DRUG DESCRIPTION
INVOKANA (CANAGLIFLOZIN) CONTAINS CANAGLIFLOZIN, AN INHIBITOR OF SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2), THE TRANSPORTER RESPONSIBLE FOR REABSORBING THE MAJORITY OF GLUCOSE FILTERED BY THE KIDNEY. CANAGLIFLOZIN, THE ACTIVE INGREDIENT OF INVOKANA, IS CHEMICALLY KNOWN AS (1S)-1,5-ANHYDRO-1-[3-[[5-(4-FLUOROPHENYL)-2-THIENYL]METHYL]-4-METHYLPHENYL]-D-GLUCITOL HEMIHYDRATE AND ITS MOLECULAR FORMULA AND WEIGHT ARE C24H25FO5Sā¢Ā½ H2O AND 453.53, RESPECTIVELY. THE STRUCTURAL FORMULA FOR CANAGLIFLOZIN IS:
CANAGLIFLOZIN IS PRACTICALLY INSOLUBLE IN AQUEOUS MEDIA FROM PH 1.1 TO 12.9.
INVOKANA IS SUPPLIED AS FILM-COATED TABLETS FOR ORAL ADMINISTRATION, CONTAINING 102 AND 306 MG OF CANAGLIFLOZIN IN EACH TABLET STRENGTH, CORRESPONDING TO 100 MG AND 300 MG OF CANAGLIFLOZIN (ANHYDROUS), RESPECTIVELY.
INACTIVE INGREDIENTS OF THE CORE TABLET ARE CROSCARMELLOSE SODIUM, HYDROXYPROPYL CELLULOSE, LACTOSE ANHYDROUS, MAGNESIUM STEARATE, AND MICROCRYSTALLINE CELLULOSE. THE MAGNESIUM STEARATE IS VEGETABLE-SOURCED. THE TABLETS ARE FINISHED WITH A COMMERCIALLY AVAILABLE FILM-COATING CONSISTING OF THE FOLLOWING EXCIPIENTS: POLYVINYL ALCOHOL (PARTIALLY HYDROLYZED), TITANIUM DIOXIDE, MACROGOL/PEG, TALC, AND IRON OXIDE YELLOW, E172 (100 MG TABLET ONLY).
INDICATIONS
INVOKANAā¢ (CANAGLIFLOZIN) 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
INVOKANA IS NOT RECOMMENDED IN PATIENTS WITH TYPE 1 DIABETES MELLITUS OR FOR THE TREATMENT OF DIABETIC KETOACIDOSIS.
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSAGE
THE RECOMMENDED STARTING DOSE OF INVOKANA (CANAGLIFLOZIN) IS 100 MG ONCE DAILY, TAKEN BEFORE THE FIRST MEAL OF THE DAY. IN PATIENTS TOLERATING INVOKANA 100 MG ONCE DAILY WHO HAVE AN EGFR OF 60 ML/MIN/1.73 MĀ² OR GREATER AND REQUIRE ADDITIONAL GLYCEMIC CONTROL, THE DOSE CAN BE INCREASED TO 300 MG ONCE DAILY [SEE WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY, AND PATIENT INFORMATION].
IN PATIENTS WITH VOLUME DEPLETION, CORRECTING THIS CONDITION PRIOR TO INITIATION OF INVOKANA IS RECOMMENDED [SEE WARNINGS AND PRECAUTIONS, USE IN SPECIFIC POPULATIONS, AND PATIENT INFORMATION].
PATIENTS WITH RENAL IMPAIRMENT
NO DOSE ADJUSTMENT IS NEEDED IN PATIENTS WITH MILD RENAL IMPAIRMENT (EGFR OF 60 ML/MIN/1.73 MĀ² OR GREATER).
THE DOSE OF INVOKANA IS LIMITED TO 100 MG ONCE DAILY IN PATIENTS WITH MODERATE RENAL IMPAIRMENT WITH AN EGFR OF 45 TO LESS THAN 60 ML/MIN/1.73 MĀ².
INVOKANA SHOULD NOT BE INITIATED IN PATIENTS WITH AN EGFR LESS THAN 45 ML/MIN/1.73 MĀ².
ASSESSMENT OF RENAL FUNCTION IS RECOMMENDED PRIOR TO INITIATION OF INVOKANA THERAPY AND PERIODICALLY THEREAFTER. INVOKANA SHOULD BE DISCONTINUED WHEN EGFR IS PERSISTENTLY LESS THAN 45 ML/MIN/1.73 MĀ² [SEE WARNINGS AND PRECAUTIONS AND USE IN SPECIFIC POPULATIONS].
CONCOMITANT USE WITH UDP-GLUCURONOSYL TRANSFERASE (UGT) ENZYME INDUCERS
IF AN INDUCER OF UGTS (E.G., RIFAMPIN, PHENYTOIN, PHENOBARBITAL, RITONAVIR) IS CO-ADMINISTERED WITH INVOKANA, CONSIDER INCREASING THE DOSAGE TO 300 MG ONCE DAILY IN PATIENTS CURRENTLY TOLERATING INVOKANA 100 MG ONCE DAILY WHO HAVE AN EGFR OF 60 ML/MIN/1.73 MĀ² OR GREATER AND REQUIRE ADDITIONAL GLYCEMIC CONTROL [SEE DRUG INTERACTIONS].
CONSIDER ANOTHER ANTIHYPERGLYCEMIC AGENT IN PATIENTS WITH AN EGFR OF 45 TO LESS THAN 60 ML/MIN/1.73 MĀ² RECEIVING CONCURRENT THERAPY WITH A UGT INDUCER.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
INVOKANA 100 MG TABLETS ARE YELLOW, CAPSULE-SHAPED, FILM-COATED TABLETS WITH āCFZā ON ONE SIDE AND ā100ā ON THE OTHER SIDE.
