HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`GLYXAMBI safely and effectively. See full prescribing information for
`GLYXAMBI.
`
`GLYXAMBI® (empagliflozin and linagliptin) tablets, for oral use
`Initial U.S. Approval: 2015
`----------------------------RECENT MAJOR CHANGES--------------------------
`Warnings and Precautions
` 8/2015
`
`
` Severe and Disabling Arthralgia (5.9)
`----------------------------INDICATIONS AND USAGE---------------------------
`GLYXAMBI is a sodium-glucose co-transporter 2 (SGLT2) inhibitor and
`dipeptidyl peptidase-4 (DPP-4) inhibitor 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 empagliflozin and linagliptin is
`appropriate. (1)
`
`Limitations of use:
`Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis
`•
`(1.1)
`Has not been studied in patients with a history of pancreatitis (1.1)
`•
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`The recommended dose of GLYXAMBI is
`•
`10 mg empagliflozin/5 mg linagliptin once daily, taken in the morning,
`with or without food (2.1)
`Dose may be increased to 25 mg empagliflozin/5 mg linagliptin once
`daily (2.1)
`Assess renal function before initiating GLYXAMBI. Do not initiate
`GLYXAMBI if eGFR is below 45 mL/min/1.73 m2 (2.2)
`Discontinue GLYXAMBI if eGFR falls persistently below
`45 mL/min/1.73 m2 (2.2)
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`Tablets:
`10 mg empagliflozin/5 mg linagliptin
`25 mg empagliflozin/5 mg linagliptin (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`Severe renal impairment, end-stage renal disease, or dialysis (4)
`•
`History of hypersensitivity reaction to linagliptin, such as anaphylaxis,
`•
`angioedema, exfoliative skin conditions, urticaria, or bronchial
`hyperreactivity (4)
`History of serious hypersensitivity reaction to empagliflozin (4)
`•
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`Pancreatitis: There have been postmarketing reports of acute
`•
`pancreatitis, including fatal pancreatitis. If pancreatitis is suspected,
`promptly discontinue GLYXAMBI. (5.1)
`
`•
`
`•
`
`•
`
` 1
`
`
`
` INDICATIONS AND USAGE
`1.1 Limitations of Use
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Patients with Renal Impairment
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`5.2 Hypotension
`Impairment in Renal Function
`5.3
`5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin
`Secretagogues
`5.5 Genital Mycotic Infections
`5.6 Urinary Tract Infections
`5.7 Hypersensitivity Reactions
`Increased Low-Density Lipoprotein Cholesterol (LDL-C)
`5.8
`5.9 Severe and Disabling Arthralgia
`5.10 Macrovascular Outcomes
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`
`Revised: 8/2015
`
`
`
`
`_______________________________________________________________________________________________________________________________________
`7 DRUG INTERACTIONS
`FULL PRESCRIBING INFORMATION: CONTENTS*
`7.1 Drug Interactions with Empagliflozin
`7.2 Drug Interactions with Linagliptin
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`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
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`•
`
`•
`
`•
`
`•
`•
`•
`
`•
`•
`
`•
`•
`
`•
`
`•
`
`Hypotension: Before initiating GLYXAMBI assess and correct volume
`status in patients with renal impairment, the elderly, in patients
`with low systolic blood pressure, and in patients on diuretics. Monitor
`for signs and symptoms during therapy. (5.2)
`Impairment in Renal Function: Monitor renal function during therapy.
`More frequent monitoring is recommended in patients with eGFR below
`60 mL/min/1.73 m2. (5.3)
`Hypoglycemia: Consider lowering the dose of insulin secretagogue or
`insulin to reduce the risk of hypoglycemia when initiating GLYXAMBI.
`(5.4)
`Genital Mycotic Infections: Monitor and treat as appropriate (5.5)
`Urinary Tract Infections: Monitor and treat as appropriate (5.6)
`Hypersensitivity: There have been postmarketing reports of serious
