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.

JARDIANCE (NDA-204629)

(EMPAGLIFLOZIN)

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

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09/21/2023 (SUPPL-40)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Lower Limb Amputation

Newly added subsection:

In some clinical studies with SGLT2 inhibitors an imbalance in the incidence of lower limb amputation has been observed. Across four JARDIANCE 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 JARDIANCE 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 [see Clinical Studies 14.5], 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 1000 patient- years in the placebo, and JARDIANCE 10 mg treatment arms, respectively. Amputation of the toe and mid-foot were most frequent (21 out of 28 JARDIANCE 10 mg treated patients with lower limb amputations), and some involving above and below the knee. Some patients had multiple amputations.

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 JARDIANCE 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

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

JARDIANCE has been evaluated in clinical trials in adult and pediatric patients aged 10 to 17 years with type 2 diabetes mellitus, in adults with heart failure, and in adults with chronic kidney disease. The overall safety profile of JARDIANCE was generally consistent across the studied indications.

…

Clinical Trials in Adults with Heart Failure

No new adverse reactions were identified in EMPEROR-Reduced or EMPEROR-Preserved heart failure trials.

Clinical Trial in Adults with Chronic Kidney Disease

The safety profile in patients with chronic kidney disease was generally consistent with that observed across the studied indications. In a long-term cardio-renal outcome trial [see Clinical Studies 14.5], 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 JARDIANCE 10 mg treatment arms, respectively [see Warnings and Precautions (5.7)].

…

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of JARDIANCE 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 JARDIANCE for this indication is supported by evidence from a 26-week double-blind, placebo-controlled clinical trial, 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 JARDIANCE 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 JARDIANCE regardless of concomitant insulin use [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

The safety and effectiveness of JARDIANCE have not been established in pediatric patients less than 10 years of age as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus.

The safety and effectiveness of JARDIANCE have not been established in pediatric patients to reduce the risk of:

cardiovascular death and hospitalization for heart failure in patients with heart failure.
sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in patients with chronic kidney disease at risk of progression.
cardiovascular death in patients with type 2 diabetes mellitus and established cardiovascular disease.

8.5 Geriatric Use

Additions and/or revisions underlined:

In glycemic control trials in patients with type 2 diabetes mellitus, a total of 2,721 (32%) patients treated with JARDIANCE were 65 years of age and older, and 491 (6%) were 75 years of age and older. JARDIANCE is expected to have diminished glycemic efficacy in elderly patients with renal impairment [see Use in Specific Populations (8.6)]. The risk of volume depletion-related adverse reactions increased in patients who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg. The risk of urinary tract infections increased in patients who were 75 years of age and older to 10.5%, 15.7%, and 15.1% in patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

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 JARDIANCE 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 JARDIANCE 65 years of age and older, and 1,281 (43%) patients 75 years of age and older. EMPA-KIDNEY included 2,089 (32%) patients treated with JARDIANCE 65 years of age and older, and 1,518 (23%) patients 75 years of age and older.

8.6 Renal Impairment

Additions and/or revisions underlined:

…

JARDIANCE was evaluated in 7,020 adult patients with type 2 diabetes and established cardiovascular disease (eGFR greater than or equal to 30 mL/min/1.73 m2) in the EMPA-REG OUTCOME trial, in a total of 9,718 patients with heart failure (eGFR greater than or equal to 20 mL/min/1.73 m2) in the EMPEROR-Reduced and EMPEROR-Preserved trials, and in 6,609 adult patients with chronic kidney disease (eGFR 20 to 90 mL/min/1.73 m2) in the EMPA-KIDNEY study. The safety profile across eGFR subgroups in these trials was consistent with the known safety profile [see Adverse Reactions (6.1) and Clinical Studies (14.3, 14.4, 14.5)].

