Basic & Clinical Pharmacology & Toxicology, 2015, 117, 73–84

Doi: 10.1111/bcpt.12416

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Adverse Events During Immunotherapy Against Grass PollenInduced Allergic Rhinitis – Differences Between Subcutaneous and Sublingual Treatment Kristian Aasbjerg1,2, Kim Peder Dalhoff3 and Vibeke Backer1 1

Respiratory Research Unit, Bispebjerg University Hospital, Copenhagen, Denmark, 2Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark and 3Department of Clinical Pharmacology, Bispebjerg University Hospital, Copenhagen, Denmark (Received 2 February 2015; Accepted 4 May 2015) Abstract: Allergic rhinitis (AR) triggered by grass pollen is a common disease, affecting millions of people worldwide. Treatment consists of symptom-alleviating drugs, such as topical corticosteroids or antihistamines. Another option is potentially curative immunotherapy, currently available as sublingual and subcutaneous treatment. We investigated the potential differences in the prevalence and severity of adverse events related to subcutaneous and sublingual immunotherapy (SLIT) against grass pollen-induced AR. A thorough literature search was performed with PubMed and EMBASE. The findings were compared with the available summaries of product characteristics (SPC) and with commercial pharmacology databases (Micromedex). The majority of available safety data originate from registered products of standardized allergens. A surprisingly large percentage of drugs, especially those used in the United States, have no systematically collected safety data. No sufficiently powered randomized trials comparing sublingual and subcutaneous immunotherapy (SCIT) were available, but general safety assessments indicate that sublingual tablet treatment is safer than subcutaneous treatment. Not all commonly used immunotherapy drugs are officially registered, and not all have systematically collected safety data. This is especially true for older drugs used in the United States. In contrast, newer drugs that have undergone extensive clinical testing have better documentation, but unified collection of safety data is still lacking. Considering the evidence available, most drugs elicit similar side effects from the same organ systems, and symptoms from the sublingual drug classes are probably less severe. However, a head-to-head comparison of safety and efficacy is lacking.

Allergic rhinitis (AR) is a common disease affecting millions of people worldwide. It impairs school performance and quality of life and leads to sick leave, thus costing societies billions of dollars annually. Allergic rhinitis is a classical Type I allergic reaction characterized by the pathological production of allergen-specific IgE antibodies and subsequent immune activation and inflammation build-up upon allergen contact. Although many allergens are well characterized from a biochemical perspective, is it largely unknown why certain chemical properties provoke an allergic response. Like any IgE-mediated allergy, pollen allergy, commonly known as hayfever, can be treated either strictly symptomatically with antihistamines, topical corticosteroids and other mildly immunosuppressive drugs, or with specific immunotherapy (SIT)—the only disease-modifying and potentially curative treatment available. International guidelines suggest immunotherapy treatment in all individuals who cannot achieve adequate symptom control using antihistamines and topical corticosteroids [1,2]. Prior to starting treatment with immunotherapy, a clear disease history associated with relevant allergens and a verified sensitization Author for correspondence: Kristian Aasbjerg, Department of Cardiology, Aalborg University Hospital, DK-9000 Aalborg, Denmark (e-mail [email protected]).

(e.g. skin prick test or measurement of specific IgE) should be established. Moreover, individuals should be tested for asthma, and if the tests are positive, good clinical asthma control using inhaled corticosteroids should be achieved before starting treatment with immunotherapy. Although allergen-SIT is both safe and effective in most individuals and the basic disease-modifying mechanisms of immunotherapy have been extensively investigated, they are still not fully understood. Immunotherapy was first tested in 1911 as subcutaneous injections of allergen (SCIT), later as sublingual droplets (SLIT droplets) and more recently as sublingual tablets (SLIT tablets) [3]. One of the most common pollen allergens in Europe and North America is Timothy grass, with the Latin name Phleum pratense. SCIT against grass pollen has been proven efficacious in several randomized trials [4–7], but grass pollen is also one of the allergens that causes the most adverse events during this therapy [8]. Furthermore, SCIT is time-consuming and needs weekly health-service contact, later monthly, and specialized training. Although the majority of adverse events of SCIT treatment are transient mild local reactions, although uncommon, more severe systemic effects can occur that include asthma exacerbations, generalized urticaria and anaphylaxis, which untreated may lead to death [9–11].

