Previous changes

March 2024 — minor update. Information on the use of fluoroquinolones was added to the levofloxacin prescribing section in line with a review published by the MHRA.

February 2024 — minor update. Doses of H2-receptor antagonists aligned to BNF. 

January 2024 — minor update. Information on the use of fluoroquinolones and reporting adverse reactions was added in line with the Drug Safety Update published by the MHRA [MHRA, 2023].

July 2023 — minor update. The manufacturer's SPC for metronidazole has been updated to note that QT prolongation has been reported (unknown frequency), particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. The summary of the manufacturer’s product characteristics for clarithromycin was updated to include a warning regarding concomitant treatment with domperidone (due to the risk of QT prolongation and cardiac arrhythmias).

December 2022 — reviewed. A literature search was conducted in November 2022 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. No major changes to the recommendations have been made.

July 2022 — minor update. Severe cutaneous reactions have been added as a possible adverse effect of omeprazole in line with the updated Summary of Product Characteristics. 

September 2021 — minor update. Updated information regarding hypomagnesaemia as an adverse effect of PPIs.

October 2018 — minor update. Adverse effects updated within prescribing information - metronidazole. 

September 2017 — minor update. SPC update on quinolones to align all CKS topics prescribing advice. Prostatitis – chronic, Gonorrhoea, Pyelonephritis, Diarrhoea – prevention and advice for travellers, Dyspepsia – unidentified cause, Dyspepsia – proven functional, Dyspepsia – proven peptic ulcer, Diverticular disease, Gastroenteritis. 

April to May 2017 — reviewed. A literature search was conducted in February 2017 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials since the last revision of this topic. The recommendations on primary care management and referral have been updated in line with the National Institute for Health and Care Excellence (NICE) clinical guideline Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management (2014). The lower age limit has been changed from 16 to 18 years. The content has been amended to include second-line drug regimens for Helicobacter pylori eradication, in line with the updated NICE guidance. The prescribing information section has been expanded to include antibiotics recommended for H. pylori eradication. The topic has also undergone significant restructuring.

December 2016 — minor update. minor update. Subacute cutaneous lupus erythematosus has been added as a very infrequent adverse effect of proton pump inhibitors, in line with a Medicines and Healthcare products Regulatory Agency (MHRA) Drug Safety Update (2015).

July 2015 — minor update. The prescribing information section for clarithromycin has been re-written for clarity.

February 2015 — minor update. The prescribing information section was updated to provide additional information regarding the possible drug interaction of clarithromycin with lovastatin or simvastatin in line with the manufacturer's Summary of Product Characteristics (2014).

May 2014 — minor update. Domperidone has been removed as a treatment option in line with the European Medicines Agency (EMA) publication PRAC recommends restricting use of domperidone (March 2014).

August 2013 — minor update. Metoclopramide has been removed as a treatment option, to reduce the risk of neurological adverse effects, in line with the EMA publication European Medicines Agency recommends changes to the use of metoclopramide (July 2013).

November 2012 — reviewed. A literature search was conducted in October 2012 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. There have been minor changes to the recommendation on treatment regimens for Helicobacter pylori eradication failure.

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic.

February 2012 — minor update. The Medicines and Healthcare products Regulatory Agency (MHRA) in association with the manufacturers have published new safety data regarding the association of domperidone with an increased risk of serious ventricular arrhythmias or sudden cardiac death. This topic has been updated to reflect their advice on dosing, adverse effects, and drug interactions. 

January 2012 — minor update. Information from the manufacturer's Summary of Product Characteristics (2011) about the possible drug interaction between pantoprazole and warfarin has been added to the prescribing information section. Information from the British National Formulary (2011) about the potentially serious drug interaction between PPIs and protease inhibitors (atazanavir and saquinavir) has also been added. 

June 2011 — minor update. The 2010/2011 QIPP options for local implementation have been added to this topic. 

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

July 2009 — minor update. The Medicines and Healthcare products Regulatory Agency (MHRA) has issued advice on the interaction between clopidogrel and proton pump inhibitors (2009). Healthcare professionals are advised to avoid concomitant use of these drugs unless considered essential. 

November 2008 — minor typographical corrections.

July 2008 — minor update. The text has been updated to reflect a Medicines and Healthcare products Regulatory Agency (MHRA) Drug Safety Update Nicorandil: risk of gastrointestinal ulceration (June 2008).

March to June 2008 — 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. There are no major changes to the recommendations.

May 2007 — minor update HeliClear triple pack discontinued and prescriptions removed. 

November 2005 — minor update. HeliMet triple pack discontinued and prescriptions removed. 

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

November 2004 — reviewed and updated to incorporate the National Institute for Health and Care Excellence (NICE) guideline on Dyspepsia (August 2004). Validated in March 2005 and issued in April 2005.

July 2003 — updated to incorporate information from the Scottish Intercollegiate Guidelines Network (SIGN) guideline Dyspepsia (March 2003). Validated in September 2003 and issued in October 2003.

