2.1       Dose

One ODACTRA tablet daily.

2.2       Administration

Administer the first dose of ODACTRA 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 ODACTRA, 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. The patient should administer ODACTRA as follows:

• Take the tablet from the blister unit after carefully removing the foil with dry hands.
  
• Place the tablet immediately under the tongue where it will dissolve within 10 seconds. 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 5 minutes after taking the tablet.

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

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

5.1       Severe Allergic Reactions

ODACTRA can cause systemic allergic reactions including anaphylaxis which may be life-threatening. In addition, ODACTRA 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 ODACTRA. Instruct patients or their parents/guardians to recognize the signs and symptoms of a severe allergic reaction and in the proper use of emergency auto-injectable epinephrine. Instruct patients or their parents/guardians to seek immediate medical care and to stop treatment with ODACTRA upon use of auto-injectable epinephrine [see Patient Counseling Information (17).] See Prescribing Information for epinephrine for complete information.

ODACTRA 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, ODACTRA 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 ODACTRA 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 ODACTRA.

5.2       Upper Airway Compromise

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

5.3       Eosinophilic Esophagitis

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

5.4       Asthma

Withhold immunotherapy with ODACTRA if the patient is experiencing an acute asthma exacerbation. Re-evaluate patients who have recurrent asthma exacerbations and consider discontinuation of ODACTRA.

5.5       Concomitant Allergen Immunotherapy

ODACTRA 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.

5.6       Oral Conditions

Stop treatment with ODACTRA 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.

6.1       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 (18 through 65 years of age)

In four double-blind, placebo-controlled, randomized clinical studies, a total of 1279 subjects with house dust mite-induced allergic rhinitis, with or without conjunctivitis, 18 through 65 years of age was treated with at least one dose of ODACTRA 12 SQ-HDM. Of subjects treated with ODACTRA in the four studies, 50% had mild to moderate asthma and 71% were polysensitized to other allergens in addition to HDM, including trees, grasses, weeds, molds, and animal danders. The study population was 88% White, 6% African American, 4% Asian and 55% female.

Study 1 (NCT01700192) was a randomized, double-blind, placebo-controlled study conducted in the US and Canada evaluating ODACTRA in 1482 subjects 12 years of age and older with house dust mite-induced allergic rhinitis with or without conjunctivitis. Of the 1482 subjects, 640 subjects 18 through 65 years of age received at least one dose of ODACTRA, with a median treatment duration of 267 days (range 1 to 368 days). 631 subjects received placebo. Placebo tablets contained the same inactive ingredients as ODACTRA without allergen extract and were packaged identically so that treatment blind/masking was maintained. Participants were monitored for unsolicited adverse events and serious adverse events (SAEs) for the duration of therapy (up to 52 weeks). Participants were monitored for solicited adverse reactions for the first 28 days following treatment initiation.

Study participants were provided side effect report cards in which they recorded the occurrence of specific solicited adverse reactions daily for the first 28 days following treatment initiation with ODACTRA or placebo. In Study 1, the most common solicited adverse reactions reported in ≥10% of subjects treated with ODACTRA were: throat irritation/tickle (67.0% vs. 20.8% placebo), itching in the mouth (61.3% vs. 14.1%), itching in the ear (51.7% vs. 11.7%), swelling of the uvula/back of the mouth (19.8% vs. 2.4%), swelling of the lips (18.0% vs. 2.7%), swelling of the tongue (15.8% vs. 2.1%), nausea (14.2% vs. 7.1%), tongue pain (14.2% vs. 3.0%), throat swelling (13.6% vs. 2.4%), tongue ulcer/sore on the tongue (11.6% vs. 2.1%), stomach pain (11.3% vs. 5.2%), mouth ulcer/sore in the mouth (10.3% vs. 2.9%), and taste alteration/food tastes different (10.0% vs. 3.6%). Table 1 summarizes all solicited adverse reactions reported within the first 28 days of treatment initiation in subjects 18 through 65 years of age using the patient-friendly term.

