NDC 70518-1986 Jardiance

Empagliflozin

NDC Product Code 70518-1986

NDC Code: 70518-1986

Proprietary Name: Jardiance Additional informationCallout TooltipWhat is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Empagliflozin Additional informationCallout TooltipWhat is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.


Product Characteristics
Color(s):
YELLOW (C48330 - PALE YELLOW)
Shape: ROUND (C48348)
Size(s):
9 MM
Imprint(s):
S;10
Score: 1

Code Structure
  • 70518 - Remedyrepack Inc.
    • 70518-1986 - Jardiance

NDC 70518-1986-0

Package Description: 90 TABLET, FILM COATED in 1 BOTTLE, PLASTIC

NDC Product Information

Jardiance with NDC 70518-1986 is a a human prescription drug product labeled by Remedyrepack Inc.. The generic name of Jardiance is empagliflozin. The product's dosage form is tablet, film coated and is administered via oral form.

Labeler Name: Remedyrepack Inc.

Dosage Form: Tablet, Film Coated - A solid dosage form that contains medicinal substances with or without suitable diluents and is coated with a thin layer of a water-insoluble or water-soluble polymer.

Product Type: Human Prescription Drug Additional informationCallout TooltipWhat kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.


Jardiance Active Ingredient(s)

Additional informationCallout TooltipWhat is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • EMPAGLIFLOZIN 10 mg/1

Administration Route(s)

Additional informationCallout TooltipWhat are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

Additional informationCallout TooltipWhat is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Sodium-Glucose Cotransporter 2 Inhibitor - [EPC] (Established Pharmacologic Class)
  • Sodium-Glucose Transporter 2 Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

Additional informationCallout TooltipWhat is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Remedyrepack Inc.
Labeler Code: 70518
FDA Application Number: NDA204629 Additional informationCallout TooltipWhat is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. Additional informationCallout TooltipWhat is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 03-27-2019 Additional informationCallout TooltipWhat is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 Additional informationCallout TooltipWhat is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N Additional informationCallout TooltipWhat is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Jardiance Product Label Images

Jardiance Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1  Indications And Usage

  • JARDIANCE is indicated:                  as an adjunct to diet and exercise to improve glycemic control
  • In adults with type 2 diabetes mellitus,to reduce the risk of cardiovascular death in adult patients
  • With type 2 diabetes mellitus and established cardiovascular disease.Limitations of
  • UseJARDIANCE is not recommended for patients
  • With type 1 diabetes or for the treatment of diabetic ketoacidosis.

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 (


14)]


.


In patients with
volume depletion, correcting this condition prior to initiation of
JARDIANCE is recommended


[see Warnings and Precautions (


5.1), Use in Specific Populations (


8.5) and Patient Counseling Information
(


17)].

2.2 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 m


2.


No dose adjustment
is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73
m


2.


JARDIANCE should be discontinued if eGFR
is persistently less than 45 mL/min/1.73 m


2 [see Warnings and Precautions (


5.1,


5.3) and Use in Specific
Populations (


8.6)]


.

3  Dosage Forms And Strengths

  • JARDIANCE tablets available as: 10 mg 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.25 mg pale yellow, oval, biconvex, film-coated tablets debossed
  • With “S 25” on one side and the Boehringer Ingelheim company symbol
  • On the other side.

4  Contraindications

  • History of serious hypersensitivity reaction
  • To empagliflozin or any of the excipients in JARDIANCE
  • [see
  • Warnings and Precautions (
  • 5.8)]
  • .
  • History of serious hypersensitivity reaction
  • To empagliflozin or any of the excipients in JARDIANCE
  • [see
  • Warnings and Precautions (
  • 5.8)]
  • .
  • Severe renal impairment, end-stage renal disease, or dialysis
  • [see Use in Specific Populations (
  • 8.6)]
  • .

5.1 Hypotension

JARDIANCE causes intravascular
volume contraction.  Symptomatic hypotension may occur after initiating
JARDIANCE


[see Adverse Reactions (


6.1)]


particularly in patients with renal impairment,
the elderly, in patients with low systolic blood pressure, and in
patients on diuretics.  Before initiating JARDIANCE, assess for volume
contraction and correct volume status if indicated.  Monitor for signs
and symptoms of hypotension after initiating therapy and increase
monitoring in clinical situations where volume contraction is expected


[see Use in Specific Populations (


8.5)]


.

5.2 Ketoacidosis

Reports of ketoacidosis, a serious
life-threatening condition requiring urgent hospitalization have been
identified in postmarketing surveillance in patients with type 1 and
type 2 diabetes mellitus receiving sodium glucose co-transporter-2
(SGLT2) inhibitors, including JARDIANCE. Fatal cases of ketoacidosis
have been reported in patients taking JARDIANCE. JARDIANCE is not
indicated for the treatment of patients with type 1 diabetes mellitus


[see Indications and Usage (


1)]


.


Patients treated
with JARDIANCE who present with signs and symptoms consistent with
severe metabolic acidosis should be assessed for ketoacidosis regardless
of presenting blood glucose levels, as ketoacidosis associated with
JARDIANCE may be present even if blood glucose levels are less than
250 mg/dL. If ketoacidosis is suspected, JARDIANCE should be discontinued,
patient should be evaluated, and prompt treatment should be instituted.
Treatment of ketoacidosis may require insulin, fluid and carbohydrate
replacement.In many
of the postmarketing reports, and particularly in patients with type
1 diabetes, the presence of ketoacidosis was not immediately recognized
and institution of treatment was delayed because presenting blood
glucose levels were below those typically expected for diabetic ketoacidosis
(often less than 250 mg/dL). Signs and symptoms at presentation were
consistent with dehydration and severe metabolic acidosis and included
nausea, vomiting, abdominal pain, generalized malaise, and shortness
of breath. In some but not all cases, factors predisposing to ketoacidosis
such as insulin dose reduction, acute febrile illness, reduced caloric
intake due to illness or surgery, pancreatic disorders suggesting
insulin deficiency (e.g., type 1 diabetes, history of pancreatitis
or pancreatic surgery), and alcohol abuse were identified.Before initiating JARDIANCE,
consider factors in the patient history that may predispose to ketoacidosis
including pancreatic insulin deficiency from any cause, caloric restriction,
and alcohol abuse. In patients treated with JARDIANCE consider monitoring
for ketoacidosis and temporarily discontinuing JARDIANCE in clinical
situations known to predispose to ketoacidosis (e.g., prolonged fasting
due to acute illness or surgery).

5.3 Acute Kidney Injury And Impairment In Renal Function

JARDIANCE causes intravascular volume contraction


[see Warnings and Precautions (


5.1)]


and can cause renal impairment


[see Adverse Reactions
(


6.1)]


. There have been postmarketing
reports of acute kidney injury, some requiring hospitalization and
dialysis, in patients receiving SGLT2 inhibitors, including JARDIANCE;
some reports involved patients younger than 65 years of age.


Before initiating JARDIANCE,
consider factors that may predispose patients to acute kidney injury
including hypovolemia, chronic renal insufficiency, congestive heart
failure and concomitant medications (diuretics, ACE inhibitors, ARBs,
NSAIDs). Consider temporarily discontinuing JARDIANCE in any setting
of reduced oral intake (such as acute illness or fasting) or fluid
losses (such as gastrointestinal illness or excessive heat exposure);
monitor patients for signs and symptoms of acute kidney injury. If
acute kidney injury occurs, discontinue JARDIANCE promptly and institute
treatment. JARDIANCE
increases serum creatinine and decreases eGFR.  Patients with hypovolemia
may be more susceptible to these changes.  Renal function abnormalities
can occur after initiating JARDIANCE


[see Adverse Reactions
(


6.1)]


. Renal function should
be evaluated prior to initiation of JARDIANCE and monitored periodically
thereafter. More frequent renal function monitoring is recommended
in patients with an eGFR below 60 mL/min/1.73 m


2. Use of JARDIANCE is not recommended when eGFR is persistently less
than 45 mL/min/1.73 m


2 and is contraindicated
in patients with an eGFR less than 30 mL/min/1.73 m


2 [see Dosage and Administration (


2.2), Contraindications (


4)
and Use in Specific Populations (


8.6)]


.