April 2002 — updated to include Helicobacter pylori eradication regimens. 

November 2000 — reviewed and updated to incorporate the Technology appraisal guidance Guidance on the Use of Proton Pump Inhibitors (PPIs) in the Treatment of Dyspepsia issued by the National Institute for Health and Care Excellence (July 2000), and the Department of Health referral guidelines for suspected upper gastrointestinal cancers. Validated in November 2000 and issued in December 2000.

June 1998 — new topic, the topic was written.

New evidence

Evidence-based guidelines

No new guidelines published since 1 December 2022.

HTAs (Health Technology Assessments)

No new HTAs since 1 December 2022.

Economic appraisals

No new economic appraisals relevant to England since 1 December 2022.

Systematic reviews and meta-analyses

No new systematic reviews published since 1 December 2022.

Primary evidence

No new randomized controlled trials published since 1 December 2022.

New policies

No new national policies or guidelines since 1 December 2022.

New safety alerts

No new safety alerts since 1 December 2022.

Changes in product availability

• Omeprazole 10 mg and 20 mg oral solution (Glenmark). This formulation is licensed for a range of indications for adult and paediatric patients, from age over 1 year of age and ≥ 10 kg. The product is single use, and requires assembly, before administration. Licence covers use in feeding tubes from 6 to 15Fr.  See more here.
• New product: Pylera 140 mg/125 mg/125 mg capsules (bismuth subcitrate potassium, metronidazole, tetracycline hydrochloride). This is licensed for use in combination with omeprazole for the eradication of Helicobacter pylori and prevention of relapse of peptic ulcers in patients with active or a history of H. pylori associated ulcers. See more here.

Basis for recommendation

The recommendations on how to assess a person with uninvestigated dyspepsia are largely based on the National Institute for Health and Care Excellence (NICE) clinical guideline Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management [NICE, 2019] and have also been extrapolated from expert opinion in the World Gastroenterology Organisation (WGO) guideline Global perspective on gastroesophageal reflux disease [Hunt, 2017].

• The recommendation on considering checking a full blood count to look for anaemia and/or a raised platelet count is based on the NICE clinical guideline Suspected cancer: recognition and referral [NICE, 2021].
  • Unexplained iron deficiency anaemia or a raised platelet count can be an indicator of upper gastrointestinal malignancy, particularly if associated with symptoms of upper abdominal pain, dyspepsia, reflux, weight loss, nausea and/or vomiting [NICE, 2021].

Basis for recommendation

The information on the differential diagnosis of dyspepsia symptoms is based on expert opinion in the National Institute for Health and Care Excellence (NICE) clinical guideline Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management [NICE, 2019], the American Society for Gastrointestinal Endoscopy (ASGE) guideline The role of endoscopy in dyspepsia [Shaukat, 2015], the BMJ Best Practice guideline Assessment of dyspepsia [BMJ Best Practice, 2022], and review articles on dyspepsia [Harmon, 2010; Malone, 2015] and peptic ulcer disease [Fashner, 2015].

How should I initially manage a person with dyspepsia?

• Assess for any alarm symptoms that may suggest a complication or other serious underlying pathology, and manage appropriately. See the CKS topic on Gastrointestinal tract (upper) cancers - recognition and referral for more information.
• Offer written information and advice on the symptoms, self-care, and management options for dyspepsia, such as the NHS A-Z patient information leaflets on Indigestion and Gastritis.
• Offer advice on lifestyle measures that may improve symptoms. Encourage the person to:
  • Lose weight if they are overweight or obese. See the CKS topic on Obesity for more information.
  • Avoid any trigger foods, such as coffee, chocolate, tomatoes, and fatty or spicy foods.
  • Eat smaller meals and eat their evening meal 3–4 hours before going to bed, if possible.
  • Stop smoking, if appropriate. See the CKS topic on Smoking cessation for more information.
  • Reduce alcohol consumption to recommended limits, if appropriate. See the CKS topic on Alcohol - problem drinking for more information. 
• Assess for stress, anxiety, and depression, which may worsen symptoms. Encourage relaxation strategies, consider referral for psychological therapies, and manage depression symptoms if needed. See the CKS topics on Generalized anxiety disorder and Depression for more information.
• Review the person's medication:
  • Ask about any over-the-counter medication such as antacids and/or alginates that have been tried for symptom relief.
    • Advise that self-treatment with an antacid and/or alginate may be used for short-term symptom control, but long-term, continuous use is not recommended.
  • Consider reducing or stopping (if possible and appropriate) any drugs that may cause or exacerbate symptoms, such as:
    • Alpha-blockers, anticholinergics, aspirin, benzodiazepines, beta-blockers, bisphosphonates, calcium-channel blockers, corticosteroids, nitrates, nonsteroidal anti-inflammatory drugs (NSAIDs), theophyllines, and tricyclic antidepressants.
  • If dyspepsia symptoms are associated with NSAID use, encourage the person to stop the NSAID, if possible and appropriate.
  • Ask about the number and duration of any previous courses of antibiotics, which may affect the choice of Helicobacter pylori eradication regimen used (if needed).
• Offer one of the following strategies to manage uninvestigated dyspepsia symptoms, depending on clinical judgement:
  • Prescribe a full-dose proton pump inhibitor (PPI) for 1 month — see the section on Proton pump inhibitors in Prescribing information for more information, or
  • Test for Helicobacter pylori infection if the person's status is not known or uncertain. If the person tests positive for H. pylori infection, prescribe first-line eradication therapy. See the section on First-line H. pylori eradication regimens for more information.
• If symptoms persist or recur following initial management:
  • Switch to the alternative strategy (for example, offer a full-dose PPI for 1 month if the person has been tested for H. pylori infection, and vice versa).
• For the initial detection of H. pylori infection, arrange:
  • A carbon-13 urea breath test or stool antigen test — ensure the person has not taken a PPI in the past 2 weeks, or antibiotics in the past 4 weeks, or
  • Laboratory serological testing if these options are not available, providing the test has been locally validated.
    • Do not arrange for routine re-testing unless there are specific clinical circumstances. See the section on Refractory or recurrent symptoms for more information.
• Advise the person to arrange a follow-up appointment if there are refractory or recurrent symptoms following initial management. See the section on Refractory or recurrent symptoms for more information.

