, the person's ability to use the device, and resources available to supervise therapy when considering choice of delivery system.
  • If the person is likely to become fatigued, a nebulizer may be appropriate (depending on availability and local protocols) — the driving gas for nebulised therapy should always be specified in the prescription.
• If there are no contraindications, consider oral corticosteroids for people with a significant increase in breathlessness that interferes with daily activities.
  • Offer 30 mg oral prednisolone once daily for 5 days — discuss adverse effects of prolonged therapy.
  • Consider the need for osteoporosis prophylaxis for people requiring frequent courses of oral corticosteroids (3–4 courses per year).
    • See the CKS topics on Osteoporosis - prevention of fragility fractures and Corticosteroids - oral.
• Consider the need for an antibiotic taking into account:
  • Severity of symptoms (particularly sputum colour changes and increase in volume or thickness beyond normal).
  • Risk of complications.
  • Previous sputum culture and susceptibility results.
  • Risk of antimicrobial resistance and current antibiotic prophylaxis (treatment should be with an antibiotic from a different class).
• First choice oral antibiotics include:
  • Amoxicillin 500 mg three times a day for 5 days.
  • Doxycycline 200 mg on the first day, then 100mg once a day for a 5-day course in total.
  • Clarithromycin 500 mg twice a day for 5 days.
• If there is no improvement in symptoms on the first choice taken for at least 2 to 3 days, guided by susceptibility and where admission is not indicated:
  • Send a sputum sample for culture and susceptibility testing.
  • Offer an alternative first-choice antibiotic from a different class (guided by susceptibilities when available).
• If the person is at higher risk of treatment failure (for example frequent antibiotic use; previous or current sputum culture with resistant bacteria, or high risk of developing complications) consider prescribing either
  • Co-amoxiclav 500/125 mg three times a day for 5 days or
  • Co-trimoxazole 960mg twice daily for 5 days.
    • A further alternative is to prescribe levofloxacin 500mg once daily for 5 days (only if other alternative choice antibiotics are unsuitable with specialist advice).
    • Note: Note that systemic fluoroquinolones must now only be prescribed when other commonly recommended antibiotics are inappropriate. This follows a review by the MHRA which looked at the effectiveness of current measures to reduce the identified risk of disabling and potentially long-lasting or irreversible side effects. When prescribing fluoroquinolones, provide the patient information found in the MHRA Drug Safety Update on fluoroquinolone antibiotics.
    • Seek specialist advice if uncertain.
• If an antibiotic is prescribed, give advice on:
  • Potential adverse effects, including diarrhoea.
  • When to seek medical help, for example if:
    • Symptoms worsen rapidly or significantly or
    • Symptoms do not start to improve within 2–3 days (or other agreed time) or
    • They become systemically very unwell.
• If no antibiotic is given, advise the person to seek medical help immediately if:
  • Symptoms (such as sputum colour changes and increases in volume or thickness) worsen rapidly or significantly or
  • Symptoms do not start to improve within an agreed time or
  • They become systemically very unwell.
• If a sputum sample has been sent and an antibiotic given:
  • Review the choice of antibiotic when results are available.
  • Only change the antibiotic according to susceptibility results if bacteria are resistant and symptoms are not improving.
• Seek specialist advice if:
  • Symptoms are not improving with repeated courses of antibiotics or
  • Bacteria resistant to oral antibiotics are identified or
  • The person cannot take oral medication.

How should I follow up a person who has had an exacerbation of COPD?

• Reassess people with an acute exacerbation of chronic obstructive pulmonary disease (COPD) if their symptoms worsen rapidly or significantly at any time. Consider:
  • Other possible diagnoses, such as pneumonia.
  • Symptoms or signs suggestive of a more serious illness or condition, such as cardiorespiratory failure or sepsis.
  • Previous antibiotic use which may have led to resistant bacteria.
  • The need for admission.
• Send a sputum sample for culture and sensitivity testing if symptoms have not improved following antibiotic treatment and this has not already been done.
• Follow up all people who have had an exacerbation of COPD when they are clinically stable (for example, 6 weeks after the onset of exacerbation). At follow up:
  • Assess any residual or changed symptoms — consider the need for further investigations (for example chest X-ray if the person has recurrent chest infections) to exclude other conditions.
  • Optimize non-pharmacological and pharmacological management to reduce the risk of further exacerbations.
  • Ensure the person knows how to use prescribed medications appropriately and assess for adverse effects.
  • Consider the need for referral to a respiratory specialist and/or referral or re-referral for pulmonary rehabilitation.
  • Offer a short course of oral corticosteroids and a short course of oral antibiotics to keep at home as part of the person’s exacerbation action plan if they:
    • Have had an exacerbation within the last year, and remain at risk of exacerbations.
    • Understand and are confident about when and how to take the medication, and are aware of associated risks and benefits.
    • Know to when to seek help and when to ask for replacements once medication has been used.
  • For people who have used 3 or more courses of oral corticosteroids and/or oral antibiotics in the last year, investigate the possible reasons for this — consider alternative causes.
  • Review the person’s self-management plan.

When should I suspect a person has end-stage COPD?

• There is no commonly accepted definition of “end-stage COPD” and prediction of life expectancy in COPD is difficult. In most people, disease progression will follow a course of gradual decline punctuated by acute exacerbations that increase the risk of dying.
• Factors associated with increased risk of mortality in people with COPD include:
  • Frequency and severity of exacerbations.
  • Hospitalization during an exacerbation.
  • Poor lung function on spirometry.
  • Low body mass index.
  • Comorbidities such as cardiovascular disease and malignancy.
• Tools, such as those from the Gold Standards Framework are available help healthcare professionals identify people who are likely to be approaching the end of their life.

How should I manage a person with end-stage COPD?

• For people with end-stage COPD, the focus is on palliative care to relieve symptoms and improve quality of life.
• Ensure the person has an advance care plan (if they wish) and discuss end-of-life issues (where appropriate) including advance decisions.
  • Choosing the right time to discuss prognosis and the person’s views on care can be difficult. However, early discussion and good advance palliative care planning are important in reducing anxiety for the person and their family/carer(s) and ensuring that care is consistent with wishes.
  • Advance care plans should be reviewed whenever there is a clinical event, deterioration, or change in social circumstances (for example a move into supported care).
• Coordinate care with a respiratory nurse specialist, district nurse, palliative care team, and social services as appropriate.
• Optimize treatment associated with COPD symptoms such as:
  • Breathlessness:
    • Discuss simple measures (such as keeping the room cool, improving air circulation with a fan or open window, and relaxation and breathing techniques) to help relieve breathlessness.
    • Consider the need for drug treatments (such as opiates) and oxygen.
    • For more information, see the CKS topic on Palliative care - dyspnoea.
  • Cough — for information, see the CKS topic on Palliative care - cough.
  • Secretions — for information, see the CKS topic on Palliative care - secretions.
  • Pain — for information see the CKS topic on Palliative cancer care - pain.
  • Insomnia — for information, see the CKS topic on Insomnia.
  • Depression — for information, see the CKS topic on Depression.
  • Anxiety — for information, see the CKS topic on Generalized anxiety disorder.
• Discuss with a specialist/consider admission to a hospice if symptoms are not controlled, or if this is the preferred place of death.
  • For general information on end-of-life care, see the CKS topic on Palliative care - general issues.
• Consider what practical and emotional support can be provided to family/carers of people with end stage COPD.

Which short-acting beta-2 agonists are available for COPD, and what dose should I prescribe?

