Expert Opinion on Biological Therapy
ISSN: 1471-2598 (Print) 1744-7682 (Online) Journal homepage: http://www.tandfonline.com/loi/iebt20
Occupational health and safety of anti-tumour necrosis factor alpha monoclonal antibodies with casual exposure Jeff Chang MBBS FRACP & Rupert WL Leong MBBS FRACP MD AGAF To cite this article: Jeff Chang MBBS FRACP & Rupert WL Leong MBBS FRACP MD AGAF (2014) Occupational health and safety of anti-tumour necrosis factor alpha monoclonal antibodies with casual exposure, Expert Opinion on Biological Therapy, 14:1, 27-36, DOI: 10.1517/14712598.2014.853738 To link to this article: http://dx.doi.org/10.1517/14712598.2014.853738
Published online: 09 Nov 2013.
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Date: 13 September 2015, At: 08:43
Review
Occupational health and safety of anti-tumour necrosis factor alpha monoclonal antibodies with casual exposure
1.
Introduction
2.
Background
3.
Physico-chemical properties of anti-TNF agents
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4. 5.
†
Concord Hospital, Gastroenterology and Liver Services, Concord NSW, Sydney, Australia
Adverse side effects of anti-TNF Estimation of risk from accidental mAbs exposure and routes of absorption
6.
Risk assessment scores for anti-TNF mAbs exposure
7.
Classification of anti-TNF: hazardous substance or not?
8.
Conclusions
9.
Expert opinion
Jeff Chang & Rupert WL Leong† Introduction: As the incidence of chronic inflammatory diseases continues to rise, so has cumulative use of biological therapy particularly anti-tumour necrosis factor (TNF) alpha agents. As longer term data emerges about the safety of these drugs, there is increasing attention drawn to safety of those with casual exposure. At present, there is little in the published literature to give guidance for healthcare workers regarding their health and safety in handling of anti-TNF agents, nor the appropriate precautions required. Areas covered: The aim of this review is to summarize the currently known adverse effects, risk assessment tools for classifying and handling hazardous substances, and present evidence for systemic absorption through occupational exposure in handling anti-TNF antibodies at the level of reconstitution. Expert opinion: There is no evidence for systemic absorption of these drugs in context of handling or accidental spillage and no reports of subsequent biological adverse effects. Given the need of this class of medication to be used for long-term maintenance therapy and their increasing indications, improved efficiency and cost-containing measures are recommended. As such, simple universal precautions of protective clothing of glove, gown, facemask and eye goggles are appropriate measures for reconstitution of anti-TNF antibodies. Keywords: colitis, Crohn, inflammatory bowel disease, monoclonal antibody, occupational health safety, tumour necrosis factor, ulcerative Expert Opin. Biol. Ther. (2014) 14(1):27-36
1.
Introduction
Importance of occupational health and safety risk of handling hazardous drugs is well recognized. Precautionary guidelines are in place for drugs recognized as hazardous by bodies such as Work Safe Australia nationally, with American Society of Health-System Pharmacists (ASHP) and The National Institute for Occupational Safety and Health (NIOSH) internationally [1,2]. Drugs considered hazardous are defined as those that have demonstrated carcinogenicity, teratogenicity or other developmental toxicity, reproductive toxicity, organ toxicity at low doses, genotoxicity or structure and toxicity profiles of new drugs that mimic existing drugs deemed hazardous. Whilst some monoclonal antibodies (mAbs) include anti-cancer treatments, many are not. Anti- tumour necrosis factor (anti-TNF) alpha antibodies bind free circulating TNF or membrane-TNF and have significantly improved the management of refractory chronic immune-mediated inflammatory conditions such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). Previous to their availability, many patients suffered disability through suboptimal treatment or required surgical management [3-8]. As such these drugs have been increasingly used, including for scheduled maintenance of remission over an indefinite period 10.1517/14712598.2014.853738 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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J. Chang & R. W. L. Leong
Article highlights. . . .
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Past classifications of anti-TNF antibodies together with mAbs have been misleading. Anti-TNF antibodies are not classified as a hazardous substance. Anti-TNF agents are associated with a relative increased risk of infections and lymphomas in patients receiving full doses. No evidence exists supporting either adverse outcome nor is there a scientific basis for systemic absorption through dermal, pulmonary and oral routes from occupational exposure. Simple universal precautions of protective clothing of glove, gown, facemask and eye goggles are recommended to be used in the reconstitution of anti-TNF agents in the potential chance of spillage of substance.
infliximab (IFX), adalimumab (ADA), certolizumab pegol (CZP), golimumab (GLM) and etanercept (ETA), with the initial two more extensively studied [8]. IFX is a chimeric IgG1 antibody, composed of a variable murine Fab region linked by disulfide bonds to a human IgG1 constant region [17]. ADA and GLM are fully humanised IgG antibodies, composed of human-derived Fab and IgG1 constant region. CZP is a pegylated humanized mAb, composed of an IgG4 isotype Fab fragment linked to a polyethylene glycol moiety, increasing the half-life of the drug by slowing its clearance. ETA is a fusion protein consisting of the extracellular ligand-binding protein of the TNF receptor linked to the Fc portion of human IgG1. This class of medication, therefore, is characterized by complex structure and large molecular weight unlike small molecule drugs traditionally used in the management of immune-mediated chronic diseases.
This box summarises key points contained in the article.
Physico-chemical properties of anti-TNF agents
3.
of time. With increasing indications and widespread use, including at times the requirement for acute administration for acute severe ulcerative colitis, these drugs may need to be prepared at short notice and in an efficient manner. Given the similarity of nomenclature, there have been attempts to classify toxicity of mAbs as a class irrespective of antibody drug conjugates [9]. This has led to invalidated risk assessment scores and subsequent protocols adopted by hospital pharmacies for handling of non-cytotoxic mAbs. Adverse risk assessment has resulted in cases of outsourcing for reconstitution of anti-TNF mAbs causing delays in treatment and adding to cost and inefficiency or even the inability to provide this class of medications. Thus, the aim of the article is to outline current evidence for risks to health-care workers exposed to anti-TNF mAbs through preparation or handling of the drug and provide expert opinion on their safe reconstitution and administration. 2.
Background
The advent of biological agents, specifically, anti-TNF antibodies, has been a turning point of medical therapy for many chronic inflammatory diseases, including RA [10], ankylosing spondylitis [11], psoriasis [12,13] and IBD [3-6,14]. This was made possible with the discovery of the process of generating hybridomas by Kohler and Milstein in 1975 paving the way for development of mAbs as therapeutic agents [15]. mAbs are engineered immunoglobulin proteins which are made of two light chains and two heavy chains, both comprising a variable domain or Fab (antigen binding region) and constant domain [16]. The nomenclature of mAbs are based on their isotype and can be classified as murine antibodies (-omab), chimeric (-ximab) or humanized (zu-mab). At present, five different anti-TNF antibodies are used for treatment of these chronic inflammatory conditions including 28
IFX has a molecular weight of approximately 149.1 kD. It is supplied as a sterile, white, lyophilized powder for intravenous infusion, and forms a clear, colourless solution after reconstitution with 10 ml of sterile water for injection, with a pH at approximately 7.2. It has a melting point of 71 C. The volatile component is not applicable and evaporation rate is not available [18]. ADA has a molecular weight of approximately 148 kD. It is supplied as a sterile, preservative-free solution for subcutaneous administration in a prefilled syringe [19]. No reconstitution is required beyond the manufacturer. Other components of the solution include water, mannitol, sodium chloride, sodium phosphate dehydrate, citric acid and polysorbate. The solution is clear, colourless and odourless with a pH of 4.9 -- 5.5. The volatile component and evaporation rate are not available [20]. CZP, ETA and GLM have molecular weights of 91, 150 and 150 kD, respectively. These are summarized in Table 1.
4.
