美国食品药品管理局FDA于2014年4月10日批准ORALAIR®(混合花粉变应原提取物)舌下用于治疗过敏性鼻炎，这是美国批准的首个过敏原提取物舌下制剂。 Oralair的适应症是用于某些草花粉引起的伴有或不伴有眼部炎症的10~65岁过敏性鼻炎患者的治疗。生产商申请该药物用于年龄≥5岁的患者。 该药物含有5种草的冷冻干燥提取物：肯塔基蓝草、鸭茅、多年生黑麦草、甜春季草和梯牧草。 美国过敏、哮喘和免疫学会前任主席、佛罗里达州劳德代尔堡执业过敏症专科医生Linda Cox医生称，舌下片治疗将为美国每年约3,000万过敏性鼻炎受累患者提供治疗选择。Oralair每日一次，草花粉季节来临前4个月开始服用并持续整个季节。首次服药在医生诊室，后续可在家中自行服用。制造商格里尔实验室(Greer Laboratories)声称，Oralair可减少患者首个服药过敏季节草花粉导致的过敏症状。 她认为这是一个颠覆过敏性鼻炎治疗格局的产品。 “舌下免疫疗法提供了一种家庭治疗和更易获得的治疗手段，因为其安全性非常好。这可能使得该药物可用于大约90%的没有服用其他药物而仅仅是为治疗症状的患者。” 她还指出，Oralair对过敏性鼻炎标本兼治。“这将适用于正在遭受过敏季节痛苦以及使用各种产品没有达到最佳控制的人群，使他们有可能彻底摆脱疾病痛苦。” Oralair批准令是基于在美国和欧洲纳入2,500多例成人和儿童患者的双盲安慰剂对照试验结果。为评估该药物的有效性，患者报告其症状和为控制过敏症状需要服用其他药物的情况。在一个草花粉季节治疗期间，与服用安慰剂患者相比， Oralair服用者症状和需要其他药物治疗减少16~30%。 试验表明，过敏季节前和过敏季节期间服用Oralair可减少患者过敏症状以及对症状缓解药物的需求。 据格里尔公司4月1日的声明，Oralair最常见不良事件为口腔瘙痒、咽喉刺激、耳部瘙痒、口部水肿、舌部瘙痒、咳嗽以及口咽部疼痛，发生率均小于5%。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ORALAIR safely and effectively. See full prescribing information for ORALAIR. ORALAIR ® (Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract) Tablet for Sublingual Use Initial U.S. Approval: 2014 WARNING: SEVERE ALLERGIC REACTIONSSee full prescribing information for complete boxed warning ORALAIR can cause life-threatening allergic reactions such as anaphylaxis and severe laryngopharyngeal edema. (5.1) Do not administer ORALAIR 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) ORALAIR may not be suitable for patients with certain underlying medical conditions that may reduce their ability to survive a serious allergic reaction. (5.2) ORALAIR may not be suitable for patients who may be unresponsive to epinephrine or inhaled bronchodilators, such as those taking beta-blockers. (5.2) RECENT MAJOR CHANGES Contraindications (4) 10/2014 Warnings and Precautions, Eosinophilic Esophagitis (5.3) 10/2014 INDICATIONS AND USAGE ORALAIR 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 any of the five grass species contained in this product. ORALAIR is approved for use in persons 10 through 65 years of age.  DOSAGE AND ADMINISTRATION For sublingual use only. Age (years) Dose Day 1 Day 2 Day 3 and following 10-17 100 IR 2× 100 IR 300 IR 18-65 300 IR 300 IR 300 IR Initiate treatment 4 months before the expected onset of each grass pollen season and continue treatment throughout the season. (2.2) Place the tablet under the tongue for at least 1 minute, until complete dissolution and then swallow. (2.2) Administer the first dose of ORALAIR under the supervision of a physician with experience in the diagnosis and treatment of severe allergic reactions. Observe the patient for at least 30 minutes. (2.1) DOSAGE FORMS AND STRENGTHS Tablets, 100 IR and 300 IR (3) CONTRAINDICATIONS Severe, unstable or uncontrolled asthma (4) History of any severe systemic allergic reaction or any severe local reaction to sublingual allergen immunotherapy (4) A history of eosinophilic esophagitis (4) Hypersensitivity to any of the inactive ingredients contained in this product (4) WARNINGS AND PRECAUTIONS Inform patients of the signs and symptoms of severe allergic reactions and instruct them to seek immediate medical care and discontinue therapy should any of these occur. (5.1) In case of oral inflammation or wounds, stop treatment with ORALAIR to allow complete healing of the oral cavity. (5.5) ADVERSE REACTIONS Adverse reactions reported in ≥5% of patients were: oral pruritus, throat irritation, ear pruritus, mouth edema, tongue pruritus, cough, oropharyngeal pain (6) To report SUSPECTED ADVERSE REACTIONS, contact Stallergenes at 1-855-274-1322 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 1/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE ORALAIR 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 any of the five grass species contained in this product. ORALAIR is approved for use in persons 10 through 65 years of age. ORALAIR is not indicated for the immediate relief of allergy symptoms. 