How should I manage refractory or recurrent symptoms?

• Assess for any new alarm symptoms which may suggest a complication or other serious underlying pathology, and manage appropriately. See the CKS topic on Gastrointestinal tract (upper) cancers - recognition and referral for more information.
• For people with persistent or recurrent dyspepsia symptoms despite initial management:
  • Consider whether an alternative diagnosis, such as cardiac or hepatobiliary disease, may be contributing to symptoms.
  • Check the person's adherence to initial management and reinforce lifestyle advice.
  • Consider alternative acid suppression therapy with a histamine (H₂)-receptor antagonist (H₂RA). See the section on H2-receptor antagonists in Prescribing information for more information.
  • Consider the need for long-term acid suppression therapy if symptoms have previously responded.
• If the person is taking a nonsteroidal anti-inflammatory drug (NSAID) or aspirin and is unable to stop the drug, advise on:
  • Reducing the NSAID dose, if possible, and offering long-term gastroprotection with acid suppression therapy.
  • Switching to an alternative to an NSAID, such as paracetamol or a cyclo-oxygenase (COX)-2 inhibitor, if appropriate. See the CKS topic on NSAIDs - prescribing issues for more information.
  • Switching to an alternative antiplatelet drug, if appropriate. See the CKS topic on Antiplatelet treatment for more information.
• If the person has received first-line Helicobacter pylori eradication therapy, do not routinely offer H. pylori re-testing.
  • Consider offering re-testing for H. pylori, using clinical judgement, if:
    • There has been poor compliance to first-line eradication therapy, or the initial test was performed within 2 weeks of proton pump inhibitor (PPI) or 4 weeks of antibiotic therapy.
    • Aspirin or an NSAID is indicated, especially if there is a history of peptic ulcer disease. See the CKS topic on Dyspepsia - proven peptic ulcer for more information.
    • There is a family history of gastric malignancy.
    • There are severe, persistent, or recurrent symptoms.
    • The person requests re-testing (for example if there is anxiety about whether H. pylori has been eradicated).
• If H. pylori re-testing is indicated, arrange this at least four weeks (ideally 8 weeks) after initial eradication therapy (if this was needed).
  • Offer the carbon-13 urea breath test first-line, or the stool antigen test second-line if the carbon-13 urea breath test is not available — ensure the person has not taken a PPI in the past 2 weeks, or antibiotics in the past 4 weeks.
  • If H. pylori re-testing is positive, prescribe second-line H. pylori eradication therapy. See the section on Second-line H. pylori eradication regimens for more information.
• Offer people on long-term treatment an annual review of their symptoms and treatment, and encourage the person to:
  • Step down or stop treatment, if possible and appropriate (if there is no co-morbidity or co-medication that requires long-term acid suppression therapy):
    • Use a PPI or H₂RA at the lowest effective dose to control symptoms.
    • Use a PPI or H₂RA as needed, if possible and appropriate.
    • Consider self-treatment with antacid and/or alginate therapy, although this is not recommended for long-term or continuous use.
  • See the sections on Proton pump inhibitors and H2-receptor antagonists in Prescribing information for more information.
• Advise the person to arrange a follow-up appointment if there are refractory or recurrent symptoms.
• Arrange a referral for endoscopy and/or to a gastroenterologist, depending on clinical judgement, if:
  • There are refractory or recurrent symptoms despite optimal management in primary care.
  • Treatment with a second-line H. pylori eradication regimen has been unsuccessful.
  • There are limited antibiotic options for H. pylori eradication therapy, due to hypersensitivity, known local high antibiotic resistance rates, or previous use of clarithromycin, metronidazole, and a quinolone.
    • If endoscopy is planned, ensure the person stops any acid suppression therapy for at least two weeks before the procedure date, and suggest self-treatment with antacid and/or alginate therapy if needed.
    • Note: H. pylori re-testing may be performed during endoscopic examination in secondary care.

