Adults

The safety data described below are based on 6 clinical trials which randomized 3589 subjects 18 through 65 years of age with Timothy grass pollen induced rhinitis with or without conjunctivitis, including 1669 subjects who were exposed to at least one dose of GRASTEK. Of the subjects treated with GRASTEK, 25% had mild asthma and 80% were sensitized to other allergens in addition to grass. The subject population was 88% White, 7% African American, and 3% Asian. Subjects were 52% male, and 88% of subjects were between 18 and 50 years of age. Subject demographics in placebo-treated subjects were similar to the active group.

The most common adverse reactions reported in subjects treated with GRASTEK were oral pruritus (26.7% vs 3.5% placebo), throat irritation (22.6% vs 2.8%), ear pruritus (12.5% vs 1.1%) and mouth edema (11.1% vs 0.8%). The percentage of subjects who discontinued from the clinical trials because of an adverse reaction while exposed to GRASTEK or placebo was 4.9% and 0.9%, respectively. The most common adverse reactions that led to study discontinuation in subjects who were exposed to GRASTEK were pharyngeal edema and oral pruritus.

Seven adult subjects (7/1669; 0.4%) who received GRASTEK experienced treatment-related systemic allergic reactions that led to discontinuation of GRASTEK in four out of the seven subjects.

• Five of the seven subjects had reactions on Day 1 of treatment with GRASTEK. Symptoms included swelling of lips/mouth; oral/pharyngeal itching; ear itching, sneezing, rhinorrhea, throat irritation, dysphonia, dysphagia, chest discomfort, and rash. Three of the five subjects received treatment with epinephrine and antihistamines, and one of the three also received oral corticosteroids. One of the five subjects who had a reaction on Day 1 of treatment with GRASTEK also had a reaction on Day 2 of treatment with GRASTEK. Symptoms on Day 2 included oral burning sensation; rhinorrhea; and throat irritation.
• One of the seven subjects had a reaction on Day 2 after tolerating treatment with GRASTEK on Day 1. Symptoms included edema of the lower lip, epigastric discomfort and dizziness.
• One of the seven subjects developed chest tightness and shortness of breath on Day 42 of treatment with GRASTEK.

Adverse reactions reported in ≥1% of subjects treated with GRASTEK are shown in Table 1.

Adverse reactions of interest that occurred in ≤1% of GRASTEK recipients include abdominal pain and gastroesophageal reflux.

Pediatrics

Safety data are based on 3 clinical trials which randomized 881 subjects between 5 and 17 years of age with grass pollen induced rhinitis with or without conjunctivitis. Overall, 445 subjects received at least one dose of GRASTEK. Of the subjects treated with GRASTEK, 31% had mild asthma and 86% were sensitized to other allergens in addition to grass. The subject population was 86% White, 7% African American and 3% multi-racial. The majority (66%) of subjects were male. The mean age of subjects was 11.7 years. Subject demographics in placebo-treated subjects were similar to the active group.

The most common adverse reactions in pediatric subjects treated with GRASTEK were oral pruritus (24.4% vs 2.1% placebo), throat irritation (21.3% vs 2.5%) and mouth edema (9.8% vs 0.2%). The percentage of subjects who discontinued from the clinical trials because of an adverse reaction while exposed to GRASTEK or placebo was 6.3% and 0.7%, respectively.

One pediatric subject (1/447; 0.2%) who received GRASTEK experienced a treatment-related systemic allergic reaction consisting of lip angioedema, slight dysphagia due to the sensation of a lump in the throat, and intermittent cough which was of moderate intensity on Day 1. The subject was treated with epinephrine, recovered, and was discontinued from the trial.

Adverse reactions reported in ≥1% of subjects treated with GRASTEK are shown in Table 2.

Postmarketing Safety Studies

In European post-approval studies which included 1,666 patients treated with GRASTEK (marketed under the name GRAZAX), reported serious adverse reactions assessed as related to GRASTEK use included anaphylactic reaction, asthma exacerbation, hoarseness, laryngitis, oral ulceration, and ulcerative colitis exacerbation.

