GRASTEK- timothy grass pollen allergen extract tablet

GRASTEK by

Drug Labeling and Warnings

GRASTEK by is a Other medication manufactured, distributed, or labeled by ALK-Abelló A/S, Catalent Pharma Solutions Limited. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • BOXED WARNING (What is this?)

    WARNING: SEVERE ALLERGIC REACTIONS

    • GRASTEK can cause life-threatening allergic reactions such as anaphylaxis and severe laryngopharyngeal restriction. (5.1)
    • Do not administer GRASTEK to patients with severe, unstable or uncontrolled asthma. (4)
    • Observe patients in the office for at least 30 minutes following the initial dose. (5.1)
    • Prescribe auto-injectable epinephrine, instruct and train patients on its appropriate use, and instruct patients to seek immediate medical care upon its use. (5.2)
    • GRASTEK may not be suitable for patients with certain underlying medical conditions that may reduce their ability to survive a serious allergic reaction. (5.2)
    • GRASTEK may not be suitable for patients who may be unresponsive to epinephrine or inhaled bronchodilators, such as those taking beta-blockers. (5.2)
  • 1 INDICATIONS AND USAGE

    GRASTEK® is an allergen extract indicated as immunotherapy for the treatment of grass pollen-induced allergic rhinitis with or without conjunctivitis confirmed by positive skin test or in vitro testing for pollen-specific IgE antibodies for Timothy grass or cross-reactive grass pollens. GRASTEK is approved for use in persons 5 through 65 years of age.

    GRASTEK is not indicated for the immediate relief of allergic symptoms.

  • 2 DOSAGE AND ADMINISTRATION

    For sublingual use only.

    2.1 Dose

    One GRASTEK tablet daily.

    2.2 Administration

    Administer the first dose of GRASTEK in a healthcare setting under the supervision of a physician with experience in the diagnosis and treatment of allergic diseases. After receiving the first dose of GRASTEK, observe the patient for at least 30 minutes to monitor for signs or symptoms of a severe systemic or a severe local allergic reaction. If the patient tolerates the first dose, the patient may take subsequent doses at home.

    •   Administer GRASTEK to children under adult supervision.
    •   Take the tablet from the blister unit after carefully removing the foil with dry hands.
    •   Place the tablet immediately under the tongue. Allow it to remain there until completely dissolved. Do not swallow for at least 1 minute.
    •   Wash hands after handling the tablet.
    •   Do not take the tablet with food or beverage. Food or beverage should not be taken for the following 5 minutes after taking the tablet.

    Initiate treatment at least 12 weeks before the expected onset of each grass pollen season and continue treatment throughout the season. For sustained effectiveness for one grass pollen season after cessation of treatment, GRASTEK may be taken daily for three consecutive years (including the intervals between the grass pollen seasons). The safety and efficacy of initiating treatment in season have not been established.

    Data regarding the safety of restarting treatment after missing a dose of GRASTEK are limited. In the clinical trials, treatment interruptions for up to seven days were allowed.

    Prescribe auto-injectable epinephrine to patients prescribed GRASTEK and instruct them in the proper use of emergency self-injection of epinephrine [see Warnings and Precautions (5.2)].

  • 3 DOSAGE FORMS AND STRENGTHS

    GRASTEK is available as 2800 Bioequivalent Allergy Unit (BAU) tablets that are white to off-white, circular with a debossed round detail on one side.

  • 4 CONTRAINDICATIONS

    GRASTEK is contraindicated in patients with:

    • Severe, unstable or uncontrolled asthma
    • A history of any severe systemic allergic reaction
    • A history of any severe local reaction after taking any sublingual allergen immunotherapy
    • A history of eosinophilic esophagitis
    • Hypersensitivity to any of the inactive ingredients [gelatin, mannitol and sodium hydroxide] contained in this product [see Description (11)].
  • 5 WARNINGS AND PRECAUTIONS

    5.1 Severe Allergic Reactions

    GRASTEK can cause systemic allergic reactions including anaphylaxis which may be life-threatening. In addition, GRASTEK can cause severe local reactions, including laryngopharyngeal swelling, which can compromise breathing and be life-threatening. Educate patients to recognize the signs and symptoms of these allergic reactions and instruct them to seek immediate medical care and discontinue therapy should any of these occur. Allergic reactions may require treatment with epinephrine. [See Warnings and Precautions (5.2).]

