Previous changes

October 2025 — minor update. Added information on drug interaction between rifampicin and doxycycline.

October 2024 — minor update.  The section on interpretation of ABPI has been removed from this topic and a link added to the topic on Peripheral arterial disease. 

August 2024 — reviewed.  A literature search was conducted in July 2024 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of the topic. There have been minor structural changes to align the topic with recommendations provided in updated literature sources.

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. Adverse effects of doxycycline updated in line with manufacturer's SPC. 

December 2023 — minor update. Update to drug interactions section for erythromycin to include information on interactions with lomitapide and corticosteroids, in line with the manufacturer's Summary of Product Characteristics (SPC).

November 2023 — minor update. Interactions section for flucloxacillin updated in line with updated manufacturer's summary of product characteristics.

July 2023 — minor update. The summary of 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).

May 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.

August 2021 — minor update. Adverse effects of co-trimoxazole updated in line with revised manufacturer's SPC relating to the rare problem of severe respiratory toxicity with the potential to progress to Adult Respiratory Distress Syndrome.

January 2021 — minor update. Contraindications and drug interactions for erythromycin have been updated in line with an MHRA drug safety update. 

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

February 2020 — minor update. Topic updated in line with NICE guideline, NG152 Leg ulcer infection: antimicrobial prescribing [NICE, 2020].

July 2019 — reviewed. A literature search was conducted in June 2019 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. The recommendations on managing an infected leg ulcer have been changed in line with the National Institute for Health and Care Excellence (NICE) Draft guideline on leg ulcer infection: antimicrobial prescribing [NICE, 2019]. The scope of the topic has been clarified, and the topic has been restructured. 

April 2017 — minor update. Update to incorporate feedback from the Venous Forum of the Royal Society of Medicine.

October to November 2015 — reviewed. A literature search was conducted in October 2015 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last version of this topic. 

• A recommendation to consider prescribing pentoxifylline to improve ulcer-healing rates has been added to reflect clinical guidance in the Scottish Intercollegiate Guidelines Network (SIGN) guideline Management of chronic venous leg ulcers [SIGN, 2010] and a Cochrane systematic review [July, 2015].
• The definition of leg ulcer has been updated, in line with the NICE guideline Varicose veins in the legs: The diagnosis and management of varicose veins [NICE, 2013].
• A recommendation to refer people with venous leg ulcer for specialist advice after two weeks of primary care treatment was added, in line with the NICE guideline Varicose veins in the legs: The diagnosis and management of varicose veins [NICE, 2013].
• The recommendation to consider prescribing erythromycin for infected leg ulcer has been removed in line with current prescribing guidelines and good clinical practice. 
• The topic has undergone minor restructuring, and prescribing information sections for the recommended antibiotics have been added.

July 2015 — minor update. The information on the concurrent use of clarithromycin or erythromycin with statins has been clarified.

April 2015 — minor update. Link inserted to the CKS topic on Analgesia - mild-to-moderate pain.

September 2012 — reviewed. A literature search was conducted in September 2012 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. No changes to clinical recommendations have been made.

June 2012 — minor update. Minor typographical error corrected. 

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

September 2010 — minor update. Text updated to include recommendations from the Scottish Intercollegiate Guidelines Network guideline Management of chronic venous leg ulcers.

December 2008 — minor update. Rewording of text regarding prescribing erythromycin or clarithromycin for people with penicillin allergy.

November 2007 to February 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. 

January 2007 — antibiotic prescriptions for infected leg ulcers updated. 

November 2005 — minor technical update. 

August 2004 — written. Validated in September 2004 and issued in November 2004.

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 July 2024.

HTAs (Health Technology Assessments)

• NICE (2025) Compression products for treating venous leg ulcers: late-stage assessment. National Institute for Health and Care Excellence. https://www.nice.org.uk [Free Full-text]

Economic Appraisals

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

Systematic reviews and meta-analyses

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

Primary evidence

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

New policies

No new national policies or guidelines since 1 July 2024.

New safety alerts

No new safety alerts since 1 July 2024.

Changes in product availability

No changes in product availability since 1 July 2024.

Basis for recommendation

These recommendations are based on the Scottish Intercollegiate Guidelines Network (SIGN) guideline Management of chronic venous leg ulcers [SIGN, 2010], the Primary Care Dermatology Society (PCDS) guideline Leg ulcers (and disorders of venous insufficiency) [PCDS, 2023], a joint document by the European Wound Management Association (EWMA) and Wounds Australia Management of Patients With Venous Leg Ulcers: Challenges and Current Best Practice [Franks, 2016], the Health Service Executive (HSE) guideline HSE National wound management guidelines [HSE, 2018], the Wounds UK document Best Practice Statement: Addressing complexities in the management of venous leg ulcers [Wounds UK, 2019], and expert opinion in narrative review articles  [Vivas, 2016; Singer, 2017; Lim, 2018; Bonkemeyer Millan, 2019; Bowers, 2020] and a textbook ABC of Wound Healing [Grey, 2021a; Grey, 2021b]. 

Causes of leg ulcers

• Vascular disease, both venous and arterial, is the most common cause of leg ulcers. Other causes include diabetes, rheumatoid arthritis, dermatological diseases, pressure, and malignancy [Franks, 2016; HSE, 2018; Lim, 2018; PCDS, 2023].

Leg ulcer assessments

• A thorough assessment (history, examination, and investigation) of a person with a leg ulcer will help identify underlying causes as well as any associated comorbidities and risk factors, all of which will influence management decisions [Franks, 2016; HSE, 2018; Lim, 2018; Wounds UK, 2019; PCDS, 2023].
  • About 95% of venous ulcers occur in the gaiter area of the leg, characteristically around the malleoli. Ulcers occurring above the mid-calf or on the foot are likely to have other origins [Grey, 2021a].
  • Examination of the edge of the wound may help to identify its aetiology. For example, venous leg ulcers generally have gently sloping edges; arterial ulcers often appear well demarcated and 'punched out'; and rolled or everted edges should raise the suspicion of malignancy [Grey, 2021a; Grey, 2021b].
  • Serial measurement of the surface area of the ulcer is important as it is a reliable index of ulcer healing [SIGN, 2010].
  • Assessing the depth of the ulcer is important as deep ulcers involving deep fascia, tendon, periosteum, or bone may have an arterial component [SIGN, 2010]. Bone at the base of a wound may suggest a protracted healing time and the possibility of underlying osteomyelitis [Grey, 2021a].
• Classic signs of venous hypertension include oedema, hemosiderin staining, and lipodermatosclerosis [Bowers, 2020].
• Other findings suggestive of venous ulcers include telangiectasias (dilated or broken blood vessels located near the surface of the skin), corona phlebectatica (abnormally dilated veins around the ankle and foot), atrophie blanche (atrophic, white scarring), lipodermatosclerosis, and inverted champagne-bottle deformity of the lower leg [Bonkemeyer Millan, 2019].
• Non-invasive imaging with comprehensive venous duplex ultrasonography, arterial pulse examination, and measurement of ankle-brachial index is recommended for all patients with suspected venous ulcers [Bonkemeyer Millan, 2019].

Basis for recommendation

The information on the differential diagnoses of venous leg ulcer is based on the Scottish Intercollegiate Guidelines Network (SIGN) guideline Management of chronic venous leg ulcers [SIGN, 2010], the Primary Care Dermatology Society (PCDS) guideline Leg ulcers (and disorders of venous insufficiency) [PCDS, 2023], a joint document by the European Wound Management Association (EWMA) and Wounds Australia Management of Patients With Venous Leg Ulcers: Challenges and Current Best Practice [Franks, 2016], the Wounds UK document Best Practice Statement: Addressing complexities in the management of venous leg ulcers [Wounds UK, 2019], and expert opinion in review articles [Vivas, 2016; Singer, 2017; Lim, 2018; Bonkemeyer Millan, 2019] and a textbook ABC of Wound Healing [Grey, 2021a; Grey, 2021b; Patel, 2021]. 

Overview of management of a person with a venous leg ulcer

• Assess the need for immediate referral. See the section on Referral for more information.
• If immediate referral is not indicated:
  • Ensure that compression therapy is started immediately if appropriate. See the section on Compression therapy for more information.
    • The ulcer should be cleaned and dressed appropriately before compression is applied. See the section on Cleaning and dressing the ulcer for more information.
    • Compression should only be applied by trained healthcare professionals and in accordance with the manufacturer’s instructions.
  • Consider prescribing pentoxifylline, depending on local prescribing policies, to aid ulcer healing.
    • Pentoxifylline is an effective adjunct to compression therapy for treating venous leg ulcers (off-label indication) and may be effective in the absence of compression.
    • The recommended dosage is 400 mg three times daily for up to 6 months, depending on local prescribing policies.
    • See the prescribing information for Pentoxifylline for more information.
  • Assess for (and manage):
    • Associated conditions, such as oedema and venous eczema.
    • Complications of the ulcer, such as pain and infection.
  • Provide information and lifestyle advice to promote ulcer healing and reduce the risk of recurrence, and sources of further information. See the section on Information and advice for more information.
  • Review the person appropriately. See the section on Follow up for more information.
• After a venous leg ulcer has healed, offer below-knee graduated compression stockings to prevent recurrence of ulceration. See the section on Preventing recurrence for more information.

