Sublingual Immunotherapy as a Technique of Allergen-Specific Therapy
Sublingual immunotherapy(SLIT) using Oralair®, Grastek®, or Ragwitek® may be considered medically necessary, when used according to FDA-labelling, for the treatment of pollen-induced allergic rhinitis when the following conditions are met:
Sublingual immunotherapy as a technique of allergy immunotherapy is considered investigational for all other uses.
Use of Oralair®, Grastek®, and Ragwitek® (1-3)
Documentation of Allergy
Allergy must be confirmed by positive skin test or in vitro testing for pollen-specific IgE antibodies to the species contained in the product or, for Grastek®, Timothy grass pollen extract, to cross-reactive species.
Contraindications include severe, unstable or uncontrolled asthma; history of any severe local reaction, or any severe systemic allergic reaction to SLIT or any severe local reaction to sublingual allergen immunotherapy; and history of eosinophilic esophagitis.
Administration and Dose
Table 1. Oralair® Dosing in Patients Age 10 to 17 Years (1)
IR: index of reactivity, a potency unit defined by the formation of a 7 -mm wheal in 30 sensitized individuals during product development. (1)
Pharmacotherapy of Pollen-Induced Allergic Rhinitis
Several clinical practice guidelines describe pharmacologic treatments of pollen-induced allergic rhinitis/rhinoconjunctivitis. (4-8) There is general agreement that:
Six medication classes are used to treat allergic rhinitis:
Sublingual immunotherapy (SLIT) is a potential alternative to subcutaneous immunotherapy (SCIT) for providing allergen-specific therapy. SLIT is proposed as a more convenient alternative delivery route for treating a variety of allergic disorders.
Allergen -specific immunotherapy involves administering well-characterized allergen extracts, the potencies of which are measured and compared with a reference standard. An initial induction or build-up phase progressively increases the allergen dose; this is followed by multiple years of maintenance injections at the highest dose. Allergen-specific immunotherapy has been used to treat a variety of conditions including insect allergy, allergic rhinitis, and asthma. SCIT is the standard approach. Due to the inconvenience of multiple injections, particularly in children, alternative delivery routes have been investigated; of these, SLIT is the most prominent. SLIT targets absorption to the sublingual and buccal mucosa. Allergen preparations used for SLIT are held under the tongue for one to several minutes and then swallowed or spit out.
In April 2014, FDA approved the first sublingual allergen extract tablets for treatment of pollen-induced allergic rhinitis with or without conjunctivitis.
Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.
This policy is based on a 2003 TEC Assessment. (9) The policy was updated regularly with literature reviews using MEDLINE; most recently, the literature was searched through March 11, 2015. Following is a summary of key literature to date.
At the time of the 2003 TEC Assessment, there were 21 published randomized controlled trials (RCTs) comparing sublingual immunotherapy (SLIT) to placebo suggesting that SLIT decreased 1 or more symptoms in patients who had pollen or dust mite allergies. Systemic adverse effects occurred in only one study, and these were not life -threatening. However, whether SLIT improved health outcomes when compared with subcutaneous allergen-specific immunotherapy (SCIT), the criterion standard comparison, could not be determined from the available evidence. Due to the paucity of studies comparing SLIT with SCIT and the lack of U.S. Food and Drug Administration (FDA)-approved agents for use in SLIT, the use of SLIT for allergen immunotherapy was considered investigational.
Since the TEC Assessment, numerous placebo-controlled RCTs and meta-analyses of RCTs have been published. Some of the representative meta-analyses and reviews of meta-analyses are discussed next, as well as some of the key individual RCTs.
Several reviews of meta-analyses have been published. In 2011, de Bot et al. evaluated the quality of systematic reviews and meta-analyses of SLIT for treating allergic rhinitis in children. (10) Investigators used the Assessment of Multiple Systematic Reviews (AMSTAR) quality evaluation tool to rate the reviews. The maximum score on the AMSTAR is 11; scores of 0 to 4 indicate low quality; 5 to 8, moderate quality; and 9 to 11, high quality. The authors identified 10 systematic reviews. None were rated as high quality, 6 were rated as moderate quality, and 4 as low quality. This analysis indicated that although there are numerous systematic reviews on SLIT, methodologic quality is suboptimal. This research suggests that SLIT for children may be promising, but methodologic flaws preclude definitive conclusions.
In 2009, Compalati et al. evaluated meta-analyses of RCTs on specific immunotherapy for respiratory allergy. (11) They identified 7 meta-analyses of placebo-controlled RCTs using well-defined inclusion criteria, allergens, doses, and outcome measurements; 5 assessed SLIT, and 2 assessed SCIT. Regarding SLIT, this analysis corroborated existing evidence for efficacy of SLIT compared with placebo and areas of uncertainty, particularly regarding optimal dose. This review highlighted the lack of consistent relationships between treatment dose, duration, and clinical efficacy.
Numerous individual systematic reviews with meta-analyses have been published. In 2014, Devillier et al. in France published a systematic review with meta-analyses of SLIT and pharmacotherapy for seasonal allergic rhinitis. (12) Only well-powered (≥100 patients in the smaller treatment arm), placebo-controlled, randomized trials were included (28 pharmacotherapy trials and 10 SLIT trials; total number of patients = 21,223). Studies evaluated children and adults. Because of methodologic heterogeneity across trials (e.g., in symptom scales used), results from individual trials were standardized relative to placebo effects to permit meta-analysis. Pooled percentage improvements in symptom scores were: 30% for 5-grass pollen SLIT, 24% for nasal corticosteroids, 19% for timothy pollen SLIT, 17% for combination azelastine-fluticasone, 15% for H1 antihistamines, and 7% for montelukast.
