NDC 70518-2046 Glyxambi

Empagliflozin And Linagliptin

NDC Product Code 70518-2046

NDC Code: 70518-2046

Proprietary Name: Glyxambi What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

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

Product Characteristics

Color(s):
YELLOW (C48330 - PALE YELLOW)
Shape: TRIANGLE (C48353)
Size(s):
8 MM
Imprint(s):
10;5
Score: 1

NDC Code Structure

  • 70518 - Remedyrepack Inc.
    • 70518-2046 - Glyxambi

NDC 70518-2046-0

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

NDC Product Information

Glyxambi with NDC 70518-2046 is a a human prescription drug product labeled by Remedyrepack Inc.. The generic name of Glyxambi is empagliflozin and linagliptin. The product's dosage form is tablet, film coated and is administered via oral form.

Labeler Name: Remedyrepack Inc.

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

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

Glyxambi Active Ingredient(s)

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

  • EMPAGLIFLOZIN 10 mg/1
  • LINAGLIPTIN 5 mg/1

Administration Route(s)

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

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

Pharmacological Class(es)

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

  • Sodium-Glucose Cotransporter 2 Inhibitor - [EPC] (Established Pharmacologic Class)
  • Sodium-Glucose Transporter 2 Inhibitors - [MoA] (Mechanism of Action)
  • Dipeptidyl Peptidase 4 Inhibitors - [MoA] (Mechanism of Action)
  • Dipeptidyl Peptidase 4 Inhibitor - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Remedyrepack Inc.
Labeler Code: 70518
FDA Application Number: NDA206073 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

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

Start Marketing Date: 04-29-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

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

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

* Please review the disclaimer below.

Glyxambi Product Labeling Information

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

Product Labeling Index

1  Indications And Usage

GLYXAMBI is a combination of empagliflozin
and linagliptin indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus when treatment
with both empagliflozin and linagliptin is appropriate.Empagliflozin is indicated to
reduce the risk of cardiovascular death in adults with type 2 diabetes
mellitus and established cardiovascular disease


[see Clinical
Studies (


14.2)]


. However,
the effectiveness of GLYXAMBI on reducing the risk of cardiovascular
death in adults with type 2 diabetes mellitus and cardiovascular disease
has not been established.


Limitations of UseGLYXAMBI is
not recommended for patients with type 1 diabetes or for the treatment
of diabetic ketoacidosis


[see Warnings and Precautions (


5.4)]


.


GLYXAMBI has not been studied in patients
with a history of pancreatitis. It is unknown whether patients with
a history of pancreatitis are at an increased risk for the development
of pancreatitis while using GLYXAMBI


[see Warnings and Precautions
(


5.1)].

2.1 Recommended Dosage

The recommended dose of GLYXAMBI
is 10 mg empagliflozin/5 mg linagliptin once daily in the morning,
taken with or without food. In patients tolerating GLYXAMBI, the
dose may be increased to 25 mg empagliflozin/5 mg linagliptin once
daily.In patients
with volume depletion, correcting this condition prior to initiation
of GLYXAMBI is recommended


[see Warnings and Precautions (


5.3), Use in Specific Populations (


8.5) and Patient Counseling Information
(


17)].


No studies have been performed specifically
examining the safety and efficacy of GLYXAMBI in patients previously
treated with other oral antihyperglycemic agents and switched to GLYXAMBI.
Any change in therapy of type 2 diabetes should be undertaken with
care and appropriate monitoring as changes in glycemic control can
occur.

2.2 Patients With Renal Impairment

Assessment of renal function is recommended prior to initiation of
GLYXAMBI and periodically thereafter.GLYXAMBI should not be initiated in patients
with an eGFR less than 45 mL/min/1.73 m


2.


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


2.


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


2 [see Warnings and Precautions (


5.3,


5.5) and Use in Specific
Populations (


8.6)]


.

3  Dosage Forms And Strengths

  • GLYXAMBI is a combination of
  • Empagliflozin and linagliptin. GLYXAMBI is available in the following
  • Dosage forms and strengths:10 mg empagliflozin/5 mg linagliptin tablets are pale yellow,
  • Arc triangular, flat-faced, bevel-edged, film-coated tablets. One
  • Side is debossed with the Boehringer Ingelheim company symbol; the
  • Other side is debossed with “10/5”.
  • 25 mg empagliflozin/5 mg linagliptin tablets are pale pink,
  • Arc triangular, flat-faced, bevel-edged, film-coated tablets. One
  • Side is debossed with the Boehringer Ingelheim company symbol; the
  • Other side is debossed with “25/5”.

4  Contraindications

  • GLYXAMBI
  • Is contraindicated in patients with:GLYXAMBI
  • Is contraindicated in patients with:Severe renal impairment, end-stage renal disease, or dialysis
  • [see Use in Specific Populations (
  • 8.6)].
  • A history of serious hypersensitivity
  • Reaction to empagliflozin, linagliptin, or any of the excipients in
  • GLYXAMBI such as anaphylaxis, angioedema, exfoliative skin conditions,
  • Urticaria, or bronchial hyperreactivity
  • [see Warnings and
  • Precautions (
  • 5.10) and Adverse Reactions
  • (
  • 6)]
  • .
  • A history of serious hypersensitivity
  • Reaction to empagliflozin, linagliptin, or any of the excipients in
  • GLYXAMBI such as anaphylaxis, angioedema, exfoliative skin conditions,
  • Urticaria, or bronchial hyperreactivity
  • [see Warnings and
  • Precautions (
  • 5.10) and Adverse Reactions
  • (
  • 6)]
  • .

5.1 Pancreatitis

There have been postmarketing
reports of acute pancreatitis, including fatal pancreatitis, in patients
taking linagliptin. Take careful notice of potential signs and symptoms
of pancreatitis. If pancreatitis is suspected, promptly discontinue
GLYXAMBI and initiate appropriate management. It is unknown whether
patients with a history of pancreatitis are at increased risk for
the development of pancreatitis while using GLYXAMBI.

5.2 Heart Failure

An association
between DPP-4 inhibitor treatment and heart failure has been observed
in cardiovascular outcomes trials for two other members of the DPP-4
inhibitor class. These trials evaluated patients with type 2 diabetes
mellitus and atherosclerotic cardiovascular disease.Consider the risks and benefits of GLYXAMBI prior to initiating treatment
in patients at risk for heart failure, such as those with a prior
history of heart failure and a history of renal impairment, and observe
these patients for signs and symptoms of heart failure during therapy.
Advise patients of the characteristic symptoms of heart failure and
to immediately report such symptoms. If heart failure develops, evaluate
and manage according to current standards of care and consider discontinuation
of GLYXAMBI.

5.3 Hypotension

Empagliflozin causes intravascular
volume contraction. Symptomatic hypotension may occur after initiating
empagliflozin


[see Adverse Reactions (


6.1)]


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


[see Use in Specific Populations (


8.5)]


.

5.4 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 empagliflozin. Fatal cases of ketoacidosis
have been reported in patients taking empagliflozin. GLYXAMBI is not
indicated for the treatment of patients with type 1 diabetes mellitus


[see Indications and Usage (


1)]


.