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Consequently, other options that are safer and easier to perform have been explored. Recently, two new standardized SLIT tablets to treat grass pollen-induced AR have been developed. SLIT tablets are considered a promising treatment with about the same efficacy as SCIT treatment but seemingly with a much better safety profile [5,12–14]. Aims. Here, we review the known side effects of SCIT treatment against IgE-mediated AR with focus on Phleum pratense and compare them with what is known for SLIT tablets used to treat the same allergy. SLIT droplets are addressed to a lesser extent due to the comparatively poor documentation of the treatment [5,15]. This is a challenging task as standardized guidelines for systematic registration and grading of adverse events of immunotherapy have only recently been drawn up [16,17]. Furthermore, most of the large meta-analyses of immunotherapy safety do not distinguish between the different allergens, only the treatment route (i.e. SCIT or SLIT).

Methods Reporting of adverse events in relation to immunotherapy has suffered from lack of consensus in the way adverse events are described and graded. Most studies distinguish between local and systemic reactions, but the definitions are somewhat unclear. This led to a recommendation from the World Allergy Organization (WAO) in 2010 suggesting clear definitions of adverse events and anaphylaxis in relation to SCIT [16]. An important point for the WAO task force was to ensure consensus in reporting systemic reactions, eventually forming the basis for precise recommendations for when to administer adrenalin. Similarly, a WAO task force in 2013 published guidelines for SLIT local reactions, recommending the use of MedDRA 14.1 coding of adverse events [17]. As most studies on the safety and efficacy of immunotherapy are before 2013 and 2010, adverse events are reported differently and are difficult to compare. Currently, a EAACI task force is implementing a database of immunotherapy Adverse Systemic Reactions, covering the experiences of both doctors and patients for use in real-life clinical settings (i.e. outside a clinical trial setting) [18]. General approach. We decided to focus on the prevalence of adverse events and the incidence of premature treatment termination due to adverse events. Adverse events are classified as either local or systemic reactions (i.e. outside application site). We included only trials using standardized allergen extracts in accordance with treatment recommendations [1,19], with the exception of the American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) surveillance studies where adverse events due to non-standardized allergen extracts cannot be separated from the standardized form [20]. Sources of information. Where possible, SPC were obtained from local authorities [in Denmark, Sundhedsstyrelsen (Danish Health and Medicines Authority)] [21]; the European Medicines Agency [22]; and the United States Food and Drug Administration (FDA) [23]. Only SPCs from registered products are available to the public, and many of the drugs used for immunotherapy are not officially registered for historical reasons.

Additionally, drug searches in the commercial database ‘Micromedex’ (Truven Health Analytics, Ann Arbor, MI, USA) were done using the terms ‘Immunotherapy’ and (‘Grass’ or ‘Phleum pratense’ or ‘Timoth
e’). Lastly, Medline (PubMed, www.pubmed.gov) and EMBASE (Elsevier, Amsterdam, Hollands) were searched for each commercial product name identified (free text), as well as ‘Phleum pratense’ AND ‘Immunotherapy’ using MESH terms. The English language was used in search terms, with the exception of the information originating from the Danish Health and Medicines Authority where the Danish language was used.

Results The review identified four subcutaneous products; ‘Alutard 225 Phleum pratense’ (ALK, Horsholm, Denmark) [6], ‘Standardized Timothy grass pollen extract (Phleum pratense)’ (Greer Laboratories, Lenoir, NC, USA) [24], ‘Alustal Phleum pratense’ (Stallergenes, Antony, France) and ‘Depot-Hal’ (HAL Allergy BV, Leiden, The Netherlands) [25]. In addition, two sublingual tablets ‘Grazax’ with the US trade name ‘Grastek’ (ALK) and ‘Oralair’ (Stallergenes) [26,27] were identified. Lastly, only one sublingual droplet product ‘Sublivac’ (HAL Allergy BV) [28] was identified. Overall, the most recently registered SLIT tablet had by far the most comprehensive, thorough and systematic descriptions of adverse events in the obtained SPC compared with any of the identified drugs. Similarly, the Micromedex database contained the most detailed information on SLIT tablets, whereas only general paragraphs overall could be identified for SCIT with no distinction between allergens. Conversely, most studies of immunotherapy focus on SCIT treatment, but the lack of unified registration and grading of adverse events was more troublesome especially for older studies. Subcutaneous immunotherapy. The United States Food and Drug Administration website lists the following manufacturers of standardized allergen extracts [20]: Timothy Grass (Phleum pratense)

