Risks of intramuscular injections in people taking oral anticoagulants

Intramuscular (IM) injections (injections into a muscle) are invasive procedures that can cause bruising or bleeding at the injection site.

Increasing numbers of people are prescribed oral anticoagulant medicines (blood thinners) such as warfarin, or one of the newer direct oral anticoagulants (DOACs): apixaban, dabigatran, edoxaban, or rivaroxaban, to treat or prevent blood clots.

Most of these people will need to receive an IM injection at some stage.

Due to their increased bleeding tendency, people taking oral anticoagulant medicines may be at increased risk of bleeding complications related to IM injections such as bruising or haematomas (collection of blood that has leaked from blood vessels into tissues, organs or other body spaces).

There have also been occasional reports of compartment syndrome with injections into deeply located muscles.

Guidance and Evidence

There are no clear, evidence-based guidelines for administering IM injections in patients taking anticoagulants.

With the exception of certain vaccines (see further detail below), there is also limited information published in the medical literature.

In this article we provide general advice for small volume (less than 3ml) IM injections with some more specific advice on vaccines and hydroxocobalamin injections.

Advice on large volume (3ml or more) IM injections is outside the scope of this article.

Considerations for healthcare professionals

Healthcare professionals may need to consider these factors:

• Is there an increased risk of adverse effects (e.g. bruising, haematoma)?
• Could the injection affect anticoagulant control?
• Could the anticoagulant alter the effectiveness of the injection?

Practical advice for healthcare professionals

When considering a small volume IM injection for a patient taking an oral anticoagulant:

• Avoid IM injections if possible. Do not administer an IM injection if INR is raised above the therapeutic range.
• Consider if alternative routes of administration are possible or if alternative treatment is appropriate
• If a small volume IM injection is necessary:
  • Check the relevant Summary of Product Characteristics (SmPC) for the IM injection to be administered and for the oral anticoagulant the patient is taking
  • Evaluate the risk-benefit ratio for the individual
  • Administer the IM injection into an upper extremity as a precaution. This will allow easy access for manual compression, inspection of bleeding, and/or to apply pressure bandages if needed
  • Use a fine needle and apply firm pressure for at least 2 minutes immediately after the injection
  • Advise the patient to watch out for bleeding at or around the injection site and for signs of haematoma

Advice in product prescribing information

Before administering an IM injection to a person taking an oral anticoagulant, healthcare professionals should consult the product prescribing information (SmPC) or other prescribing references such as the British National Formulary to guide them.

In some cases, you may need to seek specialist advice.

Warnings and advice in product prescribing information can be variable and inconsistent.

When checking a product SmPC (available via the MHRA products or emc websites) it’s useful to look at the following sections:

• contraindications (section 4.3)
• special warnings and precautions for use (section 4.4)
• interactions (section 4.5)
• undesirable effects (section 4.8)

IM injections

Summaries of Product Characteristics (SmPCs) for IM injections do not usually contraindicate administration in people taking anticoagulants. However, some SmPCs do advise caution, while others do not raise any particular concern.

For example, the SmPC for botulinum toxin (Botox) injection cautions that “patients on anti-coagulant therapy need to be managed appropriately to decrease the risk of bleeding”, while the SmPC for hydroxocobalamin injection makes no mention of risks or potential concerns for use in people taking anticoagulants.

In some cases, the SmPC may include advice on giving the injection by another route such as subcutaneous injection, making it possible to avoid intramuscular administration. However, healthcare professionals will need to consider the risk versus benefit of this alternative route. The medicine may not be as effective or may carry a higher risk of other side effects such as local skin reactions when given by another route.

Oral anticoagulants

Warfarin

The SmPC for warfarin does not contraindicate or offer any specific advice or warnings on administration of IM injections in people taking warfarin.

However, there is cautionary advice suggesting more frequent INR monitoring and measures to minimise bleeding risk for people at “high risk of bleeding”.

DOACs

Similarly the SmPCs for the DOACs do not contraindicate or offer any specific advice or warnings on administration of IM injections in people taking a DOAC.