5.4 Urosepsis And Pyelonephritis

There have been postmarketing
reports of serious urinary tract infections including urosepsis and
pyelonephritis requiring hospitalization in patients receiving SGLT2
inhibitors, including JARDIANCE. Treatment with SGLT2 inhibitors increases
the risk for urinary tract infections. Evaluate patients for signs
and symptoms of urinary tract infections and treat promptly, if indicated


[see Adverse Reactions (


6)]


.

5.5 Hypoglycemia With Concomitant Use With Insulin And Insulin Secretagogues

Insulin and insulin secretagogues
are known to cause hypoglycemia.  The risk of hypoglycemia is increased
when JARDIANCE is used in combination with insulin secretagogues (e.g.,
sulfonylurea) or insulin


[see Adverse Reactions (


6.1)]


. Therefore, a lower dose
of the insulin secretagogue or insulin may be required to reduce the
risk of hypoglycemia when used in combination with JARDIANCE.

5.6 Necrotizing Fasciitis Of The Perineum (Fournier’S Gangrene)

Reports
of necrotizing fasciitis of the perineum (Fournier’s gangrene), a
rare but serious and life-threatening necrotizing infection requiring
urgent surgical intervention, have been identified in postmarketing
surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors,
including JARDIANCE. Cases have been reported in both females and
males. Serious outcomes have included hospitalization, multiple surgeries,
and death.Patients treated with
JARDIANCE presenting with pain or tenderness, erythema, or swelling
in the genital or perineal area, along with fever or malaise, should
be assessed for necrotizing fasciitis. If suspected, start treatment
immediately with broad-spectrum antibiotics and, if necessary, surgical
debridement. Discontinue JARDIANCE, closely monitor blood glucose
levels, and provide appropriate alternative therapy for glycemic control.

5.7 Genital Mycotic Infections

JARDIANCE increases the risk for genital
mycotic infections


[see Adverse Reactions (


6.1)]


. Patients with a history
of chronic or recurrent genital mycotic infections were more likely
to develop genital mycotic infections. Monitor and treat as appropriate.

5.8 Hypersensitivity Reactions

There have been postmarketing
reports of serious hypersensitivity reactions, (e.g., angioedema)
in patients treated with JARDIANCE. If a hypersensitivity reaction
occurs, discontinue JARDIANCE; treat promptly per standard of care,
and monitor until signs and symptoms resolve. JARDIANCE is contraindicated
in patients with a previous serious hypersensitivity reaction to empagliflozin
or any of the excipients in JARDIANCE


[see Contraindications
(


4)]


.

5.9 Increased Low-Density Lipoprotein Cholesterol (Ldl-C)

Increases in LDL-C can occur
with JARDIANCE


[see Adverse Reactions (


6.1)]


. Monitor and treat as appropriate.

6  Adverse Reactions

  • The following important adverse reactions
  • Are described below and elsewhere in the labeling:Hypotension
  • [see Warnings and Precautions (
  • 5.1)]
  • Ketoacidosis
  • [see Warnings and Precautions (
  • 5.2)]
  • Acute Kidney Injury and Impairment in Renal Function
  • [see Warnings and Precautions (
  • 5.3)]
  • Urosepsis and Pyelonephritis
  • [see Warnings and Precautions
  • (
  • 5.4)]
  • Hypoglycemia with Concomitant Use with Insulin and Insulin
  • Secretagogues
  • [see Warnings and Precautions (
  • 5.5)]
  • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
  • [see Warnings and Precautions (
  • 5.6)]
  • Genital Mycotic Infections
  • [see Warnings and Precautions
  • (
  • 5.7)]
  • Hypersensitivity Reactions
  • [see Warnings and Precautions
  • (
  • 5.8)]
  • Increased Low-Density Lipoprotein Cholesterol (LDL-C)
  • [see Warnings and Precautions (
  • 5.9)]

6.1 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 (


14)]


.


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
m


2).


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 TherapyaPredefined 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).


 Number (%) of PatientsPlacebo


N=995


JARDIANCE
10 mg


N=999


JARDIANCE
25 mg


N=977


Urinary tract infection


a7.6%9.3%7.6%Female genital mycotic infections


b1.5%5.4%6.4%Upper respiratory tract infection3.8%3.1%4.0%Increased urination


c1.0%3.4%3.2%Dyslipidemia3.4%3.9%2.9%Arthralgia2.2%2.4%2.3%Male genital mycotic infections


d0.4%3.1%1.6%Nausea1.4%2.3%1.1%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 (


5.1) and Use in Specific
Populations (


8.5,


8.6)].


Increased Urination                          


In the pool of 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.


Acute Impairment in Renal Function                          


Treatment with 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 (


5.3) and
Use in Specific Populations (


8.5, 


8.6)]


.


In a long-term cardiovascular outcome trial,
the acute impairment in renal function was observed to reverse after
treatment discontinuation suggesting acute hemodynamic changes play
a role in the renal function changes observed with empagliflozin. 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


aObserved cases on treatment.


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


2cApproximately 3 weeks after
end of treatment.  


 Pool of 24-Week Placebo-Controlled StudiesPlaceboJARDIANCE
10 mgJARDIANCE
25 mgBaseline MeanN825830822Creatinine (mg/dL)0.840.850.85eGFR (mL/min/1.73
m


2)


87.387.187.8Week 12 ChangeN771797783Creatinine (mg/dL)0.00 0.020.01eGFR (mL/min/1.73
m


2)


-0.3-1.3-1.4Week 24 ChangeN708769754Creatinine (mg/dL)0.000.010.01eGFR (mL/min/1.73
m


2)


-0.3-0.6-1.4 Moderate Renal Impairment


bPlacebo JARDIANCE
25 mgBaseline MeanN187--187Creatinine (mg/dL)1.49--1.46eGFR (mL/min/1.73
m


2)


44.3--45.4Week 12 ChangeN176--179Creatinine (mg/dL)0.01--0.12eGFR (mL/min/1.73
m


2)


0.1---3.8Week 24 ChangeN170--171Creatinine (mg/dL)0.01--0.10eGFR (mL/min/1.73
m


2)


0.2---3.2Week 52 ChangeN164--162Creatinine (mg/dL)0.02--0.11eGFR (mL/min/1.73
m


2)


-0.3---2.8Post-treatment Change


cN98--103Creatinine (mg/dL)0.03--0.02eGFR (mL/min/1.73
m


2)


0.16--1.48Hypoglycemia                          


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 (


5.5)]


.


Table 3 Incidence of Overall


a and
Severe


b Hypoglycemic Events in Placebo-Controlled
Clinical Studies


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


bSevere hypoglycemic events: requiring
assistance regardless of blood glucose


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


dInsulin dose could not
be adjusted during the initial 18 week treatment period


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 Basal
Insulin +/-


Metformin(18 weeks


d)


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%In Combination with MDI
Insulin +/-Metformin


(18 weeks


d)


Placebo


(n=188)


JARDIANCE 10 mg


(n=186)


JARDIANCE 25 mg


(n=189)


Overall (%)37.2%39.8%41.3%Severe (%)0.5%0.5%0.5%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 (


5.4) and Use in Specific
Populations (


8.5)]


.


Laboratory TestsIncrease 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 (


5.9)]


. 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.

