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 (NDA-206111)

(EMPAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

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

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10/30/2023 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2Diabetic 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-38)

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-33)

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?

SYNJARDY is a prescription medicine that contains 2 diabetes medicines, empagliflozin (JARDIANCE) and metformin hydrochloride. SYNJARDY can be used along with diet and exercise to improve blood sugar in adults with type 2 diabetes. One of the medicines in SYNJARDY, 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 is not for people with type 1 diabetes. It may increase their risk of diabetic ketoacidosis (increased ketones in blood or urine).

SYNJARDY 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 is safe and effective in children.

10/13/2022 (SUPPL-36)

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 initiation and dosage changes.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and revisions underlined:

Assess renal function more frequently in SYNJARDY-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 in geriatric patients should usually start at the lower end of the dosage range.

03/21/2022 (SUPPL-31)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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?

SYNJARDY 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-25)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

SYNJARDY 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, 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)

…

Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.

Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Before initiating SYNJARDY, obtain an estimated glomerular filtration rate (eGFR).
SYNJARDY is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2 [see Contraindications (4)].
Obtain an eGFR at least annually in all patients taking SYNJARDY. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions: The concomitant use of SYNJARDY with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].

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 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 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 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 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 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. 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.

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 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 is not recommended during the second and third trimesters of pregnancy.

The limited available data with SYNJARDY 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, 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 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 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 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 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)].

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

MEDICATION GUIDE

(Extensive changes; please refer to label)

PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to label)

06/11/2021 (SUPPL-26)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

SYNJARDY 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, 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)

…

Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Before initiating SYNJARDY, obtain an estimated glomerular filtration rate (eGFR).
SYNJARDY is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2 [see Contraindications (4)].
Obtain an eGFR at least annually in all patients taking SYNJARDY. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

…

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 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 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)].

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

MEDICATION GUIDE

(Extensive changes; please refer to label)

PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to label)

01/24/2020 (SUPPL-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Ketoacidosis

(Additions and/or revisions underlined)

Before initiating SYNJARDY, 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 for at least 3 days prior to surgery.

Consider monitoring for ketoacidosis and temporarily discontinuing SYNJARDY 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.

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

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

17 PATIENT COUNSELING INFORMATION

(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 and seek medical attention immediately.

10/26/2018 (SUPPL-18)

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 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, 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)

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

MEDICATION GUIDE

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

Addition of the following:

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

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 XR. 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. 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-15)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

…

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

5 Warnings and Precautions

5.8 Hypersensitivity Reactions

(new subsection added)

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

6 Adverse Reactions

(addition underlined)

…

Hypersensitivity Reactions

…

6.2 Postmarketing Experience

(additions underlined)

….

Empagliflozin

Ketoacidosis [see Warnings and Precautions (5.3)]
Urosepsis and pyelonephritis [see Warnings and Precautions (5.5)]
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)

…

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 is not recommended while breastfeeding.

…

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

MEDICATION GUIDE

(additions underlined)

…

What are the possible side effects of SYNJARDY?

SYNJARDY 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. 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 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. 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-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Acute Kidney Injury and Impairment in Renal Function

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

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

Before initiating SYNJARDY, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing SYNJARDY in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue SYNJARDY promptly and institute treatment.

Empagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating SYNJARDY. Renal function should be evaluated prior to initiation of SYNJARDY and monitored periodically thereafter. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. Use of SYNJARDY is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2.

6 Adverse Reactions

(Additions and/or revisions are underlined)

Acute Kidney Injury and Impairment in Renal Function

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Acute Impairment in Renal Function

Treatment with empagliflozin…

In a long-term cardiovascular outcome trial, the acute impairment in renal function was observed to reverse after treatment discontinuation suggesting acute hemodynamic changes play a role in the renal function changes observed with empagliflozin.

(Table 3 footnote additions and/or revisions are underlined)

Superscript a: Observed cases on treatment.

(Table 4 footnote additions and/or revisions are underlined)

Superscript c: Treated set (patients who had received at least one dose of study drug)

7 Drug Interactions

7.2 Drug Interactions with Metformin Hydrochloride

(Additions and/or revisions are underlined)

Drugs that Reduce Metformin Clearance

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Empagliflozin

In studies assessing the efficacy of empagliflozin in improving glycemic control in patients with type 2 diabetes, a total of 2721…. Empagliflozin is expected to have diminished glycemic efficacy in elderly patients with renal impairment…

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Acute Kidney Injury

Inform patients that acute kidney injury has been reported during use of empagliflozin. Advise patients to seek medical advice immediately if they have reduced oral intake (such as due to acute illness or fasting) or increased fluid losses (such as due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue SYNJARDY use in those settings.

MEDICATION GUIDE

(Additions and/or revisions are underlined)

What is SYNJARDY?

