Drug Safety-related Labeling Changes (SrLC)

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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.

SYNJARDY XR (NDA-208658)

(EMPAGLIFLOZIN;METFORMIN HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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08/11/2026 (SUPPL-38)

Approved Drug Label (PDF)

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). SYNJARDY and SYNJARDY XR are not recommended in patients with mitochondrial diseases such as MELAS syndrome and MIDD.

If a patient taking SYNJARDY or SYNJARDY XR develops elevated lactic acid levels (with or without accompanying neurologic signs and symptoms), discontinue SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY XR?

. . .

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 SYNJARDY or SYNJARDY XR?

Before taking SYNJARDY or SYNJARDY 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-34)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 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. SYNJARDY and SYNJARDY XR are only indicated for use in patients with type 2 diabetes mellitus.

Patients with a history of chronic or recurrent genitourinary infections are more likely to develop genitourinary infections when using SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY 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. . .
(Fournier’s Gangrene), and Genital Mycotic Infections [see Warnings and Precautions (5.4)]
Hypoglycemia [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 SYNJARDY and SYNJARDY 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 [see Warnings and Precautions (5.4)].

. . .

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

Genital and urinary tract infections. Empagliflozin, one of the medicines in SYNJARDY and SYNJARDY 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.

. . .

03/07/2025 (SUPPL-32)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

…

In the EMPEROR-Reduced, EMPEROR-Preserved, and EMPA-KIDNEY trials, no overall differences in safety and effectiveness have been observed between patients 65 years of age and older and younger adult patients.

EMPEROR-Reduced included 1,188 (64%) patients treated with empagliflozin 65 years of age and older, and 503 (27%) patients 75 years of age and older. EMPEROR-Preserved included 2,403 (80%) patients treated with empagliflozin 65 years of age and older, and 1,281 (43%) patients 75 years of age and older. EMPA-KIDNEY included 1,803 (55%) patients treated with empagliflozin 65 years of age and older, and 758 (23%) patients 75 years of age and older.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What is SYNJARDY or SYNJARDY XR?

SYNJARDY is a prescription medicine that contains 2 diabetes medicines, empagliflozin (JARDIANCE) and metformin HCl immediate-release.
…
One of the medicines in SYNJARDY and SYNJARDY XR, empagliflozin (JARDIANCE), can also be used in adults with type 2 diabetes:
- who have known cardiovascular disease to reduce the risk of cardiovascular death.
- who have heart failure (when the heart cannot pump enough blood to the rest of your body) to reduce the risk of cardiovascular death and hospitalization for heart failure.
- to reduce the risk of further worsening of kidney disease, end-stage kidney disease (ESKD), death due to cardiovascular disease, and hospitalization in adults with chronic kidney disease.
  …
One of the medicines in SYNJARDY or SYNJARDY XR, empagliflozin (JARDIANCE), is not for people with polycystic kidney disease, or who are taking or have recently received certain types of immunosuppressive therapy to treat kidney disease. Empagliflozin (JARDIANCE) is not expected to work if you have these conditions.
…

10/30/2023 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

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

Newly added section; please refer to label for complete information

5.8 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. SYNJARDY and SYNJARDY XR are 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 SYNJARDY or SYNJARDY 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.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.2)]

…

Lower Limb Amputation [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Newly added subsection:

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. SYNJARDY and SYNJARDY XR are not indicated for the treatment of chronic kidney disease.

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 SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY XR and seek medical attention immediately [see Warnings and Precautions (5.2)].

…

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 (5.8)].

MEDICATION GUIDE

Medication Guide has undergone extensive changes; please refer to label for complete information

06/20/2023 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Hypoglycemia

Additions and revisions underlined:

Insulin and insulin secretagogues are known to cause hypoglycemia. In adult patients, the risk of hypoglycemia may be increased when SYNJARDY or SYNJARDY XR is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin. In pediatric patients aged 10 years and older, the risk of hypoglycemia was higher with empagliflozin regardless of insulin use [see Adverse Reactions (6.1)].

The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications and pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.4 Pediatric Use

Additions and revisions underlined:

SYNJARDY

The safety and effectiveness of SYNJARDY as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. Use of SYNJARDY for this indication is supported by evidence from a 26-week double-blind, placebo-controlled clinical trial of empagliflozin, with a double-blind active treatment safety extension period of up to 52 weeks in 157 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus and a pediatric pharmacokinetic study [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)].

