HIGHLIGHTS OF PRESCRIBING INFORMATION                                        •      Initiate treatment at least 12 weeks before the expected onset of These highlights do not include all the information needed to use      ragweed pollen season and continue treatment throughout the RAGWITEK safely and effectively. See full prescribing information                       season. (2.2)

for RAGWITEK.                                                                                                     •       Place the tablet immediately under the tongue. Allow it to remain there until completely dissolved. Do not swallow for at least 1

RAGWITEK® (Short Ragweed Pollen Allergen Extract)                                             minute. (2.2)

Tablet for Sublingual Use                                                                                     •      Administer the first dose of RAGWITEK under the supervision of a

Initial U.S. Approval: 2014                                                                                           physician with experience in the diagnosis and treatment of allergic diseases. Observe patients in the office for at least 30 minutes

WARNING: SEVERE ALLERGIC REACTIONS                                        following the initial dose. (2.2)

See full prescribing information for complete boxed warning.               --------------------- DOSAGE FORMS AND STRENGTHS ---------------------

•              RAGWITEK  can  cause  life-threatening  allergic  reactions               •      Tablet, 12 Amb a 1-Unit (Amb a 1-U) (3)

such   as   anaphylaxis   and   severe   laryngopharyngeal             -------------------------------CONTRAINDICATIONS------------------------------- restriction. (5.1)                                                                                  •      Severe, unstable or uncontrolled asthma. (4)

•              Do  not  administer  RAGWITEK  to  patients  with  severe,

unstable or uncontrolled asthma. (4)

•              Observe  patients  in  the  office  for  at  least  30  minutes

•      History of any severe systemic allergic reaction or any severe local

reaction to sublingual allergen immunotherapy. (4)

following the initial dose. (5.1)                                                                 •      A history of eosinophilic esophagitis. (4)

•              Prescribe  auto-injectable  epinephrine,  instruct  and  train             •      Hypersensitivity to any of the inactive ingredients contained in this

patients or parents/guardians on its appropriate use, and                    product. (4)

instruct patients or parents/guardians to seek immediate            ----------------------- WARNINGS AND PRECAUTIONS ----------------------- medical care upon its use. (5.1)                                                           •       Inform patients or parents/guardians of the signs and symptoms of

•              RAGWITEK may not be suitable for patients with certain                   serious allergic reactions and instruct them to seek immediate

underlying medical conditions that may reduce their ability                    medical care and discontinue therapy should any of these occur.

to survive a serious allergic reaction. (5.1)                                                     (5.1)

•              RAGWITEK may not be suitable for patients who may be             •       In  case  of  oral  inflammation  or  wounds,  stop  treatment  with unresponsive  to  epinephrine  or  inhaled  bronchodilators,            RAGWITEK to allow complete healing of the oral cavity. (5.7) such as those taking beta-blockers. (5.1)

------------------------------ ADVERSE REACTIONS ------------------------------

----------------------------RECENT MAJOR CHANGES--------------------------       •       Adverse reactions reported in ≥5% of adults were: throat irritation,

Indications and Usage (1) ------------ ----------------------------------- 04/2021            oral pruritus, ear pruritus, oral paraesthesia, mouth edema, and

tongue pruritus. Adverse reactions reported in ≥5% of children and

adolescents 5 through 17 years of age were: throat irritation, oral

----------------------------INDICATIONS AND USAGE ----------------------------

RAGWITEK is an allergen extract indicated as immunotherapy for the treatment  of  short  ragweed  pollen-induced  allergic  rhinitis,  with  or

pruritus, ear pruritus, lip swelling, glossodynia, nausea, oral pain, pharyngeal  edema,  swollen  tongue,  abdominal  pain  upper,

stomatitis, and enlarged uvula. (6)

without conjunctivitis, confirmed by positive skin test orin vitrotesting              To report SUSPECTED ADVERSE REACTIONS, contact ALK-Abelló for pollen-specific IgE antibodies for short ragweed pollen. RAGWITEK               Inc., a subsidiary of ALK-Abelló A/S, at +1 512-252-4241 or FDA at is approved for use in persons 5 through 65 years of age. (1)                               1-800-FDA-1088 or www.fda.gov/medwatch.