Adverse side effects of anti-TNF
Although anti-TNF agents have been used in clinical practice for over a decade, there is little published data on the safety and risks health-care workers who come into contact by occupational exposure. It is unclear whether the safety and adverse outcome literature available in patients suffering from chronic inflammatory diseases and who receive ‘full doses’ of antiTNF, can be extrapolated to hazards posed to health professional working and processing these chemicals. Side effects of patients receiving anti-TNF therapy are well published in the literature, and will be only briefly summarized in this article [12,13,21-24]. They can be broadly classified into infections risks, malignancy risks and pregnancy and fetal risks.
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Occupational health and safety of anti-TNF alpha mAbs with casual exposure
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Table 1. Properties of available anti-tumour necrosis factor alpha agents. Anti-TNF
Route of administration
Weight (kD)
Isotype
Description
IFX
IV infusion
149.1
Chimeric
ADA
SC injection
148
Human
CZP
SC injection
91
Human
GLM
SC injection
150
Human
ETA
SC injection
150
Human
IgG1 antibody, composed of a variable murine Fab region linked by disulfide bonds to a human IgG1 constant region (Fc) IgG1 antibodies, composed of human-derived Fab and IgG1 constant region Pegylated antibody, composed of an IgG4 isotype Fab fragment linked to a polyethylene glycol moiety, and is distinct from the other anti-TNF as it does not have a constant region IgG1 antibodies, composed of human-derived Fab and IgG1 constant region Dimeric fusion protein that consists of two copies of the extracellular ligand-binding domain of the human 75-kDa TNF- receptor linked to the Fc portion of human immunoglobulin IgG11
ADA: Adalimumab; CZP: Certolizumab: GLM: Golimumab; ETA: Etanercept; IFX: Infliximab.
4.1
Infectious risks
Serious infectious events are the most commonly reported side effect of anti-TNF agents [25]. Burmester et al. reported serious infections between 1.7 and 6.7 events/100 patient years, in a long-term safety follow-up analyses of 23,458 patients on ADA. This was higher in patients with RA and CD. In an analysis from the Crohn’s Therapy, Resource, Evaluation, and Assessment Tool (TREAT) registry containing data on > 6273 patients with CD with just over 50% having received IFX with 5. Two-years follow-up, rates of serious infections were also higher, with 2.04 events/100 patient years. However, when adjusted for confounding factors, disease severity, use of steroids and narcotics were more important predictors of serious infections than anti-TNF therapy (HR of 2.24, 1.57, 1.98 vs. 1.43, respectively) [23]. Opportunistic infections are also more common among those exposed to anti-TNF therapy in particular mycobacterium tuberculosis (TB) infection with mortality reported up to 13% [25]. A retrospective review of patients exposed to IFX on the Food and Drug Administration (FDA) Adverse Events Reporting System, reported a high number of patients (70 of 147,000) with overt TB despite 91% of these patients from countries with low incidence of TB (< 20 cases/100,000 population per year). Presentations of TB in those affected were generally atypical, with over 50% with extrapulmonary manifestations and a quarter with disseminated disease. Little detail, however, was known regarding their TB status prior to commencement of IFX [26]. A meta-analyses by Ford et al. of 7054 patients (4135 with IBD exposed to anti-TNF), identified 0.9% opportunistic infections among patients exposed to anti-TNF therapy, compared with 0.3% assigned to placebo. These included TB infection (0.2% of patients on anti-TNF therapy), varicella-zoster, herpes zoster, herpes simplex, cytomegalovirus and Epstein--Barr virus. This corresponded to a relative risk of 2.05 (95% CI: 1.10 -- 3.85) and the number
needed to harm to cause one opportunistic infection of 500. No differences were identified between the different anti-TNF agents [27]. Current European Crohn’s Colitis Organization (ECCO) consensus on TB screening in those planning to commence anti-TNF include a chest X-ray, tuberculin skin testing or gamma interferon assays to screen for latent TB [25]. Similar screenings are enforced by Staff Health for all prospective hospital staff prior to employment, reducing individuals with unidentified latent or overt TB [28]. Malignancy risks TNF has been implicated in both cancer development and progression, as well as possessing anti-tumour effects in mice models [29,30]. While earlier meta-analyses have been conflicting to malignancy risks from anti-TNF exposure, more recent studies are suggestive there may not be an added risk. Current evidence suggests that IBD inherently is associated with no- to minimal-risk of lymphomas through chronic inflammatory activity, whereas exposure to immunomodulators (azathioprine or 6-mercaptopurine) increases the relative risk for lymphomas by four- to sixfold [31], albeit the absolute risk increase remains low. Supportive evidence for lymphoma in anti-TNF exposure is conflicting partly due concomitant immunomodulators use. In a meta-analysis of 8905 patients with 21,178 patient years follow-up, there were a total of 13 lymphomas in the anti-TNF treated group giving a rate of 6.1 per 10,000 patient years. In comparison to expected rate of lymphoma in the general population of 1.9 per 10,000 patient years, taken from the SEER registry (Surveillance Epidemiology and End Results), the standardized incident ratio (SIR) was 3.23. Sixty-six percent of patients, however, were on concomitant immunomodulators, but when compared with the lymphoma rate in CD patients treated with immunomodulators alone (4 per 10,000 4.2
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patient--years), the SIR was 1.7 although this did not reach statistical significance suggesting that the increased rate might be secondary to anti-TNF exposure [32]. In another study, a positive correlation was also found in which 500 patients with CD treated with IFX were followed for 17 months with findings of two lymphomas. However, 86% of these patients were also on immunomodulators [33]. Results from the TREAT registry cohort demonstrated overall incidences of solid tumors (0.42 vs. 0.45 events per 100 patient--years), non-melanoma skin cancer (0.16 vs. 0.18 events per 100 patient--years) and lymphoma (0.05 vs. 0.06 events per 100 patient--years) were similar in IFX-treated patients and those who received other treatments only, respectively [23]. The lack of correlation is also supported by other meta-analyses. Peyrin-Biroulet et al. in a meta-analysis of 21 placebo-controlled trials (3995 patients) evaluating the safety and efficacy of anti-TNF agents for CD, also reported anti-TNF did not increase risk of malignancy compared to controls (0.24 vs. 0.39%, respectively) [34]. Consistent findings are also seen in the literature for RA. Although RA has been demonstrated to increase risk for lymphoma [35], when corrected for disease activity, studies also suggest no increased risk for malignancy (OR: 0.93, 95% CI: 0.59 -- 1.44), except for a higher risk of nonmelanoma skin cancers risks was noted (OR: 1.37, 95% CI: 0.71 -- 2.66) although this was not statistically significant [36]. When comparing between different anti-TNF classes (ETA, IFX and ADA), no difference were noted between rates of malignancies [37]. Pregnancy and fetal risks Anti-TNF agents are classified as category B medications in regards to safety in pregnancy with no documented human toxicity in controlled studies [38]. IFX and ADA have been demonstrated to cross the placenta in the third trimester [39], with high-drug levels in the newborn and cord blood at birth, and can be detected up to 6 months in the infant [40]. While this has not been associated increased infections [41], caution is recommended for any live vaccines given to the infant during the first 6 months following a case report of fatal disseminated BCG infection in an infant born to a mother with CD taking IFX who received a BCG live vaccination at the age of 3-months old [42]. In a recent literature review of 472 fetal exposures to IFX, ADA or CZP in patients with IBD, spontaneous abortion and still births were similar compared to the American population with the exception of IFX exposed, where still birth was 0.5% higher. Infants tended to have lighter weight at birth, be smaller for gestational age, and have pre-term births. It is likely, however, these are a reflection of the underlying disease or severity of the disease rather than anti-TNF itself [43]. Results from the PIANO registry (A 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy) were also supportive of the safety of anti-TNF therapy in pregnancy. 4.3
30
Among the 291 patients exposed to anti-TNF compared to mothers not exposed to anti-TNF, there was no increase in the rate of congenital anomalies, infections or developmental delay based on medication exposure [44]. Infant height, weight and developmental milestones, adjusted for disease activity, were similar among infants in both groups at 4, 9 and 12 months of age. Results are conflicting regarding the presence of anti-TNF agents in breast milk of mothers exposed to anti-TNF during pregnancy, although it does not appear to increase risk of infections in infants. Kane et al. reported three cases of mothers with CD exposed to IFX during pregnancy until week 30, and resumed treatment 3 -- 14 days after delivery. In all three cases, IFX was not detectable within the breast milk of the nursing mothers between 4 and 43 days post IFX tested at two separate time points [45]. Similarly, in a single case report, IFX levels were not detected in breast milk in a woman with CD exposed to IFX through her entire pregnancy. In addition, serial measurements revealed a continued slow decline of the infant’s IFX levels during the following 6 months, despite resumption of breast-feeding and ongoing treatment of the mother with IFX supporting no to minimal IFX in breast milk [46]. In contrast, another case series, three postpartum mothers who had either stopped IFX at pregnancy or at the start of the third trimester, had breast milk tested for IFX levels before recommencement of IFX due to clinical flare. IFX was undetectable in breast milk prior to the first infusion and was also not measurable in eight lactating women not exposed to IFX. Within 2 -- 3 days of the infusion, however, IFX levels in the three nursing mother’s breast milk were elevated, although these levels of IFX were roughly 1/200th of the level in blood, and were felt unlikely to result in systemic immunosuppression [47]. Results from the PIANO registry support this notion, with 72% of the infants breastfed and was not associated with increased risk of infection [44]. Importantly, these commonly quoted adverse effects of anti-TNF mAbs are a result of receiving a full parenteral dose designed to induce biological immunosuppressive effects. Minuscule exposure through casual contact such as from accidental exposure during reconstitution, therefore, will not risk the exposed individual from these adverse effects.
