2016 Section 5 Green Book

LI ET AL

J ALLERGY CLIN IMMUNOL VOLUME nnn , NUMBER nn

75% of SLIT-treated patients. 41 Itching or irritation affecting the lips, tongue, ears, or throat are the most common reported symp- toms. Isolated gastrointestinal symptoms associated with SLIT, such as abdominal pain or nausea, can be considered local reac- tions caused by swallowing the tablet contents. If gastrointestinal symptoms occur in conjunction with other systemic symptoms, they would be considered systemic reactions. The European Academy of Allergy and Clinical Immunology allergy immunotherapy guidelines recommend withholding SLIT in patients with acute gastroenteritis, 42 and the US PIs for all 3 SLIT products recommend treatment discontinuation in patients who experience severe or persistent gastroesophageal symptoms. In the nearly 3 decades of SLIT use globally, a greater safety risk in patients with inflammatory gastrointestinal conditions, such as eosinophilic esophagitis or inflammatory bowel disease, has not been apparent. To date, 2 case reports of pollen SLIT–associated eosinophilic esophagitis have been reported. 43,44 A framework for grading local side effects of SLIT is available and might be helpful. This 3-grade classification system for SLIT local reactions based on the patient’s subjective accounting was developed with the intent of ‘‘improving and harmonizing the surveillance and reporting of the safety of SLIT.’’ 45 A framework for grading possible but rare systemic reactions is also available. 46 Most SLIT-induced local reactions occur shortly after treat- ment initiation and cease within 2 weeks without any medical intervention. The duration of local reactions generally does not exceed 10 days. 47 There have been no studies evaluating the effect of antihistamine premedication on the incidence or severity of SLIT-induced local reactions, but expert opinion would support the use of antihistamines in the treatment of a local reaction. Although the overall dropout rate in double-blind, placebo- controlled trials was similar between groups, dropouts because of adverse events (mostly because of persistent local reactions) were significantly greater in the SLIT groups compared with the placebo groip. 41,48 Patients should be educated about SLIT-induced local reactions before therapy initiation. Patient education regarding treatment- related adverse events might improve adherence and decrease early withdrawal from treatment. Patients should be instructed to contact the physician’s office if local reactions persist or if they have gastrointestinal symptoms, an asthma exacerbation, difficulty breathing, or signs and symptoms of anaphylaxis. Box 2. Tablet administration in children In children SLIT doses should be administered under the direct super- vision of an adult. It is important that the tablet remain under the tongue for at least 1 minute until fully dissolved. There is no evidence that premedication with an antihistamine will prevent local reactions. Parents should be prepared for the likelihood of local reactions before their child starts SLIT and instructed to contact the office if local reactions persist and are troublesome. Box 1. Tablet administration for adults For all 3 SLIT products, the tablet should be placed under the tongue immediately after removal from the blister packet and allowed to dissolve completely. The first dose should be administered in the office under the supervision of a physician with experience in the diagnosis and treatment of acute allergic reactions. The patient should be observed for at least 30 minutes after administration for signs or symptoms of a severe systemic or local reaction. According to the PIs, the tablet should not be taken with food or beverage, and no food or beverage should be ingested for 5 minutes after taking the tablet.

The incidence of fatal and near-fatal systemic reactions with SCIT and SLIT suggests that the SLIT systemic reaction rate is significantly lower and severe systemic reactions are relatively uncommon when compared with SCIT. A comprehensive review of 104 SLIT studies published through October 2005 found that the systemic reaction rate was 0.056% of doses administered. 41 In a post hoc analysis of randomized controlled trials of timothy tablet that included 3314 adults and 881 children, there was no evidence of increased systemic allergic reactions or severe local allergic swelling in the adults or children with asthma (24 and 31%, respectively) compared with the subjects without asthma. 49 Severe anaphylaxis (World Allergy Organization grade 4) is rare with SLIT. The European experience suggests that after administration of more than a billion doses, no SLIT-related fatalities have occurred. Although the prescribing information for FDA-approved SLIT products recommends that patients have an epinephrine autoinjector, epinephrine autoinjectors usually are not prescribed in other parts of the world. Because SLIT generally is administered in a setting without direct medical supervision after the initial dose, patients should be given instructions regarding recognition and management of adverse reactions and when SLIT should be withheld (eg, asthma exacerbation and acute gastroenteritis). IS SLIT EFFECTIVE AND SAFE FOR CHILDREN? The efficacy and safety of SLIT in children is similar to the efficacy and safety in adults. 3 In Europe 3 large, pivotal, multicenter double-blind, placebo-controlled trials, each with more than 200 children and adolescents with grass pollen al- lergy, consistently demonstrated an effect size comparable with the data in the adult trials. 19,50,51 The frequency of local and systemic reactions was similar to that of adults taking SLIT. In North America a double-blind, placebo-controlled trial in children with grass pollen allergy aged 5 to 17 years was conducted with 282 patients in 41 American and 8 Canadian sites. 52 Preseasonal and coseasonal SLIT treatment with timothy grass tablets resulted in a 26% reduction in mean total combined score relative to placebo. A single mild systemic reaction to the grass tablet was reported on day 1 of treatment. Also, in North America a randomized, placebo-controlled trial of timothy grass tablets in 1501 polysensitized children with grass allergy and adults aged 5 to 65 years found reductions in symptoms over the entire season and in the peak pollen season, confirming previous research. Efficacy was similar in children and adults. 49 The timothy grass SLIT tablet has been demonstrated to be safe and effective in treating children and adolescents aged 5 to 17 years. The 5-grass product has been approved for patients aged 10 to 17 years, although a subanalysis of one of the trials demonstrated that the 5-grass tablet in schoolchildren aged between 5 and 11 years had an efficacy similar to that in the subgroup of adolescent patients aged between 12 and 17 years. 53 The grass pollen tablets gained European market authorization for ages 5 years and up. However, additional ev- idence of efficacy and safety in children aged 5 to 9 years is required by the FDA before approval for that age group can be granted (also see the section on long-term benefits of SLIT below).

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