When should I refer a person with a venous leg ulcer?

• Refer to a specialist if: 
  • There is diagnostic uncertainty — refer for specialist vascular assessment (to a leg ulcer clinic, tissue viability clinic, or a vascular specialist depending on clinical judgement and availability) or to dermatology.
  • The ulcer is rapidly deteriorating or has an atypical location (outside the gaiter area) and/or appearance — refer to dermatology for a possible skin biopsy. 
  • There is a suspected alternative cause of ulceration, such as: 
    • Arterial or mixed venous/arterial disease — refer people with an ankle brachial pressure index (ABPI) outside the normal range. For more information, see the section on Assessment in the CKS topic Peripheral arterial disease.  
    • Malignancy — refer to dermatology using the urgent suspected cancer pathway referral. See the CKS topic on Skin cancers - recognition and referral for more information.
    • Diabetes mellitus — refer to the diabetes ulcer clinic.
    • Rheumatoid arthritis or systemic vasculitis — refer to rheumatology. 
  • The person has poor ankle mobility, reduced joint function, or a history of falls. 
  • There is suspected iliac vein stenosis — these people may need investigation by CT venography and intravenous ultrasound.
• After compression therapy is initiated, arrange specialist referral if:
  • There is a complication related to the ulcer or the treatment, including:
    • Suspected contact dermatitis — refer to dermatology for consideration of patch testing. 
    • Osteomyelitis (suggested by fever, disproportionate pain, local malodour, non-healing sinus, and oedema around wound) — arrange urgent hospital admission for intravenous antibiotics. 
    • Sepsis (suggested by tachycardia, fever, and chills) — arrange urgent hospital admission for intravenous antibiotics.  
    • Necrotising fasciitis (suggested by disproportionate pain and tenderness, dusky-violaceous areas along with erythema, crepitus, blisters, and necrosis) — arrange urgent hospital admission for intravenous antibiotics. 
    • Uncontrolled pain — refer to a specialist pain team.
  • There is delayed or no healing after 2 weeks of compression therapy — refer to a vascular specialist or dermatologist depending on clinical judgement.
  • There are difficulties with adequately controlling any underlying pathologies.
• If the ulcer is recurrent, refer to a vascular specialist for consideration for superficial venous surgery.

How should a venous leg ulcer be cleaned and dressed?

A healthcare professional with expertise in wound management (such as a district nurse or tissue viability nurse) should be involved in the cleaning and dressing of a venous leg ulcer. 

• Ensure that the ulcerated leg is washed normally in tap water and carefully dried.
  • A strict aseptic technique is not required, as the aim is not to remove surface bacteria but rather to avoid cross-infection from contamination. 
  • Debridement of slough or necrotic tissue from the wound surface may facilitate wound healing. 
• Ensure that simple non-adherent dressings are used in the management of venous leg ulcers. 
  • The choice of dressing should be based on factors such as the properties of the wound (location, size, depth, exudate level, presence of infection), the stage of the healing process, the condition of the surrounding skin, the person's preference or tolerance (including allergies and concurrent medical conditions), and cost.
    • The Wound management products and elasticated garments section of the BNF provides information on the types and properties of different dressings, and lists the choices of primary dressing depending on the nature of the wound.
    • Antimicrobial dressings (for example, silver, iodine, or honey dressings) should not be used routinely. 
    • There is inadequate evidence to support regular application of topical antimicrobials or antiseptics.
  • The frequency of dressing changes depends on the exudate volume and the stage of ulcer healing. 
    • Once compression therapy has begun, dressing changes should lessen as exudate reduces. Dressing changes may only be needed weekly; the frequency should be tailored so that the dressing is neither oversaturated nor dry and is not adherent to the wound when it is removed.
    • Dressings are typically used continually until the wound has healed. Occasionally, they may be used after healing to protect fragile scar tissue.
  • The minimum quantity of dressings necessary to meet the person's needs should be provided to avoid wastage and stockpiling.
• If there is pain at dressing changes:
  • Ensure an appropriate dressing is used and that the frequency of dressing changes is minimized.
  • Advise the person to take a simple analgesia (such as paracetamol with or without codeine) at least 30 minutes before a dressing change, where possible. 
  • Manage neuropathic pain if present. See the CKS topic on Neuropathic pain - drug treatment for more information.

How should compression therapy be used to treat a venous leg ulcer?

Compression therapy should be applied by a healthcare professional trained in venous ulcer management (such as a district nurse or tissue viability nurse). 

• Before starting compression therapy, the ankle brachial pressure index (ABPI) in both legs should be measured to exclude arterial insufficiency.
  
  • ABPI should be interpreted alongside clinical findings, as it may be unreliable in people with diabetes, chronic oedema, lymphoedema, or arterial calcification.
    • Toe-brachial pressure index (TBPI) or Doppler waveform analysis may be required when ABPI is unreliable.
  • Use the following thresholds to guide compression therapy:
    
    • ABPI <0.5  — severe arterial insufficiency is likely. Compression therapy is contraindicated. Urgent vascular assessment is required.
    • ABPI 0.5–0.79  — mixed arterial and venous disease is likely. Modified or light compression may be used with caution, supported by clinical monitoring and specialist advice where needed.
    • ABPI 0.8–1.3 — no significant arterial disease. Full compression therapy is generally considered safe.
    • ABPI >1.3–1.4 — arteries may be calcified and incompressible. ABPI is unreliable. Further vascular assessment (for example, TBPI) is required before prescribing compression.
    • Note: ABPI is not required before initiating light compression (for example, Class 1 stockings) when no red flags for arterial disease are present.
  • For people with moderate to severe cardiac failure consider seeking specialist advice as there may be a risk of fluid overload if not closely monitored.
• Ensure that compression therapy is started immediately if appropriate. 
  • Select the degree of compression:
    • This should be guided by the person's underlying condition, but may need to be reduced to the highest level the person can tolerate safely.
    • Increase compression strength gradually if needed.
    • Reduce compression if pain, numbness, or skin damage occurs.
  • Use strong compression (Class 3; 25–35 mmHg) for:
    • Severe venous insufficiency.
    • Healing of venous leg ulcers.
    • Prevention of venous ulcer recurrence.
  • Multilayer compression bandaging systems are commercially available as kits. Compression is achieved by the combined effects of two or three extensible bandages applied over a layer of orthopaedic wadding and a wound contact dressing.
  • Different kits are available comprising slightly different components for different ankle sizes. Products currently available are outlined in the British National Formulary (BNF), and specific manufacturer's instructions should be followed for each product.
• Encourage compliance with compression therapy by:
  • Ensuring that the person understands the reasons for, and the benefits of, compression therapy.
  • Managing associated conditions, such as oedema and venous eczema.
  • Managing complications of the ulcer, such as pain and infection.
  • Addressing the person's concerns and offering options that suit their preferences. When deciding on the type of compression to use, the following should be considered: 
    • The person's preference, lifestyle, and likely concordance — as many elderly people find graduated compression hosiery difficult to put on, this should include an assessment of the person's mobility and the availability of any help at home.
    • The required frequency of application.
    • The size and shape of leg.
• Give general lifestyle advice to promote ulcer healing, and provide sources of further information.

How should I manage infection in a person with venous leg ulcer?

If there are symptoms or signs of infection, such as cellulitis (characterized by pain, warmth, swelling, and erythema of the infected area), fever, increased pain, rapid extension of the area of ulceration, malodour, and increased exudate:

