Previous changes

April 2024 — minor update. Some information on prevalence has been removed from the summary section of this topic.  In addition the recommendation on post-exposure prophylaxis for individuals who have had a primary course of hepatitis B vaccines has been updated in line with the UKHSA Green Book on Immunisation against infectious disease, chapter 18 Hepatitis B.

February 2023 — minor update. Added adverse effects of Infanrix hexavalent vaccine in line with an update to the manufacturer's SPC. 

September 2022 — minor update. Some information on prevalence has been removed from this topic.  

February 2022 — minor update. Added information about the hexavalent hepatitis B vaccine. 

May 2021 — minor update. Information that hepatitis B is an HIV indicator condition has been added to this topic in line with the British HIV Association/British Association for Sexual Health and HIV/British Infection Association Adult HIV testing guidelines 2020.

November 2019 — reviewed. A literature search was conducted in November 2019 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. The topic has undergone restructuring. No major changes to the recommendations have been made.

December 2013 to March 2014 — reviewed. A literature search was conducted in December 2013 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of this topic. No major changes to recommendations have been made.

December 2013 — minor update. Change to the text in Prescribing Information to reflect a change in policy in Public Health England's Immunisation against infectious diseases—'the Green Book' Chapter 18 Hepatitis B (updated December 2013), that travellers no longer require a booster vaccination after 5 years unless they are considered to be at continuing risk of infection.

September 2013 — minor update to the text to reflect current recommendations regarding metoclopramide.

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

July 2011 — minor update. More exact paracetamol dosing for children has been introduced by the Medicines and Healthcare products Regulatory Agency. Prescriptions have been updated to reflect the revised dosing. 

June 2011 — minor update. Added link to guidance issued by the Department of Health on hepatitis B antenatal screening and newborn immunization programme. 

November 2010 — minor update. The Ministry of Health of Saudi Arabia now recommend that pilgrims for the Hajj and Umrah season of 1431 (2010) consider the hepatitis B vaccine. 

September 2010 — minor update. Additional information has been included in the Prescribing information section.

April to August 2010 — this is a new CKS topic. The evidence-base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

New evidence

Evidence-based guidelines

No new evidence-based guidelines 1 July 2024.

HTAs (Health Technology Assessments)

No new HTAs since 1 July 2024.

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

The recommendations on testing for hepatitis B are based on expert opinion in guidelines from the National Institute of Health and Care Excellence (NICE) Hepatitis B and C testing: people at risk of infection [NICE, 2013a], the British Association of Sexual Health and HIV (BASHH) National Guidelines for the Management of the Viral Hepatitides [BASHH, 2017], the British Liver Trust Hepatitis B infection and immunisation in primary care [British Liver Trust, 2017],  Public Health England Hepatitis B: clinical and public health management [UKHSA, 2019a], the UK Health Security Agency Immunisation against infectious diseases (the 'Green Book'), chapter 18, Hepatitis B [UKHSA, 2024a], and the World Health Organization Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection [WHO, 2024], and expert opinion in the Oxford Textbook of Medicine Hepatitis A to E [Alexander, 2020] and BMJ Best Practice Hepatitis B [BMJ Best Practice, 2024], and are also consistent with the opinions of previous expert reviewers of this CKS topic.

Basis for recommendation

The information on testing for hepatitis B infection is based on guidelines from the National Institute of Health and Care Excellence (NICE) Hepatitis B and C testing: people at risk of infection [NICE, 2013a], the British Liver Trust Hepatitis B infection and immunisation in primary care [British Liver Trust, 2017], and the British Association of Sexual Health and HIV (BASHH) National Guidelines for the Management of the Viral Hepatitides [BASHH, 2017], the Public Health England Interim guidance on the public health management and control of acute hepatitis B [UKHSA, 2019a], and expert opinion in the BMJ Best Practice guideline Hepatitis B  [BMJ Best Practice, 2024] and are also consistent with the opinions of previous expert reviewers of this CKS topic.