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

5.5 Acute Kidney Injury And Impairment In Renal Function

Empagliflozin causes intravascular volume
contraction


[see Warnings and Precautions (


5.3)]


and can cause renal impairment


[see Adverse Reactions (


6.1)]


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


Before initiating GLYXAMBI, 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 GLYXAMBI 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
GLYXAMBI promptly and institute treatment.Empagliflozin increases serum creatinine
and decreases eGFR. Patients with hypovolemia may be more susceptible
to these changes. Renal function abnormalities can occur after initiating
GLYXAMBI


[see Adverse Reactions (


6.1)]


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


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


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


2 [see Dosage and Administration (


2.2), Contraindications (


4)
and Use in Specific Populations


(


8.6)]


.

5.6 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 empagliflozin. Treatment with SGLT2 inhibitors increases
the risk for urinary tract infections. Evaluate patients for signs
and symptoms of urinary tract infections and treat promptly, if indicated


[see Adverse Reactions (


6)]


.

5.7 Hypoglycemia With Concomitant Use With Insulin And Insulin Secretagogues

Insulin and insulin secretagogues
are known to cause hypoglycemia. The use of empagliflozin or linagliptin
in combination with an insulin secretagogue (e.g., sulfonylurea) or
insulin was associated with a higher rate of hypoglycemia compared
with placebo in a clinical trial. Therefore, a lower dose of the
insulin secretagogue or insulin may be required to reduce the risk
of hypoglycemia when used in combination with GLYXAMBI.

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

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

5.9 Genital Mycotic Infections

Empagliflozin increases the risk for genital
mycotic infections


[see Adverse Reactions (


6.1)]


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

5.10 Hypersensitivity Reactions

There have been postmarketing reports of
serious hypersensitivity reactions in patients treated with linagliptin
(one of the components of GLYXAMBI). These reactions include anaphylaxis,
angioedema, and exfoliative skin conditions. Onset of these reactions
occurred within the first 3 months after initiation of treatment with
linagliptin, with some reports occurring after the first dose.There have been postmarketing reports of
serious hypersensitivity reactions in patients treated with linagliptin
(one of the components of GLYXAMBI). These reactions include anaphylaxis,
angioedema, and exfoliative skin conditions. Onset of these reactions
occurred within the first 3 months after initiation of treatment with
linagliptin, with some reports occurring after the first dose.Angioedema has also been reported
with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution
in a patient with a history of angioedema to another DPP-4 inhibitor
because it is unknown whether such patients will be predisposed to
angioedema with GLYXAMBI.Angioedema has also been reported
with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution
in a patient with a history of angioedema to another DPP-4 inhibitor
because it is unknown whether such patients will be predisposed to
angioedema with GLYXAMBI.There have been postmarketing
reports of serious hypersensitivity reactions, (e.g., angioedema)
in patients treated with empaglifozin (one of the components of GLYXAMBI).If a hypersensitivity reaction occurs, discontinue GLYXAMBI, treat
promptly per standard of care, and monitor until signs and symptoms
resolve. GLYXAMBI is contraindicated in patients with a previous
serious hypersensitivity reaction to linagliptin or empagliflozin


[see Contraindications (


4)]


.

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

Increases in LDL-C can occur
with empagliflozin


[see Adverse Reactions (


6.1)]


. Monitor and treat as appropriate.

5.12 Severe And Disabling Arthralgia

There have been postmarketing reports of
severe and disabling arthralgia in patients taking DPP-4 inhibitors.
The time to onset of symptoms following initiation of drug therapy
varied from one day to years. Patients experienced relief of symptoms
upon discontinuation of the medication. A subset of patients experienced
a recurrence of symptoms when restarting the same drug or a different
DPP-4 inhibitor. Consider as a possible cause for severe joint pain
and discontinue drug if appropriate.

5.13 Bullous Pemphigoid

Postmarketing cases of bullous pemphigoid
requiring hospitalization have been reported with DPP-4 inhibitor
use. In reported cases, patients typically recovered with topical
or systemic immunosuppressive treatment and discontinuation of the
DPP-4 inhibitor. Tell patients to report development of blisters or
erosions while receiving GLYXAMBI. If bullous pemphigoid is suspected,
GLYXAMBI should be discontinued and referral to a dermatologist should
be considered for diagnosis and appropriate treatment.

5.14 Macrovascular Outcomes

There have been no clinical studies establishing
conclusive evidence of macrovascular risk reduction with GLYXAMBI.

6  Adverse Reactions

  • The following important adverse reactions
  • Are described below and elsewhere in the labeling:Pancreatitis
  • [see Warnings and Precautions (
  • 5.1)]
  • Heart Failure
  • [see Warnings and Precautions (
  • 5.2)]
  • Hypotension
  • [see Warnings and Precautions (
  • 5.3)]
  • Ketoacidosis
  • [see Warnings and Precautions (
  • 5.4)]
  • Acute Kidney Injury and Impairment in Renal Function
  • [see Warnings and Precautions (
  • 5.5)]
  • Urosepsis and Pyelonephritis
  • [see Warnings and Precautions
  • (
  • 5.6)]
  • Hypoglycemia with Concomitant Use with Insulin and Insulin
  • Secretagogues
  • [see Warnings and Precautions (
  • 5.7)]
  • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
  • [see Warnings and Precautions (
  • 5.8)]
  • Genital Mycotic Infections
  • [see Warnings and Precautions
  • (
  • 5.9)]
  • Hypersensitivity Reactions
  • [see Warnings and Precautions
  • (
  • 5.10)]
  • Increased Low-Density Lipoprotein Cholesterol (LDL-C)
  • [see Warnings and Precautions (
  • 5.11)]
  • Severe and Disabling Arthralgia
  • [see Warnings and
  • Precautions (
  • 5.12)]
  • Bullous Pemphigoid
  • [see Warnings and Precautions
  • (
  • 5.13)]

6.1 Clinical Trials Experience

Because clinical trials are
conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared
to rates in the clinical trials of another drug and may not reflect
the rates observed in practice.Empagliflozin and LinagliptinThe safety of concomitantly administered empagliflozin
(daily dose 10 mg or 25 mg) and linagliptin (daily dose 5 mg) has
been evaluated in a total of 1363 patients with type 2 diabetes treated
for up to 52 weeks in active-controlled clinical trials. The most
common adverse reactions with concomitant administration of empagliflozin
and linagliptin based on a pooled analyses of these studies are shown
in Table 1.


Table 1 Adverse Reactions Reported in ≥5% of Patients Treated
with Empagliflozin and LinagliptinaPredefined adverse event
grouping, including, but not limited to, urinary tract infection,
asymptomatic bacteriuria, cystitis


 GLYXAMBI


10 mg/5 mg


n=272


GLYXAMBI


25 mg/5 mg


n=273


 n (%)n (%)Urinary tract infection


a34 (12.5)31 (11.4)Nasopharyngitis16 (5.9)18 (6.6)Upper respiratory tract infection19 (7.0)19 (7.0)EmpagliflozinAdverse reactions that occurred in ≥2% of patients receiving
empagliflozin and more commonly than in patients given placebo included
(10 mg, 25 mg, and placebo): urinary tract infection (9.3%, 7.6%,
and 7.6%), female genital mycotic infections (5.4%, 6.4%, and 1.5%),
upper respiratory tract infection (3.1%, 4.0%, and 3.8%), increased
urination (3.4%, 3.2%, and 1.0%), dyslipidemia (3.9%, 2.9%, and 3.4%),
arthralgia (2.4%, 2.3%, and 2.2%), male genital mycotic infections
(3.1%, 1.6%, and 0.4%), and nausea (2.3%, 1.1%, and 1.4%).