In Table 1, the dashes represent no subjects.
*Solicited adverse reactions (modified from World Allergy Organization [WAO] list of local side effects of sublingual immunotherapy [SLIT]) were those reported by subjects within the first 28 days after treatment initiation.
†Severe adverse reactions were those assessed by the investigator as severe in intensity, which is defined as incapacitating with inability to work or do usual activity.
‡The percentage of subjects reported for the patient-friendly term of "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 back of the mouth).

In Study 1, the timing of the adverse reaction relative to exposure to ODACTRA was evaluated for 7 solicited adverse reactions (itching in the ear, itching in the mouth, swelling of the uvula/back of the mouth, swelling of the lips, swelling of the tongue, throat irritation/tickle, and throat swelling). The median time to onset of these adverse reactions following initiation of treatment with ODACTRA varied from 1 to 7 days. The median duration of these adverse reactions that occurred on the first day of treatment initiation varied from 30 to 60 minutes. These adverse reactions recurred for a median of 2 to 12 days.

In Study 1, the following unsolicited adverse events were reported in numerically more subjects treated with ODACTRA than with placebo and occurred in ≥1% of subjects 18 through 65 years of age within 28 days after initiation of treatment with ODACTRA: paresthesia oral (9.2% vs. 3.2%), tongue pruritus (4.7% vs. 1.1%), oral pain (2.7% vs. 0.6%), stomatitis (2.5% vs. 1.1%), dyspepsia (2.2% vs. 0.0%), pharyngeal erythema (2.0% vs. 0.3%), eye pruritus (1.7% vs. 1.4%), oral mucosal erythema (1.7% vs. 0.2%), upper respiratory tract infection (1.6% vs. 1.1%), sneezing (1.6% vs. 0.3%), lip pruritus (1.4% vs. 0.3%), dysphagia (1.4% vs. 0.0%), fatigue (1.3% vs. 1.0%), hypoesthesia oral (1.3% vs. 1.0%), oropharyngeal pain (1.3% vs. 0.6%), chest discomfort (1.3% vs. 0.3%), dry throat (1.3% vs. 0.3%), pruritus (1.1% vs. 1.0%), and urticaria (1.1% vs. 0.3%).

Studies 2 (NCT01454544) and 3 (NCT01644617) were randomized, double-blind, placebo-controlled studies of subjects 18 years of age and older with house dust mite-induced allergic rhinitis with or without conjunctivitis, and with or without asthma. Study 4 (NCT01433523) was a randomized, double-blind placebo-controlled study that included subjects 18 years of age and older with house dust mite-induced asthma and allergic rhinitis, with or without conjunctivitis.

Across the four clinical studies, 1279 subjects received at least one dose of ODACTRA, of whom 1104 (86%) completed at least 4 months of therapy.

The percentages of subjects in these studies who discontinued treatment because of an adverse reaction while exposed to ODACTRA or placebo were 8.1% and 3.0%, respectively. The most common adverse reactions (≥1.0%) that led to study discontinuation in subjects who received ODACTRA were throat irritation (1.5%), oral pruritus (1.3%), ear pruritus (1.1%), and mouth swelling (1.0%).

Serious adverse events were reported, 16/1279 (1.3%) among ODACTRA recipients and 23/1277 (1.8%) among placebo recipients. No deaths were reported.

Epinephrine use was reported in 5/1279 (0.4%) subjects who received ODACTRA compared to 3/1277 (0.2%) of subjects who received placebo. Of these subjects, 1 ODACTRA recipient reported a systemic allergic reaction and used epinephrine on the day of treatment initiation compared to 2 placebo recipients who reported anaphylaxis and used epinephrine 6 and 25 days after treatment initiation, respectively.

Of 1279 subjects who received ODACTRA, 34 (2.7%) reported dyspepsia compared to 0/1277 (0%) of subjects who received placebo. Twenty subjects who received ODACTRA (1.6%) reported symptoms of gastroesophageal reflux disease (GERD) compared to 3/1277 (0.2%) of subjects who received placebo.