Estimation of risk from accidental mAbs exposure and routes of absorption
5.
Assessments of occupational exposure to substances should incorporate the likelihood of harm from external effects and the potential harm from absorption into the body. Evaluation of absorption into the body should include dermal, inhalation, oral absorption and accidental intravenous or subcutaneous injection. Activities involving potential exposure include, handling of lyophilized powder, formation of aerosols in pressure equalization processes and incidents where there are leaks or spillage of substance [48]. Outside accidental spillage, they are more
Expert Opin. Biol. Ther. (2014) 14(1)
Occupational health and safety of anti-TNF alpha mAbs with casual exposure
likely to occur in the context of reconstitution of infusions, rather than circumstances of prefilled syringe or pens. Even so, the likely occurrence of these events appear remote, given these compounds are in sealed vials during mixing, and are transferred into sealed 0.9% sodium chloride for infusion. In the setting of an accidental workplace exposure, the mAbs would either be in its solid, powdered lyophilized form or mixed in a liquid medium which may affect the of route of absorption. Skin One of the important functions of the human skin is to serve as a protective barrier, both physical and biological [49]. This function is primarily served by the stratum corneum outermost layer of the epidermis, containing a lipid bilayer with hydrophilic region in between. Bos et al. in their article, reason that only smaller molecules can pass trans-cutaneous, with the likely cut-off at around 500 D. The exception to this is sweat glands and hair follicles which may allow watersoluble molecules to be absorbed but contribute to only 0.1% of the skin surface. Based on animal models, IFX and ADA are unlikely to cause irritation to the skin following contact [18,20]. There are several supportive arguments for this also in the human model. In patch testing for contact dermatitis, test allergens are all under 500 D, except for neomycin sulphate 712 D, but is comprised of two smaller neamine molecules each 322 D. Current available transdermal drug patches for nitroglycerin, nicotine, fentanyl, clonidine and oestradiol are also all under 350 D. Furthermore, cyclosporine which is 1202 D, has been used successfully in treatment of psoriasis dermatitis through intra-lesional injection, but was ineffective as a topical therapy [50,51]. The authors feel that given the lowest anti-TNF antibody’s individual molecular weight is 91 kD which far exceeds 500 D, dermal absorption is unlikely in intact skin. There are two small case reports of topical IFX gel used in chronic non-healing ulcers (> 4 months) to assess potential adverse outcomes on broken skin. Despite the small number of cases, there were no reported adverse systemic or local side effects and wound healing was improved in 86% of the ulcers treated in one study [52,53]. In summary, significant cutaneous absorption of anti-TNF to induce a systemic biological effect is not possible. Casual cutaneous contact from the anti-TNF agent from accidental spillage onto skin is, therefore, unlikely to cause local or systemic harm.
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5.1
Inhalation There is conflicting opinion regarding powder exposure having the only potential to conceivably reach alveolar absorption, compared to liquid exposure, as resultant aqueous solution theoretically has a vapour pressure and hence evaporation rate which should be considered. Studies from the US Pharmacopeia suggest that absorption through the alveoli to 5.2
the systemic circulation requires drug particles with an ideal aerodynamic diameter of < 5 µm [48]. The most significant barrier to absorption of any inhaled drugs is the epithelium of the lung [54]. In addition, proteins are subject to digestion by macrophages. In animal studies, molecules greater than 50 kD appear to have a bioavailability of < 5% [55]. Similar results were submitted in a report to NIOSH 2007, demonstrating that in more than one animal species, proteins weights above 70 kD demonstrated bioavailability of < 5% [56]. Proteins in excess of 30 kD are absent or in very low concentrations in the blood suggestive there is an upper limit of absorption. One feasible explanation for this phenomenon is precipitation or aggregation of the protein in the alveolar fluid leading to opsonisation and macrophage ingestion and degradation [57]. Oral ingestion Oral ingestion of proteins such as anti-TNF antibodies, by their chemical properties, are denatured by the acidic environment and enzymatically digested by the gastrointestinal tract. Any absorption systemically after oral ingestion, therefore, would be unlikely. 5.3
Needle stick injury Needle stick injuries continue to be a occupational risk for many health-care workers with more than 50% of nurses experiencing at least one needle stick injury in their career [58]. In the reconstitution of anti-TNF therapy, accidental inoculation subcutaneously or intravenously is certainly possible with systemic absorption. In a typical needle stick injury involving a cannula of 0.9 mm diameter, volumes of 1 µL can be transferred [48]. However, the actual drug absorbed would be a minute fraction of the actual dose taking also into account the dilution factor. It can also be argued that it is unclear whether a single dose causes harmful effects, as repeated and regular dosing are required for pharmaceutical effects [56]. In a randomized, double-blind, placebo-controlled study of single intravenous injections of differing doses (0.5 -- 10 mg/kg) of ADA of patients with active RA, no dose related increases in adverse events were observed [59]. Although two serious adverse events were reported in the treatment group (pancreatitis with history of heavy alcohol and seizure in context of known epilepsy), they were not felt to be treatment related. Given the fact that doses given in this trial were supra-therapeutic, given intravenously with likely higher systemic absorption than subcutaneous injection, and did not demonstrate increased adverse outcomes, it would be unlikely a needle stick transfer of a fraction of normal doses of anti-TNF is likely to cause harmful effects. 5.4
Risk assessment scores for anti-TNF mAbs exposure
6.