Thirst (including polydipsia)
was reported in 0%, 1.7%, and 1.5% for placebo, empagliflozin 10 mg,
and empagliflozin 25 mg, respectively.Empagliflozin causes an osmotic diuresis,
which may lead to intravascular volume contraction and adverse reactions
related to volume depletion.LinagliptinAdverse
reactions reported in ≥2% of patients treated with linagliptin 5 mg
and more commonly than in patients treated with placebo included:
nasopharyngitis (7.0% and 6.1%), diarrhea (3.3% and 3.0%), and cough
(2.1% and 1.4%).


Other
adverse reactions reported in clinical studies with treatment of linagliptin
monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized
skin exfoliation, or bronchial hyperreactivity) and myalgia.In the clinical trial program,
pancreatitis was reported in 15.2 cases per 10,000 patient year exposure
while being treated with linagliptin compared with 3.7 cases per 10,000
patient year exposure while being treated with comparator (placebo
and active comparator, sulfonylurea). Three additional cases of pancreatitis
were reported following the last administered dose of linagliptin.HypoglycemiaTable 2 summarizes the reports of hypoglycemia with empagliflozin
and linagliptin over a treatment period of 52 weeks.


Table 2 Incidence of Overall


a and Severe


b Hypoglycemic Adverse Reactions


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


bSevere hypoglycemic events:
requiring assistance regardless of blood glucose


Add-on to Metformin


(52 weeks)


GLYXAMBI


10 mg/5 mg


(n=136)


GLYXAMBI


25 mg/5 mg


(n=137)


Overall
(%)2.2%3.6%Severe
(%)0%0%Laboratory TestsEmpagliflozin and LinagliptinChanges in laboratory findings in patients treated with the combination
of empagliflozin and linagliptin included increases in cholesterol
and hematocrit compared to baseline.


EmpagliflozinIncrease in Low-Density Lipoprotein Cholesterol (LDL-C): Dose-related increases in low-density lipoprotein cholesterol (LDL-C)
were observed in patients treated with empagliflozin. LDL-C increased
by 2.3%, 4.6%, and 6.5% in patients treated with placebo, empagliflozin
10 mg, and empagliflozin 25 mg, respectively


[see Warnings
and Precautions (


5.11)]


.
The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across
treatment groups.


Increase in Hematocrit: Median hematocrit decreased by
1.3% in placebo and increased by 2.8% in empagliflozin 10 mg and 2.8%
in empagliflozin 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, empagliflozin 10 mg, and empagliflozin 25 mg,
respectively.


LinagliptinIncrease in Uric Acid: Changes in laboratory values that occurred more frequently in the
linagliptin group and ≥1% more than in the placebo group were increases
in uric acid (1.3% in the placebo group, 2.7% in the linagliptin group).


Increase in Lipase: In a placebo-controlled clinical trial with linagliptin in type
2 diabetes mellitus patients with micro- or macroalbuminuria, a mean
increase of 30% in lipase concentrations from baseline to 24 weeks
was observed in the linagliptin arm compared to a mean decrease of
2% in the placebo arm. Lipase levels above 3 times upper limit of
normal were seen in 8.2% compared to 1.7% patients in the linagliptin
and placebo arms, respectively.

6.2 Postmarketing Experience

  • Additional adverse reactions
  • Have been identified during postapproval use of linagliptin and empagliflozin.
  • 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.Acute Pancreatitis, including Fatal Pancreatitis
  • [see Indications and Usage (
  • 1) and
  • Warnings and Precautions (
  • 5.1)]
  • Ketoacidosis
  • [see Warnings and Precautions (
  • 5.4)]
  • Urosepsis and Pyelonephritis
  • [see Warnings and Precautions
  • (
  • 5.6)]
  • Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)
  • [see Warnings and Precautions (
  • 5.8)]
  • Hypersensitivity Reactions including Anaphylaxis, Angioedema,
  • And Exfoliative Skin Conditions
  • [see Warnings and Precautions
  • (
  • 5.10)]
  • Severe and Disabling Arthralgia
  • [see Warnings and
  • Precautions (
  • 5.12)]
  • Bullous Pemphigoid
  • [see Warnings and Precautions
  • (
  • 5.13)]
  • Skin Reactions (e.g., rash, urticaria)Mouth Ulceration, Stomatitis

7.1 Drug Interactions With Empagliflozin

DiureticsCoadministration
of empagliflozin with diuretics resulted in increased urine volume
and frequency of voids, which might enhance the potential for volume
depletion


[see Warnings and Precautions (


5.3)]


.


Insulin or Insulin SecretagoguesCoadministration of empagliflozin with insulin or insulin
secretagogues increases the risk for hypoglycemia


[see Warnings
and Precautions (


5.7)]


.


Positive Urine Glucose
TestMonitoring 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) AssayMonitoring
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.

Other

Inducers of P-glycoprotein or CYP3A4
Enzymes


Rifampin decreased linagliptin exposure,
suggesting that the efficacy of linagliptin may be reduced when administered
in combination with a strong P-gp or CYP3A4 inducer. Therefore, use
of alternative treatments is strongly recommended when linagliptin
is to be administered with a strong P-gp or CYP3A4 inducer


[see Clinical Pharmacology (


12.3)]


.

Risk Summary


Based on animal data showing adverse renal effects, from
empagliflozin, GLYXAMBI is not recommended during the second and third
trimesters of pregnancy.


The limited available data with GLYXAMBI,
linagliptin, or empagliflozin 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. No adverse developmental
effects were observed when the combination of linagliptin and empagliflozin
was administered to pregnant rats during the period of organogenesis
at exposures approximately 253 and 353 times the clinical exposure


(see


Data).


The estimated
background risk of major birth defects is 6-10% in women with pre-gestational
diabetes with a HbA1c >7 and has been reported to be as high as 20-25%
in women with HbA1c >10. The estimated background risk of miscarriage
for the indicated population is unknown. In the U.S. general population,
the estimated background risk of major birth defects and miscarriage
in clinically recognized pregnancies is 2-4% and 15-20%, respectively.Clinical ConsiderationsDisease-associated
maternal and/or embryo/fetal risk: Poorly controlled diabetes
in pregnancy increases the maternal risk for diabetic ketoacidosis,
pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth
and delivery complications. Poorly controlled diabetes increases
the fetal risk for major birth defects, stillbirth, and macrosomia
related morbidity.


Data


Animal Data


The combined
components administered during the period of organogenesis were not
teratogenic in rats up to and including a combined dose of 700 mg/kg/day
empagliflozin and 140 mg/kg/day linagliptin, which is 253 and 353
times the clinical exposure. A pre- and post-natal development study
was not conducted with the combined components of GLYXAMBI.


