MOMETASONE FUROATE
DULERA 100 MCG/5 MCG AND DULERA 200 MCG/5 MCG ARE COMBINATIONS OF MOMETASONE FUROATE AND FORMOTEROL FUMARATE DIHYDRATE FOR ORAL INHALATION ONLY.
ONE ACTIVE COMPONENT OF DULERA IS MOMETASONE FUROATE, A CORTICOSTEROID HAVING THE CHEMICAL NAME 9,21-DICHLORO-11(BETA),17-DIHYDROXY-16 (ALPHA)-METHYLPREGNA-1,4-DIENE-3,20-DIONE 17-(2-FUROATE) WITH THE FOLLOWING CHEMICAL STRUCTURE:
MOMETASONE FUROATE IS A WHITE POWDER WITH AN EMPIRICAL FORMULA OF C27H30CL2O6, AND MOLECULAR WEIGHT 521.44. IT IS PRACTICALLY INSOLUBLE IN WATER; SLIGHTLY SOLUBLE IN METHANOL, ETHANOL, AND ISOPROPANOL; SOLUBLE IN ACETONE.
ONE ACTIVE COMPONENT OF DULERA IS FORMOTEROL FUMARATE DIHYDRATE, A RACEMATE. FORMOTEROL FUMARATE DIHYDRATE IS A SELECTIVE BETA2-ADRENERGIC BRONCHODILATOR HAVING THE CHEMICAL NAME OF (±)-2-HYDROXY-5-[(1RS)-1-HYDROXY-2-[[(1RS)-2-(4-METHOXYPHENYL)-1-METHYLETHYL]-AMINO]ETHYL]FORMANILIDE FUMARATE DIHYDRATE WITH THE FOLLOWING CHEMICAL STRUCTURE:
FORMOTEROL FUMARATE DIHYDRATE HAS A MOLECULAR WEIGHT OF 840.9, AND ITS EMPIRICAL FORMULA IS (C19H24N2O4)2oC4H4O4o2H2O. FORMOTEROL FUMARATE DIHYDRATE IS A WHITE TO YELLOWISH POWDER, WHICH IS FREELY SOLUBLE IN GLACIAL ACETIC ACID, SOLUBLE IN METHANOL, SPARINGLY SOLUBLE IN ETHANOL AND ISOPROPANOL, SLIGHTLY SOLUBLE IN WATER, AND PRACTICALLY INSOLUBLE IN ACETONE, ETHYL ACETATE, AND DIETHYL ETHER.
EACH DULERA 100 MCG/5 MCG AND 200 MCG/5 MCG IS A HYDROFLUOROALKANE (HFA-227) PROPELLED PRESSURIZED METERED DOSE INHALER CONTAINING SUFFICIENT AMOUNT OF DRUG FOR 60 OR 120 INHALATIONS [SEE HOW SUPPLIED/STORAGE AND HANDLING]. AFTER PRIMING, EACH ACTUATION OF THE INHALER DELIVERS 115 OR 225 MCG OF MOMETASONE FUROATE AND 5.5 MCG OF FORMOTEROL FUMARATE DIHYDRATE IN 69.6 MG OF SUSPENSION FROM THE VALVE AND DELIVERS 100 OR 200 MCG OF MOMETASONE FUROATE AND 5 MCG OF FORMOTEROL FUMARATE DIHYDRATE FROM THE ACTUATOR. THE ACTUAL AMOUNT OF DRUG DELIVERED TO THE LUNG MAY DEPEND ON PATIENT FACTORS, SUCH AS THE COORDINATION BETWEEN ACTUATION OF THE DEVICE AND INSPIRATION THROUGH THE DELIVERY SYSTEM. DULERA ALSO CONTAINS ANHYDROUS ALCOHOL AS A COSOLVENT AND OLEIC ACID AS A SURFACTANT.
DULERA SHOULD BE PRIMED BEFORE USING FOR THE FIRST TIME BY RELEASING 4 TEST SPRAYS INTO THE AIR, AWAY FROM THE FACE, SHAKING WELL BEFORE EACH SPRAY. IN CASES WHERE THE INHALER HAS NOT BEEN USED FOR MORE THAN 5 DAYS, PRIME THE INHALER AGAIN BY RELEASING 4 TEST SPRAYS INTO THE AIR, AWAY FROM THE FACE, SHAKING WELL BEFORE EACH SPRAY.
INDICATIONS
TREATMENT OF ASTHMA
DULERA IS INDICATED FOR THE TREATMENT OF ASTHMA IN PATIENTS 12 YEARS OF AGE AND OLDER.
LONG-ACTING BETA2-ADRENERGIC AGONISTS, SUCH AS FORMOTEROL, ONE OF THE ACTIVE INGREDIENTS IN DULERA, INCREASE THE RISK OF ASTHMA-RELATED DEATH. AVAILABLE DATA FROM CONTROLLED CLINICAL TRIALS SUGGEST THAT LABA INCREASE THE RISK OF ASTHMA-RELATED HOSPITALIZATION IN PEDIATRIC AND ADOLESCENT PATIENTS [SEE WARNINGS AND PRECAUTIONS]. THEREFORE, WHEN TREATING PATIENTS WITH ASTHMA, DULERA SHOULD ONLY BE USED FOR PATIENTS NOT ADEQUATELY CONTROLLED ON A LONG-TERM ASTHMA CONTROL MEDICATION, SUCH AS AN INHALED CORTICOSTEROID OR WHOSE DISEASE SEVERITY CLEARLY WARRANTS INITIATION OF TREATMENT WITH BOTH AN INHALED CORTICOSTEROID AND LABA. ONCE ASTHMA CONTROL IS ACHIEVED AND MAINTAINED, ASSESS THE PATIENT AT REGULAR INTERVALS AND STEP DOWN THERAPY (E.G., DISCONTINUE DULERA) IF POSSIBLE WITHOUT LOSS OF ASTHMA CONTROL, AND MAINTAIN THE PATIENT ON A LONG-TERM ASTHMA CONTROL MEDICATION, SUCH AS AN INHALED CORTICOSTEROID. DO NOT USE DULERA FOR PATIENTS WHOSE ASTHMA IS ADEQUATELY CONTROLLED ON LOW OR MEDIUM DOSE INHALED CORTICOSTEROIDS.
IMPORTANT LIMITATION OF USE
" DULERA IS NOT INDICATED FOR THE RELIEF OF ACUTE BRONCHOSPASM.
DOSAGE AND ADMINISTRATION
GENERAL
DULERA SHOULD BE ADMINISTERED ONLY BY THE ORALLY INHALED ROUTE (SEE INSTRUCTIONS FOR USING DULERA IN THE MEDICATION GUIDE). AFTER EACH DOSE, THE PATIENT SHOULD BE ADVISED TO RINSE HIS/HER MOUTH WITH WATER WITHOUT SWALLOWING.
THE CAP FROM THE MOUTHPIECE OF THE ACTUATOR SHOULD BE REMOVED BEFORE USING DULERA.
DULERA SHOULD BE PRIMED BEFORE USING FOR THE FIRST TIME BY RELEASING 4 TEST SPRAYS INTO THE AIR, AWAY FROM THE FACE, SHAKING WELL BEFORE EACH SPRAY. IN CASES WHERE THE INHALER HAS NOT BEEN USED FOR MORE THAN 5 DAYS, PRIME THE INHALER AGAIN BY RELEASING 4 TEST SPRAYS INTO THE AIR, AWAY FROM THE FACE, SHAKING WELL BEFORE EACH SPRAY.
THE DULERA CANISTER SHOULD ONLY BE USED WITH THE DULERA ACTUATOR. THE DULERA ACTUATOR SHOULD NOT BE USED WITH ANY OTHER INHALATION DRUG PRODUCT. ACTUATORS FROM OTHER PRODUCTS SHOULD NOT BE USED WITH THE DULERA CANISTER.
DOSING
DULERA SHOULD BE ADMINISTERED AS TWO INHALATIONS TWICE DAILY EVERY DAY (MORNING AND EVENING) BY THE ORALLY INHALED ROUTE.
SHAKE WELL PRIOR TO EACH INHALATION.
THE RECOMMENDED STARTING DOSAGES FOR DULERA TREATMENT ARE BASED ON PRIOR ASTHMA THERAPY.