2 DOSAGE AND ADMINISTRATION For sublingual use only. 2.1 Dose For adults 18 through 65 years of age, the dose is 300 IR (index of reactivity) daily. For children and adolescents 10 through 17 years of age, the dose is increased over the first three days as shown in Table 1. Table 1. Dosage for Adults and Children for the Days 1-3 (and following) Age (years) Dose Day 1 Day 2 Day 3 and following 10-17 100 IR 2× 100 IR 300 IR 18-65 300 IR 300 IR 300 IR 2.2 Administration Administer the first dose of ORALAIR in a healthcare setting in which acute allergic reactions can be treated under the supervision of a physician with experience in the diagnosis and treatment of severe allergic reactions. After receiving the first dose of ORALAIR, 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 ORALAIR to children under adult supervision. Remove the ORALAIR tablet from the blister just prior to dosing. Place the ORALAIR tablet immediately under the tongue until complete dissolution for at least 1 minute before swallowing. Wash hands after handling the ORALAIR tablet. Do not take the ORALAIR tablet with food or beverage. To avoid swallowing allergen extract, food or beverage should not be taken for 5 minutes following dissolution of the tablet. Initiate treatment 4 months before the expected onset of each grass pollen season and maintain it throughout the grass pollen season. Data regarding the safety of starting treatment during the pollen season or restarting treatment after missing a dose of ORALAIR are not available. It is recommended that auto-injectable epinephrine be made available to patients prescribed ORALAIR. Patients who are prescribed epinephrine while receiving immunotherapy should be instructed in the proper use of emergency self-injection of epinephrine [See Warnings and Precautions (5.2)]. 3 DOSAGE FORMS AND STRENGTHS ORALAIR tablets are available as follows: ORALAIR 100 IR tablets are round and biconvex, slightly speckled white to beige with "100" engraved on both sides ORALAIR 300 IR tablets are round and biconvex, slightly speckled white to beige with "300" engraved on both sides 4 CONTRAINDICATIONS ORALAIR is contraindicated in patients with: Severe, unstable or uncontrolled asthma History of any severe systemic allergic reaction History of any severe local reaction to sublingual allergen immunotherapy A history of eosinophilic esophagitis Hypersensitivity to any of the inactive ingredients (mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate and lactose monohydrate) contained in this product [see Description (11)] 5 WARNINGS AND PRECAUTIONS 5.1 Severe Allergic Reactions ORALAIR can cause systemic allergic reactions including anaphylaxis which may be life-threatening. In addition, ORALAIR can cause severe local reactions, including laryngopharyngeal swelling, which can compromise breathing and be life-threatening. Patients who have a systemic allergic reaction to ORALAIR should stop taking ORALAIR. Patients who have either escalating or persistent local reactions to ORALAIR should be reevaluated and considered for discontinuation of ORALAIR. Administer the initial dose of ORALAIR in a healthcare setting under the supervision of a physician prepared to manage a severe systemic or a severe local allergic reaction. Observe patients in the office for at least 30 minutes following the initial dose of ORALAIR. Severe and serious allergic reactions may require treatment with epinephrine [See Warnings and Precautions (5.2)]. 5.2 Epinephrine Prescribe auto-injectable epinephrine to patients receiving ORALAIR. Instruct patients to recognize the signs and symptoms of a severe allergic reaction and in the proper use of emergency self-injection of epinephrine, and instruct patients to seek immediate medical care upon its use [See Patient Counseling Information (17)]. ORALAIR 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. ORALAIR 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 Eosinophilic Esophagitis Eosinophilic esophagitis has been reported in association with sublingual tablet immunotherapy [see Contraindications (4) and Adverse Reactions (6.2)]. Discontinue ORALAIR and consider a diagnosis of eosinophilic esophagitis in patients who experience severe or persistent gastro-esophageal symptoms including dysphagia or chest pain. 5.4 Asthma ORALAIR has not been studied in subjects with moderate or severe asthma or any subjects who required daily medication. Immunotherapy with ORALAIR should be withheld if the patient is experiencing an acute asthma exacerbation. Reevaluate patients who have recurrent asthma exacerbations and consider discontinuation of ORALAIR. 