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Reduced Injection Site Pain with Succinate Buffer-Based Adalimumab Biosimilar (ZRC-3197) Injection (SUFFER Study): An Observational Study

 Medical Affairs-Zydus Biovation, Cadila Healthcare Ltd., Ahmedabad, Gujarat, India

Correspondence Address:
Mihir Gharia,
Medical Affairs.Zydus Biovation, Cadila Healthcare Ltd., Ahmedabad - 380 015, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_154_18

How to cite this URL:
Gharia M, Sudhakar A. Reduced Injection Site Pain with Succinate Buffer-Based Adalimumab Biosimilar (ZRC-3197) Injection (SUFFER Study): An Observational Study. Indian J Rheumatol [Epub ahead of print] [cited 2019 May 25]. Available from:

Dear Editor,

As known, pain due to subcutaneous (s.c.) injections is often more severe and the most common reason for patient noncompliance, other than erythema, edema, hematoma, and pruritus.[1] Advances in formulation of injection are targeted at developing injectables which can cause minimal discomfort. Buffers are ideally used in injectable formulations to prevent the pH-associated degradation of the active ingredient(s) and improve the stability of the product. The choice of buffers includes citrates, carbonates, acetates, histidine, sodium bicarbonate, and phosphates. One of the contributing factors for injection site pain is the buffers which are ideally used to prevent the pH-associated degradation of the active ingredient(s) and improve the stability of the product. A placebo-controlled clinical trial of adalimumab (Humira) in Rheumatoid Arthritis (RA) patients have shown that its s.c. injection leads to injection site reaction, including erythema and/or itching, hemorrhage, related pain, and swelling.[2] The objective of this study was to understand the injection site pain with Succinate buffer-based formulation of adalimumab biosimilar (ZRC-3197) and compare it with the existing data on citrate buffer. We carried out an observational study, where a prospective questionnaire-based study in patients treated with adalimumab injection for different rheumatological conditions was carried out. Patients aged ≥12 years of either sex, who had received at least three doses of injection, were included. The study duration was over 6 months. Data pertaining to pain at the site of injection were collected with the aid of two questionnaires distributed to the patients. Primary objective was describing pain at the site within 24 h of injection. Pain was assessed using the 0–10 numeric pain rating scale (National Initiative on Pain Control™)[3] and verbal description pain scale. Study was approved by the Intersystem Biomedica Ethics Committee (IEC No: ISBEC/NR-3/DDJJ/2018, Date of approval: 09-02-2018).

Our results showed, on numeric pain scale, that 192/494 patients (38.8%) reported no pain and 291/494 (58.9%) patients reported mild pain. On verbal description pain scale, 182 (36.4%) patients reported “No Pain” and 230 (46%) patients reported “Slight Pain.” Majority of patients of both gender described their pain as absent or mild and very few had moderate or severe injection site pain. Data giving comparison of adalimumab formulated in succinate and citrate buffer, respectively, are presented in [Table 1]. From this study, it can be demonstrated that 94.6% of the patients had “No Pain” or “Mild Pain” on numeric pain rating scale and 82.4% of the patents had “No Pain” or “Slight Pain” on verbal description pain scale after adalimumab injection which contains succinate buffer. These results suggest that incidence and severity of pain associated with injection of succinate buffer formulation is less compared to citrate buffer formulation, as evident from earlier publication. Further research would be needed with a more multivariate approach comparing other factors that affect the injection site pain such as injection volume, speed of injection, osmolality, pH, anatomical region of injection site, size and quality of injection needle, presence of irritating substances, individual patient characteristics, frequency of administration, and temperature of the solution. Authors conclude that the current study shows that succinate buffer formulation offers less incidence and severity of pain as compared to citrate buffer.
Table 1: Comparison of pain intensity using succinate and citrate buffer of adalimumab

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All named authors meet the International Committee of Medical Journal Editors criteria for authorship for this article. The authors thank Mediception Science Pvt. Ltd., for providing medical writing support.

Financial support and sponsorship

Medical writing support fund was provided by Cadila Healthcare Ltd., Ahmedabad, India.

Conflicts of interest

There are no conflicts of interest.


  References Top

Laursen T, Hansen B, Fisker S. Pain perception after subcutaneous injections of media containing different buffers. Basic Clin Pharmacol Toxicol 2006;98:218-21.  Back to cited text no. 1
Navarro-Millán I, Herrinton LJ, Chen L, Harrold L, Liu L, Curtis JR, et al. Comparative effectiveness of etanercept and adalimumab in patient reported outcomes and injection-related tolerability. PLoS One 2016;11:e0149781.  Back to cited text no. 2
Available from: [Last accessed on 2017 Jan 23].  Back to cited text no. 3
Nash P, Vanhoof J, Hall S, Arulmani U, Tarzynski-Potempa R, Unnebrink K, et al. Randomized crossover comparison of injection site pain with 40 mg/0.4 or 0.8 mL formulations of adalimumab in patients with rheumatoid arthritis. Rheumatol Ther 2016;3:257-70.  Back to cited text no. 4


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