Physicians Office Resource Volume 11 Issue 01 | Page 4

Table 2 : Changes from Baseline in Serum Creatinine and eGFR a in the Pool of Four 24-week Placebo-Controlled Studies and Renal Impairment Study

Baseline Mean

Week 12 Change

Week 24 Change

Baseline Mean

Week 12 Change

Week 24 Change

Week 52 Change

Posttreatment Creatinine ( mg / dL ) 0.03 – 0.02

N 98 – 103

Change c eGFR ( mL / min / 1.73 m 2 ) 0.16 – 1.48 a

Observed cases on treatment . b

Subset of patients from renal impairment study with eGFR 30 to less than 60 mL / min / 1.73 m 2 c

Approximately 3 weeks after end of treatment .

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 Overall a and Severe b Hypoglycemic Events in Placebo- Controlled Clinical Studies c

In Combination with Metformin + Sulfonylurea ( 24 weeks )

Placebo ( n = 225 )

JARDIANCE 10 mg + Metformin + Sulfonylurea ( n = 224 )

JARDIANCE 25 mg + Metformin + Sulfonylurea ( n = 217 )

In Combination with Basal Insulin +/ - Metformin ( 18 weeks d )

Placebo ( n = 170 )

JARDIANCE 10 mg ( n = 169 )

JARDIANCE 25 mg ( n = 155 )

Table 3 ( cont ’ d ) In Combination with MDI Insulin +/ - Metformin ( 18 weeks d )

4 ! ! ! ! ! ! ! ! ! !

Placebo ( n = 188 )

JARDIANCE 10 mg ( n = 186 )

JARDIANCE 25 mg ( n = 189 )

a

Overall hypoglycemic events : plasma or capillary glucose of less than or equal to 70 mg / dL b

Severe hypoglycemic events : requiring assistance regardless of blood glucose c

Treated set ( patients who had received at least one dose of study drug ) d

Insulin dose could not be adjusted during the initial 18 week treatment period Genital Mycotic Infections : In the pool of 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 of 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 placebocontrolled 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 . Postmarketing Experience : Additional adverse reactions have been identified during postapproval use of JARDIANCE . Because these reactions are reported voluntarily from a population of uncertain size , it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure : Ketoacidosis [ see Warnings and Precautions ]; Urosepsis and pyelonephritis [ see Warnings and Precautions ].

DRUG INTERACTIONS : Diuretics : Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids , which might enhance the potential for volume depletion [ see Warnings and Precautions ]. Insulin or Insulin Secretagogues : Coadministration of empagliflozin with insulin or insulin secretagogues increases the risk for hypoglycemia [ see Warnings and Precautions ]. Positive Urine Glucose Test : Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests . Use alternative methods to monitor glycemic control . Interference with 1,5-anhydroglucitol

( 1,5-AG ) Assay : Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors . Use alternative methods to monitor glycemic control .

USE IN SPECIFIC POPULATIONS : Pregnancy : Risk Summary : Based on animal

data showing adverse renal effects , JARDIANCE is not recommended during the second and third trimesters of pregnancy . Limited data available with JARDIANCE in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage . There are risks to the mother and fetus associated

with poorly controlled diabetes in pregnancy [ see Clinical Considerations ]. In animal studies , adverse renal changes were observed in rats when empagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy . Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible . Empagliflozin was not teratogenic in rats and rabbits up to 300 mg / kg / day , which approximates 48-times and 128-times , respectively , the maximum clinical dose of 25 mg when administered during organogenesis [ see Data ]. The estimated background risk of major birth defects is 6-10 % in women with pre-gestational diabetes with a HbA1c > 7 and has been reported to be as high as 20-25 % in women with HbA1c > 10 . The estimated background risk of miscarriage for the indicated population is unknown . In the U . S . general population , the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4 % and 15-20 %, respectively . Clinical Considerations : Disease-associated maternal and / or embryo / fetal risk : Poorly controlled diabetes in pregnancy increases the maternal

risk for diabetic ketoacidosis , pre-eclampsia , spontaneous abortions , preterm delivery , stillbirth , and delivery complications . Poorly controlled diabetes increases the fetal risk for major birth defects , still birth , and macrosomia related morbidity . Data : Animal Data : Empagliflozin dosed directly to juvenile rats from postnatal day ( PND ) 21 until PND 90 at doses of 1 , 10 , 30 and 100 mg / kg / day caused increased kidney