TABLE 1: RECOMMENDED DOSAGES FOR DULERA
PREVIOUS THERAPY RECOMMENDED DOSE MAXIMUM RECOMMENDED DAILY DOSE
INHALED MEDIUM DOSE CORTICOSTEROIDS DULERA 100 MCG/5 MCG, 2 INHALATIONS TWICE DAILY 400 MCG/20 MCG
INHALED HIGH DOSE CORTICOSTEROIDS DULERA 200 MCG/5 MCG, 2 INHALATIONS TWICE DAILY 800 MCG/20 MCG
THE MAXIMUM DAILY RECOMMENDED DOSE IS TWO INHALATIONS OF DULERA 200 MCG/5 MCG TWICE DAILY. DO NOT USE MORE THAN TWO INHALATIONS TWICE DAILY OF THE PRESCRIBED STRENGTH OF DULERA AS SOME PATIENTS ARE MORE LIKELY TO EXPERIENCE ADVERSE EFFECTS WITH HIGHER DOSES OF FORMOTEROL. IF SYMPTOMS ARISE BETWEEN DOSES, AN INHALED SHORT-ACTING BETA2-AGONIST SHOULD BE TAKEN FOR IMMEDIATE RELIEF.
IF A PREVIOUSLY EFFECTIVE DOSAGE REGIMEN OF DULERA FAILS TO PROVIDE ADEQUATE CONTROL OF ASTHMA, THE THERAPEUTIC REGIMEN SHOULD BE RE-EVALUATED AND ADDITIONAL THERAPEUTIC OPTIONS, E.G., REPLACING THE CURRENT STRENGTH OF DULERA WITH A HIGHER STRENGTH, ADDING ADDITIONAL INHALED CORTICOSTEROID, OR INITIATING ORAL CORTICOSTEROIDS, SHOULD BE CONSIDERED.
THE MAXIMUM BENEFIT MAY NOT BE ACHIEVED FOR 1 WEEK OR LONGER AFTER BEGINNING TREATMENT. INDIVIDUAL PATIENTS MAY EXPERIENCE A VARIABLE TIME TO ONSET AND DEGREE OF SYMPTOM RELIEF. FOR PATIENTS ? 12 YEARS OF AGE WHO DO NOT RESPOND ADEQUATELY AFTER 2 WEEKS OF THERAPY, HIGHER STRENGTH MAY PROVIDE ADDITIONAL ASTHMA CONTROL.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
DULERA IS A PRESSURIZED METERED DOSE INHALER THAT IS AVAILABLE IN 2 STRENGTHS.
DULERA 100 MCG/5 MCG DELIVERS 100 MCG OF MOMETASONE FUROATE AND 5 MCG OF FORMOTEROL FUMARATE DIHYDRATE PER ACTUATION.
DULERA 200 MCG/5 MCG DELIVERS 200 MCG OF MOMETASONE FUROATE AND 5 MCG OF FORMOTEROL FUMARATE DIHYDRATE PER ACTUATION.
DULERA IS AVAILABLE IN TWO STRENGTHS AND SUPPLIED IN THE FOLLOWING PACKAGE SIZES (TABLE 7):
TABLE 7
PACKAGE NDC
DULERA 100 MCG/5 MCG 120 INHALATIONS 0085-7206-01
DULERA 100 MCG/5 MCG 60 INHALATIONS (INSTITUTIONAL PACK) 0085-7206-07
DULERA 200 MCG/5 MCG 120 INHALATIONS 0085-4610-01
DULERA 200 MCG/5 MCG 60 INHALATIONS (INSTITUTIONAL PACK) 0085-4610-05
EACH STRENGTH IS SUPPLIED AS A PRESSURIZED ALUMINUM CANISTER THAT HAS A BLUE PLASTIC ACTUATOR INTEGRATED WITH A DOSE COUNTER AND A BLUE DUST CAP. EACH 120-INHALATION CANISTER HAS A NET FILL WEIGHT OF 13 GRAMS AND EACH 60-INHALATION CANISTER HAS A NET FILL WEIGHT OF 8.8 GRAMS. EACH CANISTER IS PLACED INTO A CARTON. EACH CARTON CONTAINS 1 CANISTER AND A MEDICATION GUIDE.
INITIALLY THE DOSE COUNTER WILL DISPLAY "64" OR "124" ACTUATIONS. AFTER THE INITIAL PRIMING WITH 4 ACTUATIONS, THE DOSE COUNTER WILL READ "60" OR "120" AND THE INHALER IS NOW READY FOR USE.
STORAGE AND HANDLING
THE DULERA CANISTER SHOULD ONLY BE USED WITH THE DULERA ACTUATOR. THE DULERA ACTUATOR SHOULD NOT BE USED WITH ANY OTHER INHALATION DRUG PRODUCT. ACTUATORS FROM OTHER PRODUCTS SHOULD NOT BE USED WITH THE DULERA CANISTER.
THE CORRECT AMOUNT OF MEDICATION IN EACH INHALATION CANNOT BE ENSURED AFTER THE LABELED NUMBER OF ACTUATIONS FROM THE CANISTER HAS BEEN USED, EVEN THOUGH THE INHALER MAY NOT FEEL COMPLETELY EMPTY AND MAY CONTINUE TO OPERATE. THE INHALER SHOULD BE DISCARDED WHEN THE LABELED NUMBER OF ACTUATIONS HAS BEEN USED (THE DOSE COUNTER WILL READ "0").
STORE AT CONTROLLED ROOM TEMPERATURE 20-25°C (68-77°F); EXCURSIONS PERMITTED TO 15-30°C (59-86°F) [SEE USP CONTROLLED ROOM TEMPERATURE].
THE 120-INHALATION INHALER DOES NOT REQUIRE SPECIFIC STORAGE ORIENTATION. FOR THE 60-INHALATION INHALER, AFTER PRIMING, STORE THE INHALER WITH THE MOUTHPIECE DOWN OR IN A HORIZONTAL POSITION.
FOR BEST RESULTS, THE CANISTER SHOULD BE AT ROOM TEMPERATURE BEFORE USE. SHAKE WELL AND REMOVE THE CAP FROM THE MOUTHPIECE OF THE ACTUATOR BEFORE USING. KEEP OUT OF REACH OF CHILDREN. AVOID SPRAYING IN EYES.
CONTENTS UNDER PRESSURE: DO NOT PUNCTURE. DO NOT USE OR STORE NEAR HEAT OR OPEN FLAME. EXPOSURE TO TEMPERATURES ABOVE 120°F MAY CAUSE BURSTING. NEVER THROW CONTAINER INTO FIRE OR INCINERATOR.
SIDE EFFECTS
LONG-ACTING BETA2-ADRENERGIC AGONISTS, SUCH AS FORMOTEROL, ONE OF THE ACTIVE INGREDIENTS IN DULERA, INCREASE THE RISK OF ASTHMA-RELATED DEATH. CURRENTLY AVAILABLE DATA ARE INADEQUATE TO DETERMINE WHETHER CONCURRENT USE OF INHALED CORTICOSTEROIDS OR OTHER LONG-TERM ASTHMA CONTROL DRUGS MITIGATES THE INCREASED RISK OF ASTHMA-RELATED DEATH FROM LABA. AVAILABLE DATA FROM CONTROLLED CLINICAL TRIALS SUGGEST THAT LABA INCREASE THE RISK OF ASTHMA-RELATED HOSPITALIZATION IN PEDIATRIC AND ADOLESCENT PATIENTS. DATA FROM A LARGE PLACEBO-CONTROLLED US TRIAL THAT COMPARED THE SAFETY OF ANOTHER LONG-ACTING BETA2-ADRENERGIC AGONIST (SALMETEROL) OR PLACEBO ADDED TO USUAL ASTHMA THERAPY SHOWED AN INCREASE IN ASTHMA-RELATED DEATHS IN PATIENTS RECEIVING SALMETEROL [SEE WARNINGS AND PRECAUTIONS].
SYSTEMIC AND LOCAL CORTICOSTEROID USE MAY RESULT IN THE FOLLOWING:
" CANDIDA ALBICANS INFECTION [SEE WARNINGS AND PRECAUTIONS]
" IMMUNOSUPPRESSION [SEE WARNINGS AND PRECAUTIONS]
" HYPERCORTICISM AND ADRENAL SUPPRESSION [SEE WARNINGS AND PRECAUTIONS]
" GROWTH EFFECTS IN PEDIATRICS [SEE WARNINGS AND PRECAUTIONS]
" GLAUCOMA AND CATARACTS [SEE WARNINGS AND PRECAUTIONS]
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 PRACTICE.
