Get your patient on Glyxambi (Empagliflozin And Linagliptin)

GLYXAMBI is a combination of empagliflozin and linagliptin indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Empagliflozin is indicated to reduce the risk of cardiovascular (CV) death in adults with type 2 diabetes mellitus and established CV disease

[see

14.2 Empagliflozin Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease

EMPA-REG OUTCOME was a multicenter, multinational, randomized, double-blind parallel group trial that compared the risk of experiencing a major adverse cardiovascular event (MACE) between empagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes mellitus and atherosclerotic CV disease. Concomitant antidiabetic medications were kept stable for the first 12 weeks of the trial. Thereafter, antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.

A total of 7,020 patients were treated (empagliflozin 10 mg = 2,345; empagliflozin 25 mg = 2,342; placebo = 2,333) and followed for a median of 3.1 years. Approximately 72% of the trial population was White, 22% was Asian, and 5% was Black or African American. The mean age was 63 years and approximately 72% were male.

All patients in the trial had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c greater than or equal to 7%). The mean HbA1c at baseline was 8.1% and 57% of participants had diabetes mellitus for more than 10 years. Approximately 31%, 22% and 20% reported a past history of neuropathy, retinopathy and nephropathy to investigators, respectively and the mean eGFR was 74 mL/min/1.73 m². At baseline, patients were treated with one (~30%) or more (~70%) antidiabetic medications including metformin (74%), insulin (48%), sulfonylurea (43%) and dipeptidyl peptidase-4 inhibitor (11%).

All patients had established atherosclerotic CV disease at baseline including one (82%) or more (18%) of the following: a documented history of coronary artery disease (76%), stroke (23%) or peripheral artery disease (21%). At baseline, the mean systolic blood pressure was 136 mmHg, the mean diastolic blood pressure was 76 mmHg, the mean LDL was 86 mg/dL, the mean HDL was 44 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 175 mg/g. At baseline, approximately 81% of patients were treated with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 77% with statins, and 86% with antiplatelet agents (mostly aspirin).

The primary endpoint in EMPA-REG OUTCOME was the time to first occurrence of a Major Adverse Cardiac Event (MACE). A major adverse cardiac event was defined as occurrence of either a CV death or a non-fatal myocardial infarction (MI) or a non-fatal stroke. The statistical analysis plan had pre-specified that the 10 and 25 mg dosages would be combined. A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated. Type-1 error was controlled across multiples tests using a hierarchical testing strategy.

Empagliflozin significantly reduced the risk of first occurrence of primary composite endpoint of CV death, non-fatal myocardial infarction, or non-fatal stroke (HR: 0.86; 95% CI: 0.74, 0.99). The treatment effect was due to a significant reduction in the risk of CV death in subjects randomized to empagliflozin (HR: 0.62; 95% CI: 0.49, 0.77), with no change in the risk of non-fatal myocardial infarction or non-fatal stroke (see Table 7 and Figures 4 and 5). Results for the 10 mg and 25 mg empagliflozin dosages were consistent with results for the combined dosage groups.

Table 7 Treatment Effect for the Primary Composite Endpoint and its Components^a

	Placebo N=2,333	Empagliflozin N=4,687	Hazard ratio vs placebo (95% CI)
aTreated set (patients who had received at least one dose of trial drug)
bp-value for superiority (2-sided) 0.04
cTotal number of events
Composite of CV death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence)b	282 (12.1%)	490 (10.5%)	0.86 (0.74, 0.99)
Non-fatal myocardial infarctionc	121 (5.2%)	213 (4.5%)	0.87 (0.70, 1.09)
Non-fatal strokec	60 (2.6%)	150 (3.2%)	1.24 (0.92, 1.67)
CV deathc	137 (5.9%)	172 (3.7%)	0.62 (0.49, 0.77)

Figure 4 Estimated Cumulative Incidence of First MACE

Figure 5 Estimated Cumulative Incidence of CV Death

The efficacy of empagliflozin on CV death was generally consistent across major demographic and disease subgroups.

Vital status was obtained for 99.2% of subjects in the trial. A total of 463 deaths were recorded during the EMPA-REG OUTCOME trial. Most of these deaths were categorized as CV deaths. The non-CV deaths were only a small proportion of deaths and were balanced between the treatment groups (2.1% in patients treated with empagliflozin, and 2.4% of patients treated with placebo).