Workers may be exposed to a hazardous drug at many points of its manufacture, transport, distribution, receipt, storage,
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preparation, administration and disposal. Langford et al. addresses this important issue at the level of the health-care worker, with respect to mAbs preparation and administration [9]. A risk assessment tool was devised to stratify whether the specific mAbs was considered hazardous centered on (i) immunogenicity of the agent (ii) toxicity and (iii) complexity of dose calculation and complexity of dose preparation, based on the National Patient Safety Agency (NPSA) risk score for safe injectable medicines [60]. Immunogenicity was determined from a scale of 1 -- 3 based on whether the mAb isotype was human, chimeric or murine with the assumption that murine is more immunogenic than human proteins. Toxicity was assessed by a scale from 1 to 4 with the following criteria: i) potential to cause adverse events, ii) associated with well defined but rare toxic symptoms, iii) a well established risk of toxicity and iv) known or potential cytotoxic, teratogenic or embryotoxic properties, risk of initiating a cancer or possessing radioactive properties. NPSA is a division of the department of Heath identifying and reducing risks to patients receiving National Health Service (NHS) care and leads on national initiatives to improve patient safety in the UK. In March 2007, it provided a patient safety alert highlighting a number of risks in prescribing, preparing and administrating injectable medications, along with a recommendation for risk assessing these medications. Results, however, based on the above risk assessment criteria, are misleading and confusing. ADA was overall classified as low to moderate risk to health and safety, with IFX as high risk, despite several other more toxic mAbs such as rituximab classified as moderately only. Other anti-TNF agents CZP, GLM and ETA were not assessed in this paper. There are several fallacies to the assessment score. Firstly, as far as the authors are aware, the health risk assessment score is not validated. Secondly immunogenicity has been demonstrated to be present irrespective of the protein isotype of the mAb. Within the literature, the presence of anti-drug antibodies to anti-TNF agents IFX in clinical studies range from 6 to 61% with anti-drug antibodies to ADA varying from 0.04 to 87%. Smaller anti-drug antibodies percentages are seen in CZP (3 -- 25%), GLM (0 -- 7%) and ETA (0 -- 18%). While presence of these anti-drug antibodies has been associated with higher chance of subsequent infusion reactions, only one trial demonstrated adverse clinical events, reporting a higher incidence of venous and arterial thromboembolic events in RA with anti-ADA antibodies, although it could be argued this may be partly due to the underlying inflammatory disease activity [61]. Similarly in a systematic review in patients with IBD, those with higher level of antibodies against anti-TNF-a drugs demonstrated a higher likelihood of infusion reactions but not delayed hypersensitivity reactions [62]. Thirdly, the scoring incorrectly utilizes the NPSA risk assessment of intravenous medications as part of its assessment of whether a substance should be considered hazardous. The risk assessment tool recommended by this report also stratifies intravenous drugs by its complexity of 32
calculations or reconstitution into risks of adverse outcomes. Whilst increased complexity may increase likelihood of human errors, this has no reflection on the intrinsic properties of the compound, and hence has no bearing to hazards posed to those handling the medication. When questioned on his scoring system in a letter by Summerhays et al., Langford admits that the risk scoring system adopted is only a ‘relative one’ and that ‘a view could be taken that the likely exposure level of health-care staff will be insignificant, particularly if the simple precautions of wearing gloves and face masks are taken when handling mAbs’ [63].
Classification of anti-TNF: hazardous substance or not?
7.
Work Safe Australia, ASHP and NIOSH, all have their own specific criteria of assessment for classification of what is deemed hazardous, but is based on similar principles [1,2,64]. These include compounds or substances which demonstrate carcinogenicity, teratogenicity or other developmental toxicity, reproductive toxicity, organ toxicity at low doses, genotoxicity or substances with similar profiles to those considered hazardous. Several databases exist globally with information on hazardous substances which include Hazardous Substances Information System (HSIS), European chemical substances information system (ESIS), eChemPortal, European Chemicals Agency (ECHA) and NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Setting 2012 [1,64]. Importantly, all five anti-TNF a agents are not listed in any of these databases as hazardous substances. There are no direct literature reviews outlining absolute risks in occupational exposure to anti-TNF to the author’s knowledge. However, data from estimated cumulative worldwide IFX exposure from its approval to August 2012 is just under 1.8 million patients and it could be argued that the lack of adverse outcomes published in the literature strongly supports the safety the current practice of handling these agents [65]. In addition, in a recent review of practices handling mAbs in the Netherlands, anti-TNF IFX and ADA were risk classified as 3 in a scale from 1 to 5. Under Dutch national recommendations, only simple protective clothing consisting of glove and gown are required without the need for safety cabinet or isolators for preparation [66]. 8.
Conclusions
Anti-TNF a biological agents have revolutionized the treatment of chronic inflammatory diseases. They have demonstrated to be overall safe and effective with data demonstrating induction of remission and returning qualityof-life of patients back towards normality. As these biological agents are often used indefinitely for maintenance therapy often in young sufferers of these chronic diseases, there needs to be efficient and safe mechanisms in place for the
Expert Opin. Biol. Ther. (2014) 14(1)
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Occupational health and safety of anti-TNF alpha mAbs with casual exposure
administration of these drugs. This review evaluates the safety of these agents associated with casual exposure to these agents such as through occupational sources. There is currently a lack of published data in the literature to support harm on casual or accidental occupational exposure to anti-TNF at the level of the health care workers involved in the preparation of these drugs. Review of the literature demonstrates that previously formulated risk assessment tools stratifying mAbs into hazardous or non-hazardous can be challenged as they are based on incorrect assumptions on immunogenicity, used unvalidated toxicity scoring systems, and risk assessment tools incorporating complexity of calculation and preparation of formulation rather than reflecting on the compound’s intrinsic properties. This article demonstrates the low likelihood of systemic absorption through accidental skin exposure, pulmonary inhalation and oral ingestion based on scientific evidence of the physical properties of the anti-TNF agents. There is also no evidence that immune-mediated hypersensitivity reaction occurs with minute exposure. Even in cases of needle stick injury with injection of contents, the minute single dose would not result in any significant biological effects. There has been no evidence based on actual reports or the known physicochemical properties of anti-TNF drugs that these drugs may or have actually resulted in harm to hospital healthcare workers who prepare them.
9.
Expert opinion
Anti-TNF biological agents have been shown to be safe when given to appropriate patients following the recommended precautionary screening and surveillance strategies, even when full doses are given systemically. The minimal contact through occupational exposure does not induce any noticeable biological activities as the drug dosage is minute, contact time is minimal and the physicochemical properties of these complex drugs do not permit easy access into the systemic circulation. Occupational contact during handling, including reconstitution and administration, therefore, does not result in immunosuppression, development of infections, or
immune system-related cancers. As with handling of all drugs, universal precautions should be adopted. In support for this is the paucity of literature of neither adverse side effects from handling anti-TNF agents published nor safety alerts from the FDA as well as the fact that current national and international occupational health and safety agencies Work Safe Australia and National Institute for Occupational Safety and Health, do not have anti-TNF agents listed as hazardous substances on their database. In addition, recent risk assessments in the Netherlands of safety in preparation of ADA and IFX were of low risk, with recommendations of only provision of personal protection as the appropriate safety measures. Based on the evidence presented in this article, the authors recommend that simple universal precautions of protective clothing of glove, gown, facemask and eye goggles are used in the reconstitution of anti-TNF agents in the potential chance of spillage of substance. No evidence exists supporting either adverse outcome nor is there a scientific basis for systemic absorption through dermal, pulmonary and oral routes from occupational exposure. The requirement for isolation, use of negative pressure chambers, fume hoods or closed transfer systems adds to the cost of these drugs and inefficiency in service delivery. Limiting the availability of antiTNF agents to be used only in institutions that adopt such complex isolation procedures result in inequity of treatment access. In circumstances where they will be required to be used at short notice in emergencies such as for severe colitis, there needs to be responsible attitude that does not disadvantage such patients by unnecessary restrictions in reconstitution of these agents. Treatment with anti-TNF a agents has been demonstrated to be effective and with increasing use, access to these drugs should be efficient. Current protocols in hospital settings should reflect the low occupational-health risk posed by these medications.
Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.