Choice of proton pump inhibitor

• Table 1 shows the recommended doses of proton pump inhibitors (PPIs) for the management of people with dyspepsia symptoms.

Table 1. PPI doses for the management of people with dyspepsia symptoms.

• Table 2 shows the recommended doses of proton pump inhibitors (PPIs) for the H. pylori eradication therapy.

Table 2. PPI doses for H. pylori eradication therapy.

Contraindications and cautions

• Proton pump inhibitors (PPIs) should not be prescribed to people:
  • With alarm symptoms before endoscopy, as PPIs may mask the symptoms of upper gastrointestinal malignancy. If the person is already taking a PPI and subsequently needs an endoscopy, the PPI should be stopped at least 2 weeks before the procedure.
• PPIs should be prescribed with caution to people:
  • At risk of osteoporosis — the person should maintain an adequate intake of calcium and vitamin D, and if necessary, be given additional bone-sparing therapy.
  • At risk of hypomagnesaemia — if possible, magnesium levels should be checked before starting PPI therapy and intermittently during long-term treatment, for example, if the person is prescribed drugs that can cause hypomagnesaemia, such as digoxin and diuretics.

[MHRA, 2012a; BNF, 2022]

Adverse effects

Adverse effects of proton pump inhibitors (PPIs) are usually mild and reversible.

• Adverse effects include headache, diarrhoea, nausea, vomiting, abdominal pain, constipation, and dizziness.
• Less common adverse effects include dry mouth, peripheral oedema, sleep disturbance, fatigue, paraesthesia, arthralgia, myalgia, pruritus, and rash.
• Rare or very rare adverse effects include:
  • Subacute cutaneous lupus erythematosus (SCLE), which can occur weeks, months, or years after exposure to a PPI. If suspected, discontinue the PPI and seek specialist advice if needed [MHRA, 2015].
  • Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported very rarely, and rarely with omeprazole treatment.
  • Taste disturbance, hepatitis, jaundice, depression, confusion, hallucinations, hyponatraemia, interstitial nephritis, leucopenia, leucocytosis, pancytopenia, thrombocytopenia, visual disturbances, sweating, photophobia, and alopecia.
• Long-term PPI treatment may be associated with uncommon, serious adverse effects such as:
  • Hypomagnesaemia — symptoms include muscle twitching, tremors, vomiting, fatigue, and loss of appetite. Case reports after one year of PPI therapy, but may occur after 3 months. This usually improves after magnesium replacement therapy and discontinuation of the PPI [MHRA, 2012a]. Hypomagnesaemia may lead to hypocalcaemia and/or hypokalaemia.
  • Increased risk of fractures — especially when used at high doses for over a year in the elderly [MHRA, 2012b].
  • Clostridium difficile infection — due to the effect of decreasing gastric acidity.
  • Rebound acid hypersecretion syndrome — may occur after stopping long-term PPI therapy, although this may be more a theoretical risk than clinical phenomenon.

[NICE, 2019; BNF, 2022; ABPI, 2022a]

Drug interactions

Possible drug interactions with proton pump inhibitors (PPIs) include:

• Citalopram and escitalopram — co-exposure to omeprazole or esomeprazole can lead to increased levels of citalopram and escitalopram. Dose adjustment may be necessary depending on side-effects.
• Digoxin — PPIs may cause a small rise in serum digoxin levels (although not considered clinically significant). The manufacturer of lansoprazole suggests that digoxin levels should be monitored if lansoprazole is started or stopped.
• Warfarin — PPIs can occasionally enhance the effects of warfarin. The international normalized ratio (INR) should be monitored in people taking warfarin if omeprazole, pantoprazole, or esomeprazole is started or stopped.
• Methotrexate — PPIs possibly reduce excretion of methotrexate, leading to an increased risk of methotrexate toxicity.
• Phenytoin — omeprazole and esomeprazole can occasionally enhance the effects of phenytoin. The manufacturers recommend that people taking phenytoin are carefully monitored if omeprazole or esomeprazole is started or stopped.
• Azole antifungals — the absorption of ketoconazole or itraconazole may be reduced during PPI treatment. Dose adjustment of the antifungal drug may be required during long-term PPI treatment.
• Clopidogrel — omeprazole and esomeprazole reduce the antiplatelet effect of clopidogrel, and concomitant use should be avoided. The other PPIs may also reduce the efficacy of clopidogrel, and this risk should be weighed against the potential benefit of the PPI [MHRA, (2010)].
• Protease inhibitors — PPIs can significantly affect plasma levels of some protease inhibitor drugs, including:
  • Atazanavir — concurrent use of PPIs and atazanavir is not recommended as the absorption of atazanavir may be affected by a PPI (due to changes in gastric acidity). This may lead to a reduced plasma concentration of atazanavir which may affect its efficacy. If concurrent use is necessary, seek specialist advice.
  • Saquinavir — plasma concentration of saquinavir may be increased by PPI treatment, leading to increased risk of adverse effects.
  • Tipranavir — concurrent use with omeprazole or esomeprazole is not recommended, as tipranavir may reduce the plasma concentration of the PPI. If concurrent use is necessary, seek specialist advice.

