INDICATIONS
RAGWITEKā¢ 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 ADULTS 18 THROUGH 65 YEARS OF AGE.
RAGWITEK IS NOT INDICATED FOR THE IMMEDIATE RELIEF OF ALLERGIC SYMPTOMS.
HOW SUPPLIED
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.
STORAGE AND HANDLING
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:
3 BLISTER PACKAGES OF 10 TABLETS (30 TABLETS TOTAL). NDC 0006-5420-30
9 BLISTER PACKAGES OF 10 TABLETS (90 TABLETS TOTAL). NDC 0006-5420-54
STORE AT CONTROLLED ROOM TEMPERATURE, 20Ā°C-25Ā°C (68Ā°F-77Ā°F); EXCURSIONS PERMITTED BETWEEN 15Ā°C- 30Ā°C (59Ā°F-86Ā°F). STORE IN THE ORIGINAL PACKAGE UNTIL USE TO PROTECT FROM MOISTURE.
MANUFACTURED FOR: MERCK SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO INC., WHITEHOUSE STATION, NJ 08889, USA. MANUFACTURED BY: CATALENT PHARMA SOLUTIONS LIMITED, BLAGROVE, SWINDON, WILTSHIRE, SN5 8RU UK. REVISED: APRIL 2014
DOSAGE AND ADMINISTRATION
FOR SUBLINGUAL USE ONLY.
DOSE
ONE RAGWITEK TABLET DAILY.
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 IN THE PROPER USE OF EMERGENCY SELF-INJECTION OF EPINEPHRINE [SEE WARNINGS AND PRECAUTIONS].
SIDE EFFECTS
ADVERSE REACTIONS REPORTED IN ?5% OF PATIENTS WERE: THROAT IRRITATION, ORAL PRURITUS, EAR PRURITUS, ORAL PARAESTHESIA, MOUTH EDEMA, AND TONGUE PRURITUS.
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.
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 642 (61%) 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.
TABLE 1: ADVERSE REACTIONS REPORTED IN ?1% OF SUBJECTS TREATED WITH RAGWITEK (28-DAY POOLED ANALYSIS)
ADVERSE REACTION RAGWITEK
(N=1057) PLACEBO
(N=757)
EAR AND LABYRINTH DISORDERS
EAR PRURITUS 10.4% 1.1%
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
THROAT IRRITATION 16.6% 3.3%
OROPHARYNGEAL PAIN 1.5% 0.7%
THROAT TIGHTNESS 1.3% 0.5%
GASTROINTESTINAL DISORDERS
ORAL PRURITUS 10.9% 2.0%
PARAESTHESIA ORAL 10.0% 4.0%
MOUTH EDEMA 6.1% 0.5%
TONGUE PRURITUS 5.1% 0.5%
LIP SWELLING 3.0% 0.4%
SWOLLEN TONGUE 2.9% 0.5%
LIP PRURITUS 1.5% 0.1%
DRY MOUTH 1.4% 0.7%
TONGUE EDEMA 1.3% 0.5%
NAUSEA 1.1% 0.3%
PALATAL EDEMA 1.1% 0%
DYSPHAGIA 1.0% 0%
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
PRURITUS 1.8% 1.3%
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
CHEST DISCOMFORT 1.0% 0%
THE OVERALL SAFETY PROFILE BEYOND DAY 28 IN THE TWO 52-WEEK TRIALS WAS SIMILAR TO THAT OBSERVED IN THE POOLED 28-DAY ANALYSIS.
READ THE RAGWITEK (SHORT RAGWEED POLLEN ALLERGEN EXTRACT TABLETS) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
THE PRECISE MECHANISMS OF ACTION OF ALLERGEN IMMUNOTHERAPY ARE NOT KNOWN.
CLINICAL STUDIES
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 2.
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 3.
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 2 AND 3).
