December 2007
1. Dosing practical issues: build-up schedule, dose, dosing frequency and duration
a) What is the effective SLIT dosing range?
Until recently, the majority of sublingual immunotherapy (SLIT) studies had been in a relative small number of patients. In these studies, a consistent relationship between allergen dose or treatment duration and outcome has not been established.1 Efficacy has been demonstrated over a wide range of doses: ranging from 10 nanograms of Fel d 12 to 314 micrograms of Amb a 13. In some studies the effective dose was 300 times
the usual SCIT dose.3 Lack of efficacy, in at least the first year, has also been demonstrated over a similar wide range of doses.
In contrast the effective dosing range for subcutaneous immunotherapy (SCIT) appears to be 5 to 20 micrograms of major allergen.
In past few years, several studies that included large patient populations (up to 855 patients) have demonstrated a clear dose-response relationship for SLIT for single year studies.4-6 The effective dose in one of the largest multi-center studies was 15 mcg of Phl p 5 given daily as a tablet.5 The demonstrated effective dose of timothy grass by administered subcutaneoussly is between 15 – 20 mcg Phl p 5 monthly.7, 8 Therefore the demonstrated effective SLIT dose for timothy grass is equivalent to 22.5 times the cumulative monthly dose given by SCIT.
b) What is the dosing regimen used and how can these higher
doses be achieved with SLIT?
The allergen extracts used in many of the SLIT studies were the same as the SCIT extracts (glycero-saline solutions). Higher doses were achieved by administering the allergen extract more frequently. Many of the recent SLIT studies have used a daily maintenance dosing regimen with one of the rationales being improved compliance. There have been very few studies that have compared dosing frequency regimens and they have produced conflicting results: daily dosing did better than 3 times a week in one study9, 10 and the reverse was found in the other study although here each dosing group consisted of just 12 patients. 9, 10 The most effective dose was the lowest in both studies.9, 10 One study that compared three schedules: one drop given once, twice or three times a daily dosing found greater efficacy in the three times a day dosing group but this group also received the higher dose.11
2. How does the efficacy of sublingual immunotherapy compare to
injection Immunotherapy?
In a review of SLIT studies published before November 2005, 15/39 (38%) double-blind, placebo-controlled (DBPC) or randomized controlled (RC) studies that provided symptoms and mediation score for the primary disease studied demonstrated no efficacy in either parameter in the first treatment year.1 In the same review, 8 of the DBPC or RC studies which had not demonstrated efficacy the first year did demonstrate some efficacy in either symptoms, medication scores or both in the second or third year of treatment. In contrast, clinical improvement with SCIT, the standard to which SLIT is compared, may be demonstrated very shortly after the patient reaches the maintenance dose 7, 12-15 and the Allergen Immunotherapy Practice Parameter recommends considering discontinuing SCIT if clinical improvement is not apparent after one year of maintenance therapy.
One double-blind, double-dummy, placebo-controlled study of SLIT vs. SCIT in birch allergic rhinitis patients found a greater magnitude of improvement in the SCIT group compared with the SLIT group: SLIT diminished the median symptom scores to one-half and SCIT to one-third of those recorded with placebo treatment. The difference between active treatment groups was not statistically significant, possibly due to the small number of patients at the completion of study may (type II statistical error).16
A comparison of two Cochrane meta-analysis of SLIT17 and SCIT18 for allergic rhinitis also found that the magnitude of improvement with SCIT may be greater than SLIT:
Symptom reduction with SCIT [standardized mean difference (SMD) of -0.73 (CI -0.97,-0.50)] compared with SLIT [SMD of -0.42 (CI -0.69, -0.15)] and Medication reduction with SCIT [SMD of -0.57 (CI -0.82,-0.33)] compared with SLIT [SMD of -0.43 (CI-0.63, -0.23)]
3. Can SLIT be used to treat polysensitized patients?
With the exception of one study19, there have been no SLIT studies that have utilized more than one non-cross reacting allergen. This open-labeled, controlled study investigated the efficacy of combined birch and grass SLIT in comparison to single allergen SLIT or medications only in patients allergic to both allergens. Efficacy was seen during both the birch and grass season in the patients who received both allergens, but there was also improvement in clinical scores and nasal eosinophil counts scores in the patients treated with a single allergen compared with baseline and the untreated control group in both seasons (i.e., the target and unrelated pollen season). The majority of allergic US patients are sensitive to more than one allergen: in one skin test survey of a large population of asymptomatic people (NHANES III) the median number of positive skin test skin test was
three.20 The number of positive skin tests in each individual is greater in the allergic population.