6.2 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 (
  • 5.2)]
  • Urosepsis and Pyelonephritis
  • [see Warnings and Precautions
  • (
  • 5.4)]
  • Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)
  • [see Warnings and Precautions (
  • 5.6)]
  • Angioedema
  • [see Warnings and Precautions (
  • 5.8)]
  • Skin Reactions (e.g., rash, urticaria)

7.1 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 (


5.1)]


.

7.2 Insulin Or Insulin Secretagogues

Coadministration of empagliflozin with insulin or insulin secretagogues
increases the risk for hypoglycemia


[see Warnings and Precautions
(


5.5)].

7.3 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.

7.4 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.

8.1 Pregnancy

Risk SummaryBased 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 ConsiderationsDisease-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, stillbirth, and macrosomia related morbidity.


DataAnimal DataEmpagliflozin 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 weights and renal tubular and pelvic dilatation at
100 mg/kg/day, which approximates 13-times the maximum clinical dose
of 25 mg, based on AUC.  These findings were not observed after a
13 week drug-free recovery period. These outcomes occurred with drug
exposure during periods of renal development in rats that correspond
to the late second and third trimester of human renal development.


In embryo-fetal development
studies in rats and rabbits, empagliflozin was administered for intervals
coinciding with the first trimester period of organogenesis in humans.
Doses up to 300 mg/kg/day, which approximates 48-times (rats) and
128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC),
did not result in adverse developmental effects. In rats, at higher
doses of empagliflozin causing maternal toxicity, malformations of
limb bones increased in fetuses at 700 mg/kg/day or 154-times the
25 mg maximum clinical dose. Empagliflozin crosses the placenta and
reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin
resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times
the 25 mg maximum clinical dose.In pre- and postnatal development studies
in pregnant rats, empagliflozin was administered from gestation day
6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately
16 times the 25 mg maximum clinical dose) without maternal toxicity.
 Reduced body weight was observed in the offspring at greater than
or equal to 30 mg/kg/day (approximately 4 times the 25 mg maximum
clinical dose).

8.2 Lactation

Risk SummaryThere is no information
regarding the presence of JARDIANCE in human milk, the effects of
JARDIANCE on the breastfed infant or the effects on milk production. 
Empagliflozin is present in the milk of lactating rats


[see


Data]


.  Since human kidney maturation occurs


in utero and during the first 2 years of life when lactational exposure may
occur, there may be risk to the developing human kidney.


Because of the potential for
serious adverse reactions in a breastfed infant, including the potential
for empagliflozin to affect postnatal renal development, advise women
that use of JARDIANCE is not recommended while breastfeeding.Data


Empagliflozin was present at a low level
in rat fetal tissues after a single oral dose to the dams at gestation
day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634
-5, and was greater than one from 2 to 24 hours post-dose. The mean
maximal milk to plasma ratio of 5 occurred at 8 hours post-dose, suggesting
accumulation of empagliflozin in the milk. Juvenile rats directly
exposed to empagliflozin showed a risk to the developing kidney (renal
pelvic and tubular dilatations) during maturation.

8.4 Pediatric Use

The safety and effectiveness of JARDIANCE in pediatric patients
under 18 years of age have not been established.

8.5 Geriatric Use

No JARDIANCE dosage change is recommended
based on age


[see Dosage and Administration (


2)]


.  In studies assessing the efficacy
of empagliflozin in improving glycemic control in patients with type
2 diabetes, a total of 2721 (32%) patients treated with empagliflozin
were 65 years of age and older, and 491 (6%) were 75 years of age
and older.  JARDIANCE is expected to have diminished glycemic efficacy
in elderly patients with renal impairment


[see Use in Specific
Populations (


8.6)]


.  The
risk of volume depletion-related adverse reactions increased in patients
who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo,
JARDIANCE 10 mg, and JARDIANCE 25 mg.  The risk of urinary tract infections
increased in patients who were 75 years of age and older to 10.5%,
15.7%, and 15.1% in patients randomized to placebo, JARDIANCE 10 mg,
and JARDIANCE 25 mg, respectively


[see Warnings and Precautions
(


5.1) and Adverse Reactions (


6.1)]


.

8.6 Renal Impairment

The efficacy and safety of JARDIANCE
were evaluated in a study of patients with mild and moderate renal
impairment


[see Clinical Studies (


14.1)]


.  In this study, 195 patients exposed to JARDIANCE
had an eGFR between 60 and 90 mL/min/1.73 m


2, 91 patients exposed to JARDIANCE had an eGFR between 45 and 60
mL/min/1.73 m


2 and 97 patients exposed
to JARDIANCE had an eGFR between 30 and 45 mL/min/1.73 m


2.  The glucose lowering benefit of JARDIANCE 25 mg
decreased in patients with worsening renal function.  The risks of
renal impairment


[see Warnings and Precautions (


5.3)]


, volume depletion adverse
reactions and urinary tract infection-related adverse reactions increased
with worsening renal function.


In a large cardiovascular outcomes study,
there were 1819 patients with eGFR below 60 mL/min/1.73 m


2.  The cardiovascular death findings in this subgroup
were consistent with the overall findings


[see Clinical Studies
(


14.2)].


The efficacy and safety of JARDIANCE have
not been established in patients with severe renal impairment, with
ESRD, or receiving dialysis.  JARDIANCE is not expected to be effective
in these patient populations


[see Dosage and Administration
(


2.2), Contraindications (


4) and Warnings and Precautions (


5.1, 


5.3)].

8.7 Hepatic Impairment

JARDIANCE may be used in patients
with hepatic impairment


[see Clinical Pharmacology (


12.3)]


.

10  Overdosage

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.

11  Description

JARDIANCE tablets contain empagliflozin,
an orally-active inhibitor of the sodium-glucose co-transporter 2
(SGLT2).The chemical
name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-,
(1S).Its molecular
formula is C


23H


27ClO


7 and the molecular weight is 450.91. The structural
formula is:


Empagliflozin is a white to yellowish, non-hygroscopic
powder.  It is very slightly soluble in water, sparingly soluble in
methanol, slightly soluble in ethanol and acetonitrile; soluble in
50% acetonitrile/water; and practically insoluble in toluene.Each film-coated tablet of JARDIANCE
contains 10 mg or 25 mg of empagliflozin (free base) and the following
inactive ingredients: lactose monohydrate, microcrystalline cellulose,
hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon
dioxide and magnesium stearate.  In addition, the film coating contains
the following inactive ingredients: hypromellose, titanium dioxide,
talc, polyethylene glycol, and yellow ferric oxide.

12.1 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.

12.2 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 (


14)].


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 ElectrophysiologyIn 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.

12.3 Pharmacokinetics

AbsorptionThe
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 C


max 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 C


max 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.


DistributionThe 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%.


MetabolismNo 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. 


In 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.


EliminationThe
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 PopulationsRenal ImpairmentIn
patients with mild (eGFR: 60 to less than 90 mL/min/1.73 m


2), moderate (eGFR: 30 to less than 60 mL/min/1.73
m


2), and severe (eGFR: less than 30 mL/min/1.73
m


2) 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 ImpairmentIn 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 C


max increased by approximately 4%, 23%, and 48%, respectively, compared
to subjects with normal hepatic function.


Effects of Age, Body Mass Index,
Gender, and RaceBased 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 (


8.5)]


.


PediatricStudies characterizing the pharmacokinetics of empagliflozin in
pediatric patients have not been performed.


Drug Interactions


In vitro Assessment of Drug Interactions


Empagliflozin does not inhibit, inactivate, or induce
CYP450 isoforms. 