]

• Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating. (
  2.1 Testing Prior to Initiation of GLYXAMBI

  • Assess renal function before initiating GLYXAMBI and as clinically indicated
    [seeWarnings and Precautions (5.3)]
    .
  • Assess volume status. In patients with volume depletion, correct this condition before initiating GLYXAMBI
    [seeWarnings and Precautions (5.3)andUse in Specific Populations (8.5,8.6)]
    .
  )
• The recommended dosage of GLYXAMBI is 10 mg empagliflozin and 5 mg linagliptin once daily, taken in the morning, with or without food. (
  2.2 Recommended Dosage and Administration

  The recommended dosage of GLYXAMBI is 10 mg empagliflozin/5 mg linagliptin once daily in the morning, taken with or without food. GLYXAMBI may be increased to 25 mg empagliflozin/5 mg linagliptin once daily for additional glycemic control.
  )
• Dosage may be increased to 25 mg empagliflozin and 5 mg linagliptin once daily. (
  2.2 Recommended Dosage and Administration

  The recommended dosage of GLYXAMBI is 10 mg empagliflozin/5 mg linagliptin once daily in the morning, taken with or without food. GLYXAMBI may be increased to 25 mg empagliflozin/5 mg linagliptin once daily for additional glycemic control.
  )
• Withhold GLYXAMBI for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. (
  2.4 Temporary Interruption for Surgery

  Withhold GLYXAMBI for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume GLYXAMBI when the patient is clinically stable and has resumed oral intake

  [seeWarnings and Precautions (5.1)andClinical Pharmacology (12.2)].
  )

GLYXAMBI tablets available as:

• 10 mg empagliflozin/5 mg linagliptin are pale yellow, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is debossed with "10/5".
• 25 mg empagliflozin/5 mg linagliptin 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".

• Pregnancy:
  Advise females of the potential risk to a fetus especially during the second and third trimesters. (
  8.1 Pregnancy

  Risk Summary

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

  The limited available data with GLYXAMBI, linagliptin, or empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy

  (seeClinical Considerations).

  In animal studies, empagliflozin, a component of GLYXAMBI, resulted in adverse renal changes in rats when administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible. No adverse developmental effects were observed when the combination of linagliptin and empagliflozin was administered to pregnant rats

  (seeData).

  The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20% to 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 Considerations

  Disease-associated maternal and/or embryo/fetal risk

  Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

  Data

  Animal Data

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

  Empagliflozin:

  Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30, and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based on AUC. These findings were not observed after a 13-week, drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.

  In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48-times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154-times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times the 25 mg maximum clinical dose.

  In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day 6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16-times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4-times the 25 mg maximum clinical dose).

  Linagliptin:

  No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively. These doses represent approximately 943-times (rats) and 1,943-times (rabbits) the 5 mg maximum clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49-times the maximum recommended human dose, based on exposure.

  Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.
  )
• Lactation:
  Not recommended when breastfeeding. (
  8.2 Lactation

  Risk Summary

  There is limited information regarding the presence of GLYXAMBI, or its individual components in human milk, the effects on the breastfed infant, or the effects on milk production. Empagliflozin and linagliptin are present in rat milk

  (seeData)

  . Since human kidney maturation occurs

  in utero

  and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.

  Because of the potential for serious adverse reactions in a breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of GLYXAMBI is not recommended while breastfeeding

  .

  Data

  Empagliflozin was present at a low level in rat fetal tissues after a single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 to 5, and was greater than one from 2 to 24 hours post-dose. The mean maximal milk to plasma ratio of 5 occurred at 8 hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.
  )
• Pediatric Patients
  : Safety and effectiveness of GLYXAMBI in pediatric patients have not been established. (
  8.4 Pediatric Use

  Safety and effectiveness of GLYXAMBI have not been established in pediatric patients.
  )
• Geriatric Patients:
  Higher incidence of adverse reactions related to volume depletion and reduced renal function. (
  8.5 Geriatric Use

  GLYXAMBI

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

  [seeWarnings and Precautions (5.3)]

  .

