Timothy grass pollen allergen extract is a sublingual immunotherapy (SLIT) approved for treatment of allergic rhinitis with or without conjunctivitis in patients ages 5-65 years, as confirmed by positive skin test or in vitro testing for pollen-specific IgE antibodies for Timothy grass (Phleum pratense) or cross-reactive grass pollens (e.g., Sweet Vernal, Orchard, Perennial Rye, Kentucky Bluegrass, Meadow Fescue, and Redtop). In North American regions, sensitivity to these grasses is estimated to be as high as 50-70% in patients with allergic rhinoconjunctivitis. Standard therapy for allergic rhinitis consists of allergen avoidance as well as pharmacotherapy (e.g., antihistamines, leukotriene antagonists, intranasal corticosteroids) for symptom management. Allergen immunotherapy modifies the disease process and is used in patients who are not adequately controlled with environmental or medication changes. In general, SLIT is associated with fewer serious adverse reactions than subcutaneous immunotherapy; however, experience with SLIT in patients with severe asthma, a population that may be more likely to experience serious reactions, is limited. Most adverse reactions to SLIT are local and transient and do not require treatment discontinuation. Severe allergic reactions, such as anaphylaxis, which can be life-threatening, can occur. After administration of the first dose at the health care provider's office, where the patient can be observed for potential adverse reactions, Timothy grass pollen allergen extract can be taken at home. Timothy grass pollen allergen extract was approved by the FDA in April 2014.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-For sublingual use only.
-Administer the first dose of allergen extract in a healthcare setting where acute allergic reactions can be recognized and treated by an experienced clinician.
-Observe the patient for at least 30 minutes after the initial dose; monitor for signs and symptoms of a severe systemic or local allergic reaction.
-If the patient tolerates the initial dose, subsequent doses may be taken at home.-Pediatric doses should be administered under adult supervision.
-Auto-injectable epinephrine should be available to all patients receiving sublingual allergen extract outside the healthcare setting; educate on proper use.
-With dry hands, remove the tablet from the blister packaging immediately prior to dosing.
-Place the tablet under the tongue. Wait until the tablet is completely dissolved (at least 1 minute) before swallowing.
-Do not take with food or drink. To avoid swallowing the allergen extract, do not eat or drink for at least 5 minutes after tablet dissolution.
-Wash hands after handling the tablet.
As with all immunotherapy, Timothy grass pollen allergen extract can cause life-threatening serious hypersensitivity reactions or anaphylaxis, including anaphylactoid reactions, severe angioedema (e.g., laryngopharyngeal edema), and anaphylactic shock. In general, severe allergic reactions appear to be less common with sublingual immunotherapy (SLIT) than with subcutaneous immunotherapy; however, it should be noted that SLIT has not been studied in as many high-risk patients. In adult trials, 7 patients (0.4%) experienced systemic allergic reactions. Of these, 5 had reactions on the first day of treatment with symptoms including swelling of the mouth/lips, oral/pharyngeal pruritus, ear pruritus, sneezing, rhinorrhea, throat irritation, dysphonia, dysphagia, chest pain, and rash; 3 of the 5 patients were treated with epinephrine and antihistamines and 1 also received oral corticosteroids. One patient had an additional reaction on the second day of treatment (oral burning sensation, rhinorrhea, and throat irritation). Of the 7 adult patients with systemic reactions, 2 tolerated therapy on day 1; subsequently, 1 experienced edema of the lower lip, epigastric discomfort, and dizziness on day 2 of therapy, and the other developed chest tightness and shortness of breath on day 42 of therapy. During clinical trials, 1 pediatric patient experienced a systemic hypersensitivity reaction consisting of lip angioedema, slight dysphagia due to the sensation of a lump in the throat, and a moderate-intensity intermittent cough; the patient was treated with epinephrine, recovered without sequelae, and was discontinued from the trial. Anaphylactic shock has been reported during postmarketing experience; in 1 asthmatic adult patient, shock occurred within 2 minutes of extract administration and presented as wheezing, urticaria, face edema, tachycardia, low blood pressure, and a depressed level of consciousness. Oral pruritus is common with oral immunotherapy and not necessarily a symptom of anaphylaxis. During trials, oral pruritus (adults, 