INVOKANA 300 MG TABLETS ARE WHITE, CAPSULE-SHAPED, FILM-COATED TABLETS WITH āCFZā ON ONE SIDE AND ā300ā ON THE OTHER SIDE.
STORAGE AND HANDLING
INVOKANA (CANAGLIFLOZIN) TABLETS ARE AVAILABLE IN THE STRENGTHS AND PACKAGES LISTED BELOW:
100 MG TABLETS ARE YELLOW, CAPSULE-SHAPED, FILM-COATED TABLETS WITH āCFZā ON ONE SIDE AND ā100ā ON THE OTHER SIDE.
NDC 50458-140-30 BOTTLE OF 30
NDC 50458-140-90 BOTTLE OF 90
NDC 50458-140-50 BOTTLE OF 500
NDC 50458-140-10 BLISTER PACKAGE CONTAINING 100 TABLETS (10 BLISTER CARDS CONTAINING 10 TABLETS EACH)
300 MG TABLETS ARE WHITE, CAPSULE-SHAPED, FILM-COATED TABLETS WITH āCFZā ON ONE SIDE AND ā300ā ON THE OTHER SIDE.
NDC 50458-141-30 BOTTLE OF 30
NDC 50458-141-90 BOTTLE OF 90
NDC 50458-141-50 BOTTLE OF 500
NDC 50458-141-10 BLISTER PACKAGE CONTAINING 100 TABLETS (10 BLISTER CARDS CONTAINING 10 TABLETS EACH)
STORAGE
STORE AT 25Ā°C (77Ā°F); EXCURSIONS PERMITTED TO 15 TO 30Ā°C (59 TO 86Ā°F).
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]
HYPERKALEMIA [SEE WARNINGS AND PRECAUTIONS]
HYPOGLYCEMIA WITH CONCOMITANT USE WITH INSULIN AND INSULIN SECRETAGOGUES [SEE WARNINGS AND PRECAUTIONS]
GENITAL MYCOTIC INFECTIONS [SEE WARNINGS AND PRECAUTIONS]
HYPERSENSITIVITY REACTIONS [SEE WARNINGS AND PRECAUTIONS]
INCREASES IN LOW-DENSITY LIPOPROTEIN (LDL-C) [SEE WARNINGS AND PRECAUTIONS]
CLINICAL STUDIES 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 THE RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REFLECT THE RATES OBSERVED IN CLINICAL PRACTICE.
POOL OF PLACEBO-CONTROLLED TRIALS
THE DATA IN TABLE 1 IS DERIVED FROM FOUR 26-WEEK PLACEBO-CONTROLLED TRIALS. IN ONE TRIAL INVOKANA WAS USED AS MONOTHERAPY AND IN THREE TRIALS INVOKANA WAS USED AS ADD-ON THERAPY [SEE CLINICAL STUDIES]. THESE DATA REFLECT EXPOSURE OF 1667 PATIENTS TO INVOKANA AND A MEAN DURATION OF EXPOSURE TO INVOKANA OF 24 WEEKS. PATIENTS RECEIVED INVOKANA 100 MG (N=833), INVOKANA 300 MG (N=834) OR PLACEBO (N=646) ONCE DAILY. THE MEAN AGE OF THE POPULATION WAS 56 YEARS AND 2% WERE OLDER THAN 75 YEARS OF AGE. FIFTY PERCENT (50%) OF THE POPULATION WAS MALE AND 72% WERE CAUCASIAN, 12% WERE ASIAN, AND 5% WERE BLACK OR AFRICAN AMERICAN. AT BASELINE THE POPULATION HAD DIABETES FOR AN AVERAGE OF 7.3 YEARS, HAD A MEAN HBA1C OF 8.0% AND 20% HAD ESTABLISHED MICROVASCULAR COMPLICATIONS OF DIABETES. BASELINE RENAL FUNCTION WAS NORMAL OR MILDLY IMPAIRED (MEAN EGFR 88 ML/MIN/1.73 MĀ²).
TABLE 1 SHOWS COMMON ADVERSE REACTIONS ASSOCIATED WITH THE USE OF INVOKANA. THESE ADVERSE REACTIONS WERE NOT PRESENT AT BASELINE, OCCURRED MORE COMMONLY ON INVOKANA THAN ON PLACEBO, AND OCCURRED IN AT LEAST 2% OF PATIENTS TREATED WITH EITHER INVOKANA 100 MG OR INVOKANA 300 MG.
TABLE 1: ADVERSE REACTIONS FROM POOL OF FOUR 26-WEEK PLACEBO-CONTROLLED STUDIES REPORTED IN = 2% OF INVOKANA-TREATED PATIENTS*
ADVERSE REACTION
PLACEBO
N=646
INVOKANA 100 MG
N=833
INVOKANA 300 MG
N=834
FEMALE GENITAL MYCOTIC INFECTIONSā
3.2%
10.4%
11.4%
URINARY TRACT INFECTIONSā
4.0%
5.9%
4.3%
INCREASED URINATIONĀ§
0.8%
5.3%
4.6%
MALE GENITAL MYCOTIC INFECTIONSĀ¶
0.6%
4.2%
3.7%
VULVOVAGINAL PRURITUS
0.0%
1.6%
3.0%
THIRST#
0.2%
2.8%
2.3%
CONSTIPATION
0.9%
1.8%
2.3%
NAUSEA
1.5%
2.2%
2.3%
POOL OF PLACEBO- AND ACTIVE-CONTROLLED TRIALS
THE OCCURRENCE OF ADVERSE REACTIONS WAS ALSO EVALUATED IN A LARGER POOL OF PATIENTS PARTICIPATING IN PLACEBO- AND ACTIVE-CONTROLLED TRIALS.
