INDICATIONS
MAINTENAENCE TREATMENT OF COPD
STRIVERDI RESPIMAT IS A LONG-ACTING BETA2-AGONIST INDICATED FOR LONG-TERM, ONCE-DAILY MAINTENANCE BRONCHODILATOR TREATMENT OF AIRFLOW OBSTRUCTION IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), INCLUDING CHRONIC BRONCHITIS AND/OR EMPHYSEMA.
IMPORTANT LIMITATIONS OF USE
STRIVERDI RESPIMAT IS NOT INDICATED TO TREAT ACUTE DETERIORATIONS OF COPD [SEE WARNINGS AND PRECAUTIONS].
STRIVERDI RESPIMAT IS NOT INDICATED TO TREAT ASTHMA. THE SAFETY AND EFFECTIVENESS OF STRIVERDI RESPIMAT IN ASTHMA HAVE NOT BEEN ESTABLISHED.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
STRIVERDI RESPIMAT CONSISTS OF A STRIVERDI RESPIMAT INHALER AND AN ALUMINUM CYLINDER (STRIVERDI RESPIMAT CARTRIDGE) CONTAINING OLODATEROL (AS THE HYDROCHLORIDE). THE STRIVERDI RESPIMAT CARTRIDGE IS INTENDED FOR USE WITH THE STRIVERDI RESPIMAT INHALER ONLY.
EACH ACTUATION FROM THE STRIVERDI RESPIMAT INHALER DELIVERS 2.7 MCG OLODATEROL HYDROCHLORIDE, EQUIVALENT TO 2.5 MCG OLODATEROL. TWO ACTUATIONS EQUAL ONE DOSE.
STORAGE AND HANDLING
STRIVERDI RESPIMAT INHALATION SPRAY IS SUPPLIED IN A LABELED CARTON CONTAINING ONE STRIVERDI RESPIMAT CARTRIDGE AND ONE STRIVERDI RESPIMAT INHALER.
THE STRIVERDI RESPIMAT CARTRIDGE IS AN ALUMINUM CYLINDER WITH A TAMPER PROTECTION SEAL ON THE CAP. THE STRIVERDI RESPIMAT CARTRIDGE IS ONLY INTENDED FOR USE WITH THE STRIVERDI RESPIMAT INHALER.
THE STRIVERDI RESPIMAT INHALER IS A CYLINDRICAL-SHAPED PLASTIC INHALATION DEVICE WITH A GRAY-COLORED BODY AND A CLEAR BASE. THE CLEAR BASE IS REMOVED TO INSERT THE CARTRIDGE. THE INHALER CONTAINS A DOSE INDICATOR. THE YELLOW COLORED CAP AND THE WRITTEN INFORMATION ON THE LABEL OF THE GRAY INHALER BODY INDICATES THAT IT IS LABELED FOR USE WITH THE STRIVERDI RESPIMAT CARTRIDGE.
STRIVERDI RESPIMAT INHALATION SPRAY IS AVAILABLE AS:
STRIVERDI RESPIMAT INHALATION SPRAY: 60 METERED ACTUATIONS (NDC 0597-0192-61)
STRIVERDI RESPIMAT INHALATION SPRAY: 28 METERED ACTUATIONS (NDC 0597-0192-31) (INSTITUTIONAL PACK)
THE STRIVERDI RESPIMAT CARTRIDGE HAS A NET FILL WEIGHT OF AT LEAST 4 GRAMS AND WHEN USED WITH THE STRIVERDI RESPIMAT INHALER, IS DESIGNED TO DELIVER THE LABELED NUMBER OF METERED ACTUATIONS (60 OR 28) AFTER PREPARATION FOR USE; WHICH IS RESPECTIVELY EQUIVALENT TO 30 OR 14 DAYS OF MEDICATION WHEN USED ACCORDING TO THE DIRECTIONS FOR USE (ONE DOSE EQUALS TWO ACTUATIONS).
WHEN THE LABELED NUMBER OF METERED ACTUATIONS (60 OR 28) HAS BEEN DISPENSED FROM THE INHALER, THE STRIVERDI RESPIMAT LOCKING MECHANISM WILL BE ENGAGED AND NO MORE ACTUATIONS CAN BE DISPENSED.
AFTER ASSEMBLY, THE STRIVERDI RESPIMAT INHALER SHOULD BE DISCARDED AT THE LATEST 3 MONTHS AFTER FIRST USE OR WHEN THE LOCKING MECHANISM IS ENGAGED , WHICHEVER COMES FIRST.
KEEP OUT OF REACH OF CHILDREN. DO NOT SPRAY INTO EYES.
STORAGE
STORE AT 25Β°C (77Β°F); EXCURSIONS PERMITTED TO 15Β°C-30Β°C (59Β°F-86Β°F) [SEE USP CONTROLLED ROOM TEMPERATURE]. AVOID FREEZING.