• Salbutamol (off-label use)
  • Aerosol inhalation — 100 micrograms to 200 micrograms (1–2 puffs) up to four times daily.
  • Dry powder inhalation — 100 micrograms to 200 micrograms up to four times daily.
    • For acute bronchospasm, initially 100 micrograms to 200 micrograms, increased if necessary to 400 micrograms. Maximum daily dose 800 micrograms.
  • Nebulized solution — 2.5 mg to 5 mg, up to four times daily.
    • If dilution is necessary, a suitable volume of sterile sodium chloride 0.9% should be used.
  • Recommended doses may vary slightly for the different brands available. Doses for specific brands can be found in the BNF and the manufacturers' Summaries of Product Characteristics.
• Terbutaline sulfate (off-label use)
  • Dry powder inhalation — 500 micrograms (1 inhalation) up to four times daily.
  • Nebulised solution — 5 mg to 10 mg two to four times daily.
• Combination product
  • Salbutamol 2.5 mg plus ipratropium bromide 500 micrograms — 2.5 mL (one vial) three or four times daily.
  • Licensed for the treatment of bronchospasm in people with COPD.

[EMC, 2020a; EMC, 2023a; BNF, 2024; EMC, 2024a]

Which long-acting beta-2 agonists are available for COPD, and what dose should I prescribe?

• Formoterol
  • Aerosol inhalation — 12 micrograms twice daily. Additional doses may be taken to a total maximum of 48 micrograms daily (maximum single dose is 24 micrograms).
  • Dry powder inhalation — 12 micrograms twice daily.
• Salmeterol
  • By inhalation of aerosol, or inhalation of powder — 50 micrograms twice daily.
• Indacaterol (Onbrez Breezhaler®)
  • Dry powder inhalation — 150 micrograms once daily, can be increased to 300 micrograms once daily.
• Combination products
  • Formoterol with aclidinium bromide
    • For maintenance treatment in COPD by inhalation of powder – 1 inhalation twice daily.
  • Formoterol with beclometasone
    • For COPD with FEV1 less than 50% predicted by inhalation of aerosol — 2 inhalations twice daily.
    • Fostair® is more potent than traditional beclometasone dipropionate CFC-free inhalers — dose of beclometasone dipropionate in Fostair® should be lower than non-extra-fine formulations and will need to be adjusted to the individual.
  • Formoterol with beclometasone and glycopyrronium
    • For moderate to severe COPD by inhalation of aerosol — 2 inhalations twice daily.
  • Formoterol with budesonide
    • DuoResp Spiromax ® 160/4.5 — for COPD with FEV1 <70% of predicted — by inhalation of powder, 2 inhalations twice daily.
    • Symbicort Turbohaler® 400/12 — for COPD with FEV1 <70% of predicted — by inhalation of powder, one puff twice daily.
    • Fobumix ® 160/4.5 Easyhaler — for COPD with FEV1 <70% of predicted — by inhalation of powder, 2 inhalations twice daily.
    • DuoResp Spiromax ® 320/9 — for COPD with FEV1 <70% of predicted — by inhalation of powder, 1 inhalation twice daily.
    • Fobumix ® 320/9 Easyhaler9 — for COPD with FEV1 <70% of predicted — by inhalation of powder, 1 inhalation twice daily.
    • Symbicort®200/6 pressurised inhaler — for COPD with FEV1 <70% of predicted — by inhalation of aerosol, 2 inhalations twice daily.
    • Symbicort 200/6 Turbohaler® — for COPD with FEV1 <70% of predicted — by inhalation of powder, 2 puffs twice daily.
    • Other combinations of formoterol with budesonide are available but unlicensed for use in COPD.
  • Salmeterol with fluticasone
    • Seretide 500 Accuhaler® (salmeterol 50 micrograms plus fluticasone propionate 500 micrograms) — one inhalation twice daily.
    • AirFluSal Forspiro® — for COPD with FEV1 <60% of predicted by inhalation of powder, 1 inhalation twice daily.
    • Other combinations of salmeterol with fluticasone are available but are unlicensed for use in COPD.
  • Olodaterol is licensed for the maintenance treatment of COPD. However, it is a 'black triangle' drug subject to enhanced surveillance by the Medicines and Healthcare products Regulatory Agency (MHRA).
• Recommended doses may vary for different brands available — doses for specific brands can be found in the BNF and the manufacturers' Summaries of Product Characteristics.
• Clinicians should be aware of the increased risk of pneumonia associated with use of inhaled corticosteroids in people with COPD — for more information, see the section on Inhaled steroids.  

[EMC, 2021a; EMC, 2022a; EMC, 2023b; EMC, 2023c; BNF, 2024; GOLD, 2024]

Cautions

• Beta-2 agonists should be used with caution in people with:
  • Hyperthyroidism — beta-2 agonists may stimulate thyroid activity.
  • Diabetes mellitus — there is a rare risk of hyperglycaemia and ketoacidosis (especially with intravenous use). Additional blood glucose measurements are recommended when treatment with a beta-2 agonist is commenced.
  • Cardiovascular disease (including hypertension, arrhythmias, and hypertrophic obstructive cardiomyopathy) — beta-2 agonists may cause an increased risk of arrhythmias and significant changes to blood pressure and heart rate.
  • Susceptibility to QT-interval prolongation.
  • Hypokalaemia — plasma potassium concentration may be reduced by beta-2 agonists (particularly high doses).
  • Convulsive disorders.

[BNF, 2024]

What are the adverse effects of beta-2 agonists?

• The adverse effects of short-acting and long-acting beta-2 agonists are similar. They are usually dose-related and include:
  • Nervous system disorders such as tremor (occurs particularly in the hands and is usually worse in the first few days of treatment), headache, dizziness, and seizures.
  • Cardiac disorders such as palpitations, arrhythmias, peripheral vasodilation, and myocardial ischaemia.
  • Psychiatric disorders such as anxiety, restlessness, and insomnia.
  • Metabolic and nutrition disorders such as:
    • Hypokalaemia — potassium levels should be monitored in people on high doses of beta-2 agonists (for example people receiving parenteral and nebulized beta-2 agonists).
    • Hyperglycaemia.
  • Gastrointestinal disorders such as nausea and taste alteration.
  • Respiratory disorders such as oropharyngeal irritation and paradoxical bronchospasm (rare).
  • Musculoskeletal disorders such as muscle cramps.
• Ocular complications including acute angle-closure glaucoma and cataract have been reported in people using nebulized short-acting beta-2 agonists or combination products.
  • Advise people using nebulized short-acting beta-2 agonists to use a mouthpiece rather than a mask to minimize exposure of the eyes to the drug.
• Risk of adverse events may be higher in people with a predisposition to arrhythmias and in people with pre-existing cardiovascular disease, or hypertension.
• For some pressurised metered-dose inhalers there is a risk of airway obstruction from aspiration of loose objects.

[EMC, 2023a; BNF, 2024; EMC, 2024a]

What drug interactions are important with beta-2 agonists?

• Corticosteroids, diuretics, and theophylline — monitor potassium levels.
  • Beta-2 agonists can cause hypokalaemia (particularly at high doses), and this can be increased by other potassium-depleting drugs such as corticosteroids, loop diuretics, and theophylline, amiodarone, and SSRIs.
• Digoxin — monitor potassium levels and be alert to signs of digoxin toxicity, such as loss of appetite, nausea, vomiting, bradycardia, visual disturbance, and drowsiness.
• Non-selective B-blocking drugs such as propranolol — the manufacturer recommends avoiding.
• CYP3A4 inhibitors (such as ketoconazole) — may increase plasma levels of salmeterol and associated systemic effects.
• For more information on drug interactions with beta-2 agonists, see the British National Formulary.