THE DATA COMBINED EIGHT CLINICAL TRIALS [SEE CLINICAL STUDIES] AND REFLECT EXPOSURE OF 6177 PATIENTS TO INVOKANA. THE MEAN DURATION OF EXPOSURE TO INVOKANA WAS 38 WEEKS WITH 1832 INDIVIDUALS EXPOSED TO INVOKANA FOR GREATER THAN 50 WEEKS. PATIENTS RECEIVED INVOKANA 100 MG (N=3092), INVOKANA 300 MG (N=3085) OR COMPARATOR (N=3262) ONCE DAILY. THE MEAN AGE OF THE POPULATION WAS 60 YEARS AND 5% WERE OLDER THAN 75 YEARS OF AGE. FIFTY-EIGHT PERCENT (58%) OF THE POPULATION WAS MALE AND 73% WERE CAUCASIAN, 16% WERE ASIAN, AND 4% WERE BLACK OR AFRICAN AMERICAN. AT BASELINE, THE POPULATION HAD DIABETES FOR AN AVERAGE OF 11 YEARS, HAD A MEAN HBA1C OF 8.0% AND 33% HAD ESTABLISHED MICROVASCULAR COMPLICATIONS OF DIABETES. BASELINE RENAL FUNCTION WAS NORMAL OR MILDLY IMPAIRED (MEAN EGFR 81 ML/MIN/1.73 MĀ²).
THE TYPES AND FREQUENCY OF COMMON ADVERSE REACTIONS OBSERVED IN THE POOL OF EIGHT CLINICAL TRIALS WERE CONSISTENT WITH THOSE LISTED IN TABLE 1. IN THIS POOL, INVOKANA WAS ALSO ASSOCIATED WITH THE ADVERSE REACTIONS OF FATIGUE (1.7% WITH COMPARATOR, 2.2% WITH INVOKANA 100 MG, AND 2.0% WITH INVOKANA 300 MG) AND LOSS OF STRENGTH OR ENERGY (I.E., ASTHENIA) (0.6% WITH COMPARATOR, 0.7% WITH INVOKANA 100 MG AND 1.1% WITH INVOKANA 300 MG).
IN THE POOL OF EIGHT CLINICAL TRIALS, THE INCIDENCE RATE OF PANCREATITIS (ACUTE OR CHRONIC) WAS 0.9, 2.7, AND 0.9 PER 1000 PATIENT-YEARS OF EXPOSURE TO COMPARATOR, INVOKANA 100 MG, AND INVOKANA 300 MG, RESPECTIVELY.
IN THE POOL OF EIGHT CLINICAL TRIALS WITH A LONGER MEAN DURATION OF EXPOSURE TO INVOKANA (68 WEEKS), THE INCIDENCE RATE OF BONE FRACTURE WAS 14.2, 18.7, AND 17.6 PER 1000 PATIENT YEARS OF EXPOSURE TO COMPARATOR, INVOKANA 100 MG, AND INVOKANA 300 MG, RESPECTIVELY. UPPER EXTREMITY FRACTURES OCCURRED MORE COMMONLY ON INVOKANA THAN COMPARATOR.
IN THE POOL OF EIGHT CLINICAL TRIALS, HYPERSENSITIVITY-RELATED ADVERSE REACTIONS (INCLUDING ERYTHEMA, RASH, PRURITUS, URTICARIA, AND ANGIOEDEMA) OCCURRED IN 3.0%, 3.8%, AND 4.2% OF PATIENTS RECEIVING COMPARATOR, INVOKANA 100 MG AND INVOKANA 300 MG RESPECTIVELY. FIVE PATIENTS EXPERIENCED SERIOUS ADVERSE REACTIONS OF HYPERSENSITIVITY WITH INVOKANA, WHICH INCLUDED 4 PATIENTS WITH URTICARIA AND 1 PATIENT WITH A DIFFUSE RASH AND URTICARIA OCCURRING WITHIN HOURS OF EXPOSURE TO INVOKANA. AMONG THESE PATIENTS, 2 PATIENTS DISCONTINUED INVOKANA. ONE PATIENT WITH URTICARIA HAD RECURRENCE WHEN INVOKANA WAS RE-INITIATED.
PHOTOSENSITIVITY-RELATED ADVERSE REACTIONS (INCLUDING PHOTOSENSITIVITY REACTION, POLYMORPHIC LIGHT ERUPTION, AND SUNBURN) OCCURRED IN 0.1%, 0.2%, AND 0.2% OF PATIENTS RECEIVING COMPARATOR, INVOKANA 100 MG, AND INVOKANA 300 MG, RESPECTIVELY.