Providing full clinical information to the laboratory

• Request for a 'hepatitis B screen' may result in only the hepatitis B surface antigen (HBsAg) test being done. Several previous expert reviewers of this CKS topic noted that testing for both HBsAg and antibody to hepatitis B core antigen (anti-HBc) is preferable, and that detailed clinical information is essential to assist laboratories to check for the most appropriate serological markers. Expert opinion within the National Institute of Health and Care Excellence (NICE) guideline Hepatitis B (chronic): diagnosis and management recommends that all people who test positive for HBsAg in primary care should also be tested for HBeAg anti-HBe, anti-HBc lgM, and have their HBV DNA quantified [NICE, 2017].

Basis for recommendation

Information about the differential diagnoses of hepatitis B is based on expert opinion in a chapter in the Oxford Textbook of Medicine Hepatitis A to E [Alexander, 2020], the BMJ Best Practice guideline Hepatitis B [BMJ Best Practice, 2024] and a review article [Muratori, 2023].

Hepatitis B immunization for people at risk

• Offer hepatitis B immunisation to:
  • Infants, as part of the routine childhood immunisation programme to protect against future risks.
    • For more information see the CKS topic on Immunisations – childhood.
  • People at high risk of exposure to the virus or complications of the disease including: 
    • People who inject drugs and those who are likely to ‘progress’ to injecting, for example, people currently smoking heroin and/or crack cocaine.
    • Sexual partners, children, other households and close family contacts of people who inject drugs.
    • People who change sexual partners frequently, men who have sex with men, and sex workers.
    • Household and sexual contacts of a person with hepatitis B infection.
    • Families adopting children from countries with a high or intermediate prevalence of hepatitis B.
    • Foster carers, in particular short-term foster carers who accept children as emergency placements and their families.
    • People receiving regular blood or blood products and their carers.
    • People in supported living accommodation, including residential care for those with learning disabilities.
    • People travelling to or going to reside in areas of high or intermediate prevalence.
    • Individuals at occupational risk, such as healthcare workers, laboratory staff, morticians, tattoo artists and prison staff who are in regular contact with prisoners.
    • People with chronic kidney failure who are already on haemodialysis or renal transplant programmes and other people with chronic kidney failure (usually stage 4 and 5) as soon as these interventions are anticipated to ensure good immune response.
    • People with chronic liver disease due to increased risk of complications of hepatis B infection.
  • Babies born to pregnant women living with hepatitis B infection (selective neonatal immunisation programme).
    • Immunisation of infants born to women with hepatitis B infection (identified through antenatal screening) should start as soon as possible after birth, ideally within 24 hours — babies born to pregnant women with high infectivity risk should receive hepatitis B immunoglobulin (HBIG) as well as active immunisation. 
    • Vaccination of babies born to women with hepatitis B should follow an accelerated schedule — these infants should receive monovalent hepatitis-B containing vaccine at birth and 4 weeks of age; hexavalent hepatitis B containing vaccine at 8, 12 and 16 weeks of age (as part of the routine childhood immunisation programme); and a final dose of hepatitis B vaccine at 12 months of age. 
    • Post vaccination serology testing is recommended at 12 months.
    • Timely administration of all doses is vital in preventing infection.
    • Guidance for primary care staff is available from the UK Health Security Agency (UKHSA) Hepatitis B vaccine for at risk infants aide memoire.
  • All other people potentially exposed to hepatitis B-infected blood or body fluids — immediate protection against hepatitis B is required.
    • Advise people who contaminate their eyes or mouth, or fresh cuts or abrasions of the skin to wash the affected area well.
    • Seek urgent advice about prophylaxis from the nearest Emergency Department or local Health Protection Team — advice following accidental exposure may also be obtained from occupational health services and hospital infection control teams.
      • Treatment and follow-up varies depending on the specific clinical situation.
      • Hepatitis B immunoglobulin (HBIG) prophylaxis is indicated for people without proven hepatitis B immunity, following accidental inoculation (such as needlestick or other ‘sharp’, bite, or scratch injury), contamination of mucous membranes or non-intact skin or unprotected sexual contact within the past seven days with a person with hepatitis B.
      • HBIG should be given by intramuscular injection at the same time as vaccine (but different site) as soon as possible (preferably within 24 hours and ideally within 48 hours after vaccine) but no later than a week after exposure.
      • Hepatitis B vaccine should never be delayed while waiting for HBIG administration.
    • For detailed and up to date information on post- exposure prophylaxis (depending on prior vaccination status and the status of the source) and follow up testing for infection post-exposure see the UKHSA publication Hepatitis B: the green book, chaper 18 or discuss with the local health protection unit.
• The immunisation schedule for hepatitis B vaccine varies depending on vaccine product used, how quickly protection is needed and whether it is given pre or post exposure:
  • For most people an accelerated schedule (for both pre and post exposure) given at zero, one, two and 12 months may be used.
  • If very rapid protection is needed, such as imminent travel to a highly endemic area, a super-accelerated or very rapid schedule given at zero, seven, and 21 days (with a further dose at 12 months if ongoing risk) may be used.
  • If there is a high likelihood of compliance and rapid protection is not required, a three dose course of vaccine at zero, one and six months standard schedule) may be used.
  • For detailed and up-to-date information on hepatitis B immunisation schedules including for people with co-morbidities such as immunosuppression and renal insufficiency see the UKHSA publication Hepatitis B: the green book, chaper 18.
• If testing for markers of current or past infection is clinically indicated (for example, for household contacts of infected persons), this should be done at the same time as the administration of the first dose.
  • Vaccination should not be delayed while waiting for results of the tests. 
  • Further doses may not be required in those with clear evidence of past exposure.
  • If unsure if serology testing for immunity to hepatitis B is required discuss urgently with the local health protection unit.
• In addition to vaccination:
  • Where appropriate, give advice on safer sex practices including condom use and needle exchange and arrange referral to specialist services (such as local sexual health or drug misuse services) where indicated.