26.7%; pediatrics 24.4%), tongue pruritus (adults, 5.7%; pediatrics, 9.2%), and ear pruritus (adults, 12.5%; pediatrics, 7.2%) were reported. Lip and ocular pruritus were observed in 2.9% and 3.4% of pediatric patients, respectively. Throat irritation (adults, 22.6%; pediatrics, 21.3%) was another common adverse reaction. Mouth edema (adults, 11.1%; pediatrics, 9.8%), lip swelling (adults, 4%; pediatrics, 7.2%), swollen tongue (adults, 2.8%; pediatrics, 2.5%), dyspnea (adults, 1.1%; pediatrics, 2%), pharyngeal edema (adults, 3.4%; pediatrics, 2.9%), dysphagia (adults, 1%; pediatrics, 2%), stomatitis (adults, 1.1%; pediatrics, 1.3%), urticaria (adults, 1.7%; pediatrics, 1.8%), and chest discomfort (adults, 1.6%; pediatrics, 2%) were reported across all clinical trials. Additionally, pruritus (type unspecified, 2.4%), throat tightness (1.4%), glossitis (1.3%), tongue edema (1.1%), lip edema (1.3%), and palatal edema (1%) were observed in adult patients. Cough (2.7%), sneezing (1.6%), and nasal congestion (1.6%) were reported in pediatric patients. Throat pruritus, swelling of the neck, ear discomfort, ear swelling, eye swelling, and the sensation of a foreign body have been reported during postmarketing experience. Sudden onset of symptoms such as these are characteristic of anaphylaxis; monitor patients closely. Advise patients who experience a systemic allergic reaction to stop taking the extract immediately. Reevaluate those who have persistent or escalating local reactions for appropriateness of therapy and consider extract discontinuation. Administer the first dose of allergen extract in a healthcare setting where acute allergic reactions can be recognized and treated by an experienced clinician. Observe patients for at least 30 minutes after sublingual administration to monitor for signs and symptoms of a severe allergic reaction.
Nausea (adults, 1.9%; pediatrics, 1.6%) and dyspepsia (adults, 2.3%) occurred during clinical trials of Timothy grass pollen allergen extract. Cheilitis, diarrhea, gastritis, salivary hypersecretion, vomiting, ulcerative colitis exacerbation, and eosinophilic esophagitis were reported with postmarketing use. The clinical details of some eosinophilic esophagitis postmarketing reports are consistent with a drug-induced effect, including at least 1 case of symptom resolution upon extract discontinuation, relapse after extract resumption, and resolution again after secondary discontinuation. Discontinue extract therapy in patients who experience severe or persistent gastroesophageal symptoms (e.g., dysphagia, chest pain).
Local reactions are common with sublingual immunotherapy; during clinical trials with Timothy grass pollen allergen extract, throat irritation (adults, 22.6%; pediatrics, 21.3%) and oral pruritus (adults, 26.7%; pediatrics, 24.4%) were the most common adverse events reported. Other local reactions reported include oral paresthesias (adults, 9.8%; pediatrics, 5.4%), oral mucosal erythema (adults, 1.5%; pediatrics, 4.9%), oropharyngeal pain (adults, 1.6%; pediatrics, 4%), oral hypoesthesia (adults, 2.3%; pediatrics, 1.1%), and glossodynia (adults, 1%; pediatrics, 1.1%). Oral discomfort and nasal discomfort occurred in 1.6% of both adult and pediatric populations. In adult trials, dry throat/xerostomia and unspecified tongue disorder occurred in 1.7% and 1.1% of patients, respectively. Pharyngeal erythema (3.6%) was observed in pediatric patients. Hoarseness, laryngitis, oral ulceration, lip blister, facial erythema, laryngeal discomfort, enlarged uvula, stridor, dysgeusia, oral pain, and paresthesia (including hypoesthesia and burning sensation in the extremities) have been reported with postmarketing experience. Because of the risk of upper airway compromise, reevaluate patients who have persistent or escalating local reactions in the mouth or throat for appropriateness of therapy and consider extract discontinuation.
Hyperventilation, asthma exacerbations (acute bronchospasm), status asthmaticus, exercise-induced asthma, decreased oxygen saturation, decreased peak expiratory flow rate, pneumonia, stridor, and respiratory distress have been reported during postmarketing use of Timothy grass pollen allergen extract. Advise patients with difficulty breathing to discontinue the extract and contact their healthcare professional immediately. Reevaluate asthmatics with recurrent exacerbations for appropriateness of therapy and consider extract discontinuation.
Headache (adults, 2.1%; pediatrics, 3.4%) and fatigue (adults, 1.4%) have been reported during clinical trials of Timothy grass pollen allergen extract. Tremor, drowsiness, difficulty speaking/dysarthria, and altered state of consciousness have been spontaneously reported during postmarketing use.