5.5 Concomitant Allergen Immunotherapy ORALAIR has not been studied in subjects 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. 5.6 Oral Inflammation Stop treatment with ORALAIR 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. 5.7 Initiation of ORALAIR Therapy during Grass Pollen Season The risk of ORALAIR may be increased when treatment is initiated during the grass pollen season. 6 ADVERSE REACTIONS Adverse reactions reported in ≥5% of patients were: oral pruritus, throat irritation, ear pruritus, mouth edema, tongue pruritus, cough, oropharyngeal pain. 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 rate observed in practice. Adults Overall, in 6 placebo-controlled clinical trials, 1,038 adults 18 through 65 years of age received at least one dose of ORALAIR 300IR, of whom 611 (59%) completed at least four months of therapy. Of study participants, 56% were male, 17% had a history of mild intermittent asthma at study entry, and 64% were polysensitized. Data on race and ethnicity were not systematically captured in the five European studies (N=805). In the US study (N=233), a limited number of patients reported their race as other than White/Caucasian (Black/African American: 5.6%, Asian: 2.6%, Other: 2.1%) or their ethnicity as Hispanic or Latino (3.0%). Adverse events were captured on a daily diary card that did not solicit for specific adverse events. Across the six clinical studies, adverse reactions reported at an incidence of ≥2% of ORALAIR recipients and at a greater incidence than that in participants treated with placebo are listed in Table 2. Table 2. Adverse Reactions Reported by ≥2% of Adults Receiving ORALAIR 300 IR and at a Greater Incidence than that in Participants Treated with Placebo  Adverse Reactions ORALAIR 300 IR (N=1,038) PLACEBO (N=840) Ear and labyrinth disorders   Ear pruritus 8.4% 0.6% Respiratory, thoracic and mediastinal disorders   Throat irritation 22.0% 3.7%   Cough 7.3% 5.9%   Oropharyngeal pain 5.1% 3.7%   Pharyngeal edema 3.8% 0.1% Gastrointestinal disorders   Oral pruritus 25.1% 5.0%   Edema mouth 8.2% 0.6%   Tongue pruritus 7.9% 0.7%   Lip edema 4.4% 0.4%   Paraesthesia oral 4.3% 1.0%   Abdominal pain 4.2% 1.3%   Dyspepsia 3.9% 0.4%   Tongue edema 2.7% 0.1%   Hypoaesthesia oral 2.2% 0.1%   Stomatitis 2.1% 0.7% Skin and subcutaneous tissue disorders   Urticaria 2.3% 1.5% Additional adverse reactions of interest that occurred in <2% of ORALAIR recipients include dysphagia, nausea, vomiting, esophageal pain, gastritis, and gastroesophageal reflux. Children and Adolescents Overall, in placebo-controlled clinical trials, 154 children and adolescents 5 through 17 years of age received ORALAIR 300 IR, of whom 147 were exposed for more than 3 months. Of study participants, 66% were male, and 21% had a history of mild intermittent asthma at study entry. Data on race and ethnicity were not systematically captured. The safety profile in the pediatric population, was generally similar to that of adults. In pediatric patients receiving ORALAIR, additional adverse reactions reported at an incidence of ≥2% and at a greater incidence than that in participants treated with placebo are listed in Table 3. Table 3. Additional Adverse Reactions Reported by ≥2% of Children and Adolescents Receiving ORALAIR 300 IR and at a Greater Incidence than that in Participants Treated with Placebo  Adverse Reactions ORALAIR 300 IR (N=154) PLACEBO (N=158) Infections and infestations   Tonsillitis 5.8% 3.2%   Upper respiratory tract infection 3.9% 1.9% Respiratory, thoracic and mediastinal disorders   Asthma 7.1% 3.8%   Dysphonia 2.6% 1.3% Gastrointestinal disorders   Lip pruritus 3.2% 0.0% Skin and subcutaneous tissue disorders   Atopic dermatitis 3.2% 0.6% Serious Adverse Reactions At least 1 serious adverse event was reported in 22 of 1514 (1.5%) subjects who received ORALAIR at any dose, and 11 of 840 (1.1%) of placebo recipients. Of the 22 serious adverse events in the ORALAIR recipients, 2 were considered "definitely related" to ORALAIR. The first subject was an adult who experienced a severe hypersensitivity reaction which began 5 minutes after administration of ORALAIR. The symptoms were violent coughing and marked dyspnea. The subject was treated with antihistamines, salbutamol and prednisolone and the reaction resolved without sequelae. The second subject was an adult who experienced severe laryngeal edema. The subject was treated with prednisolone and event resolved without sequelae. There was also one case of gastroenteritis with an onset on Day 93 of therapy that was possibly related to ORALAIR. 6.2 Postmarketing Experience Post Marketing Safety Studies A total of 1728 individuals (808 adults; 920 children 5 through 17 years of age) received ORALAIR in post marketing safety studies. Reported adverse reactions included: anaphylactic reaction, oral allergy syndrome, flushing, dyspnea, laryngeal edema, and diarrhea. Spontaneous Postmarketing Reports In addition to adverse reactions reported in clinical and post marketing safety studies, the following adverse reactions have been identified during post approval use of ORALAIR. 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: autoimmune thyroiditis, eosinophilic myocarditis, eosinophilic esophagitis, palpitations, tachycardia, hypotension, loss of consciousness, circulatory collapse, malaise, pallor, peripheral vascular disorder, stridor, angioedema, face edema, weight decreased, wheezing, exacerbation of asthma, chest discomfort, oropharyngeal paresthesia, oropharyngeal blistering, headache, dizziness, tinnitus, asthenia, somnolence, anxiety, rash, pruritus, salivary gland enlargement and/or hypersecretion, dry mouth, dry eye, influenza-like syndrome, lymphadenopathy, eosinophil count increased. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B: Reproductive and developmental toxicity studies performed in female rats and rabbits have revealed no evidence of harm to the fetus due to ORALAIR. In these studies, the effect of ORALAIR on embryo-fetal development was evaluated. Animals were administered 1000 IR/kg/day of ORALAIR by oral gavage on days 6-17 of gestation for rats, and days 6-18 of gestation for rabbits. A dose of 1000 IR/kg/day of ORALAIR corresponds to approximately 200 fold a human dose on an IR/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, ORALAIR should be used during pregnancy only if clearly needed. Because systemic and local adverse reactions with immunotherapy may be poorly tolerated during pregnancy, ORALAIR should be used during pregnancy only if clearly needed. 8.2 Labor and Delivery Safety and effectiveness of ORALAIR in labor and delivery have not been established. 8.3 Nursing Mothers It is not known if ORALAIR is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ORALAIR is administered to a nursing woman. 8.4 Pediatric Use Efficacy and safety of ORALAIR have been established in children and adolescents 10 through 17 years of age. ORALAIR is not approved for use in children younger than 10 years of age because safety has not been established. 