A narrative review on the safety of glatiramer acetate in multiple sclerosis: focus on Europe

Abstract

Glatiramer acetate (GA) has been a pivotal therapy for relapsing multiple sclerosis (MS) due to its favorable safety profile. Long-term data spanning decades demonstrate its continued use in diverse patient populations. Adverse events include manageable localized injection site reactions, lipoatrophy or necrosis, and rare cases of liver injury. GA has minimal effects on immune function, and does not increase the risk of opportunistic infections, making it suitable for MS patients at risk for infections or reactivation of latent infections. GA’s immunomodulatory properties may pose a lower infection risk than other disease-modifying treatments. Progressive multifocal leukoencephalopathy risk with GA is low, and screening for latent infection is unnecessary before treatment. Vaccination is important for preventing infections in MS patients. GA does not compromise vaccine efficacy and is compatible with both inactivated and live attenuated vaccines. Special populations that may benefit from the characteristics of GA include older adults and patients with comorbidities and/or polypharmacy. MS patients often have comorbidities, necessitating careful management of potential drug interactions and side effects. Drug interactions with GA are not predicted, and clinical data suggest that the risk is low. GA is not contraindicated during pregnancy and exhibits a reassuring safety profile during breastfeeding, with no increased risk of adverse outcomes identified. Regulatory restrictions on GA use during breastfeeding have been removed. In summary, GA remains a safe and well-established therapy for MS patients, including those in special populations. Its favorable safety profile, compatibility with vaccination, and reassuring outcomes solidify its role in MS treatment.

Plane language summary

Glatiramer acetate safety

Glatiramer acetate is a relatively safe DMT with minimal effects on immune function that does not compromise vaccine efficacy, making it suitable for MS patients at risk for infections or requiring vaccination. A reassuring safety profile and minimal drug interactions make it a viable treatment option for special populations common among MS patients, such as older adults and patients with comorbidities or polypharmacy. Use during pregnancy is not contraindicated, and should consider the benefit-risk assessment, while regulatory restrictions on its use in breastfeeding have been removed.

Keywords

disease-modifying therapy glatiramer acetate immunomodulation multiple sclerosis non-biological complex drug patient safety relapsing/remitting tolerability

Glatiramer acetate

Glatiramer acetate (GA) was shown to reduce relapse rate and MRI disease activity in controlled clinical trials,^1–4 leading to its approval for reducing multiple sclerosis (MS) relapse rates and MRI disease activity in patients with relapsing MS in the United States in 1996,⁵ and in Europe in 2003.⁶

GA is a mixture of polypeptides with an average molecular weight of 5–9 kDa, comprising four naturally occurring amino acids. This non-biological complex drug (NBCD) is manufactured by the copolymerization of l-glycine, l-lysine, l-alanine, and l-tyrosine in a molar ratio of 1.9:4.6:6.0:1.0. Omission of any one amino acid resulted in loss of effect.⁷ In contrast to the original version, GA is currently produced with a molar ratio of 4.2:3.4:1.4:1, although the reason for this change remains unreported.⁸ The large number of possible components with different molecular weights and sequences precludes definitive structural elucidation by component analysis⁹; however, modern analytical and quantitative methods enabled reverse engineering of the synthesis procedure for the development of generics, ensuring equivalence with the originator. The development and production of follow-on GAs (FOGA) require a strictly controlled manufacturing process to avoid unanticipated consequences from even minor differences in the distribution of molecular weights or in the composition of antigenic polypeptide sequences, which can have an impact on the efficacy, toxicity, and immunogenicity profiles of the FOGA.¹⁰

GA reduces inflammation by shifting reactive T cells toward a Th2 pattern, enhancing T regulatory cells (Tregs) and increasing anti-inflammatory cytokine production, while reducing the production of inflammatory cytokines.^11–14 This Th2 skewing of the T cell response is one widely accepted mechanism of action for GA; however, a newer concept involves additional immunomodulatory effects on cells of the myelo-monocytic lineage through induction of anti-inflammatory “type II” antigen-presenting monocytes.^15,16 In recent studies, GA treatment was linked to decreased number of plasmablasts, B cells, and memory B cells, in addition to a shift of B cells from a pro-inflammatory to an anti-inflammatory phenotype.¹⁷ GA enhances NK cell cytolysis of dendritic cells,^18–22 perhaps by enhancing interaction through NK cytotoxicity receptors and reducing MHC class I expression on dendritic cells (Figure 1).

Figure 1.

Effects of glatiramer acetate on immune cell populations. (a) Glatiramer acetate increases the biological activities of NK cells, particularly their cytolytic potential. ^aHøglund et al.,²⁰ ^bAl-Falahi et al.,¹⁹ ^cSand et al.,¹⁸ ^dMaghazachi et al.,²¹ and ^eSellner et al.²² (b) Glatiramer acetate increases anti-inflammatory and reduces proinflammatory cytokine levels. Glatiramer acetate-treated B memory and regulatory cells promote the formation of Th2 T cells and regulatory cells. ^aAmrouche et al.,²³ ^bHäusler et al.,²⁴ ^cJackson,²⁵ ^dMaghazachi et al.,²¹ ^eSellner et al.,²² ^fCarrieri et al.,²⁶ ^gSellebjerg et al.,²⁷ and ^hHarp et al.²⁸ (c) Glatiramer acetate induces differentiation into type II (M2) myeloid cells and increases their phagocytic capacity. ^aVieira et al.,²⁹ ^bJung et al.,³⁰ ^cKim et al.,³¹ ^dWeber et al.,³² ^eBurger et al.,³³ ^fCarpintero et al.,³⁴ ^gChabot et al.,³⁵ ^hPul et al.,¹⁵ and ⁱMolnarfi et al.³⁶

Possible neuroprotective effects of GA (seen mainly in animal models) may be associated with increased levels of neurotrophic factors secreted by Th2-biased immune cells. Effects of GA on the neuro-proinflammatory and degenerative processes implicated in MS-associated cognitive decline may help preserve nerve cell function and integrity.³⁷ In experimental autoimmune encephalomyelitis (EAE), GA enhances the proliferation, migration, and differentiation of oligodendroglial and neuronal progenitor cells that foster repair, remyelination, and neurogenesis.^38,39 GA protects neurons by increasing levels of neurotrophic factors and may reduce glutamate-mediated neurotoxicity.^40–42 GA treatment reduced serum neurofilament light chain levels by 81% in EAE,⁴³ suggesting that it may serve as a prognostic marker during GA treatment.

Follow-on GAs

Access to disease-modifying therapies (DMTs) for MS is limited in many regions, especially in low- and middle-income countries,⁴⁴ and stakeholders suggest that biosimilars/generics may improve affordability and access to DMTs for MS patients.^45–48 Patent protection for Copaxone^® 20 mg daily (originator GA) ended in 2014. There has been debate on how to define and determine similarity between originator and FOGAs.^49–54 The manufacturing process is fundamental to the production of NBCDs that maintain the characteristics of the originator product.⁵⁵

Regulatory agencies have recognized several FOGAs as equivalent to the originator in terms of safety and efficacy. In April 2015, the US Food and Drug Administration (FDA) approved a generic form of GA (Glatopa™, originally produced by Momenta Pharmaceuticals), based on the synthesis and purification procedures used, and on its physicochemical, biological, and immunological properties in EAE.⁵⁶ Subsequently, the FDA approved 20 and 40 mg formulations of a second generic GA originally produced by Natco Pharma in October 2017. These approvals were based on the Abbreviated New Drug Application process, which did not require additional clinical data.

In contrast, the European Medicine Agency (EMA) considered GA to be an NBCD and advised a third sponsor, Synthon, to demonstrate equivalent efficacy, safety, and tolerability of its generic GA product with new clinical data. These data were collected in the 9-month randomized, placebo-controlled, double-blind, Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) study,⁵⁷ and 15-month extension.⁵⁸ Patients aged 18–55 years old with relapsing MS (⩾1 relapse in the previous year and 1–15 gadolinium-enhancing MRI lesions) were randomly assigned to receive daily sc. injections of originator GA 20 mg (n = 357), FOGA 20 mg (n = 353), or placebo (n = 84). The study had an equivalence design and a primary endpoint of MRI-related outcome as a surrogate for relapses. Safety and tolerability were similar in both groups. Study discontinuation for any reason occurred in 3.4% of patients receiving FOGA and 1.1% receiving originator GA; however, discontinuation for any reason does not necessarily reflect a higher rate of adverse events, but could also result from a subjective tolerability issue. In the same study,⁵⁷ the occurrence of any event was reported by 51.0% of subjects receiving the FOGA and 54.3% of subjects receiving the originator GA. Similarly, the percentages of subjects experiencing any serious adverse event (3.4% and 4.8%) and any severe event (4.0% and 2.8%) in the FOGA and originator GA, respectively, suggest that these variables are comparable between the two treatments.