Chest pain (unspecified) or chest discomfort (adults, 1.6%; pediatrics, 2%) has been reported during clinical trials of Timothy grass pollen allergen extract. Many of the cardiovascular effects (i.e., chest pressure, sinus tachycardia, hypotension) reported during postmarketing use could potentially be the symptoms of a severe allergic reaction. Ensure patients and their caregivers are educated on the signs and symptoms of severe allergic reactions, the proper use of auto-injectable epinephrine, and the need to seek immediate medical attention upon epinephrine use. Severe or persistent gastroesophageal symptoms such as chest pain may also be a sign of eosinophilic esophagitis.
Timothy grass pollen allergen extract can cause life-threatening allergic reactions, including a risk of serious hypersensitivity reactions or anaphylaxis. Use with great caution in patients with a history of atopy or sublingual allergen immunotherapy hypersensitivity; these patients may be predisposed to severe allergic reactions. The use of more than one type of immunotherapy (i.e. allergy shots, sublingual immunotherapy) may increase the likelihood of a severe allergic reaction. Timothy grass pollen allergen extract is contraindicated in patients with a history of severe local reaction to sublingual allergen immunotherapy and/or severe systemic allergic reactions of any type. Additionally, do not use the extract in patients with a hypersensitivity to any of the inactive ingredients present in the product, including those with mannitol hypersensitivity, gelatin hypersensitivity, or sodium hydroxide hypersensitivity. Systemic allergic reactions including life-threatening anaphylaxis and severe local reactions (e.g., laryngopharyngeal swelling) that may compromise breathing may occur; treatment with epinephrine may be required. Patients who experience a systemic reaction to Timothy grass pollen allergen extract should stop taking the extract immediately. Those who have persistent or escalating local reactions in the mouth or throat should be reevaluated, and discontinuation of the extract should be considered to avoid potential airway compromise. Administration of the first dose requires a specialized care setting due to the risk of severe allergic reactions; give the first dose in a healthcare setting where acute allergic reactions can be recognized and treated by an experienced clinician. Observe the patient for at least 30 minutes post-dose for signs or symptoms of a severe systemic or local reaction. If the patient tolerates the first dose, subsequent doses may be administered outside of the healthcare setting. Auto-injectable epinephrine should be made available to patients; instruct patients to recognize symptoms of a severe allergic reaction, about the proper use of epinephrine, and to seek immediate medical care upon use. Timothy grass pollen allergen extract may not be suitable for patients with medical conditions that may decrease the patient's ability to survive a serious allergic reaction or increase the risk of adverse reactions after epinephrine administration. These conditions may include, but are not limited to, unstable angina, recent myocardial infarction, significant cardiac arrhythmias, and uncontrolled hypertension. Further, the extract may not be suitable for patients taking medications that can potentiate or inhibit the effects of epinephrine or decrease the effectiveness of inhaled bronchodilators; these medications include beta-adrenergic blockers, alpha-adrenergic blockers, ergot alkaloids, tricyclic antidepressants, levothyroxine, monoamine oxidase inhibitors, chlorpheniramine, diphenhydramine, cardiac glycosides, and diuretics. Concomitant use of Timothy grass pollen allergen extract with other allergen immunotherapy has not been studied; concurrent use may increase the risk of local or systemic reactions to either subcutaneous or sublingual immunotherapy.
Timothy grass pollen allergen extract is contraindicated in patients with severe, unstable, or uncontrolled asthma (e.g., status asthmaticus or acute bronchospasm). Patients with recurrent asthma exacerbations should be reevaluated for appropriateness of therapy and discontinuation should be considered. The extract may not be suitable for patients who have acute or chronic compromised lung function (e.g., asthma, chronic lung disease (CLD), chronic obstructive pulmonary disease (COPD), or emphysema) that may reduce the patient's ability to survive a serious allergic reaction or increase the risk of adverse reactions after epinephrine administration. The extract has not been studied in patients with moderate or severe asthma or in those who require daily medications for asthma treatment.
Patients with any type of oral inflammation (e.g., oral lichen planus, mouth ulcers, or thrush) or oral wounds, such as those after dental work or oral surgery, should not receive Timothy grass pollen allergen extract until complete healing of the oral cavity occurs.
Timothy grass pollen allergen extract is contraindicated in patients with a history of eosinophilic esophagitis. Discontinue the extract in patients who experience severe or persistent gastro-esophageal symptoms (e.g., dysphagia, chest pain) and consider a diagnosis of eosinophilic esophagitis.
Available data on timothy grass pollen allergen extract administered to pregnant women are insufficient to inform associated risks in pregnancy. In a fetal/embryo developmental toxicity study performed in mice, administration of timothy grass pollen allergen extract during gestation did not reveal adverse developmental outcomes in fetuses.