8.5 Geriatric Use 11 DESCRIPTION ORALAIR (Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract) is a mixed allergen extract of the following five pollens: Sweet Vernal (Anthoxanthum odoratum L), Orchard (Dactylis glomerata L), Perennial Rye (Lolium perenne L), Timothy (Phleum pratense L), and Kentucky Blue Grass (Poa pratensis L). ORALAIR is available as a sublingual tablet in the following strengths: 100 IR (equivalent to approximately 3000 BAU (bioequivalent allergy units) 300 IR (equivalent to approximately 9000 BAU Inactive ingredients: mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate and lactose monohydrate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanisms of action of allergen immunotherapy are not known. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies were conducted in animals. There was no evidence of mutagenic or clastogenic activity in response to ORALAIR in the in vitro bacterial mutagenesis assay and mouse lymphoma thymidine kinase cell assay or the in vivo bone marrow micronucleus and unscheduled DNA synthesis tests in rats. No fertility study was conducted with ORALAIR. 14 CLINICAL STUDIES The efficacy of ORALAIR for the treatment of grass pollen-induced allergic rhinoconjunctivitis was investigated in five double-blind, placebo-controlled clinical trials: four natural field studies and an environmental exposure chamber study. The natural field studies included three trials, each conducted over a single season (two in adults and one in adolescents and children) and one five-year study (adults). Participants received ORALAIR or placebo daily for four months prior to grass pollen season and throughout grass pollen season. Study participants reported at least a two grass pollen season history of rhinoconjunctivitis symptoms. For the European studies, subjects had a positive skin prick test to 5-grass pollen extract and positive in vitro testing for timothy grass-specific serum IgE. For the US study, subjects had a positive skin prick test to Timothy grass pollen extract. With the exception of those with mild intermittent asthma, patients with asthma were excluded. Approximately 16% had asthma at baseline and 65% were polysensitized (i.e., sensitized to the 5-grass pollen allergen extract and at least one other unrelated allergen). Overall, the mean age of study participants was 28 years and 56% were male. Natural Field Studies In the natural field studies, efficacy of ORALAIR as immunotherapy to treat symptoms of allergic rhinoconjunctivitis due to the grass pollens included in ORALAIR was assessed via daily recording of symptoms and rescue medication use. The daily Combined Score (CS, range: 0-3) equally weights symptoms and rescue medication use. The daily Rhinoconjunctivitis Total Symptom Score (RTSS, range 0-18) is the total of the six individual symptom scores (sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus and watery eyes) each graded by participants on a 0 (no symptoms) to 3 (severe symptoms) scale. The daily Rescue Medication Score (RMS, range 0-3) grades the intake of rescue medication as 0 = absent, 1 = antihistamine, 2 = nasal corticosteroid, 3 = oral corticosteroid. In case of multiple medications, the higher score is retained. Least Squares (LS) means are within-group means adjusted for the covariates in the statistical models (i.e., analyses of covariance for average scores and linear mixed models with repeated measures for daily scores). The Relative Difference is the LS mean difference between ORALAIR and Placebo divided by the LS mean of Placebo, expressed as a percentage. US Study In this study, 473 adults aged 18 through 65 years received ORALAIR or placebo, starting approximately four months prior to the expected onset of the grass-pollen season and continuing for the duration of the pollen season. The results of the analysis of the daily Combined Score (CS), daily Rhinoconjunctivitis Total Symptom Score (RTSS), and daily Rescue Medication Score (RMS) are summarized in Table 4. Table 4. Daily Combined Score (CS), Daily Rhinoconjunctivitis Total Symptom Score (RTSS), and Daily Rescue Medication Score (RMS) during the Grass Pollen Period (US study)  Efficacy endpoint ORALAIR (N=208) LS Mean Placebo (N=228) LS Mean LS Mean Difference ORALAIR - Placebo Relative Difference Estimate 95% CI   