• Consider taking a swab (from deep within the ulcer after cleaning) for microbiological testing. 
• Prescribe an oral antibiotic. 
  • For most people, prescribe flucloxacillin 500 mg four times daily for 7 days.
  • If the person is penicillin-allergic or flucloxacillin is unsuitable, consider one of the following options:
    • Clarithromycin 500 mg twice a day for 7 days. 
    • Doxycycline 200 mg on first day, then 100 mg once a day for 6 days (7-day course in total).
    • Erythromcyin 500 mg four times daily for 7 days (in pregnant women).
  • Routine long-term use of topical antiseptics and antimicrobials is not recommended.
• Advise the person to seek medical help if symptoms of the infection worsen rapidly or significantly at any time, or do not start to improve within 2-3 days.
• Compression therapy can be continued if tolerated. Otherwise, it can be temporarily reduced or stopped to ease pain and then returned to usual compression as soon as possible.
  • Uncontrolled exudate and oedema will prolong the cellulitis, so the aim is to return to therapeutic compression as soon as possible.
• Reassess the person if the infection worsens rapidly or significantly at any time, does not start to improve within 2–3 days, or the person becomes systemically very unwell or has severe pain out of proportion to the infection.
  • When reassessing the person, take account of:
    • Any symptoms or signs suggesting a more serious illness or condition, such as sepsis (tachycardia, fever, and chills), necrotising fasciitis (disproportionate pain and tenderness, dusky-violaceous areas along with erythema, crepitus, blisters, and necrosis), osteomyelitis (fever, disproportionate pain, local malodour, non-healing sinus, and oedema around wound), or lymphangitis (fever, chills, swollen lymph glands, malaise, and aches).
    • Other comorbidities, such as diabetes or immunosuppression.
    • Possible complications, including allergic contact dermatitis (which may cause infection).
    • Whether uncontrolled oedema or poor compliance with compression therapy contributed to the cellulitis, and whether any changes to compression therapy are required.
    • Previous antibiotic use, which may have led to resistant bacteria.
  • If the infection is worsening or not improving, check swab results and change the antibiotic based on swab sensitivities, using a narrow-spectrum antibiotic if possible. Consider one of the following options (guided by microbiological results):
    • Co-amoxiclav 500/125 mg three times a day for 7 days, or 
    • Co-trimoxazole 960 mg twice a day for 7 days (in people with penicillin allergy).
  • If the infection is sensitive to the first-line antibiotic but only slowly responding, review the person after 7 days and consider continuing the antibiotic for a further 7 days. 
• Arrange urgent hospital referral if the person has any symptoms or signs suggesting a more serious illness or condition, such as sepsis, necrotising fasciitis, or osteomyelitis.
• Consider referring or seeking specialist advice if the person:
  • Has a high risk of complications.
  • Has lymphangitis.
  • Has spreading infection that is not responding to oral antibiotics.
  • Cannot take oral antibiotics (where appropriate, explore locally available options for giving intravenous antibiotics at home or in the community, rather than in hospital).

How should I manage pain in a person with a venous leg ulcer?

• Determine the nature of the pain to help exclude an underlying cause.
  • Ask about the location, severity, duration, frequency (and when it occurs), triggers and relievers, and the impact of the pain on the person’s quality of life and functional ability. 
    • Venous leg ulcers can sometimes cause constant or intermittent pain.
    • Severe or worsening pain may indicate a complication, such as an infection. 
    • Pain can also be caused by arterial disease, diabetic neuropathy, vascular structures (superficial, deep phlebitis), pitting oedema, lipodermatosclerosis, and contact dermatitis. 
    • Changing dressings, debridement, and firm bandages can also cause pain.
  • Consider using a validated pain tool, such as the Visual Analogue Scale (VAS), to assess pain.
• Advise the person:
  • To take a simple analgesic, such as paracetamol with or without codeine, as needed. See the CKS topic on Analgesia - mild-to-moderate pain for more information.
    • Nonsteroidal anti-inflammatory drugs (NSAIDs) are not recommended for pain control because they impair wound healing and may worsen leg oedema.
  • That leg elevation may help with the pain associated with oedema. 
• If there is pain at dressing changes:
  • Ensure an appropriate dressing is used and the frequency of dressing changes is minimized.
  • Advise the person to take a simple analgesia (such as paracetamol with or without codeine) at least 30 minutes before a dressing change, where possible. 
• If neuropathic pain is present, see the CKS topic on Neuropathic pain - drug treatment for management information.
• If the pain is uncontrolled or chronic, refer the person to the pain team.

How should I manage oedema in a person with venous leg ulcer?

• Check compliance with compression therapy.
  • Common reasons for non-compliance include pain, discomfort, a lack of valid lifestyle advice, and the belief that compression was unnecessary and uncomfortable.
• Advise the person to:
  • Elevate their legs (above hip level) for 30 minutes three to four times a day.
  • Consider placing pillows under their feet and legs while sleeping. 
• Exclude other causes of oedema, such as:
  • Medication, for example, calcium-channel blockers and oral corticosteroids.
  • Comorbidities, such as heart failure and chronic kidney disease. See the CKS topics on Heart failure - chronic and Chronic kidney disease for more information.
• If oedema is persistent or worsening, refer for specialist assessment.
  • Do not prescribe a diuretic for persistent or worsening oedema.

How should I manage eczema in a person with venous leg ulcer?

• If there is worsening venous eczema, assess for signs of infection, such as cellulitis (characterized by pain, warmth, swelling, and erythema of the infected area), fever, increased pain, rapid extension of the area of ulceration, malodour, and increased exudate.
  • If there are signs of infection, see the section on Managing infection for more information.
  • If there are no signs of an infection:
    • Advise regular application of an emollient, and treat flares with a topical corticosteroid. See the CKS topic on Eczema - atopic for detailed information on the use of emollients and topical steroids, and skin care advice.
    • If compression bandaging is being used, consider replacing bandages more frequently than once weekly to allow application of topical treatment.
• If there is no clinical improvement or allergic contact dermatitis is suspected, refer the person to dermatology for consideration of patch testing.
  • Advise the person to avoid any allergens subsequently identified.
  • Common allergens that may be present in creams and dressings used for venous leg ulcer management include preservatives, emulsifiers, latex, resins, lanolin, and topical steroids, antibiotics, and antiseptics.

How should I follow up a person with venous leg ulcer?

Ideally, people with uncomplicated ulcers should be reviewed at least weekly for the first 2 weeks after initiation of primary care treatment. If the ulcer is healing, this period can be extended depending on clinical judgement.

• During the review:
  • Inspect and compare the ulcer with the initial assessment to see if there is evidence of healing, suggested by reduced ulcer size, development of healthy pink granulation tissue, reduced amounts of exudate, and improved symptoms of pain and oedema. 
  • Check compliance with compression therapy — poor compliance may be due to heat, discomfort, and the impractical nature of the bandaging. 
  • Check compliance with lifestyle advice.
  • Assess for (and manage):
    • Associated conditions, such as oedema and venous eczema.
    • Complications related to the ulcer, including pain and infection.
    • Complications related to the dressings applied, including skin maceration (indicated by a marked cut-off appearance) and allergic contact dermatitis. Maceration is usually caused by the inability of the dressing to manage exudate. More frequent dressing changes, or a change in dressing type, should be considered. The surrounding skin should also be protected with an emollient. 
    • Complications related to compression bandaging, including pressure damage and arterial insufficiency. Compression bandages should be removed immediately if the person experiences a change in foot colour or temperature, or increased pain. Seek further medical advice if there is no improvement after removing the bandages. 
• Refer to a vascular specialist or dermatologist (depending on clinical judgement) if there is delayed or no healing after 2 weeks of compression therapy.
• There is no consensus among guidelines on the frequency of repeat ankle-brachial pressure index (ABPI) measurements.
  • Repeat ABPI measurements should ideally be done at the first signs of ulcer deterioration, ulcer recurrence, sudden increase in ulcer size or pain, or change in foot colour or temperature.
  • Follow local policies if available. 

How should I prevent recurrence of venous leg ulcer?

• After a venous leg ulcer has healed, offer below-knee graduated compression stockings to prevent recurrence. 
  • Advise the person that compression hosiery has been proven to reduce the rate of ulcer recurrence and that it is likely that compression will be required indefinitely.
  • See the CKS topic on Compression stockings for detailed information on the use of compression stockings, including information on:
    • The recommended strength of compression — the person should be offered the strongest compression that they can tolerate. Stockings prescribed in primary care follow the British standard for class of compression: class 3 (25–35 mmHg), class 2 (18–24 mmHg), and class 1 (14–17 mmHg). Hospital departments may provide European standard stockings, which provide a stronger degree of compression for each class. 
    • Available products — compression stockings are available in two lengths (below the knee and thigh length), with either closed toe or open toe (with or without a heel), and in a range of styles and colours. 
    • How often the stocking should be changed — compression stockings should be replaced every 3–6 months. Ideally, the leg should be re-measured each time a stocking is replaced.
    • Frequency of review — ideally, Doppler studies should be repeated every 6–12 months (or earlier if clinically indicated). Follow local policies if available. 
    • How to encourage compliance with wearing stockings — compliance should be encouraged by keeping the person well informed, addressing their concerns, and offering options that suit their preferences. 
• Give general lifestyle advice to reduce the risk of ulcer recurrence, and provide sources of further information.
• For people with chronic venous leg ulcer and superficial venous reflux, consider referring for superficial venous surgery to prevent recurrence. 

What information and advice should I give a person with a venous leg ulcer?