In 2013, Lin et al conducted a comparative effectiveness review for the Agency for Healthcare Research and Quality (AHRQ) on allergen-specific therapy for treating allergic rhinoconjunctivitis and/or asthma. (13) The authors identified 60 studies comparing SLIT with placebo or another intervention. (Studies that used SCIT as the comparator were evaluated separately; see following section on SLIT compared with SCIT.) Over two thirds of the studies (71%) compared SLIT with placebo, 14% compared SLIT with pharmacotherapy or rescue medication, and 15% compared SLIT with another intervention. Most studies (66%) evaluated seasonal allergens, 31% evaluated perennial allergens, and the remainder addressed both types of allergens. About half of studies used only 1 allergen, and the other half used multiple allergens. Only 22% of the studies were rated as having a low risk of bias. Most (68%) were considered to have a moderate risk of bias and 14% to have a high risk of bias. The authors did not pool study findings because of heterogeneity among studies, e.g., in types and sources of allergen extracts, treatment duration, and outcome scoring systems used. The review concluded that there was high-grade evidence that SLIT improved asthma symptoms compared with placebo or another intervention (13 RCTs) and moderate-grade evidence that SLIT improved rhinitis/rhinoconjunctivitis symptoms compared with placebo or another intervention (35 RCTs). There was moderate-grade evidence that SLIT improved other outcomes in this population, e.g., decreased medication use and increased quality of life. Lin et al also published the findings of the systematic review in a peer-reviewed journal in 2013. (14) The review focused on studies comparing SLIT with placebo, pharmacotherapy, or another SLIT regimen and did not address SCIT. Like the AHRQ review, study findings were not pooled. The authors noted that high-quality studies are needed to determine optimal dosing strategies.
A 2013 systematic review and meta-analyses by the U.K. National Health Service evaluated the effectiveness of SCIT and SLIT for seasonal allergic rhinitis. (15) Literature was searched to April 2011, and 28 placebo-controlled RCTs were included (17 SCIT, 11 SLIT). Statistically significant moderate effect sizes for improvements in symptom scores, medication scores, combined symptom and medication scores, and quality-of-life measures favored active treatment. However, due to substantial heterogeneity in outcome measures, standardized mean differences were used for meta-analyses, rendering conclusions about clinical significance of the results uncertain. Meta-analysis of 9 SLIT studies in children yielded statistically significant results for symptom scores but not for medication scores.
A 2013 systematic review with meta-analyses by researchers in China evaluated SLIT for allergic asthma. (16) Literature was searched to May 2012, and 16 double-blind, placebo-controlled RCTs were included. Statistically significant reductions in symptom scores (standardized mean difference [SMD], 0.74, p=0.006) and medication scores (SMD=0.78, p=0.02) favored SLIT. The relative risk of adverse events was 2.23 (p=0.01). Also in 2013, researchers from Johns Hopkins University reported a systematic review of SCIT and SLIT in pediatric asthma and rhinoconjunctivitis. (17) Literature was searched through May 2012, and 34 RCTs were included. For SLIT, strength of evidence was high that SLIT improves asthma symptoms and moderate that SLIT improves rhinitis and conjunctivitis symptoms and decreases medication usage compared with placebo. Local adverse reactions were frequent.
A 2012 meta-analysis by Di Bona et al. focused on studies of immunotherapy in adults and children with seasonal allergic rhinitis. (18) Inclusion criteria were double-blind, placebo-controlled trials that evaluated natural grass pollen extracts for treating people with a history of grass pollen allergy. The authors identified 22 trials on SLIT versus placebo; 10 used sublingual drops, and 12 used tablets. The authors also identified 14 studies on SCIT versus placebo. The investigators conducted an indirect meta-analysis, evaluating the impact of SLIT and SCIT on outcomes, compared with placebo. Results of the meta-analysis indicated reduced symptoms and reduced medication use. Because studies used different scoring symptoms, effect size was calculated as SMD. Compared with placebo, both SCIT and SLIT (drops and tablets) resulted in significantly greater reductions in symptom and medication scores. For symptom scores versus placebo, effect sizes were SMD of -0.92 (95% confidence interval [CI], -1.26 to -0.58) for SCIT; SMD of -0.40 (95% CI: -0.54 to -0.27) for SLIT administered as tablets; and SMD of -0.25 (95% CI: -0.45 to -0.05) for SLIT administered as drops. Results were similar for medication use. Investigators noted that in pooled analysis, effect sizes were larger for SCIT versus placebo than for SLIT versus placebo.
A 2011 Cochrane review addressed SLIT for treating allergic conjunctivitis in adults and/or children. (19) Fifty-seven trials met inclusion criteria, and 42 of these had data available for meta-analysis. All trials were conducted in countries other than the United States. The primary outcome of the meta-analysis was the total ocular symptom score. In a pooled analysis of 36 trials (total N=3,399), there was a significantly greater reduction in total ocular symptom scores in the SLIT group compared with placebo (SMD = -0.41; 95% CI: -0.53 to -0.28; p<0.001). This review supported the conclusion that SLIT is moderately effective in reducing ocular symptom scores compared with placebo. Concerns about the overall quality of the evidence base remain.
In 2011, Radulovic et al. published a meta-analysis of double-blind, placebo-controlled RCTs on SLIT for allergic rhinitis in adults and/or children. (20) Sixty studies met inclusion criteria, and 49 of these (total N=4,589) had available efficacy data suitable for meta-analysis. Most studies (n=23) used grass pollen allergen extract; other allergens included ragweed, house dust mites, and trees. In a pooled analysis of study findings, there was a significantly greater reduction in symptom scores with active SLIT treatment compared with placebo (SMD = -0.49; 95% CI: -0.64 to -0.34; p<0.001). Additionally, pooled analysis found a significantly greater reduction in medication use scores with SLIT versus placebo (SMD = -0.32; 95% CI: -0.43 to -0.21; p<0.001).