CLINICAL TRIALS EXPERIENCE
THE SAFETY DATA DESCRIBED BELOW IS BASED ON 3 CLINICAL TRIALS WHICH RANDOMIZED 1913 PATIENTS 12 YEARS OF AGE AND OLDER WITH ASTHMA, INCLUDING 679 PATIENTS EXPOSED TO DULERA FOR 12 TO 26 WEEKS AND 271 PATIENTS EXPOSED FOR 1 YEAR. DULERA WAS STUDIED IN TWO PLACEBO- AND ACTIVE-CONTROLLED TRIALS (N=781 AND N=728, RESPECTIVELY) AND IN A LONG-TERM 52-WEEK SAFETY TRIAL (N=404). IN THE 12 TO 26-WEEK CLINICAL TRIALS, THE POPULATION WAS 12 TO 84 YEARS OF AGE, 41% MALE AND 59% FEMALE, 73% CAUCASIANS, 27% NON-CAUCASIANS. PATIENTS RECEIVED TWO INHALATIONS TWICE DAILY OF DULERA (100 MCG/5 MCG OR 200 MCG/5 MCG), MOMETASONE FUROATE MDI (100 MCG OR 200 MCG), FORMOTEROL MDI (5 MCG) OR PLACEBO. IN THE LONG-TERM 52-WEEK ACTIVE-COMPARATOR SAFETY TRIAL, THE POPULATION WAS 12 YEARS TO 75 YEARS OF AGE WITH ASTHMA, 37% MALE AND 63% FEMALE, 47% CAUCASIANS, 53% NON-CAUCASIANS AND RECEIVED TWO INHALATIONS TWICE DAILY OF DULERA 100 MCG/5 MCG OR 200 MCG/5 MCG, OR AN ACTIVE COMPARATOR.
THE INCIDENCE OF TREATMENT EMERGENT ADVERSE REACTIONS ASSOCIATED WITH DULERA IN TABLE 2 BELOW IS BASED UPON POOLED DATA FROM 2 CLINICAL TRIALS 12 TO 26 WEEKS IN DURATION IN PATIENTS 12 YEARS AND OLDER TREATED WITH TWO INHALATIONS TWICE DAILY OF DULERA (100 MCG/5 MCG OR 200 MCG/5 MCG), MOMETASONE FUROATE MDI (100 MCG OR 200 MCG), FORMOTEROL MDI (5MCG) OR PLACEBO.
TABLE 2: TREATMENT-EMERGENT ADVERSE REACTIONS IN DULERA GROUPS OCCURRING AT AN INCIDENCE OF ? 3% AND MORE COMMONLY THAN PLACEBO
ORAL CANDIDIASIS HAS BEEN REPORTED IN CLINICAL TRIALS AT AN INCIDENCE OF 0.7% IN PATIENTS USING DULERA 100 MCG/5 MCG, 0.8 % IN PATIENTS USING DULERA 200 MCG/5 MCG AND 0.5 % IN THE PLACEBO GROUP.
LONG-TERM CLINICAL TRIAL EXPERIENCE
IN A LONG-TERM SAFETY TRIAL IN PATIENTS 12 YEARS AND OLDER TREATED FOR 52 WEEKS WITH DULERA 100 MCG/5 MCG (N=141), DULERA 200 MCG/5 MCG (N=130) OR AN ACTIVE COMPARATOR (N=133), SAFETY OUTCOMES IN GENERAL WERE SIMILAR TO THOSE OBSERVED IN THE SHORTER 12 TO 26 WEEK CONTROLLED TRIALS. NO ASTHMA-RELATED DEATHS WERE OBSERVED. DYSPHONIA WAS OBSERVED AT A HIGHER FREQUENCY IN THE LONGER TERM TREATMENT TRIAL AT A REPORTED INCIDENCE OF 7/141 (5%) PATIENTS RECEIVING DULERA 100 MCG/5 MCG AND 5/130 (3.8%) PATIENTS RECEIVING DULERA 200 MCG/5 MCG. NO CLINICALLY SIGNIFICANT CHANGES IN BLOOD CHEMISTRY, HEMATOLOGY, OR ECG WERE OBSERVED.
POSTMARKETING EXPERIENCE
THE FOLLOWING ADVERSE REACTIONS HAVE BEEN REPORTED DURING POST-APPROVAL USE OF DULERA OR POST-APPROVAL USE WITH INHALED MOMETASONE FUROATE OR INHALED FORMOTEROL FUMARATE. 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.
CARDIAC DISORDERS: ATRIAL FIBRILLATION, ANGINA PECTORIS, VENTRICULAR EXTRASYSTOLES, TACHYARRHYTHMIA
IMMUNE SYSTEM DISORDERS: IMMEDIATE AND DELAYED HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLACTIC REACTION, ANGIOEDEMA, SEVERE HYPOTENSION, RASH, PRURITUS
INVESTIGATIONS: ELECTROCARDIOGRAM QT PROLONGED, BLOOD PRESSURE INCREASED (INCLUDING HYPERTENSION)
METABOLISM AND NUTRITION DISORDERS: HYPOKALEMIA, HYPERGLYCEMIA
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: ASTHMA AGGRAVATION, WHICH MAY INCLUDE COUGH, DYSPNEA, WHEEZING AND BRONCHOSPASM
READ THE DULERA (MOMETASONE FUROATE, FORMOTEROL FUMARATE DIHYDRATE INHALATION) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS "
DRUG INTERACTIONS
IN CLINICAL TRIALS, CONCURRENT ADMINISTRATION OF DULERA AND OTHER DRUGS, SUCH AS SHORT-ACTING BETA2-AGONIST AND INTRANASAL CORTICOSTEROIDS HAVE NOT RESULTED IN AN INCREASED FREQUENCY OF ADVERSE DRUG REACTIONS. NO FORMAL DRUG INTERACTION STUDIES HAVE BEEN PERFORMED WITH DULERA. THE DRUG INTERACTIONS OF THE COMBINATION ARE EXPECTED TO REFLECT THOSE OF THE INDIVIDUAL COMPONENTS.
INHIBITORS OF CYTOCHROME P450 3A4
THE MAIN ROUTE OF METABOLISM OF CORTICOSTEROIDS, INCLUDING MOMETASONE FUROATE, A COMPONENT OF DULERA, IS VIA CYTOCHROME P450 (CYP) ISOENZYME 3A4 (CYP3A4). AFTER ORAL ADMINISTRATION OF KETOCONAZOLE, A STRONG INHIBITOR OF CYP3A4, THE MEAN PLASMA CONCENTRATION OF ORALLY INHALED MOMETASONE FUROATE INCREASED. CONCOMITANT ADMINISTRATION OF CYP3A4 INHIBITORS MAY INHIBIT THE METABOLISM OF, AND INCREASE THE SYSTEMIC EXPOSURE TO, MOMETASONE FUROATE. CAUTION SHOULD BE EXERCISED WHEN CONSIDERING THE COADMINISTRATION OF DULERA WITH LONG-TERM KETOCONAZOLE AND OTHER KNOWN STRONG CYP3A4 INHIBITORS (E.G., RITONAVIR, ATAZANAVIR, CLARITHROMYCIN, INDINAVIR, ITRACONAZOLE, NEFAZODONE, NELFINAVIR, SAQUINAVIR, TELITHROMYCIN) [SEE WARNINGS AND PRECAUTIONS AND CLINICAL PHARMACOLOGY].
ADRENERGIC AGENTS
IF ADDITIONAL ADRENERGIC DRUGS ARE TO BE ADMINISTERED BY ANY ROUTE, THEY SHOULD BE USED WITH CAUTION BECAUSE THE PHARMACOLOGICALLY PREDICTABLE SYMPATHETIC EFFECTS OF FORMOTEROL, A COMPONENT OF DULERA, MAY BE POTENTIATED.
XANTHINE DERIVATIVES
CONCOMITANT TREATMENT WITH XANTHINE DERIVATIVES MAY POTENTIATE ANY HYPOKALEMIC EFFECT OF FORMOTEROL, A COMPONENT OF DULERA.
DIURETICS
CONCOMITANT TREATMENT WITH DIURETICS MAY POTENTIATE THE POSSIBLE HYPOKALEMIC EFFECT OF ADRENERGIC AGONISTS. THE ECG CHANGES AND/OR HYPOKALEMIA THAT MAY RESULT FROM THE ADMINISTRATION OF NON-POTASSIUM-SPARING DIURETICS (SUCH AS LOOP OR THIAZIDE DIURETICS) CAN BE ACUTELY WORSENED BY BETA-AGONISTS, ESPECIALLY WHEN THE RECOMMENDED DOSE OF THE BETA-AGONIST IS EXCEEDED. ALTHOUGH THE CLINICAL SIGNIFICANCE OF THESE EFFECTS IS NOT KNOWN, CAUTION IS ADVISED IN THE COADMINISTRATION OF DULERA WITH NON-POTASSIUM-SPARING DIURETICS.