• To promote healing of the ulcer and reduce the risk of recurrence:
  • Encourage the person to be compliant with compression therapy. Advise that:
    • Compression therapy has been proven to promotes venous leg ulcer healing and reduce the risk of recurrence.
    • If there are any difficulties, they should contact the district/tissue viability nurse before deciding to stop using them. 
    • They should remove the compression immediately and seek urgent medical advice if they experience features of arterial disease, such as numbness, tingling, pain, or dusky toes.
  • Advise the person to:
    • Keep mobile with regular walking (to exercise calf muscle pump function). 
    • Elevate the legs when immobile. 
    • Avoid trauma and wear appropriate (well-fitting) footwear. 
    • Use an emollient frequently, and avoid products that may contain any identified sensitizing agents (such as lanolin and preservatives).
    • Examine their legs regularly for broken skin, blisters, swelling, or redness. 
    • Adopt a healthy lifestyle. They should: 
      • Lose weight (if overweight or obese). See the CKS topic on Obesity for more information. 
      • Eat a balanced diet (malnutrition impairs ulcer healing).
      • Drink alcohol within recommended levels. See the CKS topic on Alcohol - problem drinking for more information. 
      • Stop smoking (if applicable). See the CKS topic on Smoking cessation for more information.
• Provide sources of further information.
  • Patient information leaflets are available from:
    • The British Association of Dermatologists (BAD) website (www.bad.org.uk).
    • The NHS website (www.nhs.uk).
  • Leg ulcer support groups include:
    • Leg Ulcer Forum (www.legulcerforum.org).
    • The Lindsay Leg Club Foundation (www.legclub.org).

What are the contraindications and cautions for clarithromycin?

• Do not prescribe clarithromycin to people with:
  • A history of QT prolongation or ventricular cardiac arrhythmia, including Torsades de pointes arrhythmias.
  • Hypokalaemia or hypomagnesaemia.
  • Severe hepatic impairment in combination with renal impairment.
• Prescribe clarithromycin with caution to:
  • People with:
    • Impaired hepatic function and those 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 rarely reported with its use.
    • Conditions which predispose to QT interval prolongation (such as electrolyte disturbances) and those taking drugs that prolong the QT interval (such as amiodarone, sotalol, and amisulpride) — macrolides can also prolong the QT interval, increasing the risk of Torsades de pointes arrhythmias.
    • 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 of clarithromycin.  Avoid clarithromycin modified-release (M/R) preparations in this patient populations. If creatinine clearance is 30–60 mL/minute/1.73 m² half the normal dose should be used for M/R preparations.
    • Coronary artery disease, severe cardiac insufficiency, or bradycardia (heart rate less than 50 beats per minute) — increased risk of QT prolongation.
    • Myasthenia gravis — clarithromycin may aggravate symptoms.
  • Pregnant or breastfeeding women. See the section on Use in pregnancy and breastfeeding for more information.

[BNF, 2024; EMC, 2024a]

What are the possible adverse effects of clarithromycin?

• The most common adverse effects of clarithromycin are abdominal pain, nausea, vomiting, taste perversion, and diarrhoea.
  • Consider pseudomembranous colitis (an acute, exudative colitis caused by Clostridium difficile) if a person develops severe diarrhoea during or after treatment with clarithromycin. See the CKS topic on Diarrhoea - antibiotic associated for more information.
• Reversible hearing loss (sometimes with tinnitus) can occur after large doses of clarithromycin.
• Other adverse effects of clarithromycin include:
  • Uncommon — burping, dry mouth, epistaxis, muscle complaints, oral disorders, thrombocytosis, and tremor.
  • Rare or very rare — Myasthenia gravis, and tubulointerstitial nephritis.
  • Frequency not known — abnormal dreams, agranulocytosis, depersonalization, depression, mania, myopathy, psychotic disorder, renal failure, tooth discolouration, and urine discolouration.

[BNF, 2024; EMC, 2024a]

What are some possible drug interactions with clarithromycin?

• Drug interactions with clarithromycin include:
  • Aminophylline — aminophylline is predicted to cause hypokalaemia (potentially increasing the risk of Torsade de pointes) when given with clarithromycin.
    • Manufacturer makes no recommendation.
  • Calcium channel blockers — clarithromycin may increase serum levels of calcium channel blockers metabolized by CYP3A4 (such as verapamil, amlodipine, and diltiazem).
    • Due to an increased risk of adverse effects, particularly hypotension, caution is advised with concurrent use.
  • Carbamazepine — clarithromycin slightly increases the concentration of carbamazepine. 
    • Monitor carbamazepine levels. 
    • Advise the person to report symptoms of carbamazepine toxicity (such as nausea and vomiting, ataxia, and drowsiness).
  • Colchicine — clarithromycin possibly increases the risk of colchicine toxicity.
    • Stop or reduce the dose of colchicine.
    • Avoid concurrent use in people with renal or hepatic impairment.
  • CYP450 inducing medicines — Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate clarithromycin metabolism and alter the plasma concentration ratios of parent drug to active metabolite (which have different microbiological activity), thereby altering the therapeutic effect.
  • Digoxin — clarithromycin increases the concentration of digoxin.
    • Monitor digoxin concentration.
  • Drugs that prolong the QT interval (such as amiodarone, amisulpride, astemizole, cisapride, domperidone, fluconazole, pimozide, sildenafil, terfenadine, and tricyclic antidepressants) — macrolides can also prolong the QT interval, increasing the risk of Torsades de pointes.
    • Most manufacturers advise avoiding the use of two or more drugs that are associated with QT prolongation. Increasing age, female sex, cardiac disease, and some metabolic disturbances (notably hypokalaemia and hypomagnesaemia) predispose to QT prolongation.
  • Drugs that cause hypokalaemia (such as diuretics, corticosteroids, and short-acting beta-2 agonists) — 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.
  • Ergotamine and dihydroergotamine — clarithromycin is predicted to increase the risk of ergotism when given with ergotamine or dihydroergotamine and is contraindicated.
  • Ivabradine — concomitant treatment is contraindicated, owing to CYP3A4 inhibition by clarithromycin which can cause elevated levels of ivabradine.
  • Midazolam — manufacturer advises avoid. Concomitant use with oral midazolam has been observed to substantially increase the systemic concentration.
  • Oral hypoglycaemic drugs — clarithromycin is predicted to slightly increase the exposure to oral hypoglycaemic drugs (such as gliclazide, glibenclamide, glimepiride, and glipizide), increasing the risk of hypoglycaemia.
    • Monitor blood glucose levels more regularly, and adjust the dose of the oral hypoglycaemic drug accordingly. 
  • Statins — there is an increased risk of myopathy due to cytochrome P450 enzyme CYP3A4 inhibition [MHRA, 2014].  
    • For simvastatin (potent CYP3A4 inhibitor) — concurrent use is contraindicated. If clarithromycin treatment cannot be avoided, stop treatment with simvastatin during the course of antibiotic treatment.
    • For atorvastatin (moderate CYP3A4 inhibitor) — avoid concurrent use if possible. If clarithromycin treatment cannot be avoided, stop treatment with atorvastatin during the course of antibiotic treatment or prescribe the lowest starting dose of atorvastatin (that is 10 mg) and do not exceed 20 mg atorvastatin daily. Advise the person to seek medical advice if they experience symptoms of myopathy (for example muscle pain, tenderness, or weakness).
    • For pravastatin — prescribe clarithromycin with caution, and advise the person to report any muscle pain, tenderness, or weakness.
    • Other statins — rosuvastatin is not associated with cytochrome P450 interactions, and clinically significant interaction with clarithromycin is not expected for fluvastatin. Nevertheless, advise the person to report any muscle pain, tenderness, or weakness. 
  • Theophylline — theophylline is predicted to cause hypokalaemia (potentially increasing the risk of Torsade de pointes) when given with clarithromycin.
    • Monitor theophylline levels. Consider a dose reduction of theophylline if toxicity is suspected (for example if headache, nausea, or palpitations occur).
  • Ticagrelor — concomitant treatment is contraindicated, owing to CYP3A4 inhibition by clarithromycin which can cause elevated levels of ticagrelor.
  • Quetiapine — clarithromycin may increase the plasma concentration of quetiapine.
    • Avoid concurrent use.
  • Ranolazine — concomitant treatment is contraindicated, owing to CYP3A4 inhibition by clarithromycin which can cause elevated levels of ranolazine.
  • Ritonavir — concomitant use may inhibit clarthromycin metabolism resulting in a marked increase in the systemic concentration. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in people with normal renal function, but dosage adjustments should be considered for people with renal impairment. 
    • The manufacturer recommends that the dose should be reduced by 75% for people with an estimated glomerular filtration rate (eGFR) less than 30 mL/minute/1.73 m², and by 50% for people with an eGFR of 30-60 mL/minute/1.73 m².
    • A maximum dose of 1 g/day is recommended in people also using ritonavir.
  • Warfarin — clarithromycin may enhance the anticoagulant effect of warfarin. 
    • Increase monitoring of the international normalized ratio (INR) when both drugs are used (particularly in elderly people), and adjust the warfarin dose accordingly. 
• Oral hormonal contraception — there is no established drug interaction between clarithromycin and oral hormonal contraception.
  • However, advise women on the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the section on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods.

[BNF, 2024; EMC, 2024a]

Can clarithromycin be used during pregnancy and breastfeeding?