In vitro data suggest that the
primary route of metabolism of empagliflozin in humans is glucuronidation
by the uridine 5'-diphospho-glucuronosyltransferases UGT1A3, UGT1A8,
UGT1A9, and UGT2B7.  Empagliflozin does not inhibit UGT1A1, UGT1A3,
UGT1A8, UGT1A9, or UGT2B7.  Therefore, no effect of empagliflozin
is anticipated on concomitantly administered drugs that are substrates
of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8, UGT1A9, or
UGT2B7.  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, and simvastatin in healthy
volunteers and with or without coadministration of hydrochlorothiazide
and torsemide in patients with type 2 diabetes (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 C


max 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, torsemide, 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 C


max 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 Microgynon


®;


gadministered as ramipril

13.1 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.  These tumors may be associated
with a metabolic pathway predominantly present in the male mouse kidney.


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).

14.1 Glycemic Control

JARDIANCE has been studied as
monotherapy and in combination with metformin, sulfonylurea, pioglitazone,
linagliptin, 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.MonotherapyA
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-naïve
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 JARDIANCEaModified 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


 JARDIANCE


10 mg


N=224


JARDIANCE


25 mg


N=224


Placebo


N=228


HbA1c (%)


a Baseline (mean)7.97.97.9 Change from baseline (adjusted mean)-0.7-0.80.1 Difference from placebo (adjusted
mean) (97.5% CI)-0.7


b (-0.9, -0.6)


-0.9


b (-1.0, -0.7)


-- Patients [n (%)] achieving HbA1c <7%72 (35%)88 (44%)25 (12%)FPG (mg/dL)


c Baseline (mean)153153155 Change from baseline (adjusted mean)-19-2512 Difference from placebo (adjusted
mean) (95% CI)-31 (-37, -26)-36 (-42, -31)--Body Weight Baseline (mean) in kg787878 % change from baseline (adjusted
mean)-2.8-3.2-0.4 Difference from placebo (adjusted
mean) (95% CI)-2.5


b (-3.1, -1.9)


-2.8


b (-3.4, -2.2)


--Figure 3 Adjusted
Mean HbA1c Change at Each Time Point (Completers) and at Week 24 (mITT
Population) - LOCFAt 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.Add-On Combination Therapy with
MetforminA 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 MetforminaModified 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


 JARDIANCE


10 mg +


Metformin


N=217


JARDIANCE


25 mg +


Metformin


N=213


Placebo +


Metformin


N=207


HbA1c (%)


a Baseline (mean)7.97.97.9 Change from baseline (adjusted mean)-0.7-0.8-0.1 Difference from placebo + metformin
(adjusted mean) (95% CI)-0.6


b (-0.7, -0.4)


-0.6


b (-0.8, -0.5)


-- Patients [n (%)] achieving HbA1c
<7%75 (38%)74 (39%)23 (13%)FPG (mg/dL)


c Baseline (mean)155149156 Change from baseline (adjusted mean)-20-226 Difference from placebo + metformin
(adjusted mean)-26-29--Body Weight Baseline mean in kg828280 % change from baseline (adjusted
mean)-2.5-2.9-0.5 Difference from placebo (adjusted
mean) (95% CI)-2.0


b (-2.6, -1.4)


-2.5


b (-3.1, -1.9)


--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.Initial
Combination Therapy with MetforminA total of
1364 patients with type 2 diabetes participated in a double-blind,
randomized, active-controlled study to evaluate the efficacy and safety
of JARDIANCE in combination with metformin as initial therapy compared
to the corresponding individual components.


Treatment-naïve 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 10.5% were randomized to
one of 8 active-treatment arms: JARDIANCE 10 mg or 25 mg; metformin
1000 mg, or 2000 mg; JARDIANCE 10 mg in combination with 1000 mg or
2000 mg metformin; or JARDIANCE 25 mg in combination with 1000 mg
or 2000 mg metformin.At Week 24, initial therapy of JARDIANCE in combination with metformin
provided statistically significant reductions in HbA1c (p-value <0.01)
compared to the individual components (see Table 6).Table 6 Glycemic Parameters at 24 Weeks in a Study Comparing
JARDIANCE and Metformin to the Individual Components as Initial TherapyaMetformin total daily
dose, administered in two equally divided doses per day.


bp-value ≤0.0062 (modified intent to
treat population [observed case] MMRM model included treatment, renal
function, region, visit, visit by treatment interaction, and baseline
HbA1c).


cp-value ≤0.0056 (modified
intent to treat population [observed case] MMRM model included treatment,
renal function, region, visit, visit by treatment interaction, and
baseline HbA1c).


 JARDIANCE


10 mg +


Metformin


1000 mg


aN=161


JARDIANCE


10 mg +


Metformin


2000 mg


aN=167


JARDIANCE


25 mg +


Metformin


1000 mg


aN=165


JARDIANCE


25 mg +


Metformin


2000 mg


aN=169


JARDIANCE


10 mg


N=169


JARDIANCE


25 mg


N=163


Metformin


1000 mg


aN=167


Metformin


2000 mg


aN=162


HbA1c (%)        Baseline (mean)8.78.78.88.78.68.98.78.6Change from baseline (adjusted
mean)-2.0-2.1-1.9-2.1-1.4-1.4-1.2-1.8Comparison vs JARDIANCE (adjusted
mean) (95% CI)-0.6


b(-0.9, -0.4)


-0.7


b(-1.0, -0.5)


-0.6


c(-0.8, -0.3)


-0.7


c(-1.0, -0.5)


--------Comparison vs metformin (adjusted
mean) (95% CI)-0.8


b(-1.0, -0.6)


-0.3


b(-0.6, -0.1)


-0.8


c(-1.0, -0.5)


-0.3


c(-0.6, -0.1)


--------Add-On Combination
Therapy with Metformin and SulfonylureaA 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 (p-value <0.0001), FPG, and body weight compared
with placebo (see Table 7).Table 7 Results at Week 24 from a Placebo-Controlled Study
for JARDIANCE in Combination with Metformin and SulfonylureaaModified 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


 JARDIANCE


10 mg + Metformin


+ SU


N=225


JARDIANCE


25 mg + Metformin


+ SU


N=216


Placebo
+


Metformin + SU


N=225


HbA1c (%)


a Baseline (mean)8.18.18.2 Change from baseline (adjusted mean)-0.8-0.8-0.2 Difference from placebo (adjusted
mean) (95% CI)-0.6


b (-0.8, -0.5)


-0.6


b (-0.7, -0.4)


-- Patients [n (%)] achieving HbA1c
<7%55 (26%)65 (32%)20 (9%)FPG (mg/dL)


c Baseline (mean)151156152 Change from baseline (adjusted mean)-23-236 Difference from placebo (adjusted
mean)-29-29--Body Weight Baseline mean in kg777876 % change from baseline (adjusted
mean)-2.9-3.2-0.5 Difference from placebo (adjusted
mean) (95% CI)-2.4


b (-3.0, -1.8)


-2.7


b (-3.3, -2.1)


--In Combination
with Linagliptin as Add-On to Metformin Therapy A total of 686 patients with type 2 diabetes participated in a
double-blind, active-controlled study to evaluate the efficacy and
safety of JARDIANCE 10 mg or 25 mg in combination with linagliptin
5 mg compared to the individual components.