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Affiliation Jeff Chang1,2 MBBS FRACP & Rupert WL Leong†1,2,3 MBBS FRACP MD AGAF † Author for correspondence 1 Concord Hospital, Gastroenterology and Liver Services, Level 1 West, Hospital Rd, Concord NSW 2139, Sydney, Australia Tel: +61 2 9767 6111; Fax: +61 2 9767 6767; E-mail: [email protected] 2 The University of New South Wales, Sydney, Australia 3 Associate Professor, Concord Hospital, Gastroenterology and Liver Services, Level 1 West, Hospital Rd, Concord NSW 2139, Sydney, Australia
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Expert Opin. Biol. Ther. (2014) 14(1)
ISSN: 1471-2598 (Print) 1744-7682 (Online) Journal homepage: http://www.tandfonline.com/loi/iebt20
Occupational health and safety of anti-tumour necrosis factor alpha monoclonal antibodies with casual exposure Jeff Chang MBBS FRACP & Rupert WL Leong MBBS FRACP MD AGAF To cite this article: Jeff Chang MBBS FRACP & Rupert WL Leong MBBS FRACP MD AGAF (2014) Occupational health and safety of anti-tumour necrosis factor alpha monoclonal antibodies with casual exposure, Expert Opinion on Biological Therapy, 14:1, 27-36, DOI: 10.1517/14712598.2014.853738 To link to this article: http://dx.doi.org/10.1517/14712598.2014.853738
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Review
Occupational health and safety of anti-tumour necrosis factor alpha monoclonal antibodies with casual exposure
1.
Introduction
2.
Background
3.
Physico-chemical properties of anti-TNF agents
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4. 5.
†
Concord Hospital, Gastroenterology and Liver Services, Concord NSW, Sydney, Australia
Adverse side effects of anti-TNF Estimation of risk from accidental mAbs exposure and routes of absorption
6.
Risk assessment scores for anti-TNF mAbs exposure
7.
Classification of anti-TNF: hazardous substance or not?
8.
Conclusions
9.
Expert opinion
Jeff Chang & Rupert WL Leong† Introduction: As the incidence of chronic inflammatory diseases continues to rise, so has cumulative use of biological therapy particularly anti-tumour necrosis factor (TNF) alpha agents. As longer term data emerges about the safety of these drugs, there is increasing attention drawn to safety of those with casual exposure. At present, there is little in the published literature to give guidance for healthcare workers regarding their health and safety in handling of anti-TNF agents, nor the appropriate precautions required. Areas covered: The aim of this review is to summarize the currently known adverse effects, risk assessment tools for classifying and handling hazardous substances, and present evidence for systemic absorption through occupational exposure in handling anti-TNF antibodies at the level of reconstitution. Expert opinion: There is no evidence for systemic absorption of these drugs in context of handling or accidental spillage and no reports of subsequent biological adverse effects. Given the need of this class of medication to be used for long-term maintenance therapy and their increasing indications, improved efficiency and cost-containing measures are recommended. As such, simple universal precautions of protective clothing of glove, gown, facemask and eye goggles are appropriate measures for reconstitution of anti-TNF antibodies. Keywords: colitis, Crohn, inflammatory bowel disease, monoclonal antibody, occupational health safety, tumour necrosis factor, ulcerative Expert Opin. Biol. Ther. (2014) 14(1):27-36
1.
Introduction
Importance of occupational health and safety risk of handling hazardous drugs is well recognized. Precautionary guidelines are in place for drugs recognized as hazardous by bodies such as Work Safe Australia nationally, with American Society of Health-System Pharmacists (ASHP) and The National Institute for Occupational Safety and Health (NIOSH) internationally [1,2]. Drugs considered hazardous are defined as those that have demonstrated carcinogenicity, teratogenicity or other developmental toxicity, reproductive toxicity, organ toxicity at low doses, genotoxicity or structure and toxicity profiles of new drugs that mimic existing drugs deemed hazardous. Whilst some monoclonal antibodies (mAbs) include anti-cancer treatments, many are not. Anti- tumour necrosis factor (anti-TNF) alpha antibodies bind free circulating TNF or membrane-TNF and have significantly improved the management of refractory chronic immune-mediated inflammatory conditions such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). Previous to their availability, many patients suffered disability through suboptimal treatment or required surgical management [3-8]. As such these drugs have been increasingly used, including for scheduled maintenance of remission over an indefinite period 10.1517/14712598.2014.853738 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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J. Chang & R. W. L. Leong
Article highlights. . . .
.
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.
Past classifications of anti-TNF antibodies together with mAbs have been misleading. Anti-TNF antibodies are not classified as a hazardous substance. Anti-TNF agents are associated with a relative increased risk of infections and lymphomas in patients receiving full doses. No evidence exists supporting either adverse outcome nor is there a scientific basis for systemic absorption through dermal, pulmonary and oral routes from occupational exposure. Simple universal precautions of protective clothing of glove, gown, facemask and eye goggles are recommended to be used in the reconstitution of anti-TNF agents in the potential chance of spillage of substance.
infliximab (IFX), adalimumab (ADA), certolizumab pegol (CZP), golimumab (GLM) and etanercept (ETA), with the initial two more extensively studied [8]. IFX is a chimeric IgG1 antibody, composed of a variable murine Fab region linked by disulfide bonds to a human IgG1 constant region [17]. ADA and GLM are fully humanised IgG antibodies, composed of human-derived Fab and IgG1 constant region. CZP is a pegylated humanized mAb, composed of an IgG4 isotype Fab fragment linked to a polyethylene glycol moiety, increasing the half-life of the drug by slowing its clearance. ETA is a fusion protein consisting of the extracellular ligand-binding protein of the TNF receptor linked to the Fc portion of human IgG1. This class of medication, therefore, is characterized by complex structure and large molecular weight unlike small molecule drugs traditionally used in the management of immune-mediated chronic diseases.
This box summarises key points contained in the article.
Physico-chemical properties of anti-TNF agents
3.
of time. With increasing indications and widespread use, including at times the requirement for acute administration for acute severe ulcerative colitis, these drugs may need to be prepared at short notice and in an efficient manner. Given the similarity of nomenclature, there have been attempts to classify toxicity of mAbs as a class irrespective of antibody drug conjugates [9]. This has led to invalidated risk assessment scores and subsequent protocols adopted by hospital pharmacies for handling of non-cytotoxic mAbs. Adverse risk assessment has resulted in cases of outsourcing for reconstitution of anti-TNF mAbs causing delays in treatment and adding to cost and inefficiency or even the inability to provide this class of medications. Thus, the aim of the article is to outline current evidence for risks to health-care workers exposed to anti-TNF mAbs through preparation or handling of the drug and provide expert opinion on their safe reconstitution and administration. 2.
Background
The advent of biological agents, specifically, anti-TNF antibodies, has been a turning point of medical therapy for many chronic inflammatory diseases, including RA [10], ankylosing spondylitis [11], psoriasis [12,13] and IBD [3-6,14]. This was made possible with the discovery of the process of generating hybridomas by Kohler and Milstein in 1975 paving the way for development of mAbs as therapeutic agents [15]. mAbs are engineered immunoglobulin proteins which are made of two light chains and two heavy chains, both comprising a variable domain or Fab (antigen binding region) and constant domain [16]. The nomenclature of mAbs are based on their isotype and can be classified as murine antibodies (-omab), chimeric (-ximab) or humanized (zu-mab). At present, five different anti-TNF antibodies are used for treatment of these chronic inflammatory conditions including 28
IFX has a molecular weight of approximately 149.1 kD. It is supplied as a sterile, white, lyophilized powder for intravenous infusion, and forms a clear, colourless solution after reconstitution with 10 ml of sterile water for injection, with a pH at approximately 7.2. It has a melting point of 71 C. The volatile component is not applicable and evaporation rate is not available [18]. ADA has a molecular weight of approximately 148 kD. It is supplied as a sterile, preservative-free solution for subcutaneous administration in a prefilled syringe [19]. No reconstitution is required beyond the manufacturer. Other components of the solution include water, mannitol, sodium chloride, sodium phosphate dehydrate, citric acid and polysorbate. The solution is clear, colourless and odourless with a pH of 4.9 -- 5.5. The volatile component and evaporation rate are not available [20]. CZP, ETA and GLM have molecular weights of 91, 150 and 150 kD, respectively. These are summarized in Table 1.
4.
