JARDIANCE®
(empagliflozin) Tablets, for Oral Use
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-3furanyl]oxy]phenyl]methyl]phenyl]-,
(1S).
Its molecular formula is C23H27ClO7 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.
INDICATIONS
JARDIANCE is indicated:
as an adjunct to diet and exercise to improve glycemic control in
adults with
type 2 diabetesmellitus,to reduce the risk of
cardiovascular death in adult
patients with type 2
diabetes mellitus and
established
cardiovascular disease.
Limitations Of Use
JARDIANCE is not recommended for
patients with type 1 diabetes or for the
treatment of diabetic ketoacidosis.
DOSAGE AND ADMINISTRATION
Recommended Dosage
The recommended dose of JARDIANCE is
10 mg once daily in the morning, taken with or without food. In patients
tolerating JARDIANCE, the dose may be increased to 25 mg [see Clinical Studies].
In patients with volume depletion,
correcting this condition prior to initiation of JARDIANCE is recommended
[see WARNINGS AND PRECAUTIONS, Use In
Specific Populations and PATIENT INFORMATION].
Patients With Renal
Impairment
Assessment of renal function is
recommended prior to initiation of JARDIANCE and periodically thereafter.
JARDIANCE should not be initiated in
patients with an eGFR less than 45 mL/min/1.73 m2.
No dose adjustment is needed in
patients with an eGFR greater than or equal to 45 mL/min/1.73 m2.
JARDIANCE should be discontinued if
eGFR is persistently less than 45 mL/min/1.73 m2 [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
HOW SUPPLIED
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.
Storage And
Handling
JARDIANCE tablets are available
in 10 mg and 25 mg strengths as follows:
10 mg tablets: pale yellow,
round, biconvex and bevel-edged, film-coated tablets debossed with “S 10” on
one side and the Boehringer Ingelheim company symbol on the other side.
Bottles of 30 (NDC 0597-0152-30)
Bottles of 90 (NDC 0597-0152-90)
Cartons containing 3 blister cards of
10 tablets each (3 x 10) (NDC 0597-0152-37), institutional pack.
25 mg tablets: pale yellow,
oval, biconvex film-coated tablets, debossed with “S 25” on one side and the
Boehringer Ingelheim company symbol on the other side.
Bottles of 30 (NDC 0597-0153-30)
Bottles of 90 (NDC 0597-0153-90)
Cartons containing 3 blister cards of
10 tablets each (3 x 10) (NDC 0597-0153-37), institutional pack.
Dispense in a well-closed container
as defined in the USP.
Storage
Store at 25°C (77°F); excursions
permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].
Distributed by: Boehringer Ingelheim
Pharmaceuticals, Inc.;Ridgefield, CT 06877USA. Revised:
Dec 2017
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JARDIANCE®
(empagliflozin) Tablets, for Oral Use
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-3furanyl]oxy]phenyl]methyl]phenyl]-,
(1S).
Its molecular formula is C23H27ClO7 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.
Indications & Dosage
1. Type
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2. Diabetes
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3. Type
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INDICATIONS
JARDIANCE is indicated:
as an adjunct to diet and exercise to
improve glycemic control in adults with
type 2 diabetesmellitus,to reduce the risk of
cardiovascular death in adult patients with type 2
diabetes mellitus and established
cardiovascular disease.
Limitations
Of Use
JARDIANCE is not
recommended for patients with type 1 diabetes or
for the treatment of diabetic ketoacidosis.
DOSAGE AND
ADMINISTRATION
Recommended
Dosage
The recommended dose of
JARDIANCE is 10 mg once daily in the morning, taken with or without food. In
patients tolerating JARDIANCE, the dose may be increased to 25 mg [see Clinical Studies].
In patients with volume
depletion, correcting this condition prior to initiation of JARDIANCE is
recommended [see WARNINGS AND PRECAUTIONS, Use In Specific Populations and PATIENT INFORMATION].
Patients
With Renal Impairment
Assessment of renal
function is recommended prior to initiation of JARDIANCE and periodically
thereafter.
JARDIANCE should not be
initiated in patients with an eGFR less than 45 mL/min/1.73 m2.
No dose adjustment is
needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2.
JARDIANCE should be
discontinued if eGFR is persistently less than 45 mL/min/1.73 m2 [see WARNINGS
AND PRECAUTIONS and Use In Specific Populations].
HOW SUPPLIED
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.
Storage And
Handling
JARDIANCE tablets are
available in 10 mg and 25 mg strengths as follows:
10 mg tablets: pale
yellow, round, biconvex and bevel-edged, film-coated tablets debossed with “S 10” on one side and the
Boehringer Ingelheim company symbol on the other side.
Bottles of 30
(NDC 0597-0152-30)
Bottles of 90 (NDC 0597-0152-90)
Cartons containing 3
blister cards of 10 tablets each (3 x 10) (NDC 0597-0152-37),
institutional pack.
25 mg tablets: pale
yellow, oval, biconvex film-coated tablets, debossed with “S 25” on one side and the
Boehringer Ingelheim company symbol on the other side.
Bottles of 30
(NDC 0597-0153-30)
Bottles of 90 (NDC 0597-0153-90)
Cartons containing 3
blister cards of 10 tablets each (3 x 10) (NDC 0597-0153-37),
institutional pack.
Dispense in a well-closed
container as defined in the USP.
Storage
Store at 25°C (77°F); excursions permitted
to 15°-30°C (59°-86°F) [see USP Controlled Room
Temperature].
Distributed by: Boehringer
Ingelheim Pharmaceuticals, Inc.;Ridgefield, CT 06877USA. Revised:
Dec 2017
Side Effects & Drug Interactions
1. Type
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SIDE EFFECTS
The following important
adverse reactions are described below and elsewhere in the labeling:
Hypotension [see WARNINGS AND
PRECAUTIONS]
Ketoacidosis [see WARNINGS AND
PRECAUTIONS]Acute Kidney Injury and Impairment in Renal
Function [see WARNINGS AND
PRECAUTIONS]Urosepsis and
Pyelonephritis [see WARNINGS AND
PRECAUTIONS]
Hypoglycemia with Concomitant Use with
Insulin and Insulin Secretagogues [see WARNINGS AND
PRECAUTIONS]
Genital Mycotic Infections [see WARNINGS AND
PRECAUTIONS]Hypersensitivity Reactions
[see WARNINGS AND
PRECAUTIONS]Increased Low-Density
Lipoprotein Cholesterol (
LDL-C) [see WARNINGS AND
PRECAUTIONS]
Clinical
Trials Experience
Because clinical trials are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in
practice.
Pool Of
Placebo-Controlled Trials Evaluating JARDIANCE 10 And 25 mg
The data in Table 1 are
derived from a pool of four 24-week placebo-controlled trials and 18-week data
from a placebo-controlled trial with insulin. JARDIANCE was used as monotherapy
in one trial and as add-on therapy in four trials [see Clinical Studies].
These data reflect exposure
of 1976 patients to JARDIANCE with a mean exposure duration of approximately 23
weeks. Patients received placebo (N=995), JARDIANCE 10 mg (N=999), or JARDIANCE
25 mg (N=977) once daily. The mean age of the population was 56 years and 3%
were older than 75 years of age. More than half (55%) of the population was
male; 46% were White, 50% were Asian, and 3% were Black or African American. At baseline, 57% of the population had diabetes more
than 5 years and had a mean hemoglobin A1c (HbA1c)
of 8%. Established microvascular complications
of diabetes at baseline included diabetic nephropathy (7%), retinopathy (8%),
or neuropathy (16%).
Baseline renal function was normal or mildly impaired in 91% of patients and
moderately impaired in 9% of patients (mean eGFR 86.8 mL/min/1.73 m2).
Table 1 shows common
adverse reactions (excluding hypoglycemia) associated with the use of
JARDIANCE. The adverse reactions were not present at baseline, occurred more
commonly on JARDIANCE than on placebo and occurred in greater than or equal to
2% of patients treated with JARDIANCE 10 mg or JARDIANCE 25 mg.
Table 1:
Adverse Reactions Reported in ≥2% of
Patients Treated with JARDIANCE and Greater than Placebo in Pooled
Placebo-Controlled Clinical Studies of JARDIANCE Monotherapy or Combination
Therapy
|
|
Number (%) of
Patients
|
|
Placebo
N=995
|
JARDIANCE 10
mg
N=999
|
JARDIANCE 25
mg
N=977
|
|
Urinary tract infectiona
|
7.6%
|
9.3%
|
7.6%
|
|
Female genital mycotic
infectionsb
|
1.5%
|
5.4%
|
6.4%
|
|
Upper respiratory tract
infection
|
3.8%
|
3.1%
|
4.0%
|
|
Increased urinationc
|
1.0%
|
3.4%
|
3.2%
|
|
Dyslipidemia
|
3.4%
|
3.9%
|
2.9%
|
|
Arthralgia
|
2.2%
|
2.4%
|
2.3%
|
|
Male genital mycotic
infectionsd
|
0.4%
|
3.1%
|
1.6%
|
|
Nausea
|
1.4%
|
2.3%
|
1.1%
|
|
aPredefined adverse event grouping, including, but
not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis
b Female 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).
c Predefined adverse event grouping, including, but
not limited to, polyuria,
pollakiuria, and nocturia
d Male genital mycotic infections include the following adverse
reactions: balanoposthitis, balanitis,
genital infections fungal,genitourinary tract infection, balanitis candida,
scrotal abscess, penile infection. Percentages calculated with the number of male subjects in
each group as denominator: placebo (N=514), JARDIANCE 10 mg (N=556),
JARDIANCE 25 mg (N=557).
|
Thirst (including polydipsia) was
reported in 0%, 1.7%, and 1.5% for placebo, JARDIANCE 10 mg, and JARDIANCE 25
mg, respectively.