According to the manufacturer, Timothy grass pollen allergen extract should be used with caution in breast-feeding women. It is not known if the extract is excreted into human breast milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
-Hypersensitivity to Timothy grass or cross-reactive grass pollens (e.g., Sweet Vernal, Orchard, Perennial Rye, Kentucky Blue Grass, Meadow Fescue, and Redtop) should be confirmed by positive skin test or in vitro testing for pollen-specific IgE antibodies prior to administration.
-Initiate treatment at least 12 weeks prior to the expected onset of each grass pollen season and continue throughout the season. For sustained effectiveness for 1 grass pollen season after cessation of treatment, Timothy grass pollen allergen extract may be taken daily for 3 consecutive years, including the intervals between grass pollen seasons.
-Safety and efficacy data regarding starting treatment during the grass pollen season are not available. Safety data regarding restarting treatment after missing a dose are limited; during clinical trials, treatment interruptions for up to 7 days were allowed.
For the treatment of allergic rhinitis (with or without allergic conjunctivitis) induced by Timothy grass or cross-reactive grass pollens:
Sublingual dosage:
Adults 65 years and younger: 1 tablet (2,800 Bioequivalent Allergy Units [BAU]) SL once daily. Administer the first dose in a health care setting where acute allergic reactions can be recognized and treated by an experienced clinician; observe the patient for at least 30 minutes after administration. If the patient tolerates the initial dose, subsequent doses can be taken at home; auto-injectable epinephrine should be available. Patients who are prescribed epinephrine should be instructed in proper technique for emergency self-injection.
Children and Adolescents 5 to 17 years: 1 tablet (2,800 Bioequivalent Allergy Units [BAU]) SL once daily. Administer the first dose in a health care setting where acute allergic reactions can be recognized and treated by an experienced clinician; observe the patient for at least 30 minutes after administration. If the patient tolerates the initial dose, subsequent doses can be taken at home; auto-injectable epinephrine should be available. Patients who are prescribed epinephrine should be instructed in proper technique for emergency self-injection.
Maximum Dosage Limits:
-Adults
1 tablet (2800 BAU)/day SL.
-Geriatric
65 years: 1 tablet (2800 BAU)/day SL.
> 65 years: Safety and efficacy have not been established.
-Adolescents
1 tablet (2800 BAU)/day SL.
-Children
>= 5 years: 1 tablet (2800 BAU)/day SL.
1-4 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Timothy Grass Pollen Allergen Extract products.
When Timothy grass pollen allergen extract is allowed to dissolve sublingually, allergens bind to epithelial cells and cross the oral mucosa, where they are taken up by tolerogenic antigen-presenting cells (i.e., Langerhans cells and myeloid dendritic cells). The allergens are then processed into small immunogenic peptides, and the antigen-presenting cells migrate into local regional lymph nodes (submaxillary, cervical, internal jugular). There, allergen peptide fragments are presented to naive CD4+ T cells. This interaction stimulates suppressive T helper (Th) 1 and regulatory T cells and inhibits the activation and proliferation of Th2 cells. Subsequently, T cells encourage B cells to produce protective antibody responses, including secretion of allergen-specific IgG4 and IgA and, later, inhibition of IgE. Regulatory T cells may also suppress other inflammatory cells (e.g., eosinophils, mast cells, basophils) either by cytokine secretion or direct cell-to-cell contact. CD4+ T cells eventually migrate into the blood and tissues, resulting in allergen tolerance.
Timothy grass pollen allergen extract is administered sublingually. The pharmacokinetics of the extract are not well defined and in vivo human research is lacking. Limited pharmacokinetic data are available for sublingual immunotherapy in general. However, direct contact with the oral mucosa has been determined to be the critical step in ensuring adequate exposure.
Parietaria judaica is a perennial plant with highly allergenic pollen. Human pharmacodynamic studies of radiolabeled Parietaria judaica allergen have shown little systemic absorption into the bloodstream through the sublingual mucosa, despite its highly vascular nature. In one study, radioactivity was not detectable in the plasma until swallowing occurred, at which point the plasma radioactivity slowly rose and peaked at approximately 2 hours. In another study using Parietaria judaica, a small amount of the allergen (about 2% of the administered dose) was detected within the oral mucosa 20 hours after dosing. It has been suggested allergens bind to epithelial cells within a few minutes. In a biodistribution study of sublingual radiolabeled ovalbumin in mice, allergen crossed the oral mucosa within 15-30 minutes and was captured by antigen-presenting cells within 30-60 minutes. At 60 minutes, allergen began to disappear from the submucosa, perhaps coinciding with uptake and processing by the antigen-presenting cells. Within 12-24 hours after administration, the antigen-presenting cells migrate to the lymph nodes where they interact with CD4+ cells and further promote the desensitization process.
Affected cytochrome P450 isoenzymes: none