DISTRIBUTED BY: BOEHRINGER INGELHEIM PHARMACEUTICALS, INC. RIDGEFIELD, CT 06877 USA. REVISED: JULY 2014
DOSAGE AND ADMINISTRATION
THE RECOMMENDED DOSE OF STRIVERDI RESPIMAT IS TWO INHALATIONS ONCE-DAILY AT THE SAME TIME OF THE DAY. DO NOT USE STRIVERDI RESPIMAT MORE THAN TWO INHALATIONS EVERY 24 HOURS.
PRIOR TO FIRST USE, THE STRIVERDI RESPIMAT CARTRIDGE IS INSERTED INTO THE STRIVERDI RESPIMAT INHALER AND THE UNIT IS PRIMED. WHEN USING THE UNIT FOR THE FIRST TIME, PATIENTS ARE TO ACTUATE THE INHALER TOWARD THE GROUND UNTIL AN AEROSOL CLOUD IS VISIBLE AND THEN REPEAT THE PROCESS THREE MORE TIMES. THE UNIT IS THEN CONSIDERED PRIMED AND READY FOR USE. IF NOT USED FOR MORE THAN 3 DAYS, PATIENTS ARE TO ACTUATE THE INHALER ONCE TO PREPARE THE INHALER FOR USE. IF NOT USED FOR MORE THAN 21 DAYS, PATIENTS ARE TO ACTUATE THE INHALER UNTIL AN AEROSOL CLOUD IS VISIBLE AND THEN REPEAT THE PROCESS THREE MORE TIMES TO PREPARE THE INHALER FOR USE [SEE PATIENT INFORMATION].
NO DOSAGE ADJUSTMENT IS REQUIRED FOR GERIATRIC PATIENTS, PATIENTS WITH MILD AND MODERATE HEPATIC IMPAIRMENT, OR RENALLY-IMPAIRED PATIENTS. THERE ARE NO DATA AVAILABLE FOR USE OF STRIVERDI RESPIMAT IN SEVERE HEPATICALLY IMPAIRED PATIENTS [SEE CLINICAL PHARMACOLOGY].
SIDE EFFECTS
LONG-ACTING BETA2-ADRENERGIC AGONISTS, SUCH AS STRIVERDI RESPIMAT, INCREASE THE RISK OF ASTHMA-RELATED DEATH. STRIVERDI RESPIMAT IS NOT INDICATED FOR THE TREATMENT OF ASTHMA [SEE BOXED WARNING AND WARNINGS AND PRECAUTIONS].
CLINICAL TRIALS EXPERIENCE IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COMPARED WITH RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REFLECT THE RATES OBSERVED IN PRACTICE.
THE STRIVERDI RESPIMAT CLINICAL DEVELOPMENT PROGRAM INCLUDED SEVEN DOSE-RANGING TRIALS AND EIGHT CONFIRMATORY TRIALS. FOUR OF THE CONFIRMATORY TRIALS WERE 6-WEEK CROSS-OVER TRIALS AND FOUR WERE 48-WEEK PARALLEL GROUP TRIALS. ADVERSE REACTIONS OBSERVED IN THE DOSE-RANGING TRIALS AND FOUR 6-WEEK CROSS-OVER TRIALS WERE CONSISTENT WITH THOSE OBSERVED IN THE 48-WEEK PARALLEL GROUP TRIALS, WHICH FORMED THE PRIMARY SAFETY DATABASE.
THE PRIMARY SAFETY DATABASE CONSISTED OF POOLED DATA FROM THE FOUR 48-WEEK DOUBLE-BLIND, ACTIVE AND PLACEBO-CONTROLLED, PARALLEL GROUP CONFIRMATORY CLINICAL TRIALS. THESE TRIALS INCLUDED 3104 ADULT COPD PATIENTS (77% MALES AND 23% FEMALES) 40 YEARS OF AGE AND OLDER. OF THESE PATIENTS, 876 AND 883 PATIENTS WERE TREATED WITH STRIVERDI RESPIMAT 5 MCG AND 10 MCG ONCE-DAILY, RESPECTIVELY. THE STRIVERDI RESPIMAT GROUPS WERE COMPOSED OF MOSTLY CAUCASIANS (66%) WITH A MEAN AGE OF 64 YEARS AND A MEAN PERCENT PREDICTED FEV1 AT BASELINE OF 44% FOR BOTH THE 5 MCG AND 10 MCG TREATMENT GROUPS. CONTROL ARMS FOR COMPARISON INCLUDED PLACEBO IN ALL FOUR TRIALS PLUS FORMOTEROL 12 MCG IN TWO TRIALS.