There are dozens of RCTs in the published literature, and a comprehensive review of all RCTs is beyond the scope of this review. The key RCTs that were performed as part of the FDA approval process for specific SLIT products are reviewed next.
Information about 3 SLIT products currently FDA-approved for the treatment of pollen-induced (i.e., seasonal) allergic rhinitis with or without conjunctivitis was obtained from FDA documents and prescribing information. Published RCTs are cited when these were identified. All RCTs were placebo-controlled and double-blinded. Patients had had a minimum 2-year history of allergic rhinitis or rhinoconjunctivitis and received treatment for their symptoms during the previous pollen season. Patients with mild intermittent asthma were included (approximately 16% across all trials); all other patients with asthma were excluded. Polysensitized people were included in some trials. Precoseasonal dosing, i.e., commencing before the start of the allergen pollen season and continuing throughout the season, was used in all trials. The primary efficacy end point was the combined score (CS), defined as the mean of the Rhinoconjunctivitis Total Symptom Score (RTSS) and the Rescue Medication Score (RMS).
Although the CS is not validated, minimum clinically meaningful relative differences were prespecified. The relative difference (expressed as a percentage) was calculated by dividing the least squares mean difference by the within-group least squares mean of the placebo group. For Oralair® (Grastek® and Ragwitek®), a minimum 15 (20) percentage point relative difference favoring the active agent, with a minimum 10 (10) percentage point lower bound of the 95% CI: was required to demonstrate clinical efficacy. Analyses were intention-to-treat. (21,22)
Five pivotal trials were submitted to FDA in support of the biologics license application (BLA) for Oralair®; 4 were natural field trials (3 European, 1 United States), and 1 was an environmental exposure chamber trial conducted in Europe. Trial participants had a history of seasonal rhinoconjunctivitis for at least 2 grass pollen seasons. Patients in European trials also had a positive skin prick test to 5-grass pollen extract and positive serum immunoglobulin E (IgE) to Timothy grass; patients in U.S. trials had a positive skin prick test to Timothy grass pollen extract. Polysensitive people exposed to additional allergens during grass pollen season (e.g., who lived in areas where grass pollen season overlapped with tree or ragweed pollen season) were excluded. The pregrass pollen season treatment duration was 4 months in most trials. As shown in Table 2, all studies satisfied the FDA requirement for efficacy. (1,21) A sixth pivotal trial used a 2-month preseason treatment period and did not meet FDA criteria for efficacy. (23)
Trial 1: Phase III, Multicenter U.S. Trial (24)
Adults (N=473) age 18 to 65 years who had baseline RTSS of 12 or greater were randomized 1:1 to Oralair® 300 IR (index of reactivity) or placebo. Median duration of the grass pollen season was 43 days (range, 11-70). Median average pollen count was 32 grains/m3 (range, 4-215). Mean (SD) treatment duration was 180 (14) days, 127 (11) days before and 43 (15) days during the pollen period. Treatment adherence was 99% in both groups. Relative difference in the CS was 28% (95% CI: 13 to 43) favoring Oralair®.
Table 2. Results of 5 Pivotal Oralair® Trials
CI: confidence interval; EEC: environmental exposure chamber.
a Rhinoconjunctivitis Total Symptom Score.
Trial 2: European Dose-Finding Trial (25)
Adults (N=628) age 18 to 45 years were randomized 1:1:1:1 to 1 of 3 doses of Oralair® (100 IR, 300 IR, or 500 IR) or placebo. Mean (SD) duration of the pollen season was 30 (10) days. (Pollen season was defined by the first of 3 consecutive days with a grass pollen count above 30 grains/m3 to the last of 3 consecutive days with a pollen count below 30 grains/m3.) Mean treatment duration before the pollen period was 125 days. Adherence was 88% in the Oralair® 300 IR group and 96% in the placebo group. CS was not the original primary end point, and FDA analyzed results post hoc. Relative difference in the CS for 136 patients randomized to Oralair® 300 IR and 148 patients randomized to placebo was 30% (95% CI, 16 to 43) favoring Oralair®.
Trial 3: Phase III, 3-Year European Trial (26,27)
Adults (N=633) age 18 to 50 years who had baseline RTSS of 12 or greater were randomized 1:1:1 to 1 of 3 groups: Oralair® 300 IR initiated 4 months or 2 months before the grass pollen season or placebo. All patients were treated for 3 consecutive seasons, and efficacy outcomes were assessed during the third pollen season. Mean treatment duration for all 3 groups was 5.5 months per year. Treatment adherence exceeded 97%. CS was not the original primary end point, and FDA analyzed results post hoc. For 207 patients randomized to the 4-month Oralair® pretreatment group and 219 patients randomized to placebo, relative difference in the CS during the third pollen season was 38% (95% CI: 22 to 55) favoring Oralair®. In years 4 and 5, patients received no treatment. Relative differences in the CS did not meet FDA’s requirement for efficacy at these time points.
Trial 4: Phase III, European Pediatric Trial (28)
Children and adolescents (N=278) age 5 to 17 years (mean [SD], 11  years) who had baseline RTSS of 12 or greater were randomized 1:1 to Oralair® or placebo. The Oralair® group was dosed 100 IR on Day 1, 200 IR on Day 2, and 300 IR on each subsequent day. Mean (SD) duration of the pollen season was 39 (16) days. Mean (SD) treatment duration before pollen season was 113 (10) days. Treatment adherence was approximately 95% in both groups. CS was not the original primary end point, and FDA analyzed results post hoc. Relative difference in the CS was 30% (95% CI: 13 to 47) favoring Oralair®.
