Trijardy Xr

Limitations of Use

TRIJARDY XR is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.2)].

TRIJARDY XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using TRIJARDY XR [see Warnings and Precautions (5.3)].

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from exposure to high humidity.

In the event of an overdose with TRIJARDY XR, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Removal of empagliflozin by hemodialysis has not been studied, and removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.

TRIJARDY XR tablets for oral use contain: empagliflozin, linagliptin, and metformin HCl.

In metformin HCl clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂ levels was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. Measure hematologic parameters on an annual basis and vitamin B₁₂ at 2 to 3 year intervals in patients on TRIJARDY XR and manage any abnormalities [see Adverse Reactions (6.1)].

Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial [see Clinical 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 TRIJARDY XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using TRIJARDY XR.

Safety and effectiveness of TRIJARDY XR have not been established in pediatric patients.

Assess renal function more frequently in TRIJARDY XR-treated geriatric patients because there is a greater risk of empagliflozin-associated intravascular volume contraction and symptomatic hypotension in geriatric patients and there is a greater risk of metformin-associated lactic acidosis in geriatric patients [see Warnings and Precautions (5.1, 5.4)].

The recommended dosage for the metformin HCl component of TRIJARDY XR in geriatric patients should usually start at the lower end of the dosage range.

Of the 273 patients treated with the combination of empagliflozin, linagliptin, and metformin HCl to improve glycemic control in adults with type 2 diabetes mellitus, 58 were 65 years of age and older, while 8 were 75 years of age and older. Clinical trials of TRIJARDY XR did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger adult patients.

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 TRIJARDY XR 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 TRIJARDY XR.

TRIJARDY XR is contraindicated in patients with:

• severe renal impairment (eGFR less than 30 mL/min/1.73 m²) [see Warnings and Precautions (5.1, 5.4) and Use in Specific Populations (8.6)].
• acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1)].
• hypersensitivity to empagliflozin, linagliptin, metformin HCl or any of the excipients in TRIJARDY XR, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred [see Warnings and Precautions (5.8) and Adverse Reactions (6)].

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels, which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of TRIJARDY XR. In TRIJARDY XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue TRIJARDY XR and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

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

• Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.2)]
• Pancreatitis [see Warnings and Precautions (5.3)]
• Volume Depletion [see Warnings and Precautions (5.4)]
• Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections [see Warnings and Precautions (5.5)]
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.6)]
• Lower Limb Amputation [see Warnings and Precautions (5.7)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.8)]
• Vitamin B₁₂ Deficiency [see Warnings and Precautions (5.9)]
• Severe and Disabling Arthralgia [see Warnings and Precautions (5.10)]
• Bullous Pemphigoid [see Warnings and Precautions (5.11)]
• Heart Failure [see Warnings and Precautions (5.12)]

Table 2 describes clinically relevant interactions with TRIJARDY XR.

Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse 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 TRIJARDY XR 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 TRIJARDY XR. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

TRIJARDY XR should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m² due to the metformin HCl component and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²).

Use of metformin HCl in patients with hepatic impairment has been associated with some cases of lactic acidosis. TRIJARDY XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

TRIJARDY XR is a combination of empagliflozin, linagliptin, and metformin hydrochloride (HCl) 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 Clinical Studies (14.2)].

Bullous pemphigoid was reported in 7 (0.2%) patients treated with linagliptin compared to none in patients treated with placebo in the CARMELINA trial [see Clinical 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 TRIJARDY XR. If bullous pemphigoid is suspected, TRIJARDY XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue TRIJARDY XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

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. TRIJARDY XR 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 TRIJARDY XR 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.

• 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 TRIJARDY XR if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. (5.2)
• Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue TRIJARDY XR. (5.3)
• Volume Depletion: Before initiating TRIJARDY XR, 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. (5.4)
• 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 TRIJARDY XR, and promptly institute appropriate medical and/or surgical intervention. (5.5)
• Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating TRIJARDY XR. (5.6)
• Lower Limb Amputation: Monitor patients for infections or ulcers of lower limbs, and institute appropriate treatment. (5.7)
• Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with empagliflozin and linagliptin. If hypersensitivity reactions occur, discontinue TRIJARDY XR, treat promptly, and monitor until signs and symptoms resolve. (5.8)
• Vitamin B₁₂ Deficiency: Metformin may lower vitamin B₁₂ levels. Measure hematologic parameters annually and vitamin B₁₂ at 2 to 3 year intervals and manage any abnormalities. (5.9)
• Arthralgia: Severe and disabling arthralgia has been reported in patients taking linagliptin. Consider as a possible cause for severe joint pain and discontinue TRIJARDY XR if appropriate. (5.10)
• 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 TRIJARDY XR. (5.11)
• Heart Failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of TRIJARDY XR in patients who have known risk factors for heart failure. Monitor for signs and symptoms. (5.12)

• Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating. (2.1)
• Individualize the starting dosage based on the patient's current regimen and renal function. (2.2, 2.3)
• Initiation is not recommended in patients with an eGFR less than 45 mL/min/1.73 m², due to the metformin HCl component. (2.3)
• The maximum recommended dosage of TRIJARDY XR is 25 mg empagliflozin, 5 mg linagliptin and 2,000 mg metformin HCl. (2.2)
• Take once daily with a meal in the morning. (2.2)
• Swallow whole; do not split, crush, dissolve, or chew. (2.2)
• TRIJARDY XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.4)
• Withhold TRIJARDY XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. (2.5)

TRIJARDY XR Tablets:

Additional adverse reactions have been identified during postapproval use of linagliptin, empagliflozin, or metformin HCl. 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)], 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)
• Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury

• Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters. (8.1)
• Lactation: Not recommended when breastfeeding. (8.2)
• Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3)
• Geriatric Patients: Higher incidence of adverse reactions related to volume depletion and reduced renal function. (8.5)
• Renal Impairment: Higher incidence of adverse reactions related to reduced renal function. (8.6)
• Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7)

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 TRIJARDY XR.

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

If a hypersensitivity reaction occurs, discontinue TRIJARDY XR, treat promptly per standard of care, and monitor until signs and symptoms resolve. TRIJARDY XR is contraindicated in patients with hypersensitivity to linagliptin, empagliflozin or any of the excipients in TRIJARDY XR [see Contraindications (4)].

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

TRIJARDY XR tablets are available as follows:

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.

Withhold TRIJARDY XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume TRIJARDY XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].

• Individualize the starting dosage of TRIJARDY XR based on the patient's current regimen:
  • In patients on metformin HCl, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl and a total daily dosage of empagliflozin 10 mg and linagliptin 5 mg;
  • In patients on metformin HCl and any regimen containing empagliflozin, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl, the same total daily dosage of empagliflozin and linagliptin 5 mg.
• Monitor effectiveness and tolerability, and adjust dosing as appropriate, not to exceed the maximum recommended daily dosage of empagliflozin 25 mg, linagliptin 5 mg and metformin HCl 2,000 mg.
• Take TRIJARDY XR orally, once daily with a meal in the morning.
  • Take TRIJARDY XR 10 mg/5 mg/1,000 mg or TRIJARDY XR 25 mg/5 mg/1,000 mg as a single tablet once daily.
  • Take TRIJARDY XR 5 mg/2.5 mg/1,000 mg or TRIJARDY XR 12.5 mg/2.5 mg/1,000 mg as two tablets together once daily.
• Swallow TRIJARDY XR tablets whole. Do not split, crush, dissolve, or chew.

• If a dose is missed, instruct patients to take the dose as soon as possible.
• Advise patients not to double up the next dose.

• Assess renal function before initiating TRIJARDY XR and as clinically indicated [see Warnings and Precautions (5.1, 5.4)].
• Assess volume status. In patients with volume depletion, correct this condition before initiating TRIJARDY XR [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5, 8.6)].

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women.

• Initiation of TRIJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m², due to the metformin HCl component.
• TRIJARDY XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m² [see Contraindications (4), Warnings and Precautions (5.1, 5.4), and Use in Specific Populations (8.6)].

Discontinue TRIJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m²; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart TRIJARDY XR if renal function is stable [see Warnings and Precautions (5.1)].

NDC 0597-0380-13

Trijardy^®XR

(empagliflozin, linagliptin,

and metformin hydrochloride

extended-release tablets)

10 mg/5 mg/1,000 mg*

DISPENSE WITH ACCOMPANYING

MEDICATION GUIDE

30 tablets

Rx only

Boehringer

Ingelheim

NDC 0597-0390-71

Trijardy^®XR

(empagliflozin, linagliptin,

and metformin hydrochloride

extended-release tablets)

25 mg/5 mg/1,000 mg*

DISPENSE WITH ACCOMPANYING

MEDICATION GUIDE

30 tablets

Rx only

Boehringer

Ingelheim

NDC 0597-0395-82

Trijardy^®XR

(empagliflozin, linagliptin, and metformin

hydrochloride extended-release tablets)

5 mg/2.5 mg/1,000 mg*

DISPENSE WITH ACCOMPANYING MEDICATION GUIDE

60 tablets

Rx only

Boehringer

Ingelheim

NDC 0597-0385-77

Trijardy^®XR

(empagliflozin, linagliptin, and metformin

hydrochloride extended-release tablets)

12.5 mg/2.5 mg/1,000 mg*

DISPENSE WITH ACCOMPANYING MEDICATION GUIDE

60 tablets

Rx only

Boehringer

Ingelheim

Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when TRIJARDY XR 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 TRIJARDY XR.