`hypersensitivity reactions in patients treated with linagliptin (one of the
`components of GLYXAMBI) including anaphylaxis, angioedema, and
`exfoliative skin conditions. In such cases, promptly discontinue
`GLYXAMBI, assess for other potential causes, institute appropriate
`monitoring and treatment, and initiate alternative treatment for diabetes.
`(5.7)
`Increased LDL-C: Monitor and treat as appropriate (5.8)
`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. (5.9)
`• Macrovascular Outcomes: There have been no clinical studies
`establishing conclusive evidence of macrovascular risk reduction with
`GLYXAMBI or any other antidiabetic drug. (5.10)
`------------------------------ADVERSE REACTIONS-------------------------------
`The most common adverse reactions associated with GLYXAMBI (a
`•
`5% or greater incidence) were urinary tract infections, nasopharyngitis,
`and upper respiratory tract infections. (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.
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`Pregnancy: There are no adequate and well-controlled studies in
`•
`pregnant women. Use during pregnancy only if the potential benefit
`justifies the potential risk to the fetus. (8.1)
`Nursing Mothers: Discontinue GLYXAMBI or discontinue nursing (8.3)
`Pediatric Patients: Safety and effectiveness of GLYXAMBI in pediatric
`patients have not been established. (8.4)
`Geriatric Patients: Higher incidence of adverse reactions related to
`volume depletion and reduced renal function (5.2, 5.3, 8.5)
`Renal Impairment: Higher incidence of adverse reactions related to
`reduced renal function (2.2, 5.3, 8.6)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`Reference ID: 3812555
`
`1
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`GLYXAMBI tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with
`type 2 diabetes mellitus when treatment with both empagliflozin and linagliptin is appropriate [see Clinical
`Studies (14)].
`
`1.1 Limitations of Use
`GLYXAMBI is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
`
`GLYXAMBI has not been studied in patients with a history of pancreatitis. It is unknown whether patients with
`a history of pancreatitis are at an increased risk for the development of pancreatitis while using GLYXAMBI
`[see Warnings and Precautions (5.1)].
`
` 2
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosage
`The recommended dose of GLYXAMBI is 10 mg empagliflozin/5 mg linagliptin once daily in the morning,
`taken with or without food. In patients tolerating GLYXAMBI, the dose may be increased to 25 mg
`empagliflozin/5 mg linagliptin once daily.
`
`In patients with volume depletion, correcting this condition prior to initiation of GLYXAMBI is recommended
`[see Warnings and Precautions (5.2), Use in Specific Populations (8.5), and Patient Counseling Information
`(17)].
`
`No studies have been performed specifically examining the safety and efficacy of GLYXAMBI in patients
`previously treated with other oral antihyperglycemic agents and switched to GLYXAMBI. Any change in
`therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic
`control can occur.
`
`2.2 Patients with Renal Impairment
`Assessment of renal function is recommended prior to initiation of GLYXAMBI and periodically thereafter.
`
`GLYXAMBI should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2.
`
`No dose adjustment is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2.
`
`GLYXAMBI should be discontinued if eGFR is persistently less than 45 mL/min/1.73 m2 [see Warnings and
`Precautions (5.2, 5.3), and Use in Specific Populations (8.6)].
`
` 3
`
`DOSAGE FORMS AND STRENGTHS
`
`GLYXAMBI is a combination of empagliflozin and linagliptin. GLYXAMBI is available in the following
`dosage forms and strengths:
`
` •
`
`
`
`
`
` 10 mg empagliflozin/5 mg linagliptin tablets are pale yellow, arc triangular, flat-faced, bevel-edged film-
`coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is
`debossed with "10/5".
`
`2
`
`Reference ID: 3812555
`
`