 [EMC, 2023a; BNF, 2024; Preston, 2024]

Which short-acting muscarinic antagonists are available for COPD, and what doses should I prescribe?

• Ipratropium
  • Aerosol inhalation — usually 20 micrograms to 40 micrograms (1–2 puffs), three or four times daily.
  • Nebulized solution — 250 micrograms to 500 micrograms three to four times daily.
    • If dilution is necessary, use sterile sodium chloride 0.9%.
  • Recommended doses may vary slightly for the different brands available. Doses for specific brands can be found in the BNF and the manufacturers' Summaries of Product Characteristics.
• Combination products
  • Ipratropium with salbutamol — by inhalation of nebulised solution for bronchospasm in COPD (ipratropium bromide 500 micrograms plus salbutamol 2.5 mg) — 0.5/2.5 mg three or four times daily.

[EMC, 2020a; EMC, 2023d; BNF, 2024]

Which long-acting muscarinic antagonists are available for COPD, and what doses should I prescribe?

• Tiotropium — for maintenance treatment of COPD.
  • For Spiriva® inhalation powder, 1 capsule contains a metered-dose of 18 micrograms tiotropium; for Braltus® inhalation powder, 1 capsule contains a metered-dose of 13 micrograms tiotropium.
    • The delivered dose of Spiriva® and Braltus® inhalation powder products are the same (10 micrograms); no dose adjustment is necessary when switching between brands.
  • For Spiriva Respimat® 5 micrograms once daily by inhalation of aerosol (2 puffs is equivalent to 5 micrograms of tiotropium).
• Aclidinium, glycopyrronium and umeclidinium are licensed for the maintenance treatment of COPD. They are 'black triangle' drugs subject to enhanced surveillance by the Medicines and Healthcare products Regulatory Agency (MHRA).

[EMC, 2023d; EMC, 2023d; BNF, 2024]

When should antimuscarinics be used with caution?

• Antimuscarinics should be used with caution in:
  • Men with prostatic hyperplasia and bladder-outflow obstruction — worsened urinary retention has been reported in elderly men.
  • People with renal impairment — manufacturer advises use only if potential benefit outweighs risk if creatinine clearance is less than or equal to 50 mL/minute.
  • People with angle-closure glaucoma — nebulized mist of antimuscarinic drugs can precipitate or worsen acute angle-closure glaucoma.
  • Pregnancy or breastfeeding — the manufacturer recommends avoiding use in pregnant or breastfeeding people, seek specialist advice.
• Tiotropium should be used with caution in people with cardiac arrhythmias, heart failure or myocardial infarction in the previous 6 months.
  • There is an increased risk of all-cause mortality in this group of people following the use of this product.
• Combination ipratropium with salbutamol is contraindicated in people with hypertrophic obstructive cardiomyopathy or tachyarrhythmia — see section on Beta-2 agonists for additional information.

[BNF, 2024]

What are the adverse effects of antimuscarinics?

• The adverse effects of antimuscarinics include:
  • Cardiac disorders such as arrhythmias and palpitations.
  • Respiratory disorders such as paradoxical bronchospasm, throat irritation, and cough.
  • Gastrointestinal disorders such as dry mouth, abnormal taste in the mouth, nausea, vomiting, constipation, and diarrhoea.
  • ENT disorders such as nasal congestion, dryness of nasal mucosa, and epistaxis.
  • Nervous system disorders such as headache and dizziness.
  • Urinary disorders such as bladder outflow obstruction and prostatic hyperplasia.
  • Visual disorders including acute angle-closure glaucoma — reported in people on nebulized ipratropium, particularly when given with nebulised salbutamol. To reduce the risk of this adverse effect, advise people:
    • To use a mouthpiece rather than a mask with a nebulizer, if possible, to minimize exposure of the eyes to the drug.
    • On correct administration of dry powder and aerosol inhalers to avoid accidental release of the contents into the eye.
    • With angle-closure glaucoma who are using muscarinic antagonists to stop and consult a specialist immediately if they experience eye pain or discomfort, visual halos or coloured images, or temporary blurring of vision.
• Risk of airway obstruction from aspiration of loose objects with pressurised metered-dose inhalers.
  • The MHRA has received reports of cases where a Braltus® capsule has been inhaled from the mouthpiece into the back of the throat, resulting in coughing and risking aspiration or airway obstruction. Patients should be trained in the correct use of their inhaler and told to store capsules in the screw-top bottle provided (never in the inhaler) and to always check the mouthpiece is clear before inhaling.

[EMC, 2020a; EMC, 2021b; EMC, 2023d; BNF, 2024]

What drug interactions are important with muscarinic antagonists?

• Concurrent use of inhaled antimuscarinics with other antimuscarinic drugs is not recommended as the effects of concurrent use have not been studied.

[EMC, 2023d; BNF, 2024; Preston, 2024]

What inhaled corticosteroids are available for COPD, and what dose should I prescribe?

• Inhaled corticosteroids (ICS) should be prescribed in combination with a long-acting bronchodilator in people with chronic obstructive pulmonary disease (COPD).
• The NICE guideline on COPD [NICE, 2019] recommends that where combination therapy with long-acting bronchodilators and ICS is being considered, clinicians should be aware of, and discuss with the person, the risk of adverse effects including an increased risk of pneumonia (which may require hospitalization).

Inhaled corticosteroid preparations licensed for the management of COPD are available as combination products. They include:

• Formoterol with budesonide
  • DuoResp Spiromax® 160/4.5 — for COPD with FEV1 <70% of predicted — by inhalation of powder, 2 inhalations twice daily.
  • Symbicort Turbohaler® 400/12 — for COPD with FEV1 <70% of predicted — by inhalation of powder, one puff twice daily.
  • Fobumix® 160/4.5 Easyhaler — for COPD with FEV1 <70% of predicted — by inhalation of powder, 2 inhalations twice daily.
  • DuoResp Spiromax ® 320/9 — for COPD with FEV1 <70% of predicted — by inhalation of powder, 1 inhalation twice daily.
  • Fobumix® 320/9 Easyhaler9 — for COPD with FEV1 <70% of predicted — by inhalation of powder, 1 inhalation twice daily.
  • Symbicort® 200/6 pressurised inhaler — for COPD with FEV1 <70% of predicted — by inhalation of aerosol, 2 inhalations twice daily.
  • Symbicort 200/6 Turbohaler® — for COPD with FEV1 <70% of predicted — by inhalation of powder, 2 puffs twice daily.
  • Other combinations of formoterol with budesonide are available but are not currently licensed for use in COPD.
• Formoterol with beclometasone
  • Fostair NEXThaler® 100/6— for COPD with FEV1 <50% predicted by inhalation of powder, 2 inhalations twice daily.
  • Fostair® 100/6 — for COPD with FEV1 <50% predicted by inhalation of aerosol — 2 inhalations twice daily.
  • Clinicians should be aware that Fostair® is more potent than traditional beclometasone dipropionate CFC-free inhalers — dose of beclometasone dipropionate in Fostair® should be lower than non-extra-fine formulations and will need to be adjusted to the individual.
• Formoterol with beclometasone and glycopyrronium
  • For moderate to severe COPD by inhalation of aerosol — 2 inhalations twice daily.
• Salmeterol with fluticasone
  • Seretide 500 Accuhaler® — by inhalation of powder, one inhalation twice daily.
  • AirFluSal Forspiro® — for COPD with FEV1 <60% of predicted by inhalation of powder, 1 inhalation twice daily.
  • Other combinations of salmeterol with fluticasone are available but are not currently licensed for use in COPD.