MONOAMINE OXIDASE INHIBITORS, TRICYCLIC ANTIDEPRESSANTS, AND DRUGS KNOWN TO PROLONG THE QTC INTERVAL
DULERA SHOULD BE ADMINISTERED WITH CAUTION TO PATIENTS BEING TREATED WITH MONOAMINE OXIDASE INHIBITORS, TRICYCLIC ANTIDEPRESSANTS, OR DRUGS KNOWN TO PROLONG THE QTC INTERVAL OR WITHIN 2 WEEKS OF DISCONTINUATION OF SUCH AGENTS, BECAUSE THE ACTION OF FORMOTEROL, A COMPONENT OF DULERA, ON THE CARDIOVASCULAR SYSTEM MAY BE POTENTIATED BY THESE AGENTS. DRUGS THAT ARE KNOWN TO PROLONG THE QTC INTERVAL HAVE AN INCREASED RISK OF VENTRICULAR ARRHYTHMIAS.
BETA-ADRENERGIC RECEPTOR ANTAGONISTS
BETA-ADRENERGIC RECEPTOR ANTAGONISTS (BETA-BLOCKERS) AND FORMOTEROL MAY INHIBIT THE EFFECT OF EACH OTHER WHEN ADMINISTERED CONCURRENTLY. BETA-BLOCKERS NOT ONLY BLOCK THE THERAPEUTIC EFFECTS OF BETA2-AGONISTS, SUCH AS FORMOTEROL, A COMPONENT OF DULERA, BUT MAY PRODUCE SEVERE BRONCHOSPASM IN PATIENTS WITH ASTHMA. THEREFORE, PATIENTS WITH ASTHMA SHOULD NOT NORMALLY BE TREATED WITH BETA-BLOCKERS. HOWEVER, UNDER CERTAIN CIRCUMSTANCES, E.G., AS PROPHYLAXIS AFTER MYOCARDIAL INFARCTION, THERE MAY BE NO ACCEPTABLE ALTERNATIVES TO THE USE OF BETA-BLOCKERS IN PATIENTS WITH ASTHMA. IN THIS SETTING, CARDIOSELECTIVE BETA-BLOCKERS COULD BE CONSIDERED, ALTHOUGH THEY SHOULD BE ADMINISTERED WITH CAUTION.
PRECAUTIONS
ASTHMA-RELATED DEATH
LONG-ACTING BETA2-ADRENERGIC AGONISTS, SUCH AS FORMOTEROL, ONE OF THE ACTIVE INGREDIENTS IN DULERA, INCREASE THE RISK OF ASTHMA-RELATED DEATH. CURRENTLY AVAILABLE DATA ARE INADEQUATE TO DETERMINE WHETHER CONCURRENT USE OF INHALED CORTICOSTEROIDS OR OTHER LONG-TERM ASTHMA CONTROL DRUGS MITIGATES THE INCREASED RISK OF ASTHMA-RELATED DEATH FROM LABA. AVAILABLE DATA FROM CONTROLLED CLINICAL TRIALS SUGGEST THAT LABA INCREASE THE RISK OF ASTHMA-RELATED HOSPITALIZATION IN PEDIATRIC AND ADOLESCENT PATIENTS. THEREFORE, WHEN TREATING PATIENTS WITH ASTHMA, PHYSICIANS SHOULD ONLY PRESCRIBE DULERA FOR PATIENTS WITH ASTHMA NOT ADEQUATELY CONTROLLED ON A LONG-TERM ASTHMA CONTROL MEDICATION, SUCH AS AN INHALED CORTICOSTEROID OR WHOSE DISEASE SEVERITY CLEARLY WARRANTS INITIATION OF TREATMENT WITH BOTH AN INHALED CORTICOSTEROID AND LABA. ONCE ASTHMA CONTROL IS ACHIEVED AND MAINTAINED, ASSESS THE PATIENT AT REGULAR INTERVALS AND STEP DOWN THERAPY (E.G., DISCONTINUE DULERA) IF POSSIBLE WITHOUT LOSS OF ASTHMA CONTROL, AND MAINTAIN THE PATIENT ON A LONG-TERM ASTHMA CONTROL MEDICATION, SUCH AS AN INHALED CORTICOSTEROID. DO NOT USE DULERA FOR PATIENTS WHOSE ASTHMA IS ADEQUATELY CONTROLLED ON LOW OR MEDIUM DOSE INHALED CORTICOSTEROIDS.
A 28-WEEK, PLACEBO-CONTROLLED US STUDY COMPARING THE SAFETY OF SALMETEROL WITH PLACEBO, EACH ADDED TO USUAL ASTHMA THERAPY, SHOWED AN INCREASE IN ASTHMA-RELATED DEATHS IN PATIENTS RECEIVING SALMETEROL (13/13,176 IN PATIENTS TREATED WITH SALMETEROL VS. 3/13,179 IN PATIENTS TREATED WITH PLACEBO; RR 4.37, 95% CI 1.25, 15.34). THIS FINDING WITH SALMETEROL IS CONSIDERED A CLASS EFFECT OF THE LABAS, INCLUDING FORMOTEROL, ONE OF THE ACTIVE INGREDIENTS IN DULERA. NO STUDY ADEQUATE TO DETERMINE WHETHER THE RATE OF ASTHMA-RELATED DEATH IS INCREASED WITH DULERA HAS BEEN CONDUCTED.
CLINICAL STUDIES WITH FORMOTEROL SUGGESTED A HIGHER INCIDENCE OF SERIOUS ASTHMA EXACERBATIONS IN PATIENTS WHO RECEIVED FORMOTEROL FUMARATE THAN IN THOSE WHO RECEIVED PLACEBO. THE SIZES OF THESE STUDIES WERE NOT ADEQUATE TO PRECISELY QUANTIFY THE DIFFERENCES IN SERIOUS ASTHMA EXACERBATION RATES BETWEEN TREATMENT GROUPS.
DETERIORATION OF DISEASE AND ACUTE EPISODES
DULERA SHOULD NOT BE INITIATED IN PATIENTS DURING RAPIDLY DETERIORATING OR POTENTIALLY LIFE-THREATENING EPISODES OF ASTHMA. DULERA HAS NOT BEEN STUDIED IN PATIENTS WITH ACUTELY DETERIORATING ASTHMA. THE INITIATION OF DULERA IN THIS SETTING IS NOT APPROPRIATE.
INCREASING USE OF INHALED, SHORT-ACTING BETA2-AGONISTS IS A MARKER OF DETERIORATING ASTHMA. IN THIS SITUATION, THE PATIENT REQUIRES IMMEDIATE RE-EVALUATION WITH REASSESSMENT OF THE TREATMENT REGIMEN, GIVING SPECIAL CONSIDERATION TO THE POSSIBLE NEED FOR REPLACING THE CURRENT STRENGTH OF DULERA WITH A HIGHER STRENGTH, ADDING ADDITIONAL INHALED CORTICOSTEROID, OR INITIATING SYSTEMIC CORTICOSTEROIDS. PATIENTS SHOULD NOT USE MORE THAN 2 INHALATIONS TWICE DAILY (MORNING AND EVENING) OF DULERA.
DULERA IS NOT INDICATED FOR THE RELIEF OF ACUTE SYMPTOMS, I.E., AS RESCUE THERAPY FOR THE TREATMENT OF ACUTE EPISODES OF BRONCHOSPASM. AN INHALED, SHORT-ACTING BETA2-AGONIST, NOT DULERA, SHOULD BE USED TO RELIEVE ACUTE SYMPTOMS SUCH AS SHORTNESS OF BREATH. WHEN PRESCRIBING DULERA, THE PHYSICIAN MUST ALSO PROVIDE THE PATIENT WITH AN INHALED, SHORT-ACTING BETA2-AGONIST (E.G., ALBUTEROL) FOR TREATMENT OF ACUTE SYMPTOMS, DESPITE REGULAR TWICE-DAILY (MORNING AND EVENING) USE OF DULERA.
WHEN BEGINNING TREATMENT WITH DULERA, PATIENTS WHO HAVE BEEN TAKING ORAL OR INHALED, SHORT-ACTING BETA2-AGONISTS ON A REGULAR BASIS (E.G., 4 TIMES A DAY) SHOULD BE INSTRUCTED TO DISCONTINUE THE REGULAR USE OF THESE DRUGS.