How do I manage confirmed hepatitis B infection?

• Admit any person with hepatitis B infection to the hospital if they are severely unwell, for example, with vomiting, dehydration or signs of hepatic decompensation.
• Refer all people found to be HBsAg positive to a hepatologist, gastroenterologist or infectious disease specialist (depending on local service provision), to consider the need for additional treatment, follow up, and monitoring.
  • Use clinical judgement to decide the urgency of referral (people with suspected chronic hepatitis B infection and severe symptoms, or significantly abnormal liver function tests should be referred more urgently).
  • Pregnant women testing positive for hepatitis B through antenatal screening should have a comprehensive screening assessment within 5 working days of a positive report being received from the laboratory or known positive status being reported to the screening co-ordinator — at this appointment, results should be discussed and referral to the local specialist team made.
• While awaiting referral:
  • Advise the person to:
    • Seek medical attention urgently if symptoms worsen (particularly if they include vomiting and dehydration) or do not improve within 4 weeks and to be aware of the signs of hepatic decompensation such as confusion or change in level of consciousness.
    • Avoid drinking alcohol as this can increase the risk of cirrhosis and hepatocellular cancer in people with chronic hepatitis B.
    • Take steps to minimize the risk of transmission to partners and contacts. The person should:
      • Avoid sharing items that might be contaminated with small amounts of blood (such as toothbrushes, razors, and scissors).
      • Avoid unprotected sexual intercourse.
      • Avoid sharing needles and other drug-injecting equipment. For further information on injecting drug use, see the CKS topic on Opioid dependence.
      • Not donate blood or semen, or carry an organ donor card.
    • Be aware that treatments that affect the immune system (such as chemotherapy or immunosupressants) can cause recurrence and they may need prophylaxisis while on these medications.
  • Provide supportive symptomatic care as required:
    • Advise the person to rest when necessary and stay hydrated.
    • If pain relief is required, options include:
      • Ibuprofen — prescribe with caution in mild to moderate hepatic impairment and avoid in severe hepatic impairment.
      • Paracetamol — caution is advised with use of paracetamol in people with acute hepatitis due to increased risk of toxicity — avoid if possible.
      • Weak opioids (such as codeine) — prescribe with caution in mild liver impairment and avoid in severe hepatic impairment (due to enhanced sedative effects and reduced drug clearance).
      • For further information, see the CKS topics on Analgesia - mild-to-moderate pain and NSAIDs - prescribing issues.
    • If treatment of nausea is required, options include:
      • Metoclopramide (for people aged over 20 years for a maximum duration of treatment 5 days) or cyclizine, if liver impairment is mild.
      • For further information, see the section on Prescribing information.
    • If treatment of itch is required, options include:
      • Simple measures (such as maintaining a cool, well-ventilated environment, wearing loose clothing, and avoiding hot baths or showers).
      • Chlorphenamine at night — avoid in severe liver impairment.
      • For further information, see the section on Prescribing information.
