Important Safety Information

IMPORTANT SAFETY INFORMATION FOR GLYXAMBI, JARDIANCE, AND TRADJENTA

CONTRAINDICATIONS

GLYXAMBI and JARDIANCE are contraindicated in patients with severe renal impairment, end‐stage renal disease, or dialysis or a history of serious hypersensitivity reaction to empagliflozin.

GLYXAMBI and TRADJENTA are contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity.

GLYXAMBI (empagliflozin/linagliptin) contains the active
ingredients of JARDIANCE (empagliflozin) and TRADJENTA (linagliptin).

INDICATIONS AND LIMITATIONS OF USE FOR GLYXAMBI, JARDIANCE AND TRADJENTA

GLYXAMBI is 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.

Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease. However, the effectiveness of GLYXAMBI on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established.

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, and it is unknown if using GLYXAMBI increases the risk of developing pancreatitis in these patients.

JARDIANCE and TRADJENTA are each indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

JARDIANCE and TRADJENTA are not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. TRADJENTA has not been studied in patients with a history of pancreatitis, and it is unknown if using TRADJENTA increases the risk of developing pancreatitis in these patients.

WARNINGS AND PRECAUTIONS

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 or TRADJENTA 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 or TRADJENTA.

Hypotension

Empagliflozin causes intravascular volume contraction, and symptomatic hypotension may occur. Before initiating GLYXAMBI or JARDIANCE, assess and correct volume status in the elderly, in patients with renal impairment, low systolic blood pressure, or on diuretics. Monitor for hypotension.

Ketoacidosis

Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have been identified in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co transporter 2 (SGLT2) inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been reported in patients taking empagliflozin. Patients who present with signs and symptoms of metabolic acidosis should be assessed for ketoacidosis, even if blood glucose levels are <250 mg/dL. If suspected, discontinue GLYXAMBI or JARDIANCE, evaluate and treat promptly.

Before initiating GLYXAMBI or JARDIANCE, consider risk factors for ketoacidosis. Patients on GLYXAMBI or JARDIANCE may require monitoring and temporary discontinuation of therapy in situations known to predispose to ketoacidosis.

Acute Kidney Injury and Impairment in Renal Function

Empagliflozin causes intravascular volume contraction and can cause renal impairment. Acute kidney injury requiring hospitalization and dialysis have been identified in patients taking SGLT2 inhibitors, including empagliflozin; some reports involved patients younger than 65 years of age.

Before initiating GLYXAMBI or JARDIANCE, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporary discontinuation in settings of reduced oral intake or fluid losses. Monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue GLYXAMBI or JARDIANCE promptly and institute treatment.

Empagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function should be evaluated prior to initiating GLYXAMBI or JARDIANCE and periodically thereafter. More frequent monitoring is recommended in patients with eGFR <60 mL/min/1.73 m2. GLYXAMBI or JARDIANCE should be discontinued in patients with a persistent eGFR <45 mL/min/1.73 m2.

Urosepsis and Pyelonephritis

Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been identified in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate for signs and symptoms of urinary tract infections and treat promptly.

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 these agents was associated with a higher rate of hypoglycemia compared to placebo in clinical trials. TRADJENTA in combination with insulin in subjects with severe renal impairment was associated with a higher rate of hypoglycemia. A lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with GLYXAMBI, JARDIANCE, or TRADJENTA.

Genital Mycotic Infections

Empagliflozin increases the risk for genital mycotic infections, especially in patients with prior infections. Monitor and treat as appropriate.

Hypersensitivity Reactions

There have been reports of serious hypersensitivity reactions in patients treated with linagliptin. 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 or TRADJENTA, 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 linagliptin.

Increased Low-Density Lipoprotein Cholesterol (LDL-C)

Monitor and treat as appropriate.

Severe and Disabling Arthralgia

Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors, such as linagliptin. Consider as a possible cause for severe joint pain and discontinue drug if appropriate.

Bullous Pemphigoid

There have been reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue GLYXAMBI or TRADJENTA.

Macrovascular Outcomes

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

ADVERSE REACTIONS

Glyxambi

The most common adverse reactions (≥5%) associated with GLYXAMBI were urinary tract infections, nasopharyngitis, and upper respiratory tract infections.

jardiance

The most common adverse reactions (≥5%) associated with JARDIANCE were urinary tract infections and female genital mycotic infections.

Tradjenta

  • Adverse reactions reported in ≥5% of patients treated with TRADJENTA 5 mg and more commonly than in patients treated with placebo included nasopharyngitis.
  • Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. When TRADJENTA was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. In patients receiving TRADJENTA as add‐on therapy to a stable dose of insulin severe hypoglycemic events were reported in 11 (1.7%) patients compared with 7 (1.1%) for placebo. In a study of TRADJENTA as add-on to pre-existing antidiabetic therapy in patients with severe renal impairment, the incidence of hypoglycemia was higher in patients treated with TRADJENTA (63%) vs placebo (49%).
  • In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient‐years of exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient‐years of exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of TRADJENTA.

DRUG INTERACTIONS

Coadministration of empagliflozin with diuretics may enhance the potential for volume depletion.

The efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments to GLYXAMBI or TRADJENTA is strongly recommended.

USE IN SPECIAL POPULATIONS

Pregnancy

GLYXAMBI and JARDIANCE are not recommended during the second and third trimesters of pregnancy based on animal data showing adverse renal effects.

TRADJENTA should be used during pregnancy only if clearly needed.

Lactation

GLYXAMBI, JARDIANCE, and TRADJENTA are not recommended while breastfeeding because of the potential for serious adverse reactions in breastfed infants.

Geriatric Use

Empagliflozin is expected to have diminished efficacy in elderly patients with renal impairment. Urinary tract infections and volume depletion‐related adverse reactions increased in patients ≥75 years treated with GLYXAMBI or JARDIANCE.

GLX(JARTJ) PROF 1.11.17

References: 1. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT.2013. 2. DeFronzo RA, Lewin A, Patel S, et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015.38(3):384-393 3. DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795.