All participants then received FOGA in the 15-month open-label extension,⁵⁸ during which safety and tolerability, as well as the development of anti-drug antibodies, were found to be comparable in both incidence and titer (Figure 2).

Figure 2.

Glatiramer antibody (ADA) titer: mean (∓SD) ADA titer values in patients treated with generic glatiramer acetate (GTR) over 24 months and patients treated with brand glatiramer acetate (GA) for 9 months then switched to GTR for 15 months.

Several studies using sophisticated methodologies have demonstrated differences in physico-chemical characteristics between originator GA and other glatiramoids.^59,60 Studies have also reported different and sometimes contrasting effects on biological pathways relevant to the pathogenesis of MS (such as increased pro-inflammatory cytokine secretion by FOGAs) and effects on gene expression, raising concern about non-equivalent efficacy and antigenicity of FOGAs if not tested in appropriate clinical trials.^53,61–63 In a genome-wide expression study performed in THP-1 cells by the company Teva (Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel), originator GA modulated the expression of 6890 genes after 6 h of treatment, while treatment with the FOGA Probioglat^® (Probiomed, Mexico City, Mexico) resulted in differential expression of 136 genes at the same time point.⁶³ The authors claim that Probioglat induced a more pro-inflammatory response compared to the originator GA. Similar shifts in expression of the genes identified (CCL5, CCL2, MMP9, MMP1, CXCL10, CD14, ICAM1, and BIRC3) were not observed in the study described above (CXCL10 was down-regulated by both originator and FOGA).⁶³

A study by Hasson et al.⁶¹ showed differences between originator GA and the FOGA Polimunol^® (Synthon Bago, Autonomous City of Buenos Aires, Argentina). However, this study compared a single Polimunol batch vs. three Copaxone batches, and used a gene expression difference cut-off of 1.1-fold, which is not considered biologically relevant. Instead, the genome-wide expression study conducted by Kolitz et al. compared five FOGA batches with five originator GA batches, using 1.4-fold change cut-off value at a p-value of <0.05, which could be expected to provide more biologically meaningful results.⁶³

Furthermore, Bakshi et al. conducted an investigation using splenocytes isolated from mice that had been immunized with the GA reference standard (Teva) and subsequently exposed ex vivo to various glatiramoids. Their comparison between GA-Teva and GA-Natco revealed significant differences in the expression of 98 genes (fold change ⩾ 1.3), which are primarily associated with T cell differentiation, immune suppression, antigen presentation, induction of Tregs, inflammatory responses, and cell adhesion.⁶² In a related study, Towfic et al. developed computational methods to assess the immunological effects of branded versus generic medications.⁴⁹ Their results indicated a notable variability in gene expression following activation by the generic GA-Natco compared to GA-Teva batches. While Copaxone effectively induced the upregulation of Treg-related genes, the GA-Natco generic was associated with increased inflammatory markers linked to monocytes and macrophages (e.g., CD14, TLR2, IL1B).⁴⁹ It is important to note that these studies were performed in a healthy mouse model, which may not fully capture the complex dynamics of human MS. Nevertheless, these findings highlight the need for translational studies using human cells to better understand the distinctions between FOGA and Copaxone and their implications for treatment.^49,64

The scientific discussion in the EMA public assessment report of 2016 includes a review of the above study findings, including those related to gene expression.⁶⁵ Based on all data presented, the Board did not seek further clarification during approval of FOGAs, due to methodological issues with these studies, and concluded that Mylan GA 20 mg/mL can be regarded as therapeutically equivalent (efficacy and safety) to the reference product.⁶⁵ Moreover, these studies notwithstanding, the EMA approved the 20 mg once-daily formulation of the Mylan FOGA in 2016,⁶⁶ and the 40 mg thrice-weekly formulation in 2017⁶⁷ based on the results of the GATE study, which demonstrated equivalent efficacy, safety, and tolerability of Viatris GA to the originator GA.⁵⁷

In addition to these products, FOGA alternatives have been developed under various trade names, depending on the pharmaceutical companies that produce and distribute them (Table 1).^68,69

Table 1.

Glatiramoid class members approved as DMT for for relapsing MS.

GA	Manufacturer	FDA/EMA approval	Market	Scientific support to regulatory approval
Copaxone^®	Teva	FDA and EMA	Several countries worldwide	Originator
Brabio^®	Viatris (Legacy Mylan)	EMA	Several countries worldwide; various commercial names	Quality, preclinical, and randomized clinical data
Glatopa^®	Sandoz	FDA	USA	No
Remurel^®	Alvogen	EMA	Europe	No
GTR Polimunol^®	Synthon Bagó	EMA	Argentina	No
Escadra^®	Raffo	No	Argentina	No
Probioglat^®	Probiomed	No	Mexico	No
Glatimer^®	Natco	No	India	No
Copamer^®	Zahravi	No	Iran	No
Cinnomer^®	CinnaGen	No	Iran	NCT04928313

Source: Adapted from Annovazzi et al.⁶⁸

DMT, disease-modifying therapy; EMA, European Medicine Agency; FDA, U.S. Food and Drug Administration; GA, glatiramer acetate.

The lack of a centralized regulatory pathway for NBCDs and their follow-on versions⁷⁰ may affect the perception of their efficacy and safety by clinicians and patients; therefore, it is important to collect clinical data on efficacy and safety, and to conduct post-marketing surveillance to provide a better understanding of performance in real-world clinical practice. This is particularly relevant because variations in the GA production process have been associated with changes in efficacy, safety, immunogenicity, and biological activity compared to the originator GA,^51,53,59,60 including effects on gene expression in biological pathways relevant to the pathogenesis of MS.^61–63

This narrative review will assess the long-term safety and tolerability data for GA originator and FOGAs in the management of patients with MS. It will also present data from the Ad-hoc Safety Review Report on Viatris GA.

GA safety

After three decades and millions of patient years, GA is still a widely prescribed DMT for treating patients with relapsing MS, despite the introduction of more efficacious DMTs.⁷¹ This is likely due to its ease of management, which does not require extensive monitoring, its favorable safety profile, including in special populations including older adults, patients with comorbidities, or those planning for pregnancy and breastfeeding.⁷²

Currently, the longest continuous follow-up data for GA comes from the US Glatiramer Acetate Trial conducted by Ford et al., which has 27 years of safety data on 52 patients.^73,74 The extensive phase IV clinical data collected following the initial approval of originator GA support the continuing efficacy and safety of GA in relapsing-remitting MS,^71,72 and is used, together with post-marketing surveillance, pharmacovigilance data, scientific publications, input from expert panels, and regulatory guidance, to curate the manufacturers’ prescribing information.

Viatris, the manufacturer of a FOGA, hereafter referred to as Viatris GA, maintains a safety surveillance database of cases reported from 12 countries in Europe. Data sources include post-marketing surveys, spontaneous reports, regulatory authorities, and publications. Cumulative exposure data from Viatris for all European countries where the product has been marketed are calculated from sales data available up to March of 2022. Cumulative patient-time exposure to both of the glatiramer formulations from the launch date to June 30, 2022 is estimated at 428,168 patient years (98,955 for the 20 mg/mL dose, and 329,213 for the 40 mg/mL dose).

As of June 30, 2022, Viatris has received a total of 5366 cases from the global safety database. In 192 cases, the manufacturer of the GA product could not be established. Based on review of the cumulative data, no new safety or efficacy concerns were identified in patients switching from originator to Viatris GA, consistent with the results from patients switching from originator to Viatris GA, in the GATE Extension study,⁵⁸ and with reported results from patients switching from originator to the FOGA Copamer^®.⁷⁵ Overall, cumulative post-marketing experience with Viatris GA has been consistent with the known safety profile of originator GA. More than 80% of the reported adverse events were non-serious in nature.