    • Seek specialist advice on choice and dosage of analgesic, anti-emetic or anti-pruritic if the person has more severe hepatic impairment or symptoms are difficult to manage.
    • Withold potentially hepatotoxic drugs – seek specialist advice if unsure.
  • Consider referring the person to a:
    • Genito-urinary medicine department (or other specialist sexual health service), if screening for sexually transmitted infections is appropriate, and/or
    • Drug rehabilitation agency (if appropriate).
  • Provide patient information on hepatitis B such as that available from:
    • The NHS — Hepatitis B.
    • The British Liver Trust — Hepatitis B.
• Notify the local Health Protection Unit (HPU) promptly to facilitate appropriate surveillance, contact tracing and initiation of preventative measures for close contacts.
  • Close contacts of people with confirmed chronic hepatitis B should be offered hepatitis B vaccination and immunoglobulin if indicated — this may include sexual partners, other household members (including children), and other contacts at high risk of hepatitis B.
• Ensure pregnant women (and women planning to become pregnant) with acute or chronic hepatitis B infection are aware that:
  • The infant should be immunised against hepatitis B from birth — there is a 90% risk of the infant contracting hepatitis B unless immunisation takes place at birth.
  • There may be an increased risk of preterm delivery and low infant birth weight.
  • Breastfeeding is safe providing the infant has been immunised.
  • Patient information on hepatitis B in pregnancy is available from the UK Health Security Agency Hepatitis B: a guide to your care in pregnancy and after your baby is born and the UK teratology information service Hepatitis B vaccine.
• Ensure people with confirmed chronic hepatitis B have been vaccinated against hepatitis A if they are not already immune.
  • For more information on hepatitis A immunisation, see the CKS topic on Hepatitis A.
• Ensure hepatitis serology is repeated after 6 months in all people found to be HBsAg positive to detect or exclude chronic hepatitis B infection.
  • All people with chronic hepatitis B infection require regular review by a liver specialist. The frequency of monitoring depends on a number of factors, such as serology results (which collectively indicate the phase of disease), the person's age, and whether they are taking antiviral drugs. Specialist follow-up is required to:
    • Monitor serology.
    • Screen for complications including hepatocellular cancer.
    • Assess the person's need for treatment on an ongoing basis (depending on the findings of any tests and assessments). 
  • Antivirals initiated in secondary care may subsequently be prescribed in primary care as part of a shared care arrangement.

What types of hepatitis B vaccine are available?

Hepatitis B vaccines licensed for use in the UK are available as a single or combined products — all hepatitis B containing vaccines are inactivated.

• Monovalent hepatitis B vaccines (containing hepatitis B vaccine) include:
  • Engerix B^®.
  • Fendrix^®.
  • HBvaxPRO^®.
  • PreHevbri®.
• Bivalent combination vaccines (containing hepatitis A and B vaccine) include:
  • Twinrix^®.
  • Ambirix®.
• Hexavalent combination vaccine (containing diphtheria, tetanus, acellular pertussis, inactivated polio vaccine, Haemophilus influenzae type b and hepatitis B vaccine) include:
  • Infanrix hexa®.
  • Vaxelis®.

[UKHSA, 2022; EMC, 2023a; EMC, 2023b; EMC, 2023c; EMC, 2023d; EMC, 2023e; EMC, 2023f; EMC, 2024a; BNF, 2024; EMC, 2024b; NaTHNaC, 2024; UKHSA, 2024a]

What is the immunisation schedule for the hepatitis B vaccine?