 [ABPI, 2021; BNF, 2022; Preston, 2023]

Choice of H2-receptor antagonist

• Ranitidine is the only histamine (H₂)-receptor antagonist (H₂RA) which is licensed for the management of people with persistent dyspepsia symptoms.
  
  • However, ranitidine is not currently available in the UK or globally.
• Table 1 shows the recommended doses of ranitidine, famotidine, and nizatidine histamine (H₂)-receptor antagonists (H₂RAs) for the management of people with functional dyspepsia symptoms.

Table 1. Recommended doses of H₂RAs for the management of people with functional dyspepsia symptoms.

Contraindications and cautions

• Histamine (H₂)-receptor antagonists (H₂RAs) should not be prescribed to people:
  • With alarm symptoms before endoscopy, as H₂RAs may mask the symptoms of upper gastrointestinal malignancy. If the person is already taking an H₂RA and subsequently needs an endoscopy, the H₂RA should be stopped at least 2 weeks before the procedure.
• H₂RAs should be prescribed with caution in people with renal impairment:
  • For ranitidine, if the estimated glomerular filtration rate (eGFR) is less than 50 mL/minute/1.73m², prescribe half the normal daily dose.
  • For famotidine, if the eGFR is less than 50 mL/minute/1.73m², prescribe the normal dose once every 36–48 hours, or half the normal daily dose.
  • For nizatidine, if the eGFR is 20–50 mL/minute/1.73 m², prescribe half the normal daily dose; if the eGFR is less than 20 mL/minute/1.73 m², prescribe one-quarter of the normal daily dose.
• Nizatidine should be prescribed with caution for people with hepatic impairment.

[NICE, 2019; BNF, 2022]

Adverse effects

• Adverse effects of histamine (H₂)-receptor antagonists (H₂RAs) are uncommon and include diarrhoea, headache, dizziness, rash, and tiredness.
• Rare or very rare adverse effects include hepatitis, cholestatic jaundice, bradycardia, depression, confusion, hallucinations, leucopenia, thrombocytopenia, and pancytopenia, arthralgia, and myalgia.

[BNF, 2022]

Drug interactions

• Possible drug interactions with histamine (H₂)-receptor antagonists (H₂RAs) include:
  • Azole antifungals — because of decreased gastric acidity, the absorption of ketoconazole or itraconazole may be reduced if taken with an H₂RA.
  • Protease inhibitors — atazanavir plasma levels are reduced by H₂RAs. The manufacturer of atazanavir advises adjustment of the doses of both drugs when given with an H₂RA. Seek specialist advice as needed.

[BNF, 2022]

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.
  • History of penicillin-associated hepatic dysfunction.
• Prescribe amoxicillin with caution to people with:
  • Hypersensitivity to cephalosporins.
  • Hepatic impairment.
  • Chronic kidney disease (CKD) stages 4 or 5 — reduce the dose of amoxicillin.
    • If the estimated glomerular filtration rate (eGFR) is 10–30 mL/minute/1.73 m², prescribe a maximum of 500 mg twice a day.
    • If the eGFR is less than 10 mL/minute/1.73 m², prescribe a maximum of 500 mg once a day.

[ABPI, 2022b; BNF, 2022]

Adverse effects

• The most common adverse effects of penicillins include diarrhoea, nausea, vomiting, and skin rash.
• Consider pseudomembranous colitis if a person develops severe diarrhoea during or after treatment with amoxicillin. For more information, see the CKS topic on Diarrhoea - antibiotic associated.
• Anaphylaxis (immediate or delayed) is a serious but rare adverse effect of amoxicillin. For more information, see the CKS topic on Angio-oedema and anaphylaxis.

[ABPI, 2022b; BNF, 2022]

Drug interactions

Possible drug interactions with amoxicillin include:

• Allopurinol — concomitant use of allopurinol and amoxicillin may increase the incidence of skin rashes. Concomitant use need not be avoided for this reason.
• Anticoagulants (for example warfarin) — 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. Prolongation of prothrombin time has been reported in people taking penicillins and warfarin concurrently.
• Methotrexate — 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. Penicillins may reduce the excretion of methotrexate, however clinically this is not usually serious.
• Tetracyclines — effect of penicillins possibly antagonized by tetracyclines.