4. How does the safety of SLIT compare to injection Immunotherapy?
One of the purported advantages of SLIT over SCIT is greater safety, which would allow for home administration. Adverse reactions do occurs with oral-pharyngeal symptoms (pruritis, lip swelling, etc.) being relatively common during the build-up phase. In the double-blind, double-dummy study comparing SCIT with SLIT discussed in talking point 2, systemic reactions occurred in all three treatment groups: SLIT, 15 grade 2 reactions and in SCIT 14 grade 2 and5 grade 3 reactions plus 1 grade 4 reaction (1993 EAACI classification)
No fatalities have been reported with SLIT, but there have been two cases of anaphylaxis to mixtures of inhalant allergens and one case of anaphylaxis during latex rush 21, 22 23 One episode occurred in a 13 year old girl who had tolerated a course of SLIT one and half years earlier.22 The reaction occurred one month after she had reached the maintenance dose and during the peak of spring season, when she received high dose SLIT for house dust mite in the morning and high dose SLIT for a mix of grass pollen in the evening. The other case was a patient with allergic rhinitis and asthma who was prescribed a sublingual immunotherapy extract composed of multiple non-cross reacting allergens (Alternaria, dog, cat, ragweed mix, weed mix and grass mix).23 She developed generalized pruritus followed by angioedema, shortness of breath and dizziness within a few minutes of self-administering 6 drops of the 1:100 v/v dilution on the third day of treatment. This episode was preceded by a milder systemic reaction the previous day (generalized pruritus).
There have been no studies of SLIT to date in high risk patients (e.g., severe asthma or patients who have had multiple severe systemic reactions with SCIT).
5. What about patient compliance with SLIT?
There have been a few studies specifically designed to assess patient compliance with SLIT using either unscheduled telephone requests to count remaining tablets or measuring remaining extract on clinic visits and they reported high compliance in 70 to 97% of patients, which was defined as taking medications greater than 80 or 90 % of the time.24-26
One study prospectively investigated compliance with three immunotherapy methods, SLIT, SCIT and nasal (NIT) in 2774 children by determining the number of patients who withdrew before completing 3 years of treatment.27 The highest noncompliance rate was seen in the NIT group (73.2% of patients) followed by SLIT (21.5% of patients) and SCIT (10.9 % of patients).
6. What sort instructions should be provided to patients receiving
SLIT treatment?
One important factor to consider is that SLIT treatment is administered at home with no direct medical supervision. Physicians will need to provide specific instructions to the patients on how to manage adverse reactions, unplanned treatment interruptions, situations in which the dose should be withheld, and dosing adjustments for any or all of these variables. Other considerations include whether injectable epinephrine should be routinely prescribed, patients ability to comply with the regimen and patient’s response to potential adverse reactions.
7. Can I get reimbursed for SLIT?
There is no FDA approved formulation and no CPT (billing code)
for this therapy in the United States. An FDA approved SLIT formulation would be needed in order to apply for a new reimbursable CPT code. Medicare specifically states that it does not cover sublingual immunotherapy (see below excerpt). Most insurers would not reimburse for SLIT services if there is no CPT code or FDA approved formulation and the patient would have to pay for SLIT.
Source: Page 14 of Medicare National Coverage Determinations Manual
Chapter 1, Part 2 (Sections 90 – 160.25) Coverage Determinations (Rev. 45, 12-06-05)110.9 – Antigens Prepared for Sublingual Administration (Rev. 1, 10-03-03) CIM 45-28
For antigens provided to patients on or after November 17, 1996, Medicare does not cover such antigens if they are to be administered sublingually, i.e., by placing drops under the patient’s tongue. This kind of allergy therapy has not been proven to be safe and effective. Antigens are covered only if they are administered by injection.
8. How has the European market been impacted by the introduction
of SLIT?
In parts of Europe, such as France and Italy, SLIT is the most commonly prescribed form of new immunotherapy. According to the financial reports of one of the largest allergen extract manufacturers in Europe, the SCIT market has continued to grow despite the increased use of SLIT (http://www.alk-abello-investor.com).
9. Will SLIT be included in the practice parameters?
At the present SLIT is considered investigational in the United States and the current Allergen Immunotherapy Practice Parameter. 28 Specific practice parameters will not be developed until there is an FDA approved formulation for SLIT. The new ARIA guidelines, however, do consider SLIT as an acceptable treatment.
References
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