2016 Section 5 Green Book

75% of SLIT-treated patients.

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,

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.’’

A framework

for grading possible but rare systemic reactions is also available.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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