Trial 5: European Environmental Exposure Chamber Trial
Adults (N=89) age 18 to 50 years were randomized 1:1 to Oralair® or placebo for 4 months. Patients had pretreatment RTSS greater than 7 after challenge in an environmental exposure chamber (EEC) trial with 4 of the 5 grass pollens contained in Oralair®. Patients were again allergen challenged in the EEC at month 4. Because rescue medications are not permitted in the EEC, the primary efficacy end point was the mean RTSS during the 4-hour allergen challenge. Relative difference in mean RTSS was 29% (95% CI: 14 to 44) favoring Oralair®.
In the pooled FDA safety database, 1192 patients (13% children and adolescents) received Oralair® 300 IR. Adverse events that occurred only at higher doses were noted as potential safety signals.
In the pooled adult sample, the most common treatment-emergent adverse events (TEAEs) reported at higher frequencies with Oralair® than with placebo were oral pruritus (33% vs. 7%) and throat irritation (21% vs. 4%). Other TEAEs reported in more than 2.5% of Oralair® recipients and more commonly than in placebo recipients included tongue and ear pruritus; edema of the mouth, lip, tongue, or pharynx; oral paresthesia; and dyspepsia. Five percent of Oralair® recipients and 1% of placebo recipients withdrew from trials due to TEAEs. Serious adverse events occurred in 13 Oralair® recipients (1.3%) and 5 placebo recipients (0.6%). Of those occurring in Oralair® recipients, 1 episode of gastroenteritis requiring hospitalization was considered “possibly related” to Oralair®, and 2 episodes of laryngopharyngeal disorders occurring within 5 minutes of receiving the first dose of Oralair® were considered certainly related to Oralair®. (One laryngeal edema episode responded to intravenous prednisolone, and 1 severe hypersensitivity episode, characterized by violent coughing and extreme dyspnea, responded to antihistamine, beta-2 agonist, and prednisolone.) There were no reported deaths, cases of anaphylactic shock, or use of epinephrine in the pooled adult safety database.
The pooled child and adolescent safety database comprises 312 patients age 5 to 17 years; 45% of this sample was age 5 to 11 years (n=140). TEAEs reported at a higher frequency with Oralair® than with placebo were oral pruritus (33% vs. 4%), oral edema (13% vs 0%), and throat irritation (9% vs. 5%). Other TEAEs reported in more than 2.5% of Oralair® recipients were tongue, lip, and ear pruritus; tongue and lip edema; upper abdominal pain; and vomiting. As in the pooled adult sample, 5% of Oralair® recipients and 1% of placebo recipients withdrew from trials due to TEAEs. No serious adverse event was considered related to Oralair®. There were no reported deaths, cases of anaphylaxis, use of epinephrine, or severe laryngopharyngeal disorders in the pooled child and adolescent safety database.
Based on these findings, FDA considered Oralair® 300 IR safe in patients ages 10 to 65 years. “Because the small diameter of the upper airway of younger children may be more easily occluded during a laryngopharyngeal allergic reaction, and because of the low number of young children who have been studied in the pediatric clinical trial with Oralair®, CBER [Center for Biologics Evaluation and Research] has limited the indication of Oralair® to children 10-17 years of age. The indication for children 5-9 years of age will be re-evaluated upon completion of safety studies in these children, as mandated by PREA [Pediatric Research Equity Act].”
Subsequent observational studies have documented the tolerable adverse event profile of Oralair®. (21,29,30)
Six Phase III pivotal trials were submitted to FDA in support of the BLA for Grastek®. All were natural field trials; 4 were conducted in North America and 2 in Europe. Trial participants had a history of grass pollen-induced rhinitis with or without conjunctivitis, positive serum IgE to Timothy grass pollen, and baseline forced expiratory volume in 1 second (FEV1) greater than 70% of predicted value. Polysensitized patients who required treatment for non-grass pollen allergies during grass pollen season were excluded. Patients were randomized 1:1 to daily Grastek® 2800 BAU (bioequivalent allergy unit) or placebo. In 1 trial (Trial 3), patients continued dosing for 3 years continuously. Three of 6 studies (2480/3501 [71%] of total patients) met FDA criteria for efficacy (see Table 3).
Table 3. Results of 6 Phase III Pivotal Grastek® Trials
CI: confidence interval.
a Year 1.
b Did not meet FDA criteria for efficacy.
c Does not account for 407 patients (12%).
Trial 1: U.S. and Canada Adult and Pediatric Trial (31)
Patients (N=1501) age 5 to 65 years were randomized. Eighty-five percent of patients were polysensitized, and 25% had mild intermittent asthma. Median preseason treatment duration was 19 weeks (range, 11-27). Mean pollen season duration was 54 days. Mean pollen count was 23 grains/m3, consistent with a relatively weak pollen season. Relative difference in the CS was 23% (95% CI, 13 to 36) favoring Grastek® and meeting FDA criteria for efficacy.
Trial 2: U.S. and Canada Pediatric Trial (32)
Children and adolescents (N=345) age 5 to 18 years (mean, 12 years) were randomized. Eighty-nine percent of patients were polysensitized, and 26% had mild intermittent asthma. Median duration of grass pollen season was 56 days. Mean grass pollen count was 28 grains/m3. Median preseason treatment duration was 16 weeks (range, 2 days-22 weeks). Relative difference in the CS was 26% (95% CI, 10 to 38) favoring Grastek® and meeting FDA criteria for efficacy.