Injection site reactions

Injectable MS DMTs commonly cause localized injection site reactions and a range of dermatological adverse effects, most of which are mild and, although they do not lead to discontinuation, they may impact quality of life.⁷⁶ The most frequent treatment-emergent adverse events in pivotal trials of GA were local injection site reactions,^2,4 consisting of transient erythema, pain, edema, and pruritus that occur with decreasing frequency over time.⁷⁷ A pooled analysis of safety and tolerability among all MS patients exposed to GA in clinical trials before 2017 (10,017 patient-years, median exposure 1.8 years) confirmed that injection site reactions were the most common adverse events⁷⁸; this was also consistent with the results from long-term extension studies. No late safety issues emerged in the extension studies.^4,73,74 Injection site reactions were less frequent with the 40 mg/mL formulation administered three times weekly in the open label GLACIER study.⁷⁹ Patients in the US Glatiramer Acetate Trial had the option of switching from daily injections to three times weekly injections when the 40 mg/mL formulation became available, but many chose to continue with daily injections, suggesting that tolerability was acceptable.⁷³

Lipoatrophy or necrosis

Injection site lipoatrophy or necrosis is a more serious adverse event that was reported in approximately 2% of patients who received GA in placebo-controlled trials, and patients should practice injection site rotation, as described in the prescribing information.⁶

Immediate post-injection reaction

Immediate post-injection reaction may manifest as flushing, chest tightness/pain, palpitations, tachycardia, anxiety, dyspnea, throat constriction, and/or urticaria occurring within 1 h of injection. This is a rare occurrence, with a single or a few episodes occurring during long periods of treatment in 16% of treated patients.⁶ The exact nature of these reactions is unknown, and they are generally transient and self-limiting, with dyspnea occurring with the highest frequency (12%). Caution is warranted, however, as a recent direct healthcare professional communication from the EMA warns about the possibility of anaphylactic reactions occurring months to years after treatment initiation. While these reactions are uncommon (⩾1/1000 to <1/100), symptoms may overlap with those of post-injection reactions, potentially delaying their identification.⁸⁰

Other adverse events occurring with a frequency >10%

Consistent with findings reported in the prescribing information,^5,66 a post hoc pooled analysis of safety and tolerability identified rashes (15%), headaches (14%), infections (12%), and episodes of vasodilation (11%).⁷⁸ The rate of headache was similar to the reported rate of 15.8% in the general population on any given day.⁸¹ Infections were defined broadly, encompassing common and minor events, and the absence of a comparator arm makes interpretation difficult.⁷⁸ Transient episodes of idiopathic chest pain, including episodes not associated with other symptoms, have also been reported. While leukopenia can be an issue with some DMTs, it occurs infrequently with GA and is generally mild if present.⁸² This is likely due to its mechanism of action, which involves anti-inflammatory cytokine shifts in CD4+ and CD8+ T cells, restoration of Tregs, and reductions in memory B and T cells.

Liver injury

Cases of liver injury, including hepatitis and liver failure, have been reported in patients treated with GA, occurring days to years after starting treatment.⁶ Meunier et al. have cataloged 15 cases of GA-associated liver injury, 6 of which occurred in patients who had switched to GA from interferon (IFN) due to elevated liver enzymes (Table 2).⁸³ Among these 15 cases, only 4 were negative for anti-nuclear and anti-smooth muscle autoantibodies, and had not previously switched to GA due to elevated liver enzyme abnormalities associated with the previous treatment.⁸³

Table 2.

Cases of GA-associated liver injury.

Case	Sex	Age, (years)	Profile	Antibodies	Liver biopsy	Treatment before GA	Recovery (days)
Deltenre et al., 2009⁸⁴	F	52	Hep	ANA: 1/320 ASMA: 1/80	Centrilobular damage, lymphocyte, macrophage, eosinophil	MPDN	90
Onmez et al., 2013⁸⁵	F	36	Hep	Negative	Polymorphonuclear-rich mixed-type inflammatory cell reaction	GA + MPDN	36
Neumann et al., 2007⁸⁶	M	71	Hep	ANA: 1/1280	Drug-induced liver injury without fibrotic changes of the liver	IFN (switch due to liver function)	30
Antezana et al., 2014⁸⁷	F	28	Hep	Negative	Hepatocellular necrosis, portal bridging, and portal lymphocytic inflammation		30
Subramaniam et al., 2012⁸⁸	F	31	Hep	ASMA: 1/320	Centrilobular hepatocyte necrosis with portal-venous bridging, along with mild portal and interface hepatitis
Flaire et al., 2016⁸⁹	F	56	Hep	Negative	Centrilobular hepatocyte necrosis with inflammatory infiltrates composed of lymphocytes and eosinophils	MPDN	45
La Gioia et al., 2014⁹⁰	F	25	Hep	Negative	Inflammatory infiltration: lymphocytes, histiocytes, plasma cells, and a few eosinophil granulocytes		56
Makhani et al., 2013⁹¹	F	15	Hep	Negative	Lymphocytic inflammatory infiltration with mild portal fibrosis, no plasma cells, and no signs of chronic liver disease	IFN (switch due to liver function)	54
Fernández Fernández et al., 2015⁹²	F	42	Hep	ANA: 1/640	No biopsy	IFN (switch due to liver function)	30
Sinagra et al., 2014⁹³	F	41	Hep	ANA: 1/320	Moderate interface hepatitis with eosinophilic infiltration and porto-portal fibrosis	IFN (switch due to liver function)	30
Sinagra et al., 2014⁹³	F	29	Hep	ANA: 1/160	Lymphoplasmacytic infiltration with porto-portal fibrosis and slight ductal proliferation	IFN (switch due to liver function)
Almeida et al., 2017⁹⁴	F	65	Hep	ANA: 1/40ASMA: 1/40	No biopsy	MPDN	147
Arruti et al., 2012⁹⁵	F	46	Hep	Negative	No biopsy
von Kalckreuth et al., 2008⁹⁶	F	42	Cho	ANA, ASMA positive	Severe portal and periportal lymphocytic inflammation with necrosis	IFN (switch due to liver function)
Michels et al., 2020⁹⁷	F	23	Hep	Negative	Hepatocyte necrosis CD38-positive lymphocytes

Source: Reprinted from Meunier et al.⁸³ Open Access under Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). No special permission is required to reuse all figures or part of article published by MDPI.

ANA, anti-nuclear antibodies; ASMA, anti-smooth muscle antibodies; Cho, cholestasis; CTC, corticosteroids; Hep, hepatitis; IFN, interferon; MPDN, methylprednisolone.

Meanwhile, Villani et al. described 11 cases of autoimmune hepatitis in untreated patients with MS,⁹⁸ and Tsouris et al. identified similar frequencies of autoantibodies to hepatic antigens in treatment-naïve and treated patients with MS.⁹⁹ It is important to consider the type of liver injury involved, and consider that, while case reports can provide hints about a safety signal, they require systematic assessment for confirmation.¹⁰⁰

While it is not possible to estimate the frequency of drug-induced hepatotoxicity based on these cases, there were no reported cases in pivotal trials of GA originator,¹⁰¹ which may indicate that they are not common. Post-marketing surveillance in clinical practice is useful for monitoring drug safety and detecting safety signals. Spontaneous reporting systems like the FDA Adverse Event Reporting System can detect rare events like drug-induced liver injury.¹⁰² Disproportionality analysis of FDA Adverse Event Reporting System data acquired from 2004 through 2016 (18,591 total reports on GA) did not identify a safety signal for overall liver injury or for severe liver injury with GA, reporting odds ratios (95% CI) 0.70 (0.62–0.79), and 1.01 (0.88–1.16), respectively.¹⁰³

In the Viatris safety surveillance database, 55 cases (65 events) suggestive of hepatic injury have been reported. Ages ranged from 23 to 90 years, and 46 patients were female. Thirty-one of 55 cases were non-serious, and 53% consisted of liver enzyme elevation. Reported forms of severe liver injury included serious drug-induced hepatotoxicity, hepatitis, autoimmune hepatitis, liver cancer, and one case of liver failure. The case of liver failure occurred in the context of multi-organ failure secondary to gastrointestinal infection, thrombosis, and pulmonary embolism, excluding a direct causal role of GA in its occurrence and fatal outcome. Of the three reported cases of autoimmune hepatitis, only one was supported by a positive anti-nuclear antibody titer, whilst information was limited in the other two. The two reported cases of liver cancer were not evaluable for causal association to GA based on limited information.

GA prescribing information recommends monitoring for signs of hepatic injury, instructing patients to seek immediate medical attention in case of symptoms of liver injury, and consider discontinuing GA in case of clinically significant liver injury.^6,67

Opportunistic infections

GA modulates the immune system rather than suppressing it, promoting anti-inflammatory and regulatory pathways, while avoiding an increase in the risk of infections. DMT-associated risk of opportunistic infections is considered lowest with the injectable therapies IFN beta and GA.^78,104–106

GA treatment is associated with a reduction of pro-inflammatory B cell functions¹⁰⁷; however, leukopenia and leukocytosis are rare.¹⁰⁸ Progressive multifocal leukoencephalopathy (PML), triggered by reactivation of latent John Cunningham virus, is an important safety concern when treating MS.¹⁰⁹ Among DMTs, natalizumab is associated with the highest risk of PML, with rare cases also reported for ocrelizumab, fingolimod, and dimethyl fumarate. In contrast, GA has not been associated with an increased risk of PML or hepatitis B virus reactivation compared with the general population.^110,111 Infection risk is a key consideration when initiating or switching treatments,¹¹² and ongoing monitoring for infections is an essential practice with some DMTs.