[EMC, 2020b; EMC, 2023b; EMC, 2023c; BNF, 2024]

What are the contraindications, cautions, adverse effects, drug interactions, and recommended monitoring for inhaled corticosteroids?

• For detailed prescribing information on inhaled corticosteroids, see the CKS topic on Corticosteroids - inhaled.
• Clinicians should be aware of the increased risk of pneumonia (including pneumonia requiring hospitalisation) in people with chronic obstructive pulmonary disease treated with inhaled corticosteroids – this should be discussed with the person before prescribing.
• Consider issuing a steroid treatment card to:
  • People using prolonged high doses of inhaled corticosteroids.
  • People taking inhaled corticosteroids plus drugs that inhibit their metabolism (for example cytochrome P450 inhibitors, such as HIV protease inhibitors).

[BNF, 2024; GOLD, 2024; Preston, 2024]

What issues need to be considered when prescribing oral corticosteroids?

• Short courses of oral corticosteroids are commonly used for acute exacerbations of chronic obstructive pulmonary disease (COPD).
• Maintenance use of oral corticosteroid therapy in COPD is not normally recommended. However, some people with advanced COPD may require maintenance oral corticosteroids when these cannot be withdrawn after an exacerbation. In these cases, the dose of oral corticosteroids should be kept as low as possible.
• People on long-term corticosteroid treatment should carry a steroid treatment card and be monitored for osteoporosis/given appropriate prophylaxis.
• For detailed prescribing information on oral corticosteroids, see the CKS topic on Corticosteroids - oral.

[NICE, 2019; BNF, 2024; GOLD, 2024]

Which mucolytics can be prescribed?

• Carbocisteine and acetylcysteine are the oral mucolytics licensed for use in people with chronic obstructive pulmonary disease.
• For carbocisteine the manufacturer recommends a starting dose of 2250 mg in divided doses, reducing to 1500 mg daily in divided doses when a satisfactory response is obtained.
• For acetylcysteine, the manufacturer recommends a dose of 1 effervescent tablet of 600 mg once daily.

[EMC, 2020c; EMC, 2023e; BNF, 2024]

What contraindications and cautions are important with carbocisteine?

• Do not prescribe carbocisteine to:
  • People with active peptic ulceration.
  • Women who are pregnant or breastfeeding.
• Prescribe carbocisteine with caution to:
  • People with a history of peptic ulceration or those taking concomitant medications known to cause gastrointestinal bleeding.
  • People with a history of asthma or respiratory failure. 
• Prescribe acetylcysteine with caution to:
  • People with a history of peptic ulceration.

[EMC, 2020c; EMC, 2023e; BNF, 2024]

What drug interactions should be considered?

• The manufacturers state that combination of mucolytics with antitussives and/or substances that dry out secretions (atropinic) is not rational.
• The manufacturer recommends that for acetylcysteine:
  • The effervescent solution created using acetylcysteine should not be mixed with other drug solutions.
  • If oral antibiotics are required, these should be taken two hours before or after acetylcysteine.

[EMC, 2020c; EMC, 2023e; BNF, 2024; Preston, 2024]

What important adverse effects are associated with mucolytics?

• The adverse effects of carbocisteine include:
  • Skin reactions including Stevens-Johnson syndrome and erythema multiforma.
  • Gastrointestinal bleeding and vomiting.
• The adverse effects of acetylcysteine include:
  • Bronchospasm.
  • Skin reactions including Stevens-Johnson syndrome.
  • Dyspepsia.
  • Headache and tinnitus.
  • Diarrhoea, vomiting, nausea, gastrointestinal discomfort, and stomatitis,
  • Hypotension.

[EMC, 2020c; EMC, 2023e; BNF, 2024]

How should theophylline be prescribed?

• Prescribe theophylline by brand name as there are bioavailability differences between brands — if discharged from hospital on theophylline the brand on which they were stabilized as an inpatient should be maintained.
  • Plasma-theophylline concentration is increased in heart failure, hepatic impairment, and in viral infections. Plasma-theophylline concentration is decreased in smokers and by alcohol consumption. Differences in the half-life of theophylline are important because the toxic dose is close to the therapeutic dose.

[NICE, 2019; BNF, 2024; GOLD, 2024]

What dose of theophylline should I prescribe for COPD?

• Theophylline
  • Nuelin SA® modified release tablets:
    • Nuelin SA® 175 tablets — for reversible airways obstruction, 175 mg twice daily, increasing to 350 mg if necessary.
    • Nuelin SA® 250 tablets — for reversible airways obstruction, 250 mg twice daily, increasing to 500 mg if necessary.
  • Slo-Phyllin® modified-release capsules — for reversible airways obstruction, 250 mg to 500 mg every 12 hours, titrate from lowest dose depending on response.
  • Uniphyllin Continus® modified-release tablets — for reversible airways obstruction, 200 mg every 12 hours. This may be titrated to either 300 mg or 400 mg according to response.

[EMC, 2023f; BNF, 2024]

How should theophylline be monitored?

• Before starting theophylline, check:
  • Urea and electrolyte levels (paying particular attention to potassium levels).
  • Liver function.
• Check drug plasma levels:
  • Five days after starting oral treatment.
  • Routinely every 6–12 months. Check more regularly in older people or those with heart failure or hepatic impairment.
  • At least 3 days after any dose adjustments.
  • If the person experiences adverse effects that may suggest toxicity (such as nausea, vomiting, tremor, or palpitations).
  • If an enzyme-inhibiting drug (such as erythromycin, clarithromycin, allopurinol, or cimetidine) is prescribed (raises plasma levels) or if an enzyme-inducing drug (such as carbamazepine, rifampicin, or St John's Wort) is prescribed (lowers plasma levels).
  • If the person starts or stops smoking — a dose adjustment may be needed because tobacco can lower the plasma levels of theophylline.
• Plasma potassium concentrations may be reduced by beta-2 agonists, corticosteroids, and diuretics. This effect may be potentiated by theophylline. Check potassium levels regularly in:
  • People taking beta-2 agonists, corticosteroids, or diuretics.
  • People who are hypoxic — theophylline can potentiate hypokalaemia resulting from hypoxia.
• Careful monitoring is recommended for patients with congestive heart failure, chronic alcoholism, hepatic dysfunction, or viral infections — they may have a lower clearance of theophylline, which could lead to higher than normal plasma levels.

   [EMC, 2023f; BNF, 2024]

When should theophylline be used with caution?

• Do not prescribe theophylline to people with:
  • Recent myocardial infarction.
  • Acute tachycardia.
  • Porphyria.
• Use theophylline with caution in people with:
  • Cardiovascular disease, including cardiac arrhythmias and heart failure.
  • Hepatic impairment.
  • Hypokalaemia risk — for more information, see the section on monitoring.
  • Hypertension.
  • Hyperthyroidism and hypothyroidism.
  • Peptic ulcers.
  • Fever — decreases the clearance of theophylline.
  • Epilepsy – manufacturer recommends avoiding.
• In addition, particular caution needs to be observed in older people due to differences in pharmacokinetics, increased likelihood of comorbidities, and the use of other medications.

[EMC, 2023f; BNF, 2024; GOLD, 2024]

What important adverse effects are associated with theophylline?