Trial 3: European Sustained Effect Trial (33,34)
Adults (N=634) age 18 to 65 years were randomized. Median preseasonal treatment duration was 27 weeks (range, 16-35). Patients continued treatment during 3 consecutive grass pollen seasons. Mean (SD) duration of the first pollen season was 58 (14) days (range, 16-86). CS was not the original primary end point, and FDA analyzed results post hoc. Relative difference in the CS at the end of treatment years 1, 2, and 3 were 34% (95% CI: 26 to 42), 41% (95% CI: 30 to 52), and 34% (95% CI: 21 to 46), respectively, all favoring Grastek® and meeting FDA criteria for efficacy. For 257 patients who remained on-study for 1 year after discontinuing Grastek®, relative difference in the CS was 27% (95% CI: 12 to 40) favoring Grastek® and meeting FDA criteria for efficacy. For 241 patients who remained on-study for 2 years after discontinuing Grastek®, relative difference in the CS was 23% (95% CI: 6 to 37) favoring Grastek® but no longer meeting FDA criteria for efficacy.
Trial 4: German Pediatric Trial
Children and adolescents (N=253) age 5 and 16 years were randomized. Patients initiated treatment with approximately 17 weeks (range, 8-23) before grass pollen season. CS was not the original primary end point, and FDA analyzed results post hoc. Relative difference in the CS was 24% (95% CI: 5 to 41) favoring Grastek® but failing to meet FDA criteria for efficacy.
Trial 5: U.S. Adult Trial
Adults (N=329) age 18 to 65 years were randomized. Median preseason treatment duration was 16 weeks (range, 6-24). CS was not the original primary end point, and FDA analyzed results post hoc. Relative difference in the CS was 10% (95% CI: 4 to 24) favoring Grastek® but failing to meet FDA criteria for efficacy. Post-hoc analyses suggested that baseline symptom scores and overlapping pollen seasons may have affected results. (35)
Trial 6: U.S. and Canada Adult Trial
Adults (N=439) age 18 to 63 years were randomized. Median preseason treatment duration was 17 weeks (range, 7-24). Relative difference in the CS was 21% (95% CI: 6 to 33) favoring Grastek® but failing to meet FDA criteria for efficacy.
The pooled FDA safety database comprises 2389 patients who received Grastek® (20% children and adolescents), 2116 (86%) of whom received Grastek® 2800 BAU. (22) An overview of TEAEs in the adult and child-adolescent pooled safety databases is shown in Table 4. The pattern of adverse events observed in the FDA safety database was similar to that in post-European registration market support trials of Grazax® (total N=1666). (35)
The most common TEAEs that led to trial discontinuation were oral pruritus (n=12), oral edema (n=7), and swollen tongue (n=6) among Grastek®-treated adults, and throat irritation (n=6) and oral edema (n=5) among Grastek®-treated children or adolescents. One adult patient who had severe swollen tongue required treatment with epinephrine. Systemic treatment-related allergic reactions (e.g., angioedema, dysphagia, cough) developed in 6 Grastek®-treated adults and 1 Grastek®-treated adolescent. All were considered nonserious and not severe, although epinephrine was administered for 3 of the systemic reactions; onset ranged from immediate to Day 42 of treatment. Among adults, 2 deaths were considered unrelated to Grastek®. In pediatric studies, there were no reported deaths. (35)
Based on these data, FDA estimated a 0.1% to 0.5% risk of severe or serious laryngopharyngeal or systemic reactions with Grastek®. (36)
Table 4. Overview of Treatment-Emergent Adverse Events in Grastek® Pooled Safety Databases
NR: not reported; TEAE: treatment-emergent adverse event.
FDA documents for Ragwitek® currently are unavailable; 2 pivotal trials are included in the prescribing information. (3) Both natural field trials that enrolled adults age 18 to 50 years who had ragweed pollen-induced allergic rhinitis with or without conjunctivitis, positive serum IgE to ragweed pollen, and baseline FEV1 at least 70% of predicted. As shown in Table 5, both trials met FDA criteria for efficacy.
Table 5. Results of 2 Pivotal Ragwitek® Trials in Adults
CI: confidence interval.
Trial 1: Phase II/III U.S. and Canada Dose-Finding Trial (37)
Adults (N=565) were randomized 1:1:1 to daily Ragwitek® 6 or 12 Amb a 1 units or placebo. (Amb a 1 units are FDA reference units; 1 Amb a 1 unit equals 1 mcg of the major short ragweed allergen, Ambrosia artemisiifolia). Patients began treatment approximately 12 weeks before short ragweed pollen season and continued treatment during and after the season, for a total treatment duration of 52 weeks.
Approximately 85% of patients were polysensitized, and 22% had mild intermittent asthma. Mean ragweed season duration was 44 days. Mean pollen count was 122 grains/m3. For 187 patients in the Ragwitek® 12 Amb a 1 unit group and 188 patients in the placebo group, relative difference in CS was 26% (95% CI: 14 to 38) favoring Ragwitek® and meeting FDA criteria for efficacy.
Trial 2: Trial II: Phase 3 U.S., Canada, and Eastern Europe Trial (38)
Adults (N=784) were randomized 1:1:1:1 to Ragwitek® 1.5, 6, or 12 Amb a 1 unit or placebo. Patients began treatment approximately 16 weeks before short ragweed pollen season and continued treatment during and after the season, for a total treatment duration of 52 weeks. Approximately 78% of patients were polysensitized, and 17% had mild intermittent asthma. The short ragweed pollen season lasted approximately 46 days. Mean pollen count was approximately 127 grains/m3. For 194 patients in the Ragwitek® 12 Amb a 1 unit group and 198 patients in the placebo group, relative difference in CS was 27% (95% CI: 14 to 39) favoring Ragwitek® and meeting FDA criteria for efficacy.