Efficacy and safety trials with JARDIANCE did not enroll adult patients with an eGFR less than 20 mL/min/1.73 m2 or on dialysis. Once enrolled, adult patients in the EMPA-REG OUTCOME, EMPEROR- Reduced, EMPEROR-Preserved, and EMPA-KIDNEY trials were not required to discontinue therapy for worsening of eGFR to less than 20 mL/min/1.73 m2 or initiation of dialysis [see Clinical Studies (14.3, 14.4, 14.5)].

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What is JARDIANCE?

JARDIANCE is a prescription medicine used to:

reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure, when the heart cannot pump enough blood to the rest of your body.
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.
reduce the risk of cardiovascular death in adults with type 2 diabetes and who also have known cardiovascular disease.
lower blood sugar (glucose) along with diet and exercise in adults and children who are 10 years of age and older with type 2 diabetes.

JARDIANCE is not for use to lower blood sugar (glucose) in people with type 1 diabetes. It may increase their risk of diabetic ketoacidosis (increased ketones in blood or urine).

JARDIANCE is not for use to lower blood sugar (glucose) in people with type 2 diabetes who have severe kidney problems, because it may not work.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. JARDIANCE is not expected to work if you have these conditions.

It is not known if JARDIANCE is safe and effective in children under 10 years of age.

…

What should I tell my healthcare provider before taking JARDIANCE?

Before taking JARDIANCE, tell your healthcare provider about all of your medical conditions, including if you:

have type 1 diabetes or have had diabetic ketoacidosis.
have a decrease in your insulin dose.
have a serious infection.
have a history of infection of the vagina or penis.
have a history of amputation.

…

How should I take JARDIANCE?

…

If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take two doses of JARDIANCE at the same time. Talk with your healthcare provider if you have questions about a missed dose.

If you take too much JARDIANCE, call your healthcare provider or Poison Help line at 1-800-222-1222, or go to the nearest hospital emergency room right away.

…

What are the possible side effects of JARDIANCE?

JARDIANCE may cause serious side effects, including:

…

Low blood sugar (hypoglycemia). In adults, if you take JARDIANCE with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. In children 10 years of age and older, the risk for low blood sugar is higher with JARDIANCE even if you do not use another medicine that can also lower blood sugar. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take JARDIANCE.

…

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 people who take JARDIANCE. 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
- swelling
- redness of skin (erythema)
Amputations. SGLT2 inhibitors may increase your risk of lower limb amputations.
You may be at a higher risk of lower limb amputation if you:

have a history of amputation
have had blocked or narrowed blood vessels, usually in your leg
have had diabetic foot infection, ulcers or sores

Call your healthcare provider right away if you have new pain or tenderness, any sores, ulcers, or infections in your leg or foot. Talk to your healthcare provider about proper foot care.

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

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 (5.7)].

…

09/12/2023 (SUPPL-41)

Approved Drug Label (PDF)

5 Warnings and Precautions

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

Additions and revisions underlined:

In patients with type 1 diabetes mellitus, JARDIANCE significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose

co-transporter 2 (SGLT2) inhibitors compared to patients who received placebo and fatal ketoacidosis has occurred with JARDIANCE. JARDIANCE is not indicated for glycemic control in patients with type 1 diabetes mellitus.

Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including JARDIANCE.

Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.

Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing JARDIANCE [see Clinical Pharmacology (12.2)]; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

Consider ketone monitoring in patients with type 1 diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue JARDIANCE, promptly evaluate, and treat ketoacidosis, if confirmed.

Monitor patients for resolution of ketoacidosis before restarting JARDIANCE.

Withhold JARDIANCE, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume JARDIANCE when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.4)].

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

6 Adverse Reactions

Additions and revisions underlined:

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

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

Additions and revisions underlined:

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

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

In patients with type 1 diabetes mellitus, inform them that using JARDIANCE can increase their risk of life- threatening diabetic ketoacidosis and that fatal ketoacidosis has occurred. For all other patients, inform them that JARDIANCE 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 JARDIANCE and seek medical attention immediately [see Warnings and Precautions (5.1)].

