`
`
` These highlights do not include all the information needed to use
` JENTADUETO XR safely and effectively. See full prescribing
`
`
`
`
`
` information for JENTADUETO XR.
`
`
`
`
`
`
` JENTADUETO® XR (linagliptin and metformin hydrochloride
`
`
` extended-release) tablets, for oral use
`
` Initial U.S. Approval: 2012
`
`
`
`
`
`
`
`
`
`WARNING: RISK OF LACTIC ACIDOSIS
`
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`Postmarketing cases of metformin-associated lactic acidosis have
`
`•
`
`resulted in death, hypothermia, hypotension, and resistant
`
`
`
`bradyarrhythmias. Symptoms included malaise, myalgias,
`
`respiratory distress, somnolence, and abdominal pain.
`
`
`
`Laboratory abnormalities included elevated blood lactate levels,
`
`
`anion gap acidosis, increased lactate/pyruvate ratio; and
`
`
`
`metformin plasma levels generally >5 mcg/mL. (5.1)
`
` Risk factors include renal impairment, concomitant use of certain
` drugs, age > 65 years old, radiological studies with contrast,
`
`
`
`
`
`surgery and other procedures, hypoxic states, 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. (5.1)
`
`
`If lactic acidosis is suspected, discontinue JENTADUETO XR
`
`
`
`
`
`and institute general supportive measures in a hospital setting.
`
`
`Prompt hemodialysis is recommended. (5.1)
`
`
`
`
`
`•
`
`
`•
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------
`JENTADUETO XR is a dipeptidyl peptidase-4 (DPP-4) inhibitor and
`
`
`
`
`
`biguanide combination product 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 (1.1)
`
`
`
`
`
`Important limitations of use:
`
`
`Not for treatment of type 1 diabetes or diabetic ketoacidosis (1.2)
`
`
`
`
`
`
`•
`Has not been studied in patients with a history of pancreatitis (1.2)
`
`
`
`
`•
`----------------------DOSAGE AND ADMINISTRATION----------------------
`Individualize the starting dose of JENTADUETO XR based on the
`
`
`
`
`
`
`•
`patient's current regimen (2.1)
`
`Do not exceed a total daily dose of linagliptin 5 mg and metformin 2000
`
`
`
`
`
`
`
`mg (2.1)
`
`
`Give once daily with a meal (2.1)
`
`
`
`
`Swallow whole; do not split, crush, dissolve, or chew (2.1)
`
`
`
`Prior to initiation, assess renal function with estimated glomerular
`
`
`filtration rate (eGFR) (2.2)
`
`o Do not use in patients with eGFR below 30 mL/min/1.73 m2
`
`
`
`
`o Initiation is not recommended in patients with eGFR between
`
`
`
`
`
`30 - 45 mL/min/1.73 m2
`
`
`o Assess risk/benefit of continuing if eGFR falls below
`
`
`
`
`45 mL/min/1.73 m2
`
`
`o Discontinue if eGFR falls below 30 mL/min/1.73 m2
`
`
`
`JENTADUETO XR may need to be discontinued at time of, or prior to,
`
`
`
`
`
`iodinated contrast imaging procedures (2.3)
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`Tablets:
`
`
`5 mg linagliptin/1000 mg metformin hydrochloride extended-release
`
`
`
`
`
`
`2.5 mg linagliptin/1000 mg metformin hydrochloride extended-release (3)
`
`
`
`
`
`•
`
`
`•
`
`•
`
`•
`
`
`•
`
`-------------------------------CONTRAINDICATIONS-----------------------------
`Severe renal impairment (eGFR below 30 mL/min/1.73 m2) (4)
`
`
`
`
`•
`• Metabolic acidosis, including diabetic ketoacidosis (4)
`
`
`
`History of hypersensitivity reaction to linagliptin, such as anaphylaxis,
`
`
`
`•
`angioedema, exfoliative skin conditions, urticaria, or bronchial
`
`
`
`hyperreactivity (4)
`
`Hypersensitivity to metformin (4)
`
`
`
`•
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------
`Lactic acidosis: See boxed warning (5.1)
`
`
`
`•
`There have been postmarketing reports of acute pancreatitis, including
`
`•
`fatal pancreatitis. If pancreatitis is suspected, promptly discontinue
`
`
`
`JENTADUETO XR. (5.2)
`
`
`Hypoglycemia: When used with an insulin secretagogue (e.g.,
`
`
`
`
`sulfonylurea (SU)) or insulin, consider lowering the dose of the insulin
`
`
`
`
`secretagogue or insulin to reduce the risk of hypoglycemia (5.3)
`
`
`
`Hypersensitivity reactions: There have been postmarketing reports of
`
`
`serious hypersensitivity reactions in patients treated with linagliptin (one
`
`
`
`of the components of JENTADUETO XR) including anaphylaxis,
`
`
`
`angioedema, and exfoliative skin conditions. In such cases, promptly
`
`
`discontinue JENTADUETO XR, assess for other potential causes,
`
`
`institute appropriate monitoring and treatment, and initiate alternative
`
`
`
`treatment for diabetes. (5.4)
`
`Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
`
`
`
`
`
`Monitor hematologic parameters annually. (5.5)
`
`
`
`Arthralgia: Severe and disabling arthralgia has been reported in patients
`
`
`
`
`
`taking DPP-4 inhibitors. Consider as a possible cause for severe joint
`
`
`
`pain and discontinue drug if appropriate. (5.6)
`
`
`
`• Macrovascular outcomes: No conclusive evidence of macrovascular
`
`
`
`risk reduction with JENTADUETO XR or any other antidiabetic drug
`
`
`
`
`
`(5.7)
`
`------------------------------ADVERSE REACTIONS------------------------------
`Adverse reactions reported in ≥5% of patients treated with linagliptin
`
`
`
`
`
`•
`and metformin coadministered and more commonly than in patients
`
`
`
`treated with placebo are nasopharyngitis and diarrhea (6.1)
`
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Boehringer
`
`Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or 1-800-459-9906
`
`
`TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`------------------------------DRUG INTERACTIONS------------------------------
`Carbonic anhydrase inhibitors may increase risk of lactic acidosis.
`
`
`•
`Consider more frequent monitoring. (7.1)
`
`
`Drugs that are eliminated by renal tubular secretion (e.g., cationic drugs
`
`
`
`
`such as cimetidine), may increase the accumulation of metformin.
`
`
`
`Consider more frequent monitoring. (7.1)
`
`
`Alcohol can potentiate the effect of metformin on lactate metabolism.
`
`
`Warn patients against excessive alcohol intake. (7.1)
`
`
`Strong P-glycoprotein/CYP3A4 inducer: Efficacy may be reduced when
`
`
`
`administered in combination (e.g., rifampin). Use of alternative
`
`
`
`treatments is strongly recommended. (7.2)
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`Females and Males of Reproductive Potential: Advise premenopausal
`
`
`
`
`
`•
`females of the potential for an unintended pregnancy (8.3).
`
`
`Geriatric Use: Assess renal function more frequently. (8.5)
`
`
`
`
`Hepatic Impairment: Avoid use in patients with hepatic impairment.
`
`
`
`(8.7)
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`Guide.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 5/2016
`
`
`
`
`
`Reference ID: 3938100
`
`
`
` 1
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`8.2 Lactation
`
`
`
`
`8.3 Females and Males of Reproductive Potential
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Renal Impairment
`
`
`
`8.7 Hepatic Impairment
`
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`14 CLINICAL STUDIES
`
`
`
`
`
`14.1 Initial Combination Therapy with Linagliptin and Metformin
`
`
`
`
`
`14.2 Initial Combination Therapy with Linagliptin and Metformin vs
`
`
`
`
`Linagliptin in Treatment-Naïve Patients
`
`
`
`14.3 Add-On Combination Therapy with Metformin
`
`
`
`14.4 Active-Controlled Study vs Glimepiride in Combination with
`
`
`
`Metformin
`
`
`
`
`14.5 Add-On Combination Therapy with Metformin and a
`
`
`
`Sulfonylurea
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: RISK OF LACTIC ACIDOSIS
`
`1
`INDICATIONS AND USAGE
`
`
`
`1.1
`Indication
`
`
`
`1.2
`Important Limitations of Use
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosing
`
`
`
`2.2 Recommended Dosing in Renal Impairment
`
`
`
`
`
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Lactic Acidosis
`
`
`
`5.2 Pancreatitis
`
`
`
`5.3 Use with Medications Known to Cause Hypoglycemia
`
`
`
`
`
`
`5.4 Hypersensitivity Reactions
`
`
`
`5.5 Vitamin B12 Levels
`
`
`
`
`
`
`5.6 Severe and Disabling Arthralgia
`
`
`
`5.7 Macrovascular Outcomes
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Drug Interactions with Metformin
`
`
`
`
`7.2 Drug Interactions with Linagliptin
`
`
`
`
`7.3
`Insulin Secretagogues or Insulin
`
`
`
`7.4 Drugs Affecting Glycemic Control
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`
`
`
`
`Reference ID: 3938100
`
`
`
` 2
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`WARNING: RISK OF 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., cationic drugs 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)].
`
`
`
`
`
`
`INDICATIONS AND USAGE
`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)].
`
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`2.1 Recommended Dosing
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`2.2 Recommended Dosing in Renal Impairment
`
`
`
`
`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)].