EXCESSIVE USE OF DULERA AND USE WITH OTHER LONG-ACTING BETA2-AGONISTS
AS WITH OTHER INHALED DRUGS CONTAINING BETA2-ADRENERGIC AGENTS, DULERA SHOULD NOT BE USED MORE OFTEN THAN RECOMMENDED, AT HIGHER DOSES THAN RECOMMENDED, OR IN CONJUNCTION WITH OTHER MEDICATIONS CONTAINING LONG-ACTING BETA2-AGONISTS, AS AN OVERDOSE MAY RESULT. CLINICALLY SIGNIFICANT CARDIOVASCULAR EFFECTS AND FATALITIES HAVE BEEN REPORTED IN ASSOCIATION WITH EXCESSIVE USE OF INHALED SYMPATHOMIMETIC DRUGS. PATIENTS USING DULERA SHOULD NOT USE AN ADDITIONAL LONG-ACTING BETA2-AGONIST (E.G., SALMETEROL, FORMOTEROL FUMARATE, ARFORMOTEROL TARTRATE) FOR ANY REASON, INCLUDING PREVENTION OF EXERCISE-INDUCED BRONCHOSPASM (EIB) OR THE TREATMENT OF ASTHMA.
LOCAL EFFECTS
IN CLINICAL TRIALS, THE DEVELOPMENT OF LOCALIZED INFECTIONS OF THE MOUTH AND PHARYNX WITH CANDIDA ALBICANS HAVE OCCURRED IN PATIENTS TREATED WITH DULERA. IF OROPHARYNGEAL CANDIDIASIS DEVELOPS, IT SHOULD BE TREATED WITH APPROPRIATE LOCAL OR SYSTEMIC (I.E., ORAL) ANTIFUNGAL THERAPY WHILE REMAINING ON TREATMENT WITH DULERA THERAPY, BUT AT TIMES THERAPY WITH DULERA MAY NEED TO BE INTERRUPTED. ADVISE PATIENTS TO RINSE THE MOUTH AFTER INHALATION OF DULERA.
IMMUNOSUPPRESSION
PERSONS WHO ARE USING DRUGS THAT SUPPRESS THE IMMUNE SYSTEM ARE MORE SUSCEPTIBLE TO INFECTIONS THAN HEALTHY INDIVIDUALS.
CHICKENPOX AND MEASLES, FOR EXAMPLE, CAN HAVE A MORE SERIOUS OR EVEN FATAL COURSE IN SUSCEPTIBLE CHILDREN OR ADULTS USING CORTICOSTEROIDS. IN SUCH CHILDREN OR ADULTS WHO HAVE NOT HAD THESE DISEASES OR WHO ARE NOT PROPERLY IMMUNIZED, PARTICULAR CARE SHOULD BE TAKEN TO AVOID EXPOSURE. HOW THE DOSE, ROUTE, AND DURATION OF CORTICOSTEROID ADMINISTRATION AFFECT THE RISK OF DEVELOPING A DISSEMINATED INFECTION IS NOT KNOWN. THE CONTRIBUTION OF THE UNDERLYING DISEASE AND/OR PRIOR CORTICOSTEROID TREATMENT TO THE RISK IS ALSO NOT KNOWN. IF EXPOSED TO CHICKENPOX, PROPHYLAXIS WITH VARICELLA ZOSTER IMMUNE GLOBULIN (VZIG) OR POOLED INTRAVENOUS IMMUNOGLOBULIN (IVIG) MAY BE INDICATED. IF EXPOSED TO MEASLES, PROPHYLAXIS WITH POOLED INTRAMUSCULAR IMMUNOGLOBULIN (IG) MAY BE INDICATED. (SEE THE RESPECTIVE PACKAGE INSERTS FOR COMPLETE VZIG AND IG PRESCRIBING INFORMATION.) IF CHICKENPOX DEVELOPS, TREATMENT WITH ANTIVIRAL AGENTS MAY BE CONSIDERED.
DULERA SHOULD BE USED WITH CAUTION, IF AT ALL, IN PATIENTS WITH ACTIVE OR QUIESCENT TUBERCULOSIS INFECTION OF THE RESPIRATORY TRACT, UNTREATED SYSTEMIC FUNGAL, BACTERIAL, VIRAL, OR PARASITIC INFECTIONS; OR OCULAR HERPES SIMPLEX.
TRANSFERRING PATIENTS FROM SYSTEMIC CORTICOSTEROID THERAPY
PARTICULAR CARE IS NEEDED FOR PATIENTS WHO ARE TRANSFERRED FROM SYSTEMICALLY ACTIVE CORTICOSTEROIDS TO DULERA BECAUSE DEATHS DUE TO ADRENAL INSUFFICIENCY HAVE OCCURRED IN ASTHMATIC PATIENTS DURING AND AFTER TRANSFER FROM SYSTEMIC CORTICOSTEROIDS TO LESS SYSTEMICALLY AVAILABLE INHALED CORTICOSTEROIDS. AFTER WITHDRAWAL FROM SYSTEMIC CORTICOSTEROIDS, A NUMBER OF MONTHS ARE REQUIRED FOR RECOVERY OF HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) FUNCTION.
PATIENTS WHO HAVE BEEN PREVIOUSLY MAINTAINED ON 20 MG OR MORE PER DAY OF PREDNISONE (OR ITS EQUIVALENT) MAY BE MOST SUSCEPTIBLE, PARTICULARLY WHEN THEIR SYSTEMIC CORTICOSTEROIDS HAVE BEEN ALMOST COMPLETELY WITHDRAWN. DURING THIS PERIOD OF HPA SUPPRESSION, PATIENTS MAY EXHIBIT SIGNS AND SYMPTOMS OF ADRENAL INSUFFICIENCY WHEN EXPOSED TO TRAUMA, SURGERY, OR INFECTION (PARTICULARLY GASTROENTERITIS) OR OTHER CONDITIONS ASSOCIATED WITH SEVERE ELECTROLYTE LOSS. ALTHOUGH DULERA MAY IMPROVE CONTROL OF ASTHMA SYMPTOMS DURING THESE EPISODES, IN RECOMMENDED DOSES IT SUPPLIES LESS THAN NORMAL PHYSIOLOGICAL AMOUNTS OF CORTICOSTEROID SYSTEMICALLY AND DOES NOT PROVIDE THE MINERALOCORTICOID ACTIVITY NECESSARY FOR COPING WITH THESE EMERGENCIES.
DURING PERIODS OF STRESS OR SEVERE ASTHMA ATTACK, PATIENTS WHO HAVE BEEN WITHDRAWN FROM SYSTEMIC CORTICOSTEROIDS SHOULD BE INSTRUCTED TO RESUME ORAL CORTICOSTEROIDS (IN LARGE DOSES) IMMEDIATELY AND TO CONTACT THEIR PHYSICIANS FOR FURTHER INSTRUCTION. THESE PATIENTS SHOULD ALSO BE INSTRUCTED TO CARRY A MEDICAL IDENTIFICATION CARD INDICATING THAT THEY MAY NEED SUPPLEMENTARY SYSTEMIC CORTICOSTEROIDS DURING PERIODS OF STRESS OR SEVERE ASTHMA ATTACK.
PATIENTS REQUIRING SYSTEMIC CORTICOSTEROIDS SHOULD BE WEANED SLOWLY FROM SYSTEMIC CORTICOSTEROID USE AFTER TRANSFERRING TO DULERA. LUNG FUNCTION (FEV1 OR PEF), BETA-AGONIST USE, AND ASTHMA SYMPTOMS SHOULD BE CAREFULLY MONITORED DURING WITHDRAWAL OF SYSTEMIC CORTICOSTEROIDS. IN ADDITION TO MONITORING ASTHMA SIGNS AND SYMPTOMS, PATIENTS SHOULD BE OBSERVED FOR SIGNS AND SYMPTOMS OF ADRENAL INSUFFICIENCY SUCH AS FATIGUE, LASSITUDE, WEAKNESS, NAUSEA AND VOMITING, AND HYPOTENSION.
TRANSFER OF PATIENTS FROM SYSTEMIC CORTICOSTEROID THERAPY TO DULERA MAY UNMASK ALLERGIC CONDITIONS PREVIOUSLY SUPPRESSED BY THE SYSTEMIC CORTICOSTEROID THERAPY, E.G., RHINITIS, CONJUNCTIVITIS, ECZEMA, ARTHRITIS, AND EOSINOPHILIC CONDITIONS.
DURING WITHDRAWAL FROM ORAL CORTICOSTEROIDS, SOME PATIENTS MAY EXPERIENCE SYMPTOMS OF SYSTEMICALLY ACTIVE CORTICOSTEROID WITHDRAWAL, E.G., JOINT AND/OR MUSCULAR PAIN, LASSITUDE, AND DEPRESSION, DESPITE MAINTENANCE OR EVEN IMPROVEMENT OF RESPIRATORY FUNCTION.