Meanwhile, post-marketing surveillance has not shown a risk for opportunistic infections (including PML),^78,104 and there are no requirements for infection screening or monitoring.⁵ In the Viatris database, 148 infections excluding the SARS-CoV-2 virus were reported. Of these, 75% were non-serious, and included influenza, herpes zoster, oral herpes, Staphylococcal infections, and fungal infections. Most events were consistent with the immune-modulating mechanism of action of GA, and no fatal outcomes were reported.

Vaccination

Vaccines are not associated with an increased risk of relapses or disability in MS patients, regardless of treatment status, and their benefit greatly outweighs potential risks, as infections are frequent triggers for relapse^113–117. Nonetheless, it may be prudent to avoid vaccination in patients who are experiencing an active relapse.¹¹⁸ Inactivated vaccines can be safely used in MS patients regardless of treatment, whereas live attenuated vaccines should be limited to untreated patients or those receiving immunomodulatory therapy with GA or IFNs.¹¹⁹

Most DMTs for MS modulate or suppress components of the immune system, potentially influencing the ability to mount an immune response to vaccines. Several DMTs are known to attenuate vaccine responses (e.g., sphingosine-1-phosphate receptor modulators, anti-CD20 monoclonal antibodies, natalizumab), and care should be taken to update vaccines before initiating these treatments, observe the optimal interval from the last DMT dose when administering annual vaccinations, and consider administering additional vaccine doses.¹¹⁹ It is recommended that vaccine-induced antibody titers should be confirmed 1–2 months after the last dose of the hepatitis B, measles, mumps, tetanus, or varicella vaccines in patients who are already receiving immunosuppressive DMTs.¹¹⁹ GA does not appear to compromise response rates to influenza, tick-born encephalitis, or SARS-CoV-2 vaccines in patients with MS.^120–123

Special populations

Older adults

Older adults were not well represented in pivotal clinical studies of DMTs for MS, which generally presents in young adults^124,125; therefore, extra attention may be warranted when prescribing DMTs in older adults, because risk–benefit considerations may change with age. This is important because as survival has improved and the population ages, the peak MS prevalence has currently increased to between 55 and 65 years.^126–128 Disease characteristics change as patients with MS age. Older MS patients have lower relapse rates,¹²⁹ less inflammatory activity,^130,131 and may have less need for highly effective DMTs.¹³² Older adults with MS generally have higher rates of comorbidities, which are associated with higher risk of hospitalization,¹³³ a higher risk for adverse events,¹²⁵ and an apparent increase in MS disability progression on the Expanded Disability Status Scale.¹³⁴ Large cohort studies have shown that DMT efficacy decreases with age,¹³⁵ raising the question of whether de-escalation or discontinuation should be considered in older patients with no clinical or radiological disease activity. Such choices must be made in the context of shared decision-making. In a survey of older patients in the North American Research Committee on Multiple Sclerosis Registry who had been receiving the same DMT for at least 5 years, 88.1% of 377 respondents reported being unlikely to consider DMT discontinuation if their MS was stable¹³⁶; therefore, de-escalation may be a more attractive option to discontinuation in this situation. Moreover, the results of the DISCOMS (discontinue disease-modifying therapies) and DOT-MS studies do not support the discontinuation of DMTs in older patients.^137,138 However, the DISCOMS study had a non-inferiority design, and the difference was very small at 7.5 percentage points.¹³⁷ Thus, decisions should be made on an individual basis considering impact on quality of life and patient preference.¹³⁹

Patients with comorbidities and polypharmacy

Meta-analysis of 249 studies on comorbidities in MS identified depression, anxiety, hypertension, hypercholesterolemia, and chronic lung disease as the most prevalent comorbidities overall,¹⁴⁰ while the most prevalent autoimmune comorbidities were thyroid disease and psoriasis.¹⁴¹ Number of comorbidities may also impact the choice of MS DMT favoring GA.¹⁴² Patients with comorbid systemic autoimmune conditions may benefit from GA as a treatment option. Clinical trials investigating the potential benefit in other autoimmune disorders are not available. There is only a case series about nine patients with MS and systemic lupus erythematosus, two of whom were treated with GA and experienced no exacerbation of the lupus-associated symptoms.¹⁴³ In another case series, successful treatment of uveitis with GA was reported.¹⁴⁴

Administering DMTs for MS, together with symptomatic drugs and therapy for comorbid conditions can result in polypharmacy,^145,146 which has been shown to increase the risk of pharmacodynamic and pharmacokinetic drug–drug interactions in patients with MS.¹⁴⁷ Drug–drug interactions can cause side effects or alter the effectiveness of drugs, increasing the risk of treatment failure. In addition to toxicity, polypharmacy may be associated with a higher risk of falls in patients with MS, particularly in patients receiving anti-cholinergic agents,¹⁴⁸ as well as fatigue and cognitive impairment.¹⁴⁹ A useful strategy for avoiding this includes identifying potential interactions using a database (e.g., Hecker et al.¹⁵⁰), followed by elimination of unnecessary drugs and supplements, and considering alternative agents with lower potential for interaction, when possible.

Drug interactions involving GA do not appear to be well studied; however, results from clinical trials do not suggest significant interactions with therapies commonly used in MS patients, including concurrent corticosteroids for up to 1 month.^5,6

Use in pregnancy

Pregnancy is associated with reduced relapse rates and may be followed by a post-partum rebound of relapse frequency during the months after birth.^151–156 Safety during pregnancy is a critical issue for MS treatment with DMTs, because many of the patients are women of childbearing age. Treatment decisions around pregnancy must consider prior disease activity and whether a woman is receiving DMTs with a high risk of disease rebound after discontinuation.¹⁵⁷

For this reason, several database studies have assessed the safety of GA during pregnancy. Teva’s global pharmacovigilance database (n = 5042 pregnancies with known outcomes) revealed an incidence of congenital anomalies that was compatible with the expected rate based on large population studies.^158,159 A systematic review and meta-analysis of pregnancy and fetal outcomes in women receiving GA (or IFN or natalizumab) did not reveal an increase in the risk of spontaneous abortions, preterm birth, or major congenital malformations.¹⁶⁰ Meanwhile, analysis of data from the German Multiple Sclerosis and Pregnancy Registry also showed rates of such outcomes similar to those in the general population.¹⁶¹ Exposure to GA (20 or 40 mg formulations) throughout all three pregnancy trimesters was not associated with adverse pregnancy or infant outcomes.¹⁶²

In the Viatris database, 445 exposed pregnancies were reported. Common adverse outcomes related to pregnancy included 23 instances of (spontaneous) abortion, 7 preterm births, 3 ectopic pregnancies, 3 reports of vanishing twin syndrome, and 2 cases of oligohydramnios. Congenital malformations were reported in seven cases (1.6%); however, based on the nature of post-marketing data and the evidence available from these cases, it is not possible to determine if this incidence differs from that in unexposed pregnancies. Both originator and Viatris GA can be used in pregnancy.^6,66

Breastfeeding

Breastfeeding is advantageous for the infant and may be associated with a reduction in postpartum MS relapses¹⁶³; however, there are concerns about breastfeeding while receiving DMTs. Both originator GA and Viatris GA can be used during breastfeeding.^6,66 Data from the German MS and Pregnancy Registry did not reveal evidence of adverse effects of GA exposure during breastfeeding on infant development, hospitalization, or the use of antibiotics.^164–166 Maternal use of GA during breastfeeding did not adversely affect offspring safety outcomes assessed during the first 18 months of life. Published pharmacovigilance data on exposed pregnancies confirm the lack of adverse outcomes with originator GA during breastfeeding.¹⁵⁹

The use of Viatris GA during breastfeeding was reported in 60 cases in the Viatris database. Concurrent events reported were either injection site reactions or device or administration-related issues. No adverse events were identified in the infants that could be attributed to exposure to GA via breast milk. Currently, there are no regulatory restrictions on GA use while breastfeeding.^6,67

Patients at risk for infections and reactivation of latent infections

Individuals at increased risk of infections include those receiving immunosuppressive medications to prevent rejection of a transplanted organ, patients with HIV, oncology patients who receive chemotherapy or radiation therapy, and older adults experiencing immunosenescence. Infections contribute substantially to morbidity and mortality in MS.^108,167,168 Compared with the general population, people with MS have approximately twice the incidence of infections and infection-related hospitalizations,¹⁶⁹ most frequently involving the respiratory¹⁷⁰ and urinary tracts.¹⁷¹ Immunosuppressive therapies may further increase infection risk.¹⁷² All DMTs for MS, with the exception of IFNs and GA, can impair immune surveillance.^104,105

Patients with MS do not appear to be at higher risk of SARS-CoV-2 infection compared to healthy subjects¹⁷³; however, the rate of COVID-19 development in patients with MS is lower in those receiving GA (0.51%) or IFNs (0.61%), compared to other DMTs (p < 0.001 for both), whereas anti-CD20 therapies are associated with the highest risk (3.45%; p < 0.0001).¹⁷⁴ Pretreatment screening for latent infections is not required with GA.⁶

Conclusion

The many effective DMTs now available have improved the personalization of treatment for MS. Extensive clinical experience continues to demonstrate the enduring value of GA in the management of relapsing MS not requiring a highly effective DMT. Ease of management, good tolerability, and long-term safety data make GA an appropriate choice for diverse patient populations, including patients with comorbidities, breastfeeding individuals, older adults, and patients undergoing therapeutic de-escalation. A minimal impact on immune function makes GA a suitable option for MS patients at risk of infections, while compatibility with vaccinations ensures that essential immunizations will be effective. Localized injection site reactions, although common, do not typically lead to treatment discontinuation. More severe injection site events like lipoatrophy or necrosis are rare, and while there are reported cases of liver injury, their frequency remains low. Available evidence on product substitution from branded to FOGAs shows similar efficacy and safety reinforcing its position as a reliable and enduring therapeutic option for MS management.