• • • • • •

ALK-Abello, Inc. Allergy Laboratories, Inc. (Oklahoma City, OK, USA) Allermed Laboratories, Inc. (taken over by Greer Laboratories, Inc.) Antigen Laboratories, Inc. (taken over by Greer Laboratories, Inc.) Greer Laboratories, Inc. Jubilant HollisterStier LLC (Spokane, WA, USA)

In addition, two European manufacturers, Stallergenes and HAL Allergy BV, were identified. Of these, only three manufacturers had a publicly available SPC for standardized Phleum pratense (Timothy grass) allergen extracts: ALK [29,30], Greer Laboratories [24] and HAL Allergy BV [25]. Stallergenes and Allergy Laboratories Inc. did advertise allergen extracts on their webpage, but no SPCs were publicly available. Jubilant HollisterStier LLC did not advertise standardized pollen extracts on their webpage.

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ALK 225 Phleum pratense. The product is manufactured by ALK. ALK 225 Phleum pratense is a commonly used standardized allergen extract widely employed to treat rhinitis using the subcutaneous administration route. The product exists in an aqueous form containing saline and bicarbonate (Aquagen) [31], and a preserved version for long-term storage (Alutard) containing the preservatives phenol and aluminium hydroxide [29]. The most common side effects during treatment are displayed in table 1. Aquagen states the same known side effects [31]. Alustal Phleum pratense. The product is manufactured by Stallergenes. No SPC could be obtained from the manufacturer, who did not respond to our enquiry. We found one case report describing a fatal reaction in relation to immunotherapy with Stallergenes’ product [32]. However, the paper does not describe what allergens were used but only refers to ‘pneumallergens’. The 17-year-old girl developed symptoms of stomach pain, vomiting and diarrhoea 12 hr after treatment initiation, and 2 days later, she developed multi-organ failure and died. The doctors found no other explanation for her death other than initiation of immunotherapy. Depot-HAL. The product is manufactured by HAL Allergy AB (Leyden, The Netherlands). Local reactions at injection site are common, and granulomas do occur. Generally, any symptom related to hayfever may appear in individuals undergoing immunotherapy (itching of eyes, sneezing, coughing, atopic eczema), as well as more severe systemic reactions (shortness of breath, generalized urticaria, Quincke’s oedema). In extremely rare cases, anaphylactic shock may occur.

Sublingual (oral) immunotherapy. An overview of known side effects of SLIT is represented in table 2. Two European manufacturers of SLIT tablets were identified: ALK, who manufacture Grazax/Grastek, and Stallergenes, who manufacture Oralair. Apart from the pharmacokinetic profile, the key differences between Grazax/Grastek and Oralair are allergen composition and recommended length of treatment. Grazax/Grastek contains only Phleum pratense allergen extract, three years of consecutive treatment is recommended, and the tablet dissolves in the oral cavity within 2 sec. Oralair contains a mixture of five grasses, 4 months of pre-seasonal treatment is recommended, and the tablet dissolves within 60 sec. The differences are summarized in table 3. Oral inflammation is a well-known side effect of SLIT-tablet immunotherapy. However, most cases are mild, transient and self-limiting [9,10]. We identified no fatal reactions due to SLIT. Grazax/Grastek. The product is manufactured by ALK. Grazax is the trade name registered in Europe, whereas Grastek is the name used in the United States. The two sublingual smelt tablets are identical and consist of

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standardized 2800 Biological Allergenic Units (BAU) of Phleum pratense, suspended in a freeze-dried matrix of gelatine (fish protein), mannitol, sodium hydroxide and purified water. The tablet dissolves within 10 sec. of placement under the tongue and is approved in the United States for human beings aged 5 to 65 years [33]. Treatment should be initiated 3 months prior to the onset of the grass pollen season and continued uninterrupted for up to three years. The most common symptoms are presented in table 1. Eosinophilic oesophagitis has been reported for users of Grazax/Grastek [9]. Although clinical trials of Grazax/Grastek revealed no severe adverse events including deaths, these events may occur in a ‘real’ population where strict in- and exclusion criteria may not be met. This assumption has been endorsed by the United States Food and Drug Administration [33], but few, if any, studies have been able to confirm the suspicion [34]. Oralair. The product is manufactured by Stallergenes. Oralair is a five-grass combination tablet [Kentucky bluegrass (Poa pratensis), Orchard (Dactylis glomerata), Perennial rye (Lolium perenne), Sweet vernal (Anthoxanthum odoratum) and Timothy (Phleum pratense)] mixed with D-mannitol and freeze-dried into tablets, intended for SLIT in human beings aged 10 to 65 years [35]. Treatment with Oralair should be initiated 4 months prior to every pollen season, with a 3-day dose escalation [100 IR (index of reactivity) on Day 1, 200 IR on Day 2 and 300 IR on Day 3] and a continuation phase at a dosage of 300 IR/day continued throughout the season [12]. In contrast to Grazax/Grastek, treatment with Oralair should be terminated after the grass pollen season and resumed, as described, for 3–5 consecutive seasons. The most common symptoms are displayed in table 1 [10,35]. In line with the adverse events for Grastek/Grazax reported by Nelson et al. [61], there were two cases of severe laryngopharyngeal disorders, which occurred immediately after the first dose.