• Different hepatitis B vaccine products, doses, and primary dosing schedules are recommended depending on the person's age, risk factors, how rapidly protection is required, and the likelihood of compliance.
  • For information on hepatitis B vaccination given as a component of the routine childhood immunisation programme see the CKS topic on Immunizations - childhood.
  • For information on individual vaccine products, see the electronic Medicines Compendium (eMC), or the British National Formulary (BNF).
• For most adult and childhood risk groups, an accelerated schedule should be used, with vaccines most commonly given at zero, one, two and twelve months.
  
  • If the person is at immediate risk, a very rapid or super-accelerated schedule may be used with vaccine given at zero, seven, and twenty-one days (plus 12 months if ongoing risk).
  • An alternative schedule (usually) at zero, one and six months should only be used where rapid protection is not required and there is a high likelihood of compliance.
  • For information on vaccination schedules for babies born to women with hepatitis B, see the UK Health Security Agency information leaflet Hepatitis B vaccine for at risk infants.
• People in certain risk groups (including those at risk of occupational exposure or those with renal failure), should have their antibody titres checked one to two months after the completion of a primary course of vaccine. In all other people, antibody testing is not considered necessary.
  • It is preferable to achieve anti-HBs levels above 100mIU/ml, although levels of 10mIU/ml or more are generally accepted to protect against infection.
  • People found to have anti-HBs levels of 10 to 100mIU/ml should receive one additional dose of vaccine.
  • In immunocompetent individuals, once a response has been established, further assessment of antibody levels is not indicated.
  • In non-responders (people with antibody levels below 10mIU/ml), serology should be checked for past or current hepatitis B infection. A repeat course of vaccine is recommended, followed by retesting of antibody levels one to two months after the second course — where antibody levels remain below 10mIU/ml, and there are no markers of current or past infection, immunoglobulin will be required for protection if exposed to hepatitis B.
  • For people with chronic renal failure receiving haemodialysis, antibody levels should be monitored annually, and if they fall below 10mIU/ml, a booster dose of vaccine should be given if the person has previously responded. A booster should also be offered if travel to a high risk country is planned and it is more than one year since the last booster.
• Longer than recommended intervals between doses do not appear to reduce the final antibody level or efficacy. There is no need to repeat doses if the vaccination course is interrupted.
• Booster doses after the primary course are not routinely required for healthy, immunocompetent adults.
  • However, a booster may need to be administered following significant exposure if the exposure was from a HBsAg positive source and the last vaccine dose was administered over 1 year ago. If the exposure was non-significant and from a HBsAg negative source then no further HepB vaccine is required.
• For detailed information on immunisation schedules for the Hepatitis B vaccine see guidance from the UK Health Security Agency (UKHSA) Hepatitis B: the green book, chapter 18.

[BNF, 2024; NaTHNaC, 2024; UKHSA, 2024a]

What hepatitis B vaccination schedule should be used for people with HIV?

• Hepatitis B vaccine should be offered to people with HIV who are at risk of infection, as they are more likely to contract hepatitis B and develop chronic infection.
  • Four doses at 0, 1, 2, and 6 months are usually recommended.
  • If an unadjuvanted vaccine is being used (Engerix®, HBvaxPRO®) a high dose (40 µg) is recommended. If the adjuvanted vaccine (Fendrix®) is being used, the standard (20 µg) dose can be used.
  • An ultra-rapid vaccination course (three standard-doses given over 3 weeks) should only be considered in people with CD4 cell counts >500 cells/μL, where rapid protection is necessary, and/or where compliance with a more protracted course is considered unlikely. High dose vaccine is not recommended in these circumstances due to a lack of safety data. 
• Measure antibodies to hepatitis B surface antigen (HBsAb) 4–8 weeks after completion of the vaccination schedule.
  • If HBsAb is less than 10 IU/L, offer the person three further vaccine doses (as described above) at monthly intervals.
    • Depending on the level of risk, re-vaccination may be delayed until the viral load is suppressed on ART and the CD4 cell count has increased >350 cells/μL.
    • Retesting for HBsAb is recommended 4–8 weeks after the final dose of vaccine.
  • If HBsAb is greater than 10 IU/L but less than 100 IU/L, offer the person one additional dose of vaccine.
    • Check the response 4–8 weeks later.
• Following successful immunization (HBsAb >10 IU/L after completion of a full vaccine course) the person should be offered regular HBsAb testing (using clinical judgement to determine frequency).
  • People with initial HBsAb levels >100 IU/L, CD4 cell counts >350 cells/μL, and viral load suppression on ART should be retested at least every 2–4 years
  • Other people should receive HBsAb testing on an annual basis.
  • A booster dose of vaccine should be offered if HBsAb levels have declined to less than 10 IU/L.
• Further boosters are required following a high-risk exposure to an HBsAg-positive source.