[ABPI, 2022b; BNF, 2022]

Contraindications and cautions

• Do not prescribe clarithromycin to people with:
  • Severe hepatic impairment in combination with renal impairment.
  • Hypokalaemia — risk of prolongation of the QT interval.
  • A history of QT prolongation or ventricular cardiac arrhythmia, including Torsades de pointes.
• Prescribe clarithromycin with caution to people with:
  • Impaired hepatic function (or people concomitantly taking potentially hepatotoxic drugs) — clarithromycin is principally excreted by the liver. Hepatic dysfunction including increased liver enzymes and cholestatic hepatitis (with or without jaundice) has been reported rarely.
  • Chronic kidney disease (CKD) stages 4 and 5 — if the estimated glomerular filtration rate (eGFR) is less than 30 mL/minute/1.73 m², prescribe half the normal dose, and avoid Klaricid XL® or clarithromycin M/R preparations.
  • Coronary heart disease, severe cardiac insufficiency, hypomagnesaemia, or bradycardia (heart rate less than 50 beats per minute) — increased risk of QT prolongation.
  • Myasthenia gravis — may aggravate symptoms.

[ABPI, 2022c; BNF, 2022]

Adverse effects

• The most common adverse effects of clarithromycin include mild nausea, vomiting, abdominal discomfort, and diarrhoea.
  • Consider pseudomembranous colitis if a person develops severe diarrhoea during or after treatment with clarithromycin. For more information, see the CKS topic on Diarrhoea - antibiotic associated.
• Taste disturbance, headache, insomnia, and hyperhidrosis have also been reported.
• Hepatotoxicity (including cholestatic jaundice) and rash are reported less frequently.
• Other adverse effects reported rarely or very rarely include pancreatitis, QT interval prolongation, arrhythmias, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
• Anaphylaxis is rarely associated with clarithromycin. For more information, see the CKS topic on Angio-oedema and anaphylaxis.

[ABPI, 2022c; BNF, 2022]

Drug interactions

Possible drug interactions with clarithromycin include:

• Carbamazepine — clarithromycin increases the plasma concentration of carbamazepine. Consider reducing the dose of carbamazepine by 30–50% during treatment with clarithromycin. Advise the person to report symptoms of carbamazepine toxicity (such as dizziness, diplopia, ataxia, or confusion).
• Colchicine — clarithromycin possibly increases the risk of colchicine toxicity. Stop or reduce the dose of colchicine, and avoid concomitant use in renal or hepatic impairment.
• Drugs that prolong the QT interval (such as anti-arrhythmics like amiodarone and sotalol, antipsychotics like amisulpride, domperidone, and tricyclic antidepressants) — seek advice from a medical microbiologist regarding a suitable alternative antibiotic. Macrolides can also prolong the QT interval, increasing the risk of arrhythmias such as Torsades de pointes, and concomitant use of drugs that prolong the QT interval is not recommended.
• Drugs that cause hypokalaemia (such as diuretics, corticosteroids, short-acting beta₂-agonists) — seek advice from a medical microbiologist regarding a suitable alternative antibiotic. Hypokalaemia is a risk factor for QT prolongation.
• Edoxaban — manufacturer advises caution with concurrent treatment with edoxaban, particularly in those with a high risk of bleeding.
• Itraconazole — clarithromycin increases the plasma concentration of itraconazole.
• Ivabradine — concomitant treatment is contra-indicated, owing to CYP3A4 inhibition by clarithromycin which can cause elevated levels of ivabradine.
• Ketoconazole — the manufacturer advises avoiding the use of concomitant clarithromycin in severe renal impairment.
• Mirabegron — when given with clarithromycin, avoid or reduce the dose of mirabegron in renal or hepatic impairment.
• Omeprazole — the plasma concentrations of both drugs are increased when clarithromycin is given with omeprazole.
• Phenytoin — clarithromycin inhibits the metabolism of phenytoin, leading to increased plasma concentrations. If there are signs of phenytoin toxicity, such as blurred vision, nystagmus, ataxia, or drowsiness, stop clarithromycin and seek specialist advice if needed.
• Sildenafil — clarithromycin increases the plasma concentration of sildenafil. Consider reducing the initial dose of sildenafil.
• Statins — there is an increased risk of myopathy (due to cytochrome P450 enzyme CYP3A4 inhibition) if clarithromycin is taken with atorvastatin or simvastatin.
  • For simvastatin — avoid concomitant use, as simvastatin is extensively metabolized by CYP3A4. If clarithromycin treatment cannot be avoided, stop treatment with simvastatin during the course of the treatment.
  • For atorvastatin — avoid concurrent use with clarithromycin as atorvastatin is moderately metabolized by CYP3A4. If concurrent use cannot be avoided, prescribe the lowest starting dose of atorvastatin (that is 10 mg), and advise the person to report any muscle pain, tenderness, or weakness.
  • Other statins — clinically significant drug interactions resulting from cytochrome P450-mediated metabolism are not expected for rosuvastatin and pravastatin as they are not metabolized to a clinically significant extent by the cytochrome P450 system. Fluvastatin is not dependent on CYP3A metabolism; therefore, interaction with clarithromycin is unlikely. Nevertheless, advise the person to report any muscle pain, tenderness, or weakness.
• Theophylline — clarithromycin possibly increases the plasma concentration of theophylline. Consider a dose reduction of theophylline if toxicity is suspected (for example headache, nausea, or palpitations occur).
• Quetiapine — clarithromycin possibly increases the plasma concentration of quetiapine. The manufacturer of quetiapine advises to avoid concomitant use.
• Warfarin — clarithromycin enhances the anticoagulant effect of warfarin, and occasionally this may be a marked effect. Monitor the international normalized ratio (INR), and adjust the warfarin dose accordingly.
• Antidiabetic drugs — the concurrent use of clarithromycin and antidiabetic drugs (such as nateglinide and repaglinide) can result in significant hypoglycaemia. Monitor blood glucose levels more regularly and adjust the antidiabetic drug dose accordingly.
• Calcium channel blockers (CCBs) — clarithromycin possibly inhibits the metabolism of CCBs, increasing the risk of adverse effects such as hypotension.