The safety profile of pediatric patients treated with empagliflozin was similar to that observed in adults with type 2 diabetes mellitus, with the exception of hypoglycemia risk which was higher in pediatric patients treated with empagliflozin regardless of concomitant insulin use [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

Use of SYNJARDY for this indication is also supported by evidence from adequate and well-controlled studies of metformin HCl immediate-release tablets in adults with additional data from a controlled clinical study using metformin HCl immediate-release tablets in pediatric patients 10 to 16 years old with type 2 diabetes mellitus [see Clinical Studies (14)]. In this study, adverse reactions were similar to those described in adults.

The safety and effectiveness of SYNJARDY have not been established in pediatric patients less than 10 years of age.

SYNJARDY XR

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

8.5 Geriatric Use

Newly added information:

In heart failure trials, EMPEROR-Reduced included 1,188 (64%) patients treated with empagliflozin 65 years of age and older, and 503 (27%) patients 75 years of age and older. EMPEROR-Preserved included 2,402 (80%) patients treated with empagliflozin 65 years of age and older, and 1,281 (43%) patients 75 years of age and older. No overall differences in safety and effectiveness have been observed between patients 65 years of age and older and younger adult patients.

8.6 Renal Impairment

Newly added information:

In the trial of pediatric patients aged 10 to 17 years with type 2 diabetes mellitus, patients with an eGFR less than 60 mL/min/1.73 m2 were not enrolled.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

Additions and revisions underlined:

Hypoglycemia

Inform patients that hypoglycemia has been reported when SYNJARDY or SYNJARDY XR is used with insulin secretagogues or insulin. Hypoglycemia may occur in pediatric patients regardless of concomitant antidiabetic treatment. Educate patients or caregivers on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.5)].

. . .

Administration Instructions

Inform patients that SYNJARDY XR tablets must be swallowed whole and never split, crushed, dissolved, or chewed and that incompletely dissolved SYNJARDY XR tablets may be eliminated in the feces.

Medication Guide

Extensive changes; please refer to label

02/06/2023 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 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)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.5 Geriatric Use

…

Empagliflozin

In empagliflozin type 2 diabetes mellitus studies, 2,721 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.

In heart failure studies, EMPEROR-Reduced included 1,188 (64%) patients treated with empagliflozin 65 years of age and older, and 503 (27%) patients 75 years of age and older. EMPEROR-Preserved included 2,402 (80%) patients treated with empagliflozin 65 years of age and older, and 1,281 (43%) patients 75 years of age and older. No overall differences in safety and effectiveness have been observed between patients 65 years of age and older and younger adult patients.

Metformin

Clinical studies of metformin did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What is SYNJARDY XR?

SYNJARDY XR is a prescription medicine that contains 2 diabetes medicines, empagliflozin (JARDIANCE) and metformin hydrochloride. SYNJARDY XR can be used along with diet and exercise to improve blood sugar in adults with type 2 diabetes.

One of the medicines in SYNJARDY XR, empagliflozin (JARDIANCE), can also be used in adults with type 2 diabetes:

who have known cardiovascular disease to reduce the risk of cardiovascular death.
who have heart failure (when the heart cannot pump enough blood to the rest of your body) to reduce the risk of cardiovascular death and hospitalization for heart failure.

SYNJARDY XR is not for people with type 1 diabetes. It may increase their risk of diabetic ketoacidosis (increased ketones in blood or urine).

SYNJARDY XR is not for people with heart failure who do not have type 2 diabetes, because it contains the prescription medicine metformin hydrochloride.

It is not known if SYNJARDY XR is safe and effective in children.

10/13/2022 (SUPPL-23)

Approved Drug Label (PDF)

7 Drug Interactions

Newly added information:

Lithium

Clinical Impact Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.

Intervention Monitor serum lithium concentration more frequently during SYNJARDY XR initiation and dosage changes.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and revisions underlined:

Assess renal function more frequently in SYNJARDY 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, 5.3)].

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

03/21/2022 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Empagliflozin

Gastrointestinal Disorders: Constipation

Infections: Necrotizing fasciitis of the perineum (Fournier’s gangrene), urosepsis and pyelonephritis

Metabolism and Nutrition Disorders: Ketoacidosis

Renal and Urinary Disorders: Acute kidney injury

Skin and Subcutaneous Tissue Disorders: Angioedema, skin reactions (e.g., rash, urticaria)

Metformin Hydrochloride

Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What are the possible side effects of SYNJARDY XR?