----------------------- DOSAGE AND ADMINISTRATION -----------------------       See 17 for Patient Counseling Information and Medication Guide. For sublingual use only.

•      One tablet daily. (2.1)                                                                                                                                                                          Revised: 04/2021

FULL PRESCRIBING INFORMATION: CONTENTS*                                                   6.2    Postmarketing Experience

8      USE IN SPECIFIC POPULATIONS

WARNING: SEVERE ALLERGIC REACTIONS                                                            8.1    Pregnancy

1          INDICATIONS AND USAGE                                                                                  8.2    Lactation

2          DOSAGE AND ADMINISTRATION                                                                        8.4    Pediatric Use

2.1        Dose                                                                                                             8.5     Geriatric Use

2.2        Administration                                                                                     11   DESCRIPTION

3          DOSAGE FORMS AND STRENGTHS                                                          12    CLINICAL PHARMACOLOGY

4          CONTRAINDICATIONS                                                                                          12.1  Mechanism of Action

5          WARNINGS AND PRECAUTIONS                                                                13    NONCLINICAL TOXICOLOGY

5.1        Severe Allergic Reactions                                                                          13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility

5.2        Upper Airway Compromise                                                                14   CLINICAL STUDIES

5.3        Eosinophilic Esophagitis                                                                   16   HOW SUPPLIED/STORAGE AND HANDLING

5.4        Asthma                                                                                                  17   PATIENT COUNSELING INFORMATION

5.5        Concomitant Allergen Immunotherapy

5.6        Oral Inflammation                                                                                *Sections or subsections omitted from the full prescribing information

6          ADVERSE REACTIONS                                                                                 are not listed.

6.1        Clinical Trials Experience

WARNING: SEVERE ALLERGIC REACTIONS

•      RAGWITEK can cause life-threatening allergic reactions such as anaphylaxis and severe laryngopharyngeal restriction. (5.1)

•      Do not administer RAGWITEK 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 or parents/guardians on its appropriate use, and instruct patients or parents/guardians to seek immediate medical care upon its use. (5.1)

•      RAGWITEK may not be suitable for patients with certain underlying medical conditions that may reduce their ability to survive a serious allergic reaction. (5.1)

•      RAGWITEK may not be suitable for patients who may be unresponsive to epinephrine or inhaled bronchodilators, such as those taking beta-blockers. (5.1)

1          INDICATIONS AND USAGE

RAGWITEK® is an allergen extract indicated as immunotherapy for the treatment of short ragweed pollen- induced allergic rhinitis, with or without conjunctivitis, confirmed by positive skin test or in vitrotesting for pollen-specific IgE antibodies for short ragweed pollen. RAGWITEK is approved for use in persons 5 through 65 years of age.

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

For sublingual use only.

One RAGWITEK tablet daily.

Administer the first dose of RAGWITEK 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 RAGWITEK, 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.

•      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 ragweed pollen season and continue treatment throughout the season. 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 RAGWITEK are limited. In the clinical trials, treatment interruptions for up to seven days were allowed.

Prescribe auto-injectable epinephrine to patients prescribed RAGWITEK and instruct them (or their parents/guardians) in the proper use of auto-injectable epinephrine [see Warnings and Precautions (5.1)].

RAGWITEK is available as 12 Amb a 1-Unit (Amb a 1-U) tablets that are white to off-white, circular with a debossed double hexagon on one side.

RAGWITEK 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)]

5.1      Severe Allergic Reactions

RAGWITEK can cause systemic allergic reactions including anaphylaxis which may be life-threatening. In addition, RAGWITEK can cause severe local reactions, including laryngopharyngeal swelling, which can compromise breathing and be life-threatening.

Allergic reactions may require treatment with epinephrine. Prescribe auto-injectable epinephrine to patients receiving RAGWITEK. Instruct patients or parents/guardians to recognize the signs and symptoms of a severe allergic reaction and in the proper use of auto-injectable epinephrine. Instruct patients or parents/guardians to seek immediate medical care and to stop treatment with RAGWITEK upon use of auto-injectable epinephrine [see Patient Counseling Information (17)]. See Prescribing Information for epinephrine for complete information.