Volume
Depletion
JARDIANCE causes an
osmotic diuresis, which may
lead to intravascular volume contraction and adverse reactions related to
volume depletion. In the pool of five placebo-controlled clinical trials,
adverse reactions related to volume depletion (e.g., blood pressure
(ambulatory) decreased, blood pressure systolic decreased,
dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope) were reported by 0.3%, 0.5%, and 0.3% of patients treated with
placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. JARDIANCE may
increase the risk of hypotension in patients at risk for volume contraction
[see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Increased
Urination
In the pool 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 and Use In Specific Populations].
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 eGFRa in the Pool of Four 24-week
Placebo-Controlled Studies and Renal Impairment Study
|
|
Pool of
24-Week Placebo-Controlled Studies
|
|
Placebo
|
JARDIANCE 10
mg
|
JARDIANCE 25
mg
|
|
Baseline Mean
|
N
|
825
|
830
|
822
|
|
Creatinine (mg/dL)
|
0.84
|
0.85
|
0.85
|
|
eGFR (mL/min/1.73 m2)
|
87.3
|
87.1
|
87.8
|
|
Week 12 Change
|
N
|
771
|
797
|
783
|
|
Creatinine (mg/dL)
|
0.00
|
0.02
|
0.01
|
|
eGFR (mL/min/1.73 m2)
|
-0.3
|
-1.3
|
-1.4
|
|
Week 24 Change
|
N
|
708
|
769
|
754
|
|
Creatinine (mg/dL)
|
0.00
|
0.01
|
0.01
|
|
eGFR (mL/min/1.73 m2)
|
-0.3
|
-0.6
|
-1.4
|
|
|
Moderate
Renal Impairmentb
|
|
Placebo
|
|
JARDIANCE 25
mg
|
|
Baseline Mean
|
N
|
187
|
-
|
187
|
|
Creatinine (mg/dL)
|
1.49
|
-
|
1.49
|
|
eGFR (mL/min/1.73 m2)
|
44.3
|
-
|
45.4
|
|
Week 12 Change
|
N
|
176
|
-
|
179
|
|
Creatinine (mg/dL)
|
0.01
|
-
|
0.12
|
|
eGFR (mL/min/1.73 m2)
|
0.1
|
-
|
- 3.8
|
|
Week 24 Change
|
N
|
170
|
-
|
171
|
|
Creatinine (mg/dL)
|
0.01
|
-
|
0.10
|
|
eGFR (mL/min/1.73 m2)
|
0.2
|
-
|
- 3.2
|
|
Week 52 Change
|
N
|
164
|
-
|
162
|
|
Creatinine (mg/dL)
|
0.02
|
-
|
0.11
|
|
eGFR (mL/min/1.73 m2)
|
-0.3
|
-
|
- 2.8
|
|
Post-treatment Changec
|
N
|
98
|
-
|
103
|
|
Creatinine (mg/dL)
|
0.03
|
-
|
0.02
|
|
eGFR (mL/min/1.73 m2)
|
0.16
|
-
|
1.48
|
|
aObserved cases on treatment.
bSubset of patients from renal impairment study with eGFR 30 to
less than 60 mL/min/1.73 m2
cApproximately 3 weeks after end of treatment.
|
Hypoglycemia
The incidence of
hypoglycemia by study is shown in Table 3. The incidence of hypoglycemia
increased when JARDIANCE was administered with insulin or sulfonylurea [see WARNINGS
AND PRECAUTIONS].
Table 3
Incidence of Overalla and
Severeb Hypoglycemic
Events in Placebo-Controlled Clinical Studiesc
|
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 weeksd)
|
Placebo
(n=170)
|
JARDIANCE 10
mg
(n=169)
|
JARDIANCE 25
mg
(n=155)
|
|
Overall (%)
|
20.6%
|
19.5%
|
28.4%
|
|
Severe (%)
|
0%
|
0%
|
0%
|
|
In
Combination with MDI Insulin +/-Metformin
(18 weeksd)
|
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%
|
|
a Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL
b Severe hypoglycemic events: requiring assistance
regardless of blood glucose
c Treated set (patients who had received at least one dose of study
drug)
d Insulin dose could not be adjusted during the
initial 18 week treatment period
|
Genital
Mycotic Infections
In the pool of five
placebo-controlled clinical trials, the incidence of genital mycotic infections
(e.g., vaginal mycotic infection, vaginal infection, genital infection fungal,
vulvovaginal candidiasis, and vulvitis) was increased in patients treated with
JARDIANCE compared to placebo, occurring in 0.9%, 4.1%, and 3.7% of patients
randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.
Discontinuation from study due to genital infection occurred in 0% of
placebo-treated patients and 0.2% of patients treated with either JARDIANCE 10
or 25 mg.
Genital mycotic infections
occurred more frequently in female than male patients (see Table 1).
Phimosis occurred
more frequently in male patients treated with JARDIANCE 10 mg (less than 0.1%)
and JARDIANCE 25 mg (0.1%) than placebo (0%).
Urinary
Tract Infections
In the pool of five
placebo-controlled clinical trials, the incidence of urinary tract infections
(e.g., urinary tract infection, asymptomatic bacteriuria, and cystitis) was
increased in patients treated with JARDIANCE compared to placebo (see Table 1).
Patients with a history of chronic or recurrent urinary
tract infections were more likely to experience a urinary tract infection. The
rate of treatment discontinuation due to urinary tract infections was 0.1%,
0.2%, and 0.1% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.
Urinary tract infections
occurred more frequently in female patients. The incidence of urinary tract
infections in female patients randomized to placebo, JARDIANCE 10 mg, and
JARDIANCE 25 mg was 16.6%, 18.4%, and 17.0%, respectively. The incidence of
urinary tract infections in male patients randomized to placebo, JARDIANCE 10
mg, and JARDIANCE 25 mg was 3.2%, 3.6%, and 4.1%, respectively
[see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Laboratory
Tests
Increase in Low-Density
Lipoprotein Cholesterol (LDL-C)
Dose-related increases in
low-density lipoprotein cholesterol (LDL-C) were observed in patients treated
with JARDIANCE. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated
with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively
[see WARNINGS AND PRECAUTIONS]. The range of mean baseline LDL-C levels was 90.3
to 90.6 mg/dL across treatment groups.
Increase in Hematocrit
In a pool of four
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.
Postmarketing
Experience
Additional adverse
reactions have been identified during postapproval use of JARDIANCE. Because
these reactions are reported voluntarily from a population of uncertain size,
it is generally not possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
Ketoacidosis [see WARNINGS AND
PRECAUTIONS]Urosepsis and pyelonephritis
[see WARNINGS AND
PRECAUTIONS]
Angioedema [see WARNINGS AND
PRECAUTIONS]Skin reactions (e.g., rash,
urticaria)
DRUG INTERACTIONS
Diuretics
Coadministration of
empagliflozin with diuretics resulted
in increased urine volume and frequency of voids, which might enhance the
potential for volume depletion [see WARNINGS AND PRECAUTIONS].
Insulin Or
Insulin Secretagogues
Coadministration of
empagliflozin with insulin or insulin secretagogues increases the risk for
hypoglycemia [see WARNINGS AND PRECAUTIONS].
Positive
Urine Glucose Test
Monitoring glycemic control
with urine glucose tests is not recommended in patients taking SGLT2 inhibitors
as SGLT2 inhibitors increase urinary glucose excretion and will lead to
positive urine glucose tests. Use alternative methods to monitor glycemic
control.
Interference
With 1,5-Anhydroglucitol (1,5-AG) Assay
Monitoring glycemic control
with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable
in assessing glycemic control in patients taking SGLT2 inhibitors. Use
alternative methods to monitor glycemic control.
WARNINGS
Included as part of
the "PRECAUTIONS" Section
PRECAUTIONS
Hypotension
JARDIANCE causes intravascular volume
contraction. Symptomatic hypotension may occur
after initiating JARDIANCE [see ADVERSE
REACTIONS] 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].
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].
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 abusewere 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).
Acute Kidney Injury
And Impairment In Renal Function
JARDIANCE causes intravascular volume
contraction [see Hypotension] and can cause renal impairment [see ADVERSE REACTIONS]. 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]. 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 m2. Use of JARDIANCE is not recommended
when eGFR is persistently less than 45 mL/min/1.73 m2 and is contraindicated in
patients with an eGFR less than 30 mL/min/1.73 m2 [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS and Use In Specific Populations].