Clinical trials investigating grass pollen immunotherapy. We identified 15 clinical trials investigating the safety and efficacy of immunotherapy against grass pollen-induced AR during 1996–2013. An overview of the trials and reported adverse events are displayed in table 4. Mild systemic reactions were common regardless of immunotherapy type (SLIT/ SCIT); on average, 66% of individuals experienced mild reactions (min/max: 19–83%). Systemic reactions were seemingly higher for subcutaneous treatment with 9% of individuals being affected (min/max: 1–30%) compared with SLIT with 6% of individuals being affected (min/max: 3–9%). Nevertheless, it is difficult to generalize on SCIT trials as especially the updosing regimen may vary in speed, dose, dosage interval etc., whereas sublingual treatment should follow the course indicated by the manufacturer and is therefore standardized to a higher degree. Data for Oralair trials indicated a better tolerability for systemic reactions with 2% (min/max: 1–4%), when compared with Grazax/Grastek with 6% (min/max: 1–13%). However, both products were comparable regarding mild reactions and withdrawals. The results are illustrated in fig. 1.

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Table 1. Comparison of ‘Summary of product characteristics’. Data are extracted from product inlets where available. Where possible, the frequency of each adverse event is compared. Variations in frequencies between products are emphasized using1. Subcutaneous immunotherapy

Infections and infestations Nasopharyngitis, rhinitis Oral herpes, otitis Blood and lymphatic system disorders Lymphadenopathy Immune system disorders Hypersensitivity, oral allergy syndrome Anaphylactic chock Psychiatric disorders Depression Nervous system disorders 1 Headache Dysgeusia, somnolence, dizziness Anxiety Eye disorders Eye pruritus, conjunctivitis, lacrimation increased Eye redness, eye oedema, dry eye Ear and labyrinth disorders 1 Ear pruritus Ear discomfort Vascular disorders 1 Flushing Respiratory, thoracic and mediastinal disorders Throat irritation Wheeze, cough, dyspnoea Asthma, rhinitis allergic (nasal congestion, sneezing, rhinorrhoea, nasal discomfort), cough, oropharyngeal pain, pharyngeal oedema, sinus congestion, dyspnoea, dysphonia, dry throat, oropharyngeal blistering, oropharyngeal discomfort Pharyngeal hypoesthesia, throat tightness, wheezing, laryngeal oedema Gastrointestinal disorders Oral pruritus 1 Mouth oedema 1 Abdominal pain, diarrhoea, vomiting, mouth oedema, tongue pruritus, lip oedema, paraesthesia oral, dyspepsia, tongue oedema, hypoaesthesia oral, stomatitis, lip pruritus, oral discomfort, nausea, glossodynia, dry mouth, dysphagia Oral pain, gingivitis, cheilitis, gastritis, glossitis, salivary gland enlargement, gastro-oesophageal reflux, tongue disorder, salivary hypersecretion, mouth ulceration, oesophageal pain, palatal oedema, oral disorder, odynophagia, eructation Skin and subcutaneous tissue disorders Urticaria, pruritus, atopic dermatitis Angio-oedema, rash, acne Face oedema General disorders and administration site conditions Chest discomfort Fatigue Lump feeling in throat, asthenia, Influenza like illness

Sublingual immunotherapy

ALK AluTard 225 Phleum Pratense [30]

Greer Laboratories, standardized grass pollen Extracts [24]

Grazax, GrasTek [9]

Oralair [10,11]