RAGWITEK may not be suitable for patients with certain medical conditions that may reduce the ability to survive a serious allergic reaction or that may 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); severe mast cell disorder; or cardiovascular disease including unstable angina, recent myocardial infarction, significant arrhythmia, and uncontrolled hypertension. In addition, RAGWITEK may not be suitable for patients who are taking medications that can potentiate or inhibit the effects of epinephrine (see Prescribing Information for epinephrine for information on drug interactions).

Administer the initial dose of RAGWITEK 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 RAGWITEK.

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

and escalating adverse reactions in the mouth or throat.

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

pain.

Subjects with asthma who participated in clinical trials had asthma of a severity that required, at most, a daily medium dose of an inhaled corticosteroid. RAGWITEK has not been studied in subjects with severe asthma.

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

RAGWITEK 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.

Stop treatment with RAGWITEK 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.

Adverse reactions reported in ≥5% of adults were: throat irritation, oral pruritus, ear pruritus, oral paraesthesia, mouth edema, and tongue pruritus. Adverse reactions reported in ≥5% of children and adolescents 5 through 17 years of age were: throat irritation, oral pruritus, ear pruritus, lip swelling, glossodynia, nausea, oral pain, pharyngeal edema, swollen tongue, abdominal pain upper, stomatitis, and enlarged uvula.

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.

In 4 placebo-controlled clinical trials, 1057 subjects 18 years of age and older with short ragweed pollen- induced rhinitis, with or without conjunctivitis, received at least one dose of RAGWITEK, of whom 327 (31%) completed at least 12 weeks of therapy. Of the subjects treated with RAGWITEK, 52% were male, 25%

had mild asthma, and 82% were sensitized to other allergens in addition to ragweed pollen. The subject

population was 83% White, 12% African American, and 2% Asian. Subject demographics in placebo-treated subjects were similar to the active group. The pooled analysis includes safety data from two 28-day safety studies and safety data from the first 28 days of two 52-week safety and efficacy studies. Adverse reactions reported in ≥1% of subjects in the 28-day pooled analysis treated with RAGWITEK are shown in Table 1. The most common adverse reactions reported in subjects treated with RAGWITEK were throat irritation (16.6%  vs  3.3%  placebo),  oral  pruritus  (10.9%  vs  2.0%),  ear  pruritus  (10.4%  vs  1.1%),  and  oral paraesthesia (10.0% vs 4.0%). The percentage of subjects who discontinued from the clinical trials because of an adverse reaction while exposed to RAGWITEK or placebo was 4.4% and 0.8%, respectively. The most common adverse reactions that led to study discontinuation in subjects who were exposed to RAGWITEK were mouth edema, swollen tongue, and dysphagia.

One subject (1/1057; 0.1%) who received RAGWITEK experienced a treatment-related severe systemic allergic reaction that led to discontinuation of RAGWITEK. The subject had local reactions starting on Day 1 of treatment with RAGWITEK. On Day 6 symptoms progressed and included swelling of the throat, dyspnea, nausea, and lightheadedness. The subject fully recovered after treatment with epinephrine (self- administered), antihistamines, and oral corticosteroids.

*  1036 subjects were 18 through 65 years of age and 21 subjects were older than 65 years of age.

† 746 subjects were 18 through 65 years of age and 11 subjects were older than 65 years of age.

The overall safety profile beyond Day 28 in the two 52-week trials was similar to that observed in the pooled 28-day analysis.

In 1 placebo-controlled clinical trial, 513 subjects 5 through 17 years of age with short ragweed pollen- induced rhinitis, with or without conjunctivitis, received at least one dose of RAGWITEK. Of the subjects treated with RAGWITEK, 63% were male, 43% had asthma, and 79% were sensitized to other allergens in addition to ragweed pollen. The subject population was 93% White, 3.1% African American, 2.3% multiple race, 1% Asian, 0.5% Native Hawaiian or Other Pacific Islander, and 0.1% American Indian or Alaska Native. Approximately 40% of subjects were children (5 through 11 years of age) and 60% of subjects were adolescents (12 through 17 years of age). Subject demographics in placebo-treated subjects were similar to the active treatment group.