OTHER ADVERSE REACTIONS OCCURRING MORE FREQUENTLY ON INVOKANA THAN ON COMPARATOR WERE:
VOLUME DEPLETION-RELATED ADVERSE REACTIONS
INVOKANA RESULTS IN AN OSMOTIC DIURESIS, WHICH MAY LEAD TO REDUCTIONS IN INTRAVASCULAR VOLUME. IN CLINICAL STUDIES, TREATMENT WITH INVOKANA WAS ASSOCIATED WITH A DOSE-DEPENDENT INCREASE IN THE INCIDENCE OF VOLUME DEPLETION-RELATED ADVERSE REACTIONS (E.G., HYPOTENSION, POSTURAL DIZZINESS, ORTHOSTATIC HYPOTENSION, SYNCOPE, AND DEHYDRATION). AN INCREASED INCIDENCE WAS OBSERVED IN PATIENTS ON THE 300 MG DOSE. THE THREE FACTORS ASSOCIATED WITH THE LARGEST INCREASE IN VOLUME DEPLETION-RELATED ADVERSE REACTIONS WERE THE USE OF LOOP DIURETICS, MODERATE RENAL IMPAIRMENT (EGFR 30 TO LESS THAN 60 ML/MIN/1.73 MĀ²) AND AGE 75 YEARS AND OLDER (TABLE 2) [SEE DOSAGE AND ADMINISTRATION , WARNINGS AND PRECAUTIONS, AND USE IN SPECIFIC POPULATIONS].
TABLE 2: PROPORTION OF PATIENTS WITH AT LEAST ONE VOLUME DEPLETION-RELATED ADVERSE REACTIONS (POOLED RESULTS FROM 8 CLINICAL TRIALS)
BASELINE CHARACTERISTIC
COMPARATOR GROUP* %
INVOKANA 100 MG %
INVOKANA 300 MG %
OVERALL POPULATION
1.5%
2.3%
3.4%
75 YEARS OF AGE AND OLDERā
2.6%
4.9%
8.7%
EGFR LESS THAN 60 ML/MIN/1.73 MĀ²ā
2.5%
4.7%
8.1%
USE OF LOOP DIURETICā
4.7%
3.2%
8.8%
IMPAIRMENT IN RENAL FUNCTION
INVOKANA IS ASSOCIATED WITH A DOSE-DEPENDENT INCREASE IN SERUM CREATININE AND A CONCOMITANT FALL IN ESTIMATED GFR (TABLE 3). PATIENTS WITH MODERATE RENAL IMPAIRMENT AT BASELINE HAD LARGER MEAN CHANGES.
TABLE 3: CHANGES IN SERUM CREATININE AND EGFR ASSOCIATED WITH INVOKANA IN THE POOL OF FOUR PLACEBO-CONTROLLED TRIALS AND MODERATE RENAL IMPAIRMENT TRIAL
Ā
Ā
Ā
PLACEBO
N=646
INVOKANA 100 MG
N=833
INVOKANA 300 MG
N=834
POOL OF FOUR PLACEBO-CONTROLLED TRIALS
BASELINE
CREATININE (MG/DL)
0.84
0.82
0.82
EGFR (ML/MIN/1.73 MĀ²)
87.0
88.3
88.8
WEEK 6 CHANGE
CREATININE (MG/DL)
0.01
0.03
0.05
EGFR (ML/MIN/1.73 MĀ²)
-1.6
-3.8
-5.0
END OF TREATMENT CHANGE*
CREATININE (MG/DL)
0.01
0.02
0.03
EGFR (ML/MIN/1.73 MĀ²)
-1.6
-2.3
-3.4
Ā
Ā
Ā
PLACEBO
N=90
INVOKANA 100 MG
N=90
INVOKANA 300 MG
N=89
MODERATE RENAL IMPAIRMENT TRIAL
BASELINE
CREATININE (MG/DL)
1.61
1.62
1.63
EGFR (ML/MIN/1.73 MĀ²)
40.1
39.7
38.5
WEEK 3 CHANGE
CREATININE (MG/DL)
0.03
0.18
0.28
EGFR (ML/MIN/1.73 MĀ²)
-0.7
-4.6
-6.2
END OF TREATMENT CHANGE*
CREATININE (MG/DL)
0.07
0.16
0.18
EGFR (ML/MIN/1.73 MĀ²)
-1.5
-3.6
-4.0
* WEEK 26 IN MITT LOCF POPULATION
IN THE POOL OF FOUR PLACEBO-CONTROLLED TRIALS WHERE PATIENTS HAD NORMAL OR MILDLY IMPAIRED BASELINE RENAL FUNCTION, THE PROPORTION OF PATIENTS WHO EXPERIENCED AT LEAST ONE EVENT OF SIGNIFICANT RENAL FUNCTION DECLINE, DEFINED AS AN EGFR BELOW 80 ML/MIN/1.73 MĀ² AND 30% LOWER THAN BASELINE, WAS 2.1% WITH PLACEBO, 2.0% WITH INVOKANA 100 MG, AND 4.1% WITH INVOKANA 300 MG. AT THE END OF TREATMENT, 0.5% WITH PLACEBO, 0.7% WITH INVOKANA 100 MG, AND 1.4% WITH INVOKANA 300 MG HAD A SIGNIFICANT RENAL FUNCTION DECLINE.
IN A TRIAL CARRIED OUT IN PATIENTS WITH MODERATE RENAL IMPAIRMENT WITH A BASELINE EGFR OF 30 TO LESS THAN 50 ML/MIN/1.73 MĀ² (MEAN BASELINE EGFR 39 ML/MIN/1.73 MĀ²) [SEE CLINICAL STUDIES], THE PROPORTION OF PATIENTS WHO EXPERIENCED AT LEAST ONE EVENT OF SIGNIFICANT RENAL FUNCTION DECLINE, DEFINED AS AN EGFR 30% LOWER THAN BASELINE, WAS 6.9% WITH PLACEBO, 18% WITH INVOKANA 100 MG, AND 22.5% WITH INVOKANA 300 MG. AT THE END OF TREATMENT, 4.6% WITH PLACEBO, 3.4% WITH INVOKANA 100 MG, AND 3.4% WITH INVOKANA 300 MG HAD A SIGNIFICANT RENAL FUNCTION DECLINE.