IN THESE FOUR CLINICAL TRIALS, SEVENTY-TWO PERCENT (72%) OF PATIENTS EXPOSED TO ANY DOSE OF STRIVERDI RESPIMAT REPORTED AN ADVERSE REACTION COMPARED TO 71% IN THE PLACEBO GROUP. THE PROPORTION OF PATIENTS WHO DISCONTINUED DUE TO AN ADVERSE REACTION WAS 7.2% FOR STRIVERDI RESPIMAT TREATED PATIENTS COMPARED TO 8.8% FOR PLACEBO TREATED PATIENTS. THE ADVERSE REACTION MOST COMMONLY LEADING TO DISCONTINUATION WAS WORSENING COPD. THE MOST COMMON SERIOUS ADVERSE REACTIONS WERE COPD EXACERBATION, PNEUMONIA, AND ATRIAL FIBRILLATION.
TABLE 1 SHOWS ALL ADVERSE DRUG REACTIONS REPORTED BY AT LEAST 2% OF PATIENTS (AND HIGHER THAN PLACEBO) WHO RECEIVED STRIVERDI RESPIMAT 5 MCG DURING THE 48-WEEK TRIALS.
TABLE 1: NUMBER AND FREQUENCY OF ADVERSE DRUG REACTIONS GREATER THAN 2% (AND HIGHER THAN PLACEBO) IN COPD PATIENTS EXPOSED TO STRIVERDI RESPIMAT 5 MCG: POOLED DATA FROM THE FOUR 48-WEEK, DOUBLE-BLIND, ACTIVE-AND PLACEBO-CONTROLLED CLINICAL TRIALS IN COPD PATIENTS 40 YEARS OF AGE AND OLDER
TREATMENT STRIVERDI 5 MCG ONCE-DAILY PLACEBO
BODY SYSTEM (ADVERSE DRUG REACTION) N=876
N (%) N=885
N (%)
INFECTIONS AND INFESTATIONS
NASOPHARYNGITIS 99 (11.3) 68 (7.7)
UPPER RESPIRATORY TRACT INFECTION 72 (8.2) 66 (7.5)
BRONCHITIS 41 (4.7) 32 (3.6)
URINARY TRACT INFECTION 22 (2.5) 9 (1.0)
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS
COUGH 37 (4.2) 35 (4.0)
NERVOUS SYSTEM DISORDERS
DIZZINESS 20 (2.3) 19 (2.1)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
RASH* 19 (2.2) 10 (1.1)
GASTROINTESTINAL DISORDERS
DIARRHEA 25 (2.9) 22 (2.5)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
BACK PAIN 31 (3.5) 24 (2.7)
ARTHRALGIA 18 (2.1) 7 (0.8)
* RASH INCLUDES A GROUPING OF SIMILAR TERMS.
ADDITIONAL ADVERSE REACTIONS THAT OCCURRED IN GREATER THAN 2% (AND HIGHER THAN PLACEBO) OF PATIENTS EXPOSED TO STRIVERDI RESPIMAT 10 MCG WERE PNEUMONIA, CONSTIPATION, AND PYREXIA.
LUNG CANCERS WERE REPORTED IN 6 (0.7%), 3 (0.3%), AND 2 (0.2%) PATIENTS WHO RECEIVED STRIVERDI RESPIMAT 10 MCG, 5 MCG, AND PLACEBO, RESPECTIVELY.
READ THE STRIVERDI RESPIMAT (OLODATEROL INHALATION SPRAY) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
THE EXPECTED SIGNS AND SYMPTOMS WITH OVERDOSAGE OF STRIVERDI RESPIMAT ARE THOSE OF EXCESSIVE BETA-ADRENERGIC STIMULATION AND OCCURRENCE OR EXAGGERATION OF ANY OF THE SIGNS AND SYMPTOMS, E.G., MYOCARDIAL ISCHEMIA, ANGINA PECTORIS, HYPERTENSION OR HYPOTENSION, TACHYCARDIA, ARRHYTHMIAS, PALPITATIONS, DIZZINESS, NERVOUSNESS, INSOMNIA, ANXIETY, HEADACHE, TREMOR, DRY MOUTH, MUSCLE SPASMS, NAUSEA, FATIGUE, MALAISE, HYPOKALEMIA, HYPERGLYCEMIA, AND METABOLIC ACIDOSIS. AS WITH ALL INHALED SYMPATHOMIMETIC MEDICATIONS, CARDIAC ARREST AND EVEN DEATH MAY BE ASSOCIATED WITH AN OVERDOSE OF STRIVERDI RESPIMAT.