They do provide more detailed advice, however, for patients undergoing “invasive procedures” or “interventions”, including whether or not to temporarily stop the anticoagulant.

Healthcare professionals should check the relevant SmPC for the DOAC their patient is taking (section 4.4. Special warnings and precautions for use) and consider the person’s individual risk factors for bleeding as well as potential risks of stopping the anticoagulant.

Although there is no definitive guidance, it would be reasonable to consider most IM injections as a minimal to low risk procedure.

Advice on vaccines

Most of the published studies in the medical literature about the subject of IM injections in people taking oral anticoagulants relate to vaccines, particularly the ‘flu vaccine.

More recently specialist medical societies and expert committees have also provided guidance on the subject for administration of COVID-19 vaccines.

For individuals with bleeding disorders (e.g. haemophilia), the UK Health Security Agency Green Book: Immunisation against Infectious Diseases (Chapter 4) recommends to give vaccines normally administered IM by deep subcutaneous (under the skin) injection to reduce the risk of bleeding. Although this advice has often been extrapolated to people taking oral anticoagulants, this may not be necessary or desirable.

In the same chapter of the Green Book there is advice that the IM route is usually preferred because it is less likely to cause local reactions than deep subcutaneous (SC) injections.

Another concern for SC administration of vaccines is that this route may not be as effective as IM administration. This is highlighted in a recent review of the medical literature which found moderate-grade evidence that IM injection of vaccines gave better immune responses than SC injection.

Influenza vaccines

Choice of injection route

Most influenza (‘flu) vaccines are licensed only for IM administration, and some brands specifically advise against SC administration. However some brands are licensed for either IM or SC administration. Studies comparing the two routes of administration generally suggest the vaccines are effective by either route.

The Green Book Chapter 19 on Influenza vaccine advises  to use IM administration rather than the SC route for people who are on stable anticoagulant therapy. This includes people on warfarin who are up to date with their INR testing and whose last INR test result was below the upper end of their recommended therapeutic range

The explanation for this advice is that, as well as being more likely to cause local reactions, there is no evidence that deep SC injection is any safer than the IM route in these patients.

Practical advice for IM administration of influenza vaccine

Additional practical advice for IM administration of influenza vaccine for a person taking an oral anticoagulant:

• Use a fine needle (23 or 25 gauge)
• Apply firm pressure to the vaccination site for at least 2 minutes after
• If there is any doubt, consult with the clinician responsible for prescribing or monitoring the individual’s anticoagulant treatment
• Inform the individual/parent/carer about the possible risk of haematoma

COVID-19 Vaccines

Choice of injection route

The advice in the Green Book Chapter 14a for COVID-19 vaccination for people taking oral anticoagulants is very similar to the advice for influenza vaccine. People who are on stable anticoagulant therapy should receive the vaccine by IM injection.

None of the vaccines currently available are licensed for administration by SC injection. Since all the clinical trials have used IM administration, we do not know if the vaccines would be effective or safe when given by SC injection.

For further information and advice read our article on Using COVID-19 vaccines in patients with anticoagulation and bleeding disorders.

Guidance from professional societies

A January 2021 statement from the British Society for Haematology on COVID-19 Vaccines in patients with haematological disorders gives the following advice for people taking anticoagulants (see Appendix).

• Patients taking standard intensity warfarin (i.e. target INR of 2 to 3) can receive IM injections as long as the most recent INR is below 3. There is no need for an extra INR check prior to vaccination.
• Patients on maintenance therapy with DOACs can delay the dose of their DOAC on the day of vaccination until after the IM injection but do not need to miss any doses.
• Patients taking higher intensity warfarin (i.e. target INR above 3) or those taking more than one antithrombotic (anti-clotting) medicine, such as an antiplatelet medicine(e.g. aspirin, clopidogrel) plus an oral anticoagulant, should be managed on an individual basis. For higher intensity warfarin patients, their INR should be below 4 before vaccinating. Apply firm pressure at the injection site for at least 5 minutes afterwards to reduce risk of haematoma.