In patients with type 1 diabetes mellitus, empagliflozin, a component of TRIJARDY XR, 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. TRIJARDY XR 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 empagliflozin.

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 TRIJARDY XR [see Clinical 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 TRIJARDY XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting TRIJARDY XR.

Withhold TRIJARDY XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume TRIJARDY XR when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.5)].

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

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 HCl 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 dose 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 HCl (see Table 7, Figure 3). Treatment with empagliflozin 10 mg or 25 mg used in combination with linagliptin 5 mg also resulted in a statistically significant reduction in body weight compared to linagliptin 5 mg (p-value <0.0001). There was no statistically significant difference compared to empagliflozin alone.

Figure 3 Adjusted Mean HbA1c Change at Each Time Point (Completers) and at Week 24 (mITT population)

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 HCl (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 doses 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 8 and Figures 4 and 5). Results for the 10 mg and 25 mg empagliflozin dosages were consistent with results for the combined dose groups.

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).

Empagliflozin increases urinary glucose excretion [see Clinical Pharmacology (12.2)] and increases the risk of genitourinary infections including urinary tract infections and genital mycotic infections in both male and female patients [see Adverse 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 and without diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin [see Adverse Reactions (6.2)]. Cases have required hospitalization. In patients with Fournier's gangrene, serious outcomes have included multiple surgeries and death. TRIJARDY XR is only indicated for use in patients with type 2 diabetes mellitus.

Patients with history of chronic or recurrent genitourinary infections are more likely to develop genitourinary infections when using TRIJARDY XR. 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 TRIJARDY XR and promptly institute appropriate medical and/or surgical intervention.

Limitations of Use

TRIJARDY XR is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.2)].

TRIJARDY XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using TRIJARDY XR [see Warnings and Precautions (5.3)].

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from exposure to high humidity.

In the event of an overdose with TRIJARDY XR, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Removal of empagliflozin by hemodialysis has not been studied, and removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.

TRIJARDY XR tablets for oral use contain: empagliflozin, linagliptin, and metformin HCl.

In metformin HCl clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂ levels was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. Measure hematologic parameters on an annual basis and vitamin B₁₂ at 2 to 3 year intervals in patients on TRIJARDY XR and manage any abnormalities [see Adverse Reactions (6.1)].

Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial [see Clinical 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 TRIJARDY XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using TRIJARDY XR.

Safety and effectiveness of TRIJARDY XR have not been established in pediatric patients.

Assess renal function more frequently in TRIJARDY XR-treated geriatric patients because there is a greater risk of empagliflozin-associated intravascular volume contraction and symptomatic hypotension in geriatric patients and there is a greater risk of metformin-associated lactic acidosis in geriatric patients [see Warnings and Precautions (5.1, 5.4)].

The recommended dosage for the metformin HCl component of TRIJARDY XR in geriatric patients should usually start at the lower end of the dosage range.

Of the 273 patients treated with the combination of empagliflozin, linagliptin, and metformin HCl to improve glycemic control in adults with type 2 diabetes mellitus, 58 were 65 years of age and older, while 8 were 75 years of age and older. Clinical trials of TRIJARDY XR did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger adult patients.

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 TRIJARDY XR 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 TRIJARDY XR.

TRIJARDY XR is contraindicated in patients with:

• severe renal impairment (eGFR less than 30 mL/min/1.73 m²) [see Warnings and Precautions (5.1, 5.4) and Use in Specific Populations (8.6)].
• acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1)].
• hypersensitivity to empagliflozin, linagliptin, metformin HCl or any of the excipients in TRIJARDY XR, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred [see Warnings and Precautions (5.8) and Adverse Reactions (6)].