Patients with type 2 diabetes inadequately
controlled on at least 1500 mg of metformin per day entered a single-blind
placebo run-in period for 2 weeks.  At the end of the run-in period,
patients who remained inadequately controlled and had an HbA1c between
7 and 10.5% were randomized 1:1:1:1:1 to one of 5 active-treatment
arms of JARDIANCE 10 mg or 25 mg, linagliptin 5 mg, or linagliptin
5 mg in combination with 10 mg or 25 mg JARDIANCE as a fixed dose
combination tablet.At Week 24, JARDIANCE 10 mg or 25 mg used in combination with linagliptin
5 mg provided statistically significant improvement in HbA1c (p-value
<0.0001) and FPG (p-value <0.001) compared to the individual
components in patients who had been inadequately controlled on metformin. 
Treatment with JARDIANCE/linagliptin 25 mg/5 mg or JARDIANCE/linagliptin
10 mg/5 mg daily also resulted in a statistically significant reduction
in body weight compared to linagliptin 5 mg (p-value <0.0001). 
There was no statistically significant difference in body weight compared
to JARDIANCE alone.Active-Controlled Study versus Glimepiride in Combination
with MetforminThe 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 8,
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 8  Results at Week 52 from an Active-Controlled Study
Comparing JARDIANCE to Glimepiride as Add-On Therapy in Patients Inadequately
Controlled on MetforminaModified 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 glimepiride, n=779


 JARDIANCE
25 mg +


Metformin


N=765


Glimepiride
+


Metformin


N=780


HbA1c (%)


a Baseline (mean)7.97.9 Change from baseline (adjusted mean)-0.7-0.7 Difference from glimepiride (adjusted
mean) (97.5% CI)-0.07


b (-0.15, 0.01)


--FPG (mg/dL)


d Baseline (mean)150150 Change from baseline (adjusted mean)-19-9 Difference from glimepiride (adjusted
mean)-11--Body Weight Baseline mean in kg82.583 % change from baseline (adjusted
mean)-3.92.0 Difference from glimepiride (adjusted
mean) (95% CI)-5.9


c (-6.3, -5.5)


--Figure 4 Adjusted
mean HbA1c Change at Each Time Point (Completers) and at Week 52 (mITT
Population) - LOCFAt 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).At Week 104, the adjusted mean
change from baseline in HbA1c was -0.75% for JARDIANCE 25 mg and
-0.66% for glimepiride.  The adjusted mean treatment difference was
-0.09% with a 97.5% confidence interval of (-0.32%, 0.15%), excluding
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.   The Week 104 analysis included data
with and without concomitant glycemic rescue medication, as well as
off-treatment data.  Missing data for patients not providing any information
at the visit were imputed based on the observed off-treatment data. 
In this multiple imputation analysis, 13.9% of the data were imputed
for JARDIANCE 25 mg and 12.9% for glimepiride.At Week 104, JARDIANCE 25 mg daily resulted
in a statistically significant difference in change from baseline
for body weight compared to glimepiride (-3.1 kg for JARDIANCE 25
mg vs. +1.3 kg for glimepiride; ANCOVA-LOCF, p-value <0.0001).Add-On Combination Therapy
with Pioglitazone with or without MetforminA
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 (p-value <0.0001), FPG, and body weight compared
with placebo (see Table 9).Table 9 Results of Placebo-Controlled Study for JARDIANCE
in Combination Therapy with PioglitazoneaModified 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


 JARDIANCE


10 mg +


Pioglitazone


N=165


JARDIANCE


25 mg +


Pioglitazone


N=168


Placebo +


Pioglitazone


N=165


HbA1c (%)


a Baseline (mean)8.18.18.2 Change from baseline (adjusted mean)-0.6-0.7-0.1 Difference from placebo + pioglitazone
(adjusted mean) (95% CI)-0.5


b (-0.7, -0.3)


-0.6


b (-0.8, -0.4)


-- Patients [n (%)] achieving HbA1c
<7% 36 (24%)48 (30%)12 (8%)FPG (mg/dL)


c Baseline (mean)152152152 Change from baseline (adjusted mean)-17-227 Difference from placebo + pioglitazone
(adjusted mean) (97.5% CI)-23


b (-31.8, -15.2)


-28


b (-36.7, -20.2)


--Body Weight Baseline mean in kg787978 % change from baseline (adjusted
mean)-2.0-1.80.6 Difference from placebo (adjusted
mean) (95% CI)-2.6


b (-3.4, -1.8)


-2.4


b (-3.2, -1.6)


--Add-On Combination
with Insulin with or without Metformin and/or SulfonylureasA 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 10).  JARDIANCE
10 mg or 25 mg daily also resulted in statistically significantly
greater percent body weight reduction compared to placebo.Table 10 Results at Week 18 and 78 for a Placebo-Controlled
Study for JARDIANCE in Combination with InsulinaModified intent to treat
population. Last observation on study (LOCF) was used to impute missing
data at Week 18 and 78. At Week 18, 21.3%, 30.3%, and 21.8% was imputed
for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo,
respectively. At Week 78, 32.5%, 38.1% and 42.4% 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, and region;
FPG: MMRM model includes baseline FPG, baseline HbA1c, treatment,
region, visit and visit by treatment interaction. Body weight: MMRM
model includes baseline body weight, baseline HbA1c, treatment, region,
visit and visit by treatment interaction.


cp-value=0.0049


dp-value=0.0052


ep-value=0.0463


 18 weeks


(no insulin adjustment)


78 weeks


(adjustable insulin dose after
18 weeks)


 JARDIANCE


10 mg +


Insulin


N=169


JARDIANCE


25 mg +


Insulin


N=155


Placebo +


Insulin


N=170


JARDIANCE


10 mg +


Insulin


N=169


JARDIANCE


25 mg +


Insulin


N=155


Placebo +


Insulin


N=170


HbA1c (%)


a Baseline (mean)8.38.38.28.38.38.2 Change from baseline (adjusted mean)-0.6-0.70-0.4-0.60.1 Difference from placebo (adjusted
mean) (97.5% CI)-0.6


b(-0.8, -0.4)


-0.7


b(-0.9, -0.5)


---0.5


b(-0.7, -0.3)


-0.7


b(-0.9, -0.5)


-- Patients (%) achieving HbA1c <7%18.019.55.512.017.56.7FPG (mg/dL)  Baseline (mean)138146142138146142 Change from baseline (adjusted mean,
SE)-17.9


(3.2)


-19.1


(3.3)


10.4 (3.1)-10.1 (3.2)-15.2 (3.4)2.8 (3.2) Difference from placebo (adjusted
mean) (95% CI)-28.2


b (-37.0, -19.5)


-29.5


b (-38.4, -20.6)


---12.9


c(-21.9, 3.9)


-17.9


b(-27.0, -8.8)


--Body Weight Baseline mean in kg929590929590 % change from baseline (adjusted
mean)-1.8-1.4-0.1-2.4-2.40.7 Difference from placebo (adjusted
mean) (95% CI)-1.7


d(-3.0, -0.5)


-1.3


e(-2.5, -0.0)


---3.0


b(-4.4, -1.7)


-3.0


b(-4.4, -1.6)


--Add-on Combination
with MDI Insulin with or without MetforminA total
of 563 patients with type 2 diabetes inadequately controlled on multiple
daily injections (MDI) of insulin (total daily dose >60 IU), alone
or in combination with metformin, participated in a double-blind,
placebo-controlled study to evaluate the efficacy of JARDIANCE as
add-on therapy to MDI insulin over 18 weeks.


Patients entered a 2-week placebo run-in
period on MDI insulin with or without metformin 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. The mean total daily insulin dose at baseline
for JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo was 88.6 IU, 90.4
IU, and 89.9 IU, respectively.JARDIANCE 10 mg or 25 mg daily used in combination
with MDI insulin (with or without metformin) provided statistically
significant reductions in HbA1c compared to placebo after 18 weeks
of treatment (see Table 11).Table 11 Results at Week 18 for a Placebo-Controlled Study
for JARDIANCE in Combination with Insulin and with or without MetforminaModified intent to treat
population. Last observation on study (LOCF) was used to impute missing
data at Week 18. At Week 18, 23.7%, 22.8% and 23.4% 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,
geographical region, and background medication).