TREATMENT OF OVERDOSAGE CONSISTS OF DISCONTINUATION OF STRIVERDI RESPIMAT TOGETHER WITH INSTITUTION OF APPROPRIATE SYMPTOMATIC AND SUPPORTIVE THERAPY. THE JUDICIOUS USE OF A CARDIOSELECTIVE BETA-RECEPTOR BLOCKER MAY BE CONSIDERED, BEARING IN MIND THAT SUCH MEDICATION CAN PRODUCE BRONCHOSPASM. THERE IS INSUFFICIENT EVIDENCE TO DETERMINE IF DIALYSIS IS BENEFICIAL FOR OVERDOSAGE OF STRIVERDI RESPIMAT. CARDIAC MONITORING IS RECOMMENDED IN CASES OF OVERDOSAGE.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
OLODATEROL IS A LONG-ACTING BETA2-ADRENERGIC AGONIST (LABA). THE COMPOUND EXERTS ITS PHARMACOLOGICAL EFFECTS BY BINDING AND ACTIVATION OF BETA2-ADRENOCEPTORS AFTER TOPICAL ADMINISTRATION BY INHALATION. ACTIVATION OF THESE RECEPTORS IN THE AIRWAYS RESULTS IN A STIMULATION OF INTRACELLULAR ADENYL CYCLASE, AN ENZYME THAT MEDIATES THE SYNTHESIS OF CYCLIC-3', 5' ADENOSINE MONOPHOSPHATE (CAMP). ELEVATED LEVELS OF CAMP INDUCE BRONCHODILATION BY RELAXATION OF AIRWAY SMOOTH MUSCLE CELLS. IIN VITRO STUDIES HAVE SHOWN THAT OLODATEROL HAS 241-FOLD GREATER AGONIST ACTIVITY AT BETA2-ADRENOCEPTORS COMPARED TO BETA1-ADRENOCEPTORS AND 2,299-FOLD GREATER AGONIST ACTIVITY COMPARED TO BETA3-ADRENOCEPTORS. THE CLINICAL SIGNIFICANCE OF THESE FINDINGS IS UNKNOWN.
BETA-ADRENOCEPTORS ARE DIVIDED INTO THREE SUBTYPES: BETA1-ADRENOCEPTORS PREDOMINANTLY EXPRESSED ON CARDIAC SMOOTH MUSCLE, BETA2ADRENOCEPTORS PREDOMINANTLY EXPRESSED ON AIRWAY SMOOTH MUSCLE, AND BETA3-ADRENOCEPTORS PREDOMINANTLY EXPRESSED ON ADIPOSE TISSUE. BETA2-AGONISTS CAUSE BRONCHODILATION. ALTHOUGH THE BETA2-ADRENOCEPTOR IS THE PREDOMINANT ADRENERGIC RECEPTOR IN THE AIRWAY SMOOTH MUSCLE, IT IS ALSO PRESENT ON THE SURFACE OF A VARIETY OF OTHER CELLS, INCLUDING LUNG EPITHELIAL AND ENDOTHELIAL CELLS AND IN THE HEART. THE PRECISE FUNCTION OF BETA2-RECEPTORS IN THE HEART IS NOT KNOWN, BUT THEIR PRESENCE RAISES THE POSSIBILITY THAT EVEN HIGHLY SELECTIVE BETA2-AGONISTS MAY HAVE CARDIAC EFFECTS.
PHARMACODYNAMICS
SYSTEMIC SAFETY
THE MAJOR ADVERSE EFFECTS OF INHALED BETA2-ADRENERGIC AGONISTS OCCUR AS A RESULT OF EXCESSIVE ACTIVATION OF SYSTEMIC BETA-ADRENERGIC RECEPTORS. THE MOST COMMON ADVERSE EFFECTS IN ADULTS INCLUDE SKELETAL MUSCLE TREMOR AND CRAMPS, INSOMNIA, TACHYCARDIA, DECREASES IN SERUM POTASSIUM, AND INCREASES IN PLASMA GLUCOSE.
CHANGES IN SERUM POTASSIUM WERE EVALUATED IN COPD PATIENTS IN DOUBLE-BLIND PHASE 3 STUDIES. IN POOLED DATA, AT THE RECOMMENDED 5 MCG DOSE THERE WAS NO CLINICALLY RELEVANT CHANGE COMPARED TO PLACEBO IN SERUM POTASSIUM.
ELECTROPHYSIOLOGY
THE EFFECT OF STRIVERDI RESPIMAT ON THE QT/QTC INTERVAL OF THE ECG WAS INVESTIGATED IN 24 HEALTHY MALE AND FEMALE VOLUNTEERS IN A DOUBLE-BLIND, RANDOMIZED, PLACEBO-AND ACTIVE (MOXIFLOXACIN)-CONTROLLED STUDY AT SINGLE DOSES OF 10, 20, 30, AND 50 MCG. DOSE-DEPENDENT QTCI (INDIVIDUAL SUBJECT CORRECTED QT INTERVAL) PROLONGATION WAS OBSERVED. THE MAXIMUM MEAN (ONE-SIDED 95% UPPER CONFIDENCE BOUND) DIFFERENCE IN QTCI FROM PLACEBO AFTER BASELINE CORRECTION WAS 2.5 (5.6) MS, 6.1 (9.2) MS, 7.5 (10.7) MS AND 8.5 (11.6) MS FOLLOWING DOSES OF 10, 20, 30 AND 50 MCG, RESPECTIVELY.