• Pregnancy
  • The manufacturer states that the use of clarithromycin is not advised in pregnancy, particularly in the first trimester, unless the potential benefit outweighs the risk [EMC, 2024a].
  • Available data for clarithromycin does not suggest an increased risk of congenital malformation, and although studies have described associations between clarithromycin use in pregnancy and miscarriage, these findings are considered inconclusive [UKTIS, 2020].
  • Certain infections arising during pregnancy can cause serious harm to both to the mother and baby if not treated appropriately. Where the benefits of treatment are expected to outweigh the risks, and where no suitable safe alternative is available, a macrolide can be used during pregnancy [UKTIS, 2020; MHRA, 2021].
• Breastfeeding
  • Clarithromycin passes into breast milk in small amounts. With maternal use of 500 mg/day, it is estimated that a breastfed infant would receive approximately 1% of the recommended paediatric (<6 months) dosage [LactMed, 2022; SPS, 2024a].
  • The manufacturer states that the use of clarithromycin during breastfeeding is not advised unless the potential benefit outweighs the risk [EMC, 2024a].
  • Inconclusive epidemiological evidence has suggested that there may be an increased risk of hypertrophic pyloric stenosis in infants following maternal macrolide use whilst breastfeeding, especially in infants exposed in the first 2 weeks after birth [SPS, 2024a].
  • Clarithromycin can be used during breastfeeding with precautionary infant monitoring for gastro-intestinal disturbances such as diarrhoea and vomiting, oral candida infection, rashes, sleep disturbances, irritability, sweating, and loss of appetite [SPS, 2024a].
• Although clarithromycin use may be justifiable following a careful evaluation of the risks and benefits, erythromycin is the macrolide of choice in pregnant and breastfeeding women.
  • Clarithromycin use should only be considered if the woman cannot tolerate erythromycin and there is no suitable alternative.
  • For more details see the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy, and recommendations from the Specialist Pharmacy Service on using macrolide antibiotics during breastfeeding.

What are the contraindications and cautions for co-amoxiclav?

• Do not prescribe co-amoxiclav to people with:
  • A true penicillin hypersensitivity.
    • Note that 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.
  • A history of severe immediate hypersensitivity reaction to cephalosporins — there is some evidence of partial cross-allergenicity. 
  • A history of co-amoxiclav- or penicillin-associated jaundice or hepatic dysfunction.
• Prescribe co-amoxiclav with caution to people with:
  • Hepatic impairment — monitor closely.
  • Chronic kidney disease (CKD) — reduce the dose of co-amoxiclav based on the estimated glomerular filtration rate (eGFR):
    • If the eGFR is 10–30 mL/minute/1.73 m², prescribe one 500/125 strength tablet every 12 hours.
    • If the eGFR is less than 10 mL/minute/1.73 m², prescribe one 500/125 strength tablet every 24 hours.
  • Acute lymphocytic leukaemia, chronic lymphocytic leukaemia, cytomegalovirus infection, or glandular fever — increased risk of erythematous rashes.

[BNF, 2024; EMC, 2024b]

What are the possible adverse effects of co-amoxiclav?

• Gastrointestinal — diarrhoea (very common), nausea and vomiting (common), antibiotic-associated colitis, drug-induced enterocolitis syndrome, acute pancreatitis, black hairy tongue (unknown frequency). 
• Hepatobiliary disorders — Rises in aspartate transaminase (AST) and/or alanine transaminase (ALT; uncommon).
• Nervous system — headache, dizziness (uncommon), reversible hyperactivity, convulsions, aseptic meningitis (unknown frequency).
• Skin — skin rash, urticaria, pruritus (uncommon), erythema multiforme (rare).
  • Unknown frequency: Drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP).
• Other rare adverse effects, or adverse effects of unknown frequency include:
  • Crystalluria (including acute renal injury).
  • Hepatitis, cholestatic jaundice.
  • Hyperactivity, convulsions.
  • Hypersensitivity reactions (serious and occasionally fatal).  
  • Interstitial nephritis.
  • Linear IgA disease (renal deposition of IgA).  
  • Leucopenia, thrombocytopenia, haemolytic anaemia.
  • Prolonged prothrombin time.
  • Kounis syndrome (an allergic reaction which can cause myocardial infarction). 
• Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) are adverse effects of unknown frequency.

[BNF, 2024; EMC, 2024b]

What are the possible drug interactions with co-amoxiclav?

• Possible drug interactions with co-amoxiclav include:
  • Allopurinol — concurrent use of allopurinol and co-amoxiclav may increase the incidence of skin rashes.
    • Manufacturer advises to consider alternatives.
  • Methotrexate — amoxicillin is predicted to increase the risk of toxicity when given with methotrexate.
    • If concurrent treatment is indicated, 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.
  • Probenecid — the renal tubular secretion of amoxicillin is decreased by probenecid. Concurrent use may result in increased and prolonged blood levels of amoxicillin, but not of clavulanic acid.
    • Manufacturer recommends avoiding concurrent use.
  • Oral anticoagulants — penicillins may alter the effect of oral anticoagulants (including, acenocoumarol, phenindione and warfarin).
    • Monitor the prothrombin time or international normalized ratio (INR) more closely with the addition or withdrawal of a penicillin. Adjustment of the oral anticoagulant dose may be necessary.
  • Mycophenolate mofetil — concurrent use with o-amoxiclav may reduce the concentration of the active metabolite of mycophenolate.
    • Manufacturer advises close clinical monitoring when used in combination.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of penicillins.
  • There is no established drug interaction between co-amoxiclav and oral hormonal contraception.
  • However, advise women on the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the section on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods.

[BNF, 2024; EMC, 2024b]

Can co-amoxiclav be used during pregnancy and breastfeeding?

• Pregnancy
  • Co-amoxiclav is not known to be harmful in pregnancy [BNF, 2024].
  • Although evidence is limited for co-amoxiclav specifically, the vast majority of a large amount of safety data for penicillins as a class do not indicate increased risks of congenital malformation, miscarriage, intrauterine death, low birth weight, preterm delivery, or neonatal complications [UKTIS, 2019].
• Breastfeeding
  • Trace amounts of co-amoxiclav are found in breastmilk, but it is appropriate to use in women who are breastfeeding [BNF, 2024].
  • Broad-spectrum penicillins, such as amoxicillin, are one of the preferred choices of antibiotic for breastfeeding women as there is more evidence and experience to support its use [SPS, 2024b].

What are the contraindications and cautions for co-trimoxazole?

• Do not prescribe co-trimoxazole (trimethoprim/sulfamethoxazole) to people with:
  • Severe hepatic impairment.
  • Severe renal impairment (estimated glomerular filtration rate [eGFR] less than 15 mL/minute/1.73 m² ), unless plasma levels of co-trimoxazole can be monitored regularly.
    • If plasma levels of co-trimoxazole can be monitored regularly, prescribe half the recommended dose.
    • The manufacturer recommends that the plasma concentration of sulfamethoxazole is checked at 2 to 3 days using samples obtained 12 hours after administration of co-trimoxazole, with treatment interrupted if the concentration exceeds 150 microgram/ml. Treatment should only be restarted when the concentration falls below 120 microgram/ml. This is only likely to be available in secondary care settings. 
  • Severe haematological disorders, such as blood dyscrasias (unless under specialist supervision).
  • Acute porphyria — both trimethoprim and sulfonamides (although not specifically sulfamethoxazole) have been associated with clinical exacerbation of porphyria.
• Prescribe co-trimoxazole with caution to:
  • Elderly people — increased risk of serious adverse effects, particularly when complicating conditions exist, for example renal impairment, hepatic impairment, and/or concurrent use of other drugs.
    • Use half the normal dose if creatinine clearance is between 15 and 30 mL/minute/1.73 m².
  • People with:
    • Glucose-6-phosphate dehydrogenase (G6PD) deficiency — risk of haemolytic anaemia.
    • Severe allergy and asthma.
    • A predisposition to folate deficiency (for example elderly people).
    • Predisposition to hyperkalaemia — close monitoring of serum potassium is warranted.
  • Pregnant or breastfeeding women. See the section on Use in pregnancy and breastfeeding for more information.
• During treatment with co-trimoxazole, an adequate urinary output should be maintained. 
  • Evidence of crystalluria in vivo is rare, although sulfonamide crystals have been noted in cooled urine from people treated with co-trimoxazole. The risk may be increased in people who are malnourished.

[BNF, 2024; EMC, 2024c]

What are the possible adverse effects of co-trimoxazole?