SYNJARDY XR may cause serious side effects, including:

Yeast infection of the penis (balanitis or balanoposthitis). Swelling of an uncircumcised penis may develop …

PATIENT COUNSELING INFORMATION

‘with Concomitant Use with Insulin and Insulin Secretagogues’ added to Hypoglycemia heading

06/11/2021 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

SYNJARDY XR is contraindicated in patients with:

Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease, or dialysis [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].
Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1)].
Hypersensitivity to empagliflozin, metformin or any of the excipients in SYNJARDY XR, reactions such as angioedema have occurred [see Warnings and Precautions (5.8)].

5 Warnings and Precautions

5.1 Lactic Acidosis

(Additions and/or revisions underlined)

…

Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin- treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop SYNJARDY 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 m^2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart SYNJARDY XR if renal function is stable.

…

5.2 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. SYNJARDY XR is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].

…

5.3 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 SYNJARDY 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 SYNJARDY XR. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

(Additions and/or revisions underlined)

Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when empagliflozin is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin [see Adverse Reactions (6.1)]. Metformin may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with SYNJARDY XR.

5.9 Vitamin B12 Deficiency

(Subsection title revised; Additions and/or revisions underlined)

In metformin 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 SYNJARDY XR and manage any abnormalities [see Adverse Reactions (6.1)].

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

Volume Depletion [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

7 Drug Interactions

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

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

The limited available data with SYNJARDY XR or empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).

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

…

8.2 Lactation

(Additions and/or revisions underlined)

Risk Summary

There is limited information regarding the presence of SYNJARDY XR or its components (empagliflozin or metformin) in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk (see Data). Empagliflozin is present in the milk of lactating rats (see Data). Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.

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

Data

Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.

Empagliflozin was present at a low level in rat fetal tissues after a single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 to 5, and was greater than one from 2 to 24 hours post-dose. The mean maximal milk to plasma ratio of 5 occurred at 8 hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

8.4 Pediatric Use

(Additions and/or revisions underlined)

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

8.5 Geriatric Use

(Additions and/or revisions underlined)

Because renal function abnormalities can occur after initiating empagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, renal function should be assessed more frequently in elderly patients [see Dosage and Administration (2.1) and Warnings and Precautions (5.1, 5.3)].

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.

Metformin hydrochloride

Clinical studies of metformin did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger adult patients.

8.6 Renal Impairment

(Additions and/or revisions underlined)

SYNJARDY 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.

Empagliflozin

The glucose lowering benefit of empagliflozin 25 mg decreased in patients with worsening renal function. The risks of renal impairment [see Warnings and Precautions (5.2)], volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function.

Metformin hydrochloride

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment [see Warnings and Precautions (5.1)].

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PATIENT COUNSELING INFORMATION

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06/11/2021 (SUPPL-15)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

SYNJARDY XR is contraindicated in patients with:

Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease, or dialysis [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].
Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1)].
Hypersensitivity to empagliflozin, metformin or any of the excipients in SYNJARDY XR, reactions such as angioedema have occurred [see Warnings and Precautions (5.8)].

5 Warnings and Precautions

5.1 Lactic Acidosis

(Additions and/or revisions underlined)

…

5.2 Ketoacidosis

(Additions and/or revisions underlined)

…

5.3 Volume Depletion

(Subsection title revised; Additions and/or revisions underlined)

5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

(Additions and/or revisions underlined)

5.9 Vitamin B12 Deficiency

(Subsection title revised; Additions and/or revisions underlined)

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

Volume Depletion [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

7 Drug Interactions

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

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

…

8.2 Lactation

(Additions and/or revisions underlined)

Risk Summary

Data

8.4 Pediatric Use

(Additions and/or revisions underlined)

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

8.5 Geriatric Use

(Additions and/or revisions underlined)

Empagliflozin

Metformin hydrochloride

Clinical studies of metformin did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger adult patients.

8.6 Renal Impairment

(Additions and/or revisions underlined)

Empagliflozin

Metformin hydrochloride

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment [see Warnings and Precautions (5.1)].