  Empagliflozin

  In empagliflozin type 2 diabetes mellitus trials, 2,721 empagliflozin-treated patients were 65 years of age and older and 491 patients were 75 years of age and older. In these trials, volume depletion-related adverse reactions occurred in 2.1%, 2.3%, and 4.4% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively; and urinary tract infections occurred in 10.5%, 15.7%, and 15.1% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively.

  Linagliptin

  In linagliptin trials, 1,085 linagliptin-treated patients were 65 years of age and older and 131 patients were 75 years of age and older. In these linagliptin trials, no overall differences in safety or effectiveness of linagliptin were observed between geriatric patients and younger adult patients.
  )
• Renal Impairment:
  Higher incidence of adverse reactions related to reduced renal function. (
  8.6 Renal Impairment

  Empagliflozin

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

  [seeWarnings and Precautions (5.3)]

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

  Efficacy and safety trials with empagliflozin for glycemic control and the EMPA-REG OUTCOME trial did not enroll patients with ESRD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m².

  [seeIndications and Usage (1)]

  .
  )

GLYXAMBI is contraindicated in patients:

• with a hypersensitivity to empagliflozin, linagliptin, or any of the excipients in GLYXAMBI, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred
  [see

  5.7 Hypersensitivity Reactions

  There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly within the first 3 months after initiation of treatment with linagliptin, with some reports occurring after the first dose.

  Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with GLYXAMBI.

  There have been postmarketing reports of serious hypersensitivity reactions, (e.g., angioedema) in patients treated with empagliflozin.

  If a hypersensitivity reaction occurs, discontinue GLYXAMBI, treat promptly per standard of care, and monitor until signs and symptoms resolve. GLYXAMBI is contraindicated in patients with hypersensitivity to linagliptin, empagliflozin or any of the excipients in GLYXAMBI

  [seeContraindications (4)]

  .

  and

  6 ADVERSE REACTIONS

  The following important adverse reactions are described below and elsewhere in the labeling:

  • Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
    [seeWarnings and Precautions (5.1)]
  • Pancreatitis
    [seeWarnings and Precautions (5.2)]
  • Volume Depletion
    [seeWarnings and Precautions (5.3)]
  • Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections
    [seeWarnings and Precautions (5.4)]
  • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
    [seeWarnings and Precautions (5.5)]
  • Lower Limb Amputation
    [seeWarnings and Precautions (5.6)]
  • Hypersensitivity Reactions
    [seeWarnings and Precautions (5.7)]
  • Severe and Disabling Arthralgia
    [seeWarnings and Precautions (5.8)]
  • Bullous Pemphigoid
    [seeWarnings and Precautions (5.9)]
  • Heart Failure
    [seeWarnings and Precautions (5.10)]

  Most common adverse reactions (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 FDA at 1-800-FDA-1088 or

  www.fda.gov/medwatch

  .

  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 dosage 10 mg or 25 mg) and linagliptin (daily dosage 5 mg) has been evaluated in a total of 1,363 patients with type 2 diabetes mellitus 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 trials are shown in Table 1.

  Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Empagliflozin and Linagliptin

  Adverse Reactions	GLYXAMBI (%) 10 mg/5 mg n=272	GLYXAMBI (%) 25 mg/5 mg n=273
  aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis
  Urinary tract infectiona	12.5	11.4
  Nasopharyngitis	5.9	6.6
  Upper respiratory tract infection	7.0	7.0

  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%).

  Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.

  Empagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. Events related to volume depletion (hypotension and syncope) were reported in 3 patients (1.1%) treated with GLYXAMBI plus metformin.

  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 trials 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.

  Other Adverse Reactions

  Hypoglycemia

  Empagliflozin and Linagliptin

  Table 2 summarizes the reports of hypoglycemia with empagliflozin and linagliptin over a treatment period of 52 weeks.

  Table 2 Incidence of Overall^aand Severe^bHypoglycemic Adverse Reactions

  Add-on to Metformin (52 weeks)	GLYXAMBI (%) 10 mg/5 mg (n=136)	GLYXAMBI (%) 25 mg/5 mg (n=137)
  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
  Overall	2.2	3.6
  Severe	0	0

  Empagliflozin

  • Genital Mycotic Infections
    : In the pool of five placebo-controlled clinical trials, the incidence of genital mycotic infections (e.g., vaginal mycotic infection, vaginal infection, genital infection fungal, vulvovaginal candidiasis, and vulvitis) was increased in patients treated with empagliflozin compared to placebo, occurring in 0.9%, 4.1%, and 3.7% of patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Discontinuation from trial due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with either empagliflozin 10 mg or 25 mg.
    