Adverse side effects of anti-TNF
Although anti-TNF agents have been used in clinical practice for over a decade, there is little published data on the safety and risks health-care workers who come into contact by occupational exposure. It is unclear whether the safety and adverse outcome literature available in patients suffering from chronic inflammatory diseases and who receive ‘full doses’ of antiTNF, can be extrapolated to hazards posed to health professional working and processing these chemicals. Side effects of patients receiving anti-TNF therapy are well published in the literature, and will be only briefly summarized in this article [12,13,21-24]. They can be broadly classified into infections risks, malignancy risks and pregnancy and fetal risks.
Expert Opin. Biol. Ther. (2014) 14(1)
Occupational health and safety of anti-TNF alpha mAbs with casual exposure
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Table 1. Properties of available anti-tumour necrosis factor alpha agents. Anti-TNF
Route of administration
Weight (kD)
Isotype
Description
IFX
IV infusion
149.1
Chimeric
ADA
SC injection
148
Human
CZP
SC injection
91
Human
GLM
SC injection
150
Human
ETA
SC injection
150
Human
IgG1 antibody, composed of a variable murine Fab region linked by disulfide bonds to a human IgG1 constant region (Fc) IgG1 antibodies, composed of human-derived Fab and IgG1 constant region Pegylated antibody, composed of an IgG4 isotype Fab fragment linked to a polyethylene glycol moiety, and is distinct from the other anti-TNF as it does not have a constant region IgG1 antibodies, composed of human-derived Fab and IgG1 constant region Dimeric fusion protein that consists of two copies of the extracellular ligand-binding domain of the human 75-kDa TNF- receptor linked to the Fc portion of human immunoglobulin IgG11
ADA: Adalimumab; CZP: Certolizumab: GLM: Golimumab; ETA: Etanercept; IFX: Infliximab.
4.1
Infectious risks
Serious infectious events are the most commonly reported side effect of anti-TNF agents [25]. Burmester et al. reported serious infections between 1.7 and 6.7 events/100 patient years, in a long-term safety follow-up analyses of 23,458 patients on ADA. This was higher in patients with RA and CD. In an analysis from the Crohn’s Therapy, Resource, Evaluation, and Assessment Tool (TREAT) registry containing data on > 6273 patients with CD with just over 50% having received IFX with 5. Two-years follow-up, rates of serious infections were also higher, with 2.04 events/100 patient years. However, when adjusted for confounding factors, disease severity, use of steroids and narcotics were more important predictors of serious infections than anti-TNF therapy (HR of 2.24, 1.57, 1.98 vs. 1.43, respectively) [23]. Opportunistic infections are also more common among those exposed to anti-TNF therapy in particular mycobacterium tuberculosis (TB) infection with mortality reported up to 13% [25]. A retrospective review of patients exposed to IFX on the Food and Drug Administration (FDA) Adverse Events Reporting System, reported a high number of patients (70 of 147,000) with overt TB despite 91% of these patients from countries with low incidence of TB (< 20 cases/100,000 population per year). Presentations of TB in those affected were generally atypical, with over 50% with extrapulmonary manifestations and a quarter with disseminated disease. Little detail, however, was known regarding their TB status prior to commencement of IFX [26]. A meta-analyses by Ford et al. of 7054 patients (4135 with IBD exposed to anti-TNF), identified 0.9% opportunistic infections among patients exposed to anti-TNF therapy, compared with 0.3% assigned to placebo. These included TB infection (0.2% of patients on anti-TNF therapy), varicella-zoster, herpes zoster, herpes simplex, cytomegalovirus and Epstein--Barr virus. This corresponded to a relative risk of 2.05 (95% CI: 1.10 -- 3.85) and the number
needed to harm to cause one opportunistic infection of 500. No differences were identified between the different anti-TNF agents [27]. Current European Crohn’s Colitis Organization (ECCO) consensus on TB screening in those planning to commence anti-TNF include a chest X-ray, tuberculin skin testing or gamma interferon assays to screen for latent TB [25]. Similar screenings are enforced by Staff Health for all prospective hospital staff prior to employment, reducing individuals with unidentified latent or overt TB [28]. Malignancy risks TNF has been implicated in both cancer development and progression, as well as possessing anti-tumour effects in mice models [29,30]. While earlier meta-analyses have been conflicting to malignancy risks from anti-TNF exposure, more recent studies are suggestive there may not be an added risk. Current evidence suggests that IBD inherently is associated with no- to minimal-risk of lymphomas through chronic inflammatory activity, whereas exposure to immunomodulators (azathioprine or 6-mercaptopurine) increases the relative risk for lymphomas by four- to sixfold [31], albeit the absolute risk increase remains low. Supportive evidence for lymphoma in anti-TNF exposure is conflicting partly due concomitant immunomodulators use. In a meta-analysis of 8905 patients with 21,178 patient years follow-up, there were a total of 13 lymphomas in the anti-TNF treated group giving a rate of 6.1 per 10,000 patient years. In comparison to expected rate of lymphoma in the general population of 1.9 per 10,000 patient years, taken from the SEER registry (Surveillance Epidemiology and End Results), the standardized incident ratio (SIR) was 3.23. Sixty-six percent of patients, however, were on concomitant immunomodulators, but when compared with the lymphoma rate in CD patients treated with immunomodulators alone (4 per 10,000 4.2
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patient--years), the SIR was 1.7 although this did not reach statistical significance suggesting that the increased rate might be secondary to anti-TNF exposure [32]. In another study, a positive correlation was also found in which 500 patients with CD treated with IFX were followed for 17 months with findings of two lymphomas. However, 86% of these patients were also on immunomodulators [33]. Results from the TREAT registry cohort demonstrated overall incidences of solid tumors (0.42 vs. 0.45 events per 100 patient--years), non-melanoma skin cancer (0.16 vs. 0.18 events per 100 patient--years) and lymphoma (0.05 vs. 0.06 events per 100 patient--years) were similar in IFX-treated patients and those who received other treatments only, respectively [23]. The lack of correlation is also supported by other meta-analyses. Peyrin-Biroulet et al. in a meta-analysis of 21 placebo-controlled trials (3995 patients) evaluating the safety and efficacy of anti-TNF agents for CD, also reported anti-TNF did not increase risk of malignancy compared to controls (0.24 vs. 0.39%, respectively) [34]. Consistent findings are also seen in the literature for RA. Although RA has been demonstrated to increase risk for lymphoma [35], when corrected for disease activity, studies also suggest no increased risk for malignancy (OR: 0.93, 95% CI: 0.59 -- 1.44), except for a higher risk of nonmelanoma skin cancers risks was noted (OR: 1.37, 95% CI: 0.71 -- 2.66) although this was not statistically significant [36]. When comparing between different anti-TNF classes (ETA, IFX and ADA), no difference were noted between rates of malignancies [37]. Pregnancy and fetal risks Anti-TNF agents are classified as category B medications in regards to safety in pregnancy with no documented human toxicity in controlled studies [38]. IFX and ADA have been demonstrated to cross the placenta in the third trimester [39], with high-drug levels in the newborn and cord blood at birth, and can be detected up to 6 months in the infant [40]. While this has not been associated increased infections [41], caution is recommended for any live vaccines given to the infant during the first 6 months following a case report of fatal disseminated BCG infection in an infant born to a mother with CD taking IFX who received a BCG live vaccination at the age of 3-months old [42]. In a recent literature review of 472 fetal exposures to IFX, ADA or CZP in patients with IBD, spontaneous abortion and still births were similar compared to the American population with the exception of IFX exposed, where still birth was 0.5% higher. Infants tended to have lighter weight at birth, be smaller for gestational age, and have pre-term births. It is likely, however, these are a reflection of the underlying disease or severity of the disease rather than anti-TNF itself [43]. Results from the PIANO registry (A 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy) were also supportive of the safety of anti-TNF therapy in pregnancy. 4.3
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Among the 291 patients exposed to anti-TNF compared to mothers not exposed to anti-TNF, there was no increase in the rate of congenital anomalies, infections or developmental delay based on medication exposure [44]. Infant height, weight and developmental milestones, adjusted for disease activity, were similar among infants in both groups at 4, 9 and 12 months of age. Results are conflicting regarding the presence of anti-TNF agents in breast milk of mothers exposed to anti-TNF during pregnancy, although it does not appear to increase risk of infections in infants. Kane et al. reported three cases of mothers with CD exposed to IFX during pregnancy until week 30, and resumed treatment 3 -- 14 days after delivery. In all three cases, IFX was not detectable within the breast milk of the nursing mothers between 4 and 43 days post IFX tested at two separate time points [45]. Similarly, in a single case report, IFX levels were not detected in breast milk in a woman with CD exposed to IFX through her entire pregnancy. In addition, serial measurements revealed a continued slow decline of the infant’s IFX levels during the following 6 months, despite resumption of breast-feeding and ongoing treatment of the mother with IFX supporting no to minimal IFX in breast milk [46]. In contrast, another case series, three postpartum mothers who had either stopped IFX at pregnancy or at the start of the third trimester, had breast milk tested for IFX levels before recommencement of IFX due to clinical flare. IFX was undetectable in breast milk prior to the first infusion and was also not measurable in eight lactating women not exposed to IFX. Within 2 -- 3 days of the infusion, however, IFX levels in the three nursing mother’s breast milk were elevated, although these levels of IFX were roughly 1/200th of the level in blood, and were felt unlikely to result in systemic immunosuppression [47]. Results from the PIANO registry support this notion, with 72% of the infants breastfed and was not associated with increased risk of infection [44]. Importantly, these commonly quoted adverse effects of anti-TNF mAbs are a result of receiving a full parenteral dose designed to induce biological immunosuppressive effects. Minuscule exposure through casual contact such as from accidental exposure during reconstitution, therefore, will not risk the exposed individual from these adverse effects.
