Immunoglobulins (IgG) are fractionated blood products derived from pooled human plasma of over a thousand healthy blood donors. The end products are composed of mainly immunoglobulin G (IgG) molecules (>90%), traces of other immunoglobulins, and excipients such as stabilizers and sodium (Abolhassani et al., 2015). The FDA has approved various preparations of immunoglobulin which can be administered either through intravenous, subcutaneous, or intramuscular. The intramuscular (IM) administration of IgG is uncommon, and the only product available in the market that can be given as IM is GamaSTAN, that is used as post-exposure prophylaxis for measles, hepatitis A, varicella, and rubella. The intravenous and subcutaneous formulation is usually given as IgG replacement, anti-inflammatory and immunomodulatory therapy. Although the subcutaneous is gaining popularity, the intravenous route of administering IgG is still the most common mode of IgG replacement therapy (Abolhassani et al., 2015).

The intravenous immunoglobulin (IVIG) was initially indicated for treating primary immunodeficiencies (PI) (Bruton, 1952; Abolhassani et al., 2015). Upon recognizing the anti-inflammatory and immunoregulatory properties of IgG, it has become an important treatment option for a range of autoimmune and acute inflammatory diseases with various success levels (Perez et al., 2017). There are presently more than 150 off-label uses of IVIG (Leong et al., 2008) and the usage is expected to continue growing. Common examples of off-label uses of IVIG which are supported by other guidelines but not FDA approved include neurological conditions such as Guillain-Barre Syndrome and myasthenia gravis as well as dermatological conditions such as toxic epidermal necrolysis (Department of Health, 2011; Jurisdictional Blood Committee, 2012; Prairie Collaborative, 2018). Despite insufficient evidence, the use of IVIG for off-label indications is commonly practiced by physicians worldwide (Dawoud et al., 2012; Tonkovic and Rutishauser, 2014; Shemer et al., 2018; Rezaie et al., 2019).

The supply of IVIG is limited because the products are derived from human plasma. Malaysia has a national policy for self-sufficiency in blood-derived therapies which is based on voluntary non-remunerated blood donation. Annually, approximately 80,000 packs of blood are sent to the Commonwealth Serum Laboratory (CSL), Australia for fractionation under the national fractionation contract (Burnouf, 2011; Isahak, 2021). However, the collection of immunoglobulin G is insufficient, thus most of the IVIG products are obtain from the global commercial market (Burnouf, 2011; Isahak, 2021). Scarcity remains the major concern regarding the increasing usage of IVIG for off-label indications, unlike the usual concern of drug safety in off-label use of medicine. For instance, a 9-year retrospective study conducted in Israel from 2007 to 2015 showed increased rates of 185 and 417% in the total number of patients treated with IVIG and the amount (in grams) of IVIG administered, respectively (Shemer et al., 2018). In Taiwan, a 10-years population study from 2008 to 2017 reflected an average of 10% per year increase in the distribution of IVIG (Hsu et al., 2021). Major worldwide shortages were noted in the late 1990s, whereby the demand for IVIG exceeded the supply by 20% in 1997 and by 30% in 1998 (Boulis et al., 2002). These events have impacted patients negatively, especially those who need it the most. In 2019, the United States was again faced with insufficient supply of IVIG, resulting in local shortages and rationing (HartmannGoogle, 2020). Additional tension on global plasma supply was introduced by the coronavirus disease 2019 (COVID-19) pandemic. The unprecedented global health crisis has not only resulted in a reduction in donor pool (Hartmann and Klein, 2020), but the demand has also increased due to the use of IVIG as an off-label adjunctive treatment for COVID-19 infection (Herth et al., 2020; Nguyen et al., 2020; Shao et al., 2020) and vaccine-induced thrombotic thrombocytopenia (VITT) caused by adenovirus-vectored COVID-19 vaccines (Bourguignon et al., 2021; Guetl et al., 2021; Karnam et al., 2021; Thaler et al., 2021).