06/20/2023 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 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 JARDIANCE 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 JARDIANCE 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:

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

8.6 Renal Impairment

Additions and revisions underlined:

The efficacy and safety of JARDIANCE for glycemic control were evaluated in a study of adult patients with type 2 diabetes mellitus with mild and moderate renal impairment (eGFR 30 to less than 90 mL/min/1.73 m2) [see Clinical Studies (14)]. In this study, 195 adult patients exposed to JARDIANCE had an eGFR between 60 and 90 mL/min/1.73 m2, 91 adult patients exposed to JARDIANCE had an eGFR between 45 and 60 mL/min/1.73 m2, and 97 patients exposed to JARDIANCE had an eGFR between 30 and 45 mL/min/1.73 m2. The glucose lowering benefit of JARDIANCE 25 mg decreased in adult patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function [see Warnings and Precautions (5.2)]. Use of JARDIANCE for glycemic control in patients without established cardiovascular disease or cardiovascular risk factors is not recommended when eGFR is less than 30 mL/min/1.73 m2.

In a large cardiovascular outcomes study of adult patients with type 2 diabetes mellitus and established cardiovascular disease, there were 1819 patients with eGFR below 60 mL/min/1.73 m2. The cardiovascular death findings in this subgroup were consistent with the overall findings [see Clinical Studies (14)].

Studies of adult patients with heart failure [see Clinical Studies (14)] enrolled patients with eGFR equal to or above 20 mL/min/1.73 m2. No dosage adjustment is recommended for these patients. There are insufficient data to support a dosing recommendation in patients with eGFR below 20 mL/min/1.73 m2.

Efficacy and safety trials with JARDIANCE did not enroll adult patients with an eGFR less than 20 mL/min/1.73 m2. JARDIANCE is contraindicated in patients on dialysis [see Contraindications (4)].

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 JARDIANCE 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 (5.4)].

Medication Guide

Additions and revisions underlined:

What is JARDIANCE?

JARDIANCE is a prescription medicine used to:

reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure, when the heart cannot pump enough blood to the rest of your body.
reduce the risk of cardiovascular death in adults with type 2 diabetes and who also have known cardiovascular disease.
lower blood sugar along with diet and exercise in adults and children who are 10 years of age and older with type 2 diabetes.
JARDIANCE is not for people with type 1 diabetes. It may increase their risk of diabetic ketoacidosis (increased ketones in blood or urine).
JARDIANCE is not for use to lower blood sugar in adults with type 2 diabetes who have severe kidney problems, because it may not work.

It is not known if JARDIANCE is safe and effective in children under 10 years of age.

. . .

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

See “What is the most important information I should know about JARDIANCE?”
Serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking JARDIANCE. Tell your healthcare provider if you have any signs or symptoms of a urinary tract infection such as a burning feeling when passing urine, a need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have a fever, back pain, nausea or vomiting.
Low blood sugar (hypoglycemia). In adults, if you take JARDIANCE with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. In children 10 years of age and older, the risk for low blood sugar may be higher with JARDIANCE regardless of use with another medicine that can also lower blood sugar. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take JARDIANCE.

10/13/2022 (SUPPL-39)

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 JARDIANCE initiation and dosage changes.

03/21/2022 (SUPPL-34)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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)

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 JARDIANCE?

JARDIANCE 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

02/24/2022 (SUPPL-33)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

Clinical Trials in Patients with Heart Failure

The EMPEROR-Reduced study included 3730 patients with heart failure and left ventricular ejection fraction (LVEF) less than or equal to 40% followed for a median of 16 months, and EMPEROR-Preserved included 5988 patients with heart failure and LVEF >40% followed for a median of 26 months. In both studies, patients were randomized to JARDIANCE 10 mg or placebo. The safety profile in patients with heart failure was generally consistent with that observed in patients with type 2 diabetes mellitus.

…

8 Use in Specific Populations

8.5 Geriatric Use

Additions underlined

…

In heart failure studies, EMPEROR-Reduced included 1188 (64%) patients treated with JARDIANCE 65 years of age and older, and 503 (27%) patients 75 years of age and older. EMPEROR-Preserved included 2402 (80%) patients treated with JARDIANCE 65 years of age and older, and 1281 (43%) patients 75 years of age and older. Safety and efficacy were similar for patients 65 years and younger and those older than 65 years.