 JARDIANCE 10 mg


+ Insulin


+/- Metformin


N=186


JARDIANCE 25 mg


+ Insulin


+/- Metformin


N=189


Placebo


+ Insulin


+/- Metformin


N=188


HbA1c (%)


a      Baseline (mean)8.48.38.3      Change from baseline (adjusted
mean)-0.9-1.0-0.5      Difference from placebo
(adjusted mean) (95% CI)-0.4


b (-0.6, -0.3)


-0.5


b (-0.7, -0.4)


--During an extension period
with treatment for up to 52 weeks, insulin could be adjusted to achieve
defined glucose target levels.  The change from baseline in HbA1c
was maintained from 18 to 52 weeks with both JARDIANCE 10 mg and 25
mg.  After 52 weeks, JARDIANCE 10 mg or 25 mg daily resulted in statistically
greater percent body weight reduction compared to placebo (p-value
<0.0001).  The mean change in body weight from baseline was -1.95
kg for JARDIANCE 10 mg, and -2.04 kg for JARDIANCE 25 mg.Renal ImpairmentA total of 738 patients with type 2 diabetes and a baseline
eGFR less than 90 mL/min/1.73 m


2 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 m


2), 374 patients with moderate
renal impairment (eGFR 30 to less than 60 mL/min/1.73 m


2), and 74 with severe renal impairment (eGFR less
than 30 mL/min/1.73 m


2).  A total of 194
patients with moderate renal impairment had a baseline eGFR of 30
to less than 45 mL/min/1.73 m


2 and 180
patients a baseline eGFR of 45 to less than 60 mL/min/1.73 m


2. 


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 12).  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 m


2, 45
to less than 60 mL/min/1.73 m


2, and 30
to less than 45 mL/min/1.73 m


2, respectively


[see Dosage and Administration (


2)
and Use in Specific Populations (


8.6)]


. 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 m


2, 45 to less
than 60 mL/min/1.73 m


2, and 30 to less
than 45 mL/min/1.73 m


2, respectively.


Table 12 Results at Week 24 (LOCF) of Placebo-Controlled
Study for JARDIANCE in Patients with Type 2 Diabetes and Renal Impairmentap-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 m


2- 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.


 Mild and
Moderate Impairment


b JARDIANCE
25 mgHbA1c Number of patients n=284 Comparison vs placebo
(adjusted mean) (95% CI)-0.5


a (-0.6, -0.4)


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 (


2.2) and Use in Specific Populations (


8.6)]


.

14.2 Cardiovascular Outcomes In Patients With Type 2 Diabetes Mellitus And Atherosclerotic Cardiovascular Disease

The effect of JARDIANCE on cardiovascular
risk in adult patients with type 2 diabetes and established, stable,
atherosclerotic cardiovascular disease was evaluated in the EMPA-REG
OUTCOME study, a multicenter, multi-national, randomized, double-blind
parallel group trial.  The study compared the risk of experiencing
a major adverse cardiovascular event (MACE) between JARDIANCE and
placebo when these were added to and used concomitantly with standard
of care treatments for diabetes and atherosclerotic cardiovascular
disease. Coadministered antidiabetic medications were to be kept stable
for the first 12 weeks of the trial.  Thereafter, antidiabetic and
atherosclerotic therapies could be adjusted, at the discretion of
investigators, to ensure participants were treated according to the
standard care for these diseases. A total of 7020 patients were treated (JARDIANCE
10 mg = 2345; JARDIANCE 25 mg = 2342; placebo = 2333) and followed
for a median of 3.1 years.  Approximately 72% of the study population
was Caucasian, 22% was Asian, and 5% was Black.  The mean age was
63 years and approximately 72% were male.All patients in the study had inadequately
controlled type 2 diabetes mellitus at baseline (HbA1c greater than
or equal to 7%).  The mean HbA1c at baseline was 8.1% and 57% of participants
had had diabetes for more than 10 years.  Approximately 31%, 22% and
20% reported a past history of neuropathy, retinopathy and nephropathy
to investigators respectively and the mean eGFR was 74 mL/min/1.73
m


2.  At baseline, patients were treated
with one (~30%) or more (~70%) antidiabetic medications including
metformin (74%), insulin (48%), and sulfonylurea (43%).


All patients had established
atherosclerotic cardiovascular disease at baseline including one (82%)
or more (18%) of the following; a documented history of coronary artery
disease (76%), stroke (23%) or peripheral artery disease (21%).  At
baseline, the mean systolic blood pressure was 136 mmHg, the mean
diastolic blood pressure was 76 mmHg, the mean LDL was 86 mg/dL, the
mean HDL was 44 mg/dL, and the mean urinary albumin to creatinine
ratio (UACR) was 175 mg/g.  At baseline, approximately 81% of patients
were treated with renin angiotensin system inhibitors, 65% with beta-blockers,
43% with diuretics, 77% with statins, and 86% with antiplatelet agents
(mostly aspirin).The primary endpoint in EMPA-REG OUTCOME was the time to first occurrence
of a Major Adverse Cardiac Event (MACE).  A major adverse cardiac
event was defined as occurrence of either a cardiovascular death or
a nonfatal myocardial infarction (MI) or a nonfatal stroke.  The statistical
analysis plan had pre-specified that the 10 and 25 mg doses would
be combined.  A Cox proportional hazards model was used to test for
non-inferiority against the pre-specified risk margin of 1.3 for the
hazard ratio of MACE and superiority on MACE if non-inferiority was
demonstrated. Type-1 error was controlled across multiples tests using
a hierarchical testing strategy.JARDIANCE significantly reduced the risk
of first occurrence of primary composite endpoint of cardiovascular
death, non-fatal myocardial infarction, or non-fatal stroke (HR: 0.86;
95% CI 0.74, 0.99). The treatment effect was due to a significant
reduction in the risk of cardiovascular death in subjects randomized
to empagliflozin (HR: 0.62; 95% CI 0.49, 0.77), with no change in
the risk of non-fatal myocardial infarction or non-fatal stroke (see
Table 13 and Figure 5 and 6). Results for the 10 mg and 25 mg empagliflozin
doses were consistent with results for the combined dose groups.Table 13   Treatment Effect for the Primary Composite Endpoint,
and its Components


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


bp−value for superiority (2−sided) 0.04


cTotal number of events


 PlaceboN=2333


JARDIANCEN=4687


Hazard
ratio vs


placebo


(95% CI) Composite of
cardiovascular death, non-fatal myocardial infarction, non-fatal
stroke (time to first occurrence)


b 282 (12.1%)
490 (10.5%)
0.86 (0.74,
0.99) Non-fatal myocardial infarction


c 121 (5.2%)
213 (4.5%)
0.87 (0.70,
1.09) Non-fatal stroke


c 60 (2.6%) 150 (3.2%)
1.24 (0.92,
1.67) Cardiovascular death


c 137 (5.9%)
172 (3.7%)
0.62 (0.49,
0.77) The efficacy of JARDIANCE on cardiovascular
death was generally consistent across major demographic and disease
subgroups. Vital
status was obtained for 99.2% of subjects in the trial.  A total of
463 deaths were recorded during the EMPA-REG OUTCOME trial.  Most
of these deaths were categorized as cardiovascular deaths.  The non-cardiovascular
deaths were only a small proportion of deaths, and were balanced between
the treatment groups (2.1% in patients treated with JARDIANCE, and
2.4% of patients treated with placebo).

16  How Supplied/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.StorageStore at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

17  Patient Counseling Information

Advise the patient to read the FDA-approved
patient labeling (Medication Guide).InstructionsInstruct patients to read the Medication Guide before starting JARDIANCE
therapy and to reread it each time the prescription is renewed. Instruct
patients to inform their doctor or pharmacist if they develop any
unusual symptom, or if any known symptom persists or worsens.


