INDICATIONS
JARDIANCE IS INDICATED AS AN ADJUNCT TO DIET AND EXERCISE TO IMPROVE GLYCEMIC CONTROL IN ADULTS WITH TYPE 2 DIABETES MELLITUS [SEE CLINICAL STUDIES].
LIMITATION OF USE
JARDIANCE IS NOT RECOMMENDED FOR PATIENTS WITH TYPE 1 DIABETES OR FOR THE TREATMENT OF DIABETIC KETOACIDOSIS.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
" JARDIANCE (EMPAGLIFLOZIN) 10 MG TABLETS ARE PALE YELLOW, ROUND, BICONVEX AND BEVEL-EDGED, FILM-COATED TABLETS DEBOSSED WITH "S 10" ON ONE SIDE AND THE BOEHRINGER INGELHEIM COMPANY SYMBOL ON THE OTHER SIDE.
" JARDIANCE (EMPAGLIFLOZIN) 25 MG TABLETS ARE PALE YELLOW, OVAL, BICONVEX, FILM-COATED TABLETS DEBOSSED WITH "S 25" ON ONE SIDE AND THE BOEHRINGER INGELHEIM COMPANY SYMBOL ON THE OTHER SIDE.
STORAGE AND HANDLING
JARDIANCE TABLETS ARE AVAILABLE IN 10 MG AND 25 MG STRENGTHS AS FOLLOWS:
10 MG TABLETS: PALE YELLOW, ROUND, BICONVEX AND BEVEL-EDGED, FILM-COATED TABLETS DEBOSSED WITH "S 10" ON ONE SIDE AND THE BOEHRINGER INGELHEIM COMPANY SYMBOL ON THE OTHER SIDE.
BOTTLES OF 30 (NDC 0597-0152-30)
BOTTLES OF 90 (NDC 0597-0152-90)
CARTONS CONTAINING 3 BLISTER CARDS OF 10 TABLETS EACH (3 X 10) (NDC 0597-0152-37), INSTITUTIONAL PACK.
25 MG TABLETS: PALE YELLOW, OVAL, BICONVEX FILM-COATED TABLETS, DEBOSSED WITH "S 25" ON ONE SIDE AND THE BOEHRINGER INGELHEIM COMPANY SYMBOL ON THE OTHER SIDE.
BOTTLES OF 30 (NDC 0597-0153-30)
BOTTLES OF 90 (NDC 0597-0153-90)
CARTONS CONTAINING 3 BLISTER CARDS OF 10 TABLETS EACH (3 X 10) (NDC 0597-0153-37), INSTITUTIONAL PACK.
DISPENSE IN A WELL-CLOSED CONTAINER AS DEFINED IN THE USP.
STORAGE
STORE AT 25°C (77°F); EXCURSIONS PERMITTED TO 15°-30°C (59°-86°F) [SEE USP CONTROLLED ROOM TEMPERATURE].
DISTRIBUTED BY: BOEHRINGER INGELHEIM PHARMACEUTICALS, INC. RIDGEFIELD, CT 06877 USA. MARKETED BY: BOEHRINGER INGELHEIM PHARMACEUTICALS, INC. RIDGEFIELD, CT 06877 USA AND ELI LILLY AND COMPANY INDIANAPOLIS, IN 46285 USA. REVISED: AUG 2014
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSAGE
THE RECOMMENDED DOSE OF JARDIANCE IS 10 MG ONCE DAILY IN THE MORNING, TAKEN WITH OR WITHOUT FOOD. IN PATIENTS TOLERATING JARDIANCE, THE DOSE MAY BE INCREASED TO 25 MG [SEE CLINICAL STUDIES].
IN PATIENTS WITH VOLUME DEPLETION, CORRECTING THIS CONDITION PRIOR TO INITIATION OF JARDIANCE IS RECOMMENDED [SEE WARNINGS AND PRECAUTIONS, USE IN SPECIFIC POPULATIONS, AND PATIENT INFORMATION].
PATIENTS WITH RENAL IMPAIRMENT
ASSESSMENT OF RENAL FUNCTION IS RECOMMENDED PRIOR TO INITIATION OF JARDIANCE AND PERIODICALLY THEREAFTER.
JARDIANCE SHOULD NOT BE INITIATED IN PATIENTS WITH AN EGFR LESS THAN 45 ML/MIN/1.73 M² .
NO DOSE ADJUSTMENT IS NEEDED IN PATIENTS WITH AN EGFR GREATER THAN OR EQUAL TO 45 ML/MIN/1.73 M² .
JARDIANCE SHOULD BE DISCONTINUED IF EGFR IS PERSISTENTLY LESS THAN 45 ML/MIN/1.73 M² [SEE WARNINGS AND PRECAUTIONS, AND USE IN SPECIFIC POPULATIONS].
SIDE EFFECTS
THE FOLLOWING IMPORTANT ADVERSE REACTIONS ARE DESCRIBED BELOW AND ELSEWHERE IN THE LABELING:
" HYPOTENSION [SEE WARNINGS AND PRECAUTIONS]
" IMPAIRMENT IN RENAL FUNCTION [SEE WARNINGS AND PRECAUTIONS]
" HYPOGLYCEMIA WITH CONCOMITANT USE WITH INSULIN AND INSULIN SECRETAGOGUES [SEE WARNINGS AND PRECAUTIONS]
" GENITAL MYCOTIC INFECTIONS [SEE WARNINGS AND PRECAUTIONS]
" URINARY TRACT INFECTIONS [SEE WARNINGS AND PRECAUTIONS]
" INCREASED LOW-DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C) [SEE WARNINGS AND PRECAUTIONS]
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 PRACTICE.
POOL OF PLACEBO-CONTROLLED TRIALS EVALUATING JARDIANCE 10 AND 25 MG
THE DATA IN TABLE 1 ARE DERIVED FROM A POOL OF FOUR 24-WEEK PLACEBO-CONTROLLED TRIALS AND 18-WEEK DATA FROM A PLACEBO-CONTROLLED TRIAL WITH INSULIN. JARDIANCE WAS USED AS MONOTHERAPY IN ONE TRIAL AND AS ADD-ON THERAPY IN FOUR TRIALS [SEE CLINICAL STUDIES].
THESE DATA REFLECT EXPOSURE OF 1976 PATIENTS TO JARDIANCE WITH A MEAN EXPOSURE DURATION OF APPROXIMATELY 23 WEEKS. PATIENTS RECEIVED PLACEBO (N=995), JARDIANCE 10 MG (N=999), OR JARDIANCE 25 MG (N=977) ONCE DAILY. THE MEAN AGE OF THE POPULATION WAS 56 YEARS AND 3% WERE OLDER THAN 75 YEARS OF AGE. MORE THAN HALF (55%) OF THE POPULATION WAS MALE; 46% WERE WHITE, 50% WERE ASIAN, AND 3% WERE BLACK OR AFRICAN AMERICAN. AT BASELINE, 57% OF THE POPULATION HAD DIABETES MORE THAN 5 YEARS AND HAD A MEAN HEMOGLOBIN A1C (HBA1C) OF 8%. ESTABLISHED MICROVASCULAR COMPLICATIONS OF DIABETES AT BASELINE INCLUDED DIABETIC NEPHROPATHY (7%), RETINOPATHY (8%), OR NEUROPATHY (16%). BASELINE RENAL FUNCTION WAS NORMAL OR MILDLY IMPAIRED IN 91% OF PATIENTS AND MODERATELY IMPAIRED IN 9% OF PATIENTS (MEAN EGFR 86.8 ML/MIN/1.73 M²).
TABLE 1 SHOWS COMMON ADVERSE REACTIONS (EXCLUDING HYPOGLYCEMIA) ASSOCIATED WITH THE USE OF JARDIANCE. THE ADVERSE REACTIONS WERE NOT PRESENT AT BASELINE, OCCURRED MORE COMMONLY ON JARDIANCE THAN ON PLACEBO AND OCCURRED IN GREATER THAN OR EQUAL TO 2% OF PATIENTS TREATED WITH JARDIANCE 10 MG OR JARDIANCE 25 MG.
TABLE 1 : ADVERSE REACTIONS REPORTED IN ? 2% OF PATIENTS TREATED WITH JARDIANCE AND GREATER THAN PLACEBO IN POOLED PLACEBO-CONTROLLED CLINICAL STUDIES OF JARDIANCE MONOTHERAPY OR COMBINATION THERAPY
NUMBER (%) OF PATIENTS
PLACEBO
N=995 JARDIANCE 10 MG
N=999 JARDIANCE 25 MG
N=977
URINARY TRACT INFECTIONA 7.6% 9.3% 7.6%
FEMALE GENITAL MYCOTIC INFECTIONSB 1.5% 5.4% 6.4%
UPPER RESPIRATORY TRACT INFECTION 3.8% 3.1% 4.0%
INCREASED URINATIONC 1.0% 3.4% 3.2%
DYSLIPIDEMIA 3.4% 3.9% 2.9%
ARTHRALGIA 2.2% 2.4% 2.3%
MALE GENITAL MYCOTIC INFECTIONSD 0.4% 3.1% 1.6%
NAUSEA 1.4% 2.3% 1.1%
APREDEFINED ADVERSE EVENT GROUPING, INCLUDING, BUT NOT LIMITED TO, URINARY TRACT INFECTION, ASYMPTOMATIC BACTERIURIA, CYSTITIS
BFEMALE GENITAL MYCOTIC INFECTIONS INCLUDE THE FOLLOWING ADVERSE REACTIONS: VULVOVAGINAL MYCOTIC INFECTION, VAGINAL INFECTION, VULVITIS, VULVOVAGINAL CANDIDIASIS, GENITAL INFECTION, GENITAL CANDIDIASIS, GENITAL INFECTION FUNGAL, GENITOURINARY TRACT INFECTION, VULVOVAGINITIS, CERVICITIS, UROGENITAL INFECTION FUNGAL, VAGINITIS BACTERIAL. PERCENTAGES CALCULATED WITH THE NUMBER OF FEMALE SUBJECTS IN EACH GROUP AS DENOMINATOR: PLACEBO (N=481), JARDIANCE 10 MG (N=443), JARDIANCE 25 MG (N=420).
CPREDEFINED ADVERSE EVENT GROUPING, INCLUDING, BUT NOT LIMITED TO, POLYURIA, POLLAKIURIA, AND NOCTURIA
DMALE GENITAL MYCOTIC INFECTIONS INCLUDE THE FOLLOWING ADVERSE REACTIONS: BALANOPOSTHITIS, BALANITIS, GENITAL INFECTIONS FUNGAL, GENITOURINARY TRACT INFECTION, BALANITIS CANDIDA, SCROTAL ABSCESS, PENILE INFECTION. PERCENTAGES CALCULATED WITH THE NUMBER OF MALE SUBJECTS IN EACH GROUP AS DENOMINATOR: PLACEBO (N=514), JARDIANCE 10 MG (N=556), JARDIANCE 25 MG (N=557).
THIRST (INCLUDING POLYDIPSIA) WAS REPORTED IN 0%, 1.7%, AND 1.5% FOR PLACEBO, JARDIANCE 10 MG, AND JARDIANCE 25 MG, RESPECTIVELY.
VOLUME DEPLETION
JARDIANCE CAUSES AN OSMOTIC DIURESIS, WHICH MAY LEAD TO INTRAVASCULAR VOLUME CONTRACTION AND ADVERSE REACTIONS RELATED TO VOLUME DEPLETION. IN THE POOL OF FIVE PLACEBO-CONTROLLED CLINICAL TRIALS, ADVERSE REACTIONS RELATED TO VOLUME DEPLETION (E.G., BLOOD PRESSURE (AMBULATORY) DECREASED, BLOOD PRESSURE SYSTOLIC DECREASED, DEHYDRATION, HYPOTENSION, HYPOVOLEMIA, ORTHOSTATIC HYPOTENSION, AND SYNCOPE) WERE REPORTED BY 0.3%, 0.5%, AND 0.3% OF PATIENTS TREATED WITH PLACEBO, JARDIANCE 10 MG, AND JARDIANCE 25 MG RESPECTIVELY.
JARDIANCE MAY INCREASE THE RISK OF HYPOTENSION IN PATIENTS AT RISK FOR VOLUME CONTRACTION [SEE WARNINGS AND PRECAUTIONS AND USE IN SPECIFIC POPULATIONS].
INCREASED URINATION
IN THE POOL FIVE PLACEBO-CONTROLLED CLINICAL TRIALS, ADVERSE REACTIONS OF INCREASED URINATION (E.G., POLYURIA, POLLAKIURIA, AND NOCTURIA) OCCURRED MORE FREQUENTLY ON JARDIANCE THAN ON PLACEBO (SEE TABLE 1). SPECIFICALLY, NOCTURIA WAS REPORTED BY 0.4%, 0.3%, AND 0.8% OF PATIENTS TREATED WITH PLACEBO, JARDIANCE 10 MG, AND JARDIANCE 25 MG, RESPECTIVELY.
IMPAIRMENT IN RENAL FUNCTION
USE OF JARDIANCE WAS ASSOCIATED WITH INCREASES IN SERUM CREATININE AND DECREASES IN EGFR (SEE TABLE 2). PATIENTS WITH MODERATE RENAL IMPAIRMENT AT BASELINE HAD LARGER MEAN CHANGES. [SEE WARNINGS AND PRECAUTIONS AND USE IN SPECIFIC POPULATIONS].
TABLE 2 : CHANGES FROM BASELINE IN SERUM CREATININE AND EGFR IN THE POOL OF FOUR 24-WEEK PLACEBO-CONTROLLED STUDIES AND RENAL IMPAIRMENT STUDY
POOL OF 24-WEEK PLACEBO-CONTROLLED STUDIES
PLACEBO JARDIANCE 10 MG JARDIANCE 25 MG
BASELINE MEAN N 825 830 822
CREATININE (MG/DL) 0.84 0.85 0.85
EGFR (ML/MIN/1.73 M²) 87.3 87.1 87.8
WEEK 12 CHANGE N 771 797 783
CREATININE (MG/DL) 0.00 0.02 0.01
EGFR (ML/MIN/1.73 M²) -0.3 -1.3 -1.4
WEEK 24 CHANGE N 708 769 754
CREATININE (MG/DL) 0.00 0.01 0.01
EGFR (ML/MIN/1.73 M²) -0.3 -0.6 -1.4
MODERATE RENAL IMPAIRMENTA
PLACEBO JARDIANCE 25 MG
BASELINE N 187 -- 187
CREATININE (MG/DL) 1.49 -- 1.46
EGFR (ML/MIN/1.73 M²) 44.3 -- 45.4
WEEK 12 CHANGE N 176 -- 179
CREATININE (MG/DL) 0.01 -- 0.12
EGFR (ML/MIN/1.73 M²) 0.1 -- -3.8
WEEK 24 CHANGE N 170 -- 171
CREATININE (MG/DL) 0.01 -- 0.10
EGFR (ML/MIN/1.73 M²) 0.2 -- -3.2
WEEK 52 CHANGE N 164 -- 162
CREATININE (MG/DL) 0.02 -- 0.11
EGFR (ML/MIN/1.73 M²) -0.3 -- -2.8
ASUBSET OF PATIENTS FROM RENAL IMPAIRMENT STUDY WITH EGFR 30 TO LESS THAN 60 ML/MIN/1.73 M²
HYPOGLYCEMIA
THE INCIDENCE OF HYPOGLYCEMIA BY STUDY IS SHOWN IN TABLE 3. THE INCIDENCE OF HYPOGLYCEMIA INCREASED WHEN JARDIANCE WAS ADMINISTERED WITH INSULIN OR SULFONYLUREA [SEE WARNINGS AND PRECAUTIONS].
TABLE 3 : INCIDENCE OF OVERALLA AND SEVEREB HYPOGLYCEMIC EVENTS IN CONTROLLED CLINICAL STUDIES
MONOTHERAPY (24 WEEKS) PLACEBO
(N=229) JARDIANCE 10 MG
(N=224) JARDIANCE 25 MG
(N=223)
OVERALL (%) 0.4% 0.4% 0.4%
SEVERE (%) 0% 0% 0%
IN COMBINATION WITH METFORMIN (24 WEEKS) PLACEBO + METFORMIN
(N=206) JARDIANCE 10 MG +METFORMIN
(N=217) JARDIANCE 25 MG +METFORMIN
(N=214)
OVERALL (%) 0.5% 1.8% 1.4%
SEVERE (%) 0% 0% 0%
IN COMBINATION WITH METFORMIN + SULFONYLUREA (24 WEEKS) PLACEBO (N=225) JARDIANCE 10 MG + METFORMIN +SULFONYLUREA
(N=224) JARDIANCE 25 MG + METFORMIN +SULFONYLUREA
(N=217)
OVERALL (%) 8.4% 16.1% 11.5%
SEVERE (%) 0% 0% 0%
IN COMBINATION WITH PIOGLITAZONE +/- METFORMIN (24 WEEKS) PLACEBO
(N=165) JARDIANCE 10 MG + PIOGLITAZONE +/- METFORMIN
(N=165) JARDIANCE 25 MG + PIOGLITAZONE +/- METFORMIN
(N=168)
OVERALL (%) 1.8% 1.2% 2.4%
SEVERE (%) 0% 0% 0%
IN COMBINATION WITH INSULIN (18 WEEKSC) PLACEBO
(N=170) JARDIANCE 10 MG
(N=169) JARDIANCE 25 MG
(N=155)
OVERALL (%) 20.6% 19.5% 28.4%
SEVERE (%) 0% 0% 1.3%
AOVERALL HYPOGLYCEMIC EVENTS: PLASMA OR CAPILLARY GLUCOSE OF LESS THAN OR EQUAL TO 70 MG/DL
BSEVERE HYPOGLYCEMIC EVENTS: REQUIRING ASSISTANCE REGARDLESS OF BLOOD GLUCOSE
CINSULIN DOSE COULD NOT BE ADJUSTED DURING THE INITIAL 18 WEEK TREATMENT PERIOD
GENITAL MYCOTIC INFECTIONS
IN THE POOL FIVE PLACEBO-CONTROLLED CLINICAL TRIALS, THE INCIDENCE OF GENITAL MYCOTIC INFECTIONS (E.G., VAGINAL MYCOTIC INFECTION, VAGINAL INFECTION, GENITAL INFECTION FUNGAL, VULVOVAGINAL CANDIDIASIS, AND VULVITIS) WAS INCREASED IN PATIENTS TREATED WITH JARDIANCE COMPARED TO PLACEBO, OCCURRING IN 0.9%, 4.1%. AND 3.7% OF PATIENTS RANDOMIZED TO PLACEBO, JARDIANCE 10 MG, AND JARDIANCE 25 MG, RESPECTIVELY. DISCONTINUATION FROM STUDY DUE TO GENITAL INFECTION OCCURRED IN 0% OF PLACEBO-TREATED PATIENTS AND 0.2% OF PATIENTS TREATED WITH EITHER JARDIANCE 10 OR 25 MG.
GENITAL MYCOTIC INFECTIONS OCCURRED MORE FREQUENTLY IN FEMALE THAN MALE PATIENTS (SEE TABLE 1).
PHIMOSIS OCCURRED MORE FREQUENTLY IN MALE PATIENTS TREATED WITH JARDIANCE 10 MG (LESS THAN 0.1%) AND JARDIANCE 25 MG (0.1%) THAN PLACEBO (0%).
URINARY TRACT INFECTIONS
IN THE POOL FIVE PLACEBO-CONTROLLED CLINICAL TRIALS, THE INCIDENCE OF URINARY TRACT INFECTIONS (E.G., URINARY TRACT INFECTION, ASYMPTOMATIC BACTERIURIA, AND CYSTITIS) WAS INCREASED IN PATIENTS TREATED WITH JARDIANCE COMPARED TO PLACEBO (SEE TABLE 1). PATIENTS WITH A HISTORY OF CHRONIC OR RECURRENT URINARY TRACT INFECTIONS WERE MORE LIKELY TO EXPERIENCE A URINARY TRACT INFECTION. THE RATE OF TREATMENT DISCONTINUATION DUE TO URINARY TRACT INFECTIONS WAS 0.1%, 0.2%, AND 0.1% FOR PLACEBO, JARDIANCE 10 MG, AND JARDIANCE 25 MG, RESPECTIVELY.
URINARY TRACT INFECTIONS OCCURRED MORE FREQUENTLY IN FEMALE PATIENTS. THE INCIDENCE OF URINARY TRACT INFECTIONS IN FEMALE PATIENTS RANDOMIZED TO PLACEBO, JARDIANCE 10 MG, AND JARDIANCE 25 MG WAS 16.6%, 18.4%, AND 17.0%, RESPECTIVELY. THE INCIDENCE OF URINARY TRACT INFECTIONS IN MALE PATIENTS RANDOMIZED TO PLACEBO, JARDIANCE 10 MG, AND JARDIANCE 25 MG WAS 3.2%, 3.6%, AND 4.1%, RESPECTIVELY [SEE WARNINGS AND PRECAUTIONS AND USE IN SPECIFIC POPULATIONS]
LABORATORY TESTS
INCREASE IN LOW-DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C)
DOSE-RELATED INCREASES IN LOW-DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C) WERE OBSERVED IN PATIENTS TREATED WITH JARDIANCE. LDL-C INCREASED BY 2.3%, 4.6%, AND 6.5% IN PATIENTS TREATED WITH PLACEBO, JARDIANCE 10 MG, AND JARDIANCE 25 MG, RESPECTIVELY [SEE WARNINGS AND PRECAUTIONS]. THE RANGE OF MEAN BASELINE LDL-C LEVELS WAS 90.3 TO 90.6 MG/DL ACROSS TREATMENT GROUPS.
INCREASE IN HEMATOCRIT
IN A POOL OF FOUR PLACEBO-CONTROLLED STUDIES, MEDIAN HEMATOCRIT DECREASED BY 1.3% IN PLACEBO AND INCREASED BY 2.8% IN JARDIANCE 10 MG AND 2.8% IN JARDIANCE 25 MG TREATED PATIENTS. AT THE END OF TREATMENT, 0.6%, 2.7%, AND 3.5% OF PATIENTS WITH HEMATOCRITS INITIALLY WITHIN THE REFERENCE RANGE HAD VALUES ABOVE THE UPPER LIMIT OF THE REFERENCE RANGE WITH PLACEBO, JARDIANCE 10 MG, AND JARDIANCE 25 MG, RESPECTIVELY.
READ THE JARDIANCE (EMPAGLIFLOZIN TABLETS) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
IN THE EVENT OF AN OVERDOSE WITH JARDIANCE, CONTACT THE POISON CONTROL CENTER. EMPLOY THE USUAL SUPPORTIVE MEASURES (E.G., REMOVE UNABSORBED MATERIAL FROM THE GASTROINTESTINAL TRACT, EMPLOY CLINICAL MONITORING, AND INSTITUTE SUPPORTIVE TREATMENT) AS DICTATED BY THE PATIENT'S CLINICAL STATUS. REMOVAL OF EMPAGLIFLOZIN BY HEMODIALYSIS HAS NOT BEEN STUDIED.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) IS THE PREDOMINANT TRANSPORTER RESPONSIBLE FOR REABSORPTION OF GLUCOSE FROM THE GLOMERULAR FILTRATE BACK INTO THE CIRCULATION. EMPAGLIFLOZIN IS AN INHIBITOR OF SGLT2. BY INHIBITING SGLT2, EMPAGLIFLOZIN REDUCES RENAL REABSORPTION OF FILTERED GLUCOSE AND LOWERS THE RENAL THRESHOLD FOR GLUCOSE, AND THEREBY INCREASES URINARY GLUCOSE EXCRETION.
PHARMACODYNAMICS
URINARY GLUCOSE EXCRETION
IN PATIENTS WITH TYPE 2 DIABETES, URINARY GLUCOSE EXCRETION INCREASED IMMEDIATELY FOLLOWING A DOSE OF JARDIANCE AND WAS MAINTAINED AT THE END OF A 4-WEEK TREATMENT PERIOD AVERAGING AT APPROXIMATELY 64 GRAMS PER DAY WITH 10 MG EMPAGLIFLOZIN AND 78 GRAMS PER DAY WITH 25 MG JARDIANCE ONCE DAILY [SEE CLINICAL STUDIES].
URINARY VOLUME
IN A 5-DAY STUDY, MEAN 24-HOUR URINE VOLUME INCREASE FROM BASELINE WAS 341 ML ON DAY 1 AND 135 ML ON DAY 5 OF EMPAGLIFLOZIN 25 MG ONCE DAILY TREATMENT.
CARDIAC ELECTROPHYSIOLOGY
IN A RANDOMIZED, PLACEBO-CONTROLLED, ACTIVE-COMPARATOR, CROSSOVER STUDY, 30 HEALTHY SUBJECTS WERE ADMINISTERED A SINGLE ORAL DOSE OF JARDIANCE 25 MG, JARDIANCE 200 MG (8 TIMES THE MAXIMUM DOSE), MOXIFLOXACIN, AND PLACEBO. NO INCREASE IN QTC WAS OBSERVED WITH EITHER 25 MG OR 200 MG EMPAGLIFLOZIN.
PHARMACOKINETICS
ABSORPTION
THE PHARMACOKINETICS OF EMPAGLIFLOZIN HAS BEEN CHARACTERIZED IN HEALTHY VOLUNTEERS AND PATIENTS WITH TYPE 2 DIABETES AND NO CLINICALLY RELEVANT DIFFERENCES WERE NOTED BETWEEN THE TWO POPULATIONS. AFTER ORAL ADMINISTRATION, PEAK PLASMA CONCENTRATIONS OF EMPAGLIFLOZIN WERE REACHED AT 1.5 HOURS POST-DOSE. THEREAFTER, PLASMA CONCENTRATIONS DECLINED IN A BIPHASIC MANNER WITH A RAPID DISTRIBUTION PHASE AND A RELATIVELY SLOW TERMINAL PHASE. THE STEADY STATE MEAN PLASMA AUC AND CMAX WERE 1870 NMOL¡H/L AND 259 NMOL/L, RESPECTIVELY, WITH 10 MG EMPAGLIFLOZIN ONCE DAILY TREATMENT, AND 4740 NMOL¡H/L AND 687 NMOL/L, RESPECTIVELY, WITH 25 MG EMPAGLIFLOZIN ONCE DAILY TREATMENT. SYSTEMIC EXPOSURE OF EMPAGLIFLOZIN INCREASED IN A DOSE-PROPORTIONAL MANNER IN THE THERAPEUTIC DOSE RANGE. THE SINGLE-DOSE AND STEADY-STATE PHARMACOKINETIC PARAMETERS OF EMPAGLIFLOZIN WERE SIMILAR, SUGGESTING LINEAR PHARMACOKINETICS WITH RESPECT TO TIME.
ADMINISTRATION OF 25 MG EMPAGLIFLOZIN AFTER INTAKE OF A HIGH-FAT AND HIGH-CALORIE MEAL RESULTED IN SLIGHTLY LOWER EXPOSURE; AUC DECREASED BY APPROXIMATELY 16% AND CMAX DECREASED BY APPROXIMATELY 37%, COMPARED TO FASTED CONDITION. THE OBSERVED EFFECT OF FOOD ON EMPAGLIFLOZIN PHARMACOKINETICS WAS NOT CONSIDERED CLINICALLY RELEVANT AND EMPAGLIFLOZIN MAY BE ADMINISTERED WITH OR WITHOUT FOOD.
DISTRIBUTION
THE APPARENT STEADY-STATE VOLUME OF DISTRIBUTION WAS ESTIMATED TO BE 73.8 L BASED ON A POPULATION PHARMACOKINETIC ANALYSIS. FOLLOWING ADMINISTRATION OF AN ORAL [14C]-EMPAGLIFLOZIN SOLUTION TO HEALTHY SUBJECTS, THE RED BLOOD CELL PARTITIONING WAS APPROXIMATELY 36.8% AND PLASMA PROTEIN BINDING WAS 86.2%
METABOLISM
NO MAJOR METABOLITES OF EMPAGLIFLOZIN WERE DETECTED IN HUMAN PLASMA AND THE MOST ABUNDANT METABOLITES WERE THREE GLUCURONIDE CONJUGATES (2-O-, 3-O-, AND 6-O-GLUCURONIDE). SYSTEMIC EXPOSURE OF EACH METABOLITE WAS LESS THAN 10% OF TOTAL DRUG-RELATED MATERIAL. IIN VITRO STUDIES SUGGESTED THAT THE PRIMARY ROUTE OF METABOLISM OF EMPAGLIFLOZIN IN HUMANS IS GLUCURONIDATION BY THE URIDINE 5'-DIPHOSPHO-GLUCURONOSYLTRANSFERASES UGT2B7, UGT1A3, UGT1A8, AND UGT1A9.
ELIMINATION
THE APPARENT TERMINAL ELIMINATION HALF-LIFE OF EMPAGLIFLOZIN WAS ESTIMATED TO BE 12.4 H AND APPARENT ORAL CLEARANCE WAS 10.6 L/H BASED ON THE POPULATION PHARMACOKINETIC ANALYSIS. FOLLOWING ONCE-DAILY DOSING, UP TO 22% ACCUMULATION, WITH RESPECT TO PLASMA AUC, WAS OBSERVED AT STEADY-STATE, WHICH WAS CONSISTENT WITH EMPAGLIFLOZIN HALF-LIFE. FOLLOWING ADMINISTRATION OF AN ORAL [14C]-EMPAGLIFLOZIN SOLUTION TO HEALTHY SUBJECTS, APPROXIMATELY 95.6% OF THE DRUG-RELATED RADIOACTIVITY WAS ELIMINATED IN FECES (41.2%) OR URINE (54.4%). THE MAJORITY OF DRUG-RELATED RADIOACTIVITY RECOVERED IN FECES WAS UNCHANGED PARENT DRUG AND APPROXIMATELY HALF OF DRUG-RELATED RADIOACTIVITY EXCRETED IN URINE WAS UNCHANGED PARENT DRUG.
SPECIFIC POPULATIONS
RENAL IMPAIRMENT IN PATIENTS WITH MILD (EGFR: 60 TO LESS THAN 90 ML/MIN/1.73 M²), MODERATE (EGFR: 30 TO LESS THAN 60 ML/MIN/1.73 M²), AND SEVERE (EGFR: LESS THAN 30 ML/MIN/1.73 M²) RENAL IMPAIRMENT AND SUBJECTS WITH KIDNEY FAILURE/END STAGE RENAL DISEASE (ESRD) PATIENTS, AUC OF EMPAGLIFLOZIN INCREASED BY APPROXIMATELY 18%, 20%, 66%, AND 48%, RESPECTIVELY, COMPARED TO SUBJECTS WITH NORMAL RENAL FUNCTION. PEAK PLASMA LEVELS OF EMPAGLIFLOZIN WERE SIMILAR IN SUBJECTS WITH MODERATE RENAL IMPAIRMENT AND KIDNEY FAILURE/ESRD COMPARED TO PATIENTS WITH NORMAL RENAL FUNCTION. PEAK PLASMA LEVELS OF EMPAGLIFLOZIN WERE ROUGHLY 20% HIGHER IN SUBJECTS WITH MILD AND SEVERE RENAL IMPAIRMENT AS COMPARED TO SUBJECTS WITH NORMAL RENAL FUNCTION. POPULATION PHARMACOKINETIC ANALYSIS SHOWED THAT THE APPARENT ORAL CLEARANCE OF EMPAGLIFLOZIN DECREASED, WITH A DECREASE IN EGFR LEADING TO AN INCREASE IN DRUG EXPOSURE. HOWEVER, THE FRACTION OF EMPAGLIFLOZIN THAT WAS EXCRETED UNCHANGED IN URINE, AND URINARY GLUCOSE EXCRETION, DECLINED WITH DECREASE IN EGFR.
HEPATIC IMPAIRMENT
IN SUBJECTS WITH MILD, MODERATE, AND SEVERE HEPATIC IMPAIRMENT ACCORDING TO THE CHILD-PUGH CLASSIFICATION, AUC OF EMPAGLIFLOZIN INCREASED BY APPROXIMATELY 23%, 47%, AND 75%, AND CMAX INCREASED BY APPROXIMATELY 4%, 23%, AND 48%, RESPECTIVELY, COMPARED TO SUBJECTS WITH NORMAL HEPATIC FUNCTION.
EFFECTS OF AGE, BODY MASS INDEX, GENDER, AND RACE
BASED ON THE POPULATION PK ANALYSIS, AGE, BODY MASS INDEX (BMI), GENDER AND RACE (ASIANS VERSUS PRIMARILY WHITES) DO NOT HAVE A CLINICALLY MEANINGFUL EFFECT ON PHARMACOKINETICS OF EMPAGLIFLOZIN [SEE USE IN SPECIFIC POPULATIONS].
PEDIATRIC
STUDIES CHARACTERIZING THE PHARMACOKINETICS OF EMPAGLIFLOZIN IN PEDIATRIC PATIENTS HAVE NOT BEEN PERFORMED.
DRUG INTERACTIONS
IN VITRO ASSESSMENT OF DRUG INTERACTIONS
IIN VITRO DATA SUGGEST THAT THE PRIMARY ROUTE OF METABOLISM OF EMPAGLIFLOZIN IN HUMANS IS GLUCURONIDATION BY THE URIDINE 5'-DIPHOSPHO-GLUCURONOSYLTRANSFERASES UGT2B7, UGT1A3, UGT1A8, AND UGT1A9. EMPAGLIFLOZIN DOES NOT INHIBIT, INACTIVATE, OR INDUCE CYP450 ISOFORMS. EMPAGLIFLOZIN ALSO DOES NOT INHIBIT UGT1A1. THEREFORE, NO EFFECT OF EMPAGLIFLOZIN IS ANTICIPATED ON CONCOMITANTLY ADMINISTERED DRUGS THAT ARE SUBSTRATES OF THE MAJOR CYP450 ISOFORMS OR UGT1A1. THE EFFECT OF UGT INDUCTION (E.G., INDUCTION BY RIFAMPICIN OR ANY OTHER UGT ENZYME INDUCER) ON EMPAGLIFLOZIN EXPOSURE HAS NOT BEEN EVALUATED.
EMPAGLIFLOZIN IS A SUBSTRATE FOR P-GLYCOPROTEIN (P-GP) AND BREAST CANCER RESISTANCE PROTEIN (BCRP), BUT IT DOES NOT INHIBIT THESE EFFLUX TRANSPORTERS AT THERAPEUTIC DOSES. BASED ON IN VITRO STUDIES, EMPAGLIFLOZIN IS CONSIDERED UNLIKELY TO CAUSE INTERACTIONS WITH DRUGS THAT ARE P-GP SUBSTRATES. EMPAGLIFLOZIN IS A SUBSTRATE OF THE HUMAN UPTAKE TRANSPORTERS OAT3, OATP1B1, AND OATP1B3, BUT NOT OAT1 AND OCT2. EMPAGLIFLOZIN DOES NOT INHIBIT ANY OF THESE HUMAN UPTAKE TRANSPORTERS AT CLINICALLY RELEVANT PLASMA CONCENTRATIONS AND, THEREFORE, NO EFFECT OF EMPAGLIFLOZIN IS ANTICIPATED ON CONCOMITANTLY ADMINISTERED DRUGS THAT ARE SUBSTRATES OF THESE UPTAKE TRANSPORTERS.
IN VIVO ASSESSMENT OF DRUG INTERACTIONS
NO DOSE ADJUSTMENT OF JARDIANCE IS RECOMMENDED WHEN COADMINISTERED WITH COMMONLY PRESCRIBED MEDICINAL PRODUCTS BASED ON RESULTS OF THE DESCRIBED PHARMACOKINETIC STUDIES. EMPAGLIFLOZIN PHARMACOKINETICS WERE SIMILAR WITH AND WITHOUT COADMINISTRATION OF METFORMIN, GLIMEPIRIDE, PIOGLITAZONE, SITAGLIPTIN, LINAGLIPTIN, WARFARIN, VERAPAMIL, RAMIPRIL, SIMVASTATIN, HYDROCHLOROTHIAZIDE, AND TORASEMIDE IN HEALTHY VOLUNTEERS (SEE FIGURE 1). THE OBSERVED INCREASES IN OVERALL EXPOSURE (AUC) OF EMPAGLIFLOZIN FOLLOWING COADMINISTRATION WITH GEMFIBROZIL, RIFAMPICIN, OR PROBENECID ARE NOT CLINICALLY RELEVANT. IN SUBJECTS WITH NORMAL RENAL FUNCTION, COADMINISTRATION OF EMPAGLIFLOZIN WITH PROBENECID RESULTED IN A 30% DECREASE IN THE FRACTION OF EMPAGLIFLOZIN EXCRETED IN URINE WITHOUT ANY EFFECT ON 24-HOUR URINARY GLUCOSE EXCRETION. THE RELEVANCE OF THIS OBSERVATION TO PATIENTS WITH RENAL IMPAIRMENT IS UNKNOWN.
FIGURE 1 : EFFECT OF VARIOUS MEDICATIONS ON THE PHARMACOKINETICS OF EMPAGLIFLOZIN AS DISPLAYED AS 90% CONFIDENCE INTERVAL OF GEOMETRIC MEAN AUC AND CMAX RATIOS [REFERENCE LINES INDICATE 100% (80% -125%)]
AEMPAGLIFLOZIN, 50 MG, ONCE DAILY; BEMPAGLIFLOZIN, 25 MG, SINGLE DOSE; CEMPAGLIFLOZIN, 25 MG, ONCE DAILY; DEMPAGLIFLOZIN, 10 MG, SINGLE DOSE
EMPAGLIFLOZIN HAD NO CLINICALLY RELEVANT EFFECT ON THE PHARMACOKINETICS OF METFORMIN, GLIMEPIRIDE, PIOGLITAZONE, SITAGLIPTIN, LINAGLIPTIN, WARFARIN, DIGOXIN, RAMIPRIL, SIMVASTATIN, HYDROCHLOROTHIAZIDE, TORASEMIDE, AND ORAL CONTRACEPTIVES WHEN COADMINISTERED IN HEALTHY VOLUNTEERS (SEE FIGURE 2).
FIGURE 2 : EFFECT OF EMPAGLIFLOZIN ON THE PHARMACOKINETICS OF VARIOUS MEDICATIONS AS DISPLAYED AS 90% CONFIDENCE INTERVAL OF GEOMETRIC MEAN AUC AND CMAX RATIOS [REFERENCE LINES INDICATE 100% (80% -125%)]
AEMPAGLIFLOZIN, 50 MG, ONCE DAILY;BEMPAGLIFLOZIN, 25 MG, ONCE DAILY; CEMPAGLIFLOZIN, 25 MG, SINGLE DOSE; DADMINISTERED AS SIMVASTATIN; EADMINISTERED AS WARFARIN RACEMIC MIXTURE; FADMINISTERED AS MICROGYNONÂŽ; GADMINISTERED AS RAMIPRIL
NONCLINICA TOXICOLOGY
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
CARCINOGENESIS
CARCINOGENESIS WAS EVALUATED IN 2-YEAR STUDIES CONDUCTED IN CD-1 MICE AND WISTAR RATS. EMPAGLIFLOZIN DID NOT INCREASE THE INCIDENCE OF TUMORS IN FEMALE RATS DOSED AT 100, 300, OR 700 MG/KG/DAY (UP TO 72 TIMES THE EXPOSURE FROM THE MAXIMUM CLINICAL DOSE OF 25 MG). IN MALE RATS, HEMANGIOMAS OF THE MESENTERIC LYMPH NODE WERE INCREASED SIGNIFICANTLY AT 700 MG/KG/DAY OR APPROXIMATELY 42 TIMES THE EXPOSURE FROM A 25 MG CLINICAL DOSE. EMPAGLIFLOZIN DID NOT INCREASE THE INCIDENCE OF TUMORS IN FEMALE MICE DOSED AT 100, 300, OR 1000 MG/KG/DAY (UP TO 62 TIMES THE EXPOSURE FROM A 25 MG CLINICAL DOSE). RENAL TUBULE ADENOMAS AND CARCINOMAS WERE OBSERVED IN MALE MICE AT 1000 MG/KG/DAY, WHICH IS APPROXIMATELY 45 TIMES THE EXPOSURE OF THE MAXIMUM CLINICAL DOSE OF 25 MG.
MUTAGENESIS
EMPAGLIFLOZIN WAS NOT MUTAGENIC OR CLASTOGENIC WITH OR WITHOUT METABOLIC ACTIVATION IN THE IN VITRO AMES BACTERIAL MUTAGENICITY ASSAY, THE IN VITRO L5178Y TK+/-MOUSE LYMPHOMA CELL ASSAY, AND AN IN VIVO MICRONUCLEUS ASSAY IN RATS.
IMPAIRMENT OF FERTILITY
EMPAGLIFLOZIN HAD NO EFFECTS ON MATING, FERTILITY OR EARLY EMBRYONIC DEVELOPMENT IN TREATED MALE OR FEMALE RATS UP TO THE HIGH DOSE OF 700 MG/KG/DAY (APPROXIMATELY 155 TIMES THE 25 MG CLINICAL DOSE IN MALES AND FEMALES, RESPECTIVELY).
CLINICAL STUDIES
JARDIANCE HAS BEEN STUDIED AS MONOTHERAPY AND IN COMBINATION WITH METFORMIN, SULFONYLUREA, PIOGLITAZONE, AND INSULIN. JARDIANCE HAS ALSO BEEN STUDIED IN PATIENTS WITH TYPE 2 DIABETES WITH MILD OR MODERATE RENAL IMPAIRMENT.
IN PATIENTS WITH TYPE 2 DIABETES, TREATMENT WITH JARDIANCE REDUCED HEMOGLOBIN A1C (HBA1C), COMPARED TO PLACEBO. THE REDUCTION IN HBA1C FOR JARDIANCE COMPARED WITH PLACEBO WAS OBSERVED ACROSS SUBGROUPS INCLUDING GENDER, RACE, GEOGRAPHIC REGION, BASELINE BMI AND DURATION OF DISEASE.
MONOTHERAPY
A TOTAL OF 986 PATIENTS WITH TYPE 2 DIABETES PARTICIPATED IN A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF JARDIANCE MONOTHERAPY.
TREATMENT-NAĂVE PATIENTS WITH INADEQUATELY CONTROLLED TYPE 2 DIABETES ENTERED AN OPEN-LABEL PLACEBO RUN-IN FOR 2 WEEKS. AT THE END OF THE RUN-IN PERIOD, PATIENTS WHO REMAINED INADEQUATELY CONTROLLED AND HAD AN HBA1C BETWEEN 7 AND 10% WERE RANDOMIZED TO PLACEBO, JARDIANCE 10 MG, JARDIANCE 25 MG, OR A REFERENCE COMPARATOR.
AT WEEK 24, TREATMENT WITH JARDIANCE 10 MG OR 25 MG DAILY PROVIDED STATISTICALLY SIGNIFICANT REDUCTIONS IN HBA1C (P-VALUE < 0.0001), FASTING PLASMA GLUCOSE (FPG), AND BODY WEIGHT COMPARED WITH PLACEBO (SEE TABLE 4 AND FIGURE 3).
TABLE 4 RESULTS AT WEEK 24 FROM A PLACEBO-CONTROLLED MONOTHERAPY STUDY OF JARDIANCE
JARDIANCE 10 MG
N=224 JARDIANCE 25 MG
N=224 PLACEBO
N=228
HBA1C (%)A
BASELINE (MEAN) 7.9 7.9 7.9
CHANGE FROM BASELINE (ADJUSTED MEAN) -0.7 -0.8 0.1
DIFFERENCE FROM PLACEBO (ADJUSTED MEAN) (97.5% CI) -0.7B (-0.9, -0.6) -0.9B (-1.0, -0.7) --
PATIENTS [N (%)] ACHIEVING HBA1C < 7% 72 (35%) 88 (44%) 25 (12%)
FPG (MG/DL)C
BASELINE (MEAN) 153 153 155
CHANGE FROM BASELINE (ADJUSTED MEAN) -19 -25 12
DIFFERENCE FROM PLACEBO (ADJUSTED MEAN) (95% CI) -31 (-37, -26) -36 (-42, -31) --
BODY WEIGHT
BASELINE (MEAN) IN KG 78 78 78
% CHANGE FROM BASELINE (ADJUSTED MEAN) -2.8 -3.2 -0.4
DIFFERENCE FROM PLACEBO (ADJUSTED MEAN) (95% CI) -2.5B (-3.1, -1.9) -2.8B (-3.4, -2.2) --
AMODIFIED INTENT TO TREAT POPULATION. LAST OBSERVATION ON STUDY (LOCF) WAS USED TO IMPUTE MISSING DATA AT WEEK 24. AT WEEK 24, 9.4%, 9.4%, AND 30.7% WAS IMPUTED FOR PATIENTS RANDOMIZED TO JARDIANCE 10 MG, JARDIANCE 25 MG, AND PLACEBO, RESPECTIVELY.
BANCOVA DERIVED P-VALUE < 0.0001 (HBA1C: ANCOVA MODEL INCLUDES BASELINE HBA1C, TREATMENT, RENAL FUNCTION, AND REGION. BODY WEIGHT AND FPG: SAME MODEL USED AS FOR HBA1C BUT ADDITIONALLY INCLUDING BASELINE BODY WEIGHT/BASELINE FPG, RESPECTIVELY.)
CFPG (MG/DL); FOR JARDIANCE 10 MG, N=223, FOR JARDIANCE 25 MG, N=223, AND FOR PLACEBO, N=226
FIGURE 3 : ADJUSTED MEAN HBA1C CHANGE AT EACH TIME POINT (COMPLETERS) AND AT WEEK 24 (MITT POPULATION) -LOCF
AT WEEK 24, THE SYSTOLIC BLOOD PRESSURE WAS STATISTICALLY SIGNIFICANTLY REDUCED COMPARED TO PLACEBO BY -2.6 MMHG (PLACEBO-ADJUSTED, P-VALUE=0.0231) IN PATIENTS RANDOMIZED TO 10 MG OF JARDIANCE AND BY -3.4 MMHG (PLACEBO-CORRECTED, P-VALUE=0.0028) IN PATIENTS RANDOMIZED TO 25 MG OF JARDIANCE.
COMBINATION THERAPY
ADD-ON COMBINATION THERAPY WITH METFORMIN
A TOTAL OF 637 PATIENTS WITH TYPE 2 DIABETES PARTICIPATED IN A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF JARDIANCE IN COMBINATION WITH METFORMIN.
PATIENTS WITH TYPE 2 DIABETES INADEQUATELY CONTROLLED ON AT LEAST 1500 MG OF METFORMIN PER DAY ENTERED AN OPEN-LABEL 2 WEEK PLACEBO RUN-IN. AT THE END OF THE RUN-IN PERIOD, PATIENTS WHO REMAINED INADEQUATELY CONTROLLED AND HAD AN HBA1C BETWEEN 7 AND 10% WERE RANDOMIZED TO PLACEBO, JARDIANCE 10 MG, OR JARDIANCE 25 MG.
AT WEEK 24, TREATMENT WITH JARDIANCE 10 MG OR 25 MG DAILY PROVIDED STATISTICALLY SIGNIFICANT REDUCTIONS IN HBA1C (P-VALUE < 0.0001), FPG, AND BODY WEIGHT COMPARED WITH PLACEBO (SEE TABLE 5).
TABLE 5 : RESULTS AT WEEK 24 FROM A PLACEBO-CONTROLLED STUDY FOR JARDIANCE USED IN COMBINATION WITH METFORMIN
JARDIANCE 10 MG + METFORMIN
N=217 JARDIANCE 25 MG + METFORMIN
N=213 PLACEBO + METFORMIN
N=207
HBA1C (%)A
BASELINE (MEAN) 7.9 7.9 7.9
CHANGE FROM BASELINE (ADJUSTED MEAN) -0.7 -0.8 -0.1
DIFFERENCE FROM PLACEBO + METFORMIN (ADJUSTED MEAN) (95% CI) -0.6B (-0.7, -0.4) -0.6B (-0.8, -0.5) --
PATIENTS [N (%)] ACHIEVING HBA1C < 7% 75 (38%) 74 (39%) 23 (13%)
FPG (MG/DL)C
BASELINE (MEAN) 155 149 156
CHANGE FROM BASELINE (ADJUSTED MEAN) -20 -22 6
DIFFERENCE FROM PLACEBO + METFORMIN (ADJUSTED MEAN) -26 -29 --
BODY WEIGHT
BASELINE MEAN IN KG 82 82 80
% CHANGE FROM BASELINE (ADJUSTED MEAN) -2.5 -2.9 -0.5
DIFFERENCE FROM PLACEBO (ADJUSTED MEAN) (95%CI) -2.0B (-2.6, -1.4) -2.5B (-3.1, -1.9) --
AMODIFIED INTENT TO TREAT POPULATION. LAST OBSERVATION ON STUDY (LOCF) WAS USED TO IMPUTE MISSING DATA AT WEEK 24. AT WEEK 24, 9.7%, 14.1%, AND 24.6% WAS IMPUTED FOR PATIENTS RANDOMIZED TO JARDIANCE 10 MG, JARDIANCE 25 MG, AND PLACEBO, RESPECTIVELY.
BANCOVA P-VALUE < 0.0001 (HBA1C: ANCOVA MODEL INCLUDES BASELINE HBA1C, TREATMENT, RENAL FUNCTION, AND REGION. BODY WEIGHT AND FPG: SAME MODEL USED AS FOR HBA1C BUT ADDITIONALLY INCLUDING BASELINE BODY WEIGHT/BASELINE FPG, RESPECTIVELY.)
CFPG (MG/DL); FOR JARDIANCE 10 MG, N=216, FOR JARDIANCE 25 MG, N=213, AND FOR PLACEBO, N=207
AT WEEK 24, THE SYSTOLIC BLOOD PRESSURE WAS STATISTICALLY SIGNIFICANTLY REDUCED COMPARED TO PLACEBO BY -4.1 MMHG (PLACEBO-CORRECTED, P-VALUE < 0.0001) FOR JARDIANCE 10 MG AND -4.8 MMHG (PLACEBO-CORRECTED, P-VALUE < 0.0001) FOR JARDIANCE 25 MG.
ADD-ON COMBINATION THERAPY WITH METFORMIN AND SULFONYLUREA
A TOTAL OF 666 PATIENTS WITH TYPE 2 DIABETES PARTICIPATED IN A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF JARDIANCE IN COMBINATION WITH METFORMIN PLUS A SULFONYLUREA.
PATIENTS WITH INADEQUATELY CONTROLLED TYPE 2 DIABETES ON AT LEAST 1500 MG PER DAY OF METFORMIN AND ON A SULFONYLUREA, ENTERED A 2 WEEK OPEN-LABEL PLACEBO RUN-IN. AT THE END OF THE RUN-IN, PATIENTS WHO REMAINED INADEQUATELY CONTROLLED AND HAD AN HBA1C BETWEEN 7% AND 10% WERE RANDOMIZED TO PLACEBO, JARDIANCE 10 MG, OR JARDIANCE 25 MG.
TREATMENT WITH JARDIANCE 10 MG OR 25 MG DAILY PROVIDED STATISTICALLY SIGNIFICANT REDUCTIONS IN HBA1C (PVALUE < 0.0001), FPG, AND BODY WEIGHT COMPARED WITH PLACEBO (SEE TABLE 6).
TABLE 6 : RESULTS AT WEEK 24 FROM A PLACEBO-CONTROLLED STUDY FOR JARDIANCE IN COMBINATION WITH METFORMIN AND SULFONYLUREA
JARDIANCE 10 MG + METFORMIN + SU
N=225 JARDIANCE 25 MG + METFORMIN + SU
N=216 PLACEBO + METFORMIN + SU
N=225
HBALC (%)A
BASELINE (MEAN) 8.1 8.1 8.2
CHANGE FROM BASELINE (ADJUSTED MEAN) -0.8 -0.8 -0.2
DIFFERENCE FROM PLACEBO (ADJUSTED MEAN) (95% CI) -0.6B (-0.8, -0.5) -0.6B (-0.7, -0.4) --
PATIENTS [N (%)] ACHIEVING HBA1C < 7% 55 (26%) 65 (32%) 20 (9%)
FPG (MG/DL)C
BASELINE (MEAN) 151 156 152
CHANGE FROM BASELINE (ADJUSTED MEAN) -23 -23 6
DIFFERENCE FROM PLACEBO (ADJUSTED MEAN) -29 -29 --
BODY WEIGHT
BASELINE MEAN IN KG 77 78 76
% CHANGE FROM BASELINE (ADJUSTED MEAN) -2.9 -3.2 -0.5
DIFFERENCE FROM PLACEBO (ADJUSTED MEAN) (95% CI) -2.4B (-3.0, -1.8) -2.7B (-3.3, -2.1) --
AMODIFIED INTENT TO TREAT POPULATION. LAST OBSERVATION ON STUDY (LOCF) WAS USED TO IMPUTE MISSING DATA AT WEEK 24. AT WEEK 24, 17.8%, 16.7%, AND 25.3% WAS IMPUTED FOR PATIENTS RANDOMIZED TO JARDIANCE 10 MG, JARDIANCE 25 MG, AND PLACEBO, RESPECTIVELY.
BANCOVA P-VALUE < 0.0001 (HBA1C: ANCOVA MODEL INCLUDES BASELINE HBA1C, TREATMENT, RENAL FUNCTION, AND REGION. BODY WEIGHT AND FPG: SAME MODEL USED AS FOR HBA1C BUT ADDITIONALLY INCLUDING BASELINE BODY WEIGHT/BASELINE FPG, RESPECTIVELY.)
CFPG (MG/DL); FOR JARDIANCE 10 MG, N=225, FOR JARDIANCE 25 MG, N=215, FOR PLACEBO, N=224
ACTIVE-CONTROLLED STUDY VERSUS GLIMEPIRIDE IN COMBINATION WITH METFORMIN
THE EFFICACY OF JARDIANCE WAS EVALUATED IN A DOUBLE-BLIND, GLIMEPIRIDE-CONTROLLED, STUDY IN 1545 PATIENTS WITH TYPE 2 DIABETES WITH INSUFFICIENT GLYCEMIC CONTROL DESPITE METFORMIN THERAPY.
PATIENTS WITH INADEQUATE GLYCEMIC CONTROL AND AN HBA1C BETWEEN 7% AND 10% AFTER A 2-WEEK RUN-IN PERIOD WERE RANDOMIZED TO GLIMEPIRIDE OR JARDIANCE 25 MG.
AT WEEK 52, JARDIANCE 25 MG AND GLIMEPIRIDE LOWERED HBA1C AND FPG (SEE TABLE 7, FIGURE 4). THE DIFFERENCE IN OBSERVED EFFECT SIZE BETWEEN JARDIANCE 25 MG AND GLIMEPIRIDE EXCLUDED THE PRE-SPECIFIED NON-INFERIORITY MARGIN OF 0.3%. THE MEAN DAILY DOSE OF GLIMEPIRIDE WAS 2.7 MG AND THE MAXIMAL APPROVED DOSE IN THE UNITED STATES IS 8 MG PER DAY.
TABLE 7 : RESULTS AT WEEK 52 FROM AN ACTIVE-CONTROLLED STUDY COMPARING JARDIANCE TO GLIMEPIRIDE AS ADD-ON THERAPY IN PATIENTS INADEQUATELY CONTROLLED ON METFORMIN
JARDIANCE 25 MG + METFORMIN
N=765 GLIMEPIRIDE + METFORMIN
N=780
HBA1C (%)A
BASELINE (MEAN) 7.9 7.9
CHANGE FROM BASELINE (ADJUSTED MEAN) -0.7 -0.7
DIFFERENCE FROM GLIMEPIRIDE (ADJUSTED MEAN) (97.5% CI) -0.07B (-0.15, 0.01) --
FPG (MG/DL)D
BASELINE (MEAN) 150 150
CHANGE FROM BASELINE (ADJUSTED MEAN) -19 -9
BODY WEIGHT
BASELINE MEAN IN KG 82.5 83
% CHANGE FROM BASELINE (ADJUSTED MEAN) -3.9 2.0
DIFFERENCE FROM COMPARATOR (ADJUSTED MEAN) (95% CI) -5.9C (-6.3, -5.5) --
AMODIFIED INTENT TO TREAT POPULATION. LAST OBSERVATION ON STUDY (LOCF) WAS USED TO IMPUTE DATA MISSING AT WEEK 52. AT WEEK 52 DATA WAS IMPUTED FOR 15.3% AND 21.9% OF PATIENTS RANDOMIZED TO JARDIANCE 25 MG AND GLIMEPIRIDE, RESPECTIVELY.
BNON-INFERIOR, ANCOVA MODEL P-VALUE < 0.0001 (HBA1C: ANCOVA MODEL INCLUDES BASELINE HBA1C, TREATMENT, RENAL FUNCTION, AND REGION)
CANCOVA P-VALUE < 0.0001 (BODY WEIGHT AND FPG: SAME MODEL USED AS FOR HBA1C BUT ADDITIONALLY INCLUDING BASELINE BODY WEIGHT/BASELINE FPG, RESPECTIVELY.)
DFPG (MG/DL); FOR JARDIANCE 25 MG, N=764, FOR PLACEBO, N=779
FIGURE 4 : ADJUSTED MEAN HBA1C CHANGE AT EACH TIME POINT (COMPLETERS) AND AT WEEK 52 (MITT POPULATION) -LOCF
AT WEEK 52, THE ADJUSTED MEAN CHANGE FROM BASELINE IN SYSTOLIC BLOOD PRESSURE WAS -3.6 MMHG, COMPARED TO 2.2 MMHG FOR GLIMEPIRIDE. THE DIFFERENCES BETWEEN TREATMENT GROUPS FOR SYSTOLIC BLOOD PRESSURE WAS STATISTICALLY SIGNIFICANT (P-VALUE < 0.0001).
ADD-ON COMBINATION THERAPY WITH PIOGLITAZONE WITH OR WITHOUT METFORMIN
A TOTAL OF 498 PATIENTS WITH TYPE 2 DIABETES PARTICIPATED IN A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF JARDIANCE IN COMBINATION WITH PIOGLITAZONE, WITH OR WITHOUT METFORMIN.
PATIENTS WITH INADEQUATELY CONTROLLED TYPE 2 DIABETES ON METFORMIN AT A DOSE OF AT LEAST 1500 MG PER DAY AND PIOGLITAZONE AT A DOSE OF AT LEAST 30 MG PER DAY WERE PLACED INTO AN OPEN-LABEL PLACEBO RUN-IN FOR 2 WEEKS. PATIENTS WITH INADEQUATE GLYCEMIC CONTROL AND AN HBA1C BETWEEN 7% AND 10% AFTER THE RUN-IN PERIOD WERE RANDOMIZED TO PLACEBO, JARDIANCE 10 MG, OR JARDIANCE 25 MG.
TREATMENT WITH JARDIANCE 10 MG OR 25 MG DAILY RESULTED IN STATISTICALLY SIGNIFICANT REDUCTIONS IN HBA1C (PVALUE < 0.0001), FPG, AND BODY WEIGHT COMPARED WITH PLACEBO (SEE TABLE 8).
TABLE 8: RESULTS OF PLACEBO-CONTROLLED STUDY FOR JARDIANCE IN COMBINATION THERAPY WITH PIOGLITAZONE
JARDIANCE 10 MG + PIOGLITAZONE N=165 JARDIANCE 25 MG + PIOGLITAZONE N=168 PLACEBO + PIOGLITAZONE N=165
HBA1C (%)A
BASELINE (MEAN) 8.1 8.1 8.2
CHANGE FROM BASELINE (ADJUSTED MEAN) -0.6 -0.7 -0.1
DIFFERENCE FROM PLACEBO + PIOGLITAZONE (ADJUSTED MEAN) (95% CI) -0.5B (-0.7, -0.3) -0.6B (-0.8, -0.4) --
PATIENTS [N (%)] ACHIEVING HBA1C < 7% 36 (24%) 48 (30%) 12 (8%)
FPG (MG/DL)C
BASELINE (MEAN) 152 152 152
CHANGE FROM BASELINE (ADJUSTED MEAN) -17 -22 7
DIFFERENCE FROM PLACEBO + PIOGLITAZONE (ADJUSTED MEAN) (97.5% CI) -23B (-31.8, -15.2) -28B (-36.7, -20.2) --
BODY WEIGHT
BASELINE MEAN IN KG 78 79 78
% CHANGE FROM BASELINE (ADJUSTED MEAN) -2.0 -1.8 -0.6
DIFFERENCE FROM PLACEBO (ADJUSTED MEAN) (95% CI) -2.6B (-3.4, -1.8) -2.4B (-3.2, -1.6) --
AMODIFIED INTENT TO TREAT POPULATION. LAST OBSERVATION ON STUDY (LOCF) WAS USED TO IMPUTE MISSING DATA AT WEEK 24. AT WEEK 24, 10.9%, 8.3% AND 20.6% WAS IMPUTED FOR PATIENTS RANDOMIZED TO JARDIANCE 10 MG, JARDIANCE 25 MG, AND PLACEBO RESPECTIVELY.
BANCOVA P-VALUE < 0.0001 (HBA1C: ANCOVA MODEL INCLUDES BASELINE HBA1C, TREATMENT, RENAL FUNCTION, AND BACKGROUND MEDICATION. BODY WEIGHT AND FPG: SAME MODEL USED AS FOR HBA1C BUT ADDITIONALLY INCLUDING BASELINE BODY WEIGHT/BASELINE FPG, RESPECTIVELY.) CFPG (MG/DL); FOR JARDIANCE 10 MG, N=163
ADD-ON COMBINATION WITH INSULIN WITH OR WITHOUT METFORMIN AND/OR SULFONYLUREAS
A TOTAL OF 494 PATIENTS WITH TYPE 2 DIABETES INADEQUATELY CONTROLLED ON INSULIN, OR INSULIN IN COMBINATION WITH ORAL DRUGS PARTICIPATED IN A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY OF JARDIANCE AS ADD-ON THERAPY TO INSULIN OVER 78 WEEKS.
PATIENTS ENTERED A 2-WEEK PLACEBO RUN-IN PERIOD ON BASAL INSULIN (E.G., INSULIN GLARGINE, INSULIN DETEMIR, OR NPH INSULIN) WITH OR WITHOUT METFORMIN AND/OR SULFONYLUREA BACKGROUND THERAPY. FOLLOWING THE RUN-IN PERIOD, PATIENTS WITH INADEQUATE GLYCEMIC CONTROL WERE RANDOMIZED TO THE ADDITION OF JARDIANCE 10 MG, JARDIANCE 25 MG, OR PLACEBO. PATIENTS WERE MAINTAINED ON A STABLE DOSE OF INSULIN PRIOR TO ENROLLMENT, DURING THE RUN-IN PERIOD, AND DURING THE FIRST 18 WEEKS OF TREATMENT. FOR THE REMAINING 60 WEEKS, INSULIN COULD BE ADJUSTED. THE MEAN TOTAL DAILY INSULIN DOSE AT BASELINE FOR JARDIANCE 10 MG, 25 MG, AND PLACEBO WAS 45 IU, 48 IU, AND 48 IU, RESPECTIVELY.
JARDIANCE USED IN COMBINATION WITH INSULIN (WITH OR WITHOUT METFORMIN AND/OR SULFONYLUREA) PROVIDED STATISTICALLY SIGNIFICANT REDUCTIONS IN HBA1C AND FPG COMPARED TO PLACEBO AFTER BOTH 18 AND 78 WEEKS OF TREATMENT (SEE TABLE 9). JARDIANCE 10 MG OR 25 MG DAILY ALSO RESULTED IN STATISTICALLY SIGNIFICANTLY GREATER PERCENT BODY WEIGHT REDUCTION COMPARED TO PLACEBO.
TABLE 9 : RESULTS AT WEEK 18 AND 78 FOR A PLACEBO-CONTROLLED STUDY FOR JARDIANCE IN COMBINATION WITH INSULIN
RENAL IMPAIRMENT
A TOTAL OF 738 PATIENTS WITH TYPE 2 DIABETES AND A BASELINE EGFR LESS THAN 90 ML/MIN/1.73 M² PARTICIPATED IN A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP TO EVALUATE THE EFFICACY AND SAFETY OF JARDIANCE IN PATIENTS WITH TYPE 2 DIABETES AND RENAL IMPAIRMENT. THE TRIAL POPULATION COMPRISED OF 290 PATIENTS WITH MILD RENAL IMPAIRMENT (EGFR 60 TO LESS THAN 90 ML/MIN/1.73 M²), 374 PATIENTS WITH MODERATE RENAL IMPAIRMENT (EGFR 30 TO LESS THAN 60 ML/MIN/1.73 M²), AND 74 WITH SEVERE RENAL IMPAIRMENT (EGFR LESS THAN 30 ML/MIN/1.73 M²). A TOTAL OF 194 PATIENTS WITH MODERATE RENAL IMPAIRMENT HAD A BASELINE EGFR OF 30 TO LESS THAN 45 ML/MIN/1.73 M² AND 180 PATIENTS A BASELINE EGFR OF 45 TO LESS THAN 60 ML/MIN/1.73 M² .
AT WEEK 24, JARDIANCE 25 MG PROVIDED STATISTICALLY SIGNIFICANT REDUCTION IN HBA1C RELATIVE TO PLACEBO IN PATIENTS WITH MILD TO MODERATE RENAL IMPAIRMENT (SEE TABLE 10). A STATISTICALLY SIGNIFICANT REDUCTION RELATIVE TO PLACEBO WAS ALSO OBSERVED WITH JARDIANCE 25 MG IN PATIENTS WITH EITHER MILD [-0.7 (95% CI: -0.9, -0.5)] OR MODERATE [-0.4 (95% CI: -0.6, -0.3)] RENAL IMPAIRMENT AND WITH JARDIANCE 10 MG IN PATIENTS WITH MILD [-0.5 (95% CI: -0.7, -0.3)] RENAL IMPAIRMENT.
THE GLUCOSE LOWERING EFFICACY OF JARDIANCE 25 MG DECREASED WITH DECREASING LEVEL OF RENAL FUNCTION IN THE MILD TO MODERATE RANGE. LEAST SQUARE MEAN HB1AC CHANGES AT 24 WEEKS WERE -0.6%, -0.5%, AND -0.2% FOR THOSE WITH A BASELINE EGFR OF 60 TO LESS THAN 90 ML/MIN/1.73 M², 45 TO LESS THAN 60 ML/MIN/1.73 M², AND 30 TO LESS THAN 45 ML/MIN/1.73 M², RESPECTIVELY [SEE DOSAGE AND ADMINISTRATION AND USE IN SPECIFIC POPULATIONS]. FOR PLACEBO, LEAST SQUARE MEAN HBA1C CHANGES AT 24 WEEKS WERE 0.1%, -0.1%, AND 0.2% FOR PATIENTS WITH A BASELINE EGFR OF 60 TO LESS THAN 90 ML/MIN/1.73 M², 45 TO LESS THAN 60 ML/MIN/1.73 M², AND 30 TO LESS THAN 45 ML/MIN/1.73 M², RESPECTIVELY.
TABLE 10 : RESULTS AT WEEK 24 (LOCF) OF PLACEBO-CONTROLLED STUDY FOR JARDIANCE IN PATIENTS WITH TYPE 2 DIABETES AND RENAL IMPAIRMENT
MILD AND MODERATE IMPAIRMENTB
JARDIANCE 25 MG
HBA1C
NUMBER OF PATIENTS N=284
COMPARISON VS PLACEBO (ADJUSTED MEAN) (95% CI) -0.5A (-0.6, -0.4)
AP-VALUE < 0.0001 (HBA1C: ANCOVA MODEL INCLUDES BASELINE HBA1C, TREATMENT, RENAL FUNCTION, AND BACKGROUND MEDICATION)
BEGFR 30 TO LESS THAN 90 ML/MIN/1.73 M²-MODIFIED INTENT TO TREAT POPULATION. LAST OBSERVATION ON STUDY (LOCF) WAS USED TO IMPUTE MISSING DATA AT WEEK 24. AT WEEK 24, 24.6% AND 26.2% WAS IMPUTED FOR PATIENTS RANDOMIZED TO JARDIANCE 25 MG AND PLACEBO, RESPECTIVELY.
FOR PATIENTS WITH SEVERE RENAL IMPAIRMENT, THE ANALYSES OF CHANGES IN HBA1C AND FPG SHOWED NO DISCERNIBLE TREATMENT EFFECT OF JARDIANCE 25 MG COMPARED TO PLACEBO [SEE DOSAGE AND ADMINISTRATION AND USE IN SPECIFIC POPULATIONS].