08/18/2021 (SUPPL-26)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

JARDIANCE has been evaluated in clinical trials in patients with type 2 diabetes mellitus and in patients with heart failure. The overall safety profile of JARDIANCE was generally consistent across the studied indications.

Clinical Trials in Patients with Type 2 Diabetes Mellitus

The data in Table 1 are derived from a pool of four 24-week placebo-controlled trials and 18-week data from a placebo-controlled trial with insulin in patients with type 2 diabetes.

Clinical Trial in Patients with Heart Failure

The EMPEROR-Reduced study included 3726 patients with heart failure and reduced ejection fraction, treated with JARDIANCE 10 mg or placebo. No new adverse reactions were identified in the EMPEROR-Reduced heart failure study.

8 Use in Specific Populations

8.4 Geriatric Use

(Newly added information)

In the EMPEROR-Reduced study, a total of 1188 (64%) patients with heart failure 65 years of age and older were treated with 10 mg of JARDIANCE. Safety and efficacy were similar for patients 65 years and younger and those older than 65 years.

8.6 Renal Impairment

(Additions and/or revisions underlined)

The efficacy and safety of JARDIANCE for glycemic control were evaluated in a study of patients with type 2 diabetes mellitus with mild and moderate renal impairment (eGFR 30 to less than 90 mL/min/1.73 m2) [see Clinical Studies (14)]. In this study, 195 patients exposed to JARDIANCE had an eGFR between 60 and 90 mL/min/1.73 m2, 91 patients exposed to JARDIANCE had an eGFR between 45 and 60 mL/min/1.73 m2, and 97 patients exposed to JARDIANCE had an eGFR between 30 and 45 mL/min/1.73 m2. The glucose lowering benefit of JARDIANCE 25 mg decreased in patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function [see Warnings and Precautions (5.2)]. Use of JARDIANCE for glycemic control in patients without established cardiovascular disease or cardiovascular risk factors is not recommended when eGFR is less than 30 mL/min/1.73 m2.

In a large cardiovascular outcomes study of patients with type 2 diabetes and established cardiovascular disease, there were 1819 patients with eGFR below 60 mL/min/1.73 m2. The cardiovascular death findings in this subgroup were consistent with the overall findings [see Clinical Studies (14)].

In the study in patients with heart failure with reduced ejection fraction [see Clinical Studies (14)] patients with eGFR equal to or above 20 mL/min/1.73 m2 were included. No dose adjustment is recommended for these patients. There is insufficient data to support a dosing recommendation in patients with eGFR below 20 mL/min/1.73 m2.

Efficacy and safety studies with JARDIANCE did not enroll patients with an eGFR less than 20 mL/min/1.73 m2. JARDIANCE is contraindicated in patients on dialysis [see Contraindications (4)].

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

Medication Guide

(Additions and/or revisions underlined)

What is JARDIANCE?

JARDIANCE is a prescription medicine used to:

o lower blood sugar along with diet and exercise in adults with type 2 diabetes.

o reduce the risk of cardiovascular death in adults with type 2 diabetes and who also have known cardiovascular

disease.

o reduce the risk of cardiovascular death and hospitalization for heart failure (when the heart is weak and cannot

pump enough blood to the rest of your body) in adults with heart failure.

06/11/2021 (SUPPL-28)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

Hypersensitivity to empagliflozin or any of the excipients in JARDIANCE, reactions such as angioedema have occurred [see Warnings and Precautions (5.7)].
Patients on dialysis [see Use in Specific Populations (8.6)].

5 Warnings and Precautions

5.1 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 JARDIANCE. Fatal cases of ketoacidosis have been reported in patients taking JARDIANCE. 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. JARDIANCE is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].