Adolescents (12 through 17 years of age)

In two clinical studies, a total of 347 adolescent subjects were treated with at least one dose of ODACTRA. Study 1 (NCT01700192) was a double-blind, placebo-controlled, randomized clinical study. Study 5 (NCT04541004) was a single arm, open-label safety study. Because the study design and safety data presentation differ in the studies, adverse reaction rates cannot be directly compared. Overall, the safety profile in adolescents was consistent with the safety profile in adults.

Study 1 was a randomized, double-blind, placebo-controlled study conducted in the US and Canada evaluating ODACTRA in 1482 subjects 12 years of age and older with house dust mite-induced allergic rhinitis with or without conjunctivitis. Of the 1482 subjects, 94 subjects 12 through 17 years of age received at least one dose of ODACTRA, with a median treatment duration of 279 days (range 1 to 353 days). 95 subjects received placebo. Of the adolescent subjects treated with ODACTRA, 53% were male, 39% had asthma, and 72% were polysensitized to other allergens in addition to HDM. The adolescent subject population was 69% White, 13% Black or African American, 10% multiple race, 5% Asian, and 3% American Indian or Alaska Native. Subject demographics in placebo-treated subjects were similar to the active treatment group.

In Study 1, study participants were provided side effect report cards in which they recorded the occurrence of specific solicited adverse reactions daily for the first 28 days following treatment initiation with ODACTRA or placebo. The solicited adverse reactions reported in adolescent subjects 12 through 17 years of age are summarized in Table 2.

In Table 2, the dashes represent no subjects.
*Solicited adverse reactions (modified from World Allergy Organization [WAO] list of local side effects of sublingual immunotherapy [SLIT]) were those reported by subjects within the first 28 days after treatment initiation.
†The percentage of subjects reported for the patient-friendly term of "swelling of the uvula/back of the mouth" includes subjects with an enlarged uvula, palatal swelling, and/or mouth swelling/edema (which can be anywhere in the mouth, not specifically back of the mouth).
‡Of those subjects reporting any intensity of: itching in the mouth, nausea, throat irritation/tickle, or vomiting in the ODACTRA group, 1 subject (1.1%) reported severe intensity of the reaction. Adverse reactions were categorized as severe according to the definition ‘incapacitating with inability to work or do usual activity’, as assessed by the investigator.

In Study 1, participants were monitored for unsolicited adverse events and serious adverse events (SAEs) for the duration of treatment (up to 52 weeks). Unsolicited adverse events that were reported in numerically more subjects treated with ODACTRA than with placebo and occurred in ≥1% of subjects 12 through 17 years of age within 28 days after initiation of treatment with ODACTRA aresummarized in Table 3.

In Study 1, 94 adolescent subjects received at least one dose of ODACTRA, of whom 81 (86%) completed at least 4 months of treatment.

The percentage of adolescent subjects who discontinued from the study because of an adverse reaction while exposed to ODACTRA or placebo was 10% and 1%, respectively. The most common adverse reaction that led to study discontinuation in adolescent subjects who were exposed to ODACTRA were throat irritation (4%), swollen tongue (2%) and nausea (2%).

No adolescent subjects treated with ODACTRA in Study 1 reported serious adverse events, treatment-related systemic allergic reactions, or adverse reactions treated with epinephrine.

In Table 3, the dashes represent no subjects.
† Due to the population size (ODACTRA; N=94; and placebo; N=95), 1.1% represents one subject.

Study 5 was a single-arm, open label study conducted in Europe, and exposed 253 subjects 12 through 17 years of age with house dust mite-induced allergic rhinitis with or without conjunctivitis and with or without asthma to at least one dose of ODACTRA. The median treatment duration was 28 days (range 11 to 32 days). Of the subjects, 60% were male, 43% had asthma, and 56% were polysensitized to other allergens in addition to HDM. The subject population was 99.6% White and 0.4% Native Hawaiian or Other Pacific Islander.