THE EFFECT OF 5 MCG AND 10 MCG STRIVERDI RESPIMAT ON HEART RATE AND RHYTHM WAS ASSESSED USING CONTINUOUS 24-HOUR ECG RECORDING (HOLTER MONITORING) IN A SUBSET OF 772 PATIENTS IN THE 48-WEEK, PLACEBO-CONTROLLED PHASE 3 TRIALS. THERE WERE NO DOSE-OR TIME-RELATED TRENDS OR PATTERNS OBSERVED FOR THE MAGNITUDES OF MEAN CHANGES IN HEART RATE OR PREMATURE BEATS. SHIFTS FROM BASELINE TO THE END OF TREATMENT IN PREMATURE BEATS DID NOT INDICATE MEANINGFUL DIFFERENCES BETWEEN STRIVERDI RESPIMAT 5 MCG, 10 MCG, AND PLACEBO.
PHARMACOKINETICS
OLODATEROL SHOWED LINEAR PHARMACOKINETICS. ON REPEATED ONCE-DAILY INHALATION STEADY-STATE OF OLODATEROL PLASMA CONCENTRATIONS WAS ACHIEVED AFTER 8 DAYS, AND THE EXTENT OF EXPOSURE WAS INCREASED UP TO 1.8-FOLD AS COMPARED TO A SINGLE DOSE.
ABSORPTION
OLODATEROL REACHES MAXIMUM PLASMA CONCENTRATIONS GENERALLY WITHIN 10 TO 20 MINUTES FOLLOWING DRUG INHALATION. IN HEALTHY VOLUNTEERS, THE ABSOLUTE BIOAVAILABILITY OF OLODATEROL FOLLOWING INHALATION WAS ESTIMATED TO BE APPROXIMATELY 30%, WHEREAS THE ABSOLUTE BIOAVAILABILITY WAS BELOW 1% WHEN GIVEN AS AN ORAL SOLUTION. THUS, THE SYSTEMIC AVAILABILITY OF OLODATEROL AFTER INHALATION IS MAINLY DETERMINED BY LUNG ABSORPTION, WHILE ANY SWALLOWED PORTION OF THE DOSE ONLY NEGLIGIBLY CONTRIBUTES TO SYSTEMIC EXPOSURE.
DISTRIBUTION
OLODATEROL EXHIBITS MULTI-COMPARTMENTAL DISPOSITION KINETICS AFTER INHALATION AS WELL AS AFTER INTRAVENOUS ADMINISTRATION. THE VOLUME OF DISTRIBUTION IS HIGH (1110 L), SUGGESTING EXTENSIVE DISTRIBUTION INTO TISSUE. IIN VITRO BINDING OF [14C] OLODATEROL TO HUMAN PLASMA PROTEINS IS INDEPENDENT OF CONCENTRATION AND IS APPROXIMATELY 60%.
METABOLISM
OLODATEROL IS SUBSTANTIALLY METABOLIZED BY DIRECT GLUCURONIDATION AND BY O-DEMETHYLATION AT THE METHOXY MOIETY FOLLOWED BY CONJUGATION. OF THE SIX METABOLITES IDENTIFIED, ONLY THE UNCONJUGATED DEMETHYLATION PRODUCT BINDS TO BETA2-RECEPTORS. THIS METABOLITE, HOWEVER, IS NOT DETECTABLE IN PLASMA AFTER CHRONIC INHALATION OF THE RECOMMENDED THERAPEUTIC DOSE.
CYTOCHROME P450 ISOZYMES CYP2C9 AND CYP2C8, WITH NEGLIGIBLE CONTRIBUTION OF CYP3A4, ARE INVOLVED IN THE O-DEMETHYLATION OF OLODATEROL, WHILE URIDINE DIPHOSPHATE GLYCOSYL TRANSFERASE ISOFORMS UGT2B7, UGT1A1, 1A7, AND 1A9 WERE SHOWN TO BE INVOLVED IN THE FORMATION OF OLODATEROL GLUCURONIDES.
ELIMINATION
TOTAL CLEARANCE OF OLODATEROL IN HEALTHY VOLUNTEERS IS 872 ML/MIN, AND RENAL CLEARANCE IS 173 ML/MIN. THE TERMINAL HALF-LIFE FOLLOWING INTRAVENOUS ADMINISTRATION IS 22 HOURS. THE TERMINAL HALF-LIFE FOLLOWING INHALATION IN CONTRAST IS ABOUT 45 HOURS, INDICATING THAT THE LATTER IS DETERMINED BY ABSORPTION RATHER THAN BY ELIMINATION PROCESSES. HOWEVER, THE EFFECTIVE HALF-LIFE AT DAILY DOSE OF 5 ?G CALCULATED FROM CMAX FROM COPD PATIENTS IS 7.5 HOURS.
