Odactra: Package Insert / Prescribing Info

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 healthcare professional 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 epinephrine to patients prescribed ODACTRA and instruct patients (or their parents/guardians) in the proper use of 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 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 epinephrine. Instruct patients or their parents/guardians to seek immediate medical care and to stop treatment with ODACTRA upon use of 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 healthcare professional 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 participants 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, tooth loss 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 participants 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 participants 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 participants 12 years of age and older with house dust mite-induced allergic rhinitis with or without conjunctivitis. Of the 1482 participants, 640 participants 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 participants 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 participants 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 participants 18 through 65 years of age using the patient-friendly term.

In Table 1, the dashes represent no participants.

*Solicited adverse reactions (modified from World Allergy Organization [WAO] list of local side effects of sublingual immunotherapy [SLIT]) were those reported by participants 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 participants reported for the patient-friendly term of "swelling of the uvula/back of the mouth" includes participants 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 participants treated with ODACTRA than with placebo and occurred in ≥1% of participants 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 participants 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 participants 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 participants received at least one dose of ODACTRA, of whom 1104 (86%) completed at least 4 months of therapy.

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

Adolescents (12 through 17 years of age)

In two clinical studies, a total of 347 adolescent participants 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 participants 12 years of age and older with house dust mite-induced allergic rhinitis with or without conjunctivitis. Of the 1482 participants, 94 participants 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 participants received placebo. Of the adolescent participants treated with ODACTRA, 53% were male, 39% had asthma, and 72% were polysensitized to other allergens in addition to HDM. The adolescent participant population was 69% White, 13% Black or African American, 10% multiple race, 5% Asian, and 3% American Indian or Alaska Native. Participant demographics in placebo-treated participants 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 participants 12 through 17 years of age are summarized in Table 2.

In Table 2, the dashes represent no participants.

*Solicited adverse reactions (modified from World Allergy Organization [WAO] list of local side effects of sublingual immunotherapy [SLIT]) were those reported by participants within the first 28 days after treatment initiation.

†The percentage of participants reported for the patient-friendly term of "swelling of the uvula/back of the mouth" includes participants 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 participants reporting any intensity of: itching in the mouth, nausea, throat irritation/tickle, or vomiting in the ODACTRA group, 1 participant (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 participants treated with ODACTRA than with placebo and occurred in ≥1% of participants 12 through 17 years of age within 28 days after initiation of treatment with ODACTRA are summarized in Table 3.

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

The percentage of adolescent participants 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 participants who were exposed to ODACTRA were throat irritation (4%), swollen tongue (2%) and nausea (2%).

No adolescent participants 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 participants.

† Due to the population size (ODACTRA; N=94; and placebo; N=95), 1.1% represents one participant.

Study 5 (NCT04541004) was a single-arm, open label study conducted in Europe, and exposed 253 participants 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 participants, 60% were male, 43% had asthma, and 56% were polysensitized to other allergens in addition to HDM. The participant 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 participants 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 participants 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 participants received at least one dose of ODACTRA, of whom 248 (98%) completed 28 days of treatment. The percentage of participants who discontinued from the study because of an adverse reaction while exposed to ODACTRA was 1%.

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

Children (5 through 11 years of age)

Study 6 (NCT04145219) was a randomized, double-blind, placebo-controlled study conducted in Europe, US and Canada evaluating ODACTRA in 1458 participants 5 through 11 years of age with house dust mite-induced allergic rhinitis/rhinoconjunctivitis with or without asthma. Of the 1458 participants, 727 participants received at least one dose of ODACTRA, with a median treatment duration of 378 days (range 1 to 486 days) and 731 participants received placebo, with a median treatment duration of 379 days (range 1 to 449 days). Placebo tablets contained the same inactive ingredients as ODACTRA without allergen extract. Of the participants treated with ODACTRA, mean age was 8 years, 67% were male, 99% White, <1% Black or African American, <1% multiple race, <1% Asian, and <1% American Indian or Alaska Native. Participant demographics in the placebo group were similar to the ODACTRA group. In the ODACTRA group, 37% of participants had asthma and 54% were sensitized to other allergens in addition to HDM; the treatment groups were similar with respect to these baseline characteristics.

In Study 6, participants were provided an eDiary 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 investigator reviewed the symptoms with the participant and determined if they were possibly related to the study treatment. The solicited adverse reactions reported in pediatric participants 5 through 11 years of age are summarized in Table 4.

In Table 4, the dashes represent no participants.

*Solicited adverse reactions (modified from World Allergy Organization [WAO] list of local side effects of sublingual immunotherapy [SLIT]) were those reported by participants within the first 28 days after treatment initiation and determined by the investigator to be possibly related to the study treatment.

†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.

In Study 6, participants 5 through 11 years of age were monitored for unsolicited adverse events and SAEs for the entire duration of treatment (approximately 12 months). Unsolicited adverse reactions that were commonly reported (≥1%) and for which the rate for ODACTRA exceeded the rate for placebo are presented in Table 5.

In Table 5, the events are presented by SOC and PT.

In Study 6, 727 participants received at least one dose of ODACTRA, of whom 702 (97%) completed at least 3 months of treatment.

The percentage of participants who discontinued the study treatment because of an adverse reaction while exposed to ODACTRA or placebo was 1.8% and 1.0%, respectively. The most common adverse reactions that led to study discontinuation in participants who were exposed to ODACTRA were nausea (0.6%), lip swelling (0.4%) and throat irritation (0.4%).

No participants treated with ODACTRA in Study 6 reported treatment-related serious adverse events, treatment-related anaphylaxis, or adverse reactions treated with epinephrine.

Across twelve clinical studies in which individuals 5 through 85 years of age received ODACTRA or tablets containing different quantities of the same house dust mite allergen extracts and inactive ingredients as ODACTRA, eosinophilic esophagitis was reported in 3/4614 (0.07%) participants; no cases of eosinophilic esophagitis were reported among 2949 (0%) participants who received placebo. The three cases of eosinophilic esophagitis were assessed as related to study treatment. One case, which was reported as an SAE, occurred in a 10 year old participant on Day 31 of treatment. The other cases occurred in a 13 year old participant and a 34 year old participant on Day 204 and Day 99 of treatment, respectively.

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 Data (8.1)].

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 individuals 5 through 17 years of age with HDM-induced allergic rhinitis, with or without conjunctivitis. [see Adverse Reactions (6.1) and Clinical Studies (14)].

The safety and effectiveness have not been established in individuals below 5 years of age.

8.5 Geriatric Use

Safety and effectiveness have not been established in individuals 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.