A March 2021 statement from International Society on Thrombosis and Haemostasis (ISTH) offered similar recommendations as well as advising:

• the benefits of COVID-19 vaccination strongly outweigh any potential complications for people taking anticoagulant medicines or with a history of blood clots
• do not avoid vaccination on the basis of anticoagulation
• consider administration of the vaccine before the next dose of anticoagulant rather than immediately after a dose
• there is a risk of bruising at the injection site, but serious effects related to anticoagulation are not anticipated

Other vaccines

Information on giving other vaccines to people taking oral anticoagulants is limited.

Healthcare professionals should check the relevant Green Book Chapter as well as the SmPC for specific administration advice.

You will need to consider factors such as the volume of the injection and needle size (calibre), along with the risk-benefit ratio for individuals at risk of adverse effects (e.g. bruising, haematoma) from an IM injection.

For some individuals it may be necessary to seek specialist advice.

Advice on hydroxocobalamin injection

Hydroxocobalamin is a synthetic form of vitamin B12 used in the treatment of pernicious anaemia and other vitamin B12 deficiency states.

Hydroxocobalamin injections are licensed only for intramuscular (IM) injection.

Due to concerns about the potential risks of haematoma or other bleeding problems, healthcare professionals may consider the option of giving hydroxocobalamin injections by the subcutaneous (SC) route for people taking oral anticoagulants. This practice is off-label or unlicensed.

Subcutaneous hydroxocobalamin

Evidence

There is very little evidence to support this practice.

The manufacturers’ prescribing information (SmPC) for hydroxocobalamin injection do not caution or contraindicate its use by the licensed (i.e. IM) route for people receiving anticoagulant treatment.

There are no published studies providing data to compare the SC with the IM route for hydroxocobalamin.

There are only a few published studies describing administration of hydroxocobalamin by the SC route in a very select group of patients mainly for research purposes. This is not enough to provide any reassurance that the SC route is safe and as effective as the IM route.

Practical advice for healthcare professionals

Healthcare professionals should carefully consider the risk-benefit ratio for individuals before administering hydroxocobalamin by SC injection.

For some individuals it may be necessary to seek specialist advice.

Although hydroxocobalamin injections are the preferred treatment for vitamin B12 deficiency there may be alternatives that could be considered.

Possible alternatives to hydroxocobalamin injections

Oral cyanocobalamin

Cyanocobalamin is another synthetic form of vitamin B12.

Use of oral (by mouth) cyanocobalamin as an alternative to IM hydroxocobalamin was recommended by the British Society of Haematology in their guidance on vitamin B12 replacement during the COVID-19 pandemic.

The doses of oral cyanocobalamin recommended by the BSH vary according to the origin of the vitamin B12 deficiency as follows:

• 1mg per day for non-dietary vitamin B12 deficiency (e.g. pernicious anaemia, prior gastrectomy, bariatric surgery, achlorhydria, pancreatic insufficiency, short bowel syndrome, bacterial overgrowth, inflammatory bowel disease)
• 50 to 150 micrograms per day for dietary vitamin B12 deficiency (e.g. vegans)

The issue of whether oral cyanocobalamin is as effective as IM hydroxocobalamin has been debated by doctors for many years with no definite conclusion to date. A Cochrane systematic review discusses the issue in more detail.

For detail on prescribing considerations and choice of product, read our article: Oral vitamin B12 – what are the prescribing considerations and what formulations are available?

Subcutaneous (SC) cyanocobalamin

Some reference sources also suggest the possible option of SC administration of cyanocobalamin injections.

Cyanocobalamin injection is only licensed for IM administration in the UK. However, in the USA it is approved for administration by IM or deep SC injection

In general, cyanocobalamin injections are not usually recommended in the UK. Hydroxocobalamin injections are preferred because hydroxocobalamin is absorbed better and lasts longer. Cyanocobalamin injections have to be administered more often.

SC cyanocobalamin is not likely to be a useful option unless oral treatment is not possible and should only be used with specialist advice.

Acknowledgements

Sindhar, Amarpreet (Pharmacist, Guy’s and St Thomas’ Hospitals NHS Foundation Trust). Medicines Q&A: Can hydroxocobalamin injection be administered via the subcutaneous route?; April 2020.

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