• Headache, nausea, skin rashes, hyperkalaemia, fungal overgrowth, and diarrhoea are common or very common adverse effects of co-trimoxazole.
  • Consider pseudomembranous colitis (an acute, exudative colitis caused by Clostridiodes difficile) if a person develops severe diarrhoea during or after treatment with co-trimoxazole. See the CKS topic on Diarrhoea - antibiotic associated for more information.
• Blood disorders (including leucopenia, thrombocytopenia, anaemia, and eosinophilia) are rare but serious adverse effects of co-trimoxazole.
  • Discontinue treatment with co-trimoxazole immediately if blood disorders develop.
• Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been rarely reported with co-trimoxazole.
  • Advise people taking co-trimoxazole to monitor closely for skin reactions. The highest risk for occurrence of SJS, TEN, or DRESS is within the first weeks of treatment.
  • If symptoms or signs of SJS, TEN, or DRESS (for example progressive skin rash often with blisters or mucosal lesions) occur, discontinue treatment with co-trimoxazole.
  • If a person develops SJS or TEN with the use of co-trimoxazole, co-trimoxazole must not be re-started at any time.
• Other adverse effects of co-trimoxazole include:
  • Uncommon — vomiting.
  • Rare or very rare — angioedema, arthralgia, ataxia, cough, decreased appetite, depression, dizziness, dyspnoea, fever, haemolysis, hallucination, hepatic disorders, hypoglycaemia, aseptic meningitis, metabolic acidosis, myalgia, myocarditis allergic, nephritis tubulointerstitial, pancreatitis, peripheral neuritis, photosensitivity reaction, renal impairment, renal tubular acidosis, rhabdomyolysis, seizure, serum sickness, systemic lupus erythematosus (SLE), tinnitus, uveitis, vasculitis, and vertigo.
  • Severe respiratory toxicity including potential progression to Adult Respiratory Distress Syndrome.

[BNF, 2024; EMC, 2024c]

What are the possible drug interactions with co-trimoxazole?

• Interactions with co-trimoxazole (trimethoprim/sulfamethoxazole) include:
  • Azathioprine — concurrent treatment with co-trimoxazole may increase the risk of haematological abnormalities.
  • Cyclosporine — reversible deterioration in renal function has been observed in concurrent treatment with co-trimoxazole.
  • Digoxin — concurrent use of trimethoprim with digoxin has been shown to increase plasma digoxin levels in some elderly people.
    • If there are symptoms of digoxin toxicity (for example, nausea, anorexia, or disturbance of colour vision), check serum digoxin levels.
  • Diuretics — in elderly people concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.
    • Manufacturer makes no recommendation.
  • Drugs that can cause hyperkalaemia (for example angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers, and diuretics) — concurrent use with co-trimoxazole may result in clinically significant hyperkalaemia. 
    • Concurrent use should be done cautiously. 
  • Lamivudine — concurrent treatment with co-trimoxazole may increase the bioavailability of lamivudine.
  • Methotrexate — co-trimoxazole may increase free plasma levels of methotrexate. In addition, methotrexate and trimethoprim are both anti-folate drugs.
    • Avoid concurrent use with co-trimoxazole.  
    • If co-trimoxazole treatment is necessary, a folate supplement should be considered.
  • Phenytoin — co-trimoxazole may prolong the half-life of phenytoin, resulting in increased serum phenytoin levels.
    • If symptoms of phenytoin toxicity (confusion, blurred vision, nystagmus, ataxia, or drowsiness) are present, monitor serum phenytoin levels and reduce the dose if necessary.
  • Pyrimethamine — concurrent treatment with co-trimoxazole and pyrimethamine at doses in excess of 25 mg-/week may increase the risk of megaloblastic anaemia.
  • Repaglinide — concurrent treatment with co-trimoxazole may increase the exposure of repaglinide resulting in hypoglycaemia.
  • Warfarin — concurrent treatment with co-trimoxazole may increase the anticoagulant effect of warfarin. 
    • Monitor the international normalized ratio (INR), and adjust the warfarin dose accordingly.
  • Zidovudine — concurrent treatment with co-trimoxazole may increase the risk of haematological adverse reactions.
    • Monitor haematological parameters.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after a course of co-trimoxazole.
  • Although the manufacturer recommends the use of alternative methods of contraception whilst using co-trimoxazole, there is no established drug interaction between co-trimoxazole (nor clavulanic acid or trimethoprim individually) and oral hormonal contraception.
  • However, advise women on the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the section on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods. 

[BNF, 2024; EMC, 2024c]

Can co-trimoxazole be used during pregnancy and breastfeeding?

• Pregnancy
  • The manufacturer advises that co-trimoxazole (trimethoprim/sulfamethoxazole) should not be used in pregnancy, particularly in the first trimester, unless clearly necessary. 
  • Studies investigating the safety of co-trimoxazole in pregnancy are limited by small study sample sizes and study design methodologies which may have introduced bias. The findings of these studies are therefore inconclusive.
    • Case-control studies have shown that there may be an association between exposure to folate antagonists (such as trimethoprim) and birth defects in humans. In animal studies, trimethoprim and sulfamethoxazole have been shown to cause foetal abnormalities.
    • Studies have also described associations with other adverse pregnancy outcomes, including miscarriage, low birth weight and preterm delivery.
    • Also, sulfamethoxazole competes with bilirubin for binding to plasma albumin. As significantly maternally derived drug levels persist for several days in the newborn, there may be a risk of precipitating or exacerbating neonatal hyperbilirubinaemia, with an associated theoretical risk of kernicterus, when co-trimoxazole is used in the third trimester. This theoretical risk is particularly relevant in infants at increased risk of hyperbilirubinaemia, such as those who are preterm and those with glucose-6-phosphate dehydrogenase deficiency.
  • Where there are no suitable alternatives to co-trimoxazole, the benefits of treatment may outweigh the risks. Discussion with a specialist or advisory service is recommended.
    • The UK Teratology Information Service provide evidence-based advice to NHS healthcare professional about medication safety in pregnancy (0344 892 0909; available 9 am to 5 pm, Monday to Friday [excluding bank holidays]).
• Breastfeeding
  • Co-trimoxazole passes into breast milk in small amounts.
  • The manufacturer advises that co-trimoxazole should be avoided during breastfeeding if the mother or infant has, or is at particular risk of developing, hyperbilirubinaemia. 
  • There is a small risk of kernicterus in jaundiced infants, and of haemolysis in G6PD-deficient infants (due to sulfamethoxazole).

[Lactmed, 2021; UKTIS, 2023; BNF, 2024; EMC, 2024c]

What are the contraindications and cautions for doxycycline?

• Do not prescribe doxycycline to pregnant or breastfeeding women. See the section on Use in pregnancy and breastfeeding for more information.
• Prescribe doxycycline with caution to people with:
  • Hepatic impairment and those taking potentially hepatotoxic drugs.
  • Myasthenia gravis — tetracyclines may increase muscle weakness in people with myasthenia gravis.
  • Systemic lupus erythematosus (SLE) — tetracyclines may exacerbate SLE symptoms.
  • Renal impairment — studies have shown no significant difference in the serum half-life of doxycycline between individuals with normal and severely impaired renal function; avoid excessive doses.

[BNF, 2024; EMC, 2024c]

What are the possible adverse effects of doxycycline?

• Blood disorders — haemolytic anaemia, thrombocytopenia, neutropenia, eosinophilia (rare).
• Gastrointestinal — nausea, vomiting, diarrhoea (common), dyspepsia (uncommon). Abdominal discomfort, tooth discolouration, and enamel hypoplasia in children (frequency unknown).
  • Rarely: dysphagia, oesophagitis, oesophageal irritation, pseudomembranous colitis. For more information, see the CKS topic on Diarrhoea - antibiotic associated. (Advice to swallow the capsules with plenty of water, in an upright position, and well before going to bed helps to reduce the frequency of oesophagitis and oesophageal ulceration.)
• Immune system disorders – hypersensitivity common (including anaphylaxis, angioedema, exacerbation of systemic lupus erythematosus, Henoch-Schonlein purpura). Rarely drug reaction with eosinophilia and systemic symptoms (DRESS).
• Hepatic disorders – hepatotoxicity, hepatitis, jaundice, hepatic failure (frequency unknown).
• Renal disorders — blood urea increased (rare).
• Skin — photosensitivity, rash (common).
  • Rarely: toxic epidermal necrolysis, Stevens–Johnson syndrome, erythema multiforme, exfoliative dermatitis, and fixed eruption.
• Other common or very common adverse effects include:
  • Dyspnoea.
  • Hypotension
  • Peripheral oedema
  • Tachycardia.
• Other rare adverse effects include:
  
  • Anxiety.
  • Arthralgia, myalgia.
  • Decreased appetite.
  • Flushing.
  • Pancreatitis.
  • Porphyria.
  • Severe headache and/or visual disturbances — may be an early symptom of benign intracranial hypertension, a rare but serious adverse effect. Headache is a relatively common side effect.
  • Tinnitus.

[BNF, 2024; EMC, 2024c]

What are the possible drug interactions with doxycycline?

• Possible drug interactions with doxycycline include:
  • Aluminium, calcium, and magnesium preparations — the absorption of doxycycline may be impaired if it is taken with antacids containing aluminium, calcium, or magnesium, or other drugs containing these cations. 
    • Manufacturer advises separating administration by 2–3 hours.
  • Antiseizure medicines and barbiturates — the serum half-life of doxycycline may be shortened with concurrent use of barbiturates and antiseizure medicines such as carbamazepine or phenytoin.
    • Manufacturer advises considering increased doses of doxycycline.
  • Oral zinc, iron salts, or bismuth preparations — absorption of doxycycline may be impaired if it is taken with these preparations.
    • Manufacturer advises separating administration by 2–3 hours.
  • Retinoids — there is a possible increased risk of benign intracranial pressure if tetracyclines are used concurrently with retinoids (such as isotretinoin).
    • Avoid concurrent use.
  • Rifampicin — doxycycline levels are markedly reduced, which may lead to treatment failure. Monitor the effects and increase doxycycline dose if necessary.
  • Warfarin — concurrent treatment with co-trimoxazole may increase the anticoagulant effect of warfarin.
    • Monitor the international normalized ratio (INR), and adjust the warfarin dose accordingly.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of tetracyclines.
  • Although the manufacturer describes a few cases of pregnancy or breakthrough bleeding attributed to the concurrent use of tetracycline antibiotics with oral contraceptives, there is no established interaction between doxycycline and oral hormonal contraception. 
  • However, advise women on the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the section on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods.

