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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)653-660
Number of pages8
JournalCNS Drugs
Volume32
Issue number7
DOIs
Publication statusPublished - Jul 2018

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Injections
Shivering
Glatiramer Acetate
Nocebo Effect
Confidence Intervals
Relapsing-Remitting Multiple Sclerosis
Proportional Hazards Models
Nausea
Multiple Sclerosis
Vomiting
Fever

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Atypical Post-Injection Reactions with Delayed Onset Following Glatiramer Acetate 40 mg : Need for Titration? / Zecca, Chiara; Bellavia, G; Brambilla, L; Gutierrez, L P; Gerardi, C; Fiori, A M; Bernardini, L R; Camera, G; Disanto, G; Petrini, L; Perugini, J; Antozzi, C G; Torri Clerici, V; Bellino, A; Confalonieri, P A; Gobbi, C; Mantegazza, R E; Rossi, S.

In: CNS Drugs, Vol. 32, No. 7, 07.2018, p. 653-660.

Research output: Contribution to journalArticle

Zecca, Chiara ; Bellavia, G ; Brambilla, L ; Gutierrez, L P ; Gerardi, C ; Fiori, A M ; Bernardini, L R ; Camera, G ; Disanto, G ; Petrini, L ; Perugini, J ; Antozzi, C G ; Torri Clerici, V ; Bellino, A ; Confalonieri, P A ; Gobbi, C ; Mantegazza, R E ; Rossi, S. / Atypical Post-Injection Reactions with Delayed Onset Following Glatiramer Acetate 40 mg : Need for Titration?. In: CNS Drugs. 2018 ; Vol. 32, No. 7. pp. 653-660.
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title = "Atypical Post-Injection Reactions with Delayed Onset Following Glatiramer Acetate 40 mg: Need for Titration?",
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.",
author = "Chiara Zecca and G Bellavia and L Brambilla and Gutierrez, {L P} and C Gerardi and Fiori, {A M} and Bernardini, {L R} and G Camera and G Disanto and L Petrini and J Perugini and Antozzi, {C G} and {Torri Clerici}, V and A Bellino and Confalonieri, {P A} and C Gobbi and Mantegazza, {R E} and S Rossi",
year = "2018",
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doi = "10.1007/s40263-018-0529-1",
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TY - JOUR

T1 - Atypical Post-Injection Reactions with Delayed Onset Following Glatiramer Acetate 40 mg

T2 - Need for Titration?

AU - Zecca, Chiara

AU - Bellavia, G

AU - Brambilla, L

AU - Gutierrez, L P

AU - Gerardi, C

AU - Fiori, A M

AU - Bernardini, L R

AU - Camera, G

AU - Disanto, G

AU - Petrini, L

AU - Perugini, J

AU - Antozzi, C G

AU - Torri Clerici, V

AU - Bellino, A

AU - Confalonieri, P A

AU - Gobbi, C

AU - Mantegazza, R E

AU - Rossi, S

PY - 2018/7

Y1 - 2018/7

N2 - 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.

AB - 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.

U2 - 10.1007/s40263-018-0529-1

DO - 10.1007/s40263-018-0529-1

M3 - Article

C2 - 29949101

VL - 32

SP - 653

EP - 660

JO - CNS Drugs

JF - CNS Drugs

SN - 1172-7047

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ER -