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].
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]. 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.
Genital Mycotic
Infections
JARDIANCE increases the risk
for genital mycotic
infections [see ADVERSE
REACTIONS]. Patients with a history of
chronic or recurrent genital
mycotic infections were more likely to develop genital mycotic infections.
Monitor and treat as appropriate.
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].
Increased
Low-Density Lipoprotein Cholesterol (LDL-C)
Increases in LDL-C can occur with
JARDIANCE [see ADVERSE
REACTIONS]. Monitor and treat as
appropriate.
Patient Counseling
Information
Advise the patient to read the
FDA-approved patient labeling (PATIENT INFORMATION).
Instructions
Instruct patients to read the Patient
Information 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]. 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].
Hypotension
Inform patients that hypotension may
occur with JARDIANCE and advise them to contact their healthcare provider if
they experience such symptoms [see WARNINGS AND PRECAUTIONS]. Inform
patients that dehydration may increase the risk for hypotension, and to have
adequate fluid intake.
Ketoacidosis
Inform 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].
Acute Kidney Injury
Inform 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].
Serious Urinary
Tract Infections
Inform 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].
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].
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].
Hypersensitivity
Reactions
Inform 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].
Laboratory Tests
Inform 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.
Nonclinical
Toxicology
Carcinogenesis,
Mutagenesis, Impairment Of Fertility
Carcinogenesis
Carcinogenesis was evaluated in
2-year studies conducted in CD-1 mice and Wistar rats. Empagliflozin did not
increase the incidence of tumors in female rats dosed at 100, 300, or 700
mg/kg/day (up to 72 times the exposure from the maximum clinical dose of 25
mg). In male rats, hemangiomas of the mesenteric lymph node were
increased significantly at 700 mg/kg/day or approximately 42 times the exposure
from a 25 mg clinical dose. Empagliflozin did not increase the incidence of
tumors in female mice dosed at 100, 300, or 1000 mg/kg/day (up to 62 times the
exposure from a 25 mg clinical dose). Renal tubule adenomas and
carcinomas were observed in male mice at 1000 mg/kg/day, which is approximately
45 times the exposure of the maximum clinical dose of 25 mg. 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 vivomicronucleus 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).
Use In Specific Populations
Pregnancy
Risk Summary
Based on animal data showing adverse
renal effects, JARDIANCE is not recommended during the second and third
trimesters of pregnancy.
Limited data available with JARDIANCE
in pregnant women are not sufficient to determine a drug-associated risk for
major birth defects and miscarriage. There are risks
to the mother and fetus associated with poorly controlled diabetes in pregnancy
[see Clinical Considerations].
In animal studies, adverse renal
changes were observed in rats when empagliflozin was administered during a
period of renal development corresponding to the late second and third
trimesters of human pregnancy. Doses approximately 13-times the maximum
clinical dose caused renal pelvic and tubule
dilatations that were reversible. Empagliflozin was not teratogenic in
rats and rabbits up to 300 mg/kg/day, which approximates 48times 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 diabeteswith 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 theU.S.general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Clinical
Considerations
Disease-Associated Maternal And/Or
Embryo/Fetal Risk
Poorly controlled diabetes in
pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous
abortions, preterm delivery, stillbirth, and delivery complications. Poorly
controlled diabetes increases the fetal risk for major birth defects,
stillbirth, and macrosomia related
morbidity.
Data
Animal Data
Empagliflozin dosed directly to juvenile
rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30 and 100
mg/kg/day caused increased kidney 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 48times (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).
Lactation
Risk Summary
There 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.
Pediatric Use
The safety and effectiveness of
JARDIANCE in pediatric patients under 18 years of age have not been
established.
Geriatric Use
No JARDIANCE dosage change is
recommended based on age [see DOSAGE AND
ADMINISTRATION]. 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 Renal Impairment]. 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 and ADVERSE
REACTIONS].
Renal Impairment
The efficacy and safety of JARDIANCE
were evaluated in a study of patients with mild and moderate renal impairment
[see Clinical
Studies]. In this study, 195 patients
exposed to JARDIANCE had an eGFR between 60 and 90 mL/min/1.73 m2, 91 patients exposed to JARDIANCE
had an eGFR between 45 and 60 mL/min/1.73 m2 and 97 patients exposed to
JARDIANCE had an eGFR between 30 and 45 mL/min/1.73 m2. The glucose lowering benefit of
JARDIANCE 25 mg decreased in patients with worsening renal function. The risks
of renal impairment [see WARNINGS AND PRECAUTIONS], 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 m2. The cardiovascular death findings
in this subgroup were consistent with the overall findings [see Clinical Studies].
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, CONTRAINDICATIONS and WARNINGS
AND PRECAUTIONS].
Hepatic Impairment
JARDIANCE may be used in patients
with hepatic impairment [see CLINICAL
PHARMACOLOGY].
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(empagliflozin tablets) drug
Drug
Description
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JARDIANCE®
(empagliflozin) Tablets, for Oral Use
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-3furanyl]oxy]phenyl]methyl]phenyl]-,
(1S).
Its molecular formula is C23H27ClO7 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.
Indications
& Dosage
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INDICATIONS
JARDIANCE is indicated:
as an adjunct to diet and exercise to
improve glycemic control in adults with
type 2 diabetesmellitus,to reduce the risk of
cardiovascular death in adult patients with type 2
diabetes mellitus and established
cardiovascular disease.
Limitations
Of Use
JARDIANCE is not
recommended for patients with type 1 diabetes or for
the treatment of diabetic ketoacidosis.
DOSAGE AND
ADMINISTRATION
Recommended
Dosage
The recommended dose of
JARDIANCE is 10 mg once daily in the morning, taken with or without food. In
patients tolerating JARDIANCE, the dose may be increased to 25 mg [see Clinical Studies].
In patients with volume
depletion, correcting this condition prior to initiation of JARDIANCE is
recommended [see WARNINGS AND PRECAUTIONS, Use In Specific Populations and PATIENT INFORMATION].
Patients
With Renal Impairment
Assessment of renal
function is recommended prior to initiation of JARDIANCE and periodically
thereafter.
JARDIANCE should not be
initiated in patients with an eGFR less than 45 mL/min/1.73 m2.
No dose adjustment is
needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2.
JARDIANCE should be
discontinued if eGFR is persistently less than 45 mL/min/1.73 m2 [see WARNINGS
AND PRECAUTIONS and Use In Specific Populations].
HOW SUPPLIED
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.
Storage And
Handling
JARDIANCE tablets are
available in 10 mg and 25 mg strengths as follows:
10 mg tablets: pale
yellow, round, biconvex and bevel-edged, film-coated tablets debossed with “S 10” on one side and the
Boehringer Ingelheim company symbol on the other side.
Bottles of 30
(NDC 0597-0152-30)
Bottles of 90 (NDC 0597-0152-90)
Cartons containing 3
blister cards of 10 tablets each (3 x 10) (NDC 0597-0152-37),
institutional pack.
25 mg tablets: pale
yellow, oval, biconvex film-coated tablets, debossed with “S 25” on one side and the
Boehringer Ingelheim company symbol on the other side.
Bottles of 30
(NDC 0597-0153-30)
Bottles of 90 (NDC 0597-0153-90)
Cartons containing 3
blister cards of 10 tablets each (3 x 10) (NDC 0597-0153-37),
institutional pack.
Dispense in a well-closed
container as defined in the USP.
Storage
Store at 25°C (77°F); excursions permitted
to 15°-30°C (59°-86°F) [see USP Controlled Room
Temperature].
Distributed by: Boehringer
Ingelheim Pharmaceuticals, Inc.;Ridgefield, CT 06877USA. Revised:
Dec 2017
Side Effects
& Drug Interactions
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SIDE EFFECTS
The following important
adverse reactions are described below and elsewhere in the labeling:
Hypotension [see WARNINGS AND
PRECAUTIONS]
Ketoacidosis [see WARNINGS AND
PRECAUTIONS]Acute Kidney Injury and Impairment in Renal
Function [see WARNINGS AND
PRECAUTIONS]Urosepsis and
Pyelonephritis [see WARNINGS AND
PRECAUTIONS]
Hypoglycemia with Concomitant Use with
Insulin and Insulin Secretagogues [see WARNINGS AND
PRECAUTIONS]
Genital Mycotic Infections [see WARNINGS AND
PRECAUTIONS]Hypersensitivity Reactions
[see WARNINGS AND
PRECAUTIONS]Increased Low-Density
Lipoprotein Cholesterol (
LDL-C) [see WARNINGS AND
PRECAUTIONS]
Clinical
Trials Experience
Because clinical trials are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in
practice.
Pool Of
Placebo-Controlled Trials Evaluating JARDIANCE 10 And 25 mg
The data in Table 1 are
derived from a pool of four 24-week placebo-controlled trials and 18-week data
from a placebo-controlled trial with insulin. JARDIANCE was used as monotherapy
in one trial and as add-on therapy in four trials [see Clinical Studies].