Estimation of risk from accidental mAbs exposure and routes of absorption
5.
Assessments of occupational exposure to substances should incorporate the likelihood of harm from external effects and the potential harm from absorption into the body. Evaluation of absorption into the body should include dermal, inhalation, oral absorption and accidental intravenous or subcutaneous injection. Activities involving potential exposure include, handling of lyophilized powder, formation of aerosols in pressure equalization processes and incidents where there are leaks or spillage of substance [48]. Outside accidental spillage, they are more
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Occupational health and safety of anti-TNF alpha mAbs with casual exposure
likely to occur in the context of reconstitution of infusions, rather than circumstances of prefilled syringe or pens. Even so, the likely occurrence of these events appear remote, given these compounds are in sealed vials during mixing, and are transferred into sealed 0.9% sodium chloride for infusion. In the setting of an accidental workplace exposure, the mAbs would either be in its solid, powdered lyophilized form or mixed in a liquid medium which may affect the of route of absorption. Skin One of the important functions of the human skin is to serve as a protective barrier, both physical and biological [49]. This function is primarily served by the stratum corneum outermost layer of the epidermis, containing a lipid bilayer with hydrophilic region in between. Bos et al. in their article, reason that only smaller molecules can pass trans-cutaneous, with the likely cut-off at around 500 D. The exception to this is sweat glands and hair follicles which may allow watersoluble molecules to be absorbed but contribute to only 0.1% of the skin surface. Based on animal models, IFX and ADA are unlikely to cause irritation to the skin following contact [18,20]. There are several supportive arguments for this also in the human model. In patch testing for contact dermatitis, test allergens are all under 500 D, except for neomycin sulphate 712 D, but is comprised of two smaller neamine molecules each 322 D. Current available transdermal drug patches for nitroglycerin, nicotine, fentanyl, clonidine and oestradiol are also all under 350 D. Furthermore, cyclosporine which is 1202 D, has been used successfully in treatment of psoriasis dermatitis through intra-lesional injection, but was ineffective as a topical therapy [50,51]. The authors feel that given the lowest anti-TNF antibody’s individual molecular weight is 91 kD which far exceeds 500 D, dermal absorption is unlikely in intact skin. There are two small case reports of topical IFX gel used in chronic non-healing ulcers (> 4 months) to assess potential adverse outcomes on broken skin. Despite the small number of cases, there were no reported adverse systemic or local side effects and wound healing was improved in 86% of the ulcers treated in one study [52,53]. In summary, significant cutaneous absorption of anti-TNF to induce a systemic biological effect is not possible. Casual cutaneous contact from the anti-TNF agent from accidental spillage onto skin is, therefore, unlikely to cause local or systemic harm.
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5.1
Inhalation There is conflicting opinion regarding powder exposure having the only potential to conceivably reach alveolar absorption, compared to liquid exposure, as resultant aqueous solution theoretically has a vapour pressure and hence evaporation rate which should be considered. Studies from the US Pharmacopeia suggest that absorption through the alveoli to 5.2
the systemic circulation requires drug particles with an ideal aerodynamic diameter of < 5 µm [48]. The most significant barrier to absorption of any inhaled drugs is the epithelium of the lung [54]. In addition, proteins are subject to digestion by macrophages. In animal studies, molecules greater than 50 kD appear to have a bioavailability of < 5% [55]. Similar results were submitted in a report to NIOSH 2007, demonstrating that in more than one animal species, proteins weights above 70 kD demonstrated bioavailability of < 5% [56]. Proteins in excess of 30 kD are absent or in very low concentrations in the blood suggestive there is an upper limit of absorption. One feasible explanation for this phenomenon is precipitation or aggregation of the protein in the alveolar fluid leading to opsonisation and macrophage ingestion and degradation [57]. Oral ingestion Oral ingestion of proteins such as anti-TNF antibodies, by their chemical properties, are denatured by the acidic environment and enzymatically digested by the gastrointestinal tract. Any absorption systemically after oral ingestion, therefore, would be unlikely. 5.3
Needle stick injury Needle stick injuries continue to be a occupational risk for many health-care workers with more than 50% of nurses experiencing at least one needle stick injury in their career [58]. In the reconstitution of anti-TNF therapy, accidental inoculation subcutaneously or intravenously is certainly possible with systemic absorption. In a typical needle stick injury involving a cannula of 0.9 mm diameter, volumes of 1 µL can be transferred [48]. However, the actual drug absorbed would be a minute fraction of the actual dose taking also into account the dilution factor. It can also be argued that it is unclear whether a single dose causes harmful effects, as repeated and regular dosing are required for pharmaceutical effects [56]. In a randomized, double-blind, placebo-controlled study of single intravenous injections of differing doses (0.5 -- 10 mg/kg) of ADA of patients with active RA, no dose related increases in adverse events were observed [59]. Although two serious adverse events were reported in the treatment group (pancreatitis with history of heavy alcohol and seizure in context of known epilepsy), they were not felt to be treatment related. Given the fact that doses given in this trial were supra-therapeutic, given intravenously with likely higher systemic absorption than subcutaneous injection, and did not demonstrate increased adverse outcomes, it would be unlikely a needle stick transfer of a fraction of normal doses of anti-TNF is likely to cause harmful effects. 5.4
Risk assessment scores for anti-TNF mAbs exposure
6.