Empagliflozin: 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 48-times (rats) and
128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC),
did not result in adverse developmental effects. In rats, at higher
doses of empagliflozin causing maternal toxicity, malformations of
limb bones increased in fetuses at 700 mg/kg/day or 154-times the
25 mg maximum clinical dose. Empagliflozin crosses the placenta and
reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin
resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times
the 25 mg maximum clinical dose.In pre- and postnatal development studies
in pregnant rats, empagliflozin was administered from gestation day
6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately
16 times the 25 mg maximum clinical dose) without maternal toxicity.
Reduced body weight was observed in the offspring at greater than
or equal to 30 mg/kg/day (approximately 4 times the 25 mg maximum
clinical dose).Linagliptin: No adverse developmental outcome was observed
when linagliptin was administered to pregnant Wistar Han rats and
Himalayan rabbits during the period of organogenesis at doses up to
240 mg/kg/day and 150 mg/kg/day, respectively. These doses represent
approximately 943 times (rats) and 1943 times (rabbits) the 5 mg maximum
clinical dose, based on exposure. No adverse functional, behavioral,
or reproductive outcome was observed in offspring following administration
of linagliptin to Wistar Han rats from gestation day 6 to lactation
day 21 at a dose 49 times the maximum recommended human dose, based
on exposure.


Linagliptin
crosses the placenta into the fetus following oral dosing in pregnant
rats and rabbits.

Distributed by:


Boehringer
Ingelheim Pharmaceuticals, Inc.


Ridgefield, CT 06877 USA


Marketed by:


Boehringer
Ingelheim Pharmaceuticals, Inc.


Ridgefield, CT 06877 USA


and


Eli Lilly and Company


Indianapolis, IN
46285 USA


Licensed
from:


Boehringer Ingelheim International GmbH, Ingelheim,
Germany


Boehringer
Ingelheim Pharmaceuticals, Inc. either owns or uses the Glyxambi®,
Jardiance®, Tradjenta® and EMPA-REG OUTCOME® trademarks under license.
The other trademarks
referenced are owned by third parties not affiliated with Boehringer
Ingelheim Pharmaceuticals, Inc.Copyright © 2018 Boehringer Ingelheim International
GmbH


ALL RIGHTS RESERVED


IT5885MJ232018

8.2 Lactation

Risk SummaryThere is no information regarding the presence of GLYXAMBI,
or its individual components in human milk, the effects on the breastfed
infant, or the effects on milk production. Empagliflozin and linagliptin
are present in rat milk


(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 patients that use of
GLYXAMBI is not recommended while breastfeeding.Data


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

8.4 Pediatric Use

Safety and effectiveness of GLYXAMBI in
pediatric patients under 18 years of age have not been established.

8.5 Geriatric Use

GLYXAMBIEmpagliflozin
is associated with osmotic diuresis, which could affect hydration
status of patients age 75 years and older.


EmpagliflozinNo
empagliflozin dosage change is recommended based on age


[see
Dosage and Administration (


2)]


. 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.
Empagliflozin is expected to have diminished efficacy in elderly
patients with renal impairment


[see Use in Specific Populations
(


8.6)]


. The risk of volume
depletion-related adverse reactions increased in patients who were
75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, empagliflozin
10 mg, and empagliflozin 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, empagliflozin
10 mg, and empagliflozin 25 mg, respectively


[see Warnings
and Precautions (


5.3) and Adverse
Reactions (


6.1)]


.


LinagliptinThere were 4040 type 2 diabetes patients treated with linagliptin
5 mg from 15 clinical trials of linagliptin; 1085 (27%) were 65 years
and over, while 131 (3%) were 75 years and over. Of these patients,
2566 were enrolled in 12 double-blind placebo-controlled studies;
591 (23%) were 65 years and over, while 82 (3%) were 75 years and
over. No overall differences in safety or effectiveness were observed
between patients 65 years and over and younger patients. Therefore,
no dose adjustment is recommended in the elderly population. While
clinical studies of linagliptin have not identified differences in
response between the elderly and younger patients, greater sensitivity
of some older individuals cannot be ruled out.

8.6 Renal Impairment

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


[see Dosage and Administration
(


2.2), Contraindications (


4) and Warnings and Precautions (


5.3,


5.5)].


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


[see
Warnings and Precautions (


5.5)]


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

8.7 Hepatic Impairment

GLYXAMBI may be used in patients
with hepatic impairment


[see Clinical Pharmacology (


12.3)]


.

10  Overdosage

In the event of an overdose with GLYXAMBI, 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,
and removal of linagliptin by hemodialysis or peritoneal dialysis
is unlikely.

11  Description

GLYXAMBI tablets contain two
oral antihyperglycemic drugs used in the management of type 2 diabetes:
empagliflozin and linagliptin.EmpagliflozinEmpagliflozin is an orally-active inhibitor of the sodium-glucose
co-transporter (SGLT2).


The chemical name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-,
(1S).The molecular
formula is C


23H


27ClO


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


Empagliflozin is a white to
yellowish, non-hygroscopic powder. It is very slightly soluble in
water, sparingly soluble in methanol, slightly soluble in ethanol
and acetonitrile; soluble in 50% acetonitrile/water; and practically
insoluble in toluene.LinagliptinLinagliptin is an orally-active
inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.


The chemical name of linagliptin
is 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-The molecular formula is C


25H


28N


8O


2 and the molecular weight is 472.54. The
structural formula is:


Linagliptin is a white to yellowish, not
or only slightly hygroscopic solid substance. It is very slightly
soluble in water. Linagliptin is soluble in methanol, sparingly soluble
in ethanol, very slightly soluble in isopropanol, and very slightly
soluble in acetone.GLYXAMBIGLYXAMBI tablets for oral administration
are available in two dosage strengths containing 10 mg or 25 mg empagliflozin
in combination with 5 mg linagliptin. The inactive ingredients of
GLYXAMBI are the following: Tablet Core: mannitol, pregelatinized
starch, corn starch, copovidone, crospovidone, talc and magnesium
stearate. Coating: hypromellose, mannitol, talc, titanium dioxide,
polyethylene glycol and ferric oxide, yellow (10 mg/5 mg) or ferric
oxide, red (25 mg/5 mg).

12.1 Mechanism Of Action

GLYXAMBIGLYXAMBI
combines 2 antihyperglycemic agents with complementary mechanisms
of action to improve glycemic control in patients with type 2 diabetes:
empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor,
and linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor.


EmpagliflozinSodium-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.


LinagliptinLinagliptin
is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones
glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic
polypeptide (GIP). Thus, linagliptin increases the concentrations
of active incretin hormones, stimulating the release of insulin in
a glucose-dependent manner and decreasing the levels of glucagon in
the circulation. Both incretin hormones are involved in the physiological
regulation of glucose homeostasis. Incretin hormones are secreted
at a low basal level throughout the day and levels rise immediately
after meal intake. GLP-1 and GIP increase insulin biosynthesis and
secretion from pancreatic beta cells in the presence of normal and
elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon
secretion from pancreatic alpha cells, resulting in a reduction in
hepatic glucose output.