[BHIVA, 2015]

When is the hepatitis B vaccine contraindicated?

• Do not give hepatitis B vaccine if the person:
  • Is acutely unwell — postpone vaccination until fully recovered.
    • Minor illness without fever or systemic upset (such as a cold) is not an indication to postpone vaccination.
  • Has experienced a confirmed anaphylactic reaction to a previous dose of hepatitis B vaccine, or to any component of the vaccine.
• Infanrix hexa® should be used with caution in people with phenylketonuria as it contains phenylalanine.

[EMC, 2023a; EMC, 2023b; EMC, 2023c; EMC, 2023d; EMC, 2023e; EMC, 2023f; EMC, 2024a; BNF, 2024; EMC, 2024b]

Can the hepatitis B vaccine be used during pregnancy and breastfeeding?

• Hepatitis B vaccines can be used during pregnancy and breastfeeding, if clinically indicated, for women at high-risk of infection, as hepatitis B in a pregnant woman may result in severe disease for the mother and chronic infection of the infant after birth.
  • The available evidence does not indicate any risk associated with vaccinating pregnant women, or those who are breastfeeding, with inactivated viral vaccines in general or with hepatitis B vaccines specifically.

[UKTIS, 2022; UKHSA, 2024a]

How should I administer the hepatitis B vaccine?

• Obtain written or verbal consent at the time of vaccination — ensure that there are no contraindications.
• Check that the vaccine is correct and has not expired. Only clean the site of application with soap and water if it is visibly dirty.
• For adults and children older than 1 year of age, administer the vaccine by intramuscular injection into the deltoid muscle or the anterolateral aspect of the thigh — anterolateral thigh is the preferred site in infants and young children.
  • Immunisations should not be given into the buttock, due to the risk of sciatic nerve damage and the risk of reduced immunogenicity of hepatitis B vaccine when injected into fatty tissue rather than muscle. 
• If the person has a bleeding disorder, the subcutaneous route may be used to reduce the risk of bleeding.
• Record the site of administration. If an additional vaccine is required on the same day, use separate limbs if possible, or inject at sites at least 2.5 cm apart in the same limb.
• Observe for immediate adverse drug reactions.

[UKHSA, 2013; UKHSA, 2023c; BNF, 2024; UKHSA, 2024a]

What are the adverse effects of the hepatitis B vaccine?

• Hepatitis B vaccine is generally well tolerated. The most common adverse reactions are soreness and redness at the injection site.
• Other reactions that have been reported (but may not be causally related) include fever, rash, malaise, headache, an influenza-like syndrome, arthritis, arthralgia, myalgia, and abnormal liver function tests.
• Suspected serious neurological reactions (such as Guillain–Barré syndrome and demyelinating disease) have been reported, although these are very rare and a causal relationship with hepatitis B vaccine has not been established.
• The excipients in Infanrix hexavalent vaccine have been reported to cause allergic reactions and also contain phenylalanine which may be harmful in patients with phenylketonuria.  

[EMC, 2023a; EMC, 2023b; EMC, 2023c; EMC, 2024b; EMC, 2023d; EMC, 2023e; EMC, 2023f; EMC, 2024a; BNF, 2024]