FOLLOWING INTRAVENOUS ADMINISTRATION OF [14C]-LABELED OLODATEROL, 38% OF THE RADIOACTIVE DOSE WAS RECOVERED IN THE URINE AND 53% WAS RECOVERED IN FECES. THE AMOUNT OF UNCHANGED OLODATEROL RECOVERED IN THE URINE AFTER INTRAVENOUS ADMINISTRATION WAS 19%. FOLLOWING ORAL ADMINISTRATION, ONLY 9% OF OLODATEROL AND/OR ITS METABOLITES WAS RECOVERED IN URINE, WHILE THE MAJOR PORTION WAS RECOVERED IN FECES (84%). MORE THAN 90% OF THE DOSE WAS EXCRETED WITHIN 6 AND 5 DAYS FOLLOWING INTRAVENOUS AND ORAL ADMINISTRATION, RESPECTIVELY. FOLLOWING INHALATION, EXCRETION OF UNCHANGED OLODATEROL IN URINE WITHIN THE DOSING INTERVAL IN HEALTHY VOLUNTEERS AT STEADY STATE ACCOUNTED FOR 5% TO 7% OF THE DOSE.
SPECIAL POPULATIONS
A PHARMACOKINETIC META-ANALYSIS SHOWED THAT NO DOSE ADJUSTMENT IS NECESSARY BASED ON THE EFFECT OF AGE, GENDER, AND WEIGHT ON SYSTEMIC EXPOSURE IN COPD PATIENTS AFTER INHALATION OF STRIVERDI RESPIMAT.
RENAL IMPAIRMENT
OLODATEROL LEVELS WERE INCREASED BY APPROXIMATELY 40% IN SUBJECTS WITH SEVERE RENAL IMPAIRMENT. A STUDY IN SUBJECTS WITH MILD AND MODERATE RENAL IMPAIRMENT WAS NOT PERFORMED.
HEPATIC IMPAIRMENT
SUBJECTS WITH MILD AND MODERATE HEPATIC IMPAIRMENT SHOWED NO CHANGES IN CMAX OR AUC, NOR DID PROTEIN BINDING DIFFER BETWEEN MILD AND MODERATE HEPATICALLY IMPAIRED SUBJECTS AND THEIR HEALTHY CONTROLS. A STUDY IN SUBJECTS WITH SEVERE HEPATIC IMPAIRMENT WAS NOT PERFORMED.
DRUG-DRUG INTERACTIONS
DRUG-DRUG INTERACTION STUDIES WERE CARRIED OUT USING FLUCONAZOLE AS A MODEL INHIBITOR OF CYP 2C9 AND KETOCONAZOLE AS A POTENT P-GP (AND CYP3A4, 2C8, 2C9) INHIBITOR.
FLUCONAZOLE: CO-ADMINISTRATION OF 400 MG FLUCONAZOLE ONCE A DAY FOR 14 DAYS HAD NO RELEVANT EFFECT ON SYSTEMIC EXPOSURE TO OLODATEROL.
KETOCONAZOLE: CO-ADMINISTRATION OF 400 MG KETOCONAZOLE ONCE A DAY FOR 14 DAYS INCREASED OLODATEROL CMAX BY 66% AND AUC0-1 BY 68%.
TIOTROPIUM: CO-ADMINISTRATION OF TIOTROPIUM BROMIDE, DELIVERED AS FIXED-DOSE COMBINATION WITH OLODATEROL, FOR 21 DAYS HAD NO RELEVANT EFFECT ON SYSTEMIC EXPOSURE TO OLODATEROL, AND VICE VERSA.
CLINICAL STUDIES
THE STRIVERDI RESPIMAT CLINICAL DEVELOPMENT PROGRAM INCLUDED THREE DOSE-RANGING TRIALS IN COPD PATIENTS, FOUR DOSE-RANGING TRIALS IN ASTHMA PATIENTS, AND EIGHT CONFIRMATORY TRIALS IN PATIENTS WITH COPD.
DOSE-RANGING TRIALS
THE FIRST COPD DOSE-RANGING TRIAL WAS A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE-DOSE, 5-WAY CROSS-OVER TRIAL IN 36 PATIENTS. RESULTS DEMONSTRATED DOSE-RELATED IMPROVEMENTS IN FORCED EXPIRATORY VOLUME IN ONE SECOND (FEV1) COMPARED TO PLACEBO. THE DIFFERENCE IN TROUGH FEV1 FROM PLACEBO FOR THE 2, 5, 10, AND 20 MCG DOSES WERE 0.07L (95% CI 0.03, 0.11), 0.10L (0.06, 0.14), 0.11L (0.07, 0.15), AND 0.12L (0.08, 0.16), RESPECTIVELY. THE SECOND COPD DOSE-RANGING TRIAL WAS A 4-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP TRIAL IN 405 PATIENTS. DOSE-RELATED IMPROVEMENTS IN LUNG FUNCTION WERE ALSO SEEN, WITH NO ADDED BENEFIT OF THE 20 MCG DOSE OVER THE 10 MCG DOSE (FIGURE 1). THE THIRD COPD DOSE-RANGING TRIAL WAS A RANDOMIZED, DOUBLE-BLIND, 4-WAY CROSS-OVER, DOSE-REGIMEN TRIAL IN 47 PATIENTS. TREATMENT ARMS INCLUDED 2 MCG TWICE-DAILY, 5 MCG ONCE-DAILY, 5 MCG TWICE-DAILY, AND 10 MCG ONCE-DAILY. THERE WAS NO CLEAR DIFFERENCE IN TREATMENT EFFECT WHEN COMPARING TWICE-DAILY DOSING TO ONCE-DAILY DOSING.