– –

– –

– –

C UC

–

–

–

UC

UC R

UC R

–

UC

–

–

–

UC

VC – –

– – –

C2 – –

VC2 UC R

C –

– –

– –

C UC

– –

– –

VC2 –

C2 UC

C

–

–

R

C –

– – –

VC – C

VC C C

–

–

–

UC

– – C3

– – UC3

VC VC C

VC C C

–

–

–

UC

C – –

– – –

C – –

C UC R

– – –

– – –

C C –

C – UC

(continued)

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Table 1. (continued) Subcutaneous immunotherapy

Sublingual immunotherapy

ALK AluTard 225 Phleum Pratense [30]

Greer Laboratories, standardized grass pollen Extracts [24]

Grazax, GrasTek [9]

Oralair [10,11]

VC3 C3

UC3 UC3

– –

– –

–

–

–

R

–

–

–

UC

1

Oedema at the site of injection Pruritus at the site of injection Investigations Eosinophil count increased Injury, poisoning and procedural complications Excoriation 1

–, No information available; VC, Very common, >10%; C, Common, 1–10%; UC, Uncommon, 0.1–1%; R, Rare, 0.01–0.1%; VR, Very rare, 0.001–0.01%; 1 Variations in frequencies between products. 2 Variance in prevalence between sublingual products. 3 Variance in prevalence between subcutaneous products.

Immunotherapy in general. Many of the surveys assessing the safety of immunotherapy make no distinction between the allergens used. Consequently, many of the major surveys give recommendations applicable to immunotherapy in general, regardless of allergen. In a survey from 2011 of North American allergologists [36], the overall prevalence of systemic reactions to SCIT was 2 in 1000 injections or 5–7% of treated individuals, with a slightly higher frequency for rush-up dosing (cluster). In another survey reported in the same paper, physicians were asked to report systemic reactions during a 12-month period, grading them as: Grade 1: cutaneous or upper respiratory; Grade 2: asthma with reduced lung function; or Grade 3: lifethreatening. Physicians reported a prevalence of systemic reactions in 0.1% of injections, the majority of cases, in total 74%, were Grade 1, 23% Grade 2 and only 3% Grade 3, corresponding to a prevalence of one (0.003%) Grade 3 reaction in 100,000 injection visits (i.e. where allergen was administered subcutaneously). More severe events in the form of fatalities have also been investigated. Before 2002, an estimated 3.4 fatal reactions were reported annually by the American Academy of Allergy, Asthma, and Immunology members, whereas between 2008 and 2012, only one confirmed fatality was reported based on 23.3 million injections, resulting in a 0.1% fatality rate [37]. Similarly, data from Makatsori and Calderon [38] demonstrate that very serious WAO Grade 4 systemic reactions in relation to SCIT treatment occur in 1 injection per one million injections; no fatal reactions have been reported for SLIT. In a recent update of practice parameters (i.e. clinical guidelines), Wallace et al. [39] estimate the fatality rate in SCIT to be 1 per 2.5 million injections. Risk factors for systemic reactions include asthma, injections from a vial with a wrong allergen concentration, concomitant treatment with beta-blockers, a high degree of skin test reactivity, and injections administered during symptom exacerbation. Sublingual immunotherapy, however, seems a safe alternative with few, if any, reported fatal reactions [40]. The vast majority of individuals undergoing SLIT (tablets or droplets)

experience translucent, mild local reactions at the site of application. Only a minority experience systemic reactions, and no difference in serious systemic reactions can be observed between active treatment and placebo [40]. The relation between common, local, reactions and more severe systemic reactions has been investigated several times in SCIT [41,42]. It has been demonstrated that the severity of local reactions does not predict systemic reactions. Similarly, local reactions do not predict recurrent local reactions [43]. Discussion There is no doubt that SLIT is easier to dispense for any doctor than is SCIT. However, until a double-blind, placebo-controlled, randomized trial comparing SCIT with SLIT has been conducted, it is not known whether the safety profile and/or clinical efficacy of the two products differs. SLIT is probably safer than SCIT, although there is far more clinical experience of SCIT. Adverse events in SLIT are generally few and, to date, none has been fatal. In contrast, the prevalence of adverse events is greater for SCIT, and several fatalities have been reported, although most were related to erroneous treatment regimens or accident use of the wrong allergen dosage. A recent meta-analysis by Di Bona et al. [4] suggests that SCIT gives better symptom control measured by symptom relief and use of rescue medication. However, the authors acknowledge that if safety is the primary concern, SLIT treatment may be preferred over SCIT regarding more severe reactions. Paradoxically, however, when including mild events, in one study, SLIT seems to be associated with more adverse events than is SCIT [4]. Treatment duration. Dranitsaris and Ellis [44] argued that Oralair was at least as effective as Grazax/Grastek or SCIT in treating AR; consequently, Oralair should be preferred due to the shorter treatment period and lower cost. Data from the clinical trials could indicate that systemic reactions are less frequent in Oralairtreated individuals when compared with Grazax/Grastek, but treatment duration may have influenced the results.