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01/24/2020 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Ketoacidosis

(Additions and/or revisions underlined)

Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in 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. SYNJARDY XR is not indicated for the treatment of patients with type 1 diabetes mellitus.

Patients treated with SYNJARDY XR who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with SYNJARDY XR may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, SYNJARDY XR should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.

In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified. Before initiating SYNJARDY XR, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse.

For patients who undergo scheduled surgery, consider temporarily discontinuing SYNJARDY XR for at least 3 days prior to surgery.

Consider monitoring for ketoacidosis and temporarily discontinuing SYNJARDY XR in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk factors for ketoacidosis are resolved prior to restarting SYNJARDY XR.

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

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(Additions and/or revisions underlined)

Ketoacidosis

Inform patients that ketoacidosis is a serious life-threatening condition and that cases of ketoacidosis have been reported during use of empagliflozin, sometimes associated with illness or surgery among other risk factors.

Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue SYNJARDY XR and seek medical attention immediately.

10/26/2018 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.7 Necrotizing Fasciitis of the Perineum (Fornier’s Gangrene)

Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with SYNJARDY XR presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue SYNJARDY XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)

6.2 Postmarketing Experience

Addition of the following under the subheading Empagliflozin:

Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)

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What are the possible side effects of SYNJARDY? SYNJARDY may cause serious side effects, including:

See “What is the most important information I should know about SYNJARDY?”

Addition of the following:

A rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take empagliflozin, one of the medicines in SYNJARDY. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may 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)

PATIENT COUNSELING INFORMATION

Addition of the following:

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

Inform patients that necrotizing infections of the perineum (Fournier’s gangrene) have occurred with SYNJARDY XR. Counsel 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°F or malaise.

12/13/2017 (SUPPL-4)

Approved Drug Label (PDF)

4 Contraindications

…

History of serious hypersensitivity reaction to empagliflozin, metformin or any of the excipients in SYNJARDY XR.

5 Warnings and Precautions

5.8 Hypersensitivity Reactions

(additions underlined)

There have been postmarketing reports of serious hypersensitivity reactions, (e.g., angioedema) in patients treated with empagliflozin, one of the components of SYNJARDY XR. If a hypersensitivity reaction occurs, discontinue SYNJARDY XR; treat promptly per standard of care, and monitor until signs and symptoms resolve. SYNJARDY XR is contraindicated in patients with a previous serious hypersensitivity reaction to empagliflozin or any of the excipients in SYNJARDY XR.

6 Adverse Reactions

(additions underlined)

…

Hypersensitivity Reactions

…

6.2 Postmarketing Experience

(additions underlined)

Empagliflozin

Ketoacidosis
Urosepsis and pyelonephritis
Angioedema
Skin reactions (e.g., rash, urticaria)

Metformin hydrochloride
Cholestatic, hepatocellular, and mixed hepatocellular liver injury

8 Use in Specific Populations

8.1 Pregnancy

(additions underlined)

…

Animal Data

…

In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48

times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154-times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times the 25 mg maximum clinical dose.

...

8.2 Lactation

(additions underlined)

Risk Summary

…

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

...

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What are the possible side effects of SYNJARDY XR?

SYNJARDY XR may cause serious side effects, including:

…

Allergic (hypersensitivity) reactions. Serious allergic reactions have happened in people who are taking empagliflozin, one of the medicines in SYNJARDY XR. Symptoms may include
- swelling of your face, lips, throat and other areas of your skin
- difficulty with swallowing or breathing.
- raised, red areas on your skin (hives)
  If you have any of these symptoms, stop taking SYNJARDY XR and call your doctor right away or go to the nearest hospital emergency room.
  …

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions, such as urticaria and angioedema, have been reported with empagliflozin, a component of SYNJARDY XR. Advise patients to report immediately any skin reaction or angioedema, and to discontinue the drug until they have consulted prescribing physician

…

12/23/2016 (SUPPL-1)

Approved Drug Label (PDF)

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(Additions and/or revisions are underlined)

What is SYNJARDY XR?

SYNJARDY XR is a prescription medicine that contains 2 prescription diabetes medicines, empagliflozin and metformin. SYNJARDY XR can be used:

in adults with type 2 diabetes who have known cardiovascular disease when both empagliflozin and metformin is appropriate and empagliflozin is needed to reduce the risk of cardiovascular death.