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels, which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of TRIJARDY XR. In TRIJARDY XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue TRIJARDY XR and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

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

• Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.2)]
• Pancreatitis [see Warnings and Precautions (5.3)]
• Volume Depletion [see Warnings and Precautions (5.4)]
• Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections [see Warnings and Precautions (5.5)]
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.6)]
• Lower Limb Amputation [see Warnings and Precautions (5.7)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.8)]
• Vitamin B₁₂ Deficiency [see Warnings and Precautions (5.9)]
• Severe and Disabling Arthralgia [see Warnings and Precautions (5.10)]
• Bullous Pemphigoid [see Warnings and Precautions (5.11)]
• Heart Failure [see Warnings and Precautions (5.12)]

Table 2 describes clinically relevant interactions with TRIJARDY XR.

Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse 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 TRIJARDY XR 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 TRIJARDY XR. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

TRIJARDY XR should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m² due to the metformin HCl component and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²).

Use of metformin HCl in patients with hepatic impairment has been associated with some cases of lactic acidosis. TRIJARDY XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

TRIJARDY XR is a combination of empagliflozin, linagliptin, and metformin hydrochloride (HCl) 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 Clinical Studies (14.2)].

Bullous pemphigoid was reported in 7 (0.2%) patients treated with linagliptin compared to none in patients treated with placebo in the CARMELINA trial [see Clinical 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 TRIJARDY XR. If bullous pemphigoid is suspected, TRIJARDY XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue TRIJARDY XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

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. TRIJARDY XR 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 TRIJARDY XR 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.

• 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 TRIJARDY XR if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. (5.2)
• Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue TRIJARDY XR. (5.3)
• Volume Depletion: Before initiating TRIJARDY XR, 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. (5.4)
• 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 TRIJARDY XR, and promptly institute appropriate medical and/or surgical intervention. (5.5)
• Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating TRIJARDY XR. (5.6)
• Lower Limb Amputation: Monitor patients for infections or ulcers of lower limbs, and institute appropriate treatment. (5.7)
• Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with empagliflozin and linagliptin. If hypersensitivity reactions occur, discontinue TRIJARDY XR, treat promptly, and monitor until signs and symptoms resolve. (5.8)
• Vitamin B₁₂ Deficiency: Metformin may lower vitamin B₁₂ levels. Measure hematologic parameters annually and vitamin B₁₂ at 2 to 3 year intervals and manage any abnormalities. (5.9)
• Arthralgia: Severe and disabling arthralgia has been reported in patients taking linagliptin. Consider as a possible cause for severe joint pain and discontinue TRIJARDY XR if appropriate. (5.10)
• 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 TRIJARDY XR. (5.11)
• Heart Failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of TRIJARDY XR in patients who have known risk factors for heart failure. Monitor for signs and symptoms. (5.12)

• Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating. (2.1)
• Individualize the starting dosage based on the patient's current regimen and renal function. (2.2, 2.3)
• Initiation is not recommended in patients with an eGFR less than 45 mL/min/1.73 m², due to the metformin HCl component. (2.3)
• The maximum recommended dosage of TRIJARDY XR is 25 mg empagliflozin, 5 mg linagliptin and 2,000 mg metformin HCl. (2.2)
• Take once daily with a meal in the morning. (2.2)
• Swallow whole; do not split, crush, dissolve, or chew. (2.2)
• TRIJARDY XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.4)
• Withhold TRIJARDY XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. (2.5)

TRIJARDY XR Tablets:

Additional adverse reactions have been identified during postapproval use of linagliptin, empagliflozin, or metformin HCl. 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)], 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)
• Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury

• Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters. (8.1)
• Lactation: Not recommended when breastfeeding. (8.2)
• Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3)
• Geriatric Patients: Higher incidence of adverse reactions related to volume depletion and reduced renal function. (8.5)
• Renal Impairment: Higher incidence of adverse reactions related to reduced renal function. (8.6)
• Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7)

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 TRIJARDY XR.

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

If a hypersensitivity reaction occurs, discontinue TRIJARDY XR, treat promptly per standard of care, and monitor until signs and symptoms resolve. TRIJARDY XR is contraindicated in patients with hypersensitivity to linagliptin, empagliflozin or any of the excipients in TRIJARDY XR [see Contraindications (4)].

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

TRIJARDY XR tablets are available as follows:

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.

Withhold TRIJARDY XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume TRIJARDY XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].