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Table 2. Overview of the prevalence of adverse events of sublingual immunotherapy with Timothy grass pollen extract (Phleum pratense), from Micromedex(r) 2.0. Numbers represent prevalence (%) during treatment. Note that some of the adverse events may be present even if persons are treated with placebo. Sublingual immunotherapy Adult

Cardiovascular Chest discomfort Dermatological Pruritus Gastrointestinal Dysphagia Lip Oedema Oedema of oral soft tissue Eosinophilic oesophagitis Erythema of mucous membrane of oral vestibule Indigestion Lip itching Oral itching Tongue itching Oral hypoesthesia Oral paraesthesia Oropharyngeal pain Throat irritation Tongue swelling Immunological effects Anaphylaxis Hypersensitivity reaction Neurological effects Headache Ophthalmic effects Itching of eye Otic effect Ear problem, pruritus Respiratory effect Reversible airway obstruction Asthma Couch Dyspnoea Oedema of pharynx Pharyngeal erythema Laryngopharyngeal swelling

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Placebo

Active

Placebo

1.6

0.5

2

0.5

2.4

1 0 0.2 0.8

7.2 9.8

0.5 0.2

4.9

0.9

Case reported

2.3

0.1

26.7 5.7 2.3 9.8

3.5 0.5 1 2

22.6 2.8

2.9 24.4 9.2

0.1 2.1 0.9

2.8 0.1

5.4 4 21.3 2.5

1.2 1.4 2.5 0

1.3

3.4

1.8

3.4

2.1

7.2

0.5

2.7 2 2.9 3.6

1.2 0.5 0 0.7

Case reported Case reported

2.1

12.5

1.1

Case reported Case reported

3.4

Grazax/Grastek

Oralair

Dissolve time Allergen composition

83% of individuals >65% of individuals

4

9

3

0

Treatment-related withdrawals, %

>19% of individuals

475 events (on average 17 for each individual)

Common

SCIT: few (no count) SLIT droplets: None 14 individuals

Total/mild–medium

Adverse events

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(continued)

There were no significant differences between the number of adverse events recorded in the active and placebo groups (27% versus 19%). The dominant reactions were mild local reactions, followed by respiratory symptoms (asthma, rhinitis). All adverse events occurred during updosing. 80% very mild local itching and swelling. 20% infection, malaise, rhinitis (70% of the placebo group) Local reactions, characterized by itching, transient local swelling and erythema at the injection site. No life-threatening events were observed. Most commonly oral pruritus or throat irritation of mild–moderate intensity for 10.5 days. Local reactions were the most common, oral pruritus, nasopharyngitis and mouth oedema. There was no difference in the frequency of adverse events between treatment groups. The majority of adverse events were mild, local reactions like swelling, redness and discomfort. No life-threatening adverse events occurred.

Minor, local side effects.

Comments

Table 4. Summary of safety reports in clinical trials investigating immunotherapy against grass pollen (Phleum Pratense)-induced allergic rhinitis. Note that data from placebo (not shown) may be comparable to the reported incidence of individuals undergoing active treatment.

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Cox et al. [62]

Pfaar et al. [63]

2012

2012

2011

2011

Blaiss et al. [60] Nelson et al. [61]

Wahn et al. [59] Didier et al. [26]

2009

2011

Authors

Year

SCIT

SLIT tablets (Oralair)

SLIT tablets (Grazax/Grastek) SLIT tablets (Grazax/Grastek)

SLIT tablets (Oralair) SLIT tablets (Oralair)

Administration route

400

233

207 in 4 months pre-seasonal treatment 207 in 2 months pre-seasonal treatment 175 individuals (5–17 years old) 208 individuals