`
`
`
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`3
`
`
`
`
`Reference ID: 3938100
`
`
`
` 3
`
`
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 (5.4) and Adverse Reactions (6.1)]
`
`Hypersensitivity to metformin
`
`
`•
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`5.1 Lactic Acidosis
`
`Metformin
`
`
`
`
`
`
`
`
`
`
`
`There 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
`
`
`
`
`
`
`
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`metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the
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`kidney [see Clinical Pharmacology (12.3)].
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`• 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. Initiation of JENTADUETO XR is not recommended in
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`•
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`patients with eGFR between 30 – 45 mL/min/1.73 m2 .
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`• 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.,
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`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 [see Dosage
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`•
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`and Administration (2.2), Contraindications (4) and Clinical Pharmacology (12.3)].
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`Drug Interactions: The concomitant use of JENTADUETO XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal
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`function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs) [see Drug Interactions
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`(7.1)]. Therefore, consider more frequent monitoring of patients.
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`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,
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`renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].
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`Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function
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`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
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`contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart JENTADUETO XR if renal function is stable.
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`Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal
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`impairment. JENTADUETO XR should be temporarily discontinued while patients have restricted food and fluid intake.
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`Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when
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`accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia
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`have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue JENTADUETO XR.
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`Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis.
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`Warn patients against excessive alcohol intake while receiving JENTADUETO XR.
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`Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance
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`resulting in higher lactate blood levels. Therefore, avoid use of JENTADUETO XR in patients with clinical or laboratory evidence of hepatic disease.
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`Reference ID: 3938100
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` 4
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` 5.2 Pancreatitis
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` There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin. Take careful notice of potential signs and
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` 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.
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` 5.3 Use with Medications Known to Cause Hypoglycemia
` Linagliptin
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` Insulin secretagogues and insulin are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was
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` 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
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` secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO XR [see Drug Interactions (7.3)].
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`Metformin
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`Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous
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`exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly,
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`debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.
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`Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs.
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`5.4 Hypersensitivity Reactions
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`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of JENTADUETO XR). These
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`reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with
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`linagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue JENTADUETO XR, assess for other potential
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`causes for the event, and institute alternative treatment for diabetes.
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`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
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`inhibitor because it is unknown whether such patients will be predisposed to angioedema with JENTADUETO XR.
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`5.5 Vitamin B12 Levels
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`In controlled, 29-week clinical trials of metformin a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was
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`observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is,
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`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
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`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
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`basis is advised in patients on JENTADUETO XR and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with
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`inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin
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`B12 measurement at 2- to 3-year intervals may be useful.
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`5.6 Severe and Disabling Arthralgia
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`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
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`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
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`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
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`appropriate.
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`5.7 Macrovascular Outcomes
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`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or metformin or any other antidiabetic drug.
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`ADVERSE REACTIONS
`6
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`6.1 Clinical Trials Experience
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`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
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`in the clinical trials of another drug and may not reflect the rates observed in practice.
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`Linagliptin/Metformin
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`The safety of concomitantly administered linagliptin (daily dose 5 mg) and metformin (mean daily dose of approximately 1800 mg) has been evaluated in 2816 patients
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`with type 2 diabetes mellitus treated for ≥12 weeks in clinical trials.
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`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
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`placebo-controlled clinical studies, adverse reactions which occurred in ≥5% of patients receiving linagliptin + metformin (n=875) and were more common than in
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`patients given placebo + metformin (n=539) included nasopharyngitis (5.7% vs 4.3%).
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`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
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`placebo are shown in Table 1.
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`Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Linagliptin + Metformin and
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`Greater than with Placebo in a 24-week Factorial-Design Study
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` Placebo
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` n=72
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` Nasopharyngitis
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` Diarrhea
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` n (%)
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` 1 (1.4)
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` 2 (2.8)
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`Reference ID: 3938100
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`Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial
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`hyperreactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.
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` Linagliptin
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` Monotherapy
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` n=142
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` n (%)
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` 8 (5.6)
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` 5 (3.5)
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` Metformin
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` Monotherapy
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` n=291
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` n (%)
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` 8 (2.7)
` 11 (3.8)
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` Combination of
` Linagliptin with Metformin
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` n=286
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` n (%)
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` 18 (6.3)
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` 18 (6.3)
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` 5
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` Linagliptin
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` 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%
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` vs 6.1%), diarrhea (3.3% vs 3.0%), and cough (2.1% vs 1.4%).
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`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
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`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
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`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
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`therapy.
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`Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin
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`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
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`treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea).
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`Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.
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`Metformin
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`The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and
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`headache.
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`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
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`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%).
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`Hypoglycemia
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`Linagliptin/Metformin
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`In 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
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`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
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`792 patients reported hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and sulfonylurea. Adverse
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`react