[BNF, 2024; EMC, 2024c]

Can doxycycline be used during pregnancy and breastfeeding?

• Pregnancy
  • Doxycycline is contraindicated in pregnancy [EMC, 2024c].
  • Effects on skeletal development have been documented in the first trimester in animal studies [BNF, 2024; EMC, 2024c], but first trimester tetracycline use has not been convincingly associated with increased risks of malformation or miscarriage in human pregnancy [UKTIS, 2024].
  • Administration during the second or third trimester may cause discoloration of the child’s teeth, and there is a theoretical risk of impaired skeletal development [BNF, 2024; UKTIS, 2024].
• Breastfeeding
  • The manufacturer advises that doxycycline is contraindicated during breastfeeding as it may cause permanent discolouration of the teeth (yellow-grey-brown) [EMC, 2024c].
  • The NHS Specialist Pharmacy Service (SPS) states that concerns about bone deposition of tetracyclines and possible staining of infant’s dental enamel have not been confirmed and are unlikely during short-term use [SPS, 2024b]. In addition, absorption and therefore discoloration of teeth in the infant may be inhibited by calcium in the breastmilk [BNF, 2024; SPS, 2024b]
  • Short term use (a single course of less than 3 week’s duration) is acceptable for most tetracyclines, including doxycycline, with precautionary infant monitoring [SPS, 2024b].
    • Monitor for skin rashes, gastrointestinal disturbances (vomiting, diarrhoea) and candidiasis (oral thrush, nappy rash).
    • Compared with other tetracyclines, there is less binding of calcium to doxycycline in breast milk, which may result in increased infant absorption.

What are the contraindications and cautions for erythromycin?

• Do not prescribe erythromycin to people with:
  • Porphyria.
  • A history of QT interval prolongation or ventricular cardiac arrhythmia.
  • Conditions that predispose to QT interval prolongation such as electrolyte disturbances (notably hypokalaemia and hypomagnesaemia) and people taking drugs that prolong the QT interval.
• Prescribe erythromycin with caution to people with:
  • Impaired hepatic function or those taking hepatotoxic drugs — erythromycin is principally excreted by the liver. 
  • Renal impairment — give a maximum of 1.5 g daily in severe renal impairment (due to the risk of ototoxicity). 
  • Myasthenia gravis — erythromycin may aggravate weakness symptoms.
  • Coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia.

[MHRA, 2020; BNF, 2024; EMC, 2024e]

What are the possible adverse effects of erythromycin?

• The most common adverse effects of erythromycin are gastrointestinal and are dose-related. They include upper abdominal discomfort, nausea, vomiting, diarrhoea, pancreatitis, and anorexia.
  • Consider pseudomembranous colitis (an acute, exudative colitis caused by Clostridioides difficile) if a person develops severe diarrhoea during or after treatment with erythromycin. See the CKS topic on Diarrhoea - antibiotic associated for more information.
• Reversible hearing loss (sometimes with tinnitus) can rarely occur after large doses of erythromycin.
• Other adverse effects of erythromycin include:
  • Frequency not known — cerebral impairment.

[BNF, 2024; EMC, 2024e]

What are some possible drug interactions of erythromycin?

• Drug interactions with erythromycin include:
  • Alprazolam — erythromycin is predicted to increase the exposure to alprazolam.
    • Manufacturer advises caution.
  • Aminophylline — aminophylline is predicted to cause hypokalaemia (potentially increasing the risk of Torsade de pointes) when given with erythromycin.
    • Manufacturer makes no recommendation.
  • Calcium channel blockers — erythromycin may increase serum levels of calcium channel blockers metabolized by CYP3A4 (such as verapamil, amlodipine, and diltiazem).
    • Due to an increased risk of adverse effects, particularly hypotension, caution is advised with concurrent use.
  • Carbamazepine — erythromycin markedly increases the concentration of carbamazepine, leading to carbamazepine toxicity (which may present as nausea and vomiting, ataxia, and drowsiness).
    • Monitor carbamazepine levels, and adjust dose accordingly. 
    • Advise the person to report symptoms of carbamazepine toxicity.
  • Corticosteroids — levels of corticosteroids may be increased. Monitor for corticosteroid adverse effects (such as moon face, weight gain, hyperglycaemia), and adjust the corticosteroid dose or stop the macrolide as appropriate. 
  • CYP450 inducing medicines — Strong inducers of the cytochrome P450 metabolism system such as rifampicin, phenytoin, carbamazepine, phenobarbital and St John's Wort may induce the metabolism of erythromycin leading to sub-therapeutic plasma concentrations, thereby decreasing the therapeutic effect.
  • Digoxin — erythromycin increases the concentration of digoxin.
    • Monitor digoxin concentration.
  • Drugs that prolong the QT interval (such as antiarrhythmics, antipsychotics, tricyclic antidepressants) — macrolides can also prolong the QT interval.
    • Most manufacturers advise avoiding the use of two or more drugs that are associated with QT prolongation. Increasing age, female sex, cardiac disease, and some metabolic disturbances (notably hypokalaemia and hypomagnesaemia) also predispose to QT prolongation.
    • Seek advice from a microbiologist regarding a suitable alternative antibiotic.
    • The manufacturer states that concurrent use of erythromycin with simvastatin, tolterodine, mizolastine, amisulpride, astemizole, terfenadine, domperidone, cisapride or pimozide is contraindicated.
  • Drugs that cause hypokalaemia (such as diuretics, corticosteroids, short-acting beta₂-agonists) — hypokalaemia is a risk factor for QT prolongation.
    • Seek advice from a microbiologist regarding a suitable alternative antibiotic.
  • Ergotamine and dihydroergotamine — erythromycin is predicted to increase the risk of ergotism when given with ergotamine or dihydroergotamine and is contraindicated.
  • Lomitapide — concurrent use with erythromycin increases transaminase levels and is contraindicated.
  • Statins — there is an increased risk of myopathy due to cytochrome P450 enzyme CYP3A4 inhibition [MHRA, 2014].   
    • For simvastatin (potent CYP3A4 inhibitor) — concurrent use is contraindicated. If erythromycin treatment cannot be avoided, stop treatment with simvastatin during the course of the treatment.
    • For atorvastatin (moderate CYP3A4 inhibitor) — avoid concurrent use if possible. If erythromycin treatment cannot be avoided, stop treatment with simvastatin during the course of the treatment or prescribe the lowest starting dose of atorvastatin (that is 10 mg) and do not exceed 20 mg atorvastatin daily. Advise the person to seek medical advice if they experience symptoms of myopathy (for example muscle pain, tenderness, or weakness).
    • For pravastatin — prescribe erythromycin with caution, and advise the person to report any muscle pain, tenderness, or weakness.
    • Other statins — rosuvastatin is not associated with cytochrome P450 interactions, and clinically significant interaction with erythromycin is not expected for fluvastatin. Nevertheless, advise the person to report any muscle pain, tenderness, or weakness. 
  • Theophylline — erythromycin decreases the clearance of theophylline, and theophylline potentially decreases the clearance of erythromycin.
    • Monitor theophylline levels. Consider a dose reduction of theophylline if toxicity is suspected (for example if headache, nausea, or palpitations occur).
  • Rivaroxaban — erythromycin may increase levels of rivaroxaban, increasing the risk of bleeding. 
  • Warfarin — erythromycin increases the anticoagulant effect of warfarin.
    • Monitor the international normalized ratio (INR), and adjust the warfarin dose accordingly.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after a course of erythromycin.
  • There is no established drug interaction between erythromycin and oral hormonal contraception. 
  • However, advise women on the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the section on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods.

[MHRA, 2020; BNF, 2024; EMC, 2024e]

Can erythromycin be used during pregnancy and breastfeeding?