IN A POOLED POPULATION OF PATIENTS WITH MODERATE RENAL IMPAIRMENT (N=1085) WITH BASELINE EGFR OF 30 TO LESS THAN 60 ML/MIN/1.73 MĀ² (MEAN BASELINE EGFR 48 ML/MIN/1.73 MĀ²), THE OVERALL INCIDENCE OF THESE EVENTS WAS LOWER THAN IN THE DEDICATED TRIAL BUT A DOSE-DEPENDENT INCREASE IN INCIDENT EPISODES OF SIGNIFICANT RENAL FUNCTION DECLINE COMPARED TO PLACEBO WAS STILL OBSERVED.
USE OF INVOKANA WAS ASSOCIATED WITH AN INCREASED INCIDENCE OF RENAL-RELATED ADVERSE REACTIONS (E.G., INCREASED BLOOD CREATININE, DECREASED GLOMERULAR FILTRATION RATE, RENAL IMPAIRMENT, AND ACUTE RENAL FAILURE), PARTICULARLY IN PATIENTS WITH MODERATE RENAL IMPAIRMENT.
IN THE POOLED ANALYSIS OF PATIENTS WITH MODERATE RENAL IMPAIRMENT, THE INCIDENCE OF RENAL-RELATED ADVERSE REACTIONS WAS 3.7% WITH PLACEBO, 8.9% WITH INVOKANA 100 MG, AND 9.3% WITH INVOKANA 300 MG. DISCONTINUATIONS DUE TO RENAL-RELATED ADVERSE EVENTS OCCURRED IN 1.0% WITH PLACEBO, 1.2% WITH INVOKANA 100 MG, AND 1.6% WITH INVOKANA 300 MG [SEE WARNINGS AND PRECAUTIONS].
GENITAL MYCOTIC INFECTIONS
IN THE POOL OF FOUR PLACEBO-CONTROLLED CLINICAL TRIALS, FEMALE GENITAL MYCOTIC INFECTIONS (E.G., VULVOVAGINAL MYCOTIC INFECTION, VULVOVAGINAL CANDIDIASIS, AND VULVOVAGINITIS) OCCURRED IN 3.2%, 10.4%, AND 11.4% OF FEMALES TREATED WITH PLACEBO, INVOKANA 100 MG, AND INVOKANA 300 MG, RESPECTIVELY. PATIENTS WITH A HISTORY OF GENITAL MYCOTIC INFECTIONS WERE MORE LIKELY TO DEVELOP GENITAL MYCOTIC INFECTIONS ON INVOKANA. FEMALE PATIENTS WHO DEVELOPED GENITAL MYCOTIC INFECTIONS ON INVOKANA WERE MORE LIKELY TO EXPERIENCE RECURRENCE AND REQUIRE TREATMENT WITH ORAL OR TOPICAL ANTIFUNGAL AGENTS AND ANTI-MICROBIAL AGENTS [SEE WARNINGS AND PRECAUTIONS].
IN THE POOL OF FOUR PLACEBO-CONTROLLED CLINICAL TRIALS, MALE GENITAL MYCOTIC INFECTIONS (E.G., CANDIDAL BALANITIS, BALANOPOSTHITIS) OCCURRED IN 0.6%, 4.2%, AND 3.7% OF MALES TREATED WITH PLACEBO, INVOKANA 100 MG, AND INVOKANA 300 MG, RESPECTIVELY. MALE GENITAL MYCOTIC INFECTIONS OCCURRED MORE COMMONLY IN UNCIRCUMCISED MALES AND IN MALES WITH A PRIOR HISTORY OF BALANITIS OR BALANOPOSTHITIS. MALE PATIENTS WHO DEVELOPED GENITAL MYCOTIC INFECTIONS ON INVOKANA WERE MORE LIKELY TO EXPERIENCE RECURRENT INFECTIONS (22% ON INVOKANA VERSUS NONE ON PLACEBO), AND REQUIRE TREATMENT WITH ORAL OR TOPICAL ANTIFUNGAL AGENTS AND ANTI-MICROBIAL AGENTS THAN PATIENTS ON COMPARATORS. IN THE POOLED ANALYSIS OF 8 CONTROLLED TRIALS, PHIMOSIS WAS REPORTED IN 0.3% OF UNCIRCUMCISED MALE PATIENTS TREATED WITH INVOKANA AND 0.2% REQUIRED CIRCUMCISION TO TREAT THE PHIMOSIS [SEE WARNINGS AND PRECAUTIONS].
HYPOGLYCEMIA
IN ALL CLINICAL TRIALS, HYPOGLYCEMIA WAS DEFINED AS ANY EVENT REGARDLESS OF SYMPTOMS, WHERE BIOCHEMICAL HYPOGLYCEMIA WAS DOCUMENTED (ANY GLUCOSE VALUE BELOW OR EQUAL TO 70 MG/DL).
SEVERE HYPOGLYCEMIA WAS DEFINED AS AN EVENT CONSISTENT WITH HYPOGLYCEMIA WHERE THE PATIENT REQUIRED THE ASSISTANCE OF ANOTHER PERSON TO RECOVER, LOST CONSCIOUSNESS, OR EXPERIENCED A SEIZURE (REGARDLESS OF WHETHER BIOCHEMICAL DOCUMENTATION OF A LOW GLUCOSE VALUE WAS OBTAINED). IN INDIVIDUAL CLINICAL TRIALS [SEE CLINICAL STUDIES], EPISODES OF HYPOGLYCEMIA OCCURRED AT A HIGHER RATE WHEN INVOKANA WAS CO-ADMINISTERED WITH INSULIN OR SULFONYLUREAS (TABLE 4) [SEE WARNINGS AND PRECAUTIONS].
