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Atypical Post-Injection Reactions with Delayed Onset Following Glatiramer Acetate 40 mg: Need for Titration?

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Abstract

Background

Glatiramer acetate (GA) 20 mg/day (GA20) is associated with immediate post-injection reactions (PIRs). For convenience of use, approved GA 40 mg three times weekly (GA40) delivers a similar weekly dose. The dose and concentration of a single GA40 injection are, however, twice as high as for GA20, and post-injection adverse events may differ. Cases of atypical PIRs to GA40 prompted us to systematically monitor such events.

Objective

The aim was to characterize atypical PIRs in multiple sclerosis (MS) patients treated with GA40.

Methods

Clinical practice data were prospectively collected in consecutive relapsing–remitting MS patients. Descriptive statistics for categorical and continuous variables, Mann–Whitney and Chi-squared tests for baseline comparisons, and Cox regression models for association of variables to first atypical PIRs were applied.

Results

Forty-six out of 173 patients (26.6%) given GA40 experienced any PIRs. Of those, 38 (22.0%) had atypical, 14 (8.1%) had combined typical and atypical, and 26 (15.0%) had recurrent atypical PIRs, most frequently shivering (13.3%) and nausea/vomiting (8.1%). Compared to typical PIRs, onset of atypical PIRs was significantly delayed (median 30 vs 1 min, p < 0.0001), and their median duration longer (median 120 vs 6 min, p = 0.00013). Previous exposure to GA20 was associated with a lower risk of atypical PIRs [hazard ratio (HR) = 0.35, 95% confidence interval (CI) 0.17–0.72, p = 0.0039]. Patients experiencing PIRs with GA20 were at elevated risk for atypical PIRs with GA40 (HR = 5.75, 95% CI 1.66–19.94, p = 0.0059).

Conclusions

Atypical PIRs with GA40, especially gastrointestinal symptoms and/or fever/shivering, had a delayed onset and occurred in a significant proportion of our patients. Their real prevalence should be assessed in appropriately designed studies accounting for  nocebo responses. Initial dose titration might reduce PIR frequency.

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Acknowledgments

We thank all patients who consented to be enrolled in the research and Simona Curci, Istituto Neurologico Carlo Besta, for helping with manuscript finalization and submission.

Author information

Authors and Affiliations

  1. Neurocenter of Southern Switzerland, Ospedale Regionale di Lugano, Lugano, Switzerland

    Chiara Zecca, G. Disanto, L. Petrini & C. Gobbi

  2. Neuroimmunology and Neuromuscular Diseases Unit, IRCCS Fondazione Istituto Neurologico Carlo Besta, Milan, Italy

    Chiara Zecca, G. Bellavia, L. Brambilla, L. P. Gutierrez, A. M. Fiori, L. R. Bernardini, G. Camera, J. Perugini, C. G. Antozzi, V. Torri Clerici, A. Bellino, P. A. Confalonieri, R. E. Mantegazza & S. Rossi

  3. IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy

    C. Gerardi

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  1. Chiara Zecca
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  2. G. Bellavia
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  3. L. Brambilla
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  4. L. P. Gutierrez
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  8. G. Camera
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  15. P. A. Confalonieri
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  16. C. Gobbi
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Corresponding author

Correspondence to Chiara Zecca.

Ethics declarations

All patients provided written informed consent for reuse of their clinical data. For this survey, no approval from an ethics committee was necessary.

Funding

This research received no grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

Zecca C.: The Department of Neurology, Regional Hospital Lugano (EOC), Lugano, Switzerland receives financial support from Biogen, Genzyme, Merck, Novartis, Roche, Teva. Gobbi C.: The Department of Neurology, Regional Hospital Lugano (EOC), Lugano, Switzerland receives financial support from Biogen, Genzyme, Merck, Novartis, Roche, Teva. Antozzi C.G. received funding for travelling for congress attendance from Biogen, Merck, and Teva. Torri Clerici V. acted as an Advisory Board member for Biogen, Merck, Novartis, and Genzyme and received funding for travel from Biogen, Merck, Bayer, Genzyme, and Almirall and honoraria for speaking or writing from Merck, Teva, Genzyme, and Almirall. She received support for a research project from Almirall and is involved as principal investigator in clinical trials for Novartis and FISM. Confalonieri P.A. acted as an Advisory Board member for Biogen and Novartis; received funding for travel from Biogen, Merck, Teva, and Novartis; and received honoraria for speaking or writing from Biogen and Novartis. He received support for research projects from Novartis and Merck and is involved as principal investigator or co-investigator in clinical trials for Teva, Novartis, Biogen and Merck. Mantegazza R.E. acted as an Advisory Board member for Biomarin, and received funding for travel or speaker honoraria from Sanofi-Aventis, Biomarin, Grifols, Teva, Bayer, Alexion, and Argenx. He is involved as principal investigator in clinical trials for Alexion, Merck Serono, Hoffman-La Roche, Teva, Besta-Azienda Ospedaliera San Gerardo, Biogen, Biomarin, Almirall, Novartis, Genzyme Corporation, and Catalyst. Rossi S. acted as an Advisory Board member for Biogen, Bayer Schering, Merck, Teva, Novartis, Genzyme, and Mylan; received travel funding from Biogen, Merck, Teva, Novartis, Bayer Schering, Genzyme, and Almirall; and received honoraria for consultancy, speaking or writing from Biogen, Merck, Teva, Novartis, Bayer Schering, Genzyme, and Roche. She received support for research projects from Teva, Merck and Bayer Schering and is involved as principal investigator in clinical trials for Teva, Novartis, Biogen, and Roche. Bellavia G., Brambilla L., Gutierrez L.P., Gerardi C., Fiori A.M., Bernardini L.R., Disanto G., Petrini L., Perugini J., Bellino A., and Camera G. declare that they have no conflict of interest.

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Zecca, C., Bellavia, G., Brambilla, L. et al. Atypical Post-Injection Reactions with Delayed Onset Following Glatiramer Acetate 40 mg: Need for Titration?. CNS Drugs 32, 653–660 (2018). https://doi.org/10.1007/s40263-018-0529-1

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