Inform patients of the potential
risks and benefits of JARDIANCE and of alternative modes of therapy.
Also inform patients about the importance of adherence to dietary
instructions, regular physical activity, periodic blood glucose monitoring
and HbA1c testing, recognition and management of hypoglycemia and
hyperglycemia, and assessment for diabetes complications.  Advise
patients to seek medical advice promptly during periods of stress
such as fever, trauma, infection, or surgery, as medication requirements
may change.Instruct
patients to take JARDIANCE only as prescribed. If a dose is missed,
it should be taken as soon as the patient remembers.  Advise patients
not to double their next dose.Inform patients that the most common adverse
reactions associated with the use of JARDIANCE are urinary tract infections
and mycotic genital infections.Advise pregnant women, and females of reproductive
potential of the potential risk to a fetus with treatment with JARDIANCE


[see Use in Specific Populations (


8.1)]


. Instruct females of reproductive potential to report
pregnancies to their physicians as soon as possible.


Advise women that breastfeeding is not recommended
during treatment with JARDIANCE


[see Use in Specific Populations
(


8.2)].


HypotensionInform patients that hypotension may occur with JARDIANCE and advise
them to contact their healthcare provider if they experience such
symptoms


[see Warnings and Precautions (


5.1)]


. Inform patients that dehydration may increase
the risk for hypotension, and to have adequate fluid intake.


KetoacidosisInform patients that ketoacidosis is a serious life-threatening
condition. Cases of ketoacidosis have been reported during use of
JARDIANCE. Instruct patients to check ketones (when possible) if symptoms
consistent with ketoacidosis occur even if blood glucose is not elevated.
If symptoms of ketoacidosis (including nausea, vomiting, abdominal
pain, tiredness, and labored breathing) occur, instruct patients to
discontinue JARDIANCE and seek medical advice immediately


[see Warnings and Precautions (


5.2)]


.


Acute Kidney InjuryInform patients that acute
kidney injury has been reported during use of JARDIANCE. Advise patients
to seek medical advice immediately if they have reduced oral intake
(such as due to acute illness or fasting) or increased fluid losses
(such as due to vomiting, diarrhea, or excessive heat exposure), as
it may be appropriate to temporarily discontinue JARDIANCE use in
those settings


[see Warnings and Precautions (


5.3)]


.


Serious Urinary Tract InfectionsInform patients of the potential for urinary tract infections,
which may be serious. Provide them with information on the symptoms
of urinary tract infections. Advise them to seek medical advice if
such symptoms occur


[see Warnings and Precautions (


5.4)


].


Necrotizing Fasciitis
of the Perineum (Fournier’s Gangrene)Inform
patients that necrotizing infections of the perineum (Fournier’s gangrene)
have occurred with JARDIANCE. Counsel patients to promptly seek medical
attention if they develop pain or tenderness, redness, or swelling
of the genitals or the area from the genitals back to the rectum,
along with a fever above 100.4°F or malaise


[see Warnings
and Precautions (


5.6)]


.


Genital Mycotic Infections
in Females (e.g., Vulvovaginitis)Inform female
patients that vaginal yeast infections may occur and provide them
with information on the signs and symptoms of vaginal yeast infections.
Advise them of treatment options and when to seek medical advice


[see Warnings and Precautions (


5.7)]


.


Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis) Inform male patients that yeast infection of penis (e.g.,
balanitis or balanoposthitis) may occur, especially in uncircumcised
males and patients with chronic and recurrent infections. Provide
them with information on the signs and symptoms of balanitis and balanoposthitis
(rash or redness of the glans or foreskin of the penis). Advise them
of treatment options and when to seek medical advice


[see
Warnings and Precautions (


5.7)]


.


Hypersensitivity
ReactionsInform patients that serious hypersensitivity
reactions, such as urticaria and angioedema, have been reported with
JARDIANCE. Advise patients to report immediately any skin reaction
or angioedema, and to discontinue drug until they have consulted prescribing
physician


[see Warnings and Precautions (


5.8)]


.


Laboratory TestsInform patients that renal function should be assessed prior to
initiation of JARDIANCE and monitored periodically thereafter.


Inform patients that elevated
glucose in urinalysis is expected when taking JARDIANCE.Inform patients that response
to all diabetic therapies should be monitored by periodic measurements
of blood glucose and HbA1c levels, with a goal of decreasing these
levels toward the normal range.  Hemoglobin A1c monitoring is especially
useful for evaluating long-term glycemic control.

Other

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


Licensed
from:


Boehringer Ingelheim International GmbH, Ingelheim,
Germany


Boehringer
Ingelheim Pharmaceuticals, Inc. either owns or uses the Jardiance


® and EMPA-REG OUTCOME


® trademarks under license.


The other trademarks referenced are owned
by third parties not affiliated with Boehringer Ingelheim Pharmaceuticals,
Inc.Copyright © 2018
Boehringer Ingelheim International GmbH