    Genital mycotic infections occurred more frequently in female than male patients.
    
    Phimosis occurred more frequently in male patients treated with empagliflozin 10 mg (less than 0.1%) and empagliflozin 25 mg (0.1%) than placebo (0%).
  • Urinary Tract Infections

    :
    In the pool of five placebo-controlled clinical trials, the incidence of urinary tract infections (e.g., urinary tract infection, asymptomatic bacteriuria, and cystitis) was increased in patients treated with empagliflozin compared to placebo. Patients with a history of chronic or recurrent urinary tract infections were more likely to experience a urinary tract infection. The rate of treatment discontinuation due to urinary tract infections was 0.1%, 0.2%, and 0.1% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.
    
    Urinary tract infections occurred more frequently in female patients. The incidence of urinary tract infections in female patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg was 16.6%, 18.4%, and 17.0%, respectively. The incidence of urinary tract infections in male patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg was 3.2%, 3.6%, and 4.1%, respectively
    [seeUse in Specific Populations (8.5)]
    .
  • Lower Limb Amputations

    :
    Across four empagliflozin outcome trials, lower limb amputation event rates were 4.3 and 5.0 events per 1,000 patient-years in the placebo group and the empagliflozin 10 mg or 25 mg dose group, respectively, with a HR of 1.05 (95% CI) (0.81, 1.36). In a long-term cardio-renal outcome trial, in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and empagliflozin 10 mg treatment arms, respectively. GLYXAMBI is not indicated for the treatment of chronic kidney disease.

  Laboratory Test Abnormalities in Clinical Trials of Empagliflozin or Linagliptin

  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

  Increases in Serum Creatinine and Decreases in eGFR:

  Initiation of empagliflozin causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In a trial of patients with moderate renal impairment, larger mean changes were observed. In a long-term CV outcomes trial, the increase in serum creatinine and decrease in eGFR generally did not exceed 0.1 mg/dL and -9.0 mL/min/1.73 m², respectively, at Week 4, and reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with 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. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups.

  Increase in Hematocrit:

  Median hematocrit decreased by 1.3% in placebo and increased by 2.8% in empagliflozin 10 mg and 2.8% in empagliflozin 25 mg treated patients. At the end of treatment, 0.6%, 2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of the reference range with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.

  Linagliptin

  Increase 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.

  Increase in Amylase:

  In a CV safety trial comparing linagliptin versus glimepiride in patients with type 2 diabetes mellitus, amylase levels above 3 times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the linagliptin and glimepiride arms, respectively.

  The clinical significance of elevations in lipase and amylase with linagliptin is unknown in the absence of other signs and symptoms of pancreatitis

  [seeWarnings and Precautions (5.2)]

  .

  6.2 Postmarketing Experience

  Additional adverse reactions have been identified during postapproval use of linagliptin and empagliflozin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  Gastrointestinal Disorders:

  Acute pancreatitis, including fatal pancreatitis

  [seeIndications and Usage (1)]

  , constipation, mouth ulceration, stomatitis

  Immune System Disorders:

  Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions

  Infections:

  Necrotizing fasciitis of the perineum (Fournier's gangrene), urosepsis and pyelonephritis

  Metabolism and Nutrition Disorders:

  Ketoacidosis

  Musculoskeletal and Connective Tissue Disorders:

  Rhabdomyolysis, severe and disabling arthralgia

  Renal and Urinary Disorders:

  Acute kidney injury

  Skin and Subcutaneous Tissue Disorders:

  Bullous pemphigoid, skin reactions (e.g., rash, urticaria)

  ]
  .

• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis:
  Consider ketone monitoring in patients at risk of ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue GLYXAMBI if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. (
  5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

  In patients with type 1 diabetes mellitus, empagliflozin, a component of GLYXAMBI, significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose co-transporter 2 (SGLT2) inhibitors compared to patients who received placebo and fatal ketoacidosis has occurred with empagliflozin. GLYXAMBI is not indicated for glycemic control in patients with type 1 diabetes mellitus.

  Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including GLYXAMBI.

  Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.

  Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing GLYXAMBI

  [seeClinical Pharmacology (12.2)];

  however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

  Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue GLYXAMBI, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting GLYXAMBI.

  Withhold GLYXAMBI, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume GLYXAMBI when the patient is clinically stable and has resumed oral intake

  [seeDosage and Administration (2.4)].

  Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue GLYXAMBI and seek medical attention immediately if signs and symptoms occur.
  )
• Pancreatitis:
  There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue GLYXAMBI. (
  5.2 Pancreatitis

  Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial

  [seeClinical Studies (14.3)]

  , acute pancreatitis was reported in 9 (0.3%) patients treated with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients treated with linagliptin in the CARMELINA trial had acute pancreatitis with a fatal outcome. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with 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.
  )
• Volume Depletion:
  Before initiating GLYXAMBI, assess volume status and renal function in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy. (
  5.3 Volume Depletion

  Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine

  [seeAdverse Reactions (6.1)].

  There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating GLYXAMBI in patients with one or more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating GLYXAMBI. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.
  )
• Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections:
  Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated. Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis and if suspected, discontinue GLYXAMBI, and promptly institute appropriate medical and/or surgical intervention. (
  5.4 Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections

  Empagliflozin increases urinary glucose excretion

  [seeClinical Pharmacology (12.2)]

  and increases the risk of genitourinary infections including urinary tract infections and genital mycotic infections in both male and female patients

  [seeAdverse Reactions (6.1)].

  Serious genitourinary infections, including urosepsis, pyelonephritis, and necrotizing fasciitis of the perineum (Fournier's gangrene, a rare life-threatening infection requiring urgent surgical intervention), have occurred in patients with or without diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin

  [seeAdverse Reactions (6.2)].

  Cases have required hospitalization. In patients with Fournier's gangrene, serious outcomes have included multiple surgeries and death. GLYXAMBI is only indicated for use in patients with type 2 diabetes mellitus.

  Patients with a history of chronic or recurrent genitourinary infections are more likely to develop genitourinary infections when using GLYXAMBI. Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated.

  Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis. If suspected, discontinue GLYXAMBI and promptly institute appropriate medical and/or surgical intervention.
  )
• Hypoglycemia:
  Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating GLYXAMBI. (
  5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

  Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when GLYXAMBI is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Therefore, a lower dosage of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with GLYXAMBI.
  )
• Lower Limb Amputation:
  Monitor patients for infections or ulcers of lower limbs, and institute appropriate treatment. (
  5.6 Lower Limb Amputation

  In some clinical studies with SGLT2 inhibitors an imbalance in the incidence of lower limb amputation has been observed. Across four empagliflozin outcome trials, lower limb amputation event rates were 4.3 and 5.0 events per 1,000 patient-years in the placebo group and the empagliflozin 10 mg or 25 mg dose group, respectively, with a HR of 1.05 (95 % CI) (0.81, 1.36).

  In a long-term cardio-renal outcome trial, in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and empagliflozin 10 mg treatment arms, respectively. Amputation of the toe and mid-foot were most frequent (21 out of 28 empagliflozin 10 mg treated patients with lower limb amputations), and some involving above and below the knee. Some patients had multiple amputations. GLYXAMBI is not indicated for the treatment of chronic kidney disease.

  Peripheral artery disease, and diabetic foot infection (including osteomyelitis), were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of diabetic foot, peripheral artery disease (including previous amputation) or diabetes.

  Counsel patients about the importance of routine preventative foot care. Monitor patients receiving GLYXAMBI for signs and symptoms of diabetic foot infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and institute appropriate treatment.
  )
• Hypersensitivity Reactions:
  Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with empagliflozin and linagliptin. If hypersensitivity reactions occur, discontinue GLYXAMBI, treat promptly, and monitor until signs and symptoms resolve. (
  5.7 Hypersensitivity Reactions

  There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly within the first 3 months after initiation of treatment with linagliptin, with some reports occurring after the first dose.

  Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with GLYXAMBI.