Footnotes

Acknowledgements

Medical writing support was provided by Richard Vernell through Ethos srl, Rome, Italy, and funded by Viatris.

Declarations

ORCID iDs

Refik Pul

Jelena Skuljec

References

Bornstein

Miller

Teitelbaum

, et al. Multiple sclerosis: trial of a synthetic polypeptide. Ann Neurol 1982; 11: 317–319.

Johnson

Brooks

Cohen

, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995; 45: 1268–1276.

Johnson

Brooks

Cohen

, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 1998; 50: 701–708.

Comi

Filippi

Wolinsky

JS.

European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 2001; 49: 290–297.

Teva Neuroscience. Copaxone prescribing information, https://www.copaxone.com/globalassets/copaxone/prescribing-information.pdf (2023, accessed 30 May 2023).

Teva. Copaxone—summary of product characteristics. Electronic medicines compendium, https://www.medicines.org.uk/emc/product/183 (2022, accessed 11 October 2023).

Teitelbaum

Meshorer

Hirshfeld

, et al. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur J Immunol 1971; 1: 242–248.

Lalive

Neuhaus

Benkhoucha

, et al. Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action. CNS Drugs 2011; 25: 401–414.

Borchard

Crommelin

DJA

. Equivalence of glatiramer acetate products: challenges in assessing pharmaceutical equivalence and critical clinical performance attributes. Expert Opin Drug Deliv 2018; 15: 247–259.

10.

Rocco

Eberini

Musazzi

, et al. Glatiramer acetate: a complex drug beyond biologics. Eur J Pharm Sci 2019; 133: 8–14.

11.

Aharoni

Teitelbaum

Sela

, et al. Bystander suppression of experimental autoimmune encephalomyelitis by T cell lines and clones of the Th2 type induced by copolymer 1. J Neuroimmunol 1998; 91: 135–146.

12.

Haas

Korporal

Balint

, et al. Glatiramer acetate improves regulatory T-cell function by expansion of naive CD4(+)CD25(+)FOXP3(+)CD31(+) T-cells in patients with multiple sclerosis. J Neuroimmunol 2009; 216: 113–117.

13.

Aharoni

Eilam

Stock

, et al. Glatiramer acetate reduces Th-17 inflammation and induces regulatory T-cells in the CNS of mice with relapsing-remitting or chronic EAE. J Neuroimmunol 2010; 225: 100–111.

14.

Oreja-Guevara

Ramos-Cejudo

Aroeira

, et al. TH1/TH2 Cytokine profile in relapsing-remitting multiple sclerosis patients treated with Glatiramer acetate or Natalizumab. BMC Neurol 2012; 12: 95.

15.

Pul

Morbiducci

Škuljec

, et al. Glatiramer acetate increases phagocytic activity of human monocytes in vitro and in multiple sclerosis patients. PLoS One 2012; 7: e51867.

16.

Weber

Prod’homme

Youssef

, et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med 2007; 13: 935–943.

17.

Kuerten

Jackson

Kaye

, et al. Impact of glatiramer acetate on B cell-mediated pathogenesis of multiple sclerosis. CNS Drugs 2018; 32: 1039–1051.

18.

Sand

Knudsen

Rolin

, et al. Modulation of natural killer cell cytotoxicity and cytokine release by the drug glatiramer acetate. Cell Mol Life Sci 2009; 66: 1446–1456.

19.

Al-Falahi

Sand

Knudsen

, et al. Splenic natural killer cell activity in two models of experimental neurodegenerative diseases. J Cell Mol Med 2009; 13: 2693–2703.

20.

Høglund

Holmøy

Harbo

, et al. A one year follow-up study of natural killer and dendritic cells activities in multiple sclerosis patients receiving glatiramer acetate (GA). PLoS One 2013; 8: e62237.

21.

Maghazachi

Sand

Al-Jaderi

Glatiramer acetate, dimethyl fumarate, and monomethyl fumarate upregulate the expression of CCR10 on the surface of natural killer cells and enhance their chemotaxis and cytotoxicity. Front Immunol 2016; 7: 437.

22.

Sellner

Koczi

Harrer

, et al. Glatiramer acetate attenuates the pro-migratory profile of adhesion molecules on various immune cell subsets in multiple sclerosis. Clin Exp Immunol 2013; 173: 381–389.

23.

Amrouche

Pers

J-O

Jamin

Glatiramer acetate stimulates regulatory B cell functions. J Immunol 2019; 202: 1970–1980.

24.

Häusler

Hajiyeva

Traub

, et al. Glatiramer acetate immune modulates B-cell antigen presentation in treatment of MS. Neurol Neuroimmunol Neuroinflamm 2020; 7: e698.

25.

Jackson

DG.

Lymphatic regulation of cellular trafficking. J Clin Cell Immunol 2014; 5: 258.

26.

Carrieri

Carbone

Perna

, et al. Longitudinal assessment of immuno-metabolic parameters in multiple sclerosis patients during treatment with glatiramer acetate. Metabolism 2015; 64: 1112–1121.

27.

Sellebjerg

Hedegaard

Krakauer

, et al. Glatiramer acetate antibodies, gene expression and disease activity in multiple sclerosis. Mult Scler 2012; 18: 305–313.

28.

Harp

Ireland

Davis

, et al. Memory B cells from a subset of treatment-naïve relapsing-remitting multiple sclerosis patients elicit CD4(+) T-cell proliferation and IFN-γ production in response to myelin basic protein and myelin oligodendrocyte glycoprotein. Eur J Immunol 2010; 40: 2942–2956.

29.

Vieira

Heystek

Wormmeester

, et al. Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells. J Immunol 2003; 170: 4483–4488.

30.

Jung

Siglienti

Grauer

, et al. Induction of IL-10 in rat peritoneal macrophages and dendritic cells by glatiramer acetate. J Neuroimmunol 2004; 148: 63–73.

31.

Kim

Ifergan

Antel

, et al. Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J Immunol 2004; 172: 7144–7153.

32.

Weber

Starck

Wagenpfeil

, et al. Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain 2004; 127: 1370–1378.

33.

Burger

Molnarfi

Weber

, et al. Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1beta in human monocytes and multiple sclerosis. Proc Natl Acad Sci U S A 2009; 106: 4355–4359.

34.

Carpintero

Brandt

Gruaz

, et al. Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes. Proc Natl Acad Sci U S A 2010; 107: 17692–17697.

35.

Chabot

Yong

, et al. Cytokine production in T lymphocyte-microglia interaction is attenuated by glatiramer acetate: a mechanism for therapeutic efficacy in multiple sclerosis. Mult Scler 2002; 8: 299–306.

36.

Molnarfi

Prod’homme

Schulze-Topphoff

, et al. Glatiramer acetate treatment negatively regulates type I interferon signaling. Neurol Neuroimmunol Neuroinflamm 2015; 2: e179.

37.

Kasindi

Fuchs

D-T

Koronyo

, et al. Glatiramer acetate immunomodulation: evidence of neuroprotection and cognitive preservation. Cells 2022; 11: 1578.

38.

Aharoni

Arnon

Eilam

Neurogenesis and neuroprotection induced by peripheral immunomodulatory treatment of experimental autoimmune encephalomyelitis. J Neurosci 2005; 25: 8217–8228.

39.

Aharoni

Immunomodulation neuroprotection and remyelination—the fundamental therapeutic effects of glatiramer acetate: a critical review. J Autoimmun 2014; 54: 81–92.

40.

Arnon

Aharoni

Neurogenesis and neuroprotection in the CNS-fundamental elements in the effect of Glatiramer acetate on treatment of autoimmune neurological disorders. Mol Neurobiol 2007; 36: 245–253.

41.