These data reflect exposure
of 1976 patients to JARDIANCE with a mean exposure duration of approximately 23
weeks. Patients received placebo (N=995), JARDIANCE 10 mg (N=999), or JARDIANCE
25 mg (N=977) once daily. The mean age of the population was 56 years and 3%
were older than 75 years of age. More than half (55%) of the population was
male; 46% were White, 50% were Asian, and 3% were Black or African American. At baseline, 57% of the population had diabetes more
than 5 years and had a mean hemoglobin A1c (HbA1c)
of 8%. Established microvascular complications
of diabetes at baseline included diabetic nephropathy (7%), retinopathy (8%),
or neuropathy (16%).
Baseline renal function was normal or mildly impaired in 91% of patients and
moderately impaired in 9% of patients (mean eGFR 86.8 mL/min/1.73 m2).
Table 1 shows common
adverse reactions (excluding hypoglycemia) associated with the use of
JARDIANCE. The adverse reactions were not present at baseline, occurred more
commonly on JARDIANCE than on placebo and occurred in greater than or equal to
2% of patients treated with JARDIANCE 10 mg or JARDIANCE 25 mg.
Table 1:
Adverse Reactions Reported in ≥2% of
Patients Treated with JARDIANCE and Greater than Placebo in Pooled
Placebo-Controlled Clinical Studies of JARDIANCE Monotherapy or Combination
Therapy
|
|
Number (%) of
Patients
|
|
Placebo
N=995
|
JARDIANCE 10
mg
N=999
|
JARDIANCE 25
mg
N=977
|
|
Urinary tract infectiona
|
7.6%
|
9.3%
|
7.6%
|
|
Female genital mycotic
infectionsb
|
1.5%
|
5.4%
|
6.4%
|
|
Upper respiratory tract
infection
|
3.8%
|
3.1%
|
4.0%
|
|
Increased urinationc
|
1.0%
|
3.4%
|
3.2%
|
|
Dyslipidemia
|
3.4%
|
3.9%
|
2.9%
|
|
Arthralgia
|
2.2%
|
2.4%
|
2.3%
|
|
Male genital mycotic
infectionsd
|
0.4%
|
3.1%
|
1.6%
|
|
Nausea
|
1.4%
|
2.3%
|
1.1%
|
|
aPredefined adverse event grouping, including, but
not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis
b Female 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).
c Predefined adverse event grouping, including, but
not limited to, polyuria,
pollakiuria, and nocturia
d Male genital mycotic infections include the following adverse
reactions: balanoposthitis, balanitis,
genital infections fungal,genitourinary tract infection, balanitis candida,
scrotal abscess, penile infection. Percentages calculated with the number of male subjects in
each group as denominator: placebo (N=514), JARDIANCE 10 mg (N=556),
JARDIANCE 25 mg (N=557).
|
Thirst (including polydipsia) was
reported in 0%, 1.7%, and 1.5% for placebo, JARDIANCE 10 mg, and JARDIANCE 25
mg, respectively.
Volume
Depletion
JARDIANCE causes an
osmotic diuresis, which may
lead to intravascular volume contraction and adverse reactions related to
volume depletion. In the pool of five placebo-controlled clinical trials,
adverse reactions related to volume depletion (e.g., blood pressure
(ambulatory) decreased, blood pressure systolic decreased,
dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope) were reported by 0.3%, 0.5%, and 0.3% of patients treated with
placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. JARDIANCE may
increase the risk of hypotension in patients at risk for volume contraction
[see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Increased
Urination
In the pool 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 and Use In Specific Populations].
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 eGFRa in the Pool of Four 24-week
Placebo-Controlled Studies and Renal Impairment Study
|
|
Pool of
24-Week Placebo-Controlled Studies
|
|
Placebo
|
JARDIANCE 10
mg
|
JARDIANCE 25
mg
|
|
Baseline Mean
|
N
|
825
|
830
|
822
|
|
Creatinine (mg/dL)
|
0.84
|
0.85
|
0.85
|
|
eGFR (mL/min/1.73 m2)
|
87.3
|
87.1
|
87.8
|
|
Week 12 Change
|
N
|
771
|
797
|
783
|
|
Creatinine (mg/dL)
|
0.00
|
0.02
|
0.01
|
|
eGFR (mL/min/1.73 m2)
|
-0.3
|
-1.3
|
-1.4
|
|
Week 24 Change
|
N
|
708
|
769
|
754
|
|
Creatinine (mg/dL)
|
0.00
|
0.01
|
0.01
|
|
eGFR (mL/min/1.73 m2)
|
-0.3
|
-0.6
|
-1.4
|
|
|
Moderate
Renal Impairmentb
|
|
Placebo
|
|
JARDIANCE 25
mg
|
|
Baseline Mean
|
N
|
187
|
-
|
187
|
|
Creatinine (mg/dL)
|
1.49
|
-
|
1.49
|
|
eGFR (mL/min/1.73 m2)
|
44.3
|
-
|
45.4
|
|
Week 12 Change
|
N
|
176
|
-
|
179
|
|
Creatinine (mg/dL)
|
0.01
|
-
|
0.12
|
|
eGFR (mL/min/1.73 m2)
|
0.1
|
-
|
- 3.8
|
|
Week 24 Change
|
N
|
170
|
-
|
171
|
|
Creatinine (mg/dL)
|
0.01
|
-
|
0.10
|
|
eGFR (mL/min/1.73 m2)
|
0.2
|
-
|
- 3.2
|
|
Week 52 Change
|
N
|
164
|
-
|
162
|
|
Creatinine (mg/dL)
|
0.02
|
-
|
0.11
|
|
eGFR (mL/min/1.73 m2)
|
-0.3
|
-
|
- 2.8
|
|
Post-treatment Changec
|
N
|
98
|
-
|
103
|
|
Creatinine (mg/dL)
|
0.03
|
-
|
0.02
|
|
eGFR (mL/min/1.73 m2)
|
0.16
|
-
|
1.48
|
|
aObserved cases on treatment.
bSubset of patients from renal impairment study with eGFR 30 to
less than 60 mL/min/1.73 m2
cApproximately 3 weeks after end of treatment.
|
Hypoglycemia
The incidence of
hypoglycemia by study is shown in Table 3. The incidence of hypoglycemia
increased when JARDIANCE was administered with insulin or sulfonylurea [see WARNINGS
AND PRECAUTIONS].
Table 3
Incidence of Overalla and
Severeb Hypoglycemic
Events in Placebo-Controlled Clinical Studiesc
|
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 weeksd)
|
Placebo
(n=170)
|
JARDIANCE 10
mg
(n=169)
|
JARDIANCE 25
mg
(n=155)
|
|
Overall (%)
|
20.6%
|
19.5%
|
28.4%
|
|
Severe (%)
|
0%
|
0%
|
0%
|
|
In
Combination with MDI Insulin +/-Metformin
(18 weeksd)
|
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%
|
|
a Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL
b Severe hypoglycemic events: requiring assistance
regardless of blood glucose
c Treated set (patients who had received at least one dose of study
drug)
d Insulin dose could not be adjusted during the
initial 18 week treatment period
|
Genital
Mycotic Infections
In the pool of five placebo-controlled
clinical trials, the incidence of genital mycotic infections (e.g., vaginal
mycotic infection, vaginal infection, genital infection fungal, vulvovaginal
candidiasis, and vulvitis) was increased in patients treated with JARDIANCE
compared to placebo, occurring in 0.9%, 4.1%, and 3.7% of patients randomized
to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. Discontinuation
from study due to genital infection occurred in 0% of placebo-treated patients
and 0.2% of patients treated with either JARDIANCE 10 or 25 mg.
Genital mycotic infections
occurred more frequently in female than male patients (see Table 1).
Phimosis occurred
more frequently in male patients treated with JARDIANCE 10 mg (less than 0.1%)
and JARDIANCE 25 mg (0.1%) than placebo (0%).
Urinary
Tract Infections
In the pool of five
placebo-controlled clinical trials, the incidence of urinary tract infections
(e.g., urinary tract infection, asymptomatic bacteriuria, and cystitis) was
increased in patients treated with JARDIANCE compared to placebo (see Table 1).
Patients with a history of chronic or recurrent urinary
tract infections were more likely to experience a urinary tract infection. The
rate of treatment discontinuation due to urinary tract infections was 0.1%,
0.2%, and 0.1% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.
Urinary tract infections
occurred more frequently in female patients. The incidence of urinary tract
infections in female patients randomized to placebo, JARDIANCE 10 mg, and
JARDIANCE 25 mg was 16.6%, 18.4%, and 17.0%, respectively. The incidence of
urinary tract infections in male patients randomized to placebo, JARDIANCE 10
mg, and JARDIANCE 25 mg was 3.2%, 3.6%, and 4.1%, respectively
[see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Laboratory
Tests
Increase in Low-Density
Lipoprotein Cholesterol (LDL-C)
Dose-related increases in
low-density lipoprotein cholesterol (LDL-C) were observed in patients treated
with JARDIANCE. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated
with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively
[see WARNINGS AND PRECAUTIONS]. The range of mean baseline LDL-C levels was 90.3
to 90.6 mg/dL across treatment groups.
