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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
TRIJARDY XR (NDA-212614)
(EMPAGLIFLOZIN; LINAGLIPTIN; METFORMIN HYDROCHLORIDE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
08/11/2026 (SUPPL-32)
Boxed Warning
Additions and/or revisions underlined:
. . .
Risk factors include renal impairment, concomitant use of certain drugs, age greater than 65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, hepatic impairment, and mitochondrial diseases. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the Full Prescribing Information.
. . .
5 Warnings and Precautions
5.1 Lactic Acidosis
Additions and/or revisions underlined:
Mitochondrial Diseases: Metformin may increase the risk of lactic acidosis in patients with mitochondrial diseases such as mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) syndrome and maternally inherited diabetes and deafness (MIDD). TRIJARDY XR is not recommended in patients with mitochondrial diseases such as MELAS syndrome and MIDD.
If a patient taking TRIJARDY XR develops elevated lactic acid levels (with or without accompanying neurologic signs and symptoms), discontinue TRIJARDY XR. Depending on the clinical context, consider evaluating the patient for MELAS, MIDD, or other mitochondrial disease.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions and/or revisions underlined:
. . .
What is the most important information I should know about TRIJARDY XR?
TRIJARDY XR can cause serious side effects, including:
. . .
- have a genetically inherited disease affecting mitochondria (the energy-producing parts within cells) such as mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) syndrome and maternally inherited diabetes and deafness (MIDD).
. . .
What should I tell my healthcare provider before taking TRIJARDY XR?
Before taking TRIJARDY XR, tell your healthcare provider about all of your medical conditions, including if you:
. . .
- have a genetically inherited disease affecting mitochondria (the energy-producing parts within cells) such as MELAS syndrome and MIDD.
. . .
10/24/2025 (SUPPL-29)
5 Warnings and Precautions
5.5 Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene), and Genital Mycotic Infections
Subsection title revised
Additions and/or revisions underlined:
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.
6 Adverse Reactions
Additions and/or revisions underlined:
The following important adverse reactions are described below and elsewhere in the labeling:
. . .
Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene), and Genital Mycotic Infections [see Warnings and Precautions (5.5)]
. . .
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
. . .
Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene), and Genital Mycotic Infections
Counsel patients that genitourinary infections may occur when taking empagliflozin, a component of TRIJARDY XR, and may become serious. Educate them on the symptoms and advise them to seek medical advice if symptoms occur. Specifically, advise patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4 degrees F or malaise
. . .
MEDICATION GUIDE
Additions and/or revisions underlined:
Genital and urinary tract infections. Empagliflozin, one of the medicines in TRIJARDY XR, can cause serious infections in your genital area or urinary tract that could require hospitalization. A rare but serious bacterial infection called
necrotizing fasciitis can cause damage to the tissue under the skin in the area between and around the anus and genitals (perineum). This infection may require hospitalization, multiple surgeries, and could lead to death. Seek medical
attention immediately if you have a fever or you are feeling very weak, tired or uncomfortable (malaise), and you develop any of the following symptoms in the area between and around your anus and genitals:
pain or tenderness o swelling o redness of skin (erythema)
Also tell your healthcare provider if you have any of these signs or symptoms of urinary tract infections or yeast infections:
Urinary tract infection:
burning feeling when you urinate
need to urinate often or right away
pain in the lower part of your stomach (pelvis)
blood in your urine
You may also have a fever, back pain, nausea, or vomiting.
. . .
10/30/2023 (SUPPL-20)
5 Warnings and Precautions
5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
Newly added section:
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.
5.5 Urosepsis and Pyelonephritis
Additions and/or revisions underlined:
There have been reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving empagliflozin. Treatment with empagliflozin increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].
5.9 Lower Limb Amputation
Newly added section:
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.
5.12 Severe and Disabling Arthralgia
Additions and/or revisions underlined:
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.
6 Adverse Reactions
Addition of the following to the bulleted line listing:
Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
…
Lower Limb Amputation [see Warnings and Precautions (5.9)]
6.1 Clinical Trials Experience
Newly added information:
Other Adverse Reactions in Clinical Trials with Empagliflozin in Adults
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. TRIJARDY XR is not indicated for the treatment of chronic kidney disease.
Laboratory Test Abnormalities in Clinical Trials of Empagliflozin, Linagliptin, or Metformin
…
6.2 Postmarketing Experience
Additions and/or revisions underlined:
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
7 Drug Interactions
Additions and/or revisions underlined:
Table 2 describes clinically relevant interactions with TRIJARDY XR.