TABLE 2: TRIAL 1: TOTAL COMBINED SCORES (TCS), RHINOCONJUNCTIVITIS DAILY SYMPTOM SCORES (DSS), AND DAILY MEDICATION SCORES (DMS) DURING THE RAGWEED POLLEN SEASON
ENDPOINT* RAGWITEK (N)ā SCOREā” PLACEBO (N)ā SCOREā” TREATMENT DIFFERENCE (RAGWITEK - PLACEBO) DIFFERENCE RELATIVE TO PLACEBOĀ§ESTIMATE (95% CI)
TCS PEAK SEASON
(159) 6.22 (164) 8.46 -2.24 -26% (-38.7, -14.6)
TCS ENTIRE SEASON (160) 5.21 (166) 7.01 -1.80 -26% (-37.6, -13.5)
DSS PEAK SEASON (159) 4.65 (164) 5.59 -0.94 -17% (-28.6, -4.6)
DSS ENTIRE SEASON (160) 4.05 (166) 4.87 -0.82 -17% (-28.5, -4.5)
DMS PEAK SEASON (159) 1.57 (164) 2.87 -1.30 -45% (-65.4, -27.0)
TCS=TOTAL COMBINED SCORE (DSS + DMS); DSS=DAILY SYMPTOM SCORE; DMS=DAILY MEDICATION SCORE.
* PARAMETRIC ANALYSIS USING ANALYSIS OF VARIANCE MODEL FOR ALL ENDPOINTS.
ā NUMBER OF SUBJECTS IN ANALYSES.
ā” THE ESTIMATED GROUP MEANS ARE REPORTED AND DIFFERENCE RELATIVE TO PLACEBO IS BASED ON ESTIMATED GROUP MEANS.
Ā§ DIFFERENCE RELATIVE TO PLACEBO COMPUTED AS: (RAGWITEK - PLACEBO)/PLACEBO X 100.
PEAK RAGWEED SEASON WAS DEFINED AS MAXIMUM 15 DAYS WITH THE HIGHEST MOVING AVERAGE POLLEN COUNTS DURING THE RAGWEED SEASON.
TABLE 3: TRIAL 2: TOTAL COMBINED SCORES (TCS), RHINOCONJUNCTIVITIS DAILY SYMPTOM SCORES (DSS), AND DAILY MEDICATION SCORES (DMS) DURING THE RAGWEED POLLEN SEASON
ENDPOINT* RAGWITEK (N)ā SCOREā” PLACEBO (N)ā SCOREā” TREATMENT DIFFERENCE (RAGWITEK - PLACEBO) DIFFERENCE RELATIVE TO PLACEBOĀ§ ESTIMATE (95% CI)
TCS PEAK SEASON
(152) 6.41 (169) 8.46 -2.04 -24% (-36.5, -11.3)
TCS ENTIRE SEASON (158) 5.18 (174) 7.09 -1.92 -27% (-38.8, -14.1)
DSS PEAK SEASON (152) 4.43 (169) 5.37 -0.94 -18% (-29.2, -4.5)
DSS ENTIRE SEASON (158) 3.62 (174) 4.58 -0.96 -21% (-31.6, -8.8)
DMS PEAK SEASON (152) 1.99 (169) 3.09 -1.10 -36% (-55.8, -14.6)
TCS=TOTAL COMBINED SCORE (DSS + DMS); DSS=DAILY SYMPTOM SCORE; DMS=DAILY MEDICATION SCORE.
* PARAMETRIC ANALYSIS USING ANALYSIS OF VARIANCE MODEL FOR ALL ENDPOINTS.
ā NUMBER OF SUBJECTS IN ANALYSES.
ā” THE ESTIMATED GROUP MEANS ARE REPORTED AND DIFFERENCE RELATIVE TO PLACEBO IS BASED ON ESTIMATED GROUP MEANS.
Ā§ DIFFERENCE RELATIVE TO PLACEBO COMPUTED AS: (RAGWITEK - PLACEBO)/PLACEBO X 100.
PEAK RAGWEED SEASON WAS DEFINED AS MAXIMUM 15 DAYS WITH THE HIGHEST MOVING AVERAGE POLLEN COUNTS DURING THE RAGWEED SEASON.