Increase in Hematocrit
In a pool of four
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.
Postmarketing
Experience
Additional adverse
reactions have been identified during postapproval use of JARDIANCE. Because
these reactions are reported voluntarily from a population of uncertain size,
it is generally not possible to reliably estimate their frequency or establish
a causal relationship to drug exposure.
Ketoacidosis [see WARNINGS AND
PRECAUTIONS]Urosepsis and pyelonephritis
[see WARNINGS AND
PRECAUTIONS]
Angioedema [see WARNINGS AND
PRECAUTIONS]Skin reactions (e.g., rash,
urticaria)
DRUG
INTERACTIONS
Diuretics
Coadministration of
empagliflozin with diuretics resulted
in increased urine volume and frequency of voids, which might enhance the
potential for volume depletion [see WARNINGS AND PRECAUTIONS].
Insulin Or
Insulin Secretagogues
Coadministration of
empagliflozin with insulin or insulin secretagogues increases the risk for
hypoglycemia [see WARNINGS AND PRECAUTIONS].
Positive
Urine Glucose Test
Monitoring glycemic control
with urine glucose tests is not recommended in patients taking SGLT2 inhibitors
as SGLT2 inhibitors increase urinary glucose excretion and will lead to
positive urine glucose tests. Use alternative methods to monitor glycemic
control.
Interference
With 1,5-Anhydroglucitol (1,5-AG) Assay
Monitoring glycemic control
with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable
in assessing glycemic control in patients taking SGLT2 inhibitors. Use
alternative methods to monitor glycemic control.
Warnings & Precautions
1. Type
2 Diabetes: Learn the Warning Signs
2. Diabetes
Friendly Dining
3. Type
2 Diabetes Quiz
WARNINGS
Included as part of
the "PRECAUTIONS" Section
PRECAUTIONS
Hypotension
JARDIANCE causes
intravascular volume contraction. Symptomatic hypotension may
occur after initiating JARDIANCE [see ADVERSE REACTIONS]
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].
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].
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 abusewere 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).
Acute Kidney
Injury And Impairment In Renal Function
JARDIANCE causes
intravascular volume contraction [see Hypotension] and can cause renal
impairment [see ADVERSE REACTIONS].
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].
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 m2. Use
of JARDIANCE is not recommended when eGFR is persistently less than 45
mL/min/1.73 m2 and
is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS and Use In Specific
Populations].
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].
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].
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.
Genital
Mycotic Infections
JARDIANCE increases the
risk for genital mycotic
infections [see ADVERSE REACTIONS].
Patients with a history of chronic or recurrent genital
mycotic infections were more likely to develop genital mycotic infections.
Monitor and treat as appropriate.
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].
Increased
Low-Density Lipoprotein Cholesterol (LDL-C)
Increases in LDL-C can occur with JARDIANCE [see ADVERSE REACTIONS].
Monitor and treat as appropriate.
Patient
Counseling Information
Advise the patient to read
the FDA-approved patient labeling (PATIENT INFORMATION).
Instructions
Instruct patients to read
the Patient Information 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]. 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].
Hypotension
Inform patients that
hypotension may occur with JARDIANCE and advise them to contact their
healthcare provider if they experience such symptoms [see WARNINGS AND
PRECAUTIONS]. Inform patients that dehydration may increase the risk for
hypotension, and to have adequate fluid intake.
Ketoacidosis
Inform 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].
Acute Kidney
Injury
Inform 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].
Serious
Urinary Tract Infections
Inform 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].
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].
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].
Hypersensitivity
Reactions
Inform 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].
Laboratory
Tests
Inform 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.
Nonclinical
Toxicology
Carcinogenesis,
Mutagenesis, Impairment Of Fertility
Carcinogenesis
Carcinogenesis was
evaluated in 2-year studies conducted in CD-1 mice and Wistar rats.
Empagliflozin did not increase the incidence of tumors in female rats dosed at
100, 300, or 700 mg/kg/day (up to 72 times the exposure from the maximum clinical
dose of 25 mg). In male rats, hemangiomas of the mesenteric lymph node were
increased significantly at 700 mg/kg/day or approximately 42 times the exposure
from a 25 mg clinical dose. Empagliflozin did not increase the incidence of
tumors in female mice dosed at 100, 300, or 1000 mg/kg/day (up to 62 times the
exposure from a 25 mg clinical dose). Renal tubule adenomas
and carcinomas were observed in male mice at 1000 mg/kg/day, which is
approximately 45 times the exposure of the maximum clinical dose of 25 mg.
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 vivomicronucleus 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).
Use In
Specific Populations
Pregnancy
Risk Summary
Based on animal data
showing adverse renal effects, JARDIANCE is not recommended during the second
and third trimesters of pregnancy.
Limited data available with
JARDIANCE in pregnant women are not sufficient to determine a drug-associated
risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly
controlled diabetes in pregnancy [see Clinical Considerations].
In animal studies, adverse
renal changes were observed in rats when empagliflozin was administered during
a period of renal development corresponding to the late second and third
trimesters of human pregnancy. Doses approximately 13-times the maximum
clinical dose caused renal pelvic and
tubule dilatations that were reversible. Empagliflozin was not teratogenic in
rats and rabbits up to 300 mg/kg/day, which approximates 48times 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 diabeteswith a HbA1c >7 and has been reported to be as
high as 20-25% in women with HbA1c >10. The estimated background risk of
miscarriage for the indicated population is unknown. In the U.S. general
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Clinical
Considerations
Disease-Associated Maternal
And/Or Embryo/Fetal Risk
Poorly controlled diabetes
in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery
complications. Poorly controlled diabetes increases the fetal risk for major
birth defects, stillbirth, and macrosomia related
morbidity.
Data
Animal Data
Empagliflozin dosed
directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of
1, 10, 30 and 100 mg/kg/day caused increased kidney 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 48times (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).
Lactation
Risk Summary
There 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.
Pediatric
Use
The safety and effectiveness
of JARDIANCE in pediatric patients under 18 years of age have not been
established.
Geriatric
Use
No JARDIANCE dosage change
is recommended based on age [see DOSAGE AND ADMINISTRATION]. 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 Renal
Impairment]. 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 and ADVERSE REACTIONS].
Renal
Impairment
The efficacy and safety of
JARDIANCE were evaluated in a study of patients with mild and moderate renal
impairment [see Clinical Studies]. In
this study, 195 patients exposed to JARDIANCE had an eGFR between 60 and 90
mL/min/1.73 m2, 91 patients exposed to JARDIANCE had an eGFR
between 45 and 60 mL/min/1.73 m2 and
97 patients exposed to JARDIANCE had an eGFR between 30 and 45 mL/min/1.73 m2. The
glucose lowering benefit of JARDIANCE 25 mg decreased in patients with
worsening renal function. The risks of renal impairment [see WARNINGS AND
PRECAUTIONS], 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 m2. The
cardiovascular death findings in this subgroup were consistent with the overall
findings [see Clinical Studies].
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, CONTRAINDICATIONS and WARNINGS AND
PRECAUTIONS].
Hepatic
Impairment
JARDIANCE may be used in
patients with hepatic impairment [see CLINICAL PHARMACOLOGY].
OVERDOSE
In the event of an overdose
with JARDIANCE, contact the Poison Control Center. Employ the usual supportive
measures (e.g., remove unabsorbed material from the gastrointestinal tract,
employ clinical monitoring, and institute supportive treatment) as dictated by
the patient’s clinical status. Removal of empagliflozin by hemodialysis has not
been studied.
CONTRAINDICATIONS
History of serious hypersensitivity
reaction to empagliflozin or any of the excipients in JARDIANCE
[see WARNINGS AND
PRECAUTIONS].Severe renal impairment, end-stage renal
disease, or dialysis [see
Use In Specific Populations].
CLINICAL
PHARMACOLOGY
Mechanism Of Action
Sodium-glucose co-transporter 2
(SGLT2) is the predominant transporter responsible for reabsorption of glucose
from the glomerular filtrate
back into the circulation. Empagliflozin is
an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal
reabsorption of filtered glucose and lowers the renal threshold for glucose,
and thereby increases urinary glucose excretion.
Pharmacodynamics
Urinary Glucose
Excretion
In patients with type 2 diabetes, urinary glucose
excretion increased immediately following a dose of JARDIANCE and was
maintained at the end of a 4-week treatment period averaging at approximately
64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg
JARDIANCE once daily [see Clinical Studies].
Urinary Volume
In a 5-day study, mean 24-hour urine
volume increase from baseline was 341 mL on Day 1 and 135 mL on Day 5 of
empagliflozin 25 mg once daily treatment.
Cardiac
Electrophysiology
In a randomized, placebo-controlled,
active-comparator, crossover study, 30 healthy
subjects were administered a single oral dose of JARDIANCE 25 mg, JARDIANCE 200
mg (8 times the maximum dose), moxifloxacin, and placebo. No increase in QTc
was observed with either 25 mg or 200 mg empagliflozin.