The pooled FDA safety database comprises 1057 adults who received at least 1 dose of Ragwitek®. The most common TEAEs in this group were throat irritation (17% vs. 3% in the placebo group), oral pruritus (11% vs. 2%), ear pruritus (10% vs. 1%), and oral paresthesia (10% vs. 4%). Four percent and 0.8% of Ragwitek®-treated and placebo-treated patients, respectively, discontinued treatment due to adverse reactions. Among Ragwitek®-treated patients, the most common adverse reactions that led to study discontinuation were oral edema, swollen tongue, and dysphagia.
In Trial 1 and Trial 2 (total N=962 Ragwitek®-treated patients), no deaths, systemic allergic reactions, or life-threatening events occurred. TEAEs tended to occur early in the treatment course (within the first week or weeks). Most (82% in Trial 1, 96% in Trial 2) TEAEs were mild to moderate in severity. In Trial 2, the most frequently reported adverse event leading to discontinuation was swollen tongue (n=10), all assessed as mild or moderate in severity. One patient required epinephrine for what was considered a progression of treatment-related local reactions.
House Dust Mite-Specific Allergy
Several placebo-controlled RCTs published in 2013 and 2014 assessed house dust mite (HDM)-SLIT in children and adults sensitized to HDM (primarily Dermatophagoides species) who have rhinitis (39-42) and/or asthma. (43-46) HDM-SLIT generally showed statistically significant reductions in rhinitis symptom scores in these trials, with reductions of approximately 20% in 1 study, (41) and a statistically significant decrease in daily dose of inhaled corticosteroid in HDM-sensitized patients with mild-to-moderate asthma. (44,45)
In 2014, Gendelman and Lang published a systematic review of HDM-SLIT in atopic dermatitis.47 Five studies (N=344) were identified, but low methodologic quality limited conclusions that could be drawn. In 2013, Bae et al. published a systematic review and meta-analysis of HDM immunotherapy for children and adults with HDM-induced atopic dermatitis. (48) Literature was searched through November 2012, and 8 placebo-controlled RCTs were included (6 SCIT [N=307], 2 SLIT [N=90]). Using a dichotomous variable for treatment success, defined as the proportion of patients whose condition improved as assessed by investigators or patients, regardless of evaluation method used, the odds ratio was 5.35 (95% CI: 1.61 to 17.77). The significance of this finding is uncertain given the heterogeneity of treatments administered and use of a nonstandard outcome measure.
Several authors have examined the role of SLIT in desensitizing people with food allergies. Two studies suggested that SLIT may be safely used to desensitize children and adolescents with peanut allergy in comparison with oral immunotherapy (49) or placebo, (49,50) but these studies were small (total N=90) and results are preliminary. Three-year follow-up of a placebo-controlled RCT50 showed a high rate of drop-out (>50%) and sustained responsiveness in only 4 (11%) of 37 SLIT-treated patients. (51) A 2014 systematic review of the literature through September 2012 identified 5 randomized trials of SLIT in patients with food allergies, 4 of which showed symptom improvement compared with placebo. (52) However, all trials were considered low quality; for example, most did not include symptom assessments off treatment. In a subsequently published, small, double-blind RCT, Narisety et al. (2014) showed greater efficacy of oral immunotherapy compared with SLIT in 21 patients with peanut allergy. (53)
In 2014, Romantsik et al. reported on a Cochrane review of oral immunotherapy and SLIT for egg allergy. (54) No RCTs of SLIT were identified through November 2013.
SLIT Compared With SCIT
Few published RCTs have compared SLIT and SCIT head -to -head. A 2012 review by Bahceciler and Galip listed 8 RCTs comparing SLIT and SCIT. (55) Sample sizes ranged from 20 to 58 participants. Three studies were published in the 1990s, and the other 5 were published between 2004 and 2012. Pipet et al. reported that none of the studies from the 1990s found a statistically significant difference in efficacy between the two routes of administration. (56)
Allergic Rhinoconjunctivitis and Asthma
Two indirect comparative effectiveness analyses published in 2014 and 2015 reached similar conclusions regarding relative efficacy of SLIT and SCIT for grass pollen allergies. (57,58) Both studies showed comparable reductions in allergic rhinitis symptoms with SLIT and SCIT, and 1 study showed comparable reductions in medication use. (58) Both studies found evidence for publication bias.
The 2013 AHRQ comparative effectiveness review, discussed earlier, identified 8 RCTs comparing sublingual and subcutaneous immunotherapy. (13) The report stated that only 1 study was considered to be at low risk of bias, and most studies had biases related to improper allocation concealment, unblinded interventions, and incomplete reporting of missing data. The authors were unable to pool studies due to heterogeneity. Regarding the question of comparative effectiveness of SLIT and SCIT, the report concluded that there was low-grade evidence that SCIT was more effective than SLIT at controlling allergy symptoms and dust mite allergy symptoms. Moreover, the report concluded that there was moderate-grade evidence that SCIT provided better symptom control for allergic nasal and/or eye symptoms than SLIT.
Also in 2013, Dretzke et al. published a systematic review that included an indirect comparison of SCIT and SLIT for seasonal allergic rhinitis using data from placebo-controlled trials. (59) Several outcomes were examined. For symptom score, the overall standardized score difference (SSD) was 0.35 (95% CI: 0.13 to 0.59), a statistically significant result that favored SCIT. The overall SSD for medication score was 0.27 (95% CI: 0.03 to 0.53) which was statistically significant in favor of SCIT. The authors noted that heterogeneity among trials was substantial and that any conclusion about the clinical significance of the difference in outcomes between SCIT and SLIT was tentative.