[BNF, 2022; EMC, 2024]

Contraindications and cautions

• Do not prescribe metronidazole to a person with:
  • Known metronidazole or nitroimidazole hypersensitivity.
  • Cockayne syndrome. Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with Cockayne syndrome, have been reported with products containing metronidazole for systemic use (oral and suppositories). For people with Cockayne syndrome specialist advice should therefore be sought before prescribing metronidazole.
• Prescribe metronidazole with caution to people with:
  • Active or chronic severe peripheral and central nervous system disease, as there is a risk of neurological aggravation.
  • Severe liver disease or hepatic encephalopathy, due to substantial impairment of metronidazole clearance, which may contribute to symptoms of encephalopathy. Prescribe one-third of the daily dosage once daily.
  • Alcohol dependency — there may be a disulfiram-like reaction if taken with alcohol.

[EMC, 2022; BNF, 2022]

Adverse effects

Adverse effects of metronidazole include:  

• Gastrointestinal disturbances including nausea and vomiting, anorexia, and very rarely hepatitis, jaundice, or pancreatitis.
• Taste disturbances, furred tongue, oral mucositis.
• Headache, ataxia.
• Thrombocytopenia, pancytopenia. 
• Myalgia, arthralgia.
• Darkening of urine.
• Rash, pruritus, and erythema multiforme.
• Drowsiness, dizziness, confusion, hallucinations, convulsions, or transient visual disorders. Advise the person not to drive or operate machinery if these symptoms occur.
• Severe bullous skin reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or acute generalised exanthematous pustulosis (AGEP) have been reported. If symptoms/signs are present, treatment must be immediately discontinued.

[EMC, 2022; BNF, 2022]

Drug interactions

Drug interactions associated with metronidazole include:

• Alcohol — some people taking metronidazole experience a disulfiram-like reaction with alcohol.
  • Warn the person that they might experience this reaction if they drink alcohol whilst on metronidazole and for at least 48 hours afterwards. 
• Anticoagulants — the anticoagulant effects of warfarin can be markedly increased by metronidazole. 
  • Monitor the international normalized ratio (INR) and adjust the warfarin dose accordingly. 
• Ciclosporin — if co-administration of metronidazole and ciclosporin is necessary, serum ciclosporin levels and serum creatinine should be closely monitored.
• Cimetidine — metabolism of metronidazole inhibited by cimetidine, resulting in an increased plasma concentration.
• Lithium — seek specialist advice regarding the use of metronidazole with lithium, as metronidazole increases the risk of lithium toxicity. Lithium dose reduction may be required due to the risk of renal damage with concurrent use. Plasma concentrations of lithium, creatinine, and electrolytes should be monitored if metronidazole and lithium are used simultaneously.
• Phenytoin — metronidazole possibly inhibits the metabolism of phenytoin, leading to increased plasma concentrations.
• The manufacturers SPC also notes that QT prolongation has been reported (unknown frequency), particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.

[BNF, 2022; Preston, 2023; EMC, 2023]

Contraindications and cautions

• Do not prescribe tetracycline to people with:
  • Renal impairment — tetracyclines are excreted renally and may exacerbate renal failure.
• Prescribe tetracycline with caution to people with:
  • Hepatic impairment and those receiving potentially hepatotoxic drugs, such as carbamazepine, isoniazid, and methotrexate.
  • Myasthenia gravis — tetracyclines may increase muscle weakness symptoms.
  • Systemic lupus erythematosus (SLE) — tetracyclines may exacerbate the condition.

[ABPI, 2020; BNF, 2022]

Adverse effects

• Common adverse effects of tetracycline include:
  • Gastrointestinal disturbances such as nausea, vomiting, and diarrhoea.
    • Consider pseudomembranous colitis if a person develops severe diarrhoea during or after treatment with tetracycline. For more information, see the CKS topic on Diarrhoea - antibiotic associated.
  • Dysphagia and oesophageal irritation.
• Other rare adverse effects of tetracyclines include:
  • Severe headache and/or visual disturbance — may be an early symptom of benign intracranial hypertension. Stop treatment and seek immediate medical advice if this is suspected.
  • Severe oesophagitis.
  • Vulvovaginal candidiasis.
  • Photosensitivity.
  • Hepatotoxicity, pancreatitis.

