RAGWITEK: Package Insert and Label Information

RAGWITEK- ambrosia artemisiifolia pollen tablet
ALK-Abello A S

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. ( 5.2 )

RAGWITEK may not be suitable for patients with certain underlying medical conditions that may reduce their ability to survive a serious allergic reaction. ( 5.2 )

RAGWITEK may not be suitable for patients who may be unresponsive to epinephrine or inhaled bronchodilators, such as those taking beta-blockers. ( 5.2 )

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 vitro testing 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.

2 DOSAGE AND ADMINISTRATION

For sublingual use only.

2.1 Dos e

One RAGWITEK tablet daily.

2. 2 Administration

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 ( 5.2)].

3 DOSAGE FORMS AND STRENGTHS

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.

4 CONTRAINDICATIONS

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 WARNINGS AND PRECAUTIONS

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.

5. 2 Upper Airway Compromise

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.

5. 3 Eosinophilic Esophagitis

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.

5. 4 Asthma

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.

5. 5 Concomitant Allergen Immunotherapy

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.

5. 6 Oral Inflammation

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.

6 ADVERSE REACTIONS

Adverse reactions reported in ≥5% of adults were: throat irritation, oral pruritus, ear pruritus, oral paresthesia, 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.

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

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 paresthesia (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.

Table 1: Adverse Reactions Reported in ≥1% of Adults Treated with RAGWITEK or Placebo (28-day pooled analysis)
Adverse Reaction RAGWITEK (N=1057) Placebo (N=757)
Ear and Labyrinth DisordersEar pruritus 10.4% 1.1%
Respiratory, Thoracic and Mediastinal DisordersThroat irritationOropharyngeal painThroat tightness 16.6%1.5%1.3% 3.3%0.7%0.5%
Gastrointestinal DisordersOral pruritusParesthesia oralMouth edemaTongue pruritusLip swellingSwollen tongueLip pruritusDry mouthTongue edemaNauseaPalatal edemaDysphagia 10.9%10.0%6.1%5.1%3.0%2.9%1.5%1.4%1.3%1.1%1.1%1.0% 2.0%4.0%0.5%0.5%0.4%0.5%0.1%0.7%0.5%0.3%0%0%
Skin and Subcutaneous Tissue DisordersPruritus 1.8% 1.3%
General Disorders and AdministrationSite ConditionsChest discomfort 1.0% 0%

* 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.

Children and Adolescents (5 through 17 years of age)

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).

Table 2: Solicited* Adverse Reactions occurring within 28 days of Initiation of Treatment with RAGWITEK or Placebo in Children and Adolescents 5 through 17 Years of Age
Adverse Reaction ( Any Intensity ) RAGWITEK (N=513) Placebo (N=509)
Ear and Labyrinth DisordersItching in the ear 33.9% 6.3%
Gastrointestinal DisordersItching in the mouthMouth painSwelling of the lipsNauseaSwelling of the tongue Stomach painSwelling of the uvula/back of the mouth Mouth ulcer/sore in the mouthTongue ulcer/sore on the tongueDiarrheaVomiting 47.8%18.9%13.8%11.5%11.3%10.1%9.9%8.4%6.8%2.7%1.2% 11.2%4.5%1.2%3.3%0.8%4.5%0.4%2.2%2.2%1.2%0%
Nervous System DisordersTaste alteration/food tastes different 3.9% 2.0%
Respiratory, Thoracic and Mediastinal DisordersThroat irritation/tickleThroat swelling 48.3%10.7% 17.7%1.6%

* 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.

Table 3: Unsolicited Adverse Reactions occurring during the Entire Trial after Initiation of Treatment, Reported in ≥1% of Children and Adolescents 5 through 17 Years of Age Treated with RAGWITEK or Placebo
Adverse Reaction RAGWITEK (N=513) Placebo (N=509)
Ear and Labyrinth DisordersEar pruritus 4.5% 0.2%
Gastrointestinal DisordersOral pruritusTongue pruritusLip swellingParesthesia oralMouth swellingDysphagiaNauseaOral painSwollen tongue 7.8%4.5%1.9%1.9%1.8%1.6%1.6%1.6%1.4% 1.0%0.4%-0.4%-0.2%0.4%0.4%-
Respiratory, Thoracic and Mediastinal DisordersThroat irritationOropharyngeal painSneezingPharyngeal edemaRhinorrhea 7.6%1.8%1.6%1.2%1.2% 1.6%0.4%0.4%-0.4%
Skin and Subcutaneous Tissue DisordersPruritus 1.2% 0.2%

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.

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