Pharmacokinetics
Absorption
The pharmacokinetics of empagliflozin
has been characterized in healthy volunteers and patients with type 2 diabetes and no
clinically relevant differences were noted between the two populations. After
oral administration, peak plasma concentrations of empagliflozin were reached
at 1.5 hours post-dose. Thereafter, plasma concentrations declined in a biphasic
manner with a rapid distribution phase and a relatively slow terminal phase.
The steady state mean plasma AUC and Cmax were 1870 nmol¡Ph/L and 259 nmol/L,
respectively, with 10 mg empagliflozin once daily treatment, and 4740 nmol¡Ph/L
and 687 nmol/L, respectively, with 25 mg empagliflozin once daily treatment.
Systemic exposure of empagliflozin increased in a dose-proportional manner in
the therapeutic dose range. The single-dose and steady-state pharmacokinetic
parameters of empagliflozin were similar, suggesting linear pharmacokinetics
with respect to time.
Administration of 25 mg empagliflozin
after intake of a high-fat and high-calorie meal resulted
in slightly lower exposure; AUC decreased by approximately 16% and Cmax
decreased by approximately 37%, compared to fasted condition. The observed
effect of food on empagliflozin pharmacokinetics was not considered clinically
relevant and empagliflozin may be administered with or without food.
Distribution
The apparent steady-state volume of
distribution was estimated to be 73.8 L based on a population pharmacokinetic
analysis. Following administration of an oral [14C]-empagliflozin solution to
healthy subjects, the red blood cell partitioning was approximately 36.8% and
plasma protein binding was 86.2%.
Metabolism
No major metabolites of empagliflozin
were detected in human plasma and the most abundant metabolites were three
glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of
each metabolite was less than 10% of total drug-related material. 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.
Elimination
The apparent terminal elimination
half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance
was 10.6 L/h based on the population pharmacokinetic analysis. Following
once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was
observed at steady-state, which was consistent with empagliflozin half-life.
Following administration of an oral [14C]-empagliflozin solution to
healthy subjects, approximately 95.6% of the drug-related radioactivity was
eliminated in feces (41.2%) or urine (54.4%). The majority of drug-related
radioactivity recovered in feces was unchanged parent drug and approximately
half of drug-related radioactivity excreted in urine was unchanged parent drug.
Specific
Populations
Renal Impairment
In patients with mild (eGFR: 60 to
less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73 m2), and severe (eGFR: less than 30
mL/min/1.73 m2) renal impairment and subjects with kidney failure/end stage renal disease
(ESRD) patients, AUC of
empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively,
compared to subjects with normal renal function. Peak plasma levels of
empagliflozin were similar in subjects with moderate renal impairment and kidney
failure/ESRD compared to patients with normal renal function. Peak plasma
levels of empagliflozin were roughly 20% higher in subjects with mild and
severe renal impairment as compared to subjects with normal renal function.
Population pharmacokinetic analysis showed that the apparent oral clearance of
empagliflozin decreased, with a decrease in eGFR leading to an increase in drug
exposure. However, the fraction of empagliflozin that was excreted unchanged in
urine, and urinary glucose excretion, declined with decrease in eGFR.
Hepatic Impairment
In subjects with mild, moderate, and
severe hepatic impairment according to the Child-Pugh classification, AUC of
empagliflozin increased by approximately 23%, 47%, and 75%, and Cmax increased
by approximately 4%, 23%, and 48%, respectively, compared to subjects with
normal hepatic function.
Effect Of Age, Body
Mass Index, Gender, And Race
Based on the population PK analysis,
age, body mass index (BMI), gender and race
(Asians versus primarily Whites) do not have a clinically meaningful effect on
pharmacokinetics of empagliflozin [see Use In
Specific Populations].
Pediatric
Studies characterizing the
pharmacokinetics of empagliflozin in pediatric patients have not been
performed.
Drug Interactions
In Vitro Assessment
Of Drug Interactions
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'-diphosphoglucuronosyltransferases 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 Cmax Ratios [reference lines
indicate 100% (80% - 125%)]
|
![Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% - 125%)] - Illustration](file://C:/DOCUME~1/ADMINI~1/LOCALS~1/Temp/msohtml1/01/clip_image004.jpg)
|
|
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 Cmax Ratios [reference lines
indicate 100% (80% - 125%)]
|
![Effect of Empagliflozin on the Pharmacokinetics of Various Medications as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference linesindicate 100% (80% - 125%)] - Illustration](file://C:/DOCUME~1/ADMINI~1/LOCALS~1/Temp/msohtml1/01/clip_image006.jpg)
|
|
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
|
Clinical Studies
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.
Monotherapy
A total of 986 patients with type 2
diabetes participated in a double-blind, placebo-controlled study to evaluate
the efficacy and safety of JARDIANCE monotherapy.
Treatment-naive patients with
inadequately controlled type 2 diabetes entered an open-label placebo run-in
for 2 weeks. At the end of the run-in period, patients who remained
inadequately controlled and had an HbA1c between 7 and 10% were randomized to
placebo, JARDIANCE 10 mg, JARDIANCE 25 mg, or a reference comparator.
At Week 24, treatment with JARDIANCE
10 mg or 25 mg daily provided statistically significant reductions in HbA1c
(p-value <0.0001), fasting plasma glucose (FPG), and body weight compared
with placebo (see Table 4 and Figure 3).
Table 4: Results at
Week 24 From a Placebo-Controlled Monotherapy Study of JARDIANCE
|
|
JARDIANCE 10
mg
N=224
|
JARDIANCE 25
mg
N=224
|
Placebo
N=228
|
|
HbA1c (%)a
|
|
Baseline (mean)
|
7.9
|
7.9
|
7.9
|
|
Change from baseline (adjusted mean)
|
-0.7
|
-0.8
|
0.1
|
|
Difference from placebo (adjusted mean) (97.5%
CI)
|
-0.7b
(-0.9, -0.6)
|
-0.9b
(-1.0, -0.7)
|
-
|
|
Patients [n (%)] achieving HbA1c <7%
|
72 (35%)
|
88 (44%)
|
25 (12%)
|
|
FPG (mg/dL)c
|
|
Baseline (mean)
|
153
|
153
|
155
|
|
Change from baseline (adjusted mean)
|
-19
|
-25
|
12
|
|
Difference from placebo (adjusted mean) (95% CI)
|
-31 (-37, -26)
|
-36 (-42, -31)
|
-
|
|
Body Weight
|
|
Baseline mean in kg
|
78
|
78
|
78
|
|
% change from baseline (adjusted mean)
|
-2.8
|
-3.2
|
-0.4
|
|
Difference from placebo (adjusted mean) (95% CI)
|
-2.5b
(-3.1, -1.9)
|
-2.8b
(-3.4, -2.2)
|
-
|
|
aModified intent to treat population. Last
observation on study (LOCF) was used to impute missing data at Week 24. At
Week 24, 9.4%, 9.4%, and 30.7% was imputed for patients randomized to
JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively.
b ANCOVA 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: same model used as for HbA1c but additionally
including baseline body weight/baseline FPG, respectively.)
c FPG (mg/dL); for JARDIANCE 10 mg, n=223, for
JARDIANCE 25 mg, n=223, and for placebo, n=226
|
Figure 3: Adjusted
Mean HbA1c Change at Each Time Point (Completers) and at Week 24 (mITT
Population) - LOCF
At Week 24, the systolic blood
pressure was statistically significantly reduced compared to placebo by -2.6
mmHg (placebo-adjusted, p-value=0.0231) in patients randomized to 10 mg of
JARDIANCE and by -3.4 mmHg (placebo-corrected, p-value=0.0028) in patients
randomized to 25 mg of JARDIANCE.
Add-On Combination
Therapy With Metformin
A total of 637 patients with type 2
diabetes participated in a double-blind, placebo-controlled study to evaluate
the efficacy and safety of JARDIANCE in combination with metformin.
Patients with type 2 diabetes
inadequately controlled on at least 1500 mg of metformin per day entered an
open-label 2 week placebo run-in. At the end of the run-in period, patients who
remained inadequately controlled and had an HbA1c between 7 and 10% were
randomized to placebo, JARDIANCE 10 mg, or JARDIANCE 25 mg.
At Week 24, treatment with JARDIANCE
10 mg or 25 mg daily provided statistically significant reductions in HbA1c
(p-value <0.0001), FPG, and body weight compared with placebo (see Table 5).