[ABPI, 2020; BNF, 2022]

Drug interactions

Possible drug interactions with tetracycline include:

• 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.
• Anticoagulants — the concurrent use of warfarin with tetracyclines can increase the anticoagulant effect of coumarins.
  • Monitor the person's international normalized ratio (INR) regularly and within 3 days of starting the tetracycline. Adjust the warfarin dose accordingly.
• Retinoids — there is a possible increased risk of benign intracranial pressure if tetracyclines are used concurrently with retinoids.
  • Avoid the concurrent use of tetracyclines and retinoids.
• Milk — the absorption of most tetracyclines is reduced by the calcium found in milk and other dairy products.
• Carbamazepine — doxycycline levels are reduced significantly in people taking long-term carbamazepine.
• Penicillins — tetracyclines possibly antagonize the effects of penicillins.
• Sulfonylureas — tetracyclines possibly enhance the hypoglycaemic effects of sulfonylureas.
• Tripotassium dicitratobismuthate — absorption of tetracyclines is reduced.

[ABPI, 2020; BNF, 2022]

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 quinolone hypersensitivity.
  • A history of tendon disorders related to quinolone use — tendon damage (including rupture) has been reported rarely in people taking quinolones. If suspected, stop levofloxacin immediately.
• Prescribe levofloxacin with caution to people with:
  • A history of epilepsy or a condition that predisposes to seizures — quinolones may induce seizures.
  • Conditions that may prolong the QT interval (for example, electrolyte disturbances, acute myocardial infarction, heart failure with reduced ejection fraction, bradycardia, a history of symptomatic arrhythmias, and concomitant use of other drugs known to prolong the QT interval).
  • An increased risk of tendon damage (for example, people taking concomitant corticosteroids) — tendon damage (including rupture) has been reported rarely in people taking quinolones.
  • Chronic kidney disease (CKD) stages 4 and 5 — if the estimated glomerular filtration rate (eGFR) is 20–50 mL/minute/1.73 m², prescribe the usual initial dose then half the normal levofloxacin dose.
  • Glucose 6-phosphate dehydrogenase (G6PD) deficiency — possible increased risk of acute haemolytic anaemia when taking quinolones.
  • A history of psychiatric illness.
  • Myasthenia gravis — there is a risk of exacerbation of symptoms.

[BNF, 2022; MHRA, 2024]

Adverse effects

• Adverse effects of levofloxacin include nausea, vomiting, diarrhoea, headache, and dizziness.
  • Consider pseudomembranous colitis if a person develops severe diarrhoea during or after treatment with levofloxacin. For more information, see the CKS topic on Diarrhoea - antibiotic associated.
• Less frequent adverse effects include:
  • Dyspepsia, abdominal pain, anorexia, sleep disturbances, confusion, anxiety, depression, hallucinations, seizures, and tremors. Quinolones may lower the seizure threshold and may trigger seizures. Levofloxacin is contraindicated in patients with a history of epilepsy and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures, or concomitant treatment with active substances that lower the cerebral seizure threshold, such as theophylline. In case of convulsive seizures, treatment with levofloxacin should be discontinued.
  • Blood disorders (including eosinophilia, leucopenia, and thrombocytopenia), arthralgia, tendinitis, tendon rupture, myalgia, rash (very rarely Stevens-Johnson syndrome and toxic epidermal necrolysis), disturbances in vision and taste, and photosensitivity.

[BNF, 2022]

Drug interactions

Possible drug interactions with levofloxacin include:

• Amiodarone — increased risk of ventricular arrhythmias when levofloxacin is given with amiodarone. Avoid concomitant use.
• Antacids — absorption of levofloxacin reduced by antacids. Give at least 2 hours before or 4 hours after levofloxacin.
• Anticoagulants — levofloxacin possibly increases the anticoagulant effect of drugs such as warfarin. Monitor the international normalized ratio (INR), and adjust the warfarin dose accordingly.
• Iron salts and zinc — absorption of levofloxacin reduced by oral iron salts. Give at least 2 hours apart.
• Aminophylline and theophylline — possible increased risk of convulsions when levofloxacin is given with aminophylline and theophylline.
• Ciclosporin — increased risk of nephrotoxicity when levofloxacin is given with ciclosporin.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) — possible increased risk of convulsions when levofloxacin is given with NSAIDs.
• Zolmitriptan — levofloxacin possibly inhibits the metabolism of zolmitriptan. Reduce the dose of zolmitriptan.

[BNF, 2022]

Contraindications and cautions

• Bismuth subsalicylate should not be precribed to people with a history of hypersenitivity to aspirin or other salicylates.
• Prescribe bismuth subsalicylate with caution to people with:
  • Gout.
  • Blood clotting disorders.

[BNF, 2022]

Adverse effects

• Bismuth subsalicylate may darken the tongue and cause black stools.

[BNF, 2022]

Drug interactions

• Possible drug interactions with bismuth subsalicycate include:
  • Tetracyclines — bismuth reduces the absorption of tetracyclines.

[BNF, 2022]