    Administer the initial dose of GRASTEK in a healthcare setting under the supervision of a physician with experience in the diagnosis and treatment of allergic diseases and prepared to manage a life-threatening systemic or local allergic reaction. Observe patients in the office for at least 30 minutes following the initial dose of GRASTEK.

    5.2 Epinephrine

    Prescribe auto-injectable epinephrine to patients receiving GRASTEK. Instruct patients to recognize the signs and symptoms of a severe allergic reaction and in the proper use of emergency auto-injectable epinephrine. Instruct patients to seek immediate medical care upon use of auto-injectable epinephrine and to stop treatment with GRASTEK. [See Patient Counseling Information (17).]

    See the epinephrine package insert for complete information.

    GRASTEK may not be suitable for patients with certain medical conditions that may reduce the ability to survive a serious allergic reaction or increase the risk of adverse reactions after epinephrine administration. Examples of these medical conditions include but are not limited to: markedly compromised lung function (either chronic or acute), unstable angina, recent myocardial infarction, significant arrhythmia, and uncontrolled hypertension.

    GRASTEK may not be suitable for patients who are taking medications that can potentiate or inhibit the effect of epinephrine. These medications include:

    •   Beta-adrenergic blockers: Patients taking beta-adrenergic blockers may be unresponsive to the usual doses of epinephrine used to treat serious systemic reactions, including anaphylaxis. Specifically, beta-adrenergic blockers antagonize the cardiostimulating and bronchodilating effects of epinephrine.
    •   Alpha-adrenergic blockers, ergot alkaloids: Patients taking alpha-adrenergic blockers may be unresponsive to the usual doses of epinephrine used to treat serious systemic reactions, including anaphylaxis. Specifically, alpha-adrenergic blockers antagonize the vasoconstricting and hypertensive effects of epinephrine. Similarly, ergot alkaloids may reverse the pressor effects of epinephrine.
    •   Tricyclic antidepressants, levothyroxine sodium, monoamine oxidase inhibitors and certain antihistamines: The adverse effects of epinephrine may be potentiated in patients taking tricyclic antidepressants, levothyroxine sodium, monoamine oxidase inhibitors, and the antihistamines chlorpheniramine, and diphenhydramine.
    •   Cardiac glycosides, diuretics: Patients who receive epinephrine while taking cardiac glycosides or diuretics should be observed carefully for the development of cardiac arrhythmias.

    5.3 Upper Airway Compromise

    GRASTEK can cause local reactions in the mouth or throat that could compromise the upper airway [see Adverse Reactions (6.1 and 6.2)]. Consider discontinuation of GRASTEK in patients who experience persistent and escalating adverse reactions in the mouth or throat.

    5.4 Eosinophilic Esophagitis

    Eosinophilic esophagitis has been reported in association with sublingual tablet immunotherapy [see Contraindications (4) and Adverse Reactions (6.2)]. Discontinue GRASTEK and consider a diagnosis of eosinophilic esophagitis in patients who experience severe or persistent gastro-esophageal symptoms including dysphagia or chest pain.

    5.5 Asthma

    GRASTEK has not been studied in subjects with moderate or severe asthma or any subjects who required daily medication to treat asthma.

    Withhold immunotherapy with GRASTEK if the patient is experiencing an acute asthma exacerbation. Reevaluate patients who have recurrent asthma exacerbations and consider discontinuation of GRASTEK.

    5.6 Concomitant Allergen Immunotherapy

    GRASTEK has not been studied in subjects who are receiving concomitant allergen immunotherapy. Concomitant dosing with other allergen immunotherapy may increase the likelihood of local or systemic adverse reactions to either subcutaneous or sublingual allergen immunotherapy.

    5.7 Oral Inflammation

    Stop treatment with GRASTEK to allow complete healing of the oral cavity in patients with oral inflammation (e.g., oral lichen planus, mouth ulcers or thrush) or oral wounds, such as those following oral surgery or dental extraction.

  • 6 ADVERSE REACTIONS

    Adverse reactions reported in ≥5% of patients were: ear pruritus, oral pruritus, tongue pruritus, mouth edema, and throat irritation.

    6.1 Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

    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.

    Table 1: Adverse Reactions Reported in ≥1% of Adults Treated with GRASTEK

    Adverse Reaction

    GRASTEK
    (N=1669)

    PLACEBO
    (N=1645)
    Nervous System Disorders
    Headache2.1%1.3%
    Ear and Labyrinth Disorders
    Ear pruritus12.5%1.1%
    Respiratory, Thoracic and Mediastinal Disorders
    Throat irritation22.6%2.8%
    Pharyngeal edema3.4%0.1%
    Dry throat1.7%0.4%
    Oropharyngeal pain1.6%1.0%
    Nasal discomfort1.6%1.0%
    Throat tightness1.4%0.2%
    Dyspnea1.1%0.4%
    Gastrointestinal Disorders
    Oral pruritus26.7%3.5%
    Mouth edema11.1%0.8%
    Paraesthesia oral9.8%2.0%
    Tongue pruritus5.7%0.5%
    Lip swelling4.0%0.2%
    Swollen tongue2.8%0.1%
    Dyspepsia2.3%0.1%
    Hypoesthesia oral2.3%1.0%
    Nausea1.9%0.6%
    Oral discomfort1.6%0.3%
    Oral mucosal erythema1.5%0.6%
    Lip edema1.3%0.1%
    Glossitis1.3%0.1%
    Stomatitis1.1%0.3%
    Tongue disorder1.1%0.2%
    Tongue edema1.1%0.4%
    Glossodynia1.0%0.3%
    Dysphagia1.0%0.2%
    Palatal edema1.0%0.1%
    Skin and Subcutaneous Tissue Disorders
    Pruritus2.4%1.0%
    Urticaria1.7%0.9%
    General Disorders and Administration Site Conditions
    Chest discomfort1.6%0.5%
    Fatigue1.4%0.4%

    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.

    Table 2: Adverse Reactions Reported in ≥1% of Pediatric Subjects Treated with GRASTEK

    Adverse Reaction

    GRASTEK
    (N=447)

    PLACEBO
    (N=434)
    Nervous System Disorders
    Headache3.4%1.8%
    Ear and Labyrinth Disorders
    Ear pruritus7.2%0.5%
    Eye Disorders
    Eye pruritus3.4%2.1%
    Respiratory, Thoracic and Mediastinal Disorders
    Throat irritation21.3%2.5%
    Oropharyngeal pain4.0%1.4%
    Pharyngeal erythema3.6%0.7%
    Pharyngeal edema2.9%0%
    Cough2.7%1.2%
    Dyspnea2.0%0.5%
    Nasal discomfort1.6%0.9%
    Nasal congestion1.6%0.5%
    Sneezing1.6%0.7%
    Gastrointestinal Disorders
    Oral pruritus24.4%2.1%
    Mouth edema9.8%0.2%
    Tongue pruritus9.2%0.9%
    Lip swelling7.2%0.5%
    Paraesthesia oral5.4%1.2%
    Oral mucosal erythema4.9%0.9%
    Lip pruritus2.9%0.2%
    Swollen tongue2.5%0%
    Dysphagia2.0%0%
    Nausea1.6%0.5%
    Oral discomfort1.6%0.2%
    Stomatitis1.3%0%
    Hypoesthesia oral1.1%0.2%
    Glossodynia1.1%0.2%
    Skin and Subcutaneous Tissue Disorders
    Urticaria1.8%0.2%
    General Disorders and Administration Site Conditions
    Chest discomfort2.0%0.5%

    6.2 Postmarketing Experience

    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.

    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, enlarged uvula, 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, stridor, swelling of neck, throat pruritus, tremor, vital capacity decreased, vomiting, and wheezing. 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.

    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.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Available human data do not establish the presence or absence of GRASTEK-associated risks during pregnancy.

    In two reproductive and developmental toxicity studies mice were administered Timothy grass pollen extract daily by buccal cavity at doses approximately 6.7 times the human sublingual dose. In one study doses were administered during gestation and lactation. In the other study doses were administered prior to mating and during gestation. These studies revealed no evidence of harm to the mother or the fetus due to GRASTEK (see 8.1 Data).

    Data

    Animal Data

    A pre- and postnatal developmental study and a combined fertility/developmental toxicity study were conducted in mice. In these studies, the effect of Timothy grass (Phleum pratense) pollen allergen extract, the active component of GRASTEK, on embryo-fetal development was evaluated. In the pre- and postnatal developmental toxicity study female mice were administered Timothy grass pollen allergen extract by buccal cavity daily from day 6 of gestation to day 17 of lactation at doses approximately 6.7 times the human sublingual dose. In the combined fertility/developmental toxicity study, female mice were administered Timothy grass pollen allergen extract daily by buccal cavity administration from 14 days prior to mating and until day 15 of the gestation period (male animals were administered the same dose daily for 4 weeks before pairing and during pairing) at doses approximately 6.7 times the human sublingual dose. Fertility was normal and there were no treatment-related post-implementation losses, fetal malformations or variations.

    8.2 Lactation

    Risk Summary

    It is not known if GRASTEK is excreted in human milk. Data are not available to assess the effect of GRASTEK on milk production or on the breast-fed child. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for GRASTEK and any potential adverse effects on the breast-fed child from GRASTEK or from the underlying maternal condition.

    8.4 Pediatric Use

    Efficacy and safety of GRASTEK have been established in children and adolescents 5 through 17 years of age. The safety and efficacy in pediatric patients below 5 years of age have not been established.

    8.5 Geriatric Use

    There is no clinical trial experience with GRASTEK in patients over 65 years of age.

  • 11 DESCRIPTION

    GRASTEK tablets contain pollen allergen extract from Timothy grass (Phleum pratense). GRASTEK is a sublingual tablet.

    GRASTEK is available as a tablet of 2800 BAU of Timothy grass pollen allergen extract.

    Inactive ingredients: gelatin NF (fish source), mannitol USP and sodium hydroxide NF.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    The precise mechanisms of action of allergen immunotherapy are not known.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    No studies have been performed in animals to evaluate the carcinogenic potential of GRASTEK.

    There were no positive findings in the in vitro mouse lymphoma and the bacterial reverse mutation assays for mutagenicity using Timothy grass (Phleum pratense) pollen allergen extract.

    A combined fertility/developmental toxicity study in male and female mice revealed no evidence of impaired fertility due to Timothy grass pollen allergen extract administered daily prior to mating and during gestation at approximately 6.7 times the human sublingual dose (see 8.1 Data).

  • 14 CLINICAL STUDIES

    The efficacy of GRASTEK in the treatment of allergic rhinitis with or without conjunctivitis in Timothy grass pollen allergic subjects 5 years of age and older, with or without mild asthma, was evaluated during the first grass pollen season in two trials of approximately 24 weeks treatment duration. The sustained effect of GRASTEK was evaluated in one trial conducted over 5 grass pollen seasons. All three trials were randomized, double-blind, parallel group, multicenter clinical trials. Subjects had a history of grass pollen induced rhinitis with or without conjunctivitis and sensitivity to Timothy grass pollen as determined by specific testing (IgE). In these three studies, subjects initiated GRASTEK or placebo approximately 12 weeks prior to the pollen season. In the long-term study, subjects received GRASTEK or placebo daily for 3 consecutive years and were followed for 2 years without treatment.

    Efficacy was established by self-reporting of rhinoconjunctivitis daily symptom scores (DSS) and daily medication scores (DMS). Daily rhinoconjunctivitis symptoms included four nasal symptoms (runny nose, stuffy nose, sneezing, and itchy nose), and two ocular symptoms (gritty/itchy eyes and watery eyes). The rhinoconjunctivitis symptoms were measured on a scale of 0 (none) to 3 (severe). Subjects in clinical trials were allowed to take symptom-relieving medications (including systemic and topical antihistamines and topical and oral corticosteroids) as needed. The daily medication score measured the use of standard open-label allergy medications. Predefined values were assigned to each class of medication. Generally, systemic and topical antihistamines were given the lowest score, topical steroids an intermediate score, and oral corticosteroids the highest score. The sums of the DSS and DMS were combined into the Total Combined Score (TCS) which was averaged over the entire grass pollen season.

    14.1 First Season Efficacy

    Adults and Children

    This placebo-controlled trial evaluated 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).

    Table 3: Total Combined Scores (TCS), Rhinoconjunctivitis Daily Symptom Scores (DSS), and Daily Medication Scores (DMS) During the Grass Pollen Season
    Endpoint*GRASTEK
    (N)
    Score
    Placebo
    (N)
    Score
    Treatment Difference (GRASTEK – Placebo)Difference Relative to Placebo§
    Estimate
    (95% CI)
    TCS=Total Combined Score (DSS + DMS); DSS=Daily Symptom Score; DMS=Daily Medication Score.
  • * Non-parametric analysis for TCS and DSS endpoints: Parametric analysis using zero-inflated log-normal model for DMS.
  • Number of subjects in analyses.
  • For TCS and DSS endpoints the group medians are reported, treatment difference and that relative to placebo is based on group medians. For DMS, the group means are reported and difference relative to placebo is based on estimated group means.
  • § Difference relative to placebo computed as: (GRASTEK - placebo)/placebo × 100.
  • TCS Entire
    Season
    (629)
    3.24
    (672)
    4.22
    -0.98-23%
    (-36.0, -13.0)
    TCS
    Peak Season
    (620)
    3.33
    (663)
    4.67
    -1.33-29%
    (-39.0, -15.0)
    DSS Entire
    Season
    (629)
    2.49
    (672)
    3.13
    -0.64-20%
    (-32.0, -10.0)
    DMS Entire
    Season
    (629)
    0.88
    (672)
    1.36
    -0.48-35%
    (-49.3, -20.8)

    Children

    This double-blind clinical trial of approximately 24 weeks duration evaluated 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.

    Table 4: Total Combined Scores (TCS), Rhinoconjunctivitis Daily Symptom Scores (DSS) and Daily Medication Scores (DMS) During the Entire Grass Pollen Season
    Endpoint*GRASTEK
    (N=149)
    Score
    Placebo
    (N=158)
    Score
    Treatment Difference
    (GRASTEK – Placebo)
    Difference Relative to Placebo§
    Estimate
    (95% CI)
    TCS=Total combined score (DSS + DMS); DSS=Daily Symptom Score; DMS=Daily Medication Score.
  • * Parametric analysis using analysis of variance model for all endpoints.
  • Number of subjects in analyses.
  • The estimated group means are reported and difference relative to placebo is based on estimated group means.
  • § Difference relative to placebo computed as: (GRASTEK - placebo)/placebo × 100.
  • TCS
    4.62

    6.25

    -1.63
    -26%
    (-38.2, -10.1)
    DSS
    3.71

    4.91

    -1.20
    -24%
    (-36.4, -9.1)
    DMS
    0.91

    1.33

    -0.42
    -32%
    (-57.7, 4.0)

    14.2 Sustained Effect

    Adult Subjects 18 Years and Older

    The sustained effect of GRASTEK was measured in a 5-year double-blind study. The study included 634 randomized subjects between 18 and 65 years of age. The subject population was 96% White, 2% Asian and 1% African American. The majority (59%) of subjects were male. The mean age of subjects was 34 years. Subjects received either GRASTEK or placebo daily for 3 consecutive years and were then observed for 2 subsequent years during which they did not receive study drug. Subjects treated with GRASTEK had a decrease in TCS throughout the grass pollen season during the three years of active treatment. This effect was sustained during the grass pollen season in the first year after discontinuation of GRASTEK (see Table 5), but not in the second year.

    Table 5: Rhinoconjunctivitis Total Combined Score (TCS), Daily Symptom Score (DSS), and Daily Medication Score (DMS) During the Entire Grass Pollen Season from the 5-Year Study
    EndpointDifference Relative to Placebo*
    (95% CI)
    Treatment
    Year 1

    N=568
    Treatment
    Year 2

    N=316
    Treatment
    Year 3

    N=287
    Post Treatment
    Year 1

    N=257
    TCS=Total Combined Score (DSS + DMS); DSS=Daily Symptom Score; DMS=Daily Medication Score.
  • * Difference relative to placebo computed as: (GRASTEK - placebo)/placebo × 100.
  • Number of subjects in analyses.
  • Study extended from 1 to 5 years (site closures, subject unwillingness to participate beyond 1 year).
  • TCS-34.2%
    (-42.0%, -26.3%)
    -40.9%
    (-51.8%, -29.5%)
    -34.0%
    (-45.5%, -21.4%)
    -27.2%
    (-39.9%, -12.4%)
    DSS-31.2%
    (-38.8%, -23.4%)
    -36.2%
    (-46.5%, -26.2%)
    -29.0%
    (-40.3%, -16.3%)
    -26.2%
    (-37.6%, -12.2%)
    DMS-38.4%
    (-49.8%, -26.5%)
    -45.5%
    (-60.4%, -28.2%)
    -40.1%
    (-55.4%, -21.2%)
    -28.6%
    (-46.3%, -6.0%)
  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    GRASTEK 2800 BAU tablets are white to off-white, circular sublingual tablets with a debossed round detail on one side.

    GRASTEK is supplied as follows:

    3 blister packages of 10 tablets (30 tablets total). NDC: 52709-1501-3

    Store at controlled room temperature 20ºC-25ºC (68ºF-77ºF); excursions permitted between 15ºC-30ºC (59ºF-86ºF). Store in the original package until use to protect from moisture.

  • 17 PATIENT COUNSELING INFORMATION

    Advise patients to read the FDA-approved patient labeling (Medication Guide) and to keep GRASTEK and all medicines out of the reach of children.

    Severe Allergic Reactions

    Advise patients that GRASTEK may cause life-threatening systemic or local allergic reactions, including anaphylaxis. Educate patients about the signs and symptoms of these allergic reactions [see Warnings and Precautions (5.1)]. The signs and symptoms of a severe allergic reaction may include: syncope, dizziness, hypotension, tachycardia, dyspnea, wheezing, bronchospasm, chest discomfort, cough, abdominal pain, vomiting, diarrhea, rash, pruritus, flushing, and urticaria.

    Ensure that patients have auto-injectable epinephrine and instruct patients in its proper use. Instruct patients who experience a severe allergic reaction to seek immediate medical care, discontinue GRASTEK, and resume treatment only when advised by a physician to do so. [See Warnings and Precautions (5.2).]

    Advise patients to read the patient information for epinephrine.

    Inform patients that the first dose of GRASTEK must be administered in a healthcare setting under the supervision of a physician and that they will be monitored for at least 30 minutes to watch for signs and symptoms of a life-threatening systemic or local allergic reaction [see Warnings and Precautions (5.1)].

    Because of the risk of upper airway compromise, instruct patients with persistent and escalating adverse reactions in the mouth or throat to discontinue GRASTEK and to contact their healthcare professional. [See Warnings and Precautions (5.3).]

    Because of the risk of eosinophilic esophagitis, instruct patients with severe or persistent symptoms of esophagitis to discontinue GRASTEK and to contact their healthcare professional. [See Warnings and Precautions (5.4).]

    Inform parents/guardians that GRASTEK should only be administered to children under adult supervision [see Dosage and Administration (2.2)].

    Asthma

    Instruct patients with asthma that if they have difficulty breathing or if their asthma becomes difficult to control, they should stop taking GRASTEK and contact their healthcare professional immediately [see Warnings and Precautions (5.5)].

    Administration Instructions

    Instruct patients to carefully remove the foil from the blister unit with dry hands and then take the sublingual tablet immediately by placing it under the tongue where it will dissolve. Also instruct patients to wash their hands after handling the tablet, and to avoid food or beverages for 5 minutes after taking the tablet. [See Dosage and Administration (2.2).]

  • SPL UNCLASSIFIED SECTION

    Manufactured for: ALK-Abelló A/S
    ALK-Abelló A/S, Bøge Allé 6-8, DK-2970 Hørsholm, Denmark
    U.S. License No. 1292

    Manufactured by:
    Catalent Pharma Solutions Limited, Blagrove,
    Swindon, Wiltshire, SN5 8RU UK

    © 2019 ALK-Abelló A/S. All rights reserved.

  • MEDICATION GUIDE

    GRASTEK® (GRAS-tek)

    (Timothy Grass Pollen Allergen Extract)

    Carefully read this Medication Guide before you or your child start taking GRASTEK and each time you get a refill. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor or pharmacist if there is something you do not understand or you want to learn more about GRASTEK.

    What is the Most Important Information I Should Know about GRASTEK?

    GRASTEK can cause severe allergic reactions that may be life-threatening. Stop taking GRASTEK and get medical treatment right away if you or your child has any of the following symptoms after taking GRASTEK:

    • Trouble breathing
    • Throat tightness or swelling
    • Trouble swallowing or speaking
    • Dizziness or fainting
    • Rapid or weak heartbeat
    • Severe stomach cramps or pain, vomiting, or diarrhea
    • Severe flushing or itching of the skin

    For home administration of GRASTEK, your doctor will prescribe auto-injectable epinephrine, a medicine you can inject if you or your child has a severe allergic reaction after taking GRASTEK. Your doctor will train and instruct you on the proper use of auto-injectable epinephrine.

    Talk to your doctor or read the epinephrine patient information if you have any questions about the use of auto-injectable epinephrine.

    What is GRASTEK?

    GRASTEK is a prescription medicine used for sublingual (under the tongue) immunotherapy to treat Timothy and related grass pollen allergies that can cause sneezing, runny or itchy nose, stuffy or congested nose, or itchy and watery eyes. GRASTEK may be prescribed for persons 5 through 65 years of age who are allergic to grass pollen.

    GRASTEK is taken for about 12 weeks before grass pollen season and throughout grass pollen season. GRASTEK may also be taken daily for 3 years to provide a sustained effect for a fourth year in which you do not have to take GRASTEK.

    GRASTEK is NOT a medication that gives immediate relief for symptoms of grass allergy.

    Who Should Not Take GRASTEK?

    You or your child should not take GRASTEK if:

    • You or your child has severe, unstable or uncontrolled asthma
    • You or your child had a severe allergic reaction in the past that included any of these symptoms:
      • Trouble breathing
      • Dizziness or fainting
      • Rapid or weak heartbeat
    • You or your child has ever had difficulty with breathing due to swelling of the throat or upper airway after using any sublingual immunotherapy before.
    • You or your child has ever been diagnosed with eosinophilic esophagitis.
    • You or your child is allergic to any of the inactive ingredients contained in GRASTEK. The inactive ingredients contained in GRASTEK are: gelatin, mannitol and sodium hydroxide.

    What Should I Tell My Doctor Before Taking GRASTEK?

    Your doctor may decide that GRASTEK is not the best treatment if:

    • You or your child has asthma, depending on how severe it is.
    • You or your child suffers from lung disease such as chronic obstructive pulmonary disease (COPD)
    • You or your child suffers from heart disease such as coronary artery disease, an irregular heart rhythm, or you have hypertension that is not well controlled.
    • You or your daughter is pregnant, plans to become pregnant during the time you will be taking GRASTEK, or is breast-feeding.
    • You or your child is unable or unwilling to administer auto-injectable epinephrine to treat a severe allergic reaction to GRASTEK.
    • You or your child is taking certain medicines that enhance the likelihood of a severe reaction, or interfere with the treatment of a severe reaction. These medicines include:
      • beta blockers and alpha-blockers (prescribed for high blood pressure)
      • cardiac glycosides (prescribed for heart failure or problems with heart rhythm)
      • diuretics (prescribed for heart conditions and high blood pressure)
      • ergot alkaloids (prescribed for migraine headache)
      • monoamine oxidase inhibitors or tricyclic antidepressants (prescribed for depression)
      • thyroid hormone (prescribed for low thyroid activity).
    • You or your child is receiving allergy shots or other immunotherapy under the tongue. Use of more than one of these types of medicines together may increase the likelihood of a severe allergic reaction.

    You should tell your doctor if you or your child is taking or has recently taken any other medicines, including medicines obtained without a prescription and herbal supplements. Keep a list of them and show it to your doctor and pharmacist each time you get a new supply of GRASTEK. Ask your doctor or pharmacist for advice before taking GRASTEK.

    Are there any reasons to stop taking GRASTEK?

    Stop GRASTEK and contact your doctor if you or your child has any of the following after taking GRASTEK:

    • Any type of a serious allergic reaction
    • Throat tightness that worsens or swelling of the tongue or throat that causes trouble speaking, breathing or swallowing
    • Asthma or any other breathing condition that gets worse
    • Dizziness or fainting
    • Rapid or weak heartbeat
    • Severe stomach cramps or pain, vomiting, or diarrhea
    • Severe flushing or itching of the skin
    • Heartburn, difficulty swallowing, pain with swallowing, or chest pain that does not go away or worsens

    Also, stop taking GRASTEK following: mouth surgery procedures (such as tooth removal), or if you develop any mouth infections, ulcers or cuts in the mouth or throat.

    How should I take GRASTEK?

    Take GRASTEK exactly as your doctor tells you.

    GRASTEK is a prescription medicine that is placed under the tongue.

    • Take the tablet from the blister package after carefully removing the foil with dry hands.
    • Place the tablet immediately under the tongue. Allow it to remain there until completely dissolved. Do not swallow for at least 1 minute.
    • Do not take GRASTEK with food or beverage. Food and beverage should not be taken for the following 5 minutes.
    • Wash hands after taking the tablet.

    Take the first tablet of GRASTEK in your doctor's office. After taking the first tablet, you or your child will be watched for at least 30 minutes for symptoms of a serious allergic reaction.

    If you tolerate the first dose of GRASTEK, you or your child will continue GRASTEK therapy at home by taking one tablet every day. Children should be given each tablet of GRASTEK by an adult who will watch for any symptoms of a serious allergic reaction.

    Take GRASTEK as prescribed by your doctor until the end of the treatment course. If you forget to take GRASTEK, do not take a double dose. Take the next dose at your normal scheduled time the next day. If you miss more than one dose of GRASTEK, contact your healthcare provider before restarting.

    What are the possible side effects of GRASTEK?

    In children and adults, the most commonly reported side effects were itching of the mouth, lips, or tongue, swelling under the tongue, or throat irritation. These side effects, by themselves, were not dangerous or life-threatening.

    GRASTEK can cause severe allergic reactions that may be life-threatening. Symptoms of allergic reactions to GRASTEK include:

    • Trouble breathing
    • Throat tightness or swelling
    • Trouble swallowing or speaking
    • Dizziness or fainting
    • Rapid or weak heartbeat
    • Severe stomach cramps or pain, vomiting, or diarrhea
    • Severe flushing or itching of the skin
    • High-pitched unusual breathing sound that could be a sign of trouble breathing

    For additional information on the possible side effects of GRASTEK, talk with your doctor or pharmacist. You may report side effects to the U.S. Food and Drug Administration (FDA) at 1-800-FDA-1088 or www.fda.gov/medwatch.

    How should I store GRASTEK?

    Keep GRASTEK out of the reach of children.

    Throw away any unused GRASTEK after the expiration date which is stated on the carton and blister pack after "EXP."

    Store GRASTEK in a dry place at room temperature, 15ºC to 30ºC (59ºF to 86ºF), in the original package.

    General information about GRASTEK

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use GRASTEK for a condition for which it was not prescribed. Do not give GRASTEK to other people, even if they have the same symptoms. It may harm them.

    This Medication Guide summarizes the most important information about GRASTEK. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about GRASTEK that was written for healthcare professionals. For more information go to www.grastek.com or call toll-free at 1-855-782-9323.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

  • SPL UNCLASSIFIED SECTION

    Manufactured for: ALK-Abelló A/S
    ALK-Abelló A/S, Bøge Allé 6-8, DK-2970 Hørsholm, Denmark
    U.S. License No. 1292

    Manufactured by:
    Catalent Pharma Solutions Limited, Blagrove,
    Swindon, Wiltshire, SN5 8RU UK

    © 2019 ALK-Abelló A/S
    All rights reserved.

    Revised: 06/2019

  • PRINCIPAL DISPLAY PANEL - 2800 BAU Tablet Blister Pack Carton

    NDC: 52709-1501-3
    This carton contains 30 sublingual tablets in three 10-Tablet blister cards

    Timothy Grass Pollen Allergen Extract,
    Grastek® Tablet for sublingual use

    2800 BAU

    For Adults and Children 5 to 65 Years of Age
    Each Grastek tablet contains 2800 Bioequivalent Allergy Units (BAUs) of timothy grass pollen
    allergen extract.
    Dispense the enclosed Medication Guide to the patient.
    Keep this and all drugs out of the reach of children.

    Rx only

    PRINCIPAL DISPLAY PANEL - 2800 BAU Tablet Blister Pack Carton
  • INGREDIENTS AND APPEARANCE
    GRASTEK 
    timothy grass pollen allergen extract tablet
    Product Information
    Product TypeSTANDARDIZED ALLERGENICItem Code (Source)NDC: 52709-1501
    Route of AdministrationSUBLINGUAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    PHLEUM PRATENSE POLLEN (UNII: 65M88RW2EG) (PHLEUM PRATENSE POLLEN - UNII:65M88RW2EG) PHLEUM PRATENSE POLLEN2800 [BAU]
    Inactive Ingredients
    Ingredient NameStrength
    MARINE COLLAGEN, SOLUBLE (UNII: 8JC99XGU4W)  
    MANNITOL (UNII: 3OWL53L36A)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    Product Characteristics
    ColorWHITE (white to off-white) Scoreno score
    ShapeROUNDSize13mm
    FlavorImprint Code
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 52709-1501-33 in 1 CARTON
    1NDC: 52709-1501-110 in 1 BLISTER PACK; Type 0: Not a Combination Product
    2NDC: 52709-1501-51 in 1 CARTON
    25 in 1 BLISTER PACK; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    BLABLA12547304/11/2014
    Labeler - ALK-Abelló A/S (306020926)
    Establishment
    NameAddressID/FEIBusiness Operations
    Catalent Pharma Solutions Limited237676320MANUFACTURE(52709-1501)

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