`

`
`• 25 mg empagliflozin/5 mg linagliptin tablets are pale pink, arc triangular, flat-faced, bevel-edged film-
`coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is
`debossed with "25/5".
`
` 4
`
`CONTRAINDICATIONS
`
`GLYXAMBI is contraindicated in patients with:
`• Severe renal impairment, end-stage renal disease, or dialysis [see Use in Specific Populations (8.6)].
`• A history of hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin
`conditions, urticaria, or bronchial hyperreactivity [see Warnings and Precautions (5.7) and Adverse
`Reactions (6)].
`• History of serious hypersensitivity reaction to empagliflozin.
`
` 5
`
` WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking
`linagliptin. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected,
`promptly discontinue GLYXAMBI and initiate appropriate management. It is unknown whether patients with a
`history of pancreatitis are at increased risk for the development of pancreatitis while using GLYXAMBI.
`
`5.2 Hypotension
`Empagliflozin causes intravascular volume contraction. Symptomatic hypotension may occur after initiating
`empagliflozin [see Adverse Reactions (6.1)] particularly in patients with renal impairment, the elderly, in
`patients with low systolic blood pressure, and in patients on diuretics. Before initiating GLYXAMBI, assess for
`volume contraction and correct volume status if indicated. Monitor for signs and symptoms of hypotension
`after initiating therapy and increase monitoring in clinical situations where volume contraction is expected [see
`Use in Specific Populations (8.5)].
`
`5.3 Impairment in Renal Function
`Empagliflozin increases serum creatinine and decreases eGFR. The risk of impaired renal function with
`empagliflozin is increased in elderly patients and patients with moderate renal impairment. More frequent
`monitoring of renal function is recommended in these patients [see Use in Specific Populations (8.5, 8.6)].
`Renal function should be evaluated prior to initiating GLYXAMBI and periodically thereafter.
`
`5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
`Insulin and insulin secretagogues are known to cause hypoglycemia. The use of empagliflozin or linagliptin in
`combination with an insulin secretagogue (e.g., sulfonylurea) or insulin was associated with a higher rate of
`hypoglycemia compared with placebo in a clinical trial. Therefore, a lower dose of the insulin secretagogue or
`insulin may be required to reduce the risk of hypoglycemia when used in combination with GLYXAMBI.
`
`5.5 Genital Mycotic Infections
`Empagliflozin increases the risk for genital mycotic infections [see Adverse Reactions (6.1)]. Patients with a
`history of chronic or recurrent genital mycotic infections were more likely to develop mycotic genital
`infections. Monitor and treat as appropriate.
`
`5.6 Urinary Tract Infections
`Empagliflozin increases the risk for urinary tract infections [see Adverse Reactions (6.1)]. Monitor and treat as
`appropriate.
`
`
`
`3
`
`Reference ID: 3812555
`
`

`

`
`5.7 Hypersensitivity Reactions
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin
`(one of the components of GLYXAMBI). These reactions include anaphylaxis, angioedema, and exfoliative
`skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with
`linagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected,
`discontinue GLYXAMBI, 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 GLYXAMBI.
`
`5.8 Increased Low-Density Lipoprotein Cholesterol (LDL-C)
`Increases in LDL-C can occur with empagliflozin [see Adverse Reactions (6.1)]. Monitor and treat as
`appropriate.
`
`5.9 Severe and Disabling Arthralgia
`There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors.
`The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients
`experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a
`recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider as a possible
`cause for severe joint pain and discontinue drug if appropriate.
`
`5.10 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`GLYXAMBI or any other antidiabetic drug.
`
` 6
`
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
`reflect the rates observed in practice.
`
`Empagliflozin and Linagliptin
`The safety of concomitantly administered empagliflozin (daily dose 10 mg or 25 mg) and linagliptin (daily dose
`5 mg) has been evaluated in a total of 1363 patients with type 2 diabetes treated for up to 52 weeks in active-
`controlled clinical trials. The most common adverse reactions with concomitant administration of
`empagliflozin and linagliptin based on a pooled analyses of these studies are shown in Table 1.
`
`Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Empagliflozin and Linagliptin
`
`
`GLYXAMBI
`GLYXAMBI
`10 mg/5 mg
`25 mg/5 mg
`n=272
`n=273
`
`n (%)
`n (%)
`Urinary tract infectiona
`34 (12.5)
`31 (11.4)
`16 (5.9)
`18 (6.6)
`Nasopharyngitis
`19 (7.0)
`19 (7.0)
`Upper respiratory tract infection
`aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis
`
`
`
`
`Reference ID: 3812555
`
`4
`
`