• The adverse effects of theophylline include:
  • Gastrointestinal disorders such as nausea, vomiting, and gastro-oesophageal reflux.
  • Neurological disorders such as tremor, headache, dizziness, central nervous system stimulation, insomnia, and convulsion (rare).
  • Psychiatric disorders such as anxiety.
  • Metabolic and electrolyte disorders such as hypokalaemia, hyperuricaemia, hyperglycaemia, and hyperuricaemia.
  • Cardiovascular disorders such as palpitations, arrhythmias, and hypotension.
  • Skin reactions.
• Potentially serious hypokalaemia may result from beta-2 agonist therapy.
• Adverse effects can occur with plasma theophylline concentrations of 10 mg/L to 20 mg/L. However, a plasma concentration in this range is required in most people to achieve a satisfactory clinical effect.
• Both the frequency and severity of adverse effects increase when plasma concentrations of aminophylline or theophylline are above 20 mg/L.

[EMC, 2023f; BNF, 2024]

What are the key drug interactions with theophylline?

• Theophylline interacts with many drugs including:
  • Beta-2 agonists, corticosteroids, diuretics — potentially serious hypokalaemia may result from beta-2 agonist therapy.
    • Check serum potassium levels regularly.
  • Lithium — excretion of lithium may be potentiated.
    • Check plasma lithium levels and alter dose if necessary.
  • Fluvoxamine — can raise the plasma level of theophylline.
    • Avoid concomitant use if possible, or halve the dose and monitor plasma levels.
  • Digoxin — increased risk of digoxin toxicity.
  • Other xanthine containing medications — avoid concomitant administration.
• Plasma levels of theophylline can be altered by concomitant use with liver enzyme-inhibiting drugs such as verapamil, ciprofloxacin, fluconazole, erythromycin, clarithromycin, allopurinol, or cimetidine; or liver enzyme-inducing drugs such as primidone, phenobarbital, carbamazepine, phenytoin, ritonavir, rifampicin, or St John's Wort.
• Influenza vaccine — there are conflicting reports concerning the potentiation of theophylline by influenza vaccine, interaction may occur resulting in increased serum theophylline levels.
• The person should be made aware that:
  • Over-the-counter cough and decongestant preparations that contain theophylline should be avoided.
  • Coffee increases the effect of theophylline.
• Due to the many interactions of theophylline, monitoring of serum theophylline concentrations is recommended during long-term use with other drugs.
  • For a detailed list of interactions, see the BNF and Summary of Product Characteristics.

 [EMC, 2023f; BNF, 2024; Preston, 2024]   

Azithromycin

Contraindications and cautions

• Do not prescribe azithromycin in people:
  • With severe hepatic impairment.
• Prescribe azithromycin with caution in people:
  • Who may be predisposed to prolongation of the QT interval. For example, people with:
    • Congenital or documented acquired QT prolongation.
    • Currently receiving treatment with other active substances known to prolong the QT interval, such as antiarrhythmics of classes IA and III.
    • With electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia.
    • With clinically relevant bradycardia, cardiac arrhythmia, or severe cardiac insufficiency, including torsades de pointes.
  • With mild to moderate hepatic impairment.
  • With severe renal impairment.
  • With myasthenia gravis — macrolides may aggravate symptoms.

Adverse effects

• Gastrointestinal — diarrhoea, abdominal pain, nausea (very common); vomiting, dyspepsia (common); pancreatitis, and pseudomembranous colitis (frequency unknown). For more information, see the CKS topic on Diarrhoea - antibiotic associated.
• Nervous system — headache, dizziness, dysgeusia, paraesthesia (common); convulsions, hyperactivity, syncope, and myasthenia gravis (frequency unknown).
• Psychiatric — nervousness (uncommon); aggression, and anxiety (frequency unknown).
• Skin and subcutaneous tissue — rash, pruritus (common); Stevens-Johnson syndrome (uncommon); drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP) (rare); toxic epidermal necrolysis, and erythema multiforme (frequency unknown).
• Other common adverse effects include: 
  • Anorexia.
  • Arthralgia.
  • Deafness.
  • Fatigue.
  • Visual impairment.
• Other adverse effects include:
  • Acute kidney injury.
  • QT interval prolongation.

Drug interactions

• Antacids — plasma concentrations of azithromycin may be reduced. Simultaneous administration should be avoided — azithromycin should be taken at least 2 hours before, or 1 hour after antacids.
• Ciclosporin — azithromycin may increase cyclosporin levels. 
• Cisapride — macrolides increase levels of cisapride, increasing the risk of arrhythmias (Torsade de pointes). Concurrent use is contraindicated.
• Colchicine — azithromycin slightly increases the levels of colchicine. Monitor for signs of colchicine toxicity (for example, nausea, vomiting, diarrhoea, myopathy, and pancytopenia).
• Digoxin — cases of increased digoxin levels have been reported. Monitor for signs of digoxin adverse effects (such as bradycardia). Monitor and reduce the digoxin dose if required.
• Edoxaban — levels may be increased by azithromycin. Dose adjustment of edoxaban may be required.
• Rifabutin — azithromycin increases the risk of neutropenia when given with rifabutin. Monitor closely.
• Statins — there is a possible increased risk of myopathy.
  • Advise the person to report any muscle pain, tenderness, or weakness.
• Typhoid vaccine — antibacterials might reduce the immune response. The World Health Organization (WHO) recommends that the antibacterial is stopped from 3 days before to 3 days after receiving live oral typhoid vaccine.
• Warfarin — concurrent use may increase the international normalized ratio (INR). Consider increasing INR monitoring as this interaction appears to develop over the first 7 days.
• Drugs that prolong the QT interval (such as amiodarone, sotalol, and hydroxyzine) — all macrolides can prolong the QT interval, and concomitant use of drugs that prolong the QT interval is not recommended. If concurrent use is unavoidable consider ECG (electrocardiogram) monitoring.
  • Concurrent use with domperidone, hydroxyzine, or mizolastine is contraindicated.
• Drugs that cause hypokalaemia (such as diuretics, corticosteroids, and short-acting beta-2 agonists) — hypokalaemia is a risk factor for QT prolongation.

[BNF, 2024; EMC, 2022b; Preston, 2024]

Amoxicillin

Contraindications and cautions

• Do not prescribe amoxicillin to:
  • People with a true penicillin hypersensitivity — gastrointestinal adverse effects alone (such as nausea, vomiting, or diarrhoea) do not constitute an allergy to penicillin.
• Prescribe amoxicillin with caution in people with:
  • Hypersensitivity to cephalosporins.
  • Chronic kidney disease (CKD) — reduce the dose of amoxicillin.

Adverse effects

• Gastrointestinal — nausea and diarrhoea (common) and vomiting (uncommon).
  • Very rarely — antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis).
  • For more information, see the CKS topic on Diarrhoea - antibiotic associated.  
• Skin — skin rash (common), urticaria, and pruritus (uncommon).
  • Very rarely — erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis, and acute generalised exanthematous pustulosis.
• Other rare or very rare adverse effects include:
  • Hepatitis and cholestatic jaundice.
  • Hyperkinesia, dizziness, and convulsions.
  • Interstitial nephritis.
  • Leucopenia, thrombocytopenia, and haemolytic anaemia.
  • Seizure.
  • Severe allergic reactions.

Drug interactions

• Allopurinol — increased risk of rash when allopurinol is given with amoxicillin.
• Warfarin — INR may be increased. Monitor the international normalized ratio (INR) closely during concomitant use. Dosage adjustments may be necessary.
• Methotrexate — amoxicillin may reduce methotrexate clearance, causing an increased risk of toxicity. Consider measuring platelet and white cell counts twice weekly for 2 weeks initially, and measure methotrexate levels if toxicity is suspected.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of amoxicillin.
  • However, women should be advised about the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the sections on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods. 
  • For more information on drug interactions with amoxicillin, see the British National Formulary.