Skihar

Silva

Chojnacki

, et al. Promoting oligodendrogenesis and myelin repair using the multiple sclerosis medication glatiramer acetate. Proc Natl Acad Sci U S A 2009; 106: 17992–17997.

42.

Gentile

Rossi

Studer

, et al. Glatiramer acetate protects against inflammatory synaptopathy in experimental autoimmune encephalomyelitis. J Neuroimmune Pharmacol 2013; 8: 651–663.

43.

Aharoni

Eilam

Lerner

, et al. Neuroprotective effect of glatiramer acetate on neurofilament light chain leakage and glutamate excess in an animal model of multiple sclerosis. Int J Mol Sci 2021; 22: 13419.

44.

Multiple Sclerosis International Federation. Atlas of MS—3rd Edition, https://www.atlasofms.org/chart/united-kingdom/disease-modifying-treatments/barriers-to-accessing-dmts (2023, accessed 29 July 2025).

45.

Moss

Cohen

JA.

The emergence of follow-on disease-modifying therapies for multiple sclerosis. Mult Scler 2019; 25: 1560–1565.

46.

Hartung

DM.

Economics of multiple sclerosis disease-modifying therapies in the USA. Curr Neurol Neurosci Rep 2021; 21: 28.

47.

Alton

Samuel

Reddi

Providing access to high-quality, low-cost medicines across low and middle-income countries (LMICs), working with governments and generic manufacturers around the globe—a business case. Antivir Ther 2022; 27: 13596535211068617.

48.

Greenberg

Giovannoni

A place for biosimilars in the changing multiple sclerosis treatment landscape. Mult Scler Relat Disord 2023; 77: 104841.

49.

Towfic

Funt

Fowler

, et al. Comparing the biological impact of glatiramer acetate with the biological impact of a generic. PLoS One 2014; 9: e83757.

50.

D’Alessandro

Duffner

Pradines

, et al. Equivalent Gene Expression Profiles between Glatopa™ and Copaxone^®. PLoS One 2015; 10: e0140299.

51.

Rogstad

Pang

Sommers

, et al. Modern analytics for synthetically derived complex drug substances: NMR, AFFF-MALS, and MS tests for glatiramer acetate. Anal Bioanal Chem 2015; 407: 8647–8659.

52.

D’

Alessandro J

Garofalo

Zhao

, et al. Demonstration of biological and immunological equivalence of a generic glatiramer acetate. CNS Neurol Disord Drug Targets 2017; 16: 714–723.

53.

Melamed-Gal

Loupe

Timan

, et al. Physicochemical, biological, functional and toxicological characterization of the European follow-on glatiramer acetate product as compared with Copaxone. eNeurologicalSci 2018; 12: 19–30.

54.

Arends

Wang

Buurman

, et al. Comparison of Copaxone® and Synthon’s therapeutically equivalent glatiramer acetate. Pharmazie 2019; 74: 449–461.

55.

Gaspar

Silva-Lima

Magro

, et al. Non-biological complex drugs (NBCDs): complex pharmaceuticals in need of individual robust clinical assessment before any therapeutic equivalence decision. Front Med (Lausanne) 2020; 7: 590527.

56.

Anderson

Bell

Bishop

, et al. Demonstration of equivalence of a generic glatiramer acetate (Glatopa™). J Neurol Sci 2015; 359: 24–34.

57.

Cohen

Belova

Selmaj

, et al. Equivalence of generic glatiramer acetate in multiple sclerosis: a randomized clinical trial. JAMA Neurol 2015; 72: 1433–1441.

58.

Selmaj

Barkhof

Belova

, et al. Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results. Mult Scler 2017; 23: 1909–1917.

59.

Varkony

Weinstein

Klinger

, et al. The glatiramoid class of immunomodulator drugs. Expert Opin Pharmacother 2009; 10: 657–668.

60.

Schellekens

Stegemann

Weinstein

, et al. How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider. AAPS J 2014; 16: 15–21.

61.

Hasson

Kolitz

Towfic

, et al. Functional effects of the antigen glatiramer acetate are complex and tightly associated with its composition. J Neuroimmunol 2016; 290: 84–95.

62.

Bakshi

Chalifa-Caspi

Plaschkes

, et al. Gene expression analysis reveals functional pathways of glatiramer acetate activation. Expert Opin Ther Targets 2013; 17: 351–362.

63.

Kolitz

Hasson

Towfic

, et al. Gene expression studies of a human monocyte cell line identify dissimilarities between differently manufactured glatiramoids. Sci Rep 2015; 5: 10191.

64.

Seok

Warren

Cuenca

, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013; 110(9): 3507–3512.

65.

Dutch Medicines Authority CBG. Public Assessment Report Scientific discussion Glatirameeracetaat Mylan 20 mg/ml, solution for injection (glatiramer acetate) NL/H/3213/001/DC, https://db.cbg-meb.nl/pars/h115993.pdf (2016).

66.

Viatris. Brabio 20 mg/mL—summary of product characteristics. Electronic Medicines Compendium, https://www.medicines.org.uk/emc/product/8536 (2022, accessed 11 October 2023).

67.

Viatris. Brabio 40 mg/mL—summary of product characteristics. Electronic Medicines Compendium, https://www.medicines.org.uk/emc/product/9181/smpc#gref (2022, accessed 11 October 2023).

68.

Annovazzi

Bertolotto

Brescia Morra

, et al. A comprehensive review on Copemyl®. Neurol Ther 2017; 6: 161–173.

69.

Bell

Anderson

Ganguly

, et al. Development of Glatopa® (Glatiramer Acetate): the first FDA-approved generic disease-modifying therapy for relapsing forms of multiple sclerosis. J Pharm Pract 2018; 31: 481–488.

70.

Klein

Stolk

De Bruin

, et al. The EU regulatory landscape of non-biological complex drugs (NBCDs) follow-on products: observations and recommendations. Eur J Pharm Sci 2019; 133: 228–235.

71.

Wynn

DR.

Enduring clinical value of Copaxone® (glatiramer acetate) in multiple sclerosis after 20 years of use. Mult Scler Int 2019; 2019: 7151685.

72.

Mirabella

Annovazzi

Brownlee

, et al. Treatment challenges in multiple sclerosis—a continued role for glatiramer acetate? Front Neurol 2022; 13: 844873.

73.

Ford

Goodman

Johnson

, et al. Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Mult Scler 2010; 16: 342–350.

74.

Ford

Cohen

Goodman

, et al. Early versus delayed treatment with glatiramer acetate: analysis of up to 27 years of continuous follow-up in a US open-label extension study. Mult Scler 2022; 28: 1729–1743.

75.

Abolfazli

Pournourmohammadi

Shamshiri

, et al. Tolerability and safety profile of a new brand-generic product of glatiramer acetate in iranian patients with relapsing-remitting multiple sclerosis: an observational cohort study. Curr Ther Res Clin Exp 2018; 88: 47–51.

76.

Balak

DMW

Hengstman

GJD

Çakmak

, et al. Cutaneous adverse events associated with disease-modifying treatment in multiple sclerosis: a systematic review. Mult Scler 2012; 18: 1705–1717.

77.

Ziemssen

Neuhaus

Hohlfeld

Risk-benefit assessment of glatiramer acetate in multiple sclerosis. Drug Saf 2001; 24: 979–990.

78.

Ziemssen

Ashtamker

Rubinchick

, et al. Long-term safety and tolerability of glatiramer acetate 20 mg/ml in the treatment of relapsing forms of multiple sclerosis. Expert Opin Drug Saf 2017; 16: 247–255.

79.

Wolinsky

Borresen

Dietrich

, et al. GLACIER: an open-label, randomized, multicenter study to assess the safety and tolerability of glatiramer acetate 40 mg three-times weekly versus 20 mg daily in patients with relapsing-remitting multiple sclerosis. Mult Scler Relat Disord 2015; 4: 370–376.

80.

European Medicines Agency. Direct Healthcare Professional Communication (DHPC) Glatiramer acetate: anaphylactic reactions may occur months up to years after treatment initiation, https://www.ema.europa.eu/en/documents/dhpc/direct-healthcare-professional-communication-dhpc-glatiramer-acetate-anaphylactic-reactions-may-occur-months-years-after-treatment-initiation_en.pdf (2024).

81.

Stovner

Hagen

Linde

, et al. The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. J Headache Pain 2022; 23: 34.

82.

Winkelmann

Loebermann

Reisinger

, et al. Multiple sclerosis treatment and infectious issues: update 2013. Clin Exp Immunol 2014; 175: 425–438.

83.

Meunier

Larrey

Hepatotoxicity of drugs used in multiple sclerosis, diagnostic challenge, and the role of HLA genotype susceptibility. Int J Mol Sci 2023; 24: 852.

84.