Included in these reports was an adult male with asthma who experienced anaphylactic shock within two minutes of administration of GRASTEK. The patient experienced depressed level of consciousness, hypotension, increased heart rate, wheezing, urticaria, and face edema.

Spontaneous Postmarketing Reports

The following adverse reactions have been identified during post-approval use of GRASTEK (marketed under the name GRAZAX in Europe). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These include: altered state of consciousness, anaphylactic shock, angioedema, asthma exercise induced, chest pressure, diarrhea, difficulty speaking, dizziness, drowsiness, eosinophilic esophagitis, erythema facial, face edema, forced expiratory volume decreased, heart rate increased, heart rate irregular, hyperventilation, hypotension, laryngeal discomfort, oral pain, oxygen saturation decreased, peak expiratory flow rate decreased, pneumonia, rash, respiratory distress, sensation of foreign body, status asthmaticus, swelling of neck, throat pruritus, tremor, vital capacity decreased, vomiting, and wheezing.

Eosinophilic esophagitis has been reported following treatment with GRASTEK (marketed under the name GRAZAX). The clinical details of some postmarketing reports are consistent with a drug-induced effect, including at least one case with resolution of symptoms upon discontinuation of GRASTEK, relapse after resuming GRASTEK and resolution again after discontinuation of GRASTEK.

Pregnancy Category B: Reproductive and developmental toxicity studies performed in female mice have revealed no evidence of harm to the fetus due to GRASTEK. In these studies, the effect of Timothy grass (Phleum pratense) pollen allergen extract, the active component of GRASTEK, on embryo-fetal development was eva luated. Mice were administered approximately 460,000 BAU/kg/day of Timothy grass pollen allergen extract by oral gavage on days 0 to 15 of gestation. A dose of 460,000 BAU/kg/day of Timothy grass pollen allergen extract corresponds to approximately 8,200-fold a human dose on a BAU/kg/day basis. No adverse effects on embryo-fetal development were observed. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, GRASTEK should be used during pregnancy only if clearly needed.

Because systemic and local adverse reactions with immunotherapy may be poorly tolerated during pregnancy, GRASTEK should be used during pregnancy only if clearly needed.

Adults and Children

This placebo-controlled trial eva luated 1501 subjects 5 through 65 years of age (approximately 80% were 18 years and older) comparing GRASTEK (N=752) and placebo (N=749) administered as a sublingual tablet daily for approximately 24 weeks. The subject population was 84% White, 9% African American and 4% Asian. The majority of subjects were male (52%). In this study, approximately 25% of subjects had mild, intermittent asthma and 85% of all subjects were sensitized to other allergens in addition to grass pollen. Subjects with a clinical history of symptomatic allergies to non-grass pollen allergens that required treatment during the grass pollen season were excluded from the studies. All treatment groups were balanced with regard to baseline characteristics.

Subjects treated with GRASTEK had a decrease in the TCS throughout the grass pollen season compared to placebo-treated subjects. Similarly, the DSS and DMS were decreased in subjects treated with GRASTEK compared to placebo throughout the grass pollen season, and the TCS was decreased compared to placebo during the peak grass pollen season (see Table 3).

This double-blind clinical trial of approximately 24 weeks duration eva luated 344 pediatric subjects 5 to 17 years of age who were treated with either GRASTEK or placebo once daily. The subject population was 88% White, 7% African American, and 2% Asian. The majority (65%) of subjects were male. The mean age of subjects was 12.3 years. In this study, 26% of subjects had mild intermittent asthma and most subjects (89%) were sensitized to other allergens in addition to grass pollen. Subjects with a clinical history of symptomatic allergies to non-grass pollen allergens that required treatment during the grass pollen season were excluded from the studies. All treatment groups were balanced with regard to baseline characteristics.

Pediatric subjects treated with GRASTEK had a decrease in TCS throughout the grass pollen season compared to placebo treated subjects (see Table 4). Similarly, the DSS and DMS were decreased in GRASTEK compared to placebo throughout the grass pollen season.