Table 5: Results at
Week 24 From a Placebo-Controlled Study for JARDIANCE used in Combination with
Metformin
|
|
JARDIANCE
10 mg + Metformin
N=217
|
JARDIANCE
25 mg + Metformin
N=213
|
Placebo
+
Metformin
N=207
|
|
HbA1c (%)a
|
|
Baseline (mean)
|
7.9
|
7.9
|
7.9
|
|
Change from baseline (adjusted mean)
|
-0.7
|
-0.8
|
-0.1
|
|
Difference from placebo + metformin (adjusted
mean) (95% CI)
|
-0.6b
(-0.7, -0.4)
|
-0.6b
(-0.8, -0.5)
|
-
|
|
Patients [n (%)] achieving HbA1c <7%
|
75 (38%)
|
74 (39%)
|
23 (13%)
|
|
FPG (mg/dL)c
|
|
Baseline (mean)
|
155
|
149
|
156
|
|
Change from baseline (adjusted mean)
|
-20
|
-22
|
6
|
|
Difference from placebo + metformin (adjusted
mean)
|
-26
|
-29
|
-
|
|
Body Weight
|
|
Baseline mean in kg
|
82
|
82
|
80
|
|
% change from baseline (adjusted mean)
|
-2.5
|
-2.9
|
-0.5
|
|
Difference from placebo (adjusted mean) (95% CI)
|
-2.0b
(-2.6, -1.4)
|
-2.5b
(-3.1, -1.9)
|
-
|
|
a Modified 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.)
c FPG (mg/dL); for JARDIANCE 10 mg, n=216, for
JARDIANCE 25 mg, n=213, and for placebo, n=207
|
At Week 24, the systolic blood
pressure was statistically significantly reduced compared to placebo by -4.1
mmHg (placebo-corrected, p-value <0.0001) for JARDIANCE 10 mg and -4.8 mmHg
(placebo-corrected, p-value <0.0001) for JARDIANCE 25 mg.
Initial Combination
Therapy With Metformin
A 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-naive 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 Therapy
|
|
JARDIANCE
10 mg + Metformin 1000 mga
N=161
|
JARDIANCE
10 mg + Metformin 2000 mga
N=167
|
JARDIANCE
25 mg + Metformin 1000 mga
N=165
|
JARDIANCE
25 mg + Metformin 2000 mga
N=169
|
JARDIANCE
10 mg
N=169
|
JARDIANCE
25 mg
N=163
|
Metformin
1000 mga
N=167
|
Metformin
2000 mga
N=162
|
|
HbA1c (%)
|
|
Baseline (mean)
|
8.7
|
8.7
|
8.8
|
8.7
|
8.6
|
8.9
|
8.7
|
8.6
|
|
Change from baseline
(adjusted mean)
|
-2.0
|
-2.1
|
-1.9
|
-2.1
|
-1.4
|
-1.4
|
-1.2
|
-1.8
|
|
Comparison vs JARDIANCE
(adjusted mean) (95% CI)
|
-0.6b
(-0.9, -0.4)
|
-0.7b
(-1.0, -0.5)
|
-0.6c
(-0.8, -0.3)
|
-0.7c
(-1.0, -0.5)
|
-
|
-
|
-
|
-
|
|
Comparison vs metformin
(adjusted mean) (95% CI)
|
-0.8b
(-1.0, -0.6)
|
-0.3b
(-0.6, -0.1)
|
-0.8c
(-1.0, -0.5)
|
-0.3c
(-0.6, -0.1)
|
-
|
-
|
-
|
-
|
|
a Metformin total daily dose, administered in two equally divided doses
per day.
b p-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).
c p-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).
|
Add-On Combination
Therapy With MetforminAnd Sulfonylurea
A total of 666 patients with type 2
diabetes participated in a double-blind, placebo-controlled study to evaluate
the efficacy and safety of JARDIANCE in combination with metformin plus a
sulfonylurea.
Patients with inadequately controlled
type 2 diabetes on at least 1500 mg per day of metformin and on a sulfonylurea,
entered a 2 week open-label placebo run-in. At the end of the run-in, patients
who remained inadequately controlled and had an HbA1c between 7% and 10% were
randomized to placebo, JARDIANCE 10 mg, or JARDIANCE 25 mg.
Treatment with JARDIANCE 10 mg or 25
mg daily provided statistically significant reductions in HbA1c (pvalue
<0.0001), FPG, and body weight compared with placebo (see Table 7).
Table 7: Results at
Week 24 from a Placebo-Controlled Study for JARDIANCE in Combination with
Metformin and Sulfonylurea
|
|
JARDIANCE
10 mg + Metformin + SU
N=225
|
JARDIANCE
25 mg + Metformin + SU
N=216
|
Placebo +
Metformin + SU
N=225
|
|
HbA1c (%)a
|
|
Baseline (mean)
|
8.1
|
8.1
|
8.2
|
|
Change from baseline (adjusted mean)
|
-0.8
|
-0.8
|
-0.2
|
|
Difference from placebo (adjusted mean) (95% CI)
|
-0.6b
(-0.8, -0.5)
|
-0.6b
(-0.7, -0.4)
|
-
|
|
Patients [n (%)] achieving HbA1c <7%
|
55 (26%)
|
65 (32%)
|
20 (9%)
|
|
FPG (mg/dL)c
|
|
Baseline (mean)
|
151
|
156
|
152
|
|
Change from baseline (adjusted mean)
|
-23
|
-23
|
6
|
|
Difference from placebo (adjusted mean)
|
-29
|
-29
|
-
|
|
Body Weight
|
|
Baseline mean in kg
|
77
|
78
|
76
|
|
% change from baseline (adjusted mean)
|
-2.9
|
-3.2
|
-0.5
|
|
Difference from placebo (adjusted mean) (95% CI)
|
-2.4b
(-3.0, -1.8)
|
-2.7b
(-3.3, -2.1)
|
-
|
|
a Modified 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.
b ANCOVA 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.)
c FPG (mg/dL); for JARDIANCE 10 mg, n=225, for
JARDIANCE 25 mg, n=215, for placebo, n=224
|
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 Metformin
The efficacy of JARDIANCE was
evaluated in a double-blind, glimepiride-controlled, study in 1545 patients
with type 2 diabetes with insufficient glycemic control despite metformin
therapy.
Patients with inadequate glycemic
control and an HbA1c between 7% and 10% after a 2-week run-in period were
randomized to glimepiride or JARDIANCE 25 mg.
At Week 52, JARDIANCE 25 mg and
glimepiride lowered HbA1c and FPG (see Table 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 Metformin
|
|
JARDIANCE 25
mg + Metformin
N=765
|
Glimepiride +
Metformin
N=780
|
|
HbA1c (%)a
|
|
Baseline (mean)
|
7.9
|
7.9
|
|
Change from baseline (adjusted mean)
|
-0.7
|
-0.7
|
|
Difference from glimepiride (adjusted mean)
(97.5% CI)
|
-0.07b
(-0.15, 0.01)
|
-
|
|
FPG (mg/dL)d
|
|
Baseline (mean)
|
150
|
150
|
|
Change from baseline (adjusted mean)
|
-19
|
-9
|
|
Difference from glimepiride (adjusted mean)
|
-11
|
-
|
|
Body Weight
|
|
Baseline mean in kg
|
82.5
|
83
|
|
% change from baseline (adjusted mean)
|
-3.9
|
2.0
|
|
Difference from glimepiride (adjusted mean) (95%
CI)
|
-5.9c
(-6.3, -5.5)
|
-
|
|
a Modified 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.
b Non-inferior, ANCOVA model p-value <0.0001 (HbA1c: ANCOVA
model includes baseline HbA1c, treatment, renal function, and region)
c ANCOVA p-value <0.0001 (Body weight and FPG:
same model used as for HbA1c but additionally including baseline body
weight/baseline FPG, respectively.)
d FPG (mg/dL); for JARDIANCE 25 mg, n=764, for
placebo, n=779
|
Figure 4: Adjusted
mean HbA1c Change at Each Time Point (Completers) and at Week 52 (mITT
Population) - LOCF
At Week 52, the adjusted mean change
from baseline in systolic blood pressure was -3.6 mmHg, compared to 2.2 mmHg
for glimepiride. The differences between treatment groups for systolic blood
pressure was statistically significant (p-value <0.0001).
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 Metformin
A total of 498 patients with type 2
diabetes participated in a double-blind, placebo-controlled study to evaluate
the efficacy and safety of JARDIANCE in combination with pioglitazone, with or
without metformin.
Patients with inadequately controlled
type 2 diabetes on metformin at a dose of at least 1500 mg per day and
pioglitazone at a dose of at least 30 mg per day were placed into an open-label
placebo run-in for 2 weeks. Patients with inadequate glycemic control and an
HbA1c between 7% and 10% after the run-in period were randomized to placebo,
JARDIANCE 10 mg, or JARDIANCE 25 mg.
Treatment with JARDIANCE 10 mg or 25
mg daily resulted in statistically significant reductions in HbA1c (pvalue
<0.0001), FPG, and body weight compared with placebo (see Table 9).