A 2013 systematic review by researchers at Johns Hopkins University reviewed SCIT and SLIT for pediatric asthma and rhinoconjunctivitis. (17) Three head-to-head studies published before June 2012 were identified. Low strength of evidence supported SCIT over SLIT for improving asthma and rhinitis symptoms and for decreasing medication usage. This same group subsequently reviewed head-to-head RCTs comparing SCIT and SLIT in adults and children. (60) Literature was searched through November 2012, and 8 RCTs were included. Moderate-grade evidence supported the greater effectiveness of SCIT compared with SLIT for improving nasal and eye symptoms. Low-grade evidence supported greater effectiveness of SCIT compared with SLIT for improving asthma symptoms and combined rhinitis symptom and medication scores.
In 2011, Sieber et al. published a meta-analysis of individual patient data from 4 observational studies on treatment of allergic rhinitis. (61) A total of 665 patients were treated with SLIT and 182 with SCIT. Median rhinitis symptom score decreased from 3.00 to 2.00 (range, 1.00-4.00) in both treatment groups (p<0.001, for within-group changes). Median conjunctivitis symptom score decreased from 2.00 to 1.00 (range, 0.00-3.00) in each group (p<0.001, for within-group changes). Additionally, median asthma symptom score decreased from 3.00 to 2.00 (range, 1.00-4.00) in each group (p<0.001, for within-group changes). There were no significant differences in symptom scores when the SLIT group was compared with the SCIT group.
In terms of the relative safety of SCIT and SLIT, the 2009 Pipet review (56) cites reports of fatalities after SCIT, although subsequent examination of 13 deaths occurring between 1992 and 1996 suggested that unstable asthma was a major risk factor. It is generally believed that SCIT is safe when performed with proper patient selection and established security principles. A 2012 review of SLIT for allergic rhinitis stated that no SLIT-related fatalities had been reported. (62) There may be a larger number of mild-to-moderate adverse effects with SLIT than with SCIT. The 2012 meta-analysis by Di Bona et al. (18) included 22 placebo-controlled studies on SLIT and 14 on SCIT. Investigators identified 960 adverse events (AEs) in patients who received SCIT (0.86 AE per patient) and 4,046 AEs in patients who received SLIT (2.13 AEs per patient). Most AEs were moderate severity. Although the authors did not report the total number of serious AEs, they stated that there were 12 episodes of anaphylaxis requiring epinephrine treatment in patients treated with SCIT and only 1 in patients treated with SLIT. There also were 2 reported episodes of anaphylaxis in patients treated with placebo in the SCIT studies.
A 2013 systematic review and meta-analyses by the U.K. National Health Service reviewed studies of seasonal allergic rhinitis published before April 2011. (15) AEs were common with both SCIT and SLIT, but most were local reactions at the point of administration and resolved spontaneously without treatment. Systemic reactions were less common, occurring with approximately 4% of injections for SCIT, and most were mild or moderate in severity. Of all systemic reactions, 19% were considered severe in patients taking SCIT compared with 2% in patients taking SLIT. Three percent of patients in both group discontinued treatment due to adverse events. No deaths occurred in any of the trials.
Three RCTs published in 2010 and 2011 compared the efficacy of dust-mite specific SLIT and SCIT and were published by investigators in Turkey. (63-65) Similar to older studies, none found statistically significant differences between treatment with SLIT and SCIT in overall reduction of symptoms or medication use. For example, Eifan et al. published findings on 48 children who had asthma or rhinitis and had been sensitized to house dust mites. (63) Participants were randomized to receive treatment with SLIT (n=16), SCIT (n=16), or usual pharmacotherapy alone (n=16). There was no significant difference in efficacy between the SLIT and SCIT groups. Compared with pharmacotherapy alone, both immunotherapy groups demonstrated significant reduction in rhinitis and asthma symptom scores and medication use scores.
A small 2013 RCT compared HDM-SCIT and HDM-SLIT in children with rhinitis and asthma who were monosensitized to HDM. (66) Thirty children were randomized to receive 1 or 2 years of SCIT or SLIT. Symptom scores were improved after 1 year of SCIT and after 2 years of SLIT. The significance of this finding is uncertain given the small sample size.
Ongoing and Unpublished Clinical Trials
A search of the online database, ClinicalTrials.gov, found 9 active trials of SLIT for allergies. These are summarized in Table 6. The first trial listed (NCT01335139) compares SLIT with SCIT using a double-placebo design in patients with seasonal allergic rhinitis. Several studies investigate HDM SLIT, and 1 (NCT02052934) investigates SLIT for enterotoxigenic Escherichia Coli.
Table 6. Active Trials of Sublingual Immunotherapy for Allergies
NCT: national clinical trial.
Summary of Evidence
Sublingual immunotherapy (SLIT) is a potential alternative to subcutaneous immunotherapy (SCIT) for providing allergen-specific therapy. Three new sublingual pollen extracts (1 multiple-allergen product [Oralair®], 2 single-allergen products [Grastek® and Ragwitek®]) were U.S. Food and Drug Administration (FDA)‒approved for treatment of pollen-induced allergic rhinitis with or without conjunctivitis. Large, well-designed, randomized controlled trials (RCTs) supporting the marketing applications for these products provide consistent evidence of efficacy and safety. Although trials were placebo-controlled, rather than SCIT-controlled, minimum clinically important criteria for demonstrating efficacy were prespecified and were met in most studies. Patients in these trials had received previous treatment for their pollen-induced rhinitis or rhinoconjunctivitis symptoms. Therefore, SLIT using Oralair®, Grastek®, or Ragwitek® may be considered medically necessary in patients with pollen-induced allergic rhinitis or rhinoconjunctivitis who have symptoms uncontrolled by pharmacologic treatment.