In the trial in children and adolescents 5 through 17 years of age, parents/ guardians and/ or participants were provided SLIT report cards in which they recorded the occurrence of specific solicited adverse reactions daily for the first 28 days following treatment initiation with RAGWITEK or placebo (summarized in Table 2).

*      Solicited adverse reactions (modified from World Allergy Organization [WAO] list of local side effects of sublingual immunotherapy [SLIT]) were those solicited from subjects via SLIT report

card within the first 28 days after treatment initiation.

†      Of those subjects reporting any intensity of swelling of the tongue in the RAGWITEK group, 1 subject (0.2%) reported severe intensity of swelling of the tongue. Adverse reactions were

categorised as severe according to the definition ‘incapacitating with inability to work or do usual

activity’, as assessed by the investigator.

‡      The percentage of subjects reporting "swelling of the uvula/back of the mouth" includes subjects with an enlarged uvula, palatal swelling/edema, and/or mouth swelling/edema (which can be

anywhere in the mouth, not specifically at the back of the mouth).

In the clinical trial in children and adolescents, unsolicited adverse reactions occurring throughout the entire duration of the trial were recorded in electronic diaries or reported at study visits. Unsolicited adverse reactions reported by ≥1% of children and adolescents throughout the entire duration of the trial are shown in Table 3.

The percentage of subjects who discontinued from the clinical trial because of an adverse reaction while exposed to RAGWITEK or placebo was 3.9% and 1.0%, respectively. The most common adverse reaction that led to study discontinuation in subjects who were exposed to RAGWITEK was throat irritation.

Three subjects (0.6%) treated with RAGWITEK and one subject (0.2%) treated with placebo experienced treatment-related systemic allergic reactions [adverse reactions marked with an asterisk (*) were included in Table 3].

•      One subject treated with RAGWITEK reported hypersensitivity events (skin/face/neck itching*, eye itching/swelling, sneezing*, runny*/itching nose, neck/abdomen redness) beginning on day 6 (i.e., outside the ragweed pollen season) that resolved by day 26. The events resolved within minutes to less than an hour. On two occasions, the subject was treated with antihistamine. This subject subsequently discontinued the trial on day 34 due to persistent local allergic symptoms (swollen tongue).

•      The second subject treated with RAGWITEK reported hypersensitivity (generalized rash on body and face) on day 26 (i.e., outside the ragweed pollen season). The event was treated with antihistamine and systemic corticosteroids and resolved in one week; the subject discontinued the trial due to the event.

•      The third subject treated with RAGWITEK reported pruritus* (on cheeks, arms and legs) and dyspnea on day 1 (i.e., outside the ragweed pollen season) after administration of the first dose. Both adverse events resolved within 2 hours without treatment and did not reoccur upon restarting trial medication 1 week later. The subject subsequently completed the trial.

•      The subject treated with placebo reported hypersensitivity (papular rash with itching on hands, body and lower limbs) on day 7 (i.e. outside the ragweed pollen season). The event was  treated with an antihistamine and systemic corticosteroid and resolved in one week; the subject discontinued the trial due to the event.

One subject (0.2%) treated with RAGWITEK and no subjects on placebo, reported adverse reactions that were treated with epinephrine (any route).The one subject treated with RAGWITEK experienced severe laryngitis on day 126 (during the ragweed pollen season), for which the subject was hospitalized and treated with inhaled racemic epinephrine (i.e., not systemic epinephrine); the laryngitis resolved in 2 days.

The following adverse reactions have been identified during post-approval use of RAGWITEK. 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.

•     Gastrointestinal Disorders:glossodynia.

•     Skin and Subcutaneous Tissue Disorders:angioedema.

•     Respiratory, Thoracic and Mediastinal Disorders:dysphonia.

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 RAGWITEK-associated risks during pregnancy.