TABLE 4: INCIDENCE OF HYPOGLYCEMIA* IN CONTROLLED CLINICAL STUDIES
MONOTHERAPY (26 WEEKS)
PLACEBO
(N=192)
INVOKANA 100 MG
(N=195)
INVOKANA 300 MG
(N=197)
OVERALL [N (%)]
5 (2.6)
7 (3.6)
6 (3.0)
IN COMBINATION WITH METFORMIN (26 WEEKS)
PLACEBO + METFORMIN
(N=183)
INVOKANA 100 MG + METFORMIN
(N=368)
INVOKANA 300 MG + METFORMIN
(N=367)
OVERALL [N (%)]
3 (1.6)
16 (4.3)
17 (4.6)
SEVERE [N (%)]ā
0 (0)
1 (0.3)
1 (0.3)
IN COMBINATION WITH METFORMIN (52 WEEKS)
GLIMEPIRIDE + METFORMIN
(N=482)
INVOKANA 100 MG + METFORMIN
(N=483)
INVOKANA 300 MG + METFORMIN
(N=485)
OVERALL [N (%)]
165 (34.2)
27 (5.6)
24 (4.9)
SEVERE [N (%)]ā
15 (3.1)
2 (0.4)
3 (0.6)
IN COMBINATION WITH SULFONYLUREA (18 WEEKS)
PLACEBO + SULFONYLUREA
(N=69)
INVOKANA 100 MG + SULFONYLUREA
(N=74)
INVOKANA 300 MG + SULFONYLUREA
(N=72)
OVERALL [N (%)]
4 (5.8)
3 (4.1)
9 (12.5)
IN COMBINATION WITH METFORMIN + SULFONYLUREA (26 WEEKS)
PLACEBO + METFORMIN + SULFONYLUREA
(N=156)
INVOKANA100 MG + METFORMIN + SULFONYLUREA
(N=157)
INVOKANA 300 MG + METFORMIN + SULFONYLUREA
(N=156)
OVERALL [N (%)]
24 (15.4)
43 (27.4)
47 (30.1)
SEVERE [N (%)]ā
1 (0.6)
1 (0.6)
0
IN COMBINATION WITH METFORMIN + SULFONYLUREA (52 WEEKS)
SITAGLIPTIN + METFORMIN + SULFONYLUREA
(N=378)
INVOKANA 300 MG + METFORMIN + SULFONYLUREA
(N=377)
OVERALL [N (%)]
154 (40.7)
163 (43.2)
SEVERE [N (%)]ā
13 (3.4)
15 (4.0)
IN COMBINATION WITH METFORMIN + PIOGLITAZONE (26 WEEKS)
PLACEBO + METFORMIN + PIOGLITAZONE
(N=115)
INVOKANA 100 MG + METFORMIN + PIOGLITAZONE
(N=113)
INVOKANA 300 MG + METFORMIN + PIOGLITAZONE
(N=114)
OVERALL [N (%)]
3 (2.6)
3 (2.7)
6 (5.3)
IN COMBINATION WITH INSULIN (18 WEEKS)
PLACEBO
(N=565)
INVOKANA 100 MG
(N=566)
INVOKANA 300 MG
(N=587)
OVERALL [N (%)]
208 (36.8)
279 (49.3)
285 (48.6)
SEVERE [N (%)]ā
14 (2.5)
10 (1.8)
16 (2.7)
LABORATORY TESTS
INCREASES IN SERUM POTASSIUM
DOSE-RELATED, TRANSIENT MEAN INCREASES IN SERUM POTASSIUM WERE OBSERVED EARLY AFTER INITIATION OF INVOKANA (I.E., WITHIN 3 WEEKS) IN A TRIAL OF PATIENTS WITH MODERATE RENAL IMPAIRMENT [SEE CLINICAL STUDIES]. IN THIS TRIAL, INCREASES IN SERUM POTASSIUM OF GREATER THAN 5.4 MEQ/L AND 15% ABOVE BASELINE OCCURRED IN 16.1%, 12.4%, AND 27.0% OF PATIENTS TREATED WITH PLACEBO, INVOKANA 100 MG, AND INVOKANA 300 MG, RESPECTIVELY. MORE SEVERE ELEVATIONS (I.E., EQUAL OR GREATER THAN 6.5 MEQ/L) OCCURRED IN 1.1%, 2.2%, AND 2.2% OF PATIENTS TREATED WITH PLACEBO, INVOKANA 100 MG, AND INVOKANA 300 MG, RESPECTIVELY. IN PATIENTS WITH MODERATE RENAL IMPAIRMENT, INCREASES IN POTASSIUM WERE MORE COMMONLY SEEN IN THOSE WITH ELEVATED POTASSIUM AT BASELINE AND IN THOSE USING MEDICATIONS THAT REDUCE POTASSIUM EXCRETION, SUCH AS POTASSIUM-SPARING DIURETICS, ANGIOTENSIN-CONVERTING-ENZYME INHIBITORS, AND ANGIOTENSINRECEPTOR BLOCKERS [SEE WARNINGS AND PRECAUTIONS].