[CoSRH, 2022; BNF, 2024; EMC, 2024b; Preston, 2024]

Doxycycline

Contraindications and cautions

• Do not prescribe doxycycline to:
  • Pregnant or breastfeeding women.
• Prescribe doxycycline with caution in people with:
  • Liver problems.
  • Systemic lupus erythematosus.
  • Myasthenia gravis.
  • Renal impairment.
  • Porphyria.

Adverse effects

• Blood disorders — haemolytic anaemia, thrombocytopenia, neutropenia, and eosinophilia.
• Gastrointestinal — nausea, vomiting, dyspepsia, abdominal discomfort, diarrhoea, and tooth discolouration and enamel hypoplasia in children.
  • Rarely — dysphagia, oesophagitis, oesophageal irritation, and pseudomembranous colitis. For more information, see the CKS topic on Diarrhoea - antibiotic associated.
• Hepatic disorders – hepatotoxicity, hepatitis, jaundice, and hepatic failure.
• Renal disorders — blood urea increased.
• Skin — photosensitivity and rash.
  • Rarely — toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme, exfoliative dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS), and fixed eruption.
• Other rare adverse effects include:
  • Anaphylaxis.
  • Arthralgia and myalgia.
  • Bulging fontanelles in infants.
  • Flushing.
  • Severe headache and/or visual disturbances — may be an early symptom of benign intracranial hypertension, a rare but serious adverse effect.
  • Tinnitus.

Drug interactions

• Phenobarbital, carbamazepine, phenytoin, and primidone — metabolism of doxycycline may be accelerated by these drugs, leading to a reduced plasma concentration.
  • Monitor the therapeutic effect of doxycycline, as a dose adjustment may be necessary.
• Rifampicin — may cause a reduction in doxycycline levels, leading to undertreatment.
  • Monitor the effects of concurrent use, dose adjustment may be necessary.
• Antacids (containing aluminium, bismuth, calcium, or magnesium) and other medications containing iron or zinc — these reduce the absorption of tetracyclines if taken concurrently.
  • Avoid taking antacids and other medications containing iron or zinc, 2 hours before or after taking tetracyclines.
• Insulin — the blood-glucose lowering effect may be increased if taken with doxycycline. Monitor blood-glucose levels.
• Lithium — levels may be increased by doxycycline. Consider increasing the frequency of lithium monitoring.
• Methotrexate — levels may be increased by doxycycline.
• Warfarin — the concurrent use of warfarin with tetracyclines may increase the anticoagulant effect.
  • Consider monitoring the person's international normalized ratio (INR) regularly and within 3 days of starting the tetracycline. Adjust the warfarin dose accordingly.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of doxycycline.
  • However, advise women about the importance of correct contraceptive practice if they experience vomiting or diarrhoea.
  • For further information, see the sections on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods.
• Retinoids — there is a possible increased risk of benign intracranial pressure if tetracyclines are used concurrently with retinoids (such as isotretinoin).
  • Avoid the concurrent use of tetracyclines and retinoids.
• For more information on drug interactions with doxycycline, see the British National Formulary.

 [CoSRH, 2022; BNF, 2024; EMC, 2024c; Preston, 2024]

Clarithromycin

Contraindications and cautions

• Do not prescribe clarithromycin to people:
  • Taking drugs that prolong the QT interval (for example haloperidol, sotalol, terfenadine, and pimozide) — macrolides can also prolong the QT interval, which is a risk factor for torsades de pointes.
  • With a history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointes.
  • With hypokalaemia — due to the risk of prolongation of the QT interval.
  • With severe hepatic impairment if they also have renal impairment.
  • With statins (such as simvastatin) — due to the increased risk of myopathy, including rhabdomyolysis.
  • With ergot alkaloids or midazolam.
• Prescribe clarithromycin with caution to people with:
  • Coronary artery disease, severe cardiac insufficiency, or bradycardia (less than 50 beats per minute) — increased risk of QT prolongation. There is an increased risk of death for people with coronary artery disease.
  • Electrolyte disturbances, such as hypomagnesaemia.
  • Impaired hepatic function – clarithromycin is principally excreted by the liver.
  • Myasthenia gravis — macrolides may aggravate symptoms.
  • Severe renal impairment (eGFR less than 30 mL/min) — dose adjustment required. 

Adverse effects

• Gastrointestinal — diarrhoea, vomiting, dyspepsia, nausea, abdominal pain, and pancreatitis.
  • Rarely — pancreatitis and pseudomembranous colitis. For more information, see the CKS topic on Diarrhoea - antibiotic associated.
• Nervous system — headache, dysgeusia, dizziness, somnolence, and tremor.
  • Rarely — convulsions, paraesthesia.
• Psychiatric — insomnia, anxiety, and nervousness.
  • Rarely or very rarely — psychotic disorders, depression, mania, and hallucination.
• Skin — rash, hyperhidrosis, pruritus, and urticaria.
  • Rarely, or very rarely — Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens Johnson syndrome, and toxic epidermal necrolysis.
• Other adverse effects reported uncommonly, rarely, or very rarely, include:
  • Anaphylaxis.
  • Arrhythmias.
  • Deafness.
  • Hepatic failure, jaundice.
  • QT interval prolongation.

Drug interactions

• Calcium channel blockers (CCBs) — there is an increased risk of hypotension if CCBs, such as verapamil, amlodipine, and diltiazem are taken concomitantly with clarithromycin, as they are metabolised by CYP3A4. This may also lead to increased levels of clarithromycin.
• Ciclosporin — erythromycin can affect clearance of ciclosporin. If co-administration of these drugs is necessary, ciclosporin levels should be monitored and the dose adjusted accordingly.
• Colchicine — azithromycin slightly increases the levels of colchicine. Monitor for signs of colchicine toxicity (for example, nausea, vomiting, diarrhoea, myopathy, and pancytopenia).
• CYP3A enzyme inducers (rifampicin, carbamazepine, phenobarbital) — these may induce the metabolism of clarithromycin, resulting in sub-therapeutic levels.
  • It may be necessary to monitor the levels of these drugs, as CYP3A is inhibited by clarithromycin leading to higher plasma levels of the inducer.
• Digoxin — macrolides increase digoxin levels. The risk of toxicity may be lower with azithromycin than with clarithromycin. Monitor and adjust dose if required.
• Edoxaban — manufacturer advises caution with concurrent treatment with edoxaban, particularly in those with a high risk of bleeding.
• Ergot alkaloids — concomitant administration is contraindicated, due to the risk of acute ergot toxicity.
• Ivabradine — concomitant treatment is contra-indicated, owing to CYP3A4 inhibition by clarithromycin which can cause elevated levels of ivabradine.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of clarithromycin.
  • However, women should be advised that if diarrhoea, vomiting or breakthrough bleeding occur there is a possibility of contraceptive failure.
  • For further information, see the sections on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods.
• Oral hypoglycaemic drugs (sulfonylureas) and insulin — the concomitant use of clarithromycin and oral hypoglycaemic drugs and/or insulin can result in significant hypoglycaemia. Monitor glucose levels.
• Statins (atorvastatin, simvastatin) — these are extensively metabolised by CYP3A4. Concomitant administration with clarithromycin increases the plasma levels and the risk of myopathy.
  • Simvastatin — do not prescribe clarithromycin to a person taking simvastatin. If treatment with clarithromycin cannot be avoided, stop treatment with simvastatin temporarily.
  • Atorvastatin — avoid concurrent use with clarithromycin. If concurrent use cannot be avoided, prescribe the lowest dose of atorvastatin.
• Warfarin — clarithromycin increases the anticoagulant effect of warfarin. Monitor the international normalized ratio (INR), and adjust the warfarin dose accordingly.
• Drugs that prolong the QT interval (such as amiodarone, or sotalol) — all macrolides can prolong the QT interval, and concomitant use of drugs that prolong the QT interval is contraindicated.