Table 9: Results of
Placebo-Controlled Study for JARDIANCE in Combination Therapy with Pioglitazone
|
|
JARDIANCE
10 mg + Pioglitazone
N=165
|
JARDIANCE
25 mg + Pioglitazone
N=168
|
Placebo +
Pioglitazone
N=165
|
|
HbA1c (%)a
|
|
Baseline (mean)
|
8.1
|
8.1
|
8.2
|
|
Change from baseline (adjusted mean)
|
-0.6
|
-0.7
|
-0.1
|
|
Difference from placebo + pioglitazone (adjusted
mean) (95% CI)
|
-0.5b
(-0.7, -0.3)
|
-0.6b
(-0.8, -0.4)
|
-
|
|
Patients [n (%)] achieving HbA1c <7%
|
36 (24%)
|
48 (30%)
|
12 (8%)
|
|
FPG (mg/dL)c
|
|
Baseline (mean)
|
152
|
152
|
152
|
|
Change from baseline (adjusted mean)
|
-17
|
-22
|
7
|
|
Difference from placebo + pioglitazone (adjusted
mean) (97.5% CI)
|
-23b
(-31.8, -15.2)
|
-28b
(-36.7, -20.2)
|
-
|
|
Body Weight
|
|
Baseline mean in kg
|
78
|
79
|
78
|
|
% change from baseline (adjusted mean)
|
-2.0
|
-1.8
|
0.6
|
|
Difference from placebo (adjusted mean) (95% CI)
|
-2.6b
(-3.4, -1.8)
|
-2.4b
(-3.2, -1.6)
|
-
|
|
a Modified 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.
b ANCOVA 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.)
c FPG (mg/dL); for JARDIANCE 10 mg, n=163
|
Add-On Combination
With Insulin With Or Without Metformin And/Or Sulfonylureas
A total of 494 patients with type 2
diabetes inadequately controlled on insulin, or insulin in combination with
oral drugs participated in a double-blind, placebo-controlled study to evaluate
the efficacy of JARDIANCE as add-on therapy to insulin over 78 weeks.
Patients entered a 2-week placebo
run-in period on basal insulin (e.g., insulin glargine, insulin detemir,
or NPH insulin) with
or without metformin and/or sulfonylurea background therapy. Following the
run-in period, patients with inadequate glycemic control were randomized to the
addition of JARDIANCE 10 mg, JARDIANCE 25 mg, or placebo. Patients were
maintained on a stable dose of insulin prior to enrollment, during the run-in
period, and during the first 18 weeks of treatment. For the remaining 60 weeks,
insulin could be adjusted. The mean total daily insulin dose at baseline for
JARDIANCE 10 mg, 25 mg, and placebo was 45 IU, 48 IU, and 48 IU, respectively.
JARDIANCE used in combination with
insulin (with or without metformin and/or sulfonylurea) provided statistically
significant reductions in HbA1c and FPG compared to placebo after both 18 and
78 weeks of treatment (see Table 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 Insulin
|
|
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)
|
8.3
|
8.3
|
8.2
|
8.3
|
8.3
|
8.2
|
|
Change from baseline (adjusted mean)
|
-0.6
|
-0.7
|
0
|
-0.4
|
-0.6
|
0.1
|
|
Difference from placebo (adjusted mean) (97.5%
CI)
|
-0.6b
(-0.8, -0.4)
|
-0.7b
(-0.9, -0.5)
|
-
|
- 0.5b
(-0.7, -0.3)
|
-0.7b
(-0.9, -0.5)
|
-
|
|
Patients (%) achieving HbA1c <7%
|
18.0
|
19.5
|
5.5
|
12.0
|
17.5
|
6.7
|
|
FPG (mg/dL)
|
|
Baseline (mean)
|
138
|
146
|
142
|
138
|
146
|
142
|
|
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)
|
-28.2b
(-37.0, -19.5)
|
-29.5b
(-38.4, -20.6)
|
-
|
12.9c
(-21.9, 3.9)
|
-17.9b
(-27.0, -8.8)
|
-
|
|
Body Weight
|
|
Baseline mean in kg
|
92
|
95
|
90
|
92
|
95
|
90
|
|
% change from baseline (adjusted mean)
|
-1.8
|
-1.4
|
-0.1
|
-2.4
|
-2.4
|
0.7
|
|
Difference from placebo (adjusted mean) (95% CI)
|
-1.7d
(-3.0, -0.5)
|
-1.3e
(-2.5, -0.0)
|
-
|
- 3.0b
(-4.4, -1.7)
|
-3.0b
(-4.4, -1.6)
|
-
|
|
a Modified 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.
b ANCOVA 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.
c p-value=0.0049
d p-value=0.0052
e p-value=0.0463
|
Add-On Combination
With MDI InsulinWith Or Without Metformin
A 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 Metformin
|
|
JARDIANCE 10
mg
+ Insulin
+/- Metformin
N=186
|
JARDIANCE 25
mg
+ Insulin
+/- Metformin
N=189
|
Placebo
+ Insulin
+/- Metformin
N=188
|
|
HbA1c (%)a
|
|
Baseline (mean)
|
8.4
|
8.3
|
8.3
|
|
Change from baseline (adjusted mean)
|
-0.9
|
-1.0
|
-0.5
|
|
Difference from placebo (adjusted mean) (95% CI)
|
-0.4b
(-0.6, -0.3)
|
-0.5b
(-0.7, -0.4)
|
-
|
|
a Modified 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.
b ANCOVA p-value <0.0001 (HbA1c: ANCOVA model
includes baseline HbA1c, treatment, renal function, geographical region, and
background medication).
|
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 Impairment
A total of 738 patients with type 2
diabetes and a baseline eGFR less than 90 mL/min/1.73 m2 participated in a randomized,
double-blind, placebo-controlled, parallel-group to evaluate the efficacy and
safety of JARDIANCE in patients with type 2 diabetes and renal impairment. The
trial population comprised of 290 patients with mild renal impairment (eGFR 60
to less than 90 mL/min/1.73 m2), 374 patients with moderate renal impairment (eGFR 30 to less than 60
mL/min/1.73 m2), and 74 with severe renal impairment (eGFR less than 30 mL/min/1.73 m2). A total of 194 patients with
moderate renal impairment had a baseline eGFR of 30 to less than 45 mL/min/1.73
m2 and 180 patients a baseline eGFR of 45 to less than 60 mL/min/1.73
m2.
At Week 24, JARDIANCE 25 mg provided
statistically significant reduction in HbA1c relative to placebo in patients
with mild to moderate renal impairment (see Table 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 m2, 45 to less than 60 mL/min/1.73 m2, and 30 to less than 45 mL/min/1.73
m2, respectively [see DOSAGE AND
ADMINISTRATION and Use In Specific Populations]. For placebo, least square mean HbA1c changes at 24 weeks were 0.1%,
-0.1%, and 0.2% for patients with a baseline eGFR of 60 to less than 90
mL/min/1.73 m2, 45 to less than 60 mL/min/1.73 m2, and 30 to less than 45 mL/min/1.73
m2, respectively.
Table 12: Results
at Week 24 (LOCF) of Placebo-Controlled Study for JARDIANCE in Patients with
Type 2 Diabetes and Renal Impairment
|
|
Mild and
Moderate Impairmentb
|
|
JARDIANCE 25
mg
|
|
HbA1c
|
|
Number of patients
|
n=284
|
|
Comparison vs placebo (adjusted mean) (95% CI)
|
-0.5a (-0.6, -0.4)
|
|
a p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c,
treatment, renal function, and background medication)
b eGFR 30 to less than 90 mL/min/1.73 m2-
Modified intent to treat population. Last observation on study (LOCF) was
used to impute missing data at Week 24. At Week 24, 24.6% and 26.2% was
imputed for patients randomized to JARDIANCE 25 mg and placebo, respectively.
|
For patients with severe renal
impairment, the analyses of changes in HbA1c and FPG showed no discernible
treatment effect of JARDIANCE 25 mg compared to placebo [see DOSAGE AND ADMINISTRATION and Use In
Specific Populations].
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, retinopathyand nephropathy to
investigators respectively and the mean eGFR was 74 mL/min/1.73 m2. 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 Componentsa
|
|
Placebo
N=2333
|
JARDIANCE
N=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
infarctionc
|
121
(5.2%)
|
213
(4.5%)
|
0.87
(0.70, 1.09)
|
|
Non-fatal strokec
|
60
(2.6%)
|
150
(3.2%)
|
1.24
(0.92, 1.67)
|
|
Cardiovascular deathc
|
137
(5.9%)
|
172
(3.7%)
|
0.62
(0.49, 0.77)
|
|
aTreated set (patients who had received at least
one dose of study drug)
b p−value for superiority (2−sided) 0.04
c Total number of events
|
Figure 5: Estimated
Cumulative Incidence of First MACE
Figure 6: Estimated
Cumulative Incidence of Cardiovascular Death
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).
PATIENT INFORMATION
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-thecounter 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 leaflet for a list of ingredients in
JARDIANCE.have severe kidney problems or are on
dialysis
What 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:nauseatirednessvomitingtrouble breathingstomach-area (abdominal) pain
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.
Serious 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:headacheirritabilityconfusiondizzinessdrowsinesshungershaking or feeling jitterysweatingweaknessfast heartbeatKidney 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 longAllergic (hypersensitivity) reactions. Serious allergic
reactions have happened in people who are taking JARDIANCE. Symptoms may
includeswelling 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 Patient Information. 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 Patient Information 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,
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.
This Patient Information has been
approved by the U.S. Food and Drug Administration.