ALL RIGHTS RESERVED


IT5728SJ232018

Spl Medguide

  • This MEDICATION GUIDE has been approved
  • By the U.S. Food and Drug Administration.Revised: October 2018MEDICATION GUIDE
  • JARDIANCE
  • ® (jar DEE ans)
  • (empagliflozin)
  • Tablets
  • What is the
  • Most important information I should know about JARDIANCE?JARDIANCE can cause serious side effects, including:
  • Dehydration. JARDIANCE can cause some people
  • To have dehydration (the loss of body water and salt). Dehydration
  • May cause you to feel dizzy, faint, light-headed, or weak, especially
  • When you stand up (orthostatic hypotension).
  • You may be at higher risk of dehydration if you:
  • Have low blood pressuretake medicines to lower your blood pressure, including diuretics
  • (water pills)are on low sodium (salt) diethave kidney problemsare 65 years of age or olderVaginal yeast infection. Women who take JARDIANCE
  • May get vaginal yeast infections. Symptoms of a vaginal yeast infection
  • Include:
  • Vaginal odorwhite or yellowish vaginal discharge (discharge may be lumpy
  • Or look like cottage cheese)vaginal itchingYeast infection of the penis (balanitis or balanoposthitis). Men who take JARDIANCE may get a yeast infection of the skin around
  • The penis. Certain men who are not circumcised may have swelling of
  • The penis that makes it difficult to pull back the skin around the
  • Tip of the penis. Other symptoms of yeast infection of the penis include:
  • Redness, itching, or swelling of the penisrash of the penisfoul smelling discharge from the penispain in the skin around penis Talk to your doctor about what to do if you get symptoms of
  • A yeast infection of the vagina or penis. Your doctor may suggest
  • You use an over-the-counter antifungal medicine. Talk to your doctor
  • Right away if you use an over-the-counter antifungal medication and
  • Your symptoms do not go away.
  • What is JARDIANCE?JARDIANCE is a prescription medicine used:
  • Along with diet and exercise to lower blood sugar in adults
  • With type 2 diabetes.to reduce the risk of cardiovascular death in adults with
  • Type 2 diabetes who have known cardiovascular disease.JARDIANCE is not for people with type 1 diabetes.JARDIANCE is not for people with diabetic ketoacidosis (increased
  • Ketones in the blood or urine).It is not known if JARDIANCE is safe and effective in children
  • Under 18 years of age.Who should
  • Not take JARDIANCE?Do not take JARDIANCE if you:are allergic to empagliflozin or any of the ingredients
  • In JARDIANCE. See the end of this Medication Guide for a list of
  • Ingredients in JARDIANCE.have severe kidney problems or are on dialysisWhat should
  • I tell my doctor before using JARDIANCE?Before you take JARDIANCE, tell your doctor if you:have kidney problemshave liver problemshave a history of urinary tract infections or problems with
  • Urinationare going to have surgeryare eating less due to illness, surgery, or a change in
  • Your diethave or have had problems with your pancreas, including
  • Pancreatitis or surgery on your pancreasdrink alcohol very often, or drink a lot of alcohol in the
  • Short term (“binge” drinking)have any other medical conditionsare pregnant or plan to become pregnant. JARDIANCE may harm
  • Your unborn baby. If you become pregnant while taking JARDIANCE, tell
  • Your doctor as soon as possible. Talk with your doctor about the best
  • Way to control your blood sugar while you are pregnant.are breastfeeding or plan to breastfeed. JARDIANCE may pass
  • Into your breast milk and may harm your baby. Talk with your doctor
  • About the best way to feed your baby if you are taking JARDIANCE.
  • Do not breastfeed while taking JARDIANCE.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins,
  • And herbal supplements.
  • JARDIANCE may affect
  • The way other medicines work, and other medicines may affect how JARDIANCE
  • Works.
  • Especially tell your doctor if you take:diuretics (water pills)insulin or other medicines that can lower your blood sugar Ask your doctor or pharmacist for a list of these medicines
  • If you are not sure if your medicine is listed above.
  • How should
  • I take JARDIANCE?Take JARDIANCE exactly as your doctor tells you to take
  • It.Take JARDIANCE by mouth 1 time in the morning each day,
  • With or without food.Your doctor may change your dose if needed.If you miss a dose, take it as soon as you remember. If
  • You do not remember until it is time for your next dose, skip the
  • Missed dose and go back to your regular schedule. Do not take two
  • Doses of JARDIANCE at the same time. Talk with your doctor if you
  • Have questions about a missed dose.Your doctor may tell you to take JARDIANCE along with other
  • Diabetes medicines. Low blood sugar can happen more often when JARDIANCE
  • Is taken with certain other diabetes medicines. See
  • “What are
  • The possible side effects of JARDIANCE?”If you take too much JARDIANCE, call your doctor or go to
  • The nearest hospital emergency room right away.When your body is under some types of stress, such as fever,
  • Trauma (such as a car accident), infection, or surgery, the amount
  • Of diabetes medicine that you need may change. Tell your doctor right
  • Away if you have any of these conditions and follow your doctor’s
  • Instructions.Check your blood sugar as your doctor tells you to.Stay on your prescribed diet and exercise program while
  • Taking JARDIANCE.Talk to your doctor about how to prevent, recognize and
  • Manage low blood sugar (hypoglycemia), high blood sugar (hyperglycemia),
  • And complications of diabetes.Your doctor will check your diabetes with regular blood
  • Tests, including your blood sugar levels and your hemoglobin HbA1c.When taking JARDIANCE, you may have sugar in your urine,
  • Which will show up on a urine test.What are the possible
  • Side effects of JARDIANCE?JARDIANCE may cause serious side effects, including:See “
  • What is the most important information I should
  • Know about JARDIANCE?”
  • Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have
  • Type 1 diabetes
  • Or type 2 diabetes, during treatment with JARDIANCE. Ketoacidosis
  • Is a serious condition, which may need to be treated in a hospital.
  • Ketoacidosis may lead to death.
  • Ketoacidosis can happen with
  • JARDIANCE even if your blood sugar is less than 250 mg/dL. Stop taking JARDIANCE and call your doctor right away if you get
  • Any of the following symptoms:
  • Nauseavomitingstomach-area (abdominal) paintirednesstrouble breathing             If you get any of
  • These symptoms during treatment with JARDIANCE, if possible, check
  • For ketones in your urine, even if your
  • Blood
  • Sugar is less than 250 mg/dL.
  • Kidney problems. Sudden kidney injury has happened
  • To people taking JARDIANCE. Talk to your doctor right away if you:
  • Reduce the amount of food or liquid you drink for example,
  • If you are sick or cannot eat orstart to lose liquids from your body for example, from vomiting,
  • Diarrhea or being in the sun too longSerious urinary tract infections. Serious
  • Urinary tract infections that may lead to hospitalization have happened
  • In people who are taking JARDIANCE. Tell your doctor if you have any
  • Signs or symptoms of a urinary tract infection such as a burning feeling
  • When passing urine, a need to urinate often, the need to urinate right
  • Away, pain in the lower part of your stomach (pelvis), or blood in
  • The urine. Sometimes people also may have a fever, back pain, nausea
  • Or vomiting.
  • Low blood sugar (hypoglycemia). If you take
  • JARDIANCE with another medicine that can cause low blood sugar, such
  • As a sulfonylurea or insulin, your risk of getting low blood sugar
  • Is higher. The dose of your sulfonylurea medicine or insulin may need
  • To be lowered while you take JARDIANCE. Signs and symptoms of low
  • Blood sugar may include:
  • Headachedrowsinessweaknessirritabilityhungerfast heartbeatconfusionshaking or feeling jitterydizzinesssweating A rare but serious bacterial infection that causes
  • Damage to the tissue under the skin (necrotizing fasciitis) in the
  • Area between and around the anus and genitals (perineum).
  • Necrotizing fasciitis of the perineum has happened in women and men
  • Who take JARDIANCE. Necrotizing fasciitis of the perineum may lead
  • To hospitalization, may require multiple surgeries, and may lead to
  • Death.
  • Seek medical attention immediately if you have a fever
  • Or you are feeling very weak, tired or uncomfortable (malaise), and
  • You develop any of the following symptoms in the area between and
  • Around your anus and genitals: pain or tendernessswellingredness of skin (erythema)  Allergic (hypersensitivity) reactions. Serious
  • Allergic reactions have happened in people who are taking JARDIANCE.
  • Symptoms may include
  • Swelling of your face, lips, throat and other areas of your
  • Skindifficulty with swallowing or breathing.raised, red areas on your skin (hives)If you have any of these symptoms, stop taking
  • JARDIANCE and call your doctor right away or go to the nearest hospital
  • Emergency room.
  • Increased fats in your blood (cholesterol) These are not all the possible side effects of JARDIANCE.
  • For more information, ask your doctor or pharmacist.
  • Call
  • Your doctor for medical advice about side effects. You may report
  • Side effects to FDA at 1-800-FDA-1088.
  • How should
  • I store JARDIANCE?Store JARDIANCE at room temperature
  • 68°F to 77°F (20°C to 25°C).
  • General information
  • About the safe and effective use of JARDIANCE.Medicines
  • Are sometimes prescribed for purposes other than those listed in a
  • Medication Guide. Do not use JARDIANCE for a condition for which it
  • Is not prescribed. Do not give JARDIANCE to other people, even if
  • They have the same symptoms you have. It may harm them.
  • This Medication Guide summarizes the most important information
  • About JARDIANCE. If you would like more information, talk with your
  • Doctor. You can ask your pharmacist or doctor for information about
  • JARDIANCE that is written for health professionals.
  • For
  • More information about JARDIANCE including current prescribing information
  • And Medication Guide, go to
  • Www.jardiance.com, scan the code below, or call Boehringer Ingelheim Pharmaceuticals,
  • Inc. at 1-800-542-6257 or (TTY) 1-800-459-9906.
  • What are the
  • Ingredients in JARDIANCE?Active Ingredient: empagliflozin
  • Inactive Ingredients: lactose
  • Monohydrate, microcrystalline cellulose, hydroxypropyl cellulose,
  • Croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.
  • In addition, the film coating contains the following inactive ingredients:
  • Hypromellose, titanium dioxide, talc, polyethylene glycol, and yellow
  • Ferric oxide.
  • 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
  • Licensed from: Boehringer Ingelheim International GmbH, Ingelheim,
  • Germany
  • Boehringer Ingelheim Pharmaceuticals,
  • Inc. either owns or uses the Jardiance
  • ® and EMPA-REG OUTCOME
  • ® trademarks under
  • License.
  • The other trademarks referenced are owned by third
  • Parties not affiliated with Boehringer Ingelheim Pharmaceuticals,
  • Inc.
  • Copyright © 2018 Boehringer Ingelheim
  • International GmbH
  • ALL RIGHTS RESERVED
  • IT5728SJ232018

* Please review the disclaimer below.

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