…

5.2 Volume Depletion

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

JARDIANCE 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 JARDIANCE. 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 JARDIANCE 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 JARDIANCE. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

Volume Depletion [see Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

The incidence of hypoglycemia by study is shown in Table 2. The incidence of hypoglycemia increased when JARDIANCE was administered with insulin or sulfonylurea.

Table 2 Incidence of Overalla and Severeb Hypoglycemic Events in Placebo-Controlled Clinical Studiesc

…

Increases in Serum Creatinine and Decreases in eGFR

Initiation of JARDIANCE causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In a study of patients with moderate renal impairment, larger mean changes were observed. In a long-term cardiovascular outcomes trial, the increase in serum creatinine and decrease in eGFR generally did not exceed 0.1 mg/dL and -9.0 mL/min/1.73 m2, respectively, at Week 4, and reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with JARDIANCE.

…

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

The limited available data with JARDIANCE in pregnant women are not sufficient to determine a drug- associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

…

8.2 Lactation

(Additions and/or revisions underlined)

Risk Summary

There is limited information regarding the presence of JARDIANCE in human milk, the effects of JARDIANCE on the breastfed infant or the effects on milk production. 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 JARDIANCE is not recommended while breastfeeding.

Data

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)

The safety and effectiveness of JARDIANCE have not been established in pediatric patients.

8.6 Renal Impairment

(Additions and/or revisions underlined)

The efficacy and safety of JARDIANCE for glycemic control were evaluated in a study of patients with mild and moderate renal impairment (eGFR 30 to less than 90 mL/min/1.73 m2) [see Clinical Studies (14)]. In this study, 195 patients exposed to JARDIANCE had an eGFR between 60 and 90 mL/min/1.73 m2, 91 patients exposed to JARDIANCE had an eGFR between 45 and 60 mL/min/1.73 m2, and 97 patients exposed to JARDIANCE had an eGFR between 30 and 45 mL/min/1.73 m2. The glucose lowering benefit of JARDIANCE 25 mg decreased in patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function [see Warnings and Precautions (5.2)].

In a large cardiovascular outcomes study, there were 1819 patients with eGFR below 60 mL/min/1.73 m2. The cardiovascular death findings in this subgroup were consistent with the overall findings [see Clinical Studies (14)].

The efficacy and safety studies with JARDIANCE did not enroll patients with ESRD, on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2. JARDIANCE is contraindicated in patients on dialysis [see Indications and Usage (1) and Contraindications (4)].

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

MEDICATION GUIDE

(Extensive changes; please refer to label)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

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

Ketoacidosis

Inform patients that ketoacidosis is a serious life-threatening condition and that cases of ketoacidosis have been reported during use of JARDIANCE, 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 JARDIANCE and seek medical attention immediately [see Warnings and Precautions (5.1)].

Volume Depletion

Inform patients that symptomatic hypotension may occur with JARDIANCE and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.2)]. Inform patients that dehydration may increase the risk for hypotension, and to maintain adequate fluid intake.

Serious Urinary Tract Infections

Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.3)].

Hypoglycemia

Inform patients that the incidence of hypoglycemia is increased when JARDIANCE is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin and that a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4)].

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

Inform patients that necrotizing infections of the perineum (Fournier’s gangrene) have occurred with JARDIANCE. 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 [see Warnings and Precautions (5.5)].

Genital Mycotic Infections in Females (e.g., Vulvovaginitis)

Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6)].

Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)

Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with chronic and recurrent infections. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis).

Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6)].

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions, such as urticaria and angioedema, have been reported with JARDIANCE. Advise patients to report immediately any skin reaction or angioedema, and to discontinue drug until they have consulted prescribing physician [see Warnings and Precautions (5.7)].

Laboratory Tests

Inform patients that elevated glucose in urinalysis is expected when taking JARDIANCE.

Pregnancy

Advise pregnant patients, and patients of reproductive potential, of the potential risk to a fetus with treatment with JARDIANCE [see Use in Specific Populations (8.1)]. Instruct patients to report pregnancies to their physicians as soon as possible.