  There have been postmarketing reports of serious hypersensitivity reactions, (e.g., angioedema) in patients treated with empagliflozin.

  If a hypersensitivity reaction occurs, discontinue GLYXAMBI, treat promptly per standard of care, and monitor until signs and symptoms resolve. GLYXAMBI is contraindicated in patients with hypersensitivity to linagliptin, empagliflozin or any of the excipients in GLYXAMBI

  [seeContraindications (4)]

  .
  )
• Arthralgia:
  Severe and disabling arthralgia has been reported in patients taking linagliptin. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. (
  5.8 Severe and Disabling Arthralgia

  There have been postmarketing reports of severe and disabling arthralgia in patients taking linagliptin. 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.
  )
• Bullous Pemphigoid:
  There have been reports of bullous pemphigoid requiring hospitalization. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue GLYXAMBI. (
  5.9 Bullous Pemphigoid

  Bullous pemphigoid was reported in 7 (0.2%) patients treated with linagliptin compared to none in patients treated with placebo in the CARMELINA trial

  [seeClinical Studies (14.3)]

  , and 3 of these patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving GLYXAMBI. If bullous pemphigoid is suspected, GLYXAMBI should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
  )
• Heart Failure:
  Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of GLYXAMBI in patients who have known risk factors for heart failure. Monitor for signs and symptoms. (
  5.10 Heart Failure

  An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.

  Consider the risks and benefits of GLYXAMBI prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of GLYXAMBI.
  )

The following important adverse reactions are described below and elsewhere in the labeling:

• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
  [see

  5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

  In patients with type 1 diabetes mellitus, empagliflozin, a component of GLYXAMBI, significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose co-transporter 2 (SGLT2) inhibitors compared to patients who received placebo and fatal ketoacidosis has occurred with empagliflozin. GLYXAMBI is not indicated for glycemic control in patients with type 1 diabetes mellitus.

  Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including GLYXAMBI.

  Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.

  Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing GLYXAMBI

  [seeClinical Pharmacology (12.2)];

  however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

  Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue GLYXAMBI, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting GLYXAMBI.

  Withhold GLYXAMBI, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume GLYXAMBI when the patient is clinically stable and has resumed oral intake

  [seeDosage and Administration (2.4)].

  Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue GLYXAMBI and seek medical attention immediately if signs and symptoms occur.

  ]
• Pancreatitis
  [see

  5.2 Pancreatitis

  Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial

  [seeClinical Studies (14.3)]

  , acute pancreatitis was reported in 9 (0.3%) patients treated with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients treated with linagliptin in the CARMELINA trial had acute pancreatitis with a fatal outcome. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with 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.

  ]
• Volume Depletion
  [see

  5.3 Volume Depletion

  Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine

  [seeAdverse Reactions (6.1)].

  There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating GLYXAMBI in patients with one or more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating GLYXAMBI. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

  ]
• Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections
  [see

  5.4 Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections

  Empagliflozin increases urinary glucose excretion

  [seeClinical Pharmacology (12.2)]

  and increases the risk of genitourinary infections including urinary tract infections and genital mycotic infections in both male and female patients

  [seeAdverse Reactions (6.1)].

  Serious genitourinary infections, including urosepsis, pyelonephritis, and necrotizing fasciitis of the perineum (Fournier's gangrene, a rare life-threatening infection requiring urgent surgical intervention), have occurred in patients with or without diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin

  [seeAdverse Reactions (6.2)].

  Cases have required hospitalization. In patients with Fournier's gangrene, serious outcomes have included multiple surgeries and death. GLYXAMBI is only indicated for use in patients with type 2 diabetes mellitus.

  Patients with a history of chronic or recurrent genitourinary infections are more likely to develop genitourinary infections when using GLYXAMBI. Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated.

  Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis. If suspected, discontinue GLYXAMBI and promptly institute appropriate medical and/or surgical intervention.

  ]
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
  [see

  5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

  Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when GLYXAMBI is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Therefore, a lower dosage of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with GLYXAMBI.