FIGURE 1: DIFFERENCE FROM PLACEBO FOR STRIVERDI RESPIMAT FOR FEV1 AUC0-3HR AND TROUGH FEV1 AFTER 4 WEEKS
FOUR RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED DOSE-RANGING TRIALS WERE PERFORMED IN PATIENTS WITH ASTHMA, EVALUATING DOSES FROM 2 TO 20 MCG. RESULTS FROM PATIENTS WITH ASTHMA WERE CONSISTENT WITH RESULTS FROM DOSE-RANGING TRIALS IN PATIENTS WITH COPD. STRIVERDI RESPIMAT IS NOT INDICATED FOR ASTHMA.
BASED UPON THE RESULTS OF THE DOSE-RANGING TRIALS, 5 AND 10 MCG DOSES WERE FURTHER EVALUATED IN THE CONFIRMATORY COPD TRIALS.
CONFIRMATORY TRIALS
THE EIGHT CONFIRMATORY TRIALS IN THE STRIVERDI RESPIMAT CLINICAL DEVELOPMENT PROGRAM WERE FOUR PAIRS OF REPLICATE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIALS IN 3533 COPD PATIENTS (1281 RECEIVED THE 5 MCG DOSE, 1284 RECEIVED THE 10 MCG DOSE):
1. TWO REPLICATE, PLACEBO-CONTROLLED, PARALLEL GROUP, 48 WEEK TRIALS (TRIALS 1 AND 2)
2. TWO REPLICATE, PLACEBO-AND ACTIVE-[FORMOTEROL 12 MCG TWICE-DAILY] CONTROLLED, PARALLEL GROUP, 48-WEEK TRIALS (TRIALS 3 AND 4)
3. TWO REPLICATE, PLACEBO-AND ACTIVE-[FORMOTEROL 12 MCG TWICE-DAILY] CONTROLLED, 6-WEEK CROSS-OVER TRIALS (TRIALS 5 AND 6)
4. TWO REPLICATE, PLACEBO-AND ACTIVE-[TIOTROPIUM BROMIDE 18 MCG ONCE-DAILY] CONTROLLED, 6-WEEK CROSS-OVER TRIALS (TRIALS 7 AND 8).
THESE EIGHT TRIALS ENROLLED PATIENTS WHO WERE 40 YEARS OF AGE OR OLDER WITH A CLINICAL DIAGNOSIS OF COPD, A SMOKING HISTORY OF AT LEAST 10 PACK-YEARS, AND MODERATE TO VERY SEVERE PULMONARY IMPAIRMENT (POST-BRONCHODILATOR FEV1 LESS THAN 80% PREDICTED NORMAL [GOLD II - IV] AND A POST-BRONCHODILATOR FEV1 TO FVC RATIO OF LESS THAN 70%).
THE MAJORITY OF THE 3104 PATIENTS IN THE 48-WEEK TRIALS (TRIALS 1 AND 2, TRIALS 3 AND 4) WERE MALE (77%), WHITE (66%) OR ASIAN (32%), WITH A MEAN AGE OF 64 YEARS. MEAN POST-BRONCHODILATOR FEV1 WAS 1.38 L (GOLD II [50%], GOLD III [40%], GOLD IV [10%]). MEAN BETA2-AGONIST RESPONSIVENESS WAS 15% OF BASELINE (0.16 L). WITH THE EXCEPTION OF OTHER LABAS, ALL PULMONARY MEDICATIONS WERE ALLOWED AS CONCOMITANT THERAPY (E.G., TIOTROPIUM [24%], IPRATROPIUM [25%], INHALED CORTICOSTEROIDS [45%], XANTHINES [16%]); PATIENT ENROLLMENT WAS STRATIFIED BY TIOTROPIUM USE. IN ALL FOUR TRIALS, THE PRIMARY EFFICACY ENDPOINTS WERE CHANGE FROM PRE-TREATMENT BASELINE IN FEV1 AUC0-3 AND TROUGH (PRE-DOSE) FEV1 (AFTER 12 WEEKS IN TRIALS 1 AND 2; AFTER 24 WEEKS IN TRIALS 3 AND 4).