Deltenre

Peny

M-O

Dufour

, et al. Acute hepatitis induced by glatiramer acetate. BMJ Case Rep 2009; 2009: bcr09.2008.0913.

85.

Onmez

Eminler

Ergenç

, et al. Drug-induced liver injury by glatiramer acetate used for treatment of multiple sclerosis: a case report. J Investig Med High Impact Case Rep 2013; 1: 2324709613517493.

86.

Neumann

Csepregi

Sailer

, et al. Glatiramer acetate induced acute exacerbation of autoimmune hepatitis in a patient with multiple sclerosis. J Neurol 2007; 254: 816–817.

87.

Antezana

Herbert

Park

, et al. Glatiramer acetate-induced acute hepatotoxicity in an adolescent with MS. Neurology 2014; 82: 1846–1847.

88.

Subramaniam

Pavli

Llewellyn

, et al. Glatiramer acetate induced hepatotoxicity. Curr Drug Saf 2012; 7: 186–188.

89.

Flaire

Carra-Dalliere

Ayrignac

, et al. Glatiramer acetate-induced hepatitis in a patient with multiple sclerosis. Acta Neurol Belg 2016; 116: 99–100.

90.

La Gioia

Bacis

Sonzogni

, et al. Glatiramer acetate-induced hepatitis in a young female patient with multiple sclerosis. Mult Scler Relat Disord 2014; 3: 732–734.

91.

Makhani

Ngan

Kamath

, et al. Glatiramer acetate-induced acute hepatotoxicity in an adolescent with MS. Neurology 2013; 81: 850–852.

92.

Fernández

Fernández N

Joao

Matias D

Pisabarros

Blanco C

, et al. [Hepatitis induced by glatiramer acetate]. Gastroenterol Hepatol 2015; 38: 280–281.

93.

Sinagra

Raimondo

Cottone

, et al. Does glatiramer acetate provoke hepatitis in multiple sclerosis? Mult Scler Relat Disord 2014; 3: 266–268.

94.

Almeida

Solà-Valls

Pose

, et al. Liver injury and glatiramer acetate, an uncommon association: case report and literature review. Ther Adv Neurol Disord 2017; 10: 367–372.

95.

Arruti

Castillo-Triviño

de la Riva

, et al. [Autoimmune hepatitis in a patient with multiple sclerosis under treatment with glatiramer acetate]. Rev Neurol 2012; 55: 190–192.

96.

von Kalckreuth

Lohse

Schramm

Unmasking autoimmune hepatitis under immunomodulatory treatment of multiple sclerosis—not only beta interferon. Am J Gastroenterol 2008; 103: 2147–2148; author reply 2148.

97.

Michels

Zizer

Barth

, et al. Drug-induced liver injury associated with the biosimilar glatiramer acetate (Clift®). Mult Scler Relat Disord 2020; 40: 101948.

98.

Villani

Serviddio

Avolio

, et al. Autoimmune liver disease and multiple sclerosis: state of the art and future perspectives. Clin Exp Med. 2023; 23(7): 3321–3338.

99.

Tsouris

Liaskos

Dardiotis

, et al. A comprehensive analysis of antigen-specific autoimmune liver disease related autoantibodies in patients with multiple sclerosis. Auto Immun Highlights 2020; 11: 7.

100.

Björnsson

Hoofnagle

JH.

Categorization of drugs implicated in causing liver injury: critical assessment based on published case reports. Hepatology 2016; 63: 590–603.

101.

Biolato

Bianco

Lucchini

, et al. The disease-modifying therapies of relapsing-remitting multiple sclerosis and liver injury: a narrative review. CNS Drugs 2021; 35: 861–880.

102.

US Food and Drug Administration. FDA adverse event reporting system, https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-latest-quarterly-data-files (2023, accessed 29 July 2025).

103.

Antonazzo

Poluzzi

Forcesi

, et al. Liver injury with drugs used for multiple sclerosis: a contemporary analysis of the FDA Adverse Event Reporting System. Mult Scler 2019; 25: 1633–1640.

104.

Wijnands

JMA

Zhu

Kingwell

, et al. Disease-modifying drugs for multiple sclerosis and infection risk: a cohort study. J Neurol Neurosurg Psychiatry 2018; 89: 1050–1056.

105.

Luna

Alping

Burman

, et al. Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies. JAMA Neurol 2020; 77: 184–191.

106.

Tur

Dubessy

A-L

Otero-Romero

, et al. The risk of infections for multiple sclerosis and neuromyelitis optica spectrum disorder disease-modifying treatments: Eighth European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop Review. April 2021. Mult Scler 2022; 28: 1424–1456.

107.

Ireland

Guzman

O’Brien

, et al. The effect of glatiramer acetate therapy on functional properties of B cells from patients with relapsing-remitting multiple sclerosis. JAMA Neurol 2014; 71: 1421–1428.

108.

Winkelmann

Loebermann

Reisinger

, et al. Disease-modifying therapies and infectious risks in multiple sclerosis. Nat Rev Neurol 2016; 12: 217–233.

109.

Cortese

Reich

Nath

Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease. Nat Rev Neurol 2021; 17: 37–51.

110.

Berger

JR.

Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord 2017; 12: 59–63.

111.

Perrillo

Gish

Falck-Ytter

YT.

American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015; 148: 221-244.e3.

112.

Celius

EG.

Infections in patients with multiple sclerosis: implications for disease-modifying therapy. Acta Neurol Scand 2017; 136 Suppl: 34–36.

113.

Kappos

Mehling

Arroyo

, et al. Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis. Neurology 2015; 84: 872–879.

114.

Bar-Or

Calkwood

Chognot

, et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: the VELOCE study. Neurology 2020; 95: e1999–e2008.

115.

Reyes

Ramsay

Ladhani

, et al. Protecting people with multiple sclerosis through vaccination. Pract Neurol 2020; 20: 435–445.

116.

Xie

Tian

Han

, et al. Factors associated with relapses in relapsing-remitting multiple sclerosis: a systematic review and meta-analysis. Medicine (Baltimore) 2020; 99: e20885.

117.

Krbot Skorić

Rogić

Lapić

, et al. Humoral immune response to COVID-19 vaccines in people with secondary progressive multiple sclerosis treated with siponimod. Mult Scler Relat Disord 2022; 57: 103435.

118.

Farez

Correale

Armstrong

, et al. Practice guideline update summary: vaccine-preventable infections and immunization in multiple sclerosis: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2019; 93: 584–594.

119.

Otero-Romero

Lebrun-Frénay

Reyes

, et al. ECTRIMS/EAN consensus on vaccination in people with multiple sclerosis: improving immunization strategies in the era of highly active immunotherapeutic drugs. Mult Scler 2023; 29: 904–925.

120.

Olberg

Eide

Cox

, et al. Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy. Eur J Neurol 2018; 25: 527–534.

121.

Metze

Winkelmann

Loebermann

, et al. Immunogenicity and predictors of response to a single dose trivalent seasonal influenza vaccine in multiple sclerosis patients receiving disease-modifying therapies. CNS Neurosci Ther 2019; 25: 245–254.

122.

Winkelmann

Metze

Frimmel

, et al. Tick-borne encephalitis vaccination in multiple sclerosis: a prospective, multicenter study. Neurol Neuroimmunol Neuroinflamm 2020; 7: e664.

123.

Sabatino

Mittl

Rowles

, et al. Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine-induced antibody and T cell immunity and function. JCI Insight 2022; 7: e156978.

124.

Jalusic

Ellenberger

Rommer

, et al. Effect of applying inclusion and exclusion criteria of phase III clinical trials to multiple sclerosis patients in routine clinical care. Mult Scler 2021; 27: 1852–1863.

125.

Schweitzer

Laurent

Fink

, et al. Age and the risks of high-efficacy disease modifying drugs in multiple sclerosis. Curr Opin Neurol 2019; 32: 305–312.

126.

Marrie

Blanchard

, et al. The rising prevalence and changing age distribution of multiple sclerosis in Manitoba. Neurology 2010; 74: 465–471.

127.

Solaro

Ponzio

Moran

, et al. The changing face of multiple sclerosis: Prevalence and incidence in an aging population. Mult Scler 2015; 21: 1244–1250.

128.

Wallin

Culpepper

Campbell

, et al. The prevalence of MS in the United States: A population-based estimate using health claims data. Neurology 2019; 92: e1029–e1040.

129.

Tremlett

Zhao

Joseph

, et al. Relapses in multiple sclerosis are age- and time-dependent. J Neurol Neurosurg Psychiatry 2008; 79: 1368–1374.

130.

Coerver

Janssens

Ahmed

, et al. Association between age and inflammatory disease activity on magnetic resonance imaging in relapse onset multiple sclerosis during long-term follow-up. Eur J Neurol 2023; 30: 2385–2392.

131.

