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Review: Product Attributes Relevant to Injection-Site Pain, Adalimumab Treatment


A review article summarizes the product attributes of reference and biosimilar adalimumab products, such as formulation with or without citrate, delivery volume, and needle gauge, relevant to patients’ experience of injection-site pain.

A review article summarized the product attributes of reference and biosimilar adalimumab products, such as formulation with or without citrate, delivery volume, and needle gauge, relevant to patients’ experience of injection-site pain.

According to the reviewers, it is important for health care professionals to consider these features, as well as interchangeability, device preferences, and patient assistance programs, when discussing adalimumab treatment options with their patients. They added these differences in product attributes “can impact the injection experience and, by extension, treatment adherence and patient outcomes.”

injection with doctor | Image credit: terovesalainen - stock.adobe.com

Image credit: terovesalainen - stock.adobe.com

The originator adalimumab product (Humira), an antibody targeting tumor necrosis factor (TNF)- α has been marketed in the US since 2002, and adalimumab products are used to treat immune-mediated inflammatory diseases in dermatology, rheumatology, and gastroenterology practices. As of October 2023, when the review was submitted, 9 adalimumab biosimilars were available in the US. A tenth has since been approved by the FDA.

Formulation with and without citrate or glutamate

The reviewers noted that controlling the pH of a biologic drug with a buffer is necessary for its stability. Although slightly acidic formulations may be more favorable for stability, a pH lower than 3.0 can cause pain and inflammation at the injection site. Citrate and phosphate are commonly used buffers with a wide buffering range, however, citrate has been associated with injection site pain.

According to the authors, newer monoclonal antibody formulations typically use histidine or acetate instead of citrate or phosphate. Alas, their buffering ranges are narrower. Similarly, glutamate, which is used as an excipient for stability in some formulations, has also been associated with injection-site reactions and pain.

Injection-site pain is “clinically meaningful,” the authors noted, since it may contribute to lower adherence to treatment or treatment discontinuation. They cited 1 survey of patients, in whichinjection discomfort was reported among the primary reasons for discontinuing anti-TNF treatment. Another real-word study they cited found that switch failure rates were higher for patients switched from the citrate-free reference adalimumab to a citrate-containing biosimilar than for patients switched to a citrate-free biosimilar. They added the reference product and “nearly all” adalimumab biosimilars offer citrate-, phosphate-, and glutamate-free formulations.

Delivery volume

Larger subcutaneous injection volumes are also associated with pain at the injection site. The authors noted that injection-site pain associated with larger volumes may be influenced by the injection site location as well, adding that injections in the thigh have been reported to cause more pain than those in the abdomen. The reference product and 8 of the 9 adalimumab biosimilars currently on the US market offer high-concentration, lower injection volume formulations, they said.

Needle gauge, latex, and product stability

Adalimumab products are delivered with either a 27-gauge or 29-gauge needle, and the authors said it is important to consider both inner and outer needle diameters “to fully understand the potential impact of varying needle gauges.” Smaller outer diameter correlates with less injection-site pain. A standard 27-gauge needle and thin-walled 29-gauge needle have the same inner diameter. However, the reviewers noted, a 29-gauge needle has a smaller outer diameter, which may reduce pain at the injection site.

For avoiding potential allergic reactions, it is also important for the clinician to consider whether latex has been used in the manufacture of the product when discussing adalimumab options with patients. The authors noted that of the 9 currently available biosimilars, 7 offer a 29-gauge needle and 8 are made without natural rubber latex.

Adalimumab must be refrigerated under normal conditions, but may be stored at room temperature (up to 77℉ or 25℃) for 14 to 31 days, as specified in the instructions for each product. The reviewers noted that 1 adalimumab biosimilar (Abrilada; Pfizer), may be stored at temperatures of up to 86 F (30 C) for up to 30 days. Products with extended stability outside of refrigeration “offers convenience and flexibility in storage, which could improve the injection experience and may lead to better treatment adherence and patient outcomes,” the reviewers wrote.

Ease of use of pre-filled syringe vs. pre-filled pen

Adalimumab is administered by subcutaneous injection using either a prefilled syringe or prefilled pen, and patients may prefer one type of device over the other. The authors explained that many patients prefer pre-filled pens because of their convenience, ease of use, and built-in safety features, whereas other patients prefer pre-filled syringes because of the better control over speed and duration of injection.

Some prefilled pens offer features such as a viewing window to see the medication, a visual indicator to show injection progress, audible clicks to signal the start and end of injection, and/or a needle guard to prevent injury and help with fear of injection. The reference product and four biosimilars offer single-dose pens that have the Arthritis Foundation’s Ease of Use Certification, meaning they have been independently certified as easier to use for people living with arthritis, chronic pain, or limited physical function. The authors noted that device attributes should also be discussed with patients, especially when switching from the reference product to a biosimilar, since patients may find it easier to transition to a device similar to the one they have used previously.

Patient support programs

Finally, patient resources provided by the manufacturers of adalimumab products may influence treatment choices. Patient assistance programs provide financial assistance to facilitate patient access to treatment, resources for navigating insurance coverage processes, and help patients understand their disease, treatment options, and medication. The reviewers said these programs are another important factor for physicians to consider when discussing adalimumab treatment options.


Allegretti JR, Brady JH, Wicker A, Latymer M, Wells A. Relevance of adalimumab product attributes to patient experience in the biosimilar era: a narrative review. Adv Ther. Published online March 11, 2024. doi:10.1007/s12325-024-02818-9

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