HYPERCORTICISM AND ADRENAL SUPPRESSION
MOMETASONE FUROATE, A COMPONENT OF DULERA, WILL OFTEN HELP CONTROL ASTHMA SYMPTOMS WITH LESS SUPPRESSION OF HPA FUNCTION THAN THERAPEUTICALLY EQUIVALENT ORAL DOSES OF PREDNISONE. SINCE MOMETASONE FUROATE IS ABSORBED INTO THE CIRCULATION AND CAN BE SYSTEMICALLY ACTIVE AT HIGHER DOSES, THE BENEFICIAL EFFECTS OF DULERA IN MINIMIZING HPA DYSFUNCTION MAY BE EXPECTED ONLY WHEN RECOMMENDED DOSAGES ARE NOT EXCEEDED AND INDIVIDUAL PATIENTS ARE TITRATED TO THE LOWEST EFFECTIVE DOSE.
BECAUSE OF THE POSSIBILITY OF SYSTEMIC ABSORPTION OF INHALED CORTICOSTEROIDS, PATIENTS TREATED WITH DULERA SHOULD BE OBSERVED CAREFULLY FOR ANY EVIDENCE OF SYSTEMIC CORTICOSTEROID EFFECTS. PARTICULAR CARE SHOULD BE TAKEN IN OBSERVING PATIENTS POSTOPERATIVELY OR DURING PERIODS OF STRESS FOR EVIDENCE OF INADEQUATE ADRENAL RESPONSE.
IT IS POSSIBLE THAT SYSTEMIC CORTICOSTEROID EFFECTS SUCH AS HYPERCORTICISM AND ADRENAL SUPPRESSION (INCLUDING ADRENAL CRISIS) MAY APPEAR IN A SMALL NUMBER OF PATIENTS, PARTICULARLY WHEN MOMETASONE FUROATE IS ADMINISTERED AT HIGHER THAN RECOMMENDED DOSES OVER PROLONGED PERIODS OF TIME. IF SUCH EFFECTS OCCUR, THE DOSAGE OF DULERA SHOULD BE REDUCED SLOWLY, CONSISTENT WITH ACCEPTED PROCEDURES FOR REDUCING SYSTEMIC CORTICOSTEROIDS AND FOR MANAGEMENT OF ASTHMA SYMPTOMS.
DRUG INTERACTIONS WITH STRONG CYTOCHROME P450 3A4 INHIBITORS
CAUTION SHOULD BE EXERCISED WHEN CONSIDERING THE COADMINISTRATION OF DULERA WITH KETOCONAZOLE, AND OTHER KNOWN STRONG CYP3A4 INHIBITORS (E.G., RITONAVIR, ATAZANAVIR, CLARITHROMYCIN, INDINAVIR, ITRACONAZOLE, NEFAZODONE, NELFINAVIR, SAQUINAVIR, TELITHROMYCIN) BECAUSE ADVERSE EFFECTS RELATED TO INCREASED SYSTEMIC EXPOSURE TO MOMETASONE FUROATE MAY OCCUR [SEE DRUG INTERACTIONS AND CLINICAL PHARMACOLOGY].
PARADOXICAL BRONCHOSPASM AND UPPER AIRWAY SYMPTOMS
DULERA MAY PRODUCE INHALATION INDUCED BRONCHOSPASM WITH AN IMMEDIATE INCREASE IN WHEEZING AFTER DOSING THAT MAY BE LIFE-THREATENING. IF INHALATION INDUCED BRONCHOSPASM OCCURS, IT SHOULD BE TREATED IMMEDIATELY WITH AN INHALED, SHORT-ACTING BRONCHODILATOR. DULERA SHOULD BE DISCONTINUED IMMEDIATELY AND ALTERNATIVE THERAPY INSTITUTED.
IMMEDIATE HYPERSENSITIVITY REACTIONS
IMMEDIATE HYPERSENSITIVITY REACTIONS MAY OCCUR AFTER ADMINISTRATION OF DULERA, AS DEMONSTRATED BY CASES OF URTICARIA, FLUSHING, ALLERGIC DERMATITIS, AND BRONCHOSPASM.
CARDIOVASCULAR AND CENTRAL NERVOUS SYSTEM EFFECTS
EXCESSIVE BETA-ADRENERGIC STIMULATION HAS BEEN ASSOCIATED WITH SEIZURES, ANGINA, HYPERTENSION OR HYPOTENSION, TACHYCARDIA WITH RATES UP TO 200 BEATS/MIN, ARRHYTHMIAS, NERVOUSNESS, HEADACHE, TREMOR, PALPITATION, NAUSEA, DIZZINESS, FATIGUE, MALAISE, AND INSOMNIA. THEREFORE, DULERA SHOULD BE USED WITH CAUTION IN PATIENTS WITH CARDIOVASCULAR DISORDERS, ESPECIALLY CORONARY INSUFFICIENCY, CARDIAC ARRHYTHMIAS, AND HYPERTENSION.
FORMOTEROL FUMARATE, A COMPONENT OF DULERA, CAN PRODUCE A CLINICALLY SIGNIFICANT CARDIOVASCULAR EFFECT IN SOME PATIENTS AS MEASURED BY PULSE RATE, BLOOD PRESSURE, AND/OR SYMPTOMS. ALTHOUGH SUCH EFFECTS ARE UNCOMMON AFTER ADMINISTRATION OF DULERA AT RECOMMENDED DOSES, IF THEY OCCUR, THE DRUG MAY NEED TO BE DISCONTINUED. IN ADDITION, BETA-AGONISTS HAVE BEEN REPORTED TO PRODUCE ECG CHANGES, SUCH AS FLATTENING OF THE T WAVE, PROLONGATION OF THE QTC INTERVAL, AND ST SEGMENT DEPRESSION. THE CLINICAL SIGNIFICANCE OF THESE FINDINGS IS UNKNOWN. FATALITIES HAVE BEEN REPORTED IN ASSOCIATION WITH EXCESSIVE USE OF INHALED SYMPATHOMIMETIC DRUGS.
REDUCTION IN BONE MINERAL DENSITY
DECREASES IN BONE MINERAL DENSITY (BMD) HAVE BEEN OBSERVED WITH LONG-TERM ADMINISTRATION OF PRODUCTS CONTAINING INHALED CORTICOSTEROIDS, INCLUDING MOMETASONE FUROATE, ONE OF THE COMPONENTS OF DULERA. THE CLINICAL SIGNIFICANCE OF SMALL CHANGES IN BMD WITH REGARD TO LONG-TERM OUTCOMES, SUCH AS FRACTURE, IS UNKNOWN. PATIENTS WITH MAJOR RISK FACTORS FOR DECREASED BONE MINERAL CONTENT, SUCH AS PROLONGED IMMOBILIZATION, FAMILY HISTORY OF OSTEOPOROSIS, OR CHRONIC USE OF DRUGS THAT CAN REDUCE BONE MASS (E.G., ANTICONVULSANTS AND CORTICOSTEROIDS) SHOULD BE MONITORED AND TREATED WITH ESTABLISHED STANDARDS OF CARE.
IN A 2-YEAR DOUBLE-BLIND STUDY IN 103 MALE AND FEMALE ASTHMA PATIENTS 18 TO 50 YEARS OF AGE PREVIOUSLY MAINTAINED ON BRONCHODILATOR THERAPY (BASELINE FEV1 85%-88% PREDICTED), TREATMENT WITH MOMETASONE FUROATE DRY POWDER INHALER 200 MCG TWICE DAILY RESULTED IN SIGNIFICANT REDUCTIONS IN LUMBAR SPINE (LS) BMD AT THE END OF THE TREATMENT PERIOD COMPARED TO PLACEBO. THE MEAN CHANGE FROM BASELINE TO ENDPOINT IN THE LUMBAR SPINE BMD WAS -0.015 (-1.43%) FOR THE MOMETASONE FUROATE GROUP COMPARED TO 0.002 (0.25%) FOR THE PLACEBO GROUP. IN ANOTHER 2-YEAR DOUBLE-BLIND STUDY IN 87 MALE AND FEMALE ASTHMA PATIENTS 18 TO 50 YEARS OF AGE PREVIOUSLY MAINTAINED ON BRONCHODILATOR THERAPY (BASELINE FEV1 82%-83% PREDICTED), TREATMENT WITH MOMETASONE FUROATE 400 MCG TWICE DAILY DEMONSTRATED NO STATISTICALLY SIGNIFICANT CHANGES IN LUMBAR SPINE BMD AT THE END OF THE TREATMENT PERIOD COMPARED TO PLACEBO. THE MEAN CHANGE FROM BASELINE TO ENDPOINT IN THE LUMBAR SPINE BMD WAS -0.018 (-1.57%) FOR THE MOMETASONE FUROATE GROUP COMPARED TO -0.006 (-0.43%) FOR THE PLACEBO GROUP.