Daily CS 0.32 0.45 -0.13 -28.2% [-43.4%;-13.0%] Daily RTSS 3.21 4.16 -0.95 -22.9% [-38.2%;-7.5%] Daily RMS 0.11 0.20 -0.09 -46.5% [-73.9%;-19.2%] LS: Least Squares Primary efficacy analysis Secondary efficacy analysis European Study In this study, adults aged 18 to 45 years received one of 3 different doses of 5-grass pollen extract sublingual tablet or placebo. A total of 311 subjects received ORALAIR or placebo starting approximately 4 months prior to the expected onset of the grass pollen season and continuing for the duration of the grass pollen season. The results of the analysis of the daily CS, daily RTSS and daily RMS for ORALAIR (300 IR) are shown in Table 5. Table 5. Daily Combined Score (CS), Daily Rhinoconjunctivitis Total Symptom Score (RTSS), and Daily Rescue Medication Score (RMS) during the Grass Pollen Period (European study) Efficacy endpoint ORALAIR (N=136) LS  Mean Placebo (N=148) LS Mean LS Mean Difference ORALAIR - Placebo Relative Difference Estimate 95% CI   Daily CS 0.50 0.70 -0.21 -29.6% [-43.1%;-16.1%] Daily RTSS 3.48 4.91 -1.44 -29.2% [-43.4%;-15.1%] Daily RMS 0.41 0.59 -0.18 -30.1% [-49.5%;-10.6%] LS: Least Squares Long Term Study In this study, adults received ORALAIR or placebo according to two different treatment regimens. A total of 426 subjects received ORALAIR or placebo starting approximately 4 months prior to the grass pollen season and continuing for the entire season. Subjects were treated for three consecutive grass pollen seasons (Year 1 to Year 3). The primary evaluation was the Year 3 pollen period. Participants then entered two years of immunotherapy-free follow-up (Year 4 and Year 5). The results of the analysis of the daily Combined Score for ORALAIR (4M) for treatment Years 1-3 are summarized in Table 6. Data are insufficient to demonstrate efficacy for one or two years after discontinuation of ORALAIR. Table 6. Analysis of Daily Combined Score for Each Grass Pollen Period (Long Term study)  Year ORALAIR (4M) Placebo LS Mean Difference ORALAIR - Placebo Relative Difference N LS Mean N LS Mean Estimate 95% CI   Year 1 188 0.56 205 0.67 -0.11 -16.4% [-27.0%;-5.8%] Year 2 160 0.35 172 0.56 -0.21 -38.0% [-53.4%;-22.6%] Year 3 149 0.31 165 0.50 -0.19 -38.3% [-54.7%;-22.0%] LS: Least Squares Pediatric Study In this study, 278 children and adolescents received ORALAIR or placebo starting approximately 4 months prior to the grass-pollen season and continuing for the duration of the pollen season. The results of the daily CS, daily RTSS, and daily RMS are summarized in Table 7. Table 7. Daily Combined Score (CS), Daily Rhinoconjunctivitis Total Symptom Score (RTSS), Daily Rescue Medication Score (RMS) during the Grass Pollen Period (Pediatric study) Efficacy endpoint ORALAIR (N=131) LS Mean Placebo (N=135) LS Mean LS Mean Difference ORALAIR - Placebo Relative Difference Estimate 95% CI Daily CS 0.44 0.63 -0.19 -30.1% [-46.9%;-13.2%] Daily RTSS 2.52 3.63 -1.11 -30.6% [-47.0%;-14.1%] Daily RMS 0.46 0.65 -0.19 -29.5% [-50.9%;-8.0%] LS: Least Squares Allergen Environmental Chamber Study In an allergen environmental chamber study, 89 adults with grass pollen-associated allergic rhinoconjunctivitis were challenged with four of the five grass pollens contained in ORALAIR at baseline and after 4 months of treatment with ORALAIR (n=45) or placebo (n=44). The average Rhinoconjunctivitis Total Symptom Score (RTSS) of each group during the 4 hours of the allergen challenge was assessed; use of rescue medication was not permitted. The results of this study are shown in Table 8. Table 8. Average Rhinoconjunctivitis Total Symptom Score (RTSS) during Grass Pollen Allergen Challenge in an Environmental Exposure Chamber after 4 months of ORALAIR or placebo Efficacy endpoint ORALAIR (N=45) LS Mean Placebo (N=44) LS Mean LS Mean Difference ORALAIR - Placebo Relative Difference Estimate 95% CI   Average RTSS 4.88 6.84 -1.97 -28.7% [-43.7%;-13.7%] LS: Least Squares Primary efficacy analysis 16 HOW SUPPLIED/STORAGE