In an embryo/fetal developmental toxicity study, RAGWITEK subcutaneously administered to mice during gestation at doses up to approximately 3 times the human sublingual dose did not reveal adverse developmental outcomes in fetuses (see 8.1 Data).

Data

Animal Data

In a developmental toxicity study, the effect of RAGWITEK on embryo/fetal development was evaluated in mice. Animals were administered RAGWITEK subcutaneously daily from day 6 to day 15 of the gestation period at doses approximately 1 to 3 times the human sublingual dose of 12 Amb a 1-U. There were no RAGWITEK-related post-implantation losses, fetal malformations or variations.

Risk Summary

It is not known whether RAGWITEK is excreted in human milk. Data are not available to assess the effects of RAGWITEK on the breastfed child or on milk production/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RAGWITEK and any potential adverse effects on the breastfed child from RAGWITEK or from the underlying maternal condition.

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

RAGWITEK is not approved for use in patients over 65 years of age because safety and efficacy have not been established.

RAGWITEK  tablets  contain  pollen  allergen  extract  from  Short  Ragweed  (Ambrosia  artemisiifolia). RAGWITEK is a sublingual tablet that dissolves within 10 seconds.

RAGWITEK is available as a tablet of 12 Amb a 1-U of short ragweed pollen allergen extract. Inactive ingredients: gelatin NF (fish source), mannitol USP, and sodium hydroxide NF.

12.1    Mechanism of Action

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

13.1    Carcinogenesis, Mutagenesis, Impairment of Fertility

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

There were no positive findings in a combined in vivoComet and micronucleus assay in rats using Short Ragweed (Ambrosia artemisiifolia) pollen allergen extract.

Fertility studies have not been performed with Short Ragweed pollen allergen extract.

Adults

The efficacy of RAGWITEK in the treatment of ragweed pollen-induced allergic rhinitis, with or without conjunctivitis, was investigated in two double-blind, placebo-controlled clinical trials in adults 18 through 50 years of age. Subjects received RAGWITEK or placebo for approximately 12 weeks prior to the start of the ragweed pollen season and throughout the ragweed pollen season.The subject population was 86% White, 9% African American, and 3% Asian. The subject population was almost equally divided between males and females. Overall, the mean age of subjects was 36 years. Subjects with asthma who participated in clinical trials had asthma of a severity that required, at most, a daily low dose of an inhaled corticosteroid. Approximately 16% of subjects had mild asthma at baseline.

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 peak ragweed pollen season. Also, in each study, the average TCS over the entire ragweed season was assessed. Other endpoints in both studies included the average DSS during the peak and entire ragweed season, and the average DMS during the peak ragweed season.

Trial 1

The first study was a placebo-controlled trial which evaluated subjects 18 through 50 years of age comparing RAGWITEK (n=187) and placebo (n=188) administered as a sublingual tablet daily. In this trial, approximately 22% of subjects had mild asthma and 85% were sensitized to other allergens in addition to short ragweed. Subjects with asthma who participated in this trial had asthma of a severity that required, at most, a daily low dose of an inhaled corticosteroid. Subjects with a clinical history of symptomatic allergies to non-short ragweed pollen allergens that required treatment during the ragweed pollen season were excluded from the trial. The subject population was 78% White, 12% African American, and 8% Asian, and almost equally divided between males and females. The mean age of subjects in this study was 35.4 years.

The two treatment groups were balanced with regard to baseline characteristics. The results of this study are shown in Table 4.

Trial 2

The second study was a placebo-controlled trial which evaluated subjects 18 through 50 years of age comparing RAGWITEK (n=194) and placebo (n=198) administered as a sublingual tablet daily. Approximately 17% of subjects had mild asthma and 78% were sensitized to other allergens in addition to short ragweed. Subjects with asthma who participated in this trial had asthma of a severity that required, at most, a daily low dose of an inhaled corticosteroid. Subjects with a clinical history of symptomatic allergies to non-short ragweed pollen allergens that required treatment during the ragweed pollen season were excluded from the trial. The subject population was 88% White, 8.9% African American, 2% Asian, and almost equally divided between males and females. The mean age of subjects in this study was 36.4 years. The two treatment groups were balanced with regard to baseline characteristics. The results of this study are shown in Table 5.