8 Use in Specific Populations
8.5 Geriatric Use
Additions and/or revisions underlined:
Metformin
Clinical trials of metformin did not include sufficient numbers of patients 65 years of age and older to determine
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
Inform patients that TRIJARDY XR can cause potentially fatal ketoacidosis and that type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors.
Educate all patients on precipitating factors (such as insulin dose reduction or missed insulin doses, infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing). Inform patients that blood glucose may be normal even in the presence of ketoacidosis.
Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur, instruct patients to discontinue TRIJARDY XR and seek medical attention immediately [see Warnings and Precautions (5.2)].
…
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
Inform patients that the risk of hypoglycemia is increased when TRIJARDY XR is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin [see Warnings and Precautions (5.6)].
…
Lower Limb Amputation
Counsel patients about the importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or symptoms develop [see Warnings and Precautions (5.9)].
MEDICATION GUIDE
Medication Guide has undergone extensive changes; please refer to label for complete information
10/13/2022 (SUPPL-16)
06/11/2021 (SUPPL-10)
5 Warnings and Precautions
5.4 Volume Depletion(Subsection title revised; Additions and/or revisions underlined)
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.
(Additions and/or revisions underlined)
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)].
6 Adverse Reactions
(Addition of the following to the bulleted line listing)
Volume Depletion [see Warnings and Precautions (5.4)]
Heart Failure [see Warnings and Precautions (5.13)]
(Additions and/or revisions underlined)
…
Laboratory Tests
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 study of patients with moderate renal impairment, larger mean changes were observed. In a long-term cardiovascular 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.
…
8 Use in Specific Populations
8.4 Pediatric Use(Additions and/or revisions underlined)
Safety and effectiveness of TRIJARDY XR have not been established in pediatric patients.
(Additions and/or revisions underlined)
…
Empagliflozin
In empagliflozin type 2 diabetes studies, 2721 empagliflozin-treated patients were 65 years of age and older and 491 patients were 75 years of age and older. In these studies, volume depletion-related adverse reactions occurred in 2.1%, 2.3%, and 4.4% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively; and urinary tract infections occurred in 10.5%, 15.7%, and 15.1% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively.
…
(Additions and/or revisions underlined)
TRIJARDY XR should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2 due to the metformin component and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end-stage renal disease, or dialysis.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Extensive changes; please refer to label)
(Additions and/or revisions underlined)
…
Volume Depletion
Inform patients that symptomatic hypotension may occur with TRIJARDY XR and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.4)]. Inform patients that dehydration may increase the risk for hypotension, and to maintain adequate fluid intake.
…
06/11/2021 (SUPPL-8)
5 Warnings and Precautions
5.4 Volume Depletion(Subsection title revised; Additions and/or revisions underlined)
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.
(Additions and/or revisions underlined)
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)].
6 Adverse Reactions
(Addition of the following to the bulleted line listing)
Volume Depletion [see Warnings and Precautions (5.4)]
Heart Failure [see Warnings and Precautions (5.13)]
(Additions and/or revisions underlined)
…
Laboratory Tests
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 study of patients with moderate renal impairment, larger mean changes were observed. In a long-term cardiovascular 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.
…
8 Use in Specific Populations
8.4 Pediatric Use(Additions and/or revisions underlined)
Safety and effectiveness of TRIJARDY XR have not been established in pediatric patients.
(Additions and/or revisions underlined)
…
Empagliflozin
In empagliflozin type 2 diabetes studies, 2721 empagliflozin-treated patients were 65 years of age and older and 491 patients were 75 years of age and older. In these studies, volume depletion-related adverse reactions occurred in 2.1%, 2.3%, and 4.4% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively; and urinary tract infections occurred in 10.5%, 15.7%, and 15.1% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively.
…
(Additions and/or revisions underlined)
TRIJARDY XR should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2 due to the metformin component and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end-stage renal disease, or dialysis.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Extensive changes; please refer to label)
(Additions and/or revisions underlined)
…
Volume Depletion
Inform patients that symptomatic hypotension may occur with TRIJARDY XR and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.4)]. Inform patients that dehydration may increase the risk for hypotension, and to maintain adequate fluid intake.
…
10/30/2020 (SUPPL-4)
5 Warnings and Precautions
5.5 Ketoacidosis
(Additions and/or revisions underlined)
Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in clinical trials and postmarketing surveillance 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. In placebo-controlled trials of patients with type 1 diabetes, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. TRIJARDY XR is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].
5.11 Hypersensitivity Reactions
(Additions and/or revisions underlined)
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of TRIJARDY XR). 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.
6 Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions underlined)
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 cardiovascular safety study 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)].