SYNJARDY is a prescription medicine that contains 2 prescription diabetes medicines, empagliflozin and metformin. SYNJARDY 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.

What are the possible side effects of SYNJARDY?

SYNJARDY may cause serious side effects, including:

Kidney problems. Sudden kidney injury has happened to people taking SYNJARDY. Talk to your doctor right away if you:

reduce the amount of food or liquid you drink for example, if you are sick or cannot eat or
you start to lose liquids from your body for example, from vomiting, diarrhea or being in the sun too long

07/08/2016 (SUPPL-1)

Approved Drug Label (PDF)

8 Use in Specific Populations

PLLR Conversion; please refer to label.

07/08/2016 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

Ketoacidosis

Addition of the following sentence:

Fatal cases of ketoacidosis have been reported in patients taking empagliflozin.

07/08/2016 (SUPPL-9)

Approved Drug Label (PDF)

Boxed Warning

WARNING: LACTIC ACIDOSIS

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.
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. If metformin-associated lactic acidosis is suspected, immediately discontinue SYNJARDY and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

4 Contraindications

SYNJARDY is contraindicated in patients with:

Moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), end stage renal disease, or dialysis (revised).

5 Warnings and Precautions

Lactic Acidosis (entire section revised)

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:
Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.
Before initiating SYNJARDY, obtain an estimated glomerular filtration rate (eGFR).
SYNJARDY is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2.
Obtain an eGFR at least annually in all patients taking SYNJARDY. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
Drug Interactions: The concomitant use of SYNJARDY with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs). Therefore, consider more frequent monitoring of patients.
Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
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 at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 45 and 60 mL/min/1.73 m2; 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 if renal function is stable.
Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. SYNJARDY should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue SYNJARDY.
Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving SYNJARDY.
Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of SYNJARDY in patients with clinical or laboratory evidence of hepatic disease.

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 SYNJARDY. In SYNJARDY-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride 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 SYNJARDY and report these symptoms to their healthcare provider.

7 Drug Interactions

Drug Interactions with Metformin Hydrochloride

Drugs that Reduce Metformin Clearance (additional subsection added)

Drugs that are eliminated by renal tubular secretion (e.g., cationic drugs such as cimetidine) have the potential for interaction with metformin by competing for common renal tubular transport systems, and may increase the accumulation of metformin and the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Carbonic Anhydrase Inhibitors (additional sentences)

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with SYNJARDY may increase the risk of lactic acidosis. Consider more frequent monitoring of these patients.

Alcohol (additional section)

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving SYNJARDY.

8 Use in Specific Populations

Geriatric Use

… renal function should be assessed more frequently in elderly patients replaces monitor renal function more frequently after initiating SYNJARDY in the elderly and then adjust dose based on renal function

Metformin hydrochloride

... In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients.

Hepatic Impairment

Metformin hydrochloride (revised as below)

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. SYNJARDY is not recommended in patients with hepatic impairment.

Renal Impairment

Metformin hydrochloride

… SYNJARDY is contraindicated in moderate to severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m2.

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

MG - What is the most important information I should know about SYNJARDY?

Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with SYNJARDY if you: …
… The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor may decide to stop your SYNJARDY for a while if you have any of these things.

(addition of the following bullet)

are a premenopausal woman (before the “change of life”), who does not have periods regularly or at all. Talk to your doctor about birth control choices while taking SYNJARDY if you are not planning to become pregnant since SYNJARDY may increase your chance of becoming pregnant. Tell your doctor right away if you become pregnant while taking SYNJARDY.

PCI

Lactic Acidosis (new subsection heading)

Inform patients of the risks of lactic acidosis…

Monitoring of Renal Function (replaces the former heading Laboratory Tests)

Inform patients about the importance of regular testing of renal function when receiving treatment with SYNJARDY.
(addition) Instruct patients to inform their doctor that they are taking SYNJARDY prior to any surgical or radiological procedure, as temporary discontinuation of SYNJARDY may be required until renal function has been confirmed to be normal.

Hypoglycemia

Inform patients that the risk of hypoglycemia is increased when SYNJARDY is used in combination with an insulin secretagogue (e.g., sulfonylurea), and that a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia.

Pregnancy

Advise pregnant women, and females of reproductive potential of the potential risk to a fetus with treatment with SYNJARDY. Instruct females of reproductive potential to report pregnancies to their physicians as soon as possible.

Lactation

Advise women that breastfeeding is not recommended during treatment with SYNJARDY.

Females and Males of Reproductive Potential

Inform females that treatment with metformin may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy

Missed Dose

Instruct patients to take SYNJARDY only as prescribed. If a dose is missed, it should be taken as soon as the patient remembers. Advise patients not to double their next dose.

Blood Glucose and A1C Monitoring

Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels toward the normal range. Hemoglobin A1c monitoring is especially useful for evaluating long-term glycemic control.