 [CoSRH, 2022; BNF, 2024; EMC, 2024d; Preston, 2024] 

Co-amoxiclav

Contraindications and cautions

• Do not prescribe co-amoxiclav to people with:
  • A true penicillin hypersensitivity. Gastrointestinal adverse effects alone (such as nausea, vomiting, or diarrhoea) do not constitute an allergy to penicillin. See the CKS topic on Angio-oedema and anaphylaxis for more information.
  • History of penicillin or clavulanic acid-associated hepatic dysfunction.
• Prescribe co-amoxiclav with caution to people with:
  • A hypersensitivity to cephalosporins — there is some evidence of partial cross-allergenicity.
  • Hepatic impairment – monitor closely.
  • Renal impairment — reduce the dose if the estimated glomerular filtration rate (eGFR) is 30 mL/minute/1.73 m² or less.
  • Acute lymphocytic leukaemia, chronic lymphocytic leukaemia, cytomegalovirus infection, glandular fever — increased risk of erythematous rashes.

Adverse effects

• Gastrointestinal — diarrhoea (very common), nausea and vomiting (common), and drug-induced enterocolitis syndrome (unknown frequency).
  • Very rarely — antibiotic-associated colitis.
• Nervous system — headache, dizziness (uncommon), and aseptic meningitis (unknown frequency).
• Skin — skin rash, urticaria, pruritus (uncommon), and drug reaction with eosinophilia and systemic symptoms (DRESS) (unknown frequency).
  • Very rarely — erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis, and acute generalized exanthematous pustulosis.
• Other rare, or very rare adverse effects include:
  • Hepatitis and cholestatic jaundice.
  • Hyperactivity and convulsions.
  • Hypersensitivity reactions (serious and occasionally fatal).  
  • Interstitial nephritis.
  • Linear IgA disease (renal deposition of IgA).  
  • Leucopenia, thrombocytopenia, and haemolytic anaemia.
  • Kounis syndrome (an allergic reaction which can cause myocardial infarction). 
• Symmetrical Drug-related Intertriginous and Flexural Exanthema (SDRIFE) are adverse effects of unknown frequency.

Drug interactions

• Allopurinol — concomitant use of allopurinol and amoxicillin may increase the incidence of skin rashes.
• Methotrexate — co-amoxiclav may reduce methotrexate clearance, causing an increased risk of toxicity.
  • Monitor methotrexate levels more closely. One recommendation is to carry out twice weekly platelet and white cell counts for 2 weeks initially, with the measurement of methotrexate levels if toxicity is suspected.
• Mycophenolate mofetil — reduction in the level of active metabolite may occur when given with co-amoxiclav.
• Oral anticoagulants (warfarin, phenindione) — prolongation of prothrombin time has been reported in people taking penicillins and warfarin concurrently.
  • Monitor the prothrombin time or international normalized ratio (INR) more closely with the addition or withdrawal of a penicillin. Adjustment of the anticoagulant dose may be necessary.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of co-amoxiclav.
  • However, women should be advised about the importance of correct contraceptive practice if they experience vomiting or diarrhoea.
  • For further information, see the sections on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods.
• Probenecid — concomitant administration may result in increased levels of amoxicillin, but not clavulanic acid
• For more information on drug interactions with co-amoxiclav, see the British National Formulary.

[CoSRH, 2022; EMC, 2023g; BNF, 2024; Preston, 2024]

Co-trimoxazole

Contraindications and cautions

• Do not prescribe co-trimoxazole to infants who are aged less than 6 weeks, or people with:
  • Acute porpyhria.
  • Severe hepatic impairment
  • Severe renal impairment — creatinine clearance less than 15 mL/minute, or in severe insufficiency where plasma-sulfamethoxazole concentration cannot be monitored.
• Prescribe co-trimoxazole with caution to people with:
  • Severe atopy, or asthma.
  • Haematological disorders — avoid unless under specialist supervision. 
  • A predisposition to hyperkalaemia.
  • A predisposition to folate deficiency — because of the potential anti-folate effect of trimethoprim, there is a risk of further exacerbating folate deficiency in people who are folate deficient, or who are predisposed to folate deficiency (for example elderly people), or who are taking folate antagonists.
  • Glucose-6-phosphate dehydrogenase deficiency.
  • Renal impairment — use half the normal dose if creatinine clearance 15–30 mL/minute.

Adverse effects

• Blood — leucopenia, thrombocytopenia, agranulocytosis, megaloblastic anaemia, eosinophilia (very rare). 
  • Discontinue immediately if blood disorders develop.
• Gastrointestinal — nausea, diarrhoea, (common), vomiting (uncommon).
  • Very rarely: glossitis, stomatitis, pseudomembranous colitis, pacnreatitis.
• Metabolism and nutrition — hyperkalaemia (very common).
  • Very rarely: hypoglycaemia, hyponatraemia, anorexia.
• Nervous system — headache (common),
  • Very rarely: aseptic meningitis, convulsions, ataxia, vertigo, tinnitus, dizziness.
• Skin and subcutaneous tissue — rash (common), acute generalised exanthematous pustulosis (AGEP), acute febrile neutrophilic dermatosis (Sweet's syndrome), drug reaction with eosinophilia and systemic symptoms (DRESS) (unknown frequency).
  • Very rarely: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, exfoliative dermatitis. 
  • Discontinue immediately if rash develops.
• Other adverse effects include: 
  • Anaphylaxis.
  • Arthralgia, and myalgia.
  • Cough, dyspnoea.
  • Renal impairment, interstitial nephritis.
  • Liver enzyme disturbances, cholestatic jaundice.
  • Uveitis.

Drug interactions

• Coumarin anticoagulants (for example, warfarin) — anticoagulant effect may be enhanced.
  • Monitor the international normalized ratio (INR), and adjust the dose accordingly.
• Antidiabetic drugs
  • Sulfonylureas — effects may be enhanced. Increase blood-glucose monitoring and adjust dose of antidiabetic drug if necessary. 
  • Repaglinide — levels may be increased slightly, increasing risk of hypoglycaemia. Avoid concurrent use. 
• Lamivudine, zidovudine — plasma concentrations increased. Concurrent treatment may increase the risk of haematological adverse effects. Monitor full blood count. Avoid concurrent use with high-dose co-trimoxazole and lamivudine in pneumocystis pneumonia and toxoplasmosis.
• Azathioprine and mercaptopurine — increased risk of haematological toxicity if given for extended periods. transplant. Monitor the full blood count routinely.
• Clozapine — increased risk of blood dyscrasias. Concurrent use contraindicated. 
• Ciclosporin — serum creatinine levels may be increased. Possible increased risk of nephrotoxicity, monitor renal function closely. Reversible deterioration in renal function has been reported in people following renal transplantation.
• Digoxin — digoxin levels may be increased, particularly in the elderly. Monitor for digoxin adverse effects, and adjust dose accordingly.
• Methotrexate — plasma levels may be increased. If concurrent use is necessary, a folate supplement should be considered. 
• Phenytoin — phenytoin levels may be increased if taken with trimethoprim. Monitor phenytoin levels and adjust dose accordingly.
• Drugs that cause hyperkalaemia — risk of severe hyperkalaemia. Monitor potassium concentrations. Avoid, where possible, in elderly people.
  • Angiotensin-converting enzyme (ACE) inhibitors.
  • Potassium-sparing diuretics.
  • Thiazide diuretics.
• Live cholera vaccines — the efficacy of the live vaccine may be affected. Avoid concurrent use and for 14 days before, and for 10 days after, live cholera vaccines.
• Live typhoid vaccines — the immune response to the vaccine may be reduced. Antibacterials should be stopped from 3 days before to 3 days after receiving live typhoid vaccines.