12.2 Pharmacodynamics

EmpagliflozinUrinary Glucose ExcretionIn patients with
type 2 diabetes, urinary glucose excretion increased immediately following
a dose of empagliflozin 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 empagliflozin
once daily.


Urinary VolumeIn a 5-day study, mean 24-hour
urine volume increase from baseline was 341 mL on Day 1 and 135 mL
on Day 5 of empagliflozin 25 mg once daily treatment.


Cardiac ElectrophysiologyIn a randomized, placebo-controlled, active-comparator,
crossover study, 30 healthy subjects were administered a single oral
dose of empagliflozin 25 mg, empagliflozin 200 mg (8 times the maximum
recommended dose), moxifloxacin, and placebo. No increase in QTc
was observed with either 25 mg or 200 mg empagliflozin.


LinagliptinLinagliptin binds to DPP-4 in a reversible manner and
increases the concentrations of incretin hormones. Linagliptin glucose-dependently
increases insulin secretion and lowers glucagon secretion, thus resulting
in a better regulation of the glucose homeostasis. Linagliptin binds
selectively to DPP-4 and selectively inhibits DPP-4, but not DPP-8
or DPP-9 activity


in vitro at concentrations approximating
therapeutic exposures.


Cardiac ElectrophysiologyIn a
randomized, placebo-controlled, active-comparator, 4-way crossover
study, 36 healthy subjects were administered a single oral dose of
linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose),
moxifloxacin, and placebo. No increase in QTc was observed with either
the recommended dose of 5 mg or the 100-mg dose. At the 100-mg dose,
peak linagliptin plasma concentrations were approximately 38-fold
higher than the peak concentrations following a 5-mg dose.

12.3 Pharmacokinetics

GLYXAMBIThe
results of the bioequivalence study in healthy subjects demonstrated
that GLYXAMBI (25 mg empagliflozin/5 mg linagliptin) combination tablets
are bioequivalent to coadministration of corresponding doses of empagliflozin
and linagliptin as individual tablets. Administration of the fixed-dose
combination with food resulted in no change in overall exposure of
empagliflozin or linagliptin; however, the peak exposure was decreased
39% and 32% for empagliflozin and linagliptin, respectively. These
changes are not likely to be clinically significant.


AbsorptionEmpagliflozinThe pharmacokinetics of empagliflozin
has been characterized in healthy volunteers and patients with type
2 diabetes and no clinically relevant differences were noted between
the two populations. After oral administration, peak plasma concentrations
of empagliflozin were reached at 1.5 hours post-dose. Thereafter,
plasma concentrations declined in a biphasic manner with a rapid distribution
phase and a relatively slow terminal phase. The steady state mean
plasma AUC and C


max were 1870 nmol·h/L and
259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment,
and 4740 nmol·h/L and 687 nmol/L, respectively, with 25 mg empagliflozin
once daily treatment. Systemic exposure of empagliflozin increased
in a dose-proportional manner in the therapeutic dose range. The
single-dose and steady-state pharmacokinetic parameters of empagliflozin
were similar, suggesting linear pharmacokinetics with respect to time.


Administration of 25 mg empagliflozin
after intake of a high-fat and high-calorie meal resulted in slightly
lower exposure; AUC decreased by approximately 16% and C


max decreased by approximately 37%, compared to fasted
condition. The observed effect of food on empagliflozin pharmacokinetics
was not considered clinically relevant and empagliflozin may be administered
with or without food.


LinagliptinThe absolute bioavailability
of linagliptin is approximately 30%. High-fat meal reduced C


max by 15% and increased AUC by 4%; this effect is not
clinically relevant. Linagliptin may be administered with or without
food.


DistributionEmpagliflozinThe 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%.


LinagliptinThe mean apparent volume of distribution at steady state following
a single intravenous dose of linagliptin 5 mg to healthy subjects
is approximately 1110 L, indicating that linagliptin extensively distributes
to the tissues. Plasma protein binding of linagliptin is concentration-dependent,
decreasing from about 99% at 1 nmol/L to 75% to 89% at ≥30 nmol/L,
reflecting saturation of binding to DPP-4 with increasing concentration
of linagliptin. At high concentrations, where DPP-4 is fully saturated,
70% to 80% of linagliptin remains bound to plasma proteins and 20%
to 30% is unbound in plasma. Plasma binding is not altered in patients
with renal or hepatic impairment.


MetabolismEmpagliflozinNo 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.


LinagliptinFollowing oral administration,
the majority (about 90%) of linagliptin is excreted unchanged, indicating
that metabolism represents a minor elimination pathway. A small fraction
of absorbed linagliptin is metabolized to a pharmacologically inactive
metabolite, which shows a steady-state exposure of 13.3% relative
to linagliptin.


EliminationEmpagliflozinThe 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.


LinagliptinFollowing administration of an oral [


14C]-linagliptin dose to healthy subjects, approximately 85% of the
administered radioactivity was eliminated via the enterohepatic system
(80%) or urine (5%) within 4 days of dosing. Renal clearance at steady
state was approximately 70 mL/min.


Specific PopulationsRenal ImpairmentGLYXAMBI:
Studies characterizing the pharmacokinetics of empagliflozin
and linagliptin after administration of GLYXAMBI in renally impaired
patients have not been performed


[see Dosage and Administration
(


2.2)]


.


Empagliflozin: In patients
with mild (eGFR: 60 to less than 90 mL/min/1.73 m


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


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


2) renal impairment and subjects with kidney failure/end stage renal
disease (ESRD) patients, AUC of empagliflozin increased by approximately
18%, 20%, 66%, and 48%, respectively, compared to subjects with normal
renal function. Peak plasma levels of empagliflozin were similar
in subjects with moderate renal impairment and kidney failure/ESRD
compared to patients with normal renal function. Peak plasma levels
of empagliflozin were roughly 20% higher in subjects with mild and
severe renal impairment as compared to subjects with normal renal
function. Population pharmacokinetic analysis showed that the apparent
oral clearance of empagliflozin decreased, with a decrease in eGFR
leading to an increase in drug exposure. However, the fraction of
empagliflozin that was excreted unchanged in urine, and urinary glucose
excretion, declined with decrease in eGFR.


Linagliptin: An open-label
pharmacokinetic study evaluated the pharmacokinetics of linagliptin
5 mg in male and female patients with varying degrees of chronic renal
impairment. The study included 6 healthy subjects with normal renal
function (creatinine clearance [CrCl] ≥80 mL/min), 6 patients with
mild renal impairment (CrCl 50 to <80 mL/min), 6 patients with
moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients
with type 2 diabetes and severe renal impairment (CrCl <30 mL/min),
and 11 patients with type 2 diabetes and normal renal function. Creatinine
clearance was measured by 24-hour urinary creatinine clearance measurements
or estimated from serum creatinine based on the Cockcroft-Gault formula.