139 children

Number of individuals in active treatment

3 individuals experienced urticaria, and 1 experienced asthma 1 individuals experienced urticaria 2 individuals experienced asthma 1 individual experienced dysphagia, uvular oedema, and pharyngeal oedema along with a flush/macular rash and chest 4% of individuals 1 palatal disorder (not treatment related) 1 neuroendocrine carcinoma (not treatment related) 5% experienced asthma episodes 4% experienced cough 7% generalized pruritus 9% urticaria

10 individuals (3 possibly linked to treatment)

2 individuals

Systemic/Severe

7 5

5

8

>70% of individuals

>77% of individuals

70% of individuals

7

>57% of individuals

70% of individuals

5

Treatment-related withdrawals, %

>83% of individuals

Total/mild–medium

Adverse events

Table 4. (continued)

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(continued)

Most common adverse events were mild local events (erythema, pain, pruritus, swelling). No severe reactions were reported

Oral pruritus, throat irritation, and nasopharyngitis. No asthma exacerbations were reported.

Oral pruritus and throat irritations were the most common adverse events The most common symptoms were oral pruritus, 35%; throat irritation, 29%; ear pruritus, 20%; oral paraesthesia, 14%; mouth oedema, 8%; and mouth inflammation.

>30% oral pruritus >15% throat irritation >6% mouth oedema All local reactions decreased with the length of treatment.

–

Comments

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Murphy et al. [64]

2013

SLIT tablets (Grazax/Grastek)

Administration route 139

Number of individuals in active treatment

SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy.

Authors

Year 12% of individuals 2 episodes of diarrhoea and urticarial. 1 episode of abdominal pain, Eustachian tube obstruction, and lip blister. 2 asthma events. 2 individuals experienced a treatment related adverse event requiring epinephrine and withdrawal from the study; one experienced swelling of lips; itchy mouth, tongue, and throat; and dysphagia, and the other itchy throat, itchy mouth, dry cough, labial hive, post-nasal drip, and uvula erythema. Both events occurred within 5 min. of the first treatment. 1 individual experienced and adverse event requiring epinephrine administration, but managed to stay in the study (itching under the tongue, throat, ears and nose, sneezing, rhinorrhoea, and throat irritation) 2 individuals experienced other systemic reactions (one individual: symptoms of light headedness, headache, sleepiness, and itching of ears; one individual: symptoms of light headedness and itching in mouth)

Systemic/Severe >74% of individuals

Total/mild–medium

Adverse events

Table 4. (continued)

6

Treatment-related withdrawals, %

NB no treatment efficacy of immunotherapy could be observed when comparing to placebo (negative result) Common symptoms were ear pruritus, mouth oedema, oral pruritus, oral paraesthesia and throat irritation. No individuals experienced signs of hypotension.

Comments

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Fig. 1. Plot of the percentage of study participants (%) who experienced adverse events either mild (often local) or systemic (i.e. outside the application area), or who withdrew from the study due to adverse events. Whiskers are minimum and maximum percentage. The figure cannot be used to determine whether differences are significant.

Immediately afterwards, she developed an acute asthma exacerbation, which upon arrival to the general practitioner’s office had developed into systemic anaphylaxis with a blood pressure of 90/50 mmHg. She was treated with adrenaline and recovered. Consequently, individuals who cannot complete upscale dosing with SCIT due to adverse events should not be started up with SLIT tablets. Clinical conclusions. We were unable to give any exact recommendations for using SCIT or SLIT as well as different SLIT products when initiating immunotherapy against grass pollen-induced AR. This was largely due to poor drug standardization and lack of unified safety data. Consequently, we conclude that immunotherapy should be undertaken using only highly standardized allergen extracts. Adverse event reporting should be done using the

WAO position paper for systemic reactions [16], and the MedDRA 14.1 symptom reporting for local reactions to SLIT [17]. However, our data clearly indicate that both SCIT and SLIT are very safe, and the efficacy of both treatments is well documented and is most likely comparable, albeit a head-to-head trial is needed for any definite conclusion. Acknowledgements We thank consultants Birgitte Klindt Poulsen and Lars Peter Nielsen from Aalborg University Hospital for their technical assistance with Micromedex. Conflict of Interest Vibeke Backer and Kristian Aasbjerg have previously received financial support for their research from ALK (Horsholm, Denmark). Kim Peder Dalhoff has nothing to declare.

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ADVERSE EVENTS IN GRASS POLLEN IMMUNOTHERAPY

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MiniReview

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