INCREASES IN SERUM MAGNESIUM
DOSE-RELATED INCREASES IN SERUM MAGNESIUM WERE OBSERVED EARLY AFTER INITIATION OF INVOKANA (WITHIN 6 WEEKS) AND REMAINED ELEVATED THROUGHOUT TREATMENT. IN THE POOL OF FOUR PLACEBOCONTROLLED TRIALS, THE MEAN CHANGE IN SERUM MAGNESIUM LEVELS WAS 8.1% AND 9.3% WITH INVOKANA 100 MG AND INVOKANA 300 MG, RESPECTIVELY, COMPARED TO -0.6% WITH PLACEBO. IN A TRIAL OF PATIENTS WITH MODERATE RENAL IMPAIRMENT [SEE CLINICAL STUDIES], SERUM MAGNESIUM LEVELS INCREASED BY 0.2%, 9.2%, AND 14.8% WITH PLACEBO, INVOKANA 100 MG, AND INVOKANA 300 MG, RESPECTIVELY.
INCREASES IN SERUM PHOSPHATE
DOSE-RELATED INCREASES IN SERUM PHOSPHATE LEVELS WERE OBSERVED WITH INVOKANA. IN THE POOL OF FOUR PLACEBO CONTROLLED TRIALS, THE MEAN CHANGE IN SERUM PHOSPHATE LEVELS WERE 3.6% AND 5.1% WITH INVOKANA 100 MG AND INVOKANA 300 MG, RESPECTIVELY, COMPARED TO 1.5% WITH PLACEBO. IN A TRIAL OF PATIENTS WITH MODERATE RENAL IMPAIRMENT [SEE CLINICAL STUDIES], THE MEAN SERUM PHOSPHATE LEVELS INCREASED BY 1.2%, 5.0%, AND 9.3% WITH PLACEBO, INVOKANA 100 MG, AND INVOKANA 300 MG, RESPECTIVELY.
INCREASES IN LOW-DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C) AND NON-HIGH-DENSITY LIPOPROTEIN CHOLESTEROL (NON-HDL-C)
IN THE POOL OF FOUR PLACEBO-CONTROLLED TRIALS, DOSE-RELATED INCREASES IN LDL-C WITH INVOKANA WERE OBSERVED. MEAN CHANGES (PERCENT CHANGES) FROM BASELINE IN LDL-C RELATIVE TO PLACEBO WERE 4.4 MG/DL (4.5%) AND 8.2 MG/DL (8.0%) WITH INVOKANA 100 MG AND INVOKANA 300 MG, RESPECTIVELY. THE MEAN BASELINE LDL-C LEVELS WERE 104 TO 110 MG/DL ACROSS TREATMENT GROUPS [SEE WARNINGS AND PRECAUTIONS].
DOSE-RELATED INCREASES IN NON-HDL-C WITH INVOKANA WERE OBSERVED. MEAN CHANGES (PERCENT CHANGES) FROM BASELINE IN NON-HDL-C RELATIVE TO PLACEBO WERE 2.1 MG/DL (1.5%) AND 5.1 MG/DL (3.6%) WITH INVOKANA 100 MG AND 300 MG, RESPECTIVELY. THE MEAN BASELINE NON-HDL-C LEVELS WERE 140 TO 147 MG/DL ACROSS TREATMENT GROUPS.
INCREASES IN HEMOGLOBIN
IN THE POOL OF FOUR PLACEBO-CONTROLLED TRIALS, MEAN CHANGES (PERCENT CHANGES) FROM BASELINE IN HEMOGLOBIN WERE -0.18 G/DL (-1.1%) WITH PLACEBO, 0.47 G/DL (3.5%) WITH INVOKANA 100 MG, AND 0.51 G/DL (3.8%) WITH INVOKANA 300 MG. THE MEAN BASELINE HEMOGLOBIN VALUE WAS APPROXIMATELY 14.1 G/DL ACROSS TREATMENT GROUPS. AT THE END OF TREATMENT, 0.8%, 4.0%, AND 2.7% OF PATIENTS TREATED WITH PLACEBO, INVOKANA 100 MG, AND INVOKANA 300 MG, RESPECTIVELY, HAD HEMOGLOBIN ABOVE THE UPPER LIMIT OF NORMAL.
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DRUG INTERACTIONS
UGT ENZYME INDUCERS
RIFAMPIN: CO-ADMINISTRATION OF CANAGLIFLOZIN WITH RIFAMPIN, A NONSELECTIVE INDUCER OF SEVERAL UGT ENZYMES, INCLUDING UGT1A9, UGT2B4, DECREASED CANAGLIFLOZIN AREA UNDER THE CURVE (AUC) BY 51%. THIS DECREASE IN EXPOSURE TO CANAGLIFLOZIN MAY DECREASE EFFICACY. IF AN INDUCER OF THESE UGTS (E.G., RIFAMPIN, PHENYTOIN, PHENOBARBITAL, RITONAVIR) MUST BE CO-ADMINISTERED WITH INVOKANA (CANAGLIFLOZIN), CONSIDER INCREASING THE DOSE TO 300 MG ONCE DAILY IF PATIENTS ARE CURRENTLY TOLERATING INVOKANA 100 MG ONCE DAILY, HAVE AN EGFR GREATER THAN 60 ML/MIN/1.73 MĀ², AND REQUIRE ADDITIONAL GLYCEMIC CONTROL. CONSIDER OTHER ANTIHYPERGLYCEMIC THERAPY IN PATIENTS WITH AN EGFR OF 45 TO LESS THAN 60 ML/MIN/1.73 MĀ² RECEIVING CONCURRENT THERAPY WITH A UGT INDUCER AND REQUIRE ADDITIONAL GLYCEMIC CONTROL [SEE DOSAGE AND ADMINISTRATION AND CLINICAL PHARMACOLOGY].