Strijbis

Coerver

Mostert

, et al. Association of age and inflammatory disease activity in the pivotal natalizumab clinical trials in relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 2023; 94(10): 792–799.

132.

Vollmer

Wolf

Sillau

, et al. Evolution of disease modifying therapy benefits and risks: an argument for de-escalation as a treatment paradigm for patients with multiple sclerosis. Front Neurol 2021; 12: 799138.

133.

Marrie

Elliott

Marriott

, et al. Comorbidity increases the risk of hospitalizations in multiple sclerosis. Neurology 2015; 84: 350–358.

134.

Zhang

Tremlett

Zhu

, et al. Effects of physical comorbidities on disability progression in multiple sclerosis. Neurology 2018; 90: e419–e427.

135.

Weideman

Tapia-Maltos

Johnson

, et al. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol 2017; 8: 577.

136.

McGinley

Cola

Fox

, et al. Perspectives of individuals with multiple sclerosis on discontinuation of disease-modifying therapies. Mult Scler 2020; 26: 1581–1589.

137.

Corboy

Fox

Kister

, et al. Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial. Lancet Neurol 2023; 22: 568–577.

138.

Coerver

Fung

de Beukelaar

, et al Discontinuation of first-line disease-modifying therapy in stable multiple sclerosis (DOT-MS): an early-terminated multicenter randomized controlled trial. Abstract Number: 1281/O099. ECTRIMS-ACTRIMS. Milan, https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.congrex/abstracts_ectrims2023/146784.pdf (2023, accessed 29 July 2025).

139.

Manzano

Eskyté

Ford

, et al. Patient perspective on decisions to switch disease-modifying treatments in relapsing-remitting multiple sclerosis. Mult Scler Relat Disord 2020; 46: 102507.

140.

Marrie

Cohen

Stuve

, et al. A systematic review of the incidence and prevalence of comorbidity in multiple sclerosis: overview. Mult Scler 2015; 21: 263–281.

141.

Marrie

Reider

Cohen

, et al. A systematic review of the incidence and prevalence of autoimmune disease in multiple sclerosis. Mult Scler 2015; 21: 282–293.

142.

Zhang

Tremlett

Leung

, et al. Examining the effects of comorbidities on disease-modifying therapy use in multiple sclerosis. Neurology 2016; 86: 1287–1295.

143.

Fanouriakis

Mastorodemos

Pamfil

, et al. Coexistence of systemic lupus erythematosus and multiple sclerosis: prevalence, clinical characteristics, and natural history. Semin Arthritis Rheum 2014; 43: 751–758.

144.

Velazquez-Villoria

Macia-Badia

Segura-García

, et al. Efficacy of immunomodulatory therapy with interferon-β or glatiramer acetate on multiple sclerosis-associated uveitis. Arch Soc Esp Oftalmol 2017; 92: 273–279.

145.

Frahm

Hecker

Zettl

UK.

Polypharmacy among patients with multiple sclerosis: a qualitative systematic review. Expert Opin Drug Saf 2020; 19: 139–145.

146.

Chertcoff

Zhu

, et al. Polypharmacy and multiple sclerosis: a population-based study. Mult Scler 2023; 29: 107–118.

147.

Bachmann

Frahm

Debus

, et al. Prevalence and severity of potential drug-drug interactions in patients with multiple sclerosis with and without polypharmacy. Pharmaceutics 2022; 14: 592.

148.

Cameron

Karstens

Hoang

, et al. Medications are associated with falls in people with multiple sclerosis: a prospective cohort study. Int J MS Care 2015; 17: 207–214.

149.

Thelen

Lynch

Bruce

, et al. Polypharmacy in multiple sclerosis: relationship with fatigue, perceived cognition, and objective cognitive performance. J Psychosom Res 2014; 76: 400–404.

150.

Hecker

Frahm

Bachmann

, et al. Screening for severe drug-drug interactions in patients with multiple sclerosis: a comparison of three drug interaction databases. Front Pharmacol 2022; 13: 946351.

151.

Confavreux

Hutchinson

Hours

, et al. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 1998; 339: 285–291.

152.

Alroughani

Alowayesh

Ahmed

, et al. Relapse occurrence in women with multiple sclerosis during pregnancy in the new treatment era. Neurology 2018; 90: e840–e846.

153.

Dobson

Jokubaitis

Giovannoni

Change in pregnancy-associated multiple sclerosis relapse rates over time: a meta-analysis. Mult Scler Relat Disord 2020; 44: 102241.

154.

Hellwig

Verdun

Cantogno

Sabidó

A systematic review of relapse rates during pregnancy and postpartum in patients with relapsing multiple sclerosis. Ther Adv Neurol Disord 2021; 14: 17562864211051012.

155.

Lorefice

Fronza

Fenu

, et al. Effects of pregnancy and breastfeeding on clinical outcomes and MRI measurements of women with multiple sclerosis: an exploratory real-world cohort study. Neurol Ther 2022; 11: 39–49.

156.

Schubert

Steinberg

Peper

, et al. Postpartum relapse risk in multiple sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2023; 94: 718–725.

157.

Krysko

Dobson

Alroughani

, et al. Family planning considerations in people with multiple sclerosis. Lancet Neurol 2023; 22: 350–366.

158.

Sandberg-Wollheim

Neudorfer

Grinspan

, et al. Pregnancy outcomes from the branded glatiramer acetate pregnancy database. Int J MS Care 2018; 20: 9–14.

159.

Kaplan

Zeygarnik

Stern

Pregnancy, fetal, and infant outcomes following maternal exposure to glatiramer acetate during pregnancy and breastfeeding. Drug Saf 2022; 45: 345–357.

160.

Lopez-Leon

Geissbühler

Sabidó

, et al. A systematic review and meta-analyses of pregnancy and fetal outcomes in women with multiple sclerosis: a contribution from the IMI2 ConcePTION project. J Neurol 2020; 267: 2721–2731.

161.

Thiel

Ciplea

Gold

, et al. The German Multiple Sclerosis and Pregnancy Registry: rationale, objective, design, and first results. Ther Adv Neurol Disord 2021; 14: 17562864211054956.

162.

Kaplan

Zeygarnik

Stern

, et al. Pregnancy and fetal outcomes following maternal exposure to glatiramer acetate in all three trimesters of pregnancy. Eur J Neurol 2023; 30(12): 3890–3895.

163.

Krysko

Rutatangwa

Graves

, et al. Association between breastfeeding and postpartum multiple sclerosis relapses: a systematic review and meta-analysis. JAMA Neurol 2020; 77: 327–338.

164.

Ciplea

Langer-Gould

Stahl

, et al. Safety of potential breast milk exposure to IFN-β or glatiramer acetate: one-year infant outcomes. Neurol Neuroimmunol Neuroinflamm 2020; 7: e757.

165.

Ciplea

Kurzeja

Thiel

, et al. Eighteen-month safety analysis of offspring breastfed by mothers receiving glatiramer acetate therapy for relapsing multiple sclerosis—COBRA study. Mult Scler 2022; 28: 1641–1650.

166.

Ciplea

Kurzeja

Thiel

, et al. Safety evaluations of offspring breastfed by mothers receiving glatiramer acetate for relapsing multiple sclerosis. Mult Scler Relat Disord 2023; 75: 104771.

167.

Kingwell

Zhu

Evans

, et al. Causes that contribute to the excess mortality risk in multiple sclerosis: a population-based study. Neuroepidemiology 2020; 54: 131–139.

168.

Harding

Zhu

Alotaibi

, et al. Multiple cause of death analysis in multiple sclerosis: a population-based study. Neurology 2020; 94: e820–e829.

169.

Persson

Lee

Ulcickasv Yood

, et al. Infections in patients diagnosed with multiple sclerosis: a multi-database study. Mult Scler Relat Disord 2020; 41: 101982.

170.

Knapp

Hardtstock

Krieger

, et al. Serious infections in patients with relapsing and progressive forms of multiple sclerosis: a German claims data study. Mult Scler Relat Disord 2022; 68: 104245.

171.

Medeiros Junior

WLG de

Demore

Mazaro

, et al. Urinary tract infection in patients with multiple sclerosis: an overview. Mult Scler Relat Disord 2020; 46: 102462.

172.

Lechner-Scott

Waubant

Levy

, et al. Is multiple sclerosis a risk factor for infections? Mult Scler Relat Disord 2020; 41: 102184.

173.

Richter

Faissner

Bartig

, et al. Multiple sclerosis is not associated with an increased risk for severe COVID-19: a nationwide retrospective cross-sectional study from Germany. Neurol Res Pract 2021; 3: 42.

174.

Reder

Centonze

Naylor

, et al. COVID-19 in patients with multiple sclerosis: associations with disease-modifying therapies. CNS Drugs 2021; 35: 317–330.