Injection site reactions (ISRs) are reactions that occur at the site of injection of a drug. They may be mild or severe and may or may not require medical intervention. Some reactions may appear immediately after injection, and some may be delayed.^[1] Such reactions can occur withsubcutaneous,intramuscular, orintravenous administration.

Drugs commonly administered subcutaneously includelocal anesthetics, drugs used in palliative care (e.g., fentanyl and morphine), andbiopharmaceuticals (e.g., vaccines, heparin, insulin, growth hormone, hematopoietic growth factors, interferons, and monoclonal antibodies).

Some reactions, such as pain, may appear immediately. Others may be delayed, such as erythema which may appear 24–96 hours after injection.^[2]

ISRs commonly seen with subcutaneous injections include:

• Bleeding andbruising^[3]
• Erythema (redness)
• Pain
• Pruritis (itching)^[4]
• Swelling^[5]
• Induration (hardening of the skin)^[6]
• Discoloration^[6]

Severe reactions may result in cutaneousnecrosis at the injection site, typically presenting in one of two forms: (1) those associated with intravenous infusion or (2) those related to intramuscular injection.^{[7]: 123–4} Intramuscular injections may produce a syndrome calledlivedo dermatitis.^[7]: 124

There are many factors that can affect incidence of injection site reactions. They may be related to the drug formulation itself, to the method of injection, or to the patient.^[8]

Some factors such as volume of injection and speed of injection seem to not be well correlated with incidence of reaction.^[3]

• Osmolality – ideally isotonic (~300 mOsm/kg); although hypertonicity allows reduced volume of injection, an upper limit (~600 mOsm/kg) is advised to minimize hypertonicity-induced pain^[3]
• Viscosity – lower viscosity leads to more pain
• pH – pH close to physiological to minimize pain, irritation, tissue damage, except when stability or solubility considerations preclude it; a pH above 9 is associated with tissue necroses, and below 3 with pain andphlebitis
• Buffer choice – commonly citrate, phosphate, or acetate; a sodium bicarbarbonate buffer reduces pain^[9]
• Preservatives – commonly phenol and benzyl alcohol, phenoxyethanol, methylparaben, or propylparaben

Features of theneedle used for injection can affect ISRs:^[3]

• Length – shorter needles are associated with less pain
• Diameter – smaller needles are associated with less pain
• Bluntness of the needle tip
• Bevel type – geometry of the needle tip can reduce average penetration force
• Lubrication – silicone (e.g.,polydimethylsiloxane) coating decreases the resistance of insertion
• Injection angle – when injecting at a 45° angle, such as when using a long needle, having the bevel up reduces pain

• Anatomical injection site – injection into the thigh is generally more painful than the abdomen^[3]
• Injection close to blood vessels^[2]
• Low body weight
• Patient movement during injection^[8]

The exact mechanism of various reactions differs, and not all reactions areallergic or immunogenic.^[10] In some cases there is inflammatory influx, consistent withleukocytoclastic vasculitis (e.g. infiltrating neutrophils, prominent nuclear dust, lymphocytes and eosinophils with local macrophage infiltration).^[6] There may be evidence of subcutaneous fat tissue necrosis.^[6]

Adequate patient education and training on correct procedure for self-administration can lower the incidence rate of reactions.^[2]

Rotating injection sites, proper sterilization, and allowing the medication to reach room temperature before injection can help prevent ISRs. Applying a cold compress after the injection may be helpful.^[2] When possible, decreasing the frequency of administration may help.^[3]

Premedication withantihistamines orcorticosteroids does not seem to prevent ISRs.^[10]

In some cases, reactions and their severity may diminish with subsequent administrations of the drug.^[2]

For non-severe reactions, common approaches include:

• Watchful waiting – non-severe ISRs generally resolve on their own over a short duration, typically 3–5 days^[2]
• Medications for symptom relief – e.g., antihistamines for itching;paracetamol orNSAIDs for pain^[2]
• Cold compress application^[2]

For severe reactions, discontinuation of the medication and acute medical treatment of the reaction may be required.^[2]

• Ulceration or necrosis^[6][7] require medical intervention
• Discoloration may be (semi)‐permanent^[6]
• Non-severe ISRs generally resolve on their own over a short duration, typically 3–5 days^[2]

For many biologics (e.g.,monoclonal antibodies), injection site reactions are the most common adverse effect of the drug, and have been reported to have an incidence rate of 0.5–40%.^[2]

In trials of subcutaneous administration ofoligonucleotides, between 22% and 100% of subjects developed reactions depending on the oligonucleotide.^[6]

• Application site reaction
• Vitamin K reactions
• Skin lesion
• List of cutaneous conditions

• Drug eruptions

• Articles with short description
• Short description matches Wikidata