Contraindications and cautions

Metoclopramide

• Metoclopramide should not be used in people with:
  • Gastrointestinal obstruction, perforation or haemorrhage or recent gastrointestinal surgery.
  • Confirmed or suspected pheochromocytoma, due to the risk of severe hypertensive episodes.
  • History of neuroleptic or metoclopramide-induced tardive dyskinesia.
  • Epilepsy (increases crises frequency and intensity).
  • Parkinson's disease.
• Metoclopramide should be used with caution in:
  • Liver dysfunction — metoclopramide can be used in people whose metabolic and synthetic function is unaffected (such as in mild hepatitis). However, seek specialist advice before using metoclopramide in people with more severe hepatic impairment, as reduced clearance may increase the risk of gynaecomastia and extrapyramidal adverse effects. The dose should be reduced by 50% in people with severe hepatic impairment.
  • Renal impairment — metoclopramide and its metabolites are predominately excreted via the kidneys. In people with severe renal impairment (eGFR less than 30 mL/minute/1.73 m2), avoid metoclopramide or use a reduced dose. Accumulation of metoclopramide increases the risk of extrapyramidal adverse effects.
  • Children, young people and the elderly — neurological effects such as short-term extrapyramidal adverse effects have been reported. This risk is higher in children, although tardive dyskinesia was reported more often in the elderly, and the risk is increased at high doses or with long-term treatment. The European Medicines Agency recommend that metoclopramide should not be taken for longer than 5 days [EMA, 2013].
  • People with asthma, atopic allergy, bradycardia, or cardiac conduction disturbances. 

Cyclizine

• Cyclizine should be used with caution in people with:
  • Liver dysfunction — cyclizine can be used in people whose metabolic and synthetic function is unaffected (such as in mild hepatitis). However, seek specialist advice before using cyclizine in people with moderate hepatic impairment. It must be avoided in people with severe hepatic impairment, such as those with cirrhosis or encephalopathy who may decompensate, because of its sedative effects.
  • Urinary retention, prostatic hypertrophy, angle-closure glaucoma, or pyloroduodenal obstruction — if possible, avoid using sedating antihistamines such as cyclizine because of their significant antimuscarinic activity (particularly in elderly people).
  • Epilepsy — avoid cyclizine if possible, as it can reduce the seizure threshold.
  • Severe heart failure — avoid using cyclizine if possible, as it may decrease cardiac output.

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

Adverse effects

Metoclopramide

• Metoclopramide is generally well tolerated. However:
  • Extrapyramidal reactions (usually dystonic) can occur. Most reactions occur within 36 hours of starting and disappear within 24 hours of stopping treatment. The incidence of dystonic reactions is more common in young adults under the age of 20 years (especially girls and young women) and the elderly.
  • Raised serum prolactin levels with prolonged treatment can cause galactorrhoea, irregular periods, and gynaecomastia.
  • Neuroleptic malignant syndrome has very rarely been reported with metoclopramide use.
• The maximum duration of therapy with metoclopramide is 5 days [EMA, 2013].
  • Following a review by the European Medicines Agency, metoclopramide should not be prescribed for more than 5 days. The EMA review confirmed the well-known neurological risks such as short-term extrapyramidal adverse effects. This risk is higher in children, although tardive dyskinesia was reported more often in the elderly, and the risk is increased at high doses or with long-term treatment. The EMA states that the risks outweighed the benefits of metoclopramide treatment in conditions requiring long-term treatment. There have also been very rare cases of serious cardiovascular adverse effects, particularly after injection.

Cyclizine

• The most commonly reported adverse effects are nervous system disorders including agitation; angle closure glaucoma and depression:
  • Elderly people are particularly susceptible (and so lower doses are recommended).
  • Sedating antihistamines may cause drowsiness.
  • Anticholinergic adverse effects may also occur, for example, blurred vision and dry mouth.

[EMA, 2013; BNF, 2024; EMC, 2024c; EMC, 2024d]

Drug interactions

Key drug interactions include:

• Metoclopramide:
  • Levodopa or dopaminergic agonists — avoid in combination with metoclopramide due to mutual antagonism.
  • Anticholinergics and morphine derivatives — may have both a mutual antagonism with metoclopramide on digestive tract motility.
  • CNS depressants — sedative effects are potentiated.
  • Neuroleptics — additive effect with other neuroleptics on the risk of extrapyramidal disorders.
  • Serotonergenics — use of metoclopramide with serotonergic drugs such as SSRIs may increase the risk of serotonin syndrome.
  • Digoxin — metoclopramide may decrease digoxin bioavailability. Careful monitoring of digoxin plasma concentration is required.
  • Cyclosporine — metoclopramide increases cyclosporine bioavailability. Careful monitoring of cyclosporine plasma concentration is required.
  • Strong CYP2D6 inhibitors — metoclopramide levels are increased when co-administered with strong CYP2D6 inhibitors such as fluoxetine and paroxetine. People should therefore be monitored for adverse reactions.
• Cyclizine:
  • CNS depressants — additive effects may occur.
  • Anticholinergics/antimuscarinics (including atropine, TCAs and MAOIs) — additive effects may occur.

