Injection site reaction

Causes

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.

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

Product-related factors

• Osmolality – ideally isotonic (~300 mOsm/kg); although hyptertonicity allows reduced volume of injection, an upper limit (~600 mOsm/kg) is advised to minimize hypertonicity-induced pain
• 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 and phlebitis
• Buffer choice – commonly citrate, phosphate, or acetate; a sodium bicarbarbonate buffer reduces pain
• Preservatives – commonly phenol and benzyl alcohol, phenoxyethanol, methylparaben, or propylparaben

Injection-related factors

Features of the needle used for injection can affect ISRs:

• 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

Patient-related factors

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

Mechanism

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

Prevention

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

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. When possible, decreasing the frequency of administration may help.

Premedication with antihistamines or corticosteroids does not seem to prevent ISRs.

Treatment

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

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
• Medications for symptom relief – e.g., antihistamines for itching; paracetamol or NSAIDs for pain
• Cold compress application

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

Prognosis

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

Epidemiology

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%.

In trials of subcutaneous administration of oligonucleotides, between 22 and 100% of subjects developed reactions depending on the oligonucleotide.