• Pregnancy
  • The manufacturer advises that erythromycin should only be used during pregnancy if the potential benefit outweighs the risk [EMC, 2024e].
  • Available data for erythromycin does not suggest an increased risk of miscarriage, congenital malformation or cardiac malformation [UKTIS, 2020].
  • Certain infections arising during pregnancy can cause serious harm to both to the mother and baby if not treated appropriately. Where the benefits of treatment are expected to outweigh the risks, and where no suitable safe alternative is available, a macrolide can be used during pregnancy [UKTIS, 2020; MHRA, 2021].
• Breastfeeding
  • Erythromycin passes into breast milk in small amounts, and therefore the infant dose received via breast milk is expected to be far lower than the paediatric therapeutic dose [LactMed, 2019; SPS, 2024a].
  • The manufacturer advises caution when erythromycin is being considered for use during breastfeeding [EMC, 2024e].
  • Inconclusive epidemiological evidence has suggested that there may be an increased risk of hypertrophic pyloric stenosis in infants following maternal macrolide use whilst breastfeeding, especially in infants exposed in the first 2 weeks after birth [SPS, 2024a].
  • Erythromycin can be used during breastfeeding with precautionary infant monitoring for gastro-intestinal disturbances such as diarrhoea and vomiting, oral candida infection, rashes, sleep disturbances, irritability, sweating, and loss of appetite [SPS, 2024a].
• Erythromycin is the macrolide of choice in pregnant and breastfeeding women.
  • For more details see the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy, and recommendations from the Specialist Pharmacy Service on using macrolide antibiotics during breastfeeding.

What are the contraindications and cautions for flucloxacillin?

• Do not prescribe flucloxacillin to people with:
  • A true penicillin hypersensitivity.
    • Note that 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.
  • A hypersensitivity to cephalosporins — there is some evidence of partial cross-allergenicity. 
  • A history of penicillin-associated jaundice or hepatic dysfunction.
• Prescribe flucloxacillin with caution in people with:
  • Hepatic impairment (especially if they are 50 years of age or older, or have a serious underlying disease).
  • Severe renal impairment — reduce the dose of flucloxacillin, or the dosing interval, if the estimated glomerular filtration rate (eGFR) is less than 10 mL/minute/1.73 m², due to the risk of neurotoxicity.

[EMC, 2023; BNF, 2024]

What are the possible adverse effects of flucloxacillin?

• The most common adverse effects of flucloxacillin are nausea, vomiting, skin rash, and diarrhoea.
  • Consider pseudomembranous colitis (an acute, exudative colitis caused by Clostridioides difficile) if a person develops severe diarrhoea during or after treatment with flucloxacillin. See the CKS topic on Diarrhoea - antibiotic associated for more information.
• Anaphylaxis (delayed or immediate) is a serious but rare adverse effect of flucloxacillin. For more information, see the CKS topic on Angio-oedema and anaphylaxis.
• Hepatitis and cholestatic jaundice may occur very rarely after treatment with flucloxacillin. These reactions are related neither to the dose nor to the route of administration of flucloxacillin, and the onset may be delayed for several weeks (up to 2 months) after treatment has stopped. Risk factors include treatment for more than 2 weeks and increasing age.
• Other adverse effects of flucloxacillin include:
  • Rare or very rare — arthralgia, neutropenia (including agranulocytosis), thrombocytopenia, eosinophilia, fever, myalgia, interstitial nephritis, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

[EMC, 2023; BNF, 2024]

What are the possible drug interactions with flucloxacillin?

• Possible drug interactions with flucloxacillin include:
  • Paracetamol — concurrent use may increase the risk of high anion gap metabolic acidosis, particular in those with severe renal impairment, sepsis or malnutrition who are using the maximum recommended daily dose of paracetamol.
  • Caution and close monitoring is recommended by the manufacturer of flucloxacillin.
  • Methotrexate — methotrexate clearance may be reduced, causing an increased risk of toxicity, however, serious interactions are uncommon. 
  • Standard routine monitoring will identify any decreases in elimination in people on high-dose regimens. For people on low-dose regimens, consult local or national guidelines/protocols for monitoring and management.
  • Coumarin and indanedione anticoagulants (warfarin, phenidione) — consider increased monitoring of international normalized ratio (INR) and adjust the dose accordingly.
  • Posaconazole, voriconazole — concentrations of antifungal is greatly decreased. If concurrent use is unavoidable, monitor for decreased efficacy and consider increasing the dose of the azole (although this may not resolve the issue). 
  • Probenecid, sulfinpyrazone — concomitant administration may result in increased levels of flucloxacillin.
  • Live cholera vaccine — efficacy of vaccine may be reduced. Avoid flucloxacillin from 14 days before to 10 days after receiving live cholera vaccine.
  • Live typhoid vaccine — immune response to vaccine may be reduced. Avoid flucloxacillin from 3 days before to 3 days after receiving live typhoid vaccine.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of penicillins.
  • There is no established drug interaction between flucloxacillin and oral hormonal contraception.
  • However, advise women on the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the section on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods.

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

Can flucloxacillin be used during pregnancy and breastfeeding?

• Pregnancy
  • Flucloxacillin is not known to be harmful in pregnancy [BNF, 2024].
  • Although evidence is limited for flucloxacillin specifically, the vast majority of a large amount of safety data for penicillins as a class do not indicate increased risks of congenital malformation, miscarriage, intrauterine death, low birth weight, preterm delivery, or neonatal complications [UKTIS, 2019].
  • Penicillins may be used in pregnancy [UKTIS, 2019].
• Breastfeeding
  • Trace amounts of flucloxacillin are found in breastmilk, but it is appropriate to use in women who are breastfeeding [BNF, 2024].
  • Flucloxacillin is one of the preferred choices of antibiotic for breastfeeding women as there is more evidence and experience to support its use [SPS, 2024b].

What are the contraindications and cautions for pentoxifylline?

• Do not prescribe pentoxifylline to:
  • People with:
    • Recent cerebral haemorrhage.
    • Recent retinal haemorrhage.
    • Acute myocardial infarction.
    • Severe cardiac arrhythmias.
    • Acute porphyria. 
  • Pregnant women — the manufacturer does not recommend the use of pentoxifylline during pregnancy due to a lack of information on the use in human pregnancy. However, no untoward effects have been found in animal studies. 
• Prescribe pentoxifylline with caution to:
  • People with:
    • Hypotension.
    • Coronary artery disease.
    • Diabetes (may lower blood glucose levels).
    • Severe hepatic impairment — manufacturer advises consideration of a dose reduction.
    • Renal impairment — reduce dose by 30–50% if estimated glomerular filtration rate (eGFR) is less than 30 mL/minute/1.73 m².
  • Breastfeeding women — the manufacturer advises use only if the potential benefit outweighs the risk. Pentoxifylline passes into breast milk in minute quantities.

[EMC, 2023b; BNF, 2024]

What are the adverse effects of pentoxifylline?

• The following adverse effects have been reported in clinical trials or post-marketing studies (frequencies are unknown):
  • Arrhythmia, tachycardia, and angina.
  • Thrombocytopenia, leukopenia/neutropenia.
  • Dizziness, headache, aseptic meningitis (predominantly in people with underlying connective tissue disorders). 
  • Gastrointestinal disorder, epigastric discomfort, abdominal distension, nausea, vomiting, diarrhoea, constipation, and hypersalivation.
  • Pruritus, erythema, urticaria, hot flush, and rash.
  • Anaphylactic reactions, anaphylactoid reaction, and angioedema.
  • Cholestasis.
  • Agitation and sleep disorder.
  • Bronchospasm.
  • Hypotension and haemorrhage.
    • A few very rare events of bleeding have been reported in people treated with pentoxifylline with and without anticoagulants or platelet aggregation inhibitors. The serious cases are predominantly concentrated in the gastrointestinal, genitourinary, multiple site, and surgical wound areas and are associated with bleeding risk factors. A causal relationship between pentoxifylline and bleeding has not been established. Thrombocytopenia has occurred in isolated cases.

[EMC, 2023b]

What are the possible drug interactions with pentoxifylline?

• Possible drug interactions with pentoxifylline include:
  • Anticoagulants — post-marketing cases of increased anticoagulant activity have been reported in people concurrently treated with pentoxifylline and an anticoagulant.
    • Monitoring of anticoagulant activity in these people is recommended when pentoxifylline is introduced or the dose is changed.
  • Antihypertensive drugs — pentoxifylline may potentiate the effect of antihypertensive drugs.
    • The dose of the antihypertensive drug may need to be reduced. 
  • Antiplatelets (such as aspirin, clopidogrel, dipyridamole) — concurrent use may result in an increased risk of bleeding.
    • The manufacturer of pentoxifylline advises that concurrent use should be done with caution.
  • Cimetidine — concurrent use with pentoxifylline may increase the plasma concentrations of pentoxifylline and the active metabolite lisofylline.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) — concurrent use may result in an increased risk of bleeding.
    • The manufacturer of pentoxifylline advises caution with concurrent use.
  • Theophylline and aminophylline — concurrent use with pentoxifylline may increase theophylline or aminophylline levels. 
    • For theophylline, manufacturer advises to monitor and adjust dose.
    • For aminophylline, manufacturer advises to use with caution or avoid.
  • Ciprofloxacin — ciprofloxacin very slightly increases the exposure to pentoxifylline. 
    • Manufacturer advises to monitor for adverse effects. 
  • Fluvoxamine — fluvoxamine is predicted to increase the exposure to pentoxifylline.
    • Manufacturer makes no recommendation.

[EMC, 2023b; BNF, 2024]