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

Pregnancy and breastfeeding

Metoclopramide

• Pregnancy — published fetal exposure data are limited, but there is no evidence of an increase in congenital malformations in exposed pregnancies, but a possible higher incidence of premature delivery in one small cohort study [UKTIS, 2019a]. Avoid at the end of pregnancy due to potential for extrapyramidal syndrome in the newborn.
• Breastfeeding — most manufacturers recommend avoiding. The NHS Specialist Pharmacy Service states that metoclopramide can be used with caution during breastfeeding for short-term (maximum 5 days), low-dose use (dose not exceeding 30 mg a day) but monitoring is required. It should be avoided in people with depression. See the NHS Specialist Pharmacy Service website for more information.

Cyclizine

• Pregnancy — the published data for the safety of cyclizine are limited, but there is no robust evidence of an increased risk of infant congenital malformation [UKTIS, 2019a]. Manufacturer recommends avoiding.
• Breastfeeding — most manufacturers recommend avoiding. The NHS Specialist Pharmacy Service states that cyclizine, for short term use, can be used with caution during breastfeeding, but monitoring is required. Repeated use may pose a risk of infant sedation. See the NHS Specialist Pharmacy Service website for more information.

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

Contraindications and cautions

Chlorphenamine

• Chlorphenamine should be avoided in people who:
  • Have been treated with monoamine oxidase inhibitors (MAOIs) in the last 2 weeks — intensified anti-cholinergic effects.
• Sedating antihistamines should be used with caution in people with:
  • Liver dysfunction — chlorphenamine can be used in people whose metabolic and synthetic function is unaffected (such as in mild hepatitis). However, seek specialist advice before using chlorphenamine in people with more severe hepatic impairment.
  • Urinary retention, prostatic hypertrophy, angle-closure glaucoma, or pyloroduodenal obstruction — if possible, avoid using sedating antihistamines because of their significant antimuscarinic activity (particularly in elderly people).
  • Epilepsy — avoid chlorphenamine if possible, as it may reduce the seizure threshold.

[EMC, 2023g; BNF, 2024]

Adverse effects

• The most commonly reported adverse effects are nervous system disorders:
  • Children and elderly people are more susceptible to adverse effects (consideration of a lower daily dose is recommended).
  • Chlorphenamine may cause drowsiness, disturbance in concentration, dizziness and headache.
  • Anticholinergic adverse effects may also occur, for example blurred vision and dry mouth.

[EMC, 2023g; BNF, 2024]

Drug interactions

• Key drug interactions with chlorphenamine include:
  • Hypnotics and anxiolytics — increased sedative effects.
  • Phenytoin — chlorphenamine inhibits phenytoin metabolism and can lead to phenytoin toxicity.
  • Monoamine oxidase inhibitors (MAOIs) —the anticholinergic effects of chlorphenamine are intensified by MAOIs. Do not prescribe chlorphenamine to a person who has been treated with MAOIs within the last fourteen days.

[EMC, 2023g; BNF, 2024]

Pregnancy and breastfeeding

Chlorphenamine

• Pregnancy — There is currently no evidence of an increased risk of fetal toxicity following chlorphenamine use in pregnancy [UKTIS, 2019b], however most manufacturers advise avoiding use during pregnancy. Use in late pregnancy may cause adverse effects in neonates such as irritability, paradoxical excitability and tremor.
• Breastfeeding — the NHS Specialist Pharmacy Service states that there is extensive experience of safe use of chlorphenamine in breastfeeding. However, the Summary of Product Characteristics for chlorphenamine states that it should not be used in breastfeeding unless considered medically essential.

[EMC, 2023g; BNF, 2024]