Lactation

Advise patients that breastfeeding is not recommended during treatment with JARDIANCE [see Use in Specific Populations (8.2)].

Missed Dose

Instruct patients to take JARDIANCE 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.

06/11/2021 (SUPPL-29)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

Hypersensitivity to empagliflozin or any of the excipients in JARDIANCE, reactions such as angioedema have occurred [see Warnings and Precautions (5.7)].
Patients on dialysis [see Use in Specific Populations (8.6)].

5 Warnings and Precautions

5.1 Ketoacidosis

(Additions and/or revisions underlined)

…

5.2 Volume Depletion

(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 (5.2)]

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

The incidence of hypoglycemia by study is shown in Table 2. The incidence of hypoglycemia increased when JARDIANCE was administered with insulin or sulfonylurea.

Table 2 Incidence of Overalla and Severeb Hypoglycemic Events in Placebo-Controlled Clinical Studiesc

…

Increases in Serum Creatinine and Decreases in eGFR

…

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, JARDIANCE 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)

The safety and effectiveness of JARDIANCE have not been established in pediatric patients.

8.6 Renal Impairment

(Additions and/or revisions underlined)

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

MEDICATION GUIDE

(Extensive changes; please refer to label)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

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

Ketoacidosis

Volume Depletion

Serious Urinary Tract Infections

Hypoglycemia

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

Genital Mycotic Infections in Females (e.g., Vulvovaginitis)

Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)

Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6)].

Hypersensitivity Reactions

Laboratory Tests

Inform patients that elevated glucose in urinalysis is expected when taking JARDIANCE.

Pregnancy

Lactation

Advise patients that breastfeeding is not recommended during treatment with JARDIANCE [see Use in Specific Populations (8.2)].

Missed Dose

Instruct patients to take JARDIANCE 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.

01/24/2020 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Ketoacidosis

(Additions and/or revisions underlined)

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

Consider monitoring for ketoacidosis and temporarily discontinuing JARDIANCE 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 JARDIANCE.

Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue JARDIANCE 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

10/26/2018 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.6 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 JARDIANCE. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with JARDIANCE 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 JARDIANCE, 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:

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 JARDIANCE? JARDIANCE may cause serious side effects, including:

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

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 JARDIANCE. 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 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 the anus and genitals:

o pain or tenderness o swelling o redness of skin (erythema)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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

Instructions

Instruct patients to read the Medication Guide before …

Addition of the following:

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

12/13/2017 (SUPPL-16)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

History of serious hypersensitivity reaction to empagliflozin or any of the excipients in JARDIANCE
Severe renal impairment, end-stage renal disease, or dialysis

5 Warnings and Precautions

5.7 Hypersensitivity Reactions

(new subsection added)

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

6 Adverse Reactions

(additions underlined)

…

Hypersensitivity Reactions

…

6.2 Postmarketing Experience

(additions underlined)

….

Angioedema
Skin reactions (e.g., rash, urticaria)

8 Use in Specific Populations

8.1 Pregnancy

(additions underlined)

….

Data

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 JARDIANCE is not recommended while breastfeeding.

…

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

PATIENT COUNSELING INFORMATION

(additions underlined)

Instructions

…

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

Advise women that breastfeeding is not recommended during treatment with JARDIANCE

…

Hypersensitivity Reactions

PATIENT INFORMATION

(additions underlined)

…

What should I tell my doctor before using JARDIANCE? Before you take JARDIANCE, tell your doctor if you:

…

are pregnant or plan to become pregnant. JARDIANCE may harm your unborn baby. If you become pregnant while taking JARDIANCE, tell your doctor as soon as possible. Talk with your doctor about the best way to control your blood sugar while you are pregnant.
…
What are the possible side effects of JARDIANCE?
…

Allergic (hypersensitivity) reactions. Serious allergic reactions have happened in people who are taking JARDIANCE. 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 JARDIANCE and call your doctor right away or go to the nearest hospital emergency room.