EFFECT ON GROWTH
ORALLY INHALED CORTICOSTEROIDS, INCLUDING DULERA, MAY CAUSE A REDUCTION IN GROWTH VELOCITY WHEN ADMINISTERED TO PEDIATRIC PATIENTS. MONITOR THE GROWTH OF PEDIATRIC PATIENTS RECEIVING DULERA ROUTINELY (E.G., VIA STADIOMETRY). TO MINIMIZE THE SYSTEMIC EFFECTS OF ORALLY INHALED CORTICOSTEROIDS, INCLUDING DULERA, TITRATE EACH PATIENT'S DOSE TO THE LOWEST DOSAGE THAT EFFECTIVELY CONTROLS HIS/HER SYMPTOMS [SEE USE IN SPECIFIC POPULATIONS].
GLAUCOMA AND CATARACTS
GLAUCOMA, INCREASED INTRAOCULAR PRESSURE, AND CATARACTS HAVE BEEN REPORTED FOLLOWING THE USE OF LONG-TERM ADMINISTRATION OF INHALED CORTICOSTEROIDS, INCLUDING MOMETASONE FUROATE, A COMPONENT OF DULERA. THEREFORE, CLOSE MONITORING IS WARRANTED IN PATIENTS WITH A CHANGE IN VISION OR WITH A HISTORY OF INCREASED INTRAOCULAR PRESSURE, GLAUCOMA, AND/OR CATARACTS [SEE ADVERSE REACTIONS].
COEXISTING CONDITIONS
DULERA, LIKE OTHER MEDICATIONS CONTAINING SYMPATHOMIMETIC AMINES, SHOULD BE USED WITH CAUTION IN PATIENTS WITH CONVULSIVE DISORDERS OR THYROTOXICOSIS; AND IN PATIENTS WHO ARE UNUSUALLY RESPONSIVE TO SYMPATHOMIMETIC AMINES. DOSES OF THE RELATED BETA2-AGONIST ALBUTEROL, WHEN ADMINISTERED INTRAVENOUSLY, HAVE BEEN REPORTED TO AGGRAVATE PREEXISTING DIABETES MELLITUS AND KETOACIDOSIS.
HYPOKALEMIA AND HYPERGLYCEMIA
BETA2-AGONIST MEDICATIONS MAY PRODUCE SIGNIFICANT HYPOKALEMIA IN SOME PATIENTS, POSSIBLY THROUGH INTRACELLULAR SHUNTING, WHICH HAS THE POTENTIAL TO PRODUCE ADVERSE CARDIOVASCULAR EFFECTS. THE DECREASE IN SERUM POTASSIUM IS USUALLY TRANSIENT, NOT REQUIRING SUPPLEMENTATION. CLINICALLY SIGNIFICANT CHANGES IN BLOOD GLUCOSE AND/OR SERUM POTASSIUM WERE SEEN INFREQUENTLY DURING CLINICAL STUDIES WITH DULERA AT RECOMMENDED DOSES.
PATIENT COUNSELING INFORMATION
SEE FDA-APPROVED PATIENT LABELING (MEDICATION GUIDE).
ASTHMA-RELATED DEATH
PATIENTS SHOULD BE INFORMED THAT FORMOTEROL, ONE OF THE ACTIVE INGREDIENTS IN DULERA, INCREASES THE RISK OF ASTHMA-RELATED DEATH. IN PEDIATRIC AND ADOLESCENT PATIENTS, FORMOTEROL MAY INCREASE THE RISK OF ASTHMA-RELATED HOSPITALIZATION. THEY SHOULD ALSO BE INFORMED THAT DATA ARE NOT ADEQUATE TO DETERMINE WHETHER THE CONCURRENT USE OF INHALED CORTICOSTEROIDS, THE OTHER COMPONENT OF DULERA, OR OTHER LONG-TERM ASTHMA-CONTROL THERAPY MITIGATES OR ELIMINATES THIS RISK [SEE WARNINGS AND PRECAUTIONS].
NOT FOR ACUTE SYMPTOMS
DULERA IS NOT INDICATED TO RELIEVE ACUTE ASTHMA SYMPTOMS AND EXTRA DOSES SHOULD NOT BE USED FOR THAT PURPOSE. ACUTE SYMPTOMS SHOULD BE TREATED WITH AN INHALED, SHORT-ACTING, BETA2-AGONIST (THE HEALTH CARE PROVIDER SHOULD PRESCRIBE THE PATIENT WITH SUCH MEDICATION AND INSTRUCT THE PATIENT IN HOW IT SHOULD BE USED).
PATIENTS SHOULD BE INSTRUCTED TO SEEK MEDICAL ATTENTION IMMEDIATELY IF THEY EXPERIENCE ANY OF THE FOLLOWING:
" IF THEIR SYMPTOMS WORSEN
" SIGNIFICANT DECREASE IN LUNG FUNCTION AS OUTLINED BY THE PHYSICIAN
IF THEY NEED MORE INHALATIONS OF A SHORT-ACTING BETA2-AGONIST THAN USUAL
PATIENTS SHOULD BE ADVISED NOT TO INCREASE THE DOSE OR FREQUENCY OF DULERA. THE DAILY DOSAGE OF DULERA SHOULD NOT EXCEED TWO INHALATIONS TWICE DAILY. IF THEY MISS A DOSE, THEY SHOULD BE INSTRUCTED TO TAKE THEIR NEXT DOSE AT THE SAME TIME THEY NORMALLY DO. DULERA PROVIDES BRONCHODILATION FOR UP TO 12 HOURS.
PATIENTS SHOULD NOT STOP OR REDUCE DULERA THERAPY WITHOUT PHYSICIAN/PROVIDER GUIDANCE SINCE SYMPTOMS MAY RECUR AFTER DISCONTINUATION [SEE WARNINGS AND PRECAUTIONS].
DO NOT USE ADDITIONAL LONG-ACTING BETA2-AGONISTS
WHEN PATIENTS ARE PRESCRIBED DULERA, OTHER LONG-ACTING BETA2-AGONISTS SHOULD NOT BE USED [SEE WARNINGS AND PRECAUTIONS].
RISKS ASSOCIATED WITH CORTICOSTEROID THERAPY
LOCAL EFFECTS: PATIENTS SHOULD BE ADVISED THAT LOCALIZED INFECTIONS WITH CANDIDA ALBICANS OCCURRED IN THE MOUTH AND PHARYNX IN SOME PATIENTS. IF OROPHARYNGEAL CANDIDIASIS DEVELOPS, IT SHOULD BE TREATED WITH APPROPRIATE LOCAL OR SYSTEMIC (I.E., ORAL) ANTIFUNGAL THERAPY WHILE STILL CONTINUING WITH DULERA THERAPY, BUT AT TIMES THERAPY WITH DULERA MAY NEED TO BE TEMPORARILY INTERRUPTED UNDER CLOSE MEDICAL SUPERVISION. RINSING THE MOUTH AFTER INHALATION IS ADVISED [SEE WARNINGS AND PRECAUTIONS].
IMMUNOSUPPRESSION: PATIENTS WHO ARE ON IMMUNOSUPPRESSANT DOSES OF CORTICOSTEROIDS SHOULD BE WARNED TO AVOID EXPOSURE TO CHICKENPOX OR MEASLES AND, IF EXPOSED, TO CONSULT THEIR PHYSICIAN WITHOUT DELAY. PATIENTS SHOULD BE INFORMED OF POTENTIAL WORSENING OF EXISTING TUBERCULOSIS, FUNGAL, BACTERIAL, VIRAL, OR PARASITIC INFECTIONS, OR OCULAR HERPES SIMPLEX [SEE WARNINGS AND PRECAUTIONS].
HYPERCORTICISM AND ADRENAL SUPPRESSION: PATIENTS SHOULD BE ADVISED THAT DULERA MAY CAUSE SYSTEMIC CORTICOSTEROID EFFECTS OF HYPERCORTICISM AND ADRENAL SUPPRESSION. ADDITIONALLY, PATIENTS SHOULD BE INSTRUCTED THAT DEATHS DUE TO ADRENAL INSUFFICIENCY HAVE OCCURRED DURING AND AFTER TRANSFER FROM SYSTEMIC CORTICOSTEROIDS. PATIENTS SHOULD TAPER SLOWLY FROM SYSTEMIC CORTICOSTEROIDS IF TRANSFERRING TO DULERA [SEE WARNINGS AND PRECAUTIONS].
REDUCTION IN BONE MINERAL DENSITY: PATIENTS WHO ARE AT AN INCREASED RISK FOR DECREASED BMD SHOULD BE ADVISED THAT THE USE OF CORTICOSTEROIDS MAY POSE AN ADDITIONAL RISK AND SHOULD BE MONITORED AND, WHERE APPROPRIATE, BE TREATED FOR THIS CONDITION [SEE WARNINGS AND PRECAUTIONS].