• Individualize the starting dosage of TRIJARDY XR based on the patient's current regimen:
  • In patients on metformin HCl, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl and a total daily dosage of empagliflozin 10 mg and linagliptin 5 mg;
  • In patients on metformin HCl and any regimen containing empagliflozin, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl, the same total daily dosage of empagliflozin and linagliptin 5 mg.
• Monitor effectiveness and tolerability, and adjust dosing as appropriate, not to exceed the maximum recommended daily dosage of empagliflozin 25 mg, linagliptin 5 mg and metformin HCl 2,000 mg.
• Take TRIJARDY XR orally, once daily with a meal in the morning.
  • Take TRIJARDY XR 10 mg/5 mg/1,000 mg or TRIJARDY XR 25 mg/5 mg/1,000 mg as a single tablet once daily.
  • Take TRIJARDY XR 5 mg/2.5 mg/1,000 mg or TRIJARDY XR 12.5 mg/2.5 mg/1,000 mg as two tablets together once daily.
• Swallow TRIJARDY XR tablets whole. Do not split, crush, dissolve, or chew.

• If a dose is missed, instruct patients to take the dose as soon as possible.
• Advise patients not to double up the next dose.

• Assess renal function before initiating TRIJARDY XR and as clinically indicated [see Warnings and Precautions (5.1, 5.4)].
• Assess volume status. In patients with volume depletion, correct this condition before initiating TRIJARDY XR [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5, 8.6)].

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women.

• Initiation of TRIJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m², due to the metformin HCl component.
• TRIJARDY XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m² [see Contraindications (4), Warnings and Precautions (5.1, 5.4), and Use in Specific Populations (8.6)].

Discontinue TRIJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m²; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart TRIJARDY XR if renal function is stable [see Warnings and Precautions (5.1)].

NDC 0597-0380-13

Trijardy^®XR

(empagliflozin, linagliptin,

and metformin hydrochloride

extended-release tablets)

10 mg/5 mg/1,000 mg*

DISPENSE WITH ACCOMPANYING

MEDICATION GUIDE

30 tablets

Rx only

Boehringer

Ingelheim

NDC 0597-0390-71

Trijardy^®XR

(empagliflozin, linagliptin,

and metformin hydrochloride

extended-release tablets)

25 mg/5 mg/1,000 mg*

DISPENSE WITH ACCOMPANYING

MEDICATION GUIDE

30 tablets

Rx only

Boehringer

Ingelheim

NDC 0597-0395-82

Trijardy^®XR

(empagliflozin, linagliptin, and metformin

hydrochloride extended-release tablets)

5 mg/2.5 mg/1,000 mg*

DISPENSE WITH ACCOMPANYING MEDICATION GUIDE

60 tablets

Rx only

Boehringer

Ingelheim

NDC 0597-0385-77

Trijardy^®XR

(empagliflozin, linagliptin, and metformin

hydrochloride extended-release tablets)

12.5 mg/2.5 mg/1,000 mg*

DISPENSE WITH ACCOMPANYING MEDICATION GUIDE

60 tablets

Rx only

Boehringer

Ingelheim

Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when TRIJARDY XR 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 TRIJARDY XR.

In patients with type 1 diabetes mellitus, empagliflozin, a component of TRIJARDY XR, 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. TRIJARDY XR 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 empagliflozin.

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 TRIJARDY XR [see Clinical 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 TRIJARDY XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting TRIJARDY XR.

Withhold TRIJARDY XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume TRIJARDY XR when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.5)].

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

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 HCl 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 dose 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 HCl (see Table 7, Figure 3). Treatment with empagliflozin 10 mg or 25 mg used in combination with linagliptin 5 mg also resulted in a statistically significant reduction in body weight compared to linagliptin 5 mg (p-value <0.0001). There was no statistically significant difference compared to empagliflozin alone.

Figure 3 Adjusted Mean HbA1c Change at Each Time Point (Completers) and at Week 24 (mITT population)

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 HCl (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 doses 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 8 and Figures 4 and 5). Results for the 10 mg and 25 mg empagliflozin dosages were consistent with results for the combined dose groups.

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).

Empagliflozin increases urinary glucose excretion [see Clinical Pharmacology (12.2)] and increases the risk of genitourinary infections including urinary tract infections and genital mycotic infections in both male and female patients [see Adverse 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 and without diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin [see Adverse Reactions (6.2)]. Cases have required hospitalization. In patients with Fournier's gangrene, serious outcomes have included multiple surgeries and death. TRIJARDY XR is only indicated for use in patients with type 2 diabetes mellitus.

Patients with history of chronic or recurrent genitourinary infections are more likely to develop genitourinary infections when using TRIJARDY XR. 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 TRIJARDY XR and promptly institute appropriate medical and/or surgical intervention.