DIGOXIN
THERE WAS AN INCREASE IN THE AREA AUC AND MEAN PEAK DRUG CONCENTRATION (CMAX) OF DIGOXIN (20% AND 36%, RESPECTIVELY) WHEN CO-ADMINISTERED WITH INVOKANA 300 MG [SEE CLINICAL PHARMACOLOGY]. PATIENTS TAKING INVOKANA WITH CONCOMITANT DIGOXIN SHOULD BE MONITORED APPROPRIATELY.
PRECAUTIONS
HYPOTENSION
INVOKANA CAUSES INTRAVASCULAR VOLUME CONTRACTION. SYMPTOMATIC HYPOTENSION CAN OCCUR AFTER INITIATING INVOKANA [SEE ADVERSE REACTIONS] PARTICULARLY IN PATIENTS WITH IMPAIRED RENAL FUNCTION (EGFR LESS THAN 60 ML/MIN/1.73 MĀ²), ELDERLY PATIENTS, PATIENTS ON EITHER DIURETICS OR MEDICATIONS THAT INTERFERE WITH THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (E.G., ANGIOTENSINCONVERTING- ENZYME [ACE] INHIBITORS, ANGIOTENSIN RECEPTOR BLOCKERS [ARBS]), OR PATIENTS WITH LOW SYSTOLIC BLOOD PRESSURE. BEFORE INITIATING INVOKANA IN PATIENTS WITH ONE OR MORE OF THESE CHARACTERISTICS, VOLUME STATUS SHOULD BE ASSESSED AND CORRECTED. MONITOR FOR SIGNS AND SYMPTOMS AFTER INITIATING THERAPY.
IMPAIRMENT IN RENAL FUNCTION
INVOKANA INCREASES SERUM CREATININE AND DECREASES EGFR. PATIENTS WITH HYPOVOLEMIA MAY BE MORE SUSCEPTIBLE TO THESE CHANGES. RENAL FUNCTION ABNORMALITIES CAN OCCUR AFTER INITIATING INVOKANA [SEE ADVERSE REACTIONS]. MORE FREQUENT RENAL FUNCTION MONITORING IS RECOMMENDED IN PATIENTS WITH AN EGFR BELOW 60 ML/MIN/1.73 MĀ².
HYPERKALEMIA
INVOKANA CAN LEAD TO HYPERKALEMIA. PATIENTS WITH MODERATE RENAL IMPAIRMENT WHO ARE TAKING MEDICATIONS THAT INTERFERE WITH POTASSIUM EXCRETION, SUCH AS POTASSIUM-SPARING DIURETICS, OR MEDICATIONS THAT INTERFERE WITH THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM ARE MORE LIKELY TO DEVELOP HYPERKALEMIA [SEE ADVERSE REACTIONS].
MONITOR SERUM POTASSIUM LEVELS PERIODICALLY AFTER INITIATING INVOKANA IN PATIENTS WITH IMPAIRED RENAL FUNCTION AND IN PATIENTS PREDISPOSED TO HYPERKALEMIA DUE TO MEDICATIONS OR OTHER MEDICAL CONDITIONS.
HYPOGLYCEMIA WITH CONCOMITANT USE WITH INSULIN AND INSULIN SECRETAGOGUES
INSULIN AND INSULIN SECRETAGOGUES ARE KNOWN TO CAUSE HYPOGLYCEMIA. INVOKANA CAN INCREASE THE RISK OF HYPOGLYCEMIA WHEN COMBINED WITH INSULIN OR AN INSULIN SECRETAGOGUE [SEE ADVERSE REACTIONS]. THEREFORE, A LOWER DOSE OF INSULIN OR INSULIN SECRETAGOGUE MAY BE REQUIRED TO MINIMIZE THE RISK OF HYPOGLYCEMIA WHEN USED IN COMBINATION WITH INVOKANA.
GENITAL MYCOTIC INFECTIONS
INVOKANA INCREASES THE RISK OF GENITAL MYCOTIC INFECTIONS. PATIENTS WITH A HISTORY OF GENITAL MYCOTIC INFECTIONS AND UNCIRCUMCISED MALES WERE MORE LIKELY TO DEVELOP GENITAL MYCOTIC INFECTIONS [SEE ADVERSE REACTIONS].
MONITOR AND TREAT APPROPRIATELY.
HYPERSENSITIVITY REACTIONS
HYPERSENSITIVITY REACTIONS (E.G., GENERALIZED URTICARIA), SOME SERIOUS, WERE REPORTED WITH INVOKANA TREATMENT; THESE REACTIONS GENERALLY OCCURRED WITHIN HOURS TO DAYS AFTER INITIATING INVOKANA. IF HYPERSENSITIVITY REACTIONS OCCUR, DISCONTINUE USE OF INVOKANA; TREAT PER STANDARD OF CARE AND MONITOR UNTIL SIGNS AND SYMPTOMS RESOLVE [SEE CONTRAINDICATIONS AND ADVERSE REACTIONS].
INCREASES IN LOW-DENSITY LIPOPROTEIN (LDL-C)
DOSE-RELATED INCREASES IN LDL-C OCCUR WITH INVOKANA [SEE ADVERSE REACTIONS]. MONITOR LDL-C AND TREAT PER STANDARD OF CARE AFTER INITIATING INVOKANA.
MACROVASCULAR OUTCOMES
THERE HAVE BEEN NO CLINICAL STUDIES ESTABLISHING CONCLUSIVE EVIDENCE OF MACROVASCULAR RISK REDUCTION WITH INVOKANA OR ANY OTHER ANTIDIABETIC DRUG.
THIS CONFIDENCE INTERVAL IS LESS THAN THE PRE-SPECIFIED