Study participants were provided side effect report cards in which they recorded the occurrence of specific solicited adverse reactions daily for the first 28 days following treatment initiation with ODACTRA or placebo. Participants were monitored for unsolicited adverse events and serious adverse events (SAEs) for the duration of the study.

In Study 5, the proportions of subjects reporting solicited adverse reactions during the first 28 days following initiation of treatment with ODACTRA were comparable to those reported during the first 28 days following initiation of treatment with ODACTRA in Study 1.

In Study 5, the following unsolicited adverse reactions occurred in ≥1% of subjects 12 through 17 years of age during the entire study [median treatment duration 28 days (range 11 to 32 days)] after initiation of treatment with ODACTRA: oral pain (3.2%), oral pruritus (2.8%), throat irritation (1.6%), ear pruritus (1.2%), and mouth ulceration (1.2%).

In Study 5, 253 adolescent subjects received at least one dose of ODACTRA, of whom 248 (98%) completed 28 days of treatment. The percentage of subjects who discontinued from the study because of an adverse reaction while exposed to ODACTRA was 1%.

No adolescent subjects in Study 5 reported serious adverse events, treatment-related systemic allergic reactions, or adverse reactions treated with epinephrine.

Across eight clinical studies of varying durations which enrolled individuals 5 through 85 years of age and which were conducted with different doses of ODACTRA, eosinophilic esophagitis was reported in 2/2737 (0.07%) subjects who received ODACTRA compared to 0/1636 (0%) subjects who received placebo. Of these eight clinical studies, 2416 subjects received different doses of ODACTRA in four clinical studies with durations of 12 months or longer [2 cases/2416 subjects (0.08%) who received ODACTRA for 12 months or longer]. One case of eosinophilic esophagitis assessed as related to treatment occurred on Day 99 in an adult subject receiving ODACTRA. One case of eosinophilic esophagitis assessed as related to treatment occurred on Day 204 in an adolescent subject receiving ODACTRA.

6.2       Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ODACTRA. 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 disorder: esophageal irritation
  
• General Disorders and Administration Site Conditions: sensation of foreign body
  
• Immune System Disorders: serious systemic allergic reactions, including anaphylaxis
  
• Respiratory, Thoracic and Mediastinal Disorders: asthma exacerbations, cough, dysphonia
  
• Skin and Subcutaneous Tissue Disorders: angioedema, erythema.

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 data on ODACTRA administered to pregnant women are insufficient to inform associated risks in pregnancy.

In an embryo/fetal developmental toxicity study performed in mice, administration of ODACTRA during gestation did not reveal adverse developmental outcomes in fetuses (see 8.1 Data).

Data

Animal Data

In a developmental toxicity study, the effect of ODACTRA on embryo/fetal development was evaluated in mice. Animals were administered ODACTRA subcutaneously daily from day 6 to day 17 of the gestation period at doses up to 5 times the human sublingual dose. There were no ODACTRA-related post-implantation losses, fetal malformations or variations.

8.2       Lactation

Risk Summary

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

8.4       Pediatric Use

The safety and effectiveness of ODACTRA have been established in adolescents 12 through 17 years of age. The safety and effectiveness have not been established in persons below 12 years of age.

8.5       Geriatric Use

Safety and effectiveness have not been established in persons older than 65 years of age.

12.1       Mechanism of Action

The precise mechanisms of action of allergen immunotherapy have not been fully established.

13.1       Carcinogenesis, Mutagenesis, Impairment of Fertility

ODACTRA has not been evaluated for carcinogenic potential or impairment of fertility in animals. Two in vitro chromosome aberration assays, an in vitro bacterial mutagenesis assay and a combined in vivo Comet and micronucleus assay for mutagenicity in rats were performed using HDM (D. farinae and D. pteronyssinus) allergen extracts. One in vitro chromosome aberration assay was positive. Based on the aggregated results, the weight of evidence indicates that this finding is unlikely to be of clinical relevance.