GRASTEK: Package Insert and Label Information

GRASTEK- phleum pratense pollen tablet
ALK-Abello A S

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 Dos e

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 [ s ee 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 [ s ee 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 Warning s 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:

Βeta-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 [ s ee 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 [ s ee 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 Adult s Treated with GRASTEK

Adverse Reaction GRASTEK ( N =1669) PLACEBO ( N =1645)
Nervous System DisordersHeadache 2.1% 1.3%
Ear and Labyrinth DisordersEar pruritus 12.5% 1.1%
Respiratory, Thoracic and Mediastinal DisordersThroat irritationPharyngeal edemaDry throatOropharyngeal painNasal discomfortThroat tightnessDyspnea 22.6%3.4%1.7%1.6%1.6%1.4%1.1% 2.8%0.1%0.4%1.0%1.0%0.2%0.4%
Gastrointestinal DisordersOral pruritusMouth edemaParesthesia oralTongue pruritusLip swellingSwollen tongueDyspepsiaHypoesthesia oralNauseaOral discomfortOral mucosal erythemaLip edemaGlossitisStomatitisTongue disorderTongue edemaGlossodyniaDysphagiaPalatal edema 26.7%11.1%9.8%5.7%4.0%2.8%2.3%2.3%1.9%1.6%1.5%1.3%1.3%1.1%1.1%1.1%1.0%1.0%1.0% 3.5%0.8%2.0%0.5%0.2%0.1%0.1%1.0%0.6%0.3%0.6%0.1%0.1%0.3%0.2%0.4%0.3%0.2%0.1%
Skin and Subcutaneous Tissue DisordersPruritusUrticaria 2.4%1.7% 1.0%0.9%
General Disorders and Administration Site ConditionsChest discomfortFatigue 1.6%1.4% 0.5%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 DisordersHeadache 3.4% 1.8%
Ear and Labyrinth DisordersEar pruritus 7.2% 0.5%
Eye DisordersEye pruritus 3.4% 2.1%
Respiratory, Thoracic and Mediastinal DisordersThroat irritationOropharyngeal painPharyngeal erythemaPharyngeal edemaCoughDyspneaNasal discomfortNasal congestionSneezing 21.3%4.0%3.6%2.9%2.7%2.0%1.6%1.6%1.6% 2.5%1.4%0.7%0%1.2%0.5%0.9%0.5%0.7%
Gastrointestinal DisordersOral pruritusMouth edemaTongue pruritusLip swellingParesthesia oralOral mucosal erythemaLip pruritusSwollen tongueDysphagiaNauseaOral discomfortStomatitisHypoesthesia oralGlossodynia 24.4%9.8%9.2%7.2%5.4%4.9%2.9%2.5%2.0%1.6%1.6%1.3%1.1%1.1% 2.1%0.2%0.9%0.5%1.2%0.9%0.2%0%0%0.5%0.2%0%0.2%0.2%
Skin and Subcutaneous Tissue DisordersUrticaria 1.8% 0.2%
General Disorders and Administration Site ConditionsChest discomfort 2.0% 0.5%
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