`

`
`Empagliflozin
`Adverse reactions that occurred in ≥2% of patients receiving empagliflozin and more commonly than in patients
`given placebo included (10 mg, 25 mg, and placebo): urinary tract infection (9.3%, 7.6%, and 7.6%), female
`genital mycotic infections (5.4%, 6.4%, and 1.5%), upper respiratory tract infection (3.1%, 4.0%, and 3.8%),
`increased urination (3.4%, 3.2%, and 1.0%), dyslipidemia (3.9%, 2.9%, and 3.4%), arthralgia (2.4%, 2.3%, and
`2.2%), male genital mycotic infections (3.1%, 1.6%, and 0.4%), and nausea (2.3%, 1.1%, and 1.4%).
`
`Empagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse
`reactions related to volume depletion.
`
`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% and 6.1%), diarrhea (3.3% and 3.0%), and cough (2.1%
`and 1.4%).
`
`Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were
`hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and
`myalgia.
`
`In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while
`being treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with
`comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported
`following the last administered dose of linagliptin.
`
`Hypoglycemia
`Table 2 summarizes the reports of hypoglycemia with empagliflozin and linagliptin over a treatment period of
`52 weeks.
`
`Table 2 Incidence of Overalla and Severeb Hypoglycemic Adverse Reactions
`GLYXAMBI
`GLYXAMBI
`Add-on to Metformin
`25 mg/5 mg
`10 mg/5 mg
`(52 weeks)
`(n=137)
`(n=136)
`3.6%
`2.2%
`Overall (%)
`Severe (%)
`0%
`0%
`aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL or requiring assistance
`bSevere hypoglycemic events: requiring assistance regardless of blood glucose
`
`Laboratory Tests
`Empagliflozin and Linagliptin
`Changes in laboratory findings in patients treated with the combination of empagliflozin and linagliptin
`included increases in cholesterol and hematocrit compared to baseline.
`
`Empagliflozin
`Increase in Low-Density Lipoprotein Cholesterol (LDL-C): Dose-related increases in low-density lipoprotein
`cholesterol (LDL-C) were observed in patients treated with empagliflozin. LDL-C increased by 2.3%, 4.6%,
`and 6.5% in patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively [see
`Warnings and Precautions (5.8)]. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across
`treatment groups.
`
`
`
`
`
`
`Reference ID: 3812555
`
`5
`
`

`

`
`Increase in Hematocrit: Median hematocrit decreased by 1.3% in placebo and increased by 2.8% in
`empagliflozin 10 mg and 2.8% in empagliflozin 25 mg treated patients. At the end of treatment, 0.6%, 2.7%,
`and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of
`the reference range with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.
`
`Linagliptin
`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).
`
`6.2 Postmarketing Experience
`Additional adverse reactions have been identified during postapproval use of linagliptin. Because these
`reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably
`estimate their frequency or establish a causal relationship to drug exposure.
`• Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1.1) and Warnings and
`Precautions (5.1)]
`• Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions [see
`Warnings and Precautions (5.7)]
`• Severe and disabling arthralgia [see Warnings and Precautions (5.9)]
`• Rash
`
` 7
`
`DRUG INTERACTIONS
`
`7.1 Drug Interactions with Empagliflozin
`Diuretics
`Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids,
`which might enhance the potential for volume depletion [see Warnings and Precautions (5.2)].
`
`Insulin or Insulin Secretagogues
`Coadministration of empagliflozin with insulin or insulin secretagogues increases the risk for hypoglycemia
`[see Warnings and Precautions (5.4)].
`
`Positive Urine Glucose Test
`Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors
`as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use
`alternative methods to monitor glycemic control.
`
`Interference with 1,5-anhydroglucitol (1,5-AG) Assay
`Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable
`in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic
`control.
`
`7.2 Drug Interactions with Linagliptin
`Inducers of P-glycoprotein or CYP3A4 Enzymes
`Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when
`administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is
`strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer [see
`Clinical Pharmacology (12.3)].
`
`
`
`
`Reference ID: 3812555
`
`6
`
`

