Glyxambi

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

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

  Most common adverse reactions (5% or greater incidence) were urinary tract infections, nasopharyngitis, and upper respiratory tract infections

  
  
  

  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
    [see Use 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

  [see Warnings 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

  [see Indications 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)

  ]
  .