Under steady-state conditions,
linagliptin exposure in patients with mild renal impairment was comparable
to healthy subjects.In patients with moderate renal impairment under steady-state conditions,
mean exposure of linagliptin increased (AUC


τ,ss by 71% and C


max by 46%) compared with healthy
subjects. This increase was not associated with a prolonged accumulation
half-life, terminal half-life, or an increased accumulation factor.
Renal excretion of linagliptin was below 5% of the administered dose
and was not affected by decreased renal function. Patients with type
2 diabetes and severe renal impairment showed steady-state exposure
approximately 40% higher than that of patients with type 2 diabetes
and normal renal function (increase in AUC


τ,ss by 42% and C


max by 35%). For both type 2
diabetes groups, renal excretion was below 7% of the administered
dose.


These findings
were further supported by the results of population pharmacokinetic
analyses.Hepatic ImpairmentGLYXAMBI: Studies characterizing the pharmacokinetics of empagliflozin and
linagliptin after administration of GLYXAMBI in hepatically impaired
patients have not been performed.


Empagliflozin: 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 C


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


Linagliptin:
In patients with mild hepatic impairment (Child-Pugh class
A) steady-state exposure (AUC


τ,ss) of linagliptin
was approximately 25% lower and C


max,ss was
approximately 36% lower than in healthy subjects. In patients with
moderate hepatic impairment (Child-Pugh class B), AUC


ss of linagliptin was about 14% lower and C


max,ss was approximately 8% lower than in healthy subjects. Patients with
severe hepatic impairment (Child-Pugh class C) had comparable exposure
of linagliptin in terms of AUC


0-24 and approximately
23% lower C


max compared with healthy subjects.
Reductions in the pharmacokinetic parameters seen in patients with
hepatic impairment did not result in reductions in DPP-4 inhibition.


Effects of Age, Body
Mass Index, Gender, and RaceEmpagliflozin: 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 (


8.5)]


.


Linagliptin: Based on the population PK analysis, age, body mass index (BMI),
gender and race do not have a clinically meaningful effect on pharmacokinetics
of linagliptin


[see Use in Specific Populations (


8.5)]


.


PediatricStudies characterizing the pharmacokinetics of empagliflozin or
linagliptin after administration of GLYXAMBI in pediatric patients
have not been performed.


Drug InteractionsPharmacokinetic drug
interaction studies with GLYXAMBI have not been performed; however,
such studies have been conducted with the individual components of
GLYXAMBI (empagliflozin and linagliptin).


EmpagliflozinIn vitro Assessment of Drug Interactions


In vitro data suggest that the primary
route of metabolism of empagliflozin in humans is glucuronidation
by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3,
UGT1A8, and UGT1A9. Empagliflozin does not inhibit, inactivate, or
induce CYP450 isoforms. Empagliflozin also does not inhibit UGT1A1.
Therefore, no effect of empagliflozin is anticipated on concomitantly
administered drugs that are substrates of the major CYP450 isoforms
or UGT1A1. The effect of UGT induction (e.g., induction by rifampicin
or any other UGT enzyme inducer) on empagliflozin exposure has not
been evaluated.


Empagliflozin
is a substrate for P-glycoprotein (P-gp) and breast cancer resistance
protein (BCRP), but it does not inhibit these efflux transporters
at therapeutic doses. Based on


in vitro studies,
empagliflozin is considered unlikely to cause interactions with drugs
that are P-gp substrates. Empagliflozin is a substrate of the human
uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2.
Empagliflozin does not inhibit any of these human uptake transporters
at clinically relevant plasma concentrations and, therefore, no effect
of empagliflozin is anticipated on concomitantly administered drugs
that are substrates of these uptake transporters.


In vivo Assessment
of Drug Interactions


No dose adjustment of empagliflozin is recommended when coadministered
with commonly prescribed medicinal products based on results of the
described pharmacokinetic studies. Empagliflozin pharmacokinetics
were similar with and without coadministration of metformin, glimepiride,
pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril,
and simvastatin in healthy volunteers and with or without coadministration
of hydrochlorothiazide and torsemide in patients with type 2 diabetes
(see Figure 1). The observed increases in overall exposure (AUC)
of empagliflozin following coadministration with gemfibrozil, rifampicin,
or probenecid are not clinically relevant. In subjects with normal
renal function, coadministration of empagliflozin with probenecid
resulted in a 30% decrease in the fraction of empagliflozin excreted
in urine without any effect on 24-hour urinary glucose excretion.
The relevance of this observation to patients with renal impairment
is unknown.


Figure
1 Effect of Various Medications on the Pharmacokinetics of Empagliflozin
as Displayed as 90% Confidence Interval of Geometric Mean AUC and
C


max Ratios [reference lines indicate 100%
(80% - 125%)]


aempagliflozin, 50 mg, once daily;


bempagliflozin, 25 mg, single dose;


cempagliflozin, 25 mg, once daily;


dempagliflozin,
10 mg, single dose


Empagliflozin had no clinically relevant
effect on the pharmacokinetics of metformin, glimepiride, pioglitazone,
sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin,
hydrochlorothiazide, torsemide, and oral contraceptives when coadministered
in healthy volunteers (see Figure 2).Figure 2 Effect of Empagliflozin on
the Pharmacokinetics of Various Medications as Displayed as 90% Confidence
Interval of Geometric Mean AUC and C


max Ratios
[reference lines indicate 100% (80% - 125%)]


aempagliflozin,
50 mg, once daily;


bempagliflozin, 25 mg,
once daily;


cempagliflozin, 25 mg, single
dose;


dadministered as simvastatin;


eadministered as warfarin racemic mixture;


fadministered as Microgynon


®;


gadministered as ramipril


LinagliptinIn vitro Assessment of Drug Interactions


Linagliptin is a weak to moderate inhibitor of CYP isozyme
CYP3A4, but does not inhibit other CYP isozymes and is not an inducer
of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6,
2E1, and 4A11.


Linagliptin
is a P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport
of digoxin at high concentrations. Based on these results and


in vivo drug interaction studies, linagliptin is considered
unlikely to cause interactions with other P-gp substrates at therapeutic
concentrations.


In vivo Assessment of Drug Interactions


Strong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease
exposure to linagliptin to subtherapeutic and likely ineffective concentrations.
For patients requiring use of such drugs, an alternative to linagliptin
is strongly recommended.


In vivo studies indicated
evidence of a low propensity for causing drug interactions with substrates
of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT).
No dose adjustment of linagliptin is recommended based on results
of the described pharmacokinetic studies.


Table 3 Effect of Coadministered Drugs on Systemic
Exposure of LinagliptinaMultiple dose (steady
state) unless otherwise noted


bSingle dose


cAUC = AUC(0 to 24 hours)
for single dose treatments and AUC = AUC(TAU) for multiple dose treatments


QD = once dailyBID = twice dailyTID = three times dailyCoadministered DrugDosing of Coadministered Drug


aDosing of Linagliptin


aGeometric Mean Ratio


(ratio with/without
coadministered drug)


No effect = 1.0


AUC


cC


maxNo dosing adjustments required for linagliptin when given with the
following coadministered drugs:Metformin 850 mg TID10 mg QD1.201.03Glyburide 1.75 mg


b5 mg QD1.021.01Pioglitazone45 mg QD10 mg QD1.131.07Ritonavir200 mg BID5 mg


b2.012.96The efficacy of linagliptin may be
reduced when administered in combination with strong inducers of CYP3A4
or P-gp (e.g., rifampin). Use of alternative treatments is strongly
recommended


[see Drug Interactions (


7.2)].


Rifampin600 mg QD5 mg QD0.60 0.56Table 4 Effect of Linagliptin on Systemic Exposure
of Coadministered DrugsaMultiple dose (steady
state) unless otherwise noted


bSingle dose


cAUC = AUC(INF) for single
dose treatments and AUC = AUC(TAU) for multiple dose treatments


dAUC=AUC(0-168) and C


max=E


maxfor pharmacodynamic end
points


INR = International Normalized RatioPT = Prothrombin TimeQD = once dailyTID = three times dailyCoadministered
DrugDosing of
Coadministered Drug


aDosing of
Linagliptin


aGeometric
Mean Ratio


(ratio with/without coadministered drug)


No effect = 1.0


 AUC


cC


maxNo dosing adjustments required for
the following coadministered drugs:Metformin 850 mg TID10 mg QDmetformin1.010.89Glyburide 1.75 mg


b5 mg QDglyburide0.860.86Pioglitazone45 mg QD10 mg QDpioglitazonemetabolite M-IIImetabolite M-IV0.940.981.040.860.961.05Digoxin0.25 mg QD5 mg QDdigoxin1.020.94Simvastatin40 mg QD10 mg QDsimvastatin


simvastatin acid


1.341.331.101.21Warfarin10 mg


b5 mg QDR-warfarinS-warfarinINRPT0.991.030.93


d1.03


d1.001.011.04


d1.15


dEthinylestradiol and levonorgestrelethinylestradiol 0.03 mg and levonorgestrel
0.150 mg QD5 mg QDethinylestradiollevonorgestrel1.011.091.081.13

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

GLYXAMBINo animal studies have been conducted with the combination of empagliflozin
and linagliptin to evaluate carcinogenesis, mutagenesis, or impairment
of fertility. General toxicity studies in rats up to 13 weeks were
performed with the combined components. These studies indicated that
no additive toxicity is caused by the combination of empagliflozin
and linagliptin.


EmpagliflozinCarcinogenesis
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.


Empagliflozin was not mutagenic or clastogenic with or without metabolic
activation in the


in vitro Ames bacterial mutagenicity
assay, the


in vitro L5178Y tk


+/- mouse lymphoma cell assay, and an


in vivo micronucleus
assay in rats.


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).LinagliptinLinagliptin did not increase the
incidence of tumors in male and female rats in a 2-year study at doses
of 6, 18, and 60 mg/kg. The highest dose of 60 mg/kg is approximately
418 times the clinical dose of 5 mg/day based on AUC exposure. Linagliptin
did not increase the incidence of tumors in mice in a 2-year study
at doses up to 80 mg/kg (males) and 25 mg/kg (females), or approximately
35- and 270-times the clinical dose based on AUC exposure. Higher
doses of linagliptin in female mice (80 mg/kg) increased the incidence
of lymphoma at approximately 215-times the clinical dose based on
AUC exposure.


Linagliptin
was not mutagenic or clastogenic with or without metabolic activation
in the Ames bacterial mutagenicity assay, a chromosomal aberration
test in human lymphocytes, and an


in vivo micronucleus
assay.


In fertility
studies in rats, linagliptin had no adverse effects on early embryonic
development, mating, fertility, or bearing live young up to the highest
dose of 240 mg/kg (approximately 943-times the clinical dose based
on AUC exposure).

14.1 Glyxambi Glycemic Control Studies

Add-on Combination Therapy with MetforminA total of 686 patients with type 2 diabetes participated in a double-blind,
active-controlled study to evaluate the efficacy and safety of empagliflozin
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 empagliflozin
10 mg or 25 mg, linagliptin 5 mg, or linagliptin 5 mg in combination
with 10 mg or 25 mg empagliflozin as a fixed dose combination tablet.At Week 24, empagliflozin 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 (see Table 5, Figure 3).
Treatment with GLYXAMBI 25 mg/5 mg or GLYXAMBI 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 compared to empagliflozin alone.Table 5 Glycemic Parameters at 24 Weeks in a Study Comparing
GLYXAMBI to the Individual Components as Add-on Therapy in Patients
Inadequately Controlled on MetforminaFull analysis population
(observed case) using MMRM. MMRM model included treatment, renal
function, region, visit, visit by treatment interaction, and baseline
HbA1c.


bPatients with HbA1c above
7% at baseline: GLYXAMBI 25 mg/5 mg, n=123; GLYXAMBI 10 mg/5 mg,
n=128; empagliflozin 25 mg, n=132; empagliflozin 10 mg, n=125; linagliptin
5 mg, n=119. Non-completers were considered failures (NCF).


cFull analysis population
using last observation carried forward. ANCOVA model included treatment,
renal function, region, baseline weight, and baseline HbA1c.


dp<0.001 for FPG; p<0.0001
for HbA1c and body weight


 GLYXAMBI


10 mg/5 mg


GLYXAMBI


25 mg/5 mg


Empagliflozin


10 mg


Empagliflozin


25 mg


Linagliptin


5 mg


HbA1c (%)      Number of
patientsn=135n=133n=137n=139n=128 Baseline
(mean)8.07.98.08.08.0 Change from
baseline (adjusted mean)-1.1-1.2-0.7-0.6-0.7 Comparison
vs empagliflozin 25 mg or 10 mg (adjusted mean) (95% CI)


a-0.4 (-0.6, -0.2)


d-0.6 (-0.7, -0.4)


d------ Comparison
vs linagliptin 5 mg (adjusted mean) (95% CI)


a-0.4 (-0.6, -0.2)


d-0.5 (-0.7, -0.3)


d------ Patients
[n (%)] achieving HbA1c <7%


b74 (58)76 (62)35 (28)43 (33)43 (36)FPG (mg/dL)      Number of
patientsn=133n=131n=136n=137n=125 Baseline
(mean)157155162160156 Change from
baseline (adjusted mean)-33-36-21-21-13 Comparison
vs empagliflozin 25 mg or 10 mg (adjusted mean) (95% CI)


a-12 (-18, -5)


d-15 (-22, -9)


d------ Comparison
vs linagliptin 5 mg (adjusted mean) (95% CI)


a-20 (-27, -13)


d-23 (-29, -16)


d------Body Weight      Number of
patientsn=135n=134n=137n=140n=128 Baseline
(mean) in kg8785868885 % change
from baseline (adjusted mean)-3.1-3.4-3.0-3.5-0.7 Comparison
vs empagliflozin 25 mg or 10 mg (adjusted mean) (95% CI)


c0.0 (-0.9, 0.8)0.1 (-0.8, 0.9)------ Comparison vs linagliptin 5 mg (adjusted
mean) (95% CI)


c-2.4 (-3.3, -1.5)


d-2.7 (-3.6, -1.8)


d------Figure 3 Adjusted
Mean HbA1c Change at Each Time Point (Completers) and at Week 24 (mITT
population)

14.2 Empagliflozin Cardiovascular Outcome Study In Patients With Type 2 Diabetes Mellitus And Atherosclerotic Cardiovascular Disease

Empagliflozin is indicated to
reduce the risk of cardiovascular death in adults with type 2 diabetes
mellitus and established cardiovascular disease. However, the effectiveness
of GLYXAMBI on reducing the risk of cardiovascular death in adults
with type 2 diabetes mellitus and established cardiovascular disease
has not been established. The effect of empagliflozin on cardiovascular
risk in adult patients with type 2 diabetes and established, stable,
atherosclerotic cardiovascular disease is presented below.The EMPA-REG OUTCOME study,
a multicenter, multi-national, randomized, double-blind parallel group
trial compared the risk of experiencing a major adverse cardiovascular
event (MACE) between empagliflozin 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 (empagliflozin
10 mg = 2345; empagliflozin 25 mg = 2342; placebo = 2333) and followed
for a median of 3.1 years. Approximately 72% of the study population
was Caucasian, 22% was Asian, and 5% was Black. The mean age was
63 years and approximately 72% were male.All patients in the study had inadequately
controlled type 2 diabetes mellitus at baseline (HbA1c greater than
or equal to 7%). The mean HbA1c at baseline was 8.1% and 57% of participants
had had diabetes for more than 10 years. Approximately 31%, 22% and
20% reported a past history of neuropathy, retinopathy and nephropathy
to investigators respectively and the mean eGFR was 74 mL/min/1.73
m


2. At baseline, patients were treated
with one (~30%) or more (~70%) antidiabetic medications including
metformin (74%), insulin (48%), sulfonylurea (43%) and dipeptidyl
peptidase-4 inhibitor (11%).


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.Empagliflozin 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 6 and Figure 4 and 5). Results for the 10 mg and 25 mg empagliflozin
doses were consistent with results for the combined dose groups.Table 6  Treatment Effect for the Primary Composite Endpoint,
and its Components


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


bp−value for superiority (2−sided) 0.04


cTotal number of events


 Placebo


N=2333Empagliflozin


N=4687Hazard
ratio vs placebo(95% CI) Composite of
cardiovascular death, non-fatal myocardial infarction, non-fatal stroke


(time to first occurrence)


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


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


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


c 137 (5.9%)
172 (3.7%)
0.62 (0.49,
0.77) Figure 4         
Estimated Cumulative Incidence of First MACEFigure 5          Estimated
Cumulative Incidence of Cardiovascular DeathThe efficacy of empagliflozin
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 empagliflozin, and 2.4% of patients treated with placebo).

16  How Supplied/Storage And Handling

GLYXAMBI (empagliflozin and linagliptin)
tablets are available in 10 mg/5 mg and 25 mg/5 mg strengths as follows:10 mg/5 mg tablets: pale yellow, arc triangular, flat-faced, bevel-edged, film-coated
tablets. One side is debossed with the Boehringer Ingelheim company
symbol; the other side is debossed with "10/5".


Bottles of 30 (NDC 0597-0182-30)


Bottles of 90 (NDC 0597-0182-90)


Cartons containing 3
blister cards of 10 tablets each (3 x 10) (NDC 0597-0182-39), institutional
pack.


25 mg/5
mg tablets: pale pink, arc triangular, flat-faced, bevel-edged,
film-coated tablets. One side is debossed with the Boehringer Ingelheim
company symbol; the other side is debossed with "25/5".


Bottles of 30 (NDC 0597-0164-30)


Bottles of 90 (NDC 0597-0164-90)


Cartons containing 3
blister cards of 10 tablets each (3 x 10) (NDC 0597-0164-39), institutional
pack.


If repackaging
is required, dispense in a tight container as defined in USP.StorageStore at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Store in a safe place out
of reach of children.

17  Patient Counseling Information

Advise the patient to read the FDA-approved
patient labeling (Medication Guide).InstructionsInstruct patients to read the Medication Guide before starting GLYXAMBI
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 GLYXAMBI 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 GLYXAMBI
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.Advise pregnant
women, and females of reproductive potential of the potential risk
to a fetus with treatment with GLYXAMBI


[see Use in Specific
Populations (


8.1)]


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


Advise women that breastfeeding is not recommended during treatment
with GLYXAMBI


[see Use in Specific Populations (


8.2)].


PancreatitisInform patients that acute pancreatitis has been reported during
postmarketing use of linagliptin. Inform patients that persistent
severe abdominal pain, sometimes radiating to the back, which may
or may not be accompanied by vomiting, is the hallmark symptom of
acute pancreatitis. Instruct patients to discontinue GLYXAMBI promptly
and contact their physician if persistent severe abdominal pain occurs


[see Warnings and Precautions (


5.1)]


.


Heart FailureInform patients of the signs
and symptoms of heart failure. Before initiating GLYXAMBI, patients
should be asked about a history of heart failure or other risk factors
for heart failure including moderate to severe renal impairment. Instruct
patients to contact their healthcare provider as soon as possible
if they experience symptoms of heart failure, including increasing
shortness of breath, rapid increase in weight or swelling of the feet


[see Warnings and Precautions (


5.2)]


.


HypoglycemiaInform patients that the incidence
of hypoglycemia is increased when empagliflozin, linagliptin, or GLYXAMBI
is added to a sulfonylurea or insulin and that a lower dose of the
sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.


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


[see Warnings and Precautions (


5.3)]


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


KetoacidosisInform patients that ketoacidosis
is a serious life-threatening condition. Cases of ketoacidosis have
been reported during use of empagliflozin. 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 GLYXAMBI and seek
medical advice immediately


[see Warnings and Precautions (


5.4)]


.


Acute Kidney InjuryInform patients that acute kidney injury has been reported
during use of empagliflozin. 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 GLYXAMBI use in those settings


[see
Warnings and Precautions (


5.5)]


.


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


[see Warnings and Precautions (


5.6)]


.


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


[see Warnings and Precautions (


5.8)].


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


[see Warnings and Precautions (


5.9)]


.


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


[see
Warnings and Precautions (


5.9)]


.


Hypersensitivity
ReactionsInform patients that serious allergic
reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions,
have been reported during postmarketing use of linagliptin or empagliflozin,
components of GLYXAMBI. If symptoms of allergic reactions (such as
rash, skin flaking or peeling, urticaria, swelling of the skin, or
swelling of the face, lips, tongue, and throat that may cause difficulty
in breathing or swallowing) occur, patients must stop taking GLYXAMBI
and seek medical advice promptly


[see Warnings and Precautions
(


5.10)]


.


Severe and Disabling ArthralgiaInform patients that severe and disabling joint pain
may occur with this class of drugs. The time to onset of symptoms
can range from one day to years. Instruct patients to seek medical
advice if severe joint pain occurs


[see Warnings and Precautions
(


5.12)]


.


Bullous PemphigoidInform patients that bullous pemphigoid may occur with
this class of drugs. Instruct patients to seek medical advice if blisters
or erosions occur


[see Warnings and Precautions (


5.13)].


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


Inform patients that elevated
glucose in urinalysis is expected when taking GLYXAMBI.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 is especially useful
for evaluating long-term glycemic control.

* Please review the disclaimer below.

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