2016 Section 5 Green Book

LI ET AL

J ALLERGY CLIN IMMUNOL VOLUME nnn , NUMBER nn

TABLE II. Systematic reviews comparing sublingual and subcutaneous immunotherapy

Indirect

Head to head

Di Bona et al, 2012 7

Dretzke et al, 2013 8

Chelladurai et al, 2013 9

Kim et al, 2013 10

Key findings

No. of RCTs

17 SCIT vs placebo 22 SLIT vs placebo

17 SCIT vs placebo 11 SLIT vs placebo

8 SCIT vs SLIT

3 SCIT vs SLIT, pediatric only

SMD 5 SCIT vs placebo, 2 0.92 (95% CI, 2 1.26 to 2 0.58) SMD 5 SLIT-D vs placebo, 2 0.25 (95% CI, 2 0.45 to 2 0.05) SMD 5 SLIT-T vs placebo, 2 0.40 (95% CI, 2 0.54 to 2 0.27) 2 0.58 (95% CI, 2 0.86 to 2 0.30) SMD 5 SLIT-D vs placebo, 2 0.37 (95% CI, 2 0.7 to 0.0) SMD 5 SLIT-T vs placebo, 2 0.30 (95% CI, 2 0.44 to 2 0.16)

SSD 5 SCIT vs SLIT, 0.35 (95% Crl, 0.13 to 0.59) Favoring SCIT

Symptom score

Moderate-grade evidence Favoring SCIT

Low-grade evidence Favoring SCIT

Medication score SMD 5 SCIT vs placebo,

SSD 5 SCIT vs SLIT, 0.27 (95% Crl, 0.03 to 0.5) Favoring SCIT

Low-grade evidence, no difference in

Low-grade evidence Favoring SCIT

treatment effectiveness between SCIT and SLIT

Safety

SCIT: 0.86 AEs/patient SLIT: 2.13 AEs/patients Anaphylactic episodes SCIT/SLIT: 12/1

NR

Local reactions (frequency) SCIT: 20% SLIT: 7% to 56% Anaphylactic episodes SCIT: 1 SLIT: 0

Local reactions (patients) SCIT: 3 SLIT: 3 Systemic reactions (patients) SCIT: 4 SLIT: 0 Anaphylactic episodes SCIT: 1 SLIT: 0

Adapted from Chelladurai and Lin. 11 AE , Adverse event; Crl , credible interval; NR , not reported; RCTs , randomized controlled trials; SLIT-D , sublingual immunotherapy drops; SLIT-T , sublingual immunotherapy tablets; SMD , standardized mean difference; SSD , standardized score difference.

d Doses are expressed in allergy units that are different for each product and not comparable. See Table IV 30-36 for various optimal maintenance doses in micrograms based on dose-ranging studies. d The 5-grass product is available in 2 strengths (100 and 300 IR). For children and adolescents aged 10 to 17 years, the dose is increased over the first 3 days (‘‘updosing’’): on day 1, a 100-IR tablet is given; on day 2, two 100-IR tablets are given; and on day 3 and after, the 300-IR tablet (same as for adults) is given. For the ragweed and timothy grass products, children and adults take the same dose (ie, a single tablet daily over the prescribed time period) with no updosing. d Treatment with the ragweed and timothy products is initi- ated at least 12 weeks before the expected onset of the sea- son and continued throughout the season, and treatment with the 5-grass product is initiated at 16 weeks before the expected onset of the season and continued throughout the season (ie, the ‘‘precoseasonal’’ regimen). Some studies suggest that benefits might be seen if treatment is started at 8 weeks before or at onset of season. 37-39 The timothy product has an option of continuous year-round treatment. According to the PI, ‘‘for sustained effectiveness for one grass pollen season after cessation of treatment, [the product] may be taken daily for three consecutive years.’’ Regarding missed doses, the PIs for the short ragweed and timothy grass products state that ‘‘data regarding the safety of restarting treatment after missing a dose of [the product] are limited. In the clinical trials, treatment interruptions for up to seven days were allowed.’’ No data on missed doses are available for the 5-grass product. The medication guide for patients for all 3 products states the following: ‘‘If you forget to take [the product], do not take a double dose. Take the next dose at your normal

IS SLIT MORE EFFECTIVE THAN ALLERGY MEDICATIONS?

No direct head-to-head studies comparing the efficacy of SLIT with medications in the treatment of seasonal or perennial allergic rhinitis have been published because all SLIT trials have allowed for rescue medication use. Therefore only indirect comparisons are possible. An indirect comparison was conducted through a meta-analysis of large (>100 patients), double-blind, placebo- controlled trials evaluating the efficacy of SLIT 5-grass pollen/ timothy grass tablet or allergy medications for seasonal allergic rhinitis. 27 Twenty-eight publications on symptomatic medication trials and 10 publications on SLIT trials met the inclusion criteria and were evaluated (total n 5 21,223). The authors stated the following: ‘‘The SLIT tablets had a greater mean relative clinical impact than second-generation antihistamine and montelukast and much the same mean relative clinical impact as nasal corticosteroids.’’ 27 This indirect comparison suggests that SLIT can be as good or better than as-needed medications. In addition to providing a similar magnitude of improvement, SLIT can provide sustained benefits for 2 years after discontin- uation after 3 years of continuous treatment. 28 Whereas the medications for allergic rhinitis only alleviate symptoms and do not provide sustained benefits after discontinuation, 29 SLIT is a disease-modifying approach that has the potential to affect the course of the condition over time. WHAT ARE EFFECTIVE DOSE REGIMENS FOR SLIT? WHAT HAPPENS IF A DOSE IS MISSED? The 3 US-licensed products showed comparable efficacy within the investigated dose ranges. Therefore we recommend following the instructions in the product PIs, keeping the following points in mind:

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