Workers may be exposed to a hazardous drug at many points of its manufacture, transport, distribution, receipt, storage,
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preparation, administration and disposal. Langford et al. addresses this important issue at the level of the health-care worker, with respect to mAbs preparation and administration [9]. A risk assessment tool was devised to stratify whether the specific mAbs was considered hazardous centered on (i) immunogenicity of the agent (ii) toxicity and (iii) complexity of dose calculation and complexity of dose preparation, based on the National Patient Safety Agency (NPSA) risk score for safe injectable medicines [60]. Immunogenicity was determined from a scale of 1 -- 3 based on whether the mAb isotype was human, chimeric or murine with the assumption that murine is more immunogenic than human proteins. Toxicity was assessed by a scale from 1 to 4 with the following criteria: i) potential to cause adverse events, ii) associated with well defined but rare toxic symptoms, iii) a well established risk of toxicity and iv) known or potential cytotoxic, teratogenic or embryotoxic properties, risk of initiating a cancer or possessing radioactive properties. NPSA is a division of the department of Heath identifying and reducing risks to patients receiving National Health Service (NHS) care and leads on national initiatives to improve patient safety in the UK. In March 2007, it provided a patient safety alert highlighting a number of risks in prescribing, preparing and administrating injectable medications, along with a recommendation for risk assessing these medications. Results, however, based on the above risk assessment criteria, are misleading and confusing. ADA was overall classified as low to moderate risk to health and safety, with IFX as high risk, despite several other more toxic mAbs such as rituximab classified as moderately only. Other anti-TNF agents CZP, GLM and ETA were not assessed in this paper. There are several fallacies to the assessment score. Firstly, as far as the authors are aware, the health risk assessment score is not validated. Secondly immunogenicity has been demonstrated to be present irrespective of the protein isotype of the mAb. Within the literature, the presence of anti-drug antibodies to anti-TNF agents IFX in clinical studies range from 6 to 61% with anti-drug antibodies to ADA varying from 0.04 to 87%. Smaller anti-drug antibodies percentages are seen in CZP (3 -- 25%), GLM (0 -- 7%) and ETA (0 -- 18%). While presence of these anti-drug antibodies has been associated with higher chance of subsequent infusion reactions, only one trial demonstrated adverse clinical events, reporting a higher incidence of venous and arterial thromboembolic events in RA with anti-ADA antibodies, although it could be argued this may be partly due to the underlying inflammatory disease activity [61]. Similarly in a systematic review in patients with IBD, those with higher level of antibodies against anti-TNF-a drugs demonstrated a higher likelihood of infusion reactions but not delayed hypersensitivity reactions [62]. Thirdly, the scoring incorrectly utilizes the NPSA risk assessment of intravenous medications as part of its assessment of whether a substance should be considered hazardous. The risk assessment tool recommended by this report also stratifies intravenous drugs by its complexity of 32
calculations or reconstitution into risks of adverse outcomes. Whilst increased complexity may increase likelihood of human errors, this has no reflection on the intrinsic properties of the compound, and hence has no bearing to hazards posed to those handling the medication. When questioned on his scoring system in a letter by Summerhays et al., Langford admits that the risk scoring system adopted is only a ‘relative one’ and that ‘a view could be taken that the likely exposure level of health-care staff will be insignificant, particularly if the simple precautions of wearing gloves and face masks are taken when handling mAbs’ [63].
Classification of anti-TNF: hazardous substance or not?
7.
Work Safe Australia, ASHP and NIOSH, all have their own specific criteria of assessment for classification of what is deemed hazardous, but is based on similar principles [1,2,64]. These include compounds or substances which demonstrate carcinogenicity, teratogenicity or other developmental toxicity, reproductive toxicity, organ toxicity at low doses, genotoxicity or substances with similar profiles to those considered hazardous. Several databases exist globally with information on hazardous substances which include Hazardous Substances Information System (HSIS), European chemical substances information system (ESIS), eChemPortal, European Chemicals Agency (ECHA) and NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Setting 2012 [1,64]. Importantly, all five anti-TNF a agents are not listed in any of these databases as hazardous substances. There are no direct literature reviews outlining absolute risks in occupational exposure to anti-TNF to the author’s knowledge. However, data from estimated cumulative worldwide IFX exposure from its approval to August 2012 is just under 1.8 million patients and it could be argued that the lack of adverse outcomes published in the literature strongly supports the safety the current practice of handling these agents [65]. In addition, in a recent review of practices handling mAbs in the Netherlands, anti-TNF IFX and ADA were risk classified as 3 in a scale from 1 to 5. Under Dutch national recommendations, only simple protective clothing consisting of glove and gown are required without the need for safety cabinet or isolators for preparation [66]. 8.
Conclusions
Anti-TNF a biological agents have revolutionized the treatment of chronic inflammatory diseases. They have demonstrated to be overall safe and effective with data demonstrating induction of remission and returning qualityof-life of patients back towards normality. As these biological agents are often used indefinitely for maintenance therapy often in young sufferers of these chronic diseases, there needs to be efficient and safe mechanisms in place for the
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Occupational health and safety of anti-TNF alpha mAbs with casual exposure
administration of these drugs. This review evaluates the safety of these agents associated with casual exposure to these agents such as through occupational sources. There is currently a lack of published data in the literature to support harm on casual or accidental occupational exposure to anti-TNF at the level of the health care workers involved in the preparation of these drugs. Review of the literature demonstrates that previously formulated risk assessment tools stratifying mAbs into hazardous or non-hazardous can be challenged as they are based on incorrect assumptions on immunogenicity, used unvalidated toxicity scoring systems, and risk assessment tools incorporating complexity of calculation and preparation of formulation rather than reflecting on the compound’s intrinsic properties. This article demonstrates the low likelihood of systemic absorption through accidental skin exposure, pulmonary inhalation and oral ingestion based on scientific evidence of the physical properties of the anti-TNF agents. There is also no evidence that immune-mediated hypersensitivity reaction occurs with minute exposure. Even in cases of needle stick injury with injection of contents, the minute single dose would not result in any significant biological effects. There has been no evidence based on actual reports or the known physicochemical properties of anti-TNF drugs that these drugs may or have actually resulted in harm to hospital healthcare workers who prepare them.
9.
Expert opinion
Anti-TNF biological agents have been shown to be safe when given to appropriate patients following the recommended precautionary screening and surveillance strategies, even when full doses are given systemically. The minimal contact through occupational exposure does not induce any noticeable biological activities as the drug dosage is minute, contact time is minimal and the physicochemical properties of these complex drugs do not permit easy access into the systemic circulation. Occupational contact during handling, including reconstitution and administration, therefore, does not result in immunosuppression, development of infections, or
immune system-related cancers. As with handling of all drugs, universal precautions should be adopted. In support for this is the paucity of literature of neither adverse side effects from handling anti-TNF agents published nor safety alerts from the FDA as well as the fact that current national and international occupational health and safety agencies Work Safe Australia and National Institute for Occupational Safety and Health, do not have anti-TNF agents listed as hazardous substances on their database. In addition, recent risk assessments in the Netherlands of safety in preparation of ADA and IFX were of low risk, with recommendations of only provision of personal protection as the appropriate safety measures. Based on the evidence presented in this article, the authors recommend that simple universal precautions of protective clothing of glove, gown, facemask and eye goggles are used in the reconstitution of anti-TNF agents in the potential chance of spillage of substance. No evidence exists supporting either adverse outcome nor is there a scientific basis for systemic absorption through dermal, pulmonary and oral routes from occupational exposure. The requirement for isolation, use of negative pressure chambers, fume hoods or closed transfer systems adds to the cost of these drugs and inefficiency in service delivery. Limiting the availability of antiTNF agents to be used only in institutions that adopt such complex isolation procedures result in inequity of treatment access. In circumstances where they will be required to be used at short notice in emergencies such as for severe colitis, there needs to be responsible attitude that does not disadvantage such patients by unnecessary restrictions in reconstitution of these agents. Treatment with anti-TNF a agents has been demonstrated to be effective and with increasing use, access to these drugs should be efficient. Current protocols in hospital settings should reflect the low occupational-health risk posed by these medications.
Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.
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Affiliation Jeff Chang1,2 MBBS FRACP & Rupert WL Leong†1,2,3 MBBS FRACP MD AGAF † Author for correspondence 1 Concord Hospital, Gastroenterology and Liver Services, Level 1 West, Hospital Rd, Concord NSW 2139, Sydney, Australia Tel: +61 2 9767 6111; Fax: +61 2 9767 6767; E-mail: [email protected] 2 The University of New South Wales, Sydney, Australia 3 Associate Professor, Concord Hospital, Gastroenterology and Liver Services, Level 1 West, Hospital Rd, Concord NSW 2139, Sydney, Australia
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