`

`
`USE IN SPECIFIC POPULATIONS
`8
`8.1 Pregnancy
`Pregnancy Category C
`GLYXAMBI
`There are no adequate and well-controlled studies in pregnant women with GLYXAMBI or its individual
`components. GLYXAMBI should be used during pregnancy only if the potential benefit justifies the potential
`risk to the fetus.
`
`Animal Data
`The combined components administered during the period of organogenesis were not teratogenic in rats up to
`and including a combined dose of 700 mg/kg/day empagliflozin and 140 mg/kg/day linagliptin, which is 253
`and 353 times the clinical exposure. Maternal effects were limited to dose-related reduced body weight gain
`and concomitant reduced food consumption in pregnant rats administered a combination of ≥300 mg/kg/day
`empagliflozin and 60 mg/kg/day linagliptin which is 99 and 227 times the clinical exposure. A pre- and post-
`natal development study was not conducted with the combined components of GLYXAMBI.
`
`Empagliflozin
`Based on results from animal studies, empagliflozin may affect renal development and maturation. In studies
`conducted in rats, empagliflozin crosses the placenta and reaches fetal tissues. During pregnancy, consider
`appropriate alternative therapies, especially during the second and third trimesters.
`
`In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day 6
`through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16 times the 25 mg maximum
`clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or
`equal to 30 mg/kg/day (approximately 4 times the 25 mg maximum clinical dose).
`
`Linagliptin
`No functional, behavioral, or reproductive toxicity was observed in offspring of female Wistar Han rats when
`administered linagliptin from gestation day 6 to lactation day 21 at a dose 49 times the maximum recommended
`human dose, based on exposure.
`
`Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.
`
`8.3 Nursing Mothers
`No studies in lactating animals have been conducted with the combined components of GLYXAMBI.
`
`Available animal data have shown excretion of empagliflozin and linagliptin in milk. It is not known whether
`empagliflozin and linagliptin are excreted in human milk. Empagliflozin is secreted in the milk of lactating rats
`reaching levels up to 5 times higher than that in maternal plasma. Since human kidney maturation occurs in
`utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the
`developing human kidney. Because many drugs are excreted in human milk and because of the potential for
`serious adverse reactions in nursing infants from empagliflozin, a decision should be made whether to
`discontinue nursing or to discontinue GLYXAMBI, taking into account the importance of the drug to the
`mother.
`
`8.4 Pediatric Use
`Safety and effectiveness of GLYXAMBI in pediatric patients under 18 years of age have not been established.
`
`
`
`
`Reference ID: 3812555
`
`7
`
`

`

`
`8.5 Geriatric Use
`GLYXAMBI
`Empagliflozin is associated with osmotic diuresis, which could affect hydration status of patients age 75 years
`and older.
`
`Empagliflozin
`No empagliflozin dosage change is recommended based on age [see Dosage and Administration (2)]. A total of
`2721 (32%) patients treated with empagliflozin were 65 years of age and older, and 491 (6%) were 75 years of
`age and older. Empagliflozin is expected to have diminished efficacy in elderly patients with renal impairment
`[see Use in Specific Populations (8.6)]. The risk of volume depletion-related adverse reactions increased in
`patients who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, empagliflozin 10 mg, and
`empagliflozin 25 mg. The risk of urinary tract infections increased in patients who were 75 years of age and
`older to 10.5%, 15.7%, and 15.1% in patients randomized to placebo, empagliflozin 10 mg, and empagliflozin
`25 mg, respectively [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
`
`Linagliptin
`There were 4040 type 2 diabetes patients treated with linagliptin 5 mg from 15 clinical trials of linagliptin; 1085
`(27%) were 65 years and over, while 131 (3%) were 75 years and over. Of these patients, 2566 were enrolled in
`12 double-blind placebo-controlled studies; 591 (23%) were 65 years and over, while 82 (3%) were 75 years
`and over. No overall differences in safety or effectiveness were observed between patients 65 years and over
`and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical
`studies of linagliptin have not identified differences in response between the elderly and younger patients,
`greater sensitivity of some older individuals cannot be ruled out.
`
`8.6 Renal Impairment
`Empagliflozin
`The efficacy and safety of empagliflozin have not been established in patients with severe renal impairment,
`with ESRD, or receiving dialysis. Empagliflozin is not expected to be effective in these patient populations
`[see Dosage and Administration (2.2), Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
`
`The glucose lowering benefit of empagliflozin 25 mg decreased in patients with worsening renal function. The
`risks of renal impairment [see Warnings and Precautions (5.3)], volume depletion adverse reactions and urinary
`tract infection-related adverse reactions increased with worsening renal function.
`
`8.7 Hepatic Impairment
`GLYXAMBI may be used in patients with hepatic impairment [see Clinical Pharmacology (12.3)].
`
`10 OVERDOSAGE
`In the event of an overdose with GLYXAMBI, contact the Poison Control Center. Employ the usual supportive
`measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and
`institute supportive treatment) as dictated by the patient’s clinical status. Removal of empagliflozin by
`hemodialysis has not been studied, and removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.
`
`11 DESCRIPTION
`GLYXAMBI tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes:
`empagliflozin and linagliptin.
`
`
`
`
`Reference ID: 3812555
`
`8
`
`