AND HANDLING ORALAIR is available as a sublingual tablet equivalent to 100 IR and 300 IR of five grass mixed pollens allergen extract. Description NDC Number Children and Adolescents Sample Kit (10 to 17 years of age) One box of the 100 IR Starter Pack Two boxes of the 300 IR Sample Packs NDC 59617-0020-1 Adult Sample Kit (18 to 65 years of age) One box of 300 IR Starter Pack Two boxes of 300 IR Sample Packs NDC 59617-0025-1 Children and Adolescents Starter Pack (10 to 17 years of age) 1 blister pack of three 100 IR tablets NDC 59617-0010-1 Adult Starter Pack (18 to 65 years of age) 1 blister pack of three 300 IR tablets NDC 59617-0016-1 Sample Pack 1 blister pack of three 300 IR tablets NDC 59617-0015-3 Commercial Pack 1 blister pack of thirty 300 IR tablets NDC 59617-0015-2 Storage: Store at controlled room temperature (20°C-25°C/68°F-77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the Medication Guide and to keep ORALAIR and all medicines out of the reach of children. Inform patients that ORALAIR is used for sublingual immunotherapy for the treatment of grass pollen-induced allergic rhinitis with or without conjunctivitis and is not indicated for the immediate relief of allergy symptoms. Severe Allergic Reactions Advise patients that ORALAIR may cause systemic allergic reactions, including anaphylactic reactions, and severe local allergic reactions [See Warnings and Precautions (5.1)]. Educate patients about the signs and symptoms of a severe systemic allergic reaction and a severe local allergic reaction. 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 [See Warnings and Precautions (5.2)]. Ensure that patients have injectable epinephrine available and are appropriately trained in its use. Instruct patients who experience a severe allergic reaction to seek immediate medical care, discontinue therapy, and resume treatment only at the instruction of a physician [See Warnings and Precautions (5.2)]. Inform the patient that the first dose of ORALAIR is administered in a healthcare setting under the supervision of a physician and s/he will be monitored for at least 30 minutes to watch for signs and symptoms of a severe systemic or a severe local allergic reaction [See Dosage and Administration (2.2)]. Inform parents/guardians that ORALAIR should be administered to children only under adult supervision [See Dosage and Administration (2.2)]. Because of the risk of eosinophilic esophagitis, instruct patients with severe or persistent symptoms of esophagitis to discontinue ORALAIR and to contact their healthcare professional. [See Warnings and Precautions (5.3)] Asthma Instruct patients with asthma that if they have difficulty breathing or if asthma becomes difficult to control, they are to stop taking ORALAIR and contact their healthcare professional immediately [See Warnings and Precautions (5.3)]. Administration Instructions Instruct patients to carefully remove the ORALAIR tablet from the blister just prior to dosing and to take the sublingual tablet immediately by placing it under the tongue where it will dissolve. Also instruct patients to avoid swallowing for about 1 minute, 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)]. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=854c9772-63b9-44a3-a11e-77b29c59e91d 舌下脱敏片Oralair Grasses获德国批准上市 德国批准Stallergenes公司草过敏原舌下速溶片（Oralair Grasses）上市，用于治疗草花粉过敏。 本品含有多年生黑麦草、合叶子草、梯牧草、鸭茅和甜春季草5种常见的草过敏原混合物。由于一日剂量为300 IR（index of reactivity，反应指数），故模拟患者的自然接触。根据欧洲共同认可的程序以德国作为参照国，Oralair Grasses将在欧洲其它国际申请上市。根据对儿童关键的研究有效结果，该公司将立即申请此产品扩大应用于儿童。 本品在德国注册是一显著的突破，脱敏治疗可作为主流药物，并创建了一个新的治疗类别：“过敏原”。 据世界卫生组织估计，全球20％～25％的人患有呼吸道过敏症状、鼻炎和（或）哮喘。据国际儿童哮喘与过敏研究（ISAAC）预测，至2020年全世界50％的人口会有过敏症状。世界卫生组织认为，脱敏是唯一治疗过敏的免疫过程和修正这类疾病的自然途径。几乎 15％～20％患有中度至严重过敏性鼻炎、鼻-结膜炎的患者按常规治疗方法难以控制症状。 日常剂量的本品服用方便、用药安全，患者可非常显著地减轻鼻-结膜炎所有症状，大大减少原治疗症状的用药，明显提高其的生活质量。 本品系一速溶片，对春季、整个有花粉季节和环境中花粉高浓度时的草花粉过敏性鼻-结膜炎显示高效：多种和单一过敏患者和哮喘患者；每种单一症状，特别是鼻充血和流泪。 本品的临床开发计划迄今已纳入1 600例患者。一项关键的长期研究正按计划进行，现已进入第二个年头。Stallergenes公司计划在2008年向美国FDA递交成人和儿童的新药研究申请。