REDUCED GROWTH VELOCITY: PATIENTS SHOULD BE INFORMED THAT ORALLY INHALED CORTICOSTEROIDS, A COMPONENT OF DULERA, MAY CAUSE A REDUCTION IN GROWTH VELOCITY WHEN ADMINISTERED TO PEDIATRIC PATIENTS. PHYSICIANS SHOULD CLOSELY FOLLOW THE GROWTH OF PEDIATRIC PATIENTS TAKING CORTICOSTEROIDS BY ANY ROUTE [SEE WARNINGS AND PRECAUTIONS].
GLAUCOMA AND CATARACTS: LONG-TERM USE OF INHALED CORTICOSTEROIDS MAY INCREASE THE RISK OF SOME EYE PROBLEMS (GLAUCOMA OR CATARACTS); REGULAR EYE EXAMINATIONS SHOULD BE CONSIDERED [SEE WARNINGS AND PRECAUTIONS].
RISKS ASSOCIATED WITH BETA-AGONIST THERAPY
PATIENTS SHOULD BE INFORMED THAT TREATMENT WITH BETA2-AGONISTS MAY LEAD TO ADVERSE EVENTS WHICH INCLUDE PALPITATIONS, CHEST PAIN, RAPID HEART RATE, TREMOR OR NERVOUSNESS [SEE WARNINGS AND PRECAUTIONS].
NONCLINICAL TOXICOLOGY
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
MOMETASONE FUROATE: IN A 2-YEAR CARCINOGENICITY STUDY IN SPRAGUE DAWLEY® RATS, MOMETASONE FUROATE DEMONSTRATED NO STATISTICALLY SIGNIFICANT INCREASE IN THE INCIDENCE OF TUMORS AT INHALATION DOSES UP TO 67 MCG/KG (APPROXIMATELY 14 TIMES THE MRHD ON AN AUC BASIS). IN A 19-MONTH CARCINOGENICITY STUDY IN SWISS CD-1 MICE, MOMETASONE FUROATE DEMONSTRATED NO STATISTICALLY SIGNIFICANT INCREASE IN THE INCIDENCE OF TUMORS AT INHALATION DOSES UP TO 160 MCG/KG (APPROXIMATELY 9 TIMES THE MRHD ON AN AUC BASIS).
MOMETASONE FUROATE INCREASED CHROMOSOMAL ABERRATIONS IN AN IN VITRO CHINESE HAMSTER OVARY CELL ASSAY, BUT DID NOT HAVE THIS EFFECT IN AN IN VITRO CHINESE HAMSTER LUNG CELL ASSAY. MOMETASONE FUROATE WAS NOT MUTAGENIC IN THE AMES TEST OR MOUSE LYMPHOMA ASSAY, AND WAS NOT CLASTOGENIC IN AN IN VIVO MOUSE MICRONUCLEUS ASSAY, A RAT BONE MARROW CHROMOSOMAL ABERRATION ASSAY, OR A MOUSE MALE GERM-CELL CHROMOSOMAL ABERRATION ASSAY. MOMETASONE FUROATE ALSO DID NOT INDUCE UNSCHEDULED DNA SYNTHESIS IN VIVO IN RAT HEPATOCYTES.
IN REPRODUCTIVE STUDIES IN RATS, IMPAIRMENT OF FERTILITY WAS NOT PRODUCED BY SUBCUTANEOUS DOSES UP TO 15 MCG/KG (APPROXIMATELY 8 TIMES THE MRHD ON AN AUC BASIS).
FORMOTEROL FUMARATE: THE CARCINOGENIC POTENTIAL OF FORMOTEROL FUMARATE HAS BEEN EVALUATED IN 2-YEAR DRINKING WATER AND DIETARY STUDIES IN BOTH RATS AND MICE. IN RATS, THE INCIDENCE OF OVARIAN LEIOMYOMAS WAS INCREASED AT DOSES OF 15 MG/KG AND ABOVE IN THE DRINKING WATER STUDY AND AT 20 MG/KG IN THE DIETARY STUDY, BUT NOT AT DIETARY DOSES UP TO 5 MG/KG (AUC EXPOSURE APPROXIMATELY 265 TIMES HUMAN EXPOSURE AT THE MRHD). IN THE DIETARY STUDY, THE INCIDENCE OF BENIGN OVARIAN THECA-CELL TUMORS WAS INCREASED AT DOSES OF 0.5 MG/KG AND ABOVE (AUC EXPOSURE AT THE LOW DOSE OF 0.5 MG/KG WAS APPROXIMATELY 27 TIMES HUMAN EXPOSURE AT THE MRHD). THIS FINDING WAS NOT OBSERVED IN THE DRINKING WATER STUDY, NOR WAS IT SEEN IN MICE (SEE BELOW).
IN MICE, THE INCIDENCE OF ADRENAL SUBCAPSULAR ADENOMAS AND CARCINOMAS WAS INCREASED IN MALES AT DOSES OF 69 MG/KG AND ABOVE IN THE DRINKING WATER STUDY, BUT NOT AT DOSES UP TO 50 MG/KG (AUC EXPOSURE APPROXIMATELY 350 TIMES HUMAN EXPOSURE AT THE MRHD) IN THE DIETARY STUDY. THE INCIDENCE OF HEPATOCARCINOMAS WAS INCREASED IN THE DIETARY STUDY AT DOSES OF 20 AND 50 MG/KG IN FEMALES AND 50 MG/KG IN MALES, BUT NOT AT DOSES UP TO 5 MG/KG IN EITHER MALES OR FEMALES (AUC EXPOSURE APPROXIMATELY 35 TIMES HUMAN EXPOSURE AT THE MRHD). ALSO IN THE DIETARY STUDY, THE INCIDENCE OF UTERINE LEIOMYOMAS AND LEIOMYOSARCOMAS WAS INCREASED AT DOSES OF 2 MG/KG AND ABOVE (AUC EXPOSURE AT THE LOW DOSE OF 2 MG/KG WAS APPROXIMATELY 14 TIMES HUMAN EXPOSURE AT THE MRHD). INCREASES IN LEIOMYOMAS OF THE RODENT FEMALE GENITAL TRACT HAVE BEEN SIMILARLY DEMONSTRATED WITH OTHER BETA-AGONIST DRUGS.
FORMOTEROL FUMARATE WAS NOT MUTAGENIC OR CLASTOGENIC IN THE FOLLOWING TESTS: MUTAGENICITY TESTS IN BACTERIAL AND MAMMALIAN CELLS, CHROMOSOMAL ANALYSES IN MAMMALIAN CELLS, UNSCHEDULED DNA SYNTHESIS REPAIR TESTS IN RAT HEPATOCYTES AND HUMAN FIBROBLASTS, TRANSFORMATION ASSAY IN MAMMALIAN FIBROBLASTS AND MICRONUCLEUS TESTS IN MICE AND RATS.
REPRODUCTION STUDIES IN RATS REVEALED NO IMPAIRMENT OF FERTILITY AT ORAL DOSES UP TO 3 MG/KG (APPROXIMATELY 1200 TIMES THE MRHD ON A MCG/M² BASIS).
USE IN SPECIFIC POPULATIONS
PREGNANCY
DULERA: TERATOGENIC EFFECTS: PREGNANCY CATEGORY C
THERE ARE NO ADEQUATE AND WELL-CONTROLLED STUDIES OF DULERA, MOMETASONE FUROATE ONLY OR FORMOTEROL FUMARATE ONLY IN PREGNANT WOMEN. ANIMAL REPRODUCTION STUDIES OF MOMETASONE FUROATE AND FORMOTEROL IN MICE, RATS, AND/OR RABBITS REVEALED EVIDENCE OF TERATOGENICITY AS WELL AS OTHER DEVELOPMENTAL TOXIC EFFECTS. BECAUSE ANIMAL REPRODUCTION STUDIES ARE NOT ALWAYS PREDICTIVE OF HUMAN RESPONSE, DULERA SHOULD BE USED DURING PREGNANCY ONLY IF THE POTENTIAL BENEFIT JUSTIFIES THE POTENTIAL RISK TO THE FETUS.
MOMETASONE FUROATE: TERATOGENIC EFFECTS
WHEN ADMINISTERED TO PREGNANT MICE, RATS, AND RABBITS, MOMETASONE FUROATE INCREASED FETAL MALFORMATIONS AND DECREASED FETAL GROWTH (MEASURED BY LOWER FETAL WEIGHTS AND/OR DELAYED OSSIFICATION). DYSTOCIA AND RELATED COMPLICATIONS WERE ALSO OBSERVED WHEN MOMETASONE FUROATE WAS ADMINISTERED TO RATS LATE IN GESTATION. HOWEVER,