A decrease in TCS during the peak ragweed season for subjects treated with RAGWITEK compared to placebo-treated subjects was demonstrated in both trials. Subjects treated with RAGWITEK also showed a decrease in the average TCS from the start of and throughout the entire ragweed pollen season. Similar decreases were observed in subjects treated with RAGWITEK for other endpoints (see Tables 4 and 5).

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: (RAGWITEK - placebo)/placebo x 100. The 95% CI was based on the 2.5th and 97.5th percentiles of the 10,000 bootstrap samples.

¶          Peak ragweed season was defined as maximum 15 days with the highest moving average pollen counts during the ragweed season.

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: (RAGWITEK - placebo)/placebo x 100. The 95% CI was based on the 2.5th and 97.5th percentiles of the 10,000 bootstrap samples.

¶          Peak ragweed season was defined as maximum 15 days with the highest moving average pollen counts during the ragweed season.

Children and Adolescents (5 through 17 years of age)

The efficacy of RAGWITEK in the treatment of ragweed pollen-induced allergic rhinitis, with or without conjunctivitis, was investigated in a double-blind, placebo-controlled clinical trial in children and adolescents 5 through 17 years of age comparing RAGWITEK (n= 512) and placebo (n= 510) administered as a sublingual tablet daily. Subjects received RAGWITEK or placebo 12-20 weeks prior to the start of the ragweed pollen season and throughout the ragweed pollen season. The subject population was 63% male, 93% White, 3.1% African American, 2.3% multiple race, 1% Asian, 0.5% Native Hawaiian or Other Pacific Islander, and 0.1% American Indian or Alaska Native. Approximately 40% of subjects were children (5 through 11 years of age) and 60% of subjects were adolescents (12 through 17 years of age). Subjects with asthma who participated in clinical trials had asthma of a severity that required, at most, a medium dose of an inhaled corticosteroid. 43% of subjects had asthma at baseline. Treatment groups were balanced with regard to baseline characteristics.

Efficacy was established by self-reporting of rhinoconjunctivitis daily symptom scores (DSS) and daily medication scores (DMS) using a similar methodology to the adult trials.

The sums of the DSS and DMS were combined into the Total Combined Score (TCS) which was averaged over the peak ragweed pollen season. The average TCS over the entire ragweed season was also assessed.

A decrease in TCS during the peak ragweed season for subjects treated with RAGWITEK compared to placebo-treated subjects was demonstrated. Subjects treated with RAGWITEK also showed a decrease in the average TCS from the start of and throughout the entire ragweed pollen season. Similar decreases were observed in subjects treated with RAGWITEK for other endpoints (see Table 6).

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: (RAGWITEK® - placebo)/placebo x 100. The 95% CI was based on the 2.5th and 97.5th percentiles of the 10,000 bootstrap samples.

¶          Primary endpoint (pre-specified criteria for success for primary endpoint: a treatment difference relative to placebo of at least -15% and the associated upper bound of the 95% confidence interval (CI) for this difference of at least -10%); peak ragweed season was defined as maximum 15 days with the highest moving average pollen counts during the ragweed season.

Note: All statistical analyses for the 4 endpoints included fixed effects of treatment, baseline asthma status (yes, no), age group (5 through 11 years of age, 12 through 17 years of age), pollen season, and pollen region nested within pollen season.

The average DSS during the entire season was 2.27 (RAGWITEK group) and 3.26 (placebo group) (treatment difference of -0.99) with a relative treatment difference of -30% (95% CI -38.6, -20.7) and the average DMS during the entire season was 1.61 (RAGWITEK group) and 2.48 (placebo group) (treatment difference of -0.87) with a relative treatment difference of -35% (95% CI -45.5, -22.7).

RAGWITEK 12 Amb a 1-U tablets are white to off-white, circular sublingual tablets with a debossed double hexagon on one side.

RAGWITEK is supplied as follows: