NDC 0597-0275 Jentadueto Xr

Linagliptin And Metformin Hydrochloride

NDC Product Code 0597-0275

NDC CODE: 0597-0275

Proprietary Name: Jentadueto Xr 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: Linagliptin And Metformin Hydrochloride 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.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Linagliptin/metformin is used with a proper diet and exercise program to control high blood sugar in people with type 2 diabetes. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems. Proper control of diabetes may also lessen your risk of a heart attack or stroke. This product contains 2 medications: linagliptin and metformin. Linagliptin works by increasing levels of natural substances called incretins. Incretins help to control blood sugar by increasing insulin release, especially after a meal. They also decrease the amount of sugar your liver makes. Metformin works by helping to restore your body's proper response to the insulin you naturally produce. It also decreases the amount of sugar that your liver makes and that your stomach/intestines absorb.

Product Characteristics

Color(s):
YELLOW (C48330)
WHITE (C48325)
Shape: OVAL (C48345)
Size(s):
19 MM
Imprint(s):
D2;1000M
D5;1000M
Score: 1

NDC Code Structure

NDC 0597-0275-33

Package Description: 30 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE

Price per Unit: $15.49570 per EA

NDC 0597-0275-81

Package Description: 90 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE

Price per Unit: $15.49570 per EA

NDC 0597-0275-88

Package Description: 1 BOTTLE in 1 CARTON > 7 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE

NDC Product Information

Jentadueto Xr with NDC 0597-0275 is a a human prescription drug product labeled by Boehringer Ingelheim Pharmaceuticals, Inc.. The generic name of Jentadueto Xr is linagliptin and metformin hydrochloride. The product's dosage form is tablet, film coated, extended release and is administered via oral form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 1796089, 1796091, 1796094 and 1796096.

Dosage Form: Tablet, Film Coated, Extended Release - 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; the tablet is formulated in such manner as to make the contained medicament available over an extended period of time following ingestion.

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.

Jentadueto Xr 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.


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.

  • Dipeptidyl Peptidase 4 Inhibitors - [MoA] (Mechanism of Action)
  • Dipeptidyl Peptidase 4 Inhibitor - [EPC] (Established Pharmacologic Class)
  • Biguanide - [EPC] (Established Pharmacologic Class)
  • Biguanides - [CS]

Product Labeler Information

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

Labeler Name: Boehringer Ingelheim Pharmaceuticals, Inc.
Labeler Code: 0597
FDA Application Number: NDA208026 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: 05-27-2016 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: 12-31-2021 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 - NO 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 ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Linagliptin

Linagliptin is pronounced as (lin'' a glip' tin)

Why is linagliptin medication prescribed?
Linagliptin is used along with diet and exercise and sometimes with other medications to lower blood sugar levels in patients with type 2 diabetes (condition in which blo...
[Read More]
Metformin

Metformin is pronounced as (met for' min)
Why is metformin medication prescribed?
Metformin is used alone or with other medications, including insulin, to treat type 2 diabetes (condition in which the body does not use insulin normally and, therefore, ...
[Read More]

* Please review the disclaimer below.

Jentadueto Xr 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

Warning: Lactic Acidosis

Postmarketing cases of metformin-associated lactic acidosis have
resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.
The onset of metformin-associated lactic acidosis is often subtle,
accompanied only by nonspecific symptoms such as malaise, myalgias,
respiratory distress, somnolence, and abdominal pain. Metformin-associated
lactic acidosis was characterized by elevated blood lactate levels
(>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria
or ketonemia), an increased lactate/pyruvate ratio; and metformin
plasma levels generally >5 mcg/mL [see Warnings and Precautions
(5.1)].Risk factors for metformin-associated
lactic acidosis include renal impairment, concomitant use of certain
drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age
65 years old or greater, having a radiological study with contrast,
surgery and other procedures, hypoxic states (e.g., acute congestive
heart failure), excessive alcohol intake, and hepatic impairment.Steps to reduce
the risk of and manage metformin-associated lactic acidosis in these
high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2), Contraindications (4), Warnings
and Precautions (5.1), Drug Interactions
(7.1), and Use in Specific Populations
(8.6, 8.7)].If metformin-associated lactic acidosis is suspected, immediately
discontinue JENTADUETO XR and institute general supportive measures
in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

1.1 Indication

JENTADUETO XR is indicated as an adjunct to diet and exercise to
improve glycemic control in adults with type 2 diabetes mellitus when
treatment with both linagliptin and metformin is appropriate [see Dosage and Administration (2.1) and Clinical Studies (14.1)].

1.2 Important Limitations Of Use

JENTADUETO XR should not be used in patients
with type 1 diabetes or for the treatment of diabetic ketoacidosis,
as it would not be effective in these settings.JENTADUETO XR 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 JENTADUETO XR [see Warnings and
Precautions (5.2)].

  • The dosage of JENTADUETO XR
  • Should be individualized on the basis of both effectiveness and tolerability,
  • While not exceeding the maximum recommended total daily dose of linagliptin
  • 5 mg and metformin hydrochloride 2000 mg. JENTADUETO XR should be
  • Given once daily with a meal. For available dosage forms and strengths [see Dosage Forms and Strengths (3)].Recommended starting
  • Dose:In patients currently not treated with metformin, initiate
  • JENTADUETO XR treatment with 5 mg linagliptin/1000 mg metformin hydrochloride
  • Extended-release once daily with a meal.In patients already treated with metformin, start JENTADUETO
  • XR with 5 mg of linagliptin total daily dose and a similar total daily
  • Dose of metformin once daily with a meal.In patients already treated with linagliptin and metformin
  • Or JENTADUETO, switch to JENTADUETO XR containing 5 mg of linagliptin
  • Total daily dose and a similar total daily dose of metformin once
  • Daily with a meal.JENTADUETO XR should be
  • Swallowed whole. The tablets must not be split, crushed, dissolved,
  • Or chewed before swallowing. There have been reports of incompletely
  • Dissolved tablets being eliminated in the feces for other tablets
  • Containing metformin extended-release. If a patient reports seeing
  • Tablets in feces, the healthcare provider should assess adequacy of
  • Glycemic control.JENTADUETO
  • XR 5 mg linagliptin/1000 mg metformin hydrochloride extended-release
  • Tablet should be taken as a single tablet once daily. Patients using
  • 2.5 mg linagliptin/1000 mg metformin extended-release tablets should
  • Take two tablets together once daily.No studies have been performed specifically
  • Examining the safety and efficacy of JENTADUETO XR in patients previously
  • Treated with other oral antihyperglycemic agents and switched to JENTADUETO
  • XR. Any change in therapy of type 2 diabetes mellitus should be undertaken
  • With care and appropriate monitoring as changes in glycemic control
  • Can occur.

Assess renal function prior to initiation
of JENTADUETO XR and periodically thereafter.JENTADUETO XR is contraindicated in patients
with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73
m2.Initiation of JENTADUETO XR in patients with
an eGFR between 30-45 mL/min/1.73 m2 is
not recommended.In
patients taking JENTADUETO XR whose eGFR later falls below 45 mL/min/1.73
m2, assess benefit risk of continuing therapy.Discontinue JENTADUETO XR if
the patient’s eGFR later falls below 30 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1)].

2.3 Discontinuation For Iodinated Contrast Imaging Procedures

Discontinue JENTADUETO XR at
the time of, or prior to, an iodinated contrast imaging procedure
in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism
or heart failure; or in patients who will be administered intra-arterial
iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure;
restart JENTADUETO XR if renal function is stable [see Warnings
and Precautions (5.1)].

3  Dosage Forms And Strengths

  • JENTADUETO XR is a combination of linagliptin
  • And extended-release metformin hydrochloride. JENTADUETO XR tablets
  • Are available in the following dosage forms and strengths:5 mg/1000 mg are white, oval-shaped coated tablets with
  • One side printed in black ink with the Boehringer Ingelheim logo and
  • “D5” on the top line and “1000M” on the bottom line.2.5 mg /1000 mg are yellow, oval-shaped coated tablets with
  • One side printed in black ink with the Boehringer Ingelheim logo and
  • “D2” on the top line and “1000M” on the bottom line.

4  Contraindications

  • JENTADUETO
  • XR is contraindicated in patients with:Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)]Acute or chronic metabolic acidosis, including diabetic
  • Ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions (5.1)]A history of hypersensitivity reaction to linagliptin, such
  • As anaphylaxis, angioedema, exfoliative skin conditions, urticaria,
  • Or bronchial hyperreactivity [see Warnings and Precautions
  • (5.5) and Adverse Reactions (6.1)]Hypersensitivity to metformin

5.1 Lactic Acidosis

  • MetforminThere have been postmarketing cases of metformin-associated lactic
  • Acidosis, including fatal cases. These cases had a subtle onset and
  • Were accompanied by nonspecific symptoms such as malaise, myalgias,
  • Abdominal pain, respiratory distress, or increased somnolence; however,
  • Hypothermia, hypotension and resistant bradyarrhythmias have occurred
  • With severe acidosis. Metformin-associated lactic acidosis was characterized
  • By elevated blood lactate concentrations (>5 mmol/Liter), anion gap
  • Acidosis (without evidence of ketonuria or ketonemia), and an increased
  • Lactate pyruvate ratio; metformin plasma levels generally >5 mcg/mL.
  • Metformin decreases liver uptake of lactate increasing lactate blood
  • Levels which may increase risk of lactic acidosis, especially in patients
  • At risk.If metformin-associated
  • Lactic acidosis is suspected, general supportive measures should be
  • Instituted promptly in a hospital setting, along with immediate discontinuation
  • Of JENTADUETO XR. In JENTADUETO XR-treated patients with a diagnosis
  • Or strong suspicion of lactic acidosis, prompt hemodialysis is recommended
  • To correct the acidosis and remove accumulated metformin (metformin
  • Hydrochloride is dialyzable, with clearance of up to 170 mL/min under
  • Good hemodynamic conditions). Hemodialysis has often resulted in reversal
  • Of symptoms and recovery.Educate patients and their families about the symptoms of lactic
  • Acidosis and if these symptoms occur instruct them to discontinue
  • JENTADUETO XR and report these symptoms to their healthcare provider.For each of the known and possible
  • Risk factors for metformin-associated lactic acidosis, recommendations
  • To reduce the risk of and manage metformin-associated lactic acidosis
  • Are provided below:Renal Impairment: The postmarketing metformin-associated
  • Lactic acidosis cases primarily occurred in patients with significant
  • Renal impairment. The risk of metformin accumulation and metformin-associated
  • Lactic acidosis increases with the severity of renal impairment because
  • Metformin is substantially excreted by the kidney. Clinical recommendations
  • Based upon the patient’s renal function include [see Dosage
  • And Administration (2.2), Clinical
  • Pharmacology (12.3)]:Before initiating JENTADUETO XR, obtain an estimated glomerular
  • Filtration rate (eGFR).JENTADUETO XR is contraindicated in patients with an eGFR
  • Less than 30 mL/min/1.73 m2 [see
  • Contraindications (4)].Initiation of JENTADUETO XR is not recommended in patients
  • With eGFR between 30 – 45 mL/min/1.73 m2.Obtain an eGFR at least annually in all patients taking
  • JENTADUETO XR. In patients at increased risk for the development of
  • Renal impairment (e.g., the elderly), renal function should be assessed
  • More frequently.In patients taking JENTADUETO XR whose eGFR later falls
  • Below 45 mL/min/1.73 m2, assess the benefit
  • And risk of continuing therapy.Drug Interactions: The concomitant use of JENTADUETO XR with specific drugs may increase
  • The risk of metformin-associated lactic acidosis: those that impair
  • Renal function, result in significant hemodynamic change, interfere
  • With acid-base balance or increase metformin accumulation (e.g., cationic
  • Drugs) [see Drug Interactions (7.1)]. Therefore, consider more frequent monitoring of patients.Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with
  • The patient’s age because elderly patients have a greater likelihood
  • Of having hepatic, renal, or cardiac impairment than younger patients.
  • Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].Radiological Studies with Contrast: Administration of intravascular
  • Iodinated contrast agents in metformin-treated patients has led to
  • An acute decrease in renal function and the occurrence of lactic acidosis.
  • Stop JENTADUETO XR at the time of, or prior to, an iodinated contrast
  • Imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73
  • M2; in patients with a history of hepatic
  • Impairment, alcoholism, or heart failure; or in patients who will
  • Be administered intra-arterial iodinated contrast. Re-evaluate eGFR
  • 48 hours after the imaging procedure, and restart JENTADUETO XR if
  • Renal function is stable.Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures
  • May increase the risk for volume depletion, hypotension and renal
  • Impairment. JENTADUETO XR should be temporarily discontinued while
  • Patients have restricted food and fluid intake.Hypoxic States: Several
  • Of the postmarketing cases of metformin-associated lactic acidosis
  • Occurred in the setting of acute congestive heart failure (particularly
  • When accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse
  • (shock), acute myocardial infarction, sepsis, and other conditions
  • Associated with hypoxemia have been associated with lactic acidosis
  • And may also cause prerenal azotemia. When such events occur, discontinue
  • JENTADUETO XR.Excessive Alcohol Intake: Alcohol potentiates the effect
  • Of metformin on lactate metabolism and this may increase the risk
  • Of metformin-associated lactic acidosis. Warn patients against excessive
  • Alcohol intake while receiving JENTADUETO XR.Hepatic Impairment: Patients
  • With hepatic impairment have developed cases of metformin-associated
  • Lactic acidosis. This may be due to impaired lactate clearance resulting
  • In higher lactate blood levels. Therefore, avoid use of JENTADUETO
  • XR in patients with clinical or laboratory evidence of hepatic disease.

5.2 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
JENTADUETO XR 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 JENTADUETO XR.

5.3 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 JENTADUETO XR 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 JENTADUETO XR.

5.4 Use With Medications Known To Cause Hypoglycemia

LinagliptinInsulin secretagogues and insulin are known to cause
hypoglycemia. The use of linagliptin in combination with an insulin
secretagogue (e.g., sulfonylurea) was associated with a higher rate
of hypoglycemia compared with placebo in a clinical trial [see
Adverse Reactions (6.1)].
Therefore, a lower dose of the insulin secretagogue or insulin may
be required to reduce the risk of hypoglycemia when used in combination
with JENTADUETO XR [see Drug Interactions (7.3)].MetforminHypoglycemia
does not occur in patients receiving metformin alone under usual circumstances
of use, but could occur when caloric intake is deficient, when strenuous
exercise is not compensated by caloric supplementation, or during
concomitant use with other glucose-lowering agents (such as SUs and
insulin) or ethanol. Elderly, debilitated, or malnourished patients,
and those with adrenal or pituitary insufficiency or alcohol intoxication
are particularly susceptible to hypoglycemic effects. Hypoglycemia
may be difficult to recognize in the elderly, and in people who are
taking β-adrenergic blocking drugs.

5.5 Hypersensitivity Reactions

There have been postmarketing reports of
serious hypersensitivity reactions in patients treated with linagliptin
(one of the components of JENTADUETO XR). 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. If a serious hypersensitivity reaction is suspected, discontinue
JENTADUETO XR, assess for other potential causes for the event, and
institute alternative treatment for diabetes.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 JENTADUETO XR.

5.6 Vitamin B12 Levels

In controlled, 29-week clinical
trials of metformin a decrease to subnormal levels of previously normal
serum vitamin B12 levels, without clinical
manifestations, was observed in approximately 7% of metformin-treated
patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic
factor complex, is, however, very rarely associated with anemia or
neurologic manifestations due to the short duration (<1 year) of
the clinical trials. This risk may be more relevant to patients receiving
long-term treatment with metformin, and adverse hematologic and neurologic
reactions have been reported postmarketing. The decrease in vitamin
B12 levels appears to be rapidly reversible
with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual
basis is advised in patients on JENTADUETO XR and any apparent abnormalities
should be appropriately investigated and managed. Certain individuals
(those with inadequate vitamin B12 or calcium
intake or absorption) appear to be predisposed to developing subnormal
vitamin B12 levels. In these patients, routine
serum vitamin B12 measurement at 2- to 3-year
intervals may be useful.

5.7 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 DPP-4 inhibitors as a possible cause for
severe joint pain and discontinue drug if appropriate.

5.8 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 JENTADUETO XR. If bullous pemphigoid is
suspected, JENTADUETO XR should be discontinued and referral to a
dermatologist should be considered for diagnosis and appropriate treatment.

5.9 Macrovascular Outcomes

There have been no clinical studies establishing
conclusive evidence of macrovascular risk reduction with linagliptin
or metformin.

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.Linagliptin/MetforminThe safety of concomitantly administered linagliptin (daily dose
5 mg) and metformin (mean daily dose of approximately 1800 mg) has
been evaluated in 2816 patients with type 2 diabetes mellitus treated
for ≥12 weeks in clinical trials.Three placebo-controlled studies with linagliptin
+ metformin were conducted: 2 studies were 24 weeks in duration, 1
study was 12 weeks in duration. In the 3 placebo-controlled clinical
studies, adverse reactions which occurred in ≥5% of patients receiving
linagliptin + metformin (n=875) and were more common than in patients
given placebo + metformin (n=539) included nasopharyngitis (5.7% vs
4.3%).In a 24-week
factorial design study, adverse reactions reported in ≥5% of patients
receiving linagliptin + metformin and were more common than in patients
given placebo are shown in Table 1.Table 1 Adverse Reactions Reported in ≥5% of Patients Treated
with Linagliptin + Metformin and Greater than with Placebo in a 24-week
Factorial-Design Study Placebon=72LinagliptinMonotherapyn=142MetforminMonotherapyn=291Combination
ofLinagliptin with Metforminn=286 n (%)n (%)n (%)n (%)Nasopharyngitis1 (1.4)8 (5.6)8 (2.7)18 (6.3)Diarrhea2 (2.8)5 (3.5)11 (3.8)18 (6.3)Other adverse reactions
reported in clinical studies with treatment of linagliptin + metformin
were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity),
cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.Linagliptin Adverse reactions reported in ≥2% of patients treated
with linagliptin 5 mg and more commonly than in patients treated with
placebo included: nasopharyngitis (7.0% vs 6.1%), diarrhea (3.3%
vs 3.0%), and cough (2.1% vs 1.4%).Rates for other adverse reactions for linagliptin
5 mg vs placebo when linagliptin was used in combination with specific
anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and
hypertriglyceridemia (2.4% vs 0%) when linagliptin was used as add-on
to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased
(2.3% vs 0.8%) when linagliptin was used as add-on to pioglitazone;
and constipation (2.1% vs 1%) when linagliptin was used as add-on
to basal insulin therapy.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.MetforminThe most common adverse reactions due to initiation of metformin
are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion,
abdominal discomfort, and headache.In a 24-week clinical trial in which extended-release
metformin or placebo was added to glyburide therapy, the most common
(>5% and greater than placebo) adverse reactions in the combined treatment
group were hypoglycemia (13.7% vs 4.9%), diarrhea (12.5% vs 5.6%),
and nausea (6.7% vs 4.2%).HypoglycemiaLinagliptin/MetforminIn a 24-week
factorial design study, hypoglycemia was reported in 4 (1.4%) of 286
subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects
treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo.
When linagliptin was administered in combination with metformin and
a sulfonylurea, 181 (22.9%) of 792 patients reported hypoglycemia
compared with 39 (14.8%) of 263 patients administered placebo in combination
with metformin and sulfonylurea. Adverse reactions of hypoglycemia
were based on all reports of hypoglycemia. A concurrent glucose measurement
was not required or was normal in some patients. Therefore, it is
not possible to conclusively determine that all these reports reflect
true hypoglycemia.Laboratory TestsLinagliptinIncrease 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.MetforminDecrease in Vitamin B12 Absorption: Long-term treatment with metformin
has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant
vitamin B12 deficiency (e.g., megaloblastic
anemia) [see Warnings and Precautions (5.6)].

6.2 Postmarketing Experience

  • The following adverse reactions
  • Have been identified during postapproval use. 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.LinagliptinAcute pancreatitis, including fatal pancreatitis [see Indications and Usage (1.2)
  • And Warnings and Precautions (5.2)]Hypersensitivity reactions including anaphylaxis, angioedema,
  • And exfoliative skin conditions [see Warnings and Precautions
  • (5.5)]Severe and disabling arthralgia [see Warnings and
  • Precautions (5.7)]Bullous pemphigoid [see Warnings and Precautions
  • (5.8)]RashMouth ulceration, stomatitisMetforminCholestatic, hepatocellular, and mixed hepatocellular liver
  • Injury

7.1 Drug Interactions With Metformin

Carbonic Anhydrase InhibitorsTopiramate or other carbonic anhydrase inhibitors (e.g.,
zonisamide, acetazolamide or dichlorphenamide) frequently cause a
decrease in serum bicarbonate and induce non-anion gap, hyperchloremic
metabolic acidosis. Concomitant use of these drugs with JENTADUETO
XR, may increase the risk of lactic acidosis. Consider more frequent
monitoring of these patients [see Warnings and Precautions
(5.1) and Clinical Pharmacology (12.3)].Drugs that Reduce Metformin ClearanceConcomitant use of drugs that interfere with common renal
tubular transport systems involved in the renal elimination of metformin
(e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin
extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir,
and cimetidine) could increase systemic exposure to metformin and
may increase the risk for lactic acidosis [see Clinical Pharmacology
(12.3)]. Consider the benefits
and risks of concomitant use. AlcoholAlcohol
is known to potentiate the effect of metformin on lactate metabolism.
Warn patients against excessive alcohol intake while receiving JENTADUETO
XR.

7.2 Drug Interactions With Linagliptin

Inducers of P-glycoprotein and CYP3A4
EnzymesRifampin decreased linagliptin exposure,
suggesting that the efficacy of linagliptin may be reduced when administered
in combination with a strong P-gp inducer or CYP 3A4 inducer. As JENTADUETO
XR is a fixed-dose combination of linagliptin and metformin, use of
alternative treatments (not containing linagliptin) is strongly recommended
when concomitant treatment with a strong P-gp or CYP 3A4 inducer is
necessary [see Clinical Pharmacology (12.3)].

7.3 Insulin Secretagogues Or Insulin

Coadministration of JENTADUETO XR with
an insulin secretagogue (e.g., sulfonylurea) or insulin may require
lower doses of the insulin secretagogue or insulin to reduce the risk
of hypoglycemia.

7.4 Drugs Affecting Glycemic Control

Certain drugs tend to produce hyperglycemia
and may lead to loss of glycemic control. These drugs include the
thiazides and other diuretics, corticosteroids, phenothiazines, thyroid
products, estrogens, oral contraceptives, phenytoin, nicotinic acid,
sympathomimetics, calcium channel blocking drugs, and isoniazid. When
such drugs are administered to a patient receiving JENTADUETO XR,
the patient should be closely observed to maintain adequate glycemic
control [see Clinical Pharmacology (12.3)]. When such drugs are withdrawn from a patient
receiving JENTADUETO XR, the patient should be observed closely for
hypoglycemia.

8.1 Pregnancy

Risk SummaryThe limited data with JENTADUETO XR and linagliptin
use in pregnant women are not sufficient to inform a JENTADUETO XR-associated
or linagliptin-associated risk for major birth defects and miscarriage.
Published studies with metformin use during pregnancy have not reported
a clear association with metformin and major birth defect or miscarriage
risk [see Data]. There are risks to the mother and fetus associated with poorly
controlled diabetes in pregnancy [see Clinical Considerations]. In animal reproduction
studies, no adverse developmental effects were observed when the combination
of linagliptin and metformin was administered to pregnant rats during
the period of organogenesis at doses similar to the maximum recommended
clinical dose, based on 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 to 4% and 15 to 20%, respectively. Clinical ConsiderationsDisease-associated maternal
and/or embryo/fetal riskPoorly controlled diabetes
in pregnancy increases the maternal risk for diabetic ketoacidosis,
pre-eclampsia, and delivery complications. Poorly controlled diabetes
increases the fetal risk for major birth defects, still birth, and
macrosomia related morbidity.DataHuman DataPublished
data from post-marketing studies have not reported a clear association
with metformin and major birth defects, miscarriage, or adverse maternal
or fetal outcomes when metformin was used during pregnancy. However,
these studies cannot definitely establish the absence of any metformin-associated
risk because of methodological limitations, including small sample
size and inconsistent comparator groups.Animal DataLinagliptin
and metformin, the components of JENTADUETO XR, were coadministered
to pregnant Wistar Han rats during the period of organogenesis. No
adverse developmental outcome was observed at doses similar to the
maximum recommended clinical dose, based on exposure. At higher doses
associated with maternal toxicity, the metformin component of the
combination was associated with an increased incidence of fetal rib
and scapula malformations at ≥ 9-times a 2000 mg clinical dose, based
on exposure. LinagliptinNo 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 and 150 mg/kg, respectively. These doses
represent approximately 943 times (rats) and 1943 times (rabbits)
the 5 mg 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 5 mg clinical dose, based
on exposure. Metformin Hydrochloride:Metformin hydrochloride
did not cause adverse developmental effects when administered to pregnant
rabbits up to 600 mg/kg/day during the period of organogenesis. This
represents an exposure of approximately 6-times a clinical dose of
2000 mg, based on body surface area.

8.2 Lactation

Risk SummaryThere is no information regarding the presence
of JENTADUETO XR or linagliptin in human milk, the effects on the
breastfed infant, or the effects on milk production. However, linagliptin
is present in rat milk. Limited published studies report that metformin
is present in human milk [see Data]. However, there is insufficient information
to determine the effects of metformin on the breastfed infant and
no available information on the effects of metformin on milk production.
Therefore, the developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for JENTADUETO
XR and any potential adverse effects on the breastfed child from JENTADUETO
XR or from the underlying maternal condition. DataPublished clinical lactation studies report
that metformin is present in human milk which resulted in infant doses
approximately 0.11% to 1% of the maternal weight-adjusted dosage and
a milk/plasma ratio ranging between 0.13 and 1. However, the studies
were not designed to definitely establish the risk of use of metformin
during lactation because of small sample size and limited adverse
event data collected in infants.

8.3 Females And Males Of Reproductive Potential

Discuss the potential for unintended pregnancy
with premenopausal women as therapy with metformin may result in ovulation
in some anovulatory women.

8.4 Pediatric Use

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

8.5 Geriatric Use

Linagliptin
is minimally excreted by the kidney; however, metformin is substantially
excreted by the kidney [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].LinagliptinThere
were 4040 type 2 diabetes patients treated with linagliptin 5 mg from
15 clinical trials of linagliptin; 1085 (27%) patients 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.MetforminControlled
clinical studies of metformin did not include sufficient numbers of
elderly patients to determine whether they respond differently from
younger patients, although other reported clinical experience has
not identified differences in responses between the elderly and young
patients. In general, dose selection for an elderly patient should
be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy and the
higher risk of lactic acidosis. Assess renal function more frequently
in elderly patients [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Metformin is substantially excreted
by the kidney, and the risk of metformin accumulation and lactic acidosis
increases with the degree of renal impairment. JENTADUETO XR is contraindicated
in severe renal impairment: patients with an estimated glomerular
filtration rate (eGFR) below 30 mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4),
Warnings and Precautions (5.1) and
Clinical Pharmacology (12.3)].If JENTADUETO XR
is discontinued due to evidence of renal impairment, linagliptin may
be continued as a single entity tablet at the same total daily dose
of 5 mg. No dose adjustment of linagliptin is recommended in patients
with renal impairment.

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated
with some cases of lactic acidosis. JENTADUETO XR is not recommended
in patients with hepatic impairment [see Warnings and Precautions
(5.1)].

10  Overdosage

In the event
of an overdose with JENTADUETO XR, 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 linagliptin by hemodialysis or peritoneal dialysis is
unlikely. However, metformin is dialyzable with a clearance of up
to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis
may be useful partly for removal of accumulated metformin from patients
in whom JENTADUETO XR overdosage is suspected.LinagliptinDuring
controlled clinical trials in healthy subjects, with single doses
of up to 600 mg of linagliptin (equivalent to 120 times the recommended
daily dose), there were no dose-related clinical adverse drug reactions.
There is no experience with doses above 600 mg in humans.MetforminOverdose of metformin has occurred, including ingestion of amounts
greater than 50 grams. Hypoglycemia was reported in approximately
10% of cases, but no causal association with metformin has been established.
Lactic acidosis has been reported in approximately 32% of metformin
overdose cases [see Boxed Warning and Warnings and Precautions
(5.1)].

11  Description

JENTADUETO XR tablets contain 2 oral antihyperglycemic
drugs used in the management of type 2 diabetes mellitus: linagliptin
and metformin hydrochloride.LinagliptinLinagliptin
is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4)
enzyme.Linagliptin
is described chemically as 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 empirical formula is C25H28N8O2 and the molecular weight is 472.54 g/mol.
The structural formula is:Linagliptin is a white
to yellowish, not or only slightly hygroscopic solid substance. It
is very slightly soluble in water (0.9 mg/mL). Linagliptin is soluble
in methanol (ca. 60 mg/mL), sparingly soluble in ethanol (ca. 10 mg/mL),
very slightly soluble in isopropanol (<1 mg/mL), and very slightly
soluble in acetone (ca. 1 mg/mL).Metformin HydrochlorideMetformin hydrochloride (N,N-dimethylimidodicarbonimidic
diamide hydrochloride) is not chemically or pharmacologically related
to any other classes of oral antihyperglycemic agents. Metformin hydrochloride
is a white to off-white crystalline compound with a molecular formula
of C4H11N5•HCl and a molecular weight of 165.63 g/mol. Metformin
hydrochloride is freely soluble in water and is practically insoluble
in acetone, ether, and chloroform. The pKa of metformin is 12.4. The
pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The
structural formula is:JENTADUETO XR consists
of an extended-release metformin core tablet that is coated with the
immediate-release drug substance linagliptin. JENTADUETO XR is available
for oral administration as tablets containing 5 mg linagliptin and
1000 mg metformin hydrochloride extended-release (JENTADUETO XR 5
mg/1000 mg) or 2.5 mg linagliptin and 1000 mg metformin hydrochloride
extended-release (JENTADUETO XR 2.5 mg/1000 mg). Each coated tablet
of JENTADUETO XR contains the following inactive ingredients: Tablet
core: polyethylene oxide, hypromellose, and magnesium stearate. Coating:
hydroxypropyl cellulose, hypromellose, talc, titanium dioxide, arginine,
polyethylene glycol, ferric oxide yellow (2.5 mg/1000 mg), carnauba
wax, ferrosoferric oxide, propylene glycol, and isopropyl alcohol.

12.1 Mechanism Of Action

JENTADUETO XRJENTADUETO XR combines 2 antihyperglycemic agents with complementary
mechanisms of action to improve glycemic control in patients with
type 2 diabetes mellitus: linagliptin, a dipeptidyl peptidase-4 (DPP-4)
inhibitor, and metformin, a member of the biguanide class.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.MetforminMetformin
is an antihyperglycemic agent which improves glucose tolerance in
patients with type 2 diabetes mellitus, lowering both basal and postprandial
plasma glucose. Its pharmacologic mechanisms of action are different
from other classes of oral antihyperglycemic agents. Metformin decreases
hepatic glucose production, decreases intestinal absorption of glucose,
and improves insulin sensitivity by increasing peripheral glucose
uptake and utilization. Unlike SUs, metformin does not produce hypoglycemia
in either patients with type 2 diabetes mellitus or normal subjects
(except in special circumstances) [see Warnings and Precautions
(5.4)] and does not cause
hyperinsulinemia. With metformin therapy, insulin secretion remains
unchanged while fasting insulin levels and day-long plasma insulin
response may actually decrease.

12.2 Pharmacodynamics

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

JENTADUETO XRAdministration of JENTADUETO XR with a high-fat meal resulted in
up to 7-22% decrease in overall exposure (AUC0-72) of linagliptin; this effect is not clinically relevant. For metformin
extended-release, high-fat meals increased systemic exposure (AUC0-tz) by approximately 54-71% relative to fasting, while
Cmax is increased up to 11%. Meals prolonged
Tmax by approximately 3 hours.AbsorptionLinagliptinThe absolute bioavailability of
linagliptin is approximately 30%. Following oral administration, plasma
concentrations of linagliptin decline in at least a biphasic manner
with a long terminal half-life (>100 hours), related to the saturable
binding of linagliptin to DPP-4. However, the prolonged elimination
does not contribute to the accumulation of the drug. The effective
half-life for accumulation of linagliptin, as determined from oral
administration of multiple doses of linagliptin 5 mg, is approximately
12 hours. After once-daily dosing, steady state plasma concentrations
of linagliptin 5 mg are reached by the third dose, and Cmax and AUC increased by a factor of 1.3 at steady-state
compared with the first dose. Plasma AUC of linagliptin increased
in a less than dose-proportional manner in the dose range of 1 to
10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects
and in patients with type 2 diabetes.MetforminFollowing a single oral dose of 1000 mg (2 x 500 mg tablets) metformin
extended-release after a meal, the time to reach maximum plasma metformin
concentration (Tmax) is achieved at approximately
7 to 8 hours. In both single- and multiple-dose studies in healthy
subjects, once daily 1000 mg (2 x 500 mg tablets) dosing provides
equivalent systemic exposure, as measured by AUC, and up to 35% higher
Cmax of metformin relative to the immediate-release
given as 500 mg twice daily. Single oral doses of metformin extended-release
from 500 mg to 2500 mg resulted in less than proportional increase
in both AUC and Cmax. Low-fat and high-fat
meals increased the systemic exposure (as measured by AUC) from metformin
extended-release tablets by about 38% and 73%, respectively, relative
to fasting. Both meals prolonged metformin Tmax by approximately 3 hours but Cmax was not
affected.DistributionLinagliptinThe 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.MetforminThe apparent volume of distribution (V/F) of metformin
following single oral doses of immediate-release metformin hydrochloride
tablets 850 mg averaged 654±358 L. Metformin is negligibly bound to
plasma proteins, in contrast to SUs, which are more than 90% protein
bound. Metformin partitions into erythrocytes, most likely as a function
of time. At usual clinical doses and dosing schedules of metformin
tablets, steady-state plasma concentrations of metformin are reached
within 24 to 48 hours and are generally <1 mcg/mL. During controlled
clinical trials of metformin, maximum metformin plasma levels did
not exceed 5 mcg/mL, even at maximum doses.MetabolismLinagliptinFollowing 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.MetforminIntravenous single-dose studies
in normal subjects demonstrate that metformin is excreted unchanged
in the urine and does not undergo hepatic metabolism (no metabolites
have been identified in humans) nor biliary excretion.ExcretionLinagliptinFollowing 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.MetforminRenal clearance is approximately
3.5 times greater than creatinine clearance, which indicates that
tubular secretion is the major route of metformin elimination. Following
oral administration, approximately 90% of the absorbed drug is eliminated
via the renal route within the first 24 hours, with a plasma elimination
half-life of approximately 6.2 hours. In blood, the elimination half-life
is approximately 17.6 hours, suggesting that the erythrocyte mass
may be a compartment of distribution.Specific PopulationsRenal Impairment JENTADUETO
XR: Studies characterizing the pharmacokinetics of linagliptin
and metformin after administration of JENTADUETO XR in renally impaired
patients have not been performed [see Contraindications (4) and Warnings and Precautions (5.1)].Linagliptin: 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 (AUCτ,ss by
71% and Cmax 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.Metformin: In patients
with decreased renal function, the plasma and blood half-life of metformin
is prolonged and the renal clearance is decreased [see Contraindications
(4) and Warnings and Precautions (5.1)].Hepatic ImpairmentJENTADUETO XR: Studies characterizing
the pharmacokinetics of linagliptin and metformin after administration
of JENTADUETO XR in hepatically impaired patients have not been performed [see Warnings and Precautions (5.1)].Linagliptin: In patients with mild hepatic impairment (Child-Pugh
class A) steady-state exposure (AUCτ,ss) of
linagliptin was approximately 25% lower and Cmax,ss was approximately 36% lower than in healthy subjects. In patients
with moderate hepatic impairment (Child-Pugh class B), AUCss of linagliptin was about 14% lower and Cmax,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 AUC0-24 and approximately 23% lower Cmax compared
with healthy subjects. Reductions in the pharmacokinetic parameters
seen in patients with hepatic impairment did not result in reductions
in DPP-4 inhibition.Metformin hydrochloride: No pharmacokinetic studies
of metformin have been conducted in patients with hepatic impairment. Body Mass Index (BMI)/WeightLinagliptin: BMI/Weight had no clinically
meaningful effect on the pharmacokinetics of linagliptin based on
a population pharmacokinetic analysis.GenderLinagliptin: Gender had no clinically meaningful
effect on the pharmacokinetics of linagliptin based on a population
pharmacokinetic analysis.Metformin hydrochloride: Metformin pharmacokinetic parameters did not differ significantly
between normal subjects and patients with type 2 diabetes mellitus
when analyzed according to gender. Similarly, in controlled clinical
studies in patients with type 2 diabetes mellitus, the antihyperglycemic
effect of metformin was comparable in males and females.GeriatricJENTADUETO XR: Studies characterizing
the pharmacokinetics of linagliptin and metformin after administration
of JENTADUETO XR in geriatric patients have not been performed [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5)].Linagliptin: Age did not have a clinically meaningful impact
on the pharmacokinetics of linagliptin based on a population pharmacokinetic
analysis.Metformin hydrochloride: Limited data from controlled pharmacokinetic
studies of metformin in healthy elderly subjects suggest that total
plasma clearance of metformin is decreased, the half-life is prolonged,
and Cmax is increased, compared with healthy
young subjects. From these data, it appears that the change in metformin
pharmacokinetics with aging is primarily accounted for by a change
in renal function.PediatricStudies characterizing
the pharmacokinetics of linagliptin and metformin after administration
of JENTADUETO XR in pediatric patients have not yet been performed.RaceLinagliptin: Race had no clinically meaningful
effect on the pharmacokinetics of linagliptin based on available pharmacokinetic
data, including subjects of White, Hispanic, Black, and Asian racial
groups.Metformin
hydrochloride: No studies of metformin pharmacokinetic parameters
according to race have been performed. In controlled clinical studies
of metformin in patients with type 2 diabetes mellitus, the antihyperglycemic
effect was comparable in Caucasians (n=249), Blacks (n=51), and Hispanics
(n=24).Drug
InteractionsPharmacokinetic drug interaction studies with JENTADUETO XR have
not been performed; however, such studies have been conducted with
the individual components of JENTADUETO XR (linagliptin and metformin
hydrochloride).LinagliptinIn vitro Assessment of
Drug InteractionsLinagliptin 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 InteractionsStrong 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 OCT. No dose adjustment of linagliptin is recommended based
on results of the described pharmacokinetic studies. Table 2 Effect of Coadministered Drugs on Systemic Exposure
of Linagliptin*Multiple dose (steady state) unless otherwise noted# Single dose†AUC = AUC(0
to 24 hours) for single-dose treatments and AUC = AUC(TAU) for multiple-dose
treatmentsQD = once dailyBID = twice dailyTID = three times dailyCoadministered DrugDosing of Coadministered Drug*Dosing of Linagliptin*Geometric Mean Ratio(ratio with/without coadministered
drug)No effect=1.0AUC†CmaxNo dosing
adjustments required for linagliptin when given with the following
coadministered drugs:Metformin 850 mg TID10 mg QD1.201.03Glyburide 1.75 mg#5 mg QD1.021.01Pioglitazone45 mg QD10 mg QD1.131.07Ritonavir200 mg BID5 mg#2.012.96The efficacy
of JENTADUETO XR 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 QD0.600.56Table 3 Effect of Linagliptin on Systemic Exposure of Coadministered
Drugs* Multiple dose (steady state) unless otherwise noted# Single dose†AUC = AUC(INF)
for single-dose treatments and AUC = AUC(TAU) for multiple-dose treatments**AUC=AUC(0-168) and Cmax=Emax for pharmacodynamic end pointsINR = International Normalized
RatioPT = Prothrombin TimeQD = once dailyTID = three times dailyCoadministered DrugDosing of Coadministered Drug*Dosing of Linagliptin*Geometric Mean Ratio(ratio with/without coadministered
drug)No effect=1.0 AUC†CmaxNo dosing
adjustments required for the following coadministered drugs:Metformin 850 mg TID10 mg QDmetformin1.010.89Glyburide 1.75 mg#5 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 QDsimvastatinsimvastatin
acid1.341.331.101.21Warfarin10 mg#5 mg QDR-warfarinS-warfarinINRPT0.991.030.93**1.03**1.001.011.04**1.15**Ethinylestradiol andlevonorgestrelethinylestradiol 0.03 mg andlevonorgestrel 0.150 mg QD5 mg QDethinylestradiollevonorgestrel1.011.091.081.13 Metformin
hydrochlorideTable 4 Effect of Coadministered Drug on Plasma Metformin
Systemic Exposure * All metformin and coadministered drugs were given
as single doses † AUC = AUC(INF) ≠ metformin
hydrochloride extended-release tablets 500 mg‡ Ratio of
arithmetic means**At steady state with topiramate 100
mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12hCoadministered DrugDosing of Coadministered Drug*Dosing of Metformin*Geometric Mean Ratio(ratio with/without coadministered
drug)No effect=1.0 AUC†CmaxNo dosing
adjustments required for the following coadministered drugs:Glyburide5 mg500 mg ≠metformin0.98‡0.99‡Furosemide40 mg850 mgmetformin1.09‡1.22‡Nifedipine10 mg850 mgmetformin1.161.21Propranolol40 mg850 mgmetformin0.900.94Ibuprofen400 mg850 mgmetformin1.05‡1.07‡Drugs that
are eliminated by renal tubular secretion may reduce metformin elimination: [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].Cimetidine400 mg850 mgmetformin1.401.61Carbonic anhydrase
inhibitors may cause metabolic acidosis: [see Warnings and
Precautions (5.1) and Drug Interactions
(7.1)].Topiramate**100 mg500 mgmetformin1.251.17Table 5 Effect of Metformin on Coadministered Drug Systemic
Exposure * All metformin and coadministered drugs were given
as single doses † AUC = AUC(INF) unless otherwise noted ‡ Ratio of arithmetic means, p-value of difference <0.05 § AUC(0-24 hr) reported ¶ Ratio of arithmetic meansCoadministered DrugDosing of Coadministered Drug*Dosing of Metformin*Geometric Mean Ratio(ratio with/without metformin)No effect=1.0 AUC†CmaxNo dosing
adjustments required for the following coadministered drugs:Glyburide5 mg500 mg§glyburide0.78‡0.63‡Furosemide40 mg850 mgfurosemide0.87‡0.69‡Nifedipine10 mg850 mgnifedipine1.10§1.08Propranolol40 mg850 mgpropranolol1.01§0.94Ibuprofen400 mg850 mgibuprofen0.97¶1.01¶Cimetidine400 mg850 mgcimetidine0.95§1.01

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

JENTADUETO XRNo animal studies have been conducted with the combined
products in JENTADUETO XR to evaluate carcinogenesis, mutagenesis,
or impairment of fertility. General toxicity studies in rats up to
13 weeks were performed with linagliptin/metformin coadministered.The following data are based
on the findings in studies with linagliptin and metformin individually.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).Metformin HydrochlorideLong-term carcinogenicity
studies have been performed in Sprague Dawley rats at doses of 150,
300, and 450 mg/kg/day in males and 150, 450, 900, and 1200 mg/kg/day
in females. These doses are both approximately 2, 4, and 8 times
in males, and 3, 7, 12, and 16 times in females of the maximum recommended
human daily dose of 2000 mg/kg/day based on body surface area comparisons.
No evidence of carcinogenicity with metformin was found in either
male or female rats. A carcinogenicity study was also performed in
Tg.AC transgenic mice at doses of up to 2000 mg/kg/day applied dermally.
No evidence of carcinogenicity was observed in male or female mice.Genotoxicity assessments in
the Ames test, gene mutation test (mouse lymphoma cells), chromosomal
aberrations test (human lymphocytes) and in vivo mouse
micronucleus tests were negative.Fertility of male or female rats was unaffected
by metformin when administered at doses as high as 600 mg/kg/day,
which is approximately 2 times the MRHD based on body surface area
comparisons.

14  Clinical Studies

The safety and efficacy of JENTADUETO XR have been established
based on adequate and well-controlled studies of linagliptin and metformin
coadministered in patients with type 2 diabetes mellitus inadequately
controlled on diet and exercise and in combination with sulfonylurea.

14.1 Initial Combination Therapy With Linagliptin And Metformin

A total of 791 patients with type 2 diabetes
mellitus and inadequate glycemic control on diet and exercise participated
in the 24-week, randomized, double-blind, portion of this placebo-controlled
factorial study designed to assess the efficacy of linagliptin as
initial therapy with metformin. Patients on an antihyperglycemic agent
(52%) underwent a drug washout period of 4 weeks’ duration. After
the washout period and after completing a 2-week single-blind placebo
run-in period, patients with inadequate glycemic control (A1C ≥7.0%
to ≤10.5%) were randomized. Patients with inadequate glycemic control
(A1C ≥7.5% to <11.0%) not on antihyperglycemic agents at study
entry (48%) immediately entered the 2-week single-blind placebo run-in
period and then were randomized. Randomization was stratified by baseline
A1C (<8.5% vs ≥8.5%) and use of a prior oral antidiabetic drug
(none vs monotherapy). Patients were randomized in a 1:2:2:2:2:2 ratio
to either placebo or one of 5 active-treatment arms. Approximately
equal numbers of patients were randomized to receive initial therapy
with 5 mg of linagliptin once daily, 500 mg or 1000 mg of metformin
twice daily, or 2.5 mg of linagliptin twice daily in combination with
500 mg or 1000 mg of metformin twice daily. Patients who failed to
meet specific glycemic goals during the study were treated with sulfonylurea,
thiazolidinedione, or insulin rescue therapy.Initial therapy with the combination of
linagliptin and metformin provided significant improvements in A1C,
and fasting plasma glucose (FPG) compared to placebo, to metformin
alone, and to linagliptin alone (Table 6, Figure 1). The adjusted
mean treatment difference in A1C from baseline to week 24 (LOCF) was
-0.5% (95% CI -0.7, -0.3; p<0.0001) for linagliptin 2.5 mg/metformin
1000 mg twice daily compared to metformin 1000 mg twice daily; -1.1%
(95% CI -1.4, -0.9; p<0.0001) for linagliptin 2.5 mg/metformin
1000 mg twice daily compared to linagliptin 5 mg once daily; -0.6%
(95% CI -0.8, -0.4; p<0.0001) for linagliptin 2.5 mg/metformin
500 mg twice daily compared to metformin 500 mg twice daily; and -0.8%
(95% CI -1.0, -0.6; p<0.0001) for linagliptin 2.5 mg/metformin
500 mg twice daily compared to linagliptin 5 mg once daily. Lipid effects were generally
neutral. No meaningful change in body weight was noted in any of the
6 treatment groups.Table 6 Glycemic Parameters at Final Visit (24-Week Study)
for Linagliptin and Metformin, Alone and in Combination in Randomized
Patients with Type 2 Diabetes Mellitus Inadequately Controlled on
Diet and Exercise***Total daily dose of linagliptin is equal to 5 mg**Full analysis population using last observation on study***Metformin 500 mg twice daily, n=140; Linagliptin 2.5 mg twice
daily + Metformin 500 mg twice daily, n=136; Metformin 1000 mg twice
daily, n=137; Linagliptin 2.5 mg twice daily + Metformin 1000 mg twice
daily, n=138****HbA1c: ANCOVA model included treatment
and number of prior OADs as class-effects, as well as baseline HbA1c
as continuous covariates. FPG: ANCOVA model included treatment and
number of prior OADs as class-effects, as well as baseline HbA1c and
baseline FPG as continuous covariates. PlaceboLinagliptin 5 mg Once Daily*Metformin 500 mgTwice DailyLinagliptin 2.5 mgTwice Daily* + Metformin 500 mgTwice DailyMetformin1000
mg Twice DailyLinagliptin 2.5 mgTwice Daily* + Metformin 1000 mg Twice DailyA1C (%)      Number of patientsn=65n=135n=141n=137n=138n=140Baseline (mean)8.78.78.78.78.58.7Change from baseline (adjusted
mean****)0.1-0.5-0.6-1.2-1.1-1.6Difference from placebo (adjusted
mean) (95% CI)---0.6 (-0.9, -0.3)-0.8 (-1.0, -0.5)-1.3 (-1.6, -1.1)-1.2 (-1.5, -0.9)-1.7 (-2.0, -1.4)Patients [n (%)] achieving A1C
<7%***7 (10.8)14 (10.4)26 (18.6)41 (30.1)42 (30.7)74 (53.6)Patients (%) receiving rescue
medication29.211.113.57.38.04.3FPG (mg/dL)      Number of patientsn=61n=134n=136n=135n=132n=136Baseline (mean)203195191199191196Change from baseline (adjusted
mean****)10-9-16-33-32-49Difference from placebo (adjusted
mean) (95% CI)---19 (-31, -6)-26 (-38, -14)-43 (-56, -31)-42 (-55, -30)-60 (-72, -47)Figure 1 Adjusted
Mean Change from Baseline for A1C (%) over 24 Weeks with Linagliptin
and Metformin, Alone and in Combination in Patients with Type 2 Diabetes
Mellitus Inadequately Controlled with Diet and Exercise - FAS completers.

14.2 Initial Combination Therapy With Linagliptin And Metformin Vs Linagliptin In Treatment-Naïve Patients

A total of 316 patients with type 2 diabetes
diagnosed within the previous 12 months and treatment-naïve (no antidiabetic
therapy for 12 weeks prior to randomization) and inadequate glycemic
control (A1C ≥8.5% to ≤12.0%) participated in a 24-week, randomized,
double-blind, study designed to assess the efficacy of linagliptin
in combination with metformin vs linagliptin. Patients were randomized
(1:1), after a 2-week run-in period, to either linagliptin 5 mg plus
metformin (1500 to 2000 mg per day, n=159) or linagliptin 5 mg plus
placebo, (n=157) administered once daily. Patients in the linagliptin
and metformin treatment group were up-titrated to a maximum tolerated
dose of metformin (1000 to 2000 mg per day) over a three-week period.Initial therapy with the combination
of linagliptin and metformin provided statistically significant improvements
in A1C compared to linagliptin (Table 7). The mean difference between
groups in A1C change from baseline was -0.8% with 2-sided 95% confidence
interval (-1.23%, -0.45%). Table 7 Glycemic Parameters at 24 Weeks in Study Comparing
Linagliptin in Combination with Metformin to Linagliptin in Treatment-Naïve
Patients*†p<0.0001 compared to
linagliptin, ††p=0.0054 compared to linagliptin*Full analysis set population**A1C: MMRM model included
treatment, continuous baseline A1C, baseline A1C by visit interaction,
visit by treatment interaction, baseline renal impairment by treatment
interaction and baseline renal impairment by treatment by visit interaction.
FPG: MMRM model included treatment, continuous baseline A1C, continuous
baseline FPG, baseline FPG by visit interaction, visit by treatment
interaction, baseline renal impairment by treatment interaction and
baseline renal impairment by treatment by visit interaction. Linagliptin 5 mg + MetforminLinagliptin 5 mg + PlaceboA1C (%)*    Number of patientsn=153n=150 Baseline (mean)9.89.9 Change from baseline (adjusted
mean) -2.9-2 Difference from linagliptin
(adjusted mean**) (95% CI) -0.84† (-1.23, -0.45)-- Patients [n (%)] achieving
A1C <7%* 82 (53.6)45 (30)FPG (mg/dL)*    Number of patientsn=153n=150 Baseline (mean) 196198 Change from baseline (adjusted
mean) -54-35 Difference from linagliptin
(adjusted mean**) (95% CI) -18†† (-31, -5.5)--The adjusted mean changes
for A1C (%) from baseline over time for linagliptin and metformin
as compared to linagliptin alone were maintained throughout the 24
week treatment period. Using the completers analysis the respective
adjusted means for A1C (%) changes from baseline for linagliptin and
metformin as compared to linagliptin alone were -1.9 and -1.3 at week
6, -2.6 and -1.8 at week 12, -2.7 and -1.9 at week 18, and -2.7 and
-1.9 at week 24.Changes
in body weight from baseline were not clinically significant in either
treatment group.

14.3 Add-On Combination Therapy With Metformin

A total of 701 patients with type 2 diabetes
participated in a 24-week, randomized, double-blind, placebo-controlled
study designed to assess the efficacy of linagliptin in combination
with metformin. Patients already on metformin (n=491) at a dose of
at least 1500 mg per day were randomized after completing a 2-week,
open-label, placebo run-in period. Patients on metformin and another
antihyperglycemic agent (n=207) were randomized after a run-in period
of approximately 6 weeks on metformin (at a dose of at least 1500
mg per day) in monotherapy. Patients were randomized to the addition
of either linagliptin 5 mg or placebo, administered once daily. Patients
who failed to meet specific glycemic goals during the studies were
treated with glimepiride rescue.In combination with metformin, linagliptin
provided statistically significant improvements in A1C, FPG, and 2-hour
PPG compared with placebo (Table 8). Rescue glycemic therapy was
used in 7.8% of patients treated with linagliptin 5 mg and in 18.9%
of patients treated with placebo. A similar decrease in body weight
was observed for both treatment groups.Table 8 Glycemic Parameters in Placebo-Controlled Study for
Linagliptin in Combination with Metformin** Full analysis population using last observation
on study**Linagliptin 5 mg + Metformin, n=485; Placebo
+ Metformin, n=163***HbA1c: ANCOVA model included treatment
and number of prior oral OADs as class-effects, as well as baseline
HbA1c as continuous covariates. FPG: ANCOVA model included treatment
and number of prior OADs as class-effects, as well as baseline HbA1c
and baseline FPG as continuous covariates. PPG: ANCOVA model included
treatment and number of prior OADs as class-effects, as well as baseline
HbA1c and baseline postprandial glucose after two hours as covariate. Linagliptin 5 mg + Metformin Placebo + Metformin A1C (%)   Number of patientsn=513n=175Baseline (mean)8.18.0Change from baseline (adjusted
mean***) -0.50.15Difference from placebo + metformin
(adjusted mean) (95% CI) -0.6 (-0.8, -0.5)--Patients [n (%)] achieving A1C
<7%** 127 (26.2)15 (9.2)FPG (mg/dL)   Number of patientsn=495n=159Baseline (mean) 169164Change from baseline (adjusted
mean***) -1111Difference from placebo + metformin
(adjusted mean) (95% CI) -21 (-27, -15)--2-hour PPG (mg/dL)   Number of patientsn=78n=21Baseline (mean) 270274Change from baseline (adjusted
mean***) -4918Difference from placebo + metformin
(adjusted mean) (95% CI) -67 (-95, -40)--

14.4 Active-Controlled Study Vs Glimepiride In Combination With Metformin

The efficacy of linagliptin
was evaluated in a 104-week double-blind, glimepiride-controlled non-inferiority
study in type 2 diabetic patients with insufficient glycemic control
despite metformin therapy. Patients being treated with metformin
only entered a run-in period of 2 weeks’ duration, whereas patients
pretreated with metformin and one additional antihyperglycemic agent
entered a run-in treatment period of 6 weeks’ duration with metformin
monotherapy (dose of ≥1500 mg per day) and washout of the other agent.
After an additional 2-week placebo run-in period, those with inadequate
glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition
of linagliptin 5 mg once daily or glimepiride. Randomization was
stratified by baseline HbA1c (<8.5% vs ≥8.5%), and the previous
use of antidiabetic drugs (metformin alone vs metformin plus one other
OAD). Patients receiving glimepiride were given an initial dose of
1 mg/day and then electively titrated over the next 12 weeks to a
maximum dose of 4 mg/day as needed to optimize glycemic control. Thereafter,
the glimepiride dose was to be kept constant, except for down-titration
to prevent hypoglycemia.After 52 weeks and 104 weeks, linagliptin
and glimepiride both had reductions from baseline in A1C (52 weeks:
-0.4% for linagliptin, -0.6% for glimepiride; 104 weeks: -0.2% for
linagliptin, -0.4% for glimepiride) from a baseline mean of 7.7% (Table
9). The mean difference between groups in A1C change from baseline
was 0.2% with 2-sided 97.5% confidence interval (0.1%, 0.3%) for the
intent-to-treat population using last observation carried forward.
These results were consistent with the completers analysis.Table 9 Glycemic Parameters at 52 and 104 Weeks in Study
Comparing Linagliptin to Glimepiride as Add-On Therapy in Patients
Inadequately Controlled on Metformin***p<0.0001 vs glimepiride; †p=0.0012 vs glimepiride**Full analysis population using
last observation on study***HbA1c: ANCOVA model included
treatment and number of prior OADs as class-effects, as well as baseline
HbA1c as continuous covariates. FPG: ANCOVA model included treatment
and number of prior OADs as class-effects, as well as baseline HbA1c
and baseline FPG as continuous covariates. Week 52Week 104 Linagliptin 5 mg + MetforminGlimepiride + Metformin
(mean glimepiride dose 3 mg)Linagliptin 5 mg + MetforminGlimepiride + Metformin
(mean glimepiride dose 3 mg)A1C (%)    Number of patientsn=764n=755n=764 n=755 Baseline (mean)7.77.77.77.7Change from baseline (adjusted
mean***)-0.4-0.6-0.2 -0.4 Difference from glimepiride
(adjusted mean) (97.5% CI)0.2 (0.1, 0.3)--0.2 (0.1, 0.3)--FPG (mg/dL)    Number of patientsn=733n=725n=733n=725Baseline (mean)164166164166Change from baseline (adjusted
mean***)-8*-15-2†-9Patients treated with
linagliptin had a mean baseline body weight of 86 kg and were observed
to have an adjusted mean decrease in body weight of 1.1 kg at 52 weeks
and 1.4 kg at 104 weeks. Patients on glimepiride had a mean baseline
body weight of 87 kg and were observed to have an adjusted mean increase
from baseline in body weight of 1.4 kg at 52 weeks and 1.3 kg at 104
weeks (treatment difference p<0.0001 for both timepoints).

14.5 Add-On Combination Therapy With Metformin And A Sulfonylurea

A total of 1058 patients with
type 2 diabetes mellitus participated in a 24-week, randomized, double-blind,
placebo-controlled study designed to assess the efficacy of linagliptin
in combination with a sulfonylurea and metformin. The most common
sulfonylureas used by patients in the study were glimepiride (31%),
glibenclamide (26%), and gliclazide (26% [not available in the United
States]). Patients on a sulfonylurea and metformin were randomized
to receive linagliptin 5 mg or placebo, each administered once daily.
Patients who failed to meet specific glycemic goals during the study
were treated with pioglitazone rescue. Glycemic end points measured
included A1C and FPG.In combination with a sulfonylurea and metformin, linagliptin provided
statistically significant improvements in A1C and FPG compared with
placebo (Table 10). In the entire study population (patients on linagliptin
in combination with a sulfonylurea and metformin), a mean reduction
from baseline relative to placebo in A1C of -0.6% and in FPG
of -13 mg/dL was seen. Rescue therapy was used in 5.4% of patients
treated with linagliptin 5 mg and in 13% of patients treated with
placebo. Change from baseline in body weight did not differ significantly
between the groups. Table 10 Glycemic Parameters at Final Visit (24-Week Study)
for Linagliptin in Combination with Metformin and Sulfonylurea*SU=sulfonylurea*Full analysis population
using last observation on study**Linagliptin 5 mg + Metformin
+ SU, n=742; Placebo + Metformin + SU, n=247***HbA1c:
ANCOVA model included treatment as class-effects and baseline HbA1c
as continuous covariates. FPG: ANCOVA model included treatment as
class-effects, as well as baseline HbA1c and baseline FPG as continuous
covariates. Linagliptin 5 mg + Metformin
+ SUPlacebo + Metformin +
SUA1C (%)   Number of patientsn=778n=262Baseline (mean) 8.28.1Change from baseline (adjusted
mean***) -0.7-0.1Difference from placebo (adjusted
mean) (95% CI) -0.6 (-0.7, -0.5)--Patients [n (%)] achieving A1C
<7%** 217 (29.2)20 (8.1)FPG (mg/dL)   Number of patientsn=739n=248Baseline (mean) 159163Change from baseline (adjusted
mean***) -58Difference from placebo (adjusted
mean) (95% CI) -13 (-18, -7)--

16  How Supplied/Storage And Handling

JENTADUETO XR
(linagliptin and metformin hydrochloride extended-release) tablets
5 mg/1000 mg, white, oval-shaped coated tablets with one side printed
in black ink with the Boehringer Ingelheim logo and “D5” on the top
line and “1000M” on the bottom line, are supplied as follows:Bottles of 30 (NDC 0597-0275-33)Bottles of 90 (NDC 0597-0275-81)JENTADUETO XR (linagliptin and metformin
hydrochloride extended-release) tablets 2.5 mg/1000 mg, yellow, oval-shaped
coated tablets with one side printed in black ink with the Boehringer
Ingelheim logo and “D2” on the top line and “1000M” on the bottom
line, are supplied as follows:Bottles of 60 (NDC 0597-0270-73)Bottles of 180 (NDC 0597-0270-94)StorageStore at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Protect from exposure to
high humidity. 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)Medication GuideInstruct patients
to read the Medication Guide before starting JENTADUETO XR therapy
and to reread each time the prescription is renewed. Instruct patients
to inform their doctor if they develop any bothersome or unusual symptoms,
or if any symptom persists or worsens.Inform patients of the potential risks and
benefits of JENTADUETO XR 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 A1C
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.Lactic AcidosisInform patients of the risks of lactic acidosis due to
the metformin component, its symptoms, and conditions that predispose
to its development [see Warnings and Precautions (5.1)]. Advise patients to discontinue
JENTADUETO XR immediately and to notify their doctor promptly if unexplained
hyperventilation, malaise, myalgia, unusual somnolence, slow or irregular
heartbeat, sensation of feeling cold (especially in the extremities),
or other nonspecific symptoms occur. GI symptoms are common during
initiation of metformin treatment and may occur during initiation
of JENTADUETO XR therapy; however, advise patients to consult their
doctor if they develop unexplained symptoms. Although GI symptoms
that occur after stabilization are unlikely to be drug related, such
an occurrence of symptoms should be evaluated to determine if it may
be due to metformin-induced lactic acidosis or other serious disease.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 JENTADUETO XR
promptly and contact their physician if persistent severe abdominal
pain occurs [see Warnings and Precautions (5.2)].Heart FailureInform patients of the signs and symptoms of heart failure. Before
initiating JENTADUETO XR, 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 (5.3)].Monitoring of Renal
FunctionInform patients about the importance
of regular testing of renal function and hematological parameters
when receiving treatment with JENTADUETO XR.Instruct patients to inform their doctor
that they are taking JENTADUETO XR prior to any surgical or radiological
procedure, as temporary discontinuation of JENTADUETO XR may be required
until renal function has been confirmed to be normal [see
Warnings and Precautions (5.1)].HypoglycemiaInform patients that the risk of hypoglycemia is increased
when JENTADUETO XR is used in combination with an insulin secretagogue
(e.g., sulfonylurea), and that a lower dose of the insulin secretagogue
may be required to reduce the risk of hypoglycemia [see Warnings
and Precautions (5.4)].Hypersensitivity
ReactionsInform patients that serious allergic
reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions,
have been reported during postmarketing use of linagliptin (one of
the components of JENTADUETO XR). 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
JENTADUETO XR and seek medical advice promptly [see Warnings
and Precautions (5.5)].Missed DoseInstruct patients to take JENTADUETO XR only as prescribed.
If a dose is missed, advise patients not to double their next dose.Alcohol IntakeWarn patients against excessive alcohol intake, either
acute or chronic, while receiving JENTADUETO XR [see Warnings
and Precautions (5.1)].Administration InstructionsInform patients taking JENTADUETO XR that the tablets
must be swallowed whole and never split, crushed, dissolved, or chewed
and that incompletely dissolved JENTADUETO XR tablets may be eliminated
in the feces. Patients should be told that, if they see tablets in
feces, they should report this finding to their healthcare provider [see Dosage and Administration (2.1)].Blood Glucose and A1C MonitoringInform patients
that response to all diabetic therapies should be monitored by periodic
measurements of blood glucose and A1C levels, with a goal of decreasing
these levels toward the normal range. A1C monitoring is especially
useful for evaluating long-term glycemic control.Renal Function and Other Hematologic
Parameters MonitoringInform patients that
initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit
and red blood cell indices) and renal function (e.g., eGFR) should
be performed, at least on an annual basis [see Warnings and
Precautions (5.1, 5.6)].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
(5.7)].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 (5.8)].PregnancyInform female patients that treatment with metformin may result
in an unintended pregnancy in some premenopausal anovulatory females
due to its effect on ovulation [see Use in Specific Populations
(8.3)].Distributed by:Boehringer Ingelheim
Pharmaceuticals, Inc.Ridgefield, CT 06877 USAMarketed by:Boehringer
Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877 USAandEli Lilly and CompanyIndianapolis, IN
46285 USALicensed
from:Boehringer Ingelheim International GmbH, Ingelheim,
GermanyJENTADUETO
is a registered trademark of and used under license from Boehringer
Ingelheim International GmbH.Copyright © 2017 Boehringer Ingelheim International
GmbHALL RIGHTS RESERVEDIT6354FH142017

Spl Medguide

  • MEDICATION GUIDEJENTADUETO® XR (JEN ta doo e' toe XR)(linagliptin and metformin hydrochloride extended-release) TabletsRead this Medication
  • Guide carefully before you start taking JENTADUETO XR and each time
  • You get a refill. There may be new information. This information does
  • Not take the place of talking to your doctor about your medical condition
  • Or your treatment. If you have any questions about JENTADUETO XR,
  • Ask your doctor or pharmacist.What is the most important
  • Information I should know about JENTADUETO XR?Serious side effects can happen in people taking JENTADUETO XR, including:1.Lactic acidosis. Metformin,
  • One of the medicines in JENTADUETO XR, can cause a rare but serious
  • Condition called lactic acidosis (a buildup of an acid in the blood)
  • That can cause death. Lactic acidosis is a medical emergency and must
  • Be treated in the hospital.
  • Call your
  • Doctor right away if you have any of the following symptoms, which
  • Could be signs of lactic acidosis: you feel cold in your hands or feetyou feel dizzy or lightheadedyou have a slow or irregular heart beatyou feel very weak or tiredyou have unusual (not normal) muscle painyou have trouble breathingyou feel sleepy or drowsyyou have stomach pains, nausea or vomitingMost people who have had lactic acidosis with metformin
  • Have other things that, combined with metformin, led to the lactic
  • Acidosis. Tell your doctor if you have any of the following, because
  • You have a higher chance of getting lactic acidosis with JENTADUETO
  • XR if you:have severe kidney problems or your kidneys are affected
  • By certain x-ray tests that use injectable dye.have liver problemsdrink alcohol very often, or drink a lot of alcohol in short-term
  • ("binge" drinking)get dehydrated (lose a large amount of body fluids). This
  • Can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration
  • Can also happen when you sweat a lot with activity or exercise and
  • Do not drink enough fluids.have surgeryhave a heart attack, severe infection, or strokeThe best way to keep from having a problem with
  • Lactic acidosis from metformin is to tell your doctor if you have
  • Any of the problems in the list above. Your doctor may decide to stop
  • Your JENTADUETO XR for a while if you have any of these things. JENTADUETO
  • XR can have other serious side effects. See “What are the possible
  • Side effects of JENTADUETO XR?”2.Inflammation
  • Of the pancreas (pancreatitis) which may be severe and lead
  • To death. Certain medical problems make you more likely to get pancreatitis.Before you start taking JENTADUETO XR:Tell
  • Your doctor if you have ever had:inflammation of your pancreas (pancreatitis)a history of alcoholismstones in your gallbladder (gallstones)high blood triglyceride levels   Stop taking JENTADUETO
  • XR and call your doctor right away if you have pain in your stomach
  • Area (abdomen) that is severe and will not go away. The pain may be
  • Felt going from your abdomen through to your back. The pain may happen
  • With or without vomiting. These may be symptoms of pancreatitis.3.Heart failure. Heart failure means that
  • Your heart does not pump blood well enough.Before
  • You start taking JENTADUETO XR, tell your doctor if you have
  • Ever had heart failure or have problems with your kidneys. Contact
  • Your doctor right away if you have any of the following symptoms:increasing shortness of breath or trouble breathing, especially
  • When you lie downswelling or fluid retention, especially in the feet, ankles
  • Or legsan unusually fast increase in weightunusual tirednessThese may be symptoms of heart failure.What is JENTADUETO
  • XR?JENTADUETO XR is a prescription medicine that contains 2
  • Diabetes medicines, linagliptin and metformin. JENTADUETO XR can be
  • Used along with diet and exercise to lower blood sugar in adults with
  • Type 2 diabetes when treatment with both linagliptin and metformin
  • Is appropriate.JENTADUETO XR is not for people with type 1 diabetes.JENTADUETO XR is not for people with diabetic ketoacidosis
  • (increased ketones in the blood or urine).If you have had pancreatitis in the past, it is not known
  • If you have a higher chance of getting pancreatitis while you take
  • JENTADUETO XR.It is not known if JENTADUETO XR is safe and effective in
  • Children under 18 years of age.Who should
  • Not take JENTADUETO XR?Do not take JENTADUETO
  • XR if you:have severe kidney problemshave a condition called metabolic acidosis or diabetic ketoacidosis
  • (increased ketones in the blood or urine).are allergic to linagliptin, metformin, or any of the ingredients
  • In JENTADUETO XR. See the end of this Medication Guide for a complete
  • List of ingredients in JENTADUETO XR.Symptoms of a serious
  • Allergic reaction to JENTADUETO XR may include:skin rash, itching, flaking or peelingraised red patches on your skin (hives)swelling of your face, lips, tongue and throat that may
  • Cause difficulty in breathing or swallowingdifficulty with swallowing or breathingIf you have any of these symptoms, stop taking JENTADUETO XR
  • And contact your doctor or go to the nearest hospital emergency room
  • Right away.What should
  • I tell my doctor before using JENTADUETO XR?Before you take JENTADUETO XR, tell your doctor about all of your
  • Medical conditions, including if you:have or have had inflammation of your pancreas (pancreatitis).have severe kidney problemshave liver problemshave heart problems, including congestive heart failuredrink alcohol very often, or drink a lot of alcohol in short
  • Term "binge" drinkingare going to get an injection of dye or contrast agents
  • For an x-ray procedure. JENTADUETO XR may need to be stopped for a
  • Short time. Talk to your doctor about when you should stop JENTADUETO
  • XR and when you should start JENTADUETO XR again. See "What
  • Is the most important information I should know about JENTADUETO XR?"have type 1 diabetes. JENTADUETO XR should not be used
  • To treat people with type 1 diabetes.have any other medical conditionsare pregnant or plan to become pregnant. It is not known
  • If JENTADUETO XR will harm your unborn baby. If you are pregnant,
  • Talk with your doctor about the best way to control your blood sugar
  • While you are pregnant.are a premenopausal woman (before the “change of life”),
  • Who does not have periods regularly or at all. Talk to your
  • Doctor about birth control choices while taking JENTADUETO XR if you
  • Are not planning to become pregnant since JENTADUETO XR may increase
  • Your chance of becoming pregnant. Tell your doctor right away if you
  • Become pregnant while taking JENTADUETO XR.are breastfeeding or plan to breastfeed. It is not known
  • If JENTADUETO XR passes into your breast milk. Talk with your doctor
  • About the best way to feed your baby if you take JENTADUETO XR.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins,
  • And herbal supplements. JENTADUETO XR may affect the way other medicines
  • Work, and other medicines may affect how JENTADUETO XR works.Especially tell your doctor if you take:other medicines that can lower your blood sugarrifampin (Rifadin®, Rimactane®, Rifater®, Rifamate®)*, an antibiotic that is used to treat tuberculosisAsk your doctor or pharmacist for a list of these medicines
  • If you are not sure if your medicine is one that is listed above.Know the medicines you take. Keep a list of them and show it to
  • Your doctor and pharmacist when you get a new medicine.How should
  • I take JENTADUETO XR?Take JENTADUETO XR exactly as your doctor tells you to take
  • It.Take JENTADUETO XR each day with a meal. Taking JENTADUETO
  • XR with a meal may lower your chance of having an upset stomach.Take JENTADUETO XR 1 time each day.Take JENTADUETO XR tablets whole. Do not break, cut, crush,
  • Dissolve, or chew JENTADUETO XR tablets before swallowing. If you
  • Cannot swallow JENTADUETO XR tablets whole, tell your doctor.You may see something that looks like the JENTADUETO XR
  • Tablet in your stool (bowel movement). If you see tablets in your
  • Stool, talk to your doctor. Do not stop taking JENTADUETO XR without
  • Talking to your doctor.If you miss a dose, take it with food 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 2 doses
  • Of JENTADUETO XR at the same time.If you take too much JENTADUETO XR, call your doctor or
  • Poison Control Center at 1-800-222-1222 or go to the nearest hospital
  • Emergency room right away.Your doctor may tell you to take JENTADUETO XR along with
  • Other diabetes medicines. Low blood sugar can happen more often when
  • JENTADUETO XR is taken with certain other diabetes medicines. See
  • "What are the possible side effects of JENTADUETO XR?"You may need to stop taking JENTADUETO XR for a short time.
  • Call your doctor for instructions if you:are dehydrated (have lost too much body fluid). Dehydration
  • Can occur if you are sick with severe vomiting, diarrhea, or fever,
  • Or if you drink a lot less fluid than normal.plan to have surgeryare going to get an injection of dye or contrast agent for
  • An x-ray procedure. See "What is the most important information
  • I should know about JENTADUETO XR?" and "Who should not
  • Take JENTADUETO XR?"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 JENTADUETO XR.Your doctor will check your diabetes with regular blood
  • Tests, including your blood sugar levels and your hemoglobin A1C.Your doctor will do blood tests to check how well your kidneys
  • Are working before and during your treatment with JENTADUETO XR.What are the possible
  • Side effects of JENTADUETO XR?JENTADUETO
  • XR may cause serious side effects, including:See "What is the most important information I should
  • Know about JENTADUETO XR?"Low blood sugar (hypoglycemia). If you take
  • JENTADUETO XR with another medication that can cause low blood sugar,
  • Such as 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 JENTADUETO XR. Signs and symptoms of
  • Low blood sugar may include:headachefast heart beatirritabilitydizzinessdrowsinesssweatinghungerconfusionweaknessfeeling jitteryAllergic (hypersensitivity) reactions. Serious
  • Allergic reactions can happen after your first dose or up to 3 months
  • After starting JENTADUETO XR. Symptoms may include:swelling of your face, lips, throat, and other areas on
  • Your skinraised, red areas on your skin (hives)difficulty with swallowing or breathingskin rash, itching, flaking, or peeling         If you have these
  • Symptoms, stop taking JENTADUETO XR and call your doctor or go to
  • The nearest hospital emergency room right away.Joint pain. Some people who take medicines
  • Called DPP-4 inhibitors, one of the medicines in JENTADUETO XR, may
  • Develop joint pain that can be severe. Call your doctor if you have
  • Severe joint pain.Skin reaction. Some people who take medicines
  • Called DPP-4 inhibitors, one of the medicines in JENTADUETO XR, may
  • Develop a skin reaction called bullous pemphigoid that can require
  • Treatment in a hospital. Tell your doctor right away if you develop
  • Blisters or the breakdown of the outer layer of your skin (erosion).
  • Your doctor may tell you to stop taking JENTADUETO XR.The most common side effects of JENTADUETO XR include stuffy or runny nose and sore throat and diarrhea.These are not all the possible side effects of JENTADUETO XR. For
  • More information, ask your doctor or pharmacist. Tell your doctor
  • If you have any side effects that bother you or that do not go away.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 JENTADUETO XR?Store JENTADUETO XR between 68°F and 77°F (20°C and 25°C).Keep tablets dry.Keep JENTADUETO XR and all medicines out of the reach
  • Of children.General information
  • About the safe and effective use of JENTADUETO XRMedicines are sometimes prescribed for purposes other than those
  • Listed in Medication Guides. Do not use JENTADUETO XR for a condition
  • For which it was not prescribed. Do not give JENTADUETO XR to other
  • People, even if they have the same symptoms you have. It may harm
  • Them.This Medication Guide summarizes the most important
  • Information about JENTADUETO XR. If you would like more information,
  • Talk with your doctor. You can ask your pharmacist or doctor for
  • Information about JENTADUETO XR that is written for health professionals.What are the
  • Ingredients in JENTADUETO XR?Active Ingredients:
  • Linagliptin and metformin hydrochlorideInactive Ingredients:
  • Polyethylene oxide, hypromellose, and magnesium stearate. The coating
  • Contains the following inactive ingredients: hydroxypropyl cellulose,
  • Hypromellose, talc, titanium dioxide, arginine, polyethylene glycol,
  • Ferric oxide yellow (2.5 mg/1000 mg), carnauba wax, ferrosoferric
  • Oxide, propylene glycol, and isopropyl alcohol.What is type
  • 2 diabetes?Type 2 diabetes is a condition in which
  • Your body does not make enough insulin, and/or the insulin that your
  • Body produces does not work as well as it should. Your body can also
  • Make too much sugar. When this happens, sugar (glucose) builds up
  • In the blood. This can lead to serious medical problems.The main goal of treating diabetes is to lower your blood sugar
  • To a normal level. High blood sugar can be lowered by diet and exercise,
  • And by certain medicines when necessary.Talk to your doctor
  • About how to prevent, recognize, and take care of low blood sugar
  • (hypoglycemia), high blood sugar (hyperglycemia), and other problems
  • You have because of your diabetes.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.JENTADUETO is a registered
  • Trademark of and used under license from Boehringer Ingelheim International
  • GmbH.*The brands listed are trademarks of
  • Their respective owners and are not trademarks of Boehringer Ingelheim
  • Pharmaceuticals, Inc. The makers of these brands are not affiliated
  • With and do not endorse Boehringer Ingelheim Pharmaceuticals, Inc.,
  • Or its products.For more information, go to www.jentadueto.com (or scan
  • The code below to go to www.jentadueto.com) or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257,
  • Or (TTY) 1-800-459-9906.Copyright © 2017 Boehringer Ingelheim International GmbH.ALL RIGHTS RESERVEDIT6354FH142017This Medication Guide
  • Has been approved by the U. S. Food and Drug Administration.                                                                                                                                                                                                                                                                                      Revised:
  • August 2017

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