  ]
• Lower Limb Amputation
  [see

  5.6 Lower Limb Amputation

  In some clinical studies with SGLT2 inhibitors an imbalance in the incidence of lower limb amputation has been observed. Across four empagliflozin outcome trials, lower limb amputation event rates were 4.3 and 5.0 events per 1,000 patient-years in the placebo group and the empagliflozin 10 mg or 25 mg dose group, respectively, with a HR of 1.05 (95 % CI) (0.81, 1.36).

  In a long-term cardio-renal outcome trial, in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and empagliflozin 10 mg treatment arms, respectively. Amputation of the toe and mid-foot were most frequent (21 out of 28 empagliflozin 10 mg treated patients with lower limb amputations), and some involving above and below the knee. Some patients had multiple amputations. GLYXAMBI is not indicated for the treatment of chronic kidney disease.

  Peripheral artery disease, and diabetic foot infection (including osteomyelitis), were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of diabetic foot, peripheral artery disease (including previous amputation) or diabetes.

  Counsel patients about the importance of routine preventative foot care. Monitor patients receiving GLYXAMBI for signs and symptoms of diabetic foot infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and institute appropriate treatment.

  ]
• Hypersensitivity Reactions
  [see

  5.7 Hypersensitivity Reactions

  There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly within the first 3 months after initiation of treatment with linagliptin, with some reports occurring after the first dose.

  Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with GLYXAMBI.

  There have been postmarketing reports of serious hypersensitivity reactions, (e.g., angioedema) in patients treated with empagliflozin.

  If a hypersensitivity reaction occurs, discontinue GLYXAMBI, treat promptly per standard of care, and monitor until signs and symptoms resolve. GLYXAMBI is contraindicated in patients with hypersensitivity to linagliptin, empagliflozin or any of the excipients in GLYXAMBI

  [seeContraindications (4)]

  .

  ]
• Severe and Disabling Arthralgia
  [see

  5.8 Severe and Disabling Arthralgia

  There have been postmarketing reports of severe and disabling arthralgia in patients taking linagliptin. 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.

  ]
• Bullous Pemphigoid
  [see

  5.9 Bullous Pemphigoid

  Bullous pemphigoid was reported in 7 (0.2%) patients treated with linagliptin compared to none in patients treated with placebo in the CARMELINA trial

  [seeClinical Studies (14.3)]

  , and 3 of these patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving GLYXAMBI. If bullous pemphigoid is suspected, GLYXAMBI should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

  ]
• Heart Failure
  [see

  5.10 Heart Failure

  An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.

  Consider the risks and benefits of GLYXAMBI prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of GLYXAMBI.

  ]

Table 3 describes clinically relevant interactions with GLYXAMBI.

GLYXAMBI tablets for oral use contain: empagliflozin and linagliptin.

GLYXAMBI contains: empagliflozin, a SGLT2 inhibitor, and linagliptin, a DPP-4 inhibitor.

No carcinogenicity, mutagenicity, or impairment of fertility studies have been conducted with the combination of empagliflozin and linagliptin.

A total of 686 patients with type 2 diabetes mellitus participated in a double-blind, active-controlled trial to evaluate the efficacy of empagliflozin 10 mg or 25 mg in combination with linagliptin 5 mg compared to the individual components.

Patients with type 2 diabetes mellitus inadequately controlled on at least 1,500 mg of metformin per day entered a single-blind placebo run-in period for 2 weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10.5% were randomized 1:1:1:1:1 to one of 5 active-treatment arms of empagliflozin 10 mg or 25 mg, linagliptin 5 mg, or linagliptin 5 mg in combination with 10 mg or 25 mg empagliflozin as a fixed dosage combination tablet.

At Week 24, empagliflozin 10 mg or 25 mg used in combination with linagliptin 5 mg provided statistically significant improvement in HbA1c (p-value <0.0001) and FPG (p-value <0.001) compared to the individual components in patients who had been inadequately controlled on metformin (see

GLYXAMBI tablets are available as follows:

Bottles of 30 (NDC 0597-0182-30)

Bottles of 90 (NDC 0597-0182-90)

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

Bottles of 30 (NDC 0597-0164-30)

Bottles of 90 (NDC 0597-0164-90)

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

If repackaging is required, dispense in a tight container as defined in USP.

GLYXAMBI contains: empagliflozin, a SGLT2 inhibitor, and linagliptin, a DPP-4 inhibitor.