SLIT is being investigated for other allergies, (e.g., other seasonal allergies, food allergies, and in patients sensitized to house dust mites. Current evidence is insufficient to form any conclusion about the use of SLIT for these indications, and FDA-approved allergy extracts for these uses are lacking. Therefore, SLIT is investigational for all other uses.
Some evidence from clinical trials has been published on the comparative effectiveness of SLIT versus SCIT, but the quantity and quality of evidence is less than that for efficacy versus placebo. Several systematic reviews tended to find comparable outcomes or better outcomes with SCIT than with SLIT, but findings were inconclusive due to small numbers of trials and variability in study design. There also are insufficient data to draw firm conclusions about the relative safety of SLIT versus SCIT. A 2012 meta-analysis of placebo-controlled trials suggested that there may be more mild-to-moderate adverse events with SLIT than with SCIT, but there are data only on a few serious adverse events.
Practice Guidelines and Position Statements
American Academy of Allergy, Asthma and Immunology/European Academy of Allergy and Clinical Immunology
In 2013, the American Academy of Allergy, Asthma and Immunology (AAAAI) and the European Academy of Allergy and Clinical Immunology (EAACI) published a consensus report on allergy immunotherapy. (67) The report summarized the literature and current practices in the United States and Europe; it did not include clinical recommendations. The authors concluded, “AIT (allergy immunotherapy) is effective in reducing symptoms of allergic asthma and rhinitis, as well as venom-induced anaphylaxis. In addition, AIT modifies the underlying course of disease. However, AIT remains a niche treatment secondary to symptomatic drugs because of its cost, long duration of treatment and concerns regarding safety and effectiveness.…”
AAAAI Joint Task Force on Practice Parameters
In 2011, a joint task force of AAAAI, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology issued updated practice parameters for allergen immunotherapy. (68) The document stated that RCTs of SLIT in patients with allergic rhinitis and asthma have demonstrated significant improvement in symptoms. The authors noted that there were no FDA -approved extract formulations for a non-injection route of immunotherapy.
European Academy of Allergy and Clinical Immunology
In 2014, EAACI published evidence-based guidelines on the diagnosis and management of food allergy.69 Based on single-arm studies (level III evidence), guideline authors concluded: “Food allergen-specific immunotherapy for primary food allergy is a promising immunomodulatory treatment approach, but it is associated with risk of adverse reactions, including anaphylaxis; it is therefore not currently recommended for routine clinical use.” Based on expert opinion (level IV evidence), guideline authors stated: “For patients with respiratory or other allergy symptoms to inhalant allergens that may also cause cross-reactive food allergy, specific immunotherapy is only recommended for the treatment of the respiratory symptoms, not for cross-reactive food allergy.”
American Academy of Otolaryngology – Head and Neck Surgery Foundation
In 2015, the American Academy of Otolaryngology – Head and Neck Surgery Foundation published evidence-based consensus guidelines on allergic rhinitis.70 Based on RCTs and systematic reviews showing greater benefit than harm, guideline developers recommended SLIT or SCIT “for patients with allergic rhinitis who have inadequate response to symptoms with pharmacologic therapy with or without environmental controls.” The purpose of the statement was “to increase the awareness of immunotherapy as a treatment for allergic rhinitis, promote its appropriate use, and reduce unnecessary or harmful variation in care.”
World Allergy Organization
In 2013, the World Allergy Organization updated its position paper on SLIT. (71) Evidence-based conclusions included:
U.S. Preventive Services Task Force Recommendations
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
Unlisted allergy/clinical immunologic service or procedure
Type of Service
Place of Service
Add to Medicine Section - New Policy
Replace Policy - Scheduled review, no criteria changes.
Replace Policy - Policy regarding sublingual immunotherapy and SET-guided immunotherapy reviewed; policy statement unchanged.
Replace Policy - Policy revised with literature search; policy retitled, now focuses solely on sublingual immunotherapy; other forms of immunotherapy no longer addressed.
Update Scope and Disclaimer - No other changes.
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Replace Policy - Policy updated with literature search; no change to the policy statement. References added.
Replace Policy - Policy updated with literature review; no change in policy statement. References 8 and 11 added; other references renumbered/removed. ICD-10 codes added to policy.
Replace policy. Policy updated with literature review; no change in policy statement. References 2, 4, 5, 10-12 added; other references renumbered/removed.
Related Policies Update – Title to 2.01.01 has been changed to include: (i.e., Multiple Chemical Sensitivities)
Update Coding Section – ICD-10 codes are now effective 10/01/2014.
Replace policy. Policy updated with literature review through January 22, 2013; no change in policy statement. References 4, 8 and 14 added; other references renumbered/removed.
Replace policy. Policy updated with literature review through April 20, 2013. No change in policy statement. References 2, 3, 14, 17 and 18 added; other references renumbered/removed.
Annual Review. Policy statement changed to medically necessary for Oralair®, Grastek®, and Ragwitek® to treat grass or short ragweed pollen allergies when criteria are met. These medications are investigational for all other uses. Policy updated with literature review through April, 2014. References 1-8, 14-16, 20-42, 47, 52, and 55 added, 10 and 54 updated; 22 deleted; others renumbered/removed. Policy statement changed as noted. Coding update: CPT codes 95144-95165 and ICD-9 and ICD-10 diagnosis and procedure codes removed from policy.
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