`

`
`Empagliflozin
`Empagliflozin is an orally-active inhibitor of the sodium-glucose co-transporter (SGLT2).
`
`The chemical name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-
`furanyl]oxy]phenyl]methyl]phenyl]-, (1S).
`
`The molecular formula is C23H27ClO7 and the molecular weight is 450.91. The structural formula is:
`O
`Cl
`
`
`OH
`
`OH
`
`O
`
`OH
`
`OH
`
`O
`
`
`
`
`Empagliflozin is a white to yellowish, non-hygroscopic powder. It is very slightly soluble in water, sparingly
`soluble in methanol, slightly soluble in ethanol and acetonitrile; soluble in 50% acetonitrile/water; and
`practically insoluble in toluene.
`
`Linagliptin
`Linagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.
`
`The chemical name of linagliptin is 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-
`dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-
`
`The molecular formula is C25H28N8O2 and the molecular weight is 472.54. The structural formula is:
`
`
`N
`
`N N
`
`N
`
`N
`
`O
`
`N
`
`O
`
`N
`
`NH2
`
`Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in
`water. Linagliptin is soluble in methanol, sparingly soluble in ethanol, very slightly soluble in isopropanol, and
`very slightly soluble in acetone.
`
`GLYXAMBI
`GLYXAMBI tablets for oral administration are available in two dosage strengths containing 10 mg or 25 mg
`empagliflozin in combination with 5 mg linagliptin. The inactive ingredients of GLYXAMBI are the following:
`Tablet Core: mannitol, pregelatinized starch, corn starch, copovidone, crospovidone, talc and magnesium
`stearate. Coating: hypromellose, mannitol, talc, titanium dioxide, polyethylene glycol and ferric oxide, yellow
`(10 mg/5 mg) or ferric oxide, red (25 mg/5 mg).
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`GLYXAMBI
`GLYXAMBI combines 2 antihyperglycemic agents with complementary mechanisms of action to improve
`glycemic control in patients with type 2 diabetes: empagliflozin, a sodium-glucose co-transporter (SGLT2)
`inhibitor, and linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor.
`
`
`
`Reference ID: 3812555
`
`9
`
`

`

`
`Empagliflozin
`Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of
`glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By
`inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold
`for glucose, and thereby increases urinary glucose excretion.
`
`Linagliptin
`Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1
`(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations
`of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the
`levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of
`glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise
`immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta
`cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon
`secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output.
`
`12.2 Pharmacodynamics
`Empagliflozin
`Urinary Glucose Excretion
`In patients with type 2 diabetes, urinary glucose excretion increased immediately following a dose of
`empagliflozin and was maintained at the end of a 4-week treatment period averaging at approximately 64 grams
`per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily.
`
`Urinary Volume
`In a 5-day study, mean 24-hour urine volume increase from baseline was 341 mL on Day 1 and 135 mL on Day
`5 of empagliflozin 25 mg once daily treatment.
`
`Cardiac Electrophysiology
`In a randomized, placebo-controlled, active-comparator, crossover study, 30 healthy subjects were administered
`a single oral dose of empagliflozin 25 mg, empagliflozin 200 mg (8 times the maximum recommended dose),
`moxifloxacin, and placebo. No increase in QTc was observed with either 25 mg or 200 mg empagliflozin.
`
`Linagliptin
`Linagliptin 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 Electrophysiology
`In 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 th