Pregnancy

• There is a teratogenic risk in the first trimester of pregnancy. The manufacturer advises that it should not be used in pregnancy, particularly the first trimester, unless clearly necessary.
• If trimethoprim is indicated during the first trimester, concomitant folic acid 5 mg daily is recommended .

Breastfeeding

• Sulfamethoxazole and trimethoprim are excreted in breastmilk. There is a small risk of kernicterus in jaundiced infants and of haemolysis in G6PD-deficient infants (due to sulfamethoxazole).
• Co-trimoxazole should be avoided in breastfeeding mothers where the mother or infant has, or is at particular risk of developing hyperbilirubinaemia.

[UKTIS, 2019; BNF, 2023; EMC, 2023h; Preston, 2023a]

Levofloxacin

Contraindications and cautions

• Note that systemic fluoroquinolones must now only be prescribed when other commonly recommended antibiotics are inappropriate. This follows a review by the MHRA which looked at the effectiveness of current measures to reduce the identified risk of disabling and potentially long-lasting or irreversible side effects.

• Do not prescribe levofloxacin to people:
  • With a history of tendon disorders related to quinolone use.
  • With a history of epilepsy.
  • Taking corticosteroids — co-administration could exacerbate fluoroquinolone-induced tendinitis and tendon rupture.
• Do not prescribe levofloxacin to:
  • Children or growing adolescents.
• Prescribe ofloxacin with caution in:
  • People aged over 60 years. 
  • People who have had solid organ transplants.
• Prescribe levofloxacin with caution to people with:
  • A predisposition to seizures, and in people taking other medication that may predispose to seizures (such as theophylline), as quinolones can lower the seizure threshold.
  • Diabetes mellitus — may affect blood glucose. Blood glucose should be monitored closely.
  • A history of tendonitis — quinolones can very rarely cause tendon damage, and the risk of tendon rupture is increased by co-administration of corticosteroid.
  • Renal impairment — give usual initial dose, then use half normal dose if creatinine clearance 20–50 mL/minute. If creatinine clearance is less than 20 mL/minute, give the usual initial dose, then half the normal dose every 48 hours.
  • A family history of aneurysm disease or congenital heart valve disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection or heart valve disease, or in presence of other risk factors or conditions predisposing for both aortic aneurysm and dissection and heart valve regurgitation/incompetence.
  • Conditions which predispose to QT interval prolongation:
    • Congenital long QT syndrome.
    • Concomitant use of drugs that are known to prolong the QT interval (for example Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics).
    • Uncorrected electrolyte imbalance (for example hypokalaemia, or hypomagnesaemia).
    • Cardiac disease (for example, heart failure, myocardial infarction, or bradycardia).
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
  • History of a psychotic disorder.
  • Myasthenia gravis — symptoms can be exacerbated.

Adverse effects

• Cardiac — tachycardia, palpitations, ventricular arrhythmias, torsades de pointes, QT interval prolongation, aortic aneurysm and dissection, heart valve regurgitation.
  • Advise people to seek immediate medical attention if sudden-onset severe abdominal, chest, or back pain develops, or if there is acute dyspnoea, new onset heart palpitations, or development of oedema of the abdomen, or lower extremities.   
• Gastrointestinal — diarrhoea, nausea, vomiting, constipation, abdominal pain.
• Musculoskeletal — arthralgia, myalgia (uncommon), tendon disorders (rare), rhabdomyolysis.
  • Tendon rupture may occur within 48 hours of starting treatment or months after stopping a quinolone. The risk of tendonitis and tendon rupture is increased in older people, people with renal impairment, people with solid organ transplants, and those treated concurrently with corticosteroids. Advise patients to stop treatment at the first signs of a serious adverse reaction, such as tendinitis or tendon rupture, muscle pain, muscle weakness, joint pain, joint swelling, peripheral neuropathy, and central nervous system effects, and to contact their doctor immediately for further advice. 
• Central nervous system (CNS) — headache, dizziness (common), sleep disorders, taste disorders, tinnitus, tremor, vertigo, visual disturbances, paraesthesia, convulsion (rarely), peripheral neuropathy.
  • Advise people to seek medical advice if neuropathy such as pain, burning, tingling, numbness, or weakness develop.
• Psychiatric — insomnia, agitation, sleep disorder, confusion, anxiety, depression, nightmares, psychotic disorders.
• Skin — rash, pruritus, urticaria (uncommon), toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, photosensitivity reaction, leukocytoclastic vasculitis, stomatitis.
• Other adverse effects include:
  • Anaphylaxis, fever, increased risk of infection, dyspnoea.
  • Anorexia, hypoglycaemia. 
  • Dyspnoea.
  • Vertigo, tinnitus.
  • Fluoroquinolones can very rarely cause long-lasting, disabling, and potentially irreversible adverse effects, sometimes affecting multiple organ systems.

Drug interactions

• Antacids (containing aluminium, calcium, or magnesium) and other medications containing iron or zinc — these may reduce the absorption of levofloxacin if taken concurrently.
  • Levofloxacin should be taken at least 2 hours before these preparations and not less than 4–6 hours after them.
• Corticosteroids — the risk of tendonitis and tendon rupture is increased in people taking a fluoroquinolone and a corticosteroid. Avoid concurrent use. 
• Ergometrine — quinolones may increase levels of ergot derivatives, which may cause ergotism. Avoid concurrent use. 
• Mycophenolate — levels may be reduced if taken concurrently with ofloxacin. Monitor for efficacy. 
• Nonsteroidal anti-inflammatory drugs (NSAIDs) — potentially increased risk of seizures when quinolones are given with NSAIDs. Manufacturer advises caution.
• Strontium ranelate — the absorption of quinolones is reduced by strontium ranelate. Manufacturer advises to avoid.
• Coumarin anticoagulants (such as warfarin) — levofloxacin increases the anticoagulant effect of warfarin. The manufacturer advises to monitor the international normalized ratio (INR).
• Zolmitriptan — quinolones increase the plasma concentration of zolmitriptan by inhibiting its metabolism. Manufacturer recommends a maximum dose of 5 mg in 24 hours in people taking a quinolone.
• Drugs that prolong the QT interval (such as Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, and antipsychotics) — very rare cases of QT interval prolongation have been reported in people taking quinolones, and they should therefore be prescribed with caution alongside drugs known to prolong the QT interval.
  • Domperidone, mizolastine — concurrent use is contraindicated.
• Live cholera vaccines — the efficacy of the live vaccine may be affected. Avoid concurrent use and for 14 days before, and for 10 days after, live cholera vaccines.
• Live typhoid vaccines — the immune response to the vaccine may be reduced. Antibacterials should be stopped from 3 days before to 3 days after receiving live typhoid vaccines.

Pregnancy

• Levofloxacin should be avoided in women who are pregnant.

Breastfeeding

• There is insufficient information on the excretion of levofloxacin in human milk; however other fluoroquinolones are excreted in breast milk. The manufacturer advises that levofloxacin is contraindicated in women who are breastfeeding. 

[EMC, 2021c; BNF, 2023; MHRA, 2023; Preston, 2023b]