…

12/02/2016 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Ketoacidosis

(additions and/or revisions are underlined)

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

5.3 Acute Kidney Injury and Impairment in Renal Function

(additions and/or revisions are underlined)

JARDIANCE 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 JARDIANCE; some reports involved patients younger than 65 years of age.

Before initiating JARDIANCE, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing JARDIANCE 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 JARDIANCE promptly and institute treatment.

…Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating JARDIANCE. Renal function should be evaluated prior to initiation of JARDIANCE 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 JARDIANCE is not recommended when eGFR is persistently less than 45 mL/min/1.73 m2 and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2.

6 Adverse Reactions

(additions and/or revisions are underlined; Summary in italics)

Addition of Acute Kidney Injury and Impairment in Renal Function in bulleted listing

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Acute Impairment in Renal Function

Treatment with JARDIANCE was associated with increases in serum creatinine …

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 2 Changes from Baseline in Serum Creatinine and eGFR superscript (a) in the Pool of Four 24-week Placebo-Controlled Studies and Renal Impairment Study

(Addition of footnotes to this table; please refer to label)

Table 3 Incidence of Overall and Severe Hypoglycemic Events in Placebo-Controlled Clinical Studies superscript (c) (Revision of footnotes to this table; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

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

Limited data available with JARDIANCE in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

In animal studies, adverse renal changes were observed in rats when empagliflozin was 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. Empagliflozin was not teratogenic in rats and rabbits up to 300 mg/kg/day, which approximates 48- times and 128-times, respectively, the maximum clinical dose of 25 mg when administered during organogenesis.

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c greater than 7 and has been reported to be as high as 20-25% in women with HbA1c greater than 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Data

Animal Data

Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30 and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day… These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.

8.2 Lactation

(PLLR conversion)

Risk Summary

There is no information regarding the presence of JARDIANCE in human milk, the effects of JARDIANCE on the breastfed infant or the effects on milk production.

Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of JARDIANCE is not recommended while breastfeeding.

Data

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 -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.

8.5 Geriatric Use

(additions and/or revisions are underlined)

In studies assessing the efficacy of empagliflozin in improving glycemic control in patients with type 2 diabetes, a total of 2721 (32%) patients treated with empagliflozin were 65 years of age and older, and 491 (6%) were 75 years of age and older. JARDIANCE is expected to have diminished glycemic efficacy in elderly patients with renal impairment...

8.6 Renal Impairment

(additions and/or revisions are underlined)

...In a large cardiovascular outcomes study, there were 1819 patients with eGFR below 60 mL/min/1.73 m2. The cardiovascular death findings in this subgroup were consistent with the overall findings.

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

17 PATIENT COUNSELING INFORMATION

(additions and/or revisions are underlined)

Instructions

...Inform female patients of reproductive potential that the use of JARDIANCE during pregnancy has not been studied in humans...

Ketoacidosis

Inform patients that ketoacidosis is a serious life-threatening condition. Cases of ketoacidosis have been reported during use of JARDIANCE.

Acute Kidney Injury

Inform patients that acute kidney injury has been reported during use of JARDIANCE. 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 JARDIANCE use in those settings.

PATIENT INFORMATION

(additions and/or revisions are underlined)

What is JARDIANCE?

JARDIANCE is a prescription medicine used:
- to reduce the risk of cardiovascular death in adults with type 2 diabetes who have known cardiovascular disease.

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

Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type 1 diabetes or type 2 diabetes, during treatment with JARDIANCE. Ketoacidosis is a serious condition, which may need to be treated in a hospital. Ketoacidosis may lead to death.
Kidney problems. Sudden kidney injury has happened to people taking JARDIANCE. 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-12)

5 Warnings and Precautions

Ketoacidosis

Addition of the following sentence:

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

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

PCI - Ketoacidosis

Inform patients that ketoacidosis is a serious life-threatening condition. Cases of ketoacidosis have been reported during use of JARDIANCE. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated.

PI - What are the possible side effects of JARDIANCE?

JARDIANCE may cause serious side effects, including:

Ketoacidosis (addition of the following sentence)

Ketoacidosis may lead to death.