IN ALL FOUR 48-WEEK TRIALS, STRIVERDI RESPIMAT 5 MCG DEMONSTRATED SIGNIFICANT IMPROVEMENTS IN FEV1 AUC 0-3HR COMPARED TO PLACEBO AT WEEK 12 (TABLE 2) AND AT WEEK 24. IN THE FOUR 48-WEEK TRIALS, STRIVERDI RESPIMAT 5 MCG DEMONSTRATED SIGNIFICANT IMPROVEMENTS IN TROUGH FEV1 COMPARED TO PLACEBO AT WEEK 12 (TABLE 2; 3 OF 4 TRIALS) AND AT WEEK 24 (4 TRIALS). STRIVERDI RESPIMAT 5 MCG DEMONSTRATED A BRONCHODILATORY TREATMENT EFFECT AT 5 MINUTES AFTER THE FIRST DOSE WITH A MEAN INCREASE IN FEV1 COMPARED TO PLACEBO OF 0.11L (RANGE: 0.10L TO 0.12L). THE 10 MCG DOSE DEMONSTRATED NO ADDITIONAL BENEFIT OVER THE 5 MCG DOSE (DATA NOT SHOWN). PATIENTS TREATED WITH STRIVERDI RESPIMAT 5 MCG USED LESS RESCUE ALBUTEROL COMPARED TO PATIENTS TREATED WITH PLACEBO.
TABLE 2: DIFFERENCES FROM PLACEBO FOR STRIVERDI RESPIMAT 5 MCG FOR FEV1 AUC0-3HR AND TROUGH FEV1 AT WEEK 12
DIFFERENCE FROM PLACEBO [L] (95% CI)
FEV 1 AUC0-3HR TROUGH FEV1
TRIAL 1 0.16 (0.12, 0.21) 0.08 (0.04, 0.13)
TRIAL 2 0.13 (0.09, 0.18) 0.03 (-0.01, 0.08)
TRIAL 3 0.18 (0.14, 0.22) 0.08 (0.04, 0.12)
TRIAL 4 0.15 (0.11, 0.18) 0.06 (0.02, 0.10)
IN TRIALS 1 AND 2, SERIAL SPIROMETRIC EVALUATIONS WERE PERFORMED PRE-DOSE AND UP TO 12 HOURS AFTER DOSING IN A SUB-GROUP OF 562 PATIENTS (201 PATIENTS RECEIVING STRIVERDI RESPIMAT 5 MCG, 192 PATIENTS RECEIVING 10 MCG, AND 169 PATIENTS RECEIVING PLACEBO) AFTER 12 WEEKS OF TREATMENT. DOSING OCCURRED AT APPROXIMATELY THE SAME TIME OF THE DAY IN THE MORNING. THE SPIROMETRIC CURVES FROM TRIAL 1 ARE DISPLAYED IN FIGURE 2.
FIGURE 2 : FEV1 PROFILE FOR STRIVERDI RESPIMAT 5 MCG AND PLACEBO AT WEEK 12 (PRE-DOSE AND UP TO 12 HRS POST-DOSE) (TRIAL 1)
THE BRONCHODILATORY PROFILE OF STRIVERDI RESPIMAT 5 MCG OVER THE 24 HOUR DOSING INTERVAL WAS EVALUATED IN TWO PAIRS OF REPLICATE, PLACEBO-AND ACTIVE-CONTROLLED, 6 WEEK CROSS-OVER TRIALS IN 199 PATIENTS (TRIALS 5 AND 6) AND 230 PATIENTS (TRIALS 7 AND 8) WITH MODERATE TO VERY SEVERE COPD. MEAN BETA2-AGONIST RESPONSIVENESS RANGED FROM 14% -21% OF BASELINE (0.18 TO 0.22 L). ALL PULMONARY MEDICATIONS WERE ALLOWED AS CONCOMITANT THERAPY WITH THE EXCEPTION OF OTHER LABAS (ALL TRIALS) AND ANTI-CHOLINERGICS (TRIALS 7 AND 8). IN ALL FOUR TRIALS, THE PRIMARY ENDPOINTS WERE CHANGE FROM PRE-TREATMENT BASELINE IN FEV1 AUC0-12HR AND FEV1 AUC1224HR AFTER 6 WEEKS; ALTHOUGH NOT A PRIMARY ENDPOINT, TROUGH FEV1 WAS ALSO MEASURED AFTER 6 WEEKS. RESULTS ARE SHOWN IN TABLE 3.
TABLE 3: DIFFERENCES FROM PLACEBO FOR STRIVERDI RESPIMAT 5 MCG AFTER 6 WEEKS IN CROSS-OVER SPIROMETRY TRIALS
DIFFERENCE FROM PLACEBO [L] (95% CI)
FEV1 AUC0-12HR FEV1 AUC1224 HR TROUGH FEV1
TRIAL 5 0.15 (0.11, 0.18) 0.11 (0.07, 0.15) 0.11 (0.06, 0.15)
TRIAL 6 0.17 (0.14, 0.21) 0.12 (0.08, 0.15) 0.10 (0.05, 0.15)
TRIAL 7 0.19 (0.15, 0.23) 0.13 (0.09, 0.17) 0.13 (0.10, 0.17)
TRIAL 8 0.20 (0.16, 0.23) 0.15 (0.12, 0.19) 0.13 (0.10, 0.17)