Two formulations of the IgG approved for use in Malaysia are the intravenous immunoglobulin (IVIG) and the subcutaneous immunoglobulin (SCIG). However, the IVIG is the most common formulation used. Hospitals in Malaysia have started using IVIG in 1986 for the treatment of PI (Lokman et al., 1988). Since then, the demand has increased over the years because it is used as a primary or adjunct treatment in various conditions (Toh et al., 2014). Unlike countries such as Australia, Canada, and the United Kingdom which have clear prescribing guidelines and priority protocols for the supply of IVIG (Department of Health, 2011; Jurisdictional Blood Committee, 2012; Prairie Collaborative, 2018), most Malaysian hospitals do not have specific guidelines for IVIG use. The Malaysian Ministry of Health Medicines Formulary briefly states the approved indications and doses (Program Perkhidmatan Farmasi, 2021). Therefore, IVIG could potentially be overused for indications that are not well supported by recent evidence. This practice will lead to an increase in unnecessary healthcare costs to the country. Due to the increasing demand, limited availability, inadequate funding, and frequent interruptions of global plasma supply (Ruiz-Antorán et al., 2010), health care institutions are strongly advised to monitor the usage of IVIG and to reserve supplies for those with the utmost clinical need. Therefore, this study aims to evaluate the prescribing practices of IVIG in order to propose suitable approaches to regulate and to advocate its rational use in Malaysia.

A total of 348 prescriptions were given to 240 patients, with 31 of them receiving more than one course of IVIG treatment during the 1-year period. Patients who repeated the course of IVIG were for the treatment of PI (n = 7), ITP (n = 6), post-operative sepsis in children (n = 5), sepsis in children (n = 3), Kawasaki disease (n = 2), GBS (n = 2), SLE (n = 2), myasthenia gravis in crisis (n = 2), and autoimmune anti-NMDA encephalitis (n = 2). Patients’ age was not normally distributed with a median (Interquartile range, Q1 to Q3) of 5.08 years (2 months–46 years old) and ranging from 1 day old to 76 years old. Two types of IVIG preparations were used, 2.5g/50 ml (5%) and 3.0g/50 ml (6%). No adverse drug reaction was documented in this study. The total expenditure of IVIG for the year 2019 for both hospitals was MYR 3,698,529 (885,218 USD) for 15,652.5 g used. This gives an average of 50 g of IVIG used per prescription. The summarized data of included prescriptions is presented in Table 1.

The highest usage of IVIG was for neurological conditions (7,499.5 g, 47.9%), followed by immunological conditions (4,303 g, 27.5%) and hematological conditions (3,132 g, 20%) (Figure 1). Neurological conditions included Guillain-Barre syndrome (GBS), myasthenia gravis, autoimmune encephalitis, and chronic inflammatory demyelinating polyneuropathy (CIDP); immunological conditions included primary immunodeficiencies (PI), systemic lupus erythematosus (SLE), Kawasaki disease, and prevention of acute graft-versus-host disease (GVHD) whereas immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) were among the hematological conditions.

The data described in this study reflect the patterns of IVIG used in two government tertiary care hospitals in Malaysia. A total of MYR 3.7 million (885,220 USD) was spent in the two hospitals for IVIG used for treating various conditions. The array of indications reflects the growing list of indications for which IVIG is currently approved. The leading groups of conditions using a high amount of IVIG were diseases of the nervous, immune, and circulatory systems. These findings are consistent with the reports from other studies (Pendergrast et al., 2005; Constantine et al., 2007; Lin et al., 2007).

The findings revealed that more than half of the prescriptions for IVIG (57.5%) were for FDA off-label indications. Similar prescribing pattern studies have been conducted in several countries and the prevalence of prescriptions with off-label indications of IVIG ranged from 22.7 to 70.3% (Rezaie et al., 2019; Tonkovic and Rutishauser, 2014; Toh et al., 2014; Ruiz-Antorán et al., 2010; Constantine et al., 2007; Pendergrast et al., 2005; El Ajez et al., 2019) (Supplementary Table S3). Likewise, the prevalence of patients being prescribed with IVIG for an off-label indication ranged from 23.2 to 81.5% (Chen et al., 2000; Pendergrast et al., 2005; Dawoud et al., 2012; Wu et al., 2013; Fakhari et al., 2018; Rezaie et al., 2019). The wide range could be due to different categorization or interpretation of off-labels, study periods, or duration of data collection, as licensing of an indication may change over time with the availability of more studies supporting its use. The prevalence and common off-label uses of IVIG that were reported in other studies is tabulated in Supplementary Table S3.

Prescriptions written for PI were the most frequent licensed indications in this study. This is expected as these patients are required to receive life-long IVIG at replacement doses of 0.3–0.8 g/kg, every three to 4 weeks. Moreover, IVIG is the first line and the only treatment option for PI, and its administration is generally recommended to maintain serum IgG levels above 500 mg/dl (Behring, 2016; Perez et al., 2017). Nevertheless, the total usage of IVIG per year for PI patients who were on regular three to four weekly doses was lower in this study compared to patients with GBS, ITP, and myasthenia gravis. These latter conditions require a one-off and a single course of high doses immunoglobulin of up to 2 g/kg for its immunomodulatory and anti-inflammatory effects (Behring, 2016; Perez et al., 2017).

IVIG has become an effective standard of care treatment for many off-label indications that are supported by many good clinical evidence (Perez et al., 2017). For instance, the use of IVIG in GBS and myasthenia gravis in crisis or before surgery is supported since both have a level of evidence and strength of recommendation of Ib (B) (Perez et al., 2017). The use of IVIG in GBS and myasthenia gravis have always been compared to the use of plasma exchange. In GBS, IVIG is labeled as ‘definite beneficial’ and its usage is supported by two large randomized controlled trials showing comparable efficacies to plasma exchange (van der Meché et al., 1992; Plasma Exchange/Sandoglobulin Guillain-Barre Syndrome Trial Group, 1997) and it is a well-recognized indication in many countries (Jurisdictional Blood Committee, 2012; European Medicines Agency, 2018; Prairie Collaborative, 2018; NHS England Immunoglobulin Policy Working Group, 2019). In myasthenic crises, IVIG was considered as a ‘possible benefit’ as its use is supported by two small randomized controlled trials (Gajdos et al., 1997; Barth et al., 2017). A recent meta-analysis indicated a higher response rate in plasma exchange compared to IVIG in patients with acute myasthenia gravis and those undergoing thymectomy (Ipe et al., 2021). In both conditions, IVIG is reported to be used more frequently compared to plasma exchange as it is more easily available in hospitals (Barth et al., 2017; Perez et al., 2017).

In this study, off-label indications where IVIG was unlikely to provide benefits comprised of neonatal sepsis, post-operative sepsis in children, and sepsis in children (Ohlsson and Lacy, 2020; Weiss et al., 2020). The reason for the high usage in these conditions could be due to the “desperate use” of IVIG, whereby a clinician tries to rescue a seriously-ill patient who has limited available treatment options despite the low benefit of the intervention compared to treatment costs (Pendergrast et al., 2005). In these circumstances, IVIG could be an appealing treatment option as it is relatively well-tolerated, despite insufficient evidence to support its use (Pendergrast et al., 2005; Perez et al., 2017).

The factors associated with the use of IVIG for off-label indications in this study were increasing age and those admitted to the critical care units. These results corroborate the findings by (Fakhari et al., 2018), whereby older age patients were more likely to receive IVIG for an off-labeled indication. Noticeably, the studies of IVIG utilization conducted for pediatric usage were mostly for FDA-licensed indications (Wu et al., 2013; Aydin and Tanır, 2017; El Ajez et al., 2019). It appears that IVIG is more likely to be tested out for new indications in adult diseases. In a critical care setting, IVIG may be used as the final therapeutic option in critically ill patients. Therefore, physicians are likely to prescribe IVIG even when the evidence to support its use is insufficient (Pendergrast et al., 2005). This observation was supported by a retrospective evaluation of IVIG use in medical ICU, whereby the investigators demonstrated that, of the six million US dollars spent over the 8 years for IVIG use, one-third of the cost was used in indications that have low-quality of evidence (Torbic et al., 2021). This could explain the high usage of IVIG for an off-label indication in critical care units.

The identification of predictors for use of IVIG in off-label indications is important when performing inventory rationing, especially where the supply of IVIG is limited. Such a situation could arise due to various reasons, such as product recall concerning quality issues, lack of raw materials, increase in demand, or a sudden halt in production (Shukar et al., 2021). A recent threat to shortages of IVIG supply occurred during the ongoing COVID-19 pandemic characterized by an increase in demand but a decrease in plasma donation, thereby resulting in limited availability of starting material (Hartmann and Klein, 2020). These factors should be considered the focus area when planning appropriate intervention to reduce the usage of IVIG for off-label indications. Justification of IVIG use needs to be considered on a case basis and prioritizing its supply to the patients who needed it most.

In this study, the IVIG doses prescribed were appropriate for most prescriptions. The majority of prescribed doses were rounded to the nearest vial size available to avoid wastage, as recommended by many guidelines (Department of Health, 2011; Stump et al., 2017). In cases lacking in dose recommendation or doses that differed from the recommendation, the doses could likely be obtained from other guidelines or case studies. For instance, the dose of 0.4 g/kg was available in the Centers for Disease Control and Prevention (CDC) guidelines in the case of post-exposure prophylaxis of measles (Centers for Disease Control and Prevention, 20132013). Factors associated with inappropriate dosing of IVIG were negatively correlated with age and those admitted to the critical care units. From the existing literature, no information was found about the factors related to inappropriate dosing of IVIG. The lack of research in children and critically-ill patients could be a possible reason for the lack of dosing information. Therefore, closer monitoring of treatment efficacy and adverse drug reaction is required in these groups of patients.

IVIG is generally considered as well-tolerated with the majority of adverse events reported to be infusion-related reactions (Guo et al., 2018). Moreover, these infusion-related reactions have been significantly reduced in the past 2 decades due to the improved manufacturing processes (Wood et al., 2007) and refined administration protocol (Aghamohammadi et al., 2004). In the literature, the reported rates of adverse drug reactions differed between studies and ranged from 3.8 to 6.1% of total administrations (Toh et al., 2014; Güngör and Yarali, 2020). In this study, no adverse drug reactions were documented in the medical records. This might be attributed to the slow infusion rates given as per administration protocol and the concurrent medication such as paracetamol, aspirin, and steroids that was given for the underlying medical condition might have masked the adverse reactions.

Given the high usage and cost of IVIG for off-label indications, specific guidelines for the clinical use of IVIG and an approval system for IVIG prescription are required. The health systems in several countries have taken the necessary step by implementing evidence-based guidelines with priority protocols for IVIG use (Boulis et al., 2002; Department of Health, 2008; Jurisdictional Blood Committee, 2012; Prairie Collaborative, 2018). A reduction of off-label uses of IVIG was observed after the implementation of these strategies (Constantine et al., 2007). Optimization of IVIG usage through establishing priorities is vital, especially during shortages. Such a procedure will protect the supply for those with utmost clinical need, where no alternative treatments are available, such as for the treatment of patients with PI (Meyts et al., 2020; Nordin et al., 2021). In 2018, an advocacy white paper entitled “A hidden health threat–Expert Recommendations for Better Management of Primary Immunodeficiency (PID) in Malaysia” developed by the Malaysian Patient Organisation for Primary Immunodeficiencies (MyPOPI) and Malaysian Society of Allergy and Immunology (MSAI) was presented to the Ministry of Health Malaysia. One of the highlighted pleas was for the stakeholders to ensure an uninterrupted supply of immunoglobulin replacement therapy for all PI patients (Paediatrics, 2021). This would further support the call for the development of a proper guideline of IVIG use in the country. Apart from the guidelines, the use of prior authorization or IVIG request form (Constantine et al., 2007; Tonkovic and Rutishauser, 2014) and IVIG stewardship program (Rocchio et al., 2017) are other ways of managing IVIG use. These strategies have been shown to decrease the inappropriate use of IVIG (Constantine et al., 2007; Rocchio et al., 2017). Recommendation for future work include a national survey evaluating the prescribing pattern of IVIG, as it would give better representation of its utilization in Malaysia. This is necessary for the development of national guideline on IVIG use. A steering committee consisting of experts from related fields would then establish a list of prioritization to ensure judicious use of IVIG in hospitals.

The limitations of this study are well-acknowledged. Only two public hospitals were involved in the data collection, thus the findings may not be representative of all hospitals in Malaysia, especially in the private setting. In addition, the assessment of evidence level was solely based on the most possible indication targeted by IVIG treatment and the disease complexity and severity were not considered. Furthermore, this study was conducted during the pre-COVID-19 period, hence the use in COVID-19 related illnesses was not captured. Nonetheless, this study provides useful insights on IVIG utilization patterns in hospitals, for which the data could be used for developing suitable approaches to optimize IVIG use in Malaysia.

This study characterized the prescribing pattern of IVIG in two tertiary care hospitals in Malaysia. The two hospitals spent a total of MYR 3.7 million (885,220 USD) for IVIG used in various medical conditions. A high percentage of IVIG usage for off-label indications that lacked strong clinical evidence was observed. Most of the prescribed IVIG doses were appropriate while those with inappropriate doses were for indications lacking adequate clinical evidence. Admission to the critical care units and older patients were identified as risk factors for inappropriate use of IVIG, whereas admission to the critical units and younger patients were the risk factors for receiving inappropriate doses of IVIG. This group of patients requires more attention because they are likely to contribute to irrational use of IVIG. This study advocates the need for the development and implementation of evidence-based clinical guidelines with prioritization protocol to